n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Revista de la Sociedad Española de Nefrología www.revistanefrologia.com Original article Recommendations for living donor renal transplantation Miguel Ángel Frutos a,∗,1 , Marta Crespo b,1 , María de la Oliva Valentín c,1 , Ángel Alonso-Melgar d , Juana Alonso a , Constantino Fernández e , Gorka García-Erauzkin f , Esther González g , Ana M. González–Rinne h , Lluis Guirado i , Alex Gutiérrez-Dalmau j , Jorge Huguet k , José Luis López del Moral l , Mireia Musquera m , David Paredes n , Dolores Redondo b , Ignacio Revuelta o , Carlos J Van-der Hofstadt p , Antonio Alcaraz m , Ángel Alonso-Hernández e , Manuel Alonso q , Purificación Bernabeu p , Gabriel Bernal r , Alberto Breda k , Mercedes Cabello a , José Luis Caro-Oleas s , Joan Cid t , Fritz Diekmann o , Laura Espinosa d , Carme Facundo i , Marta García c , Salvador Gil-Vernet u , Miquel Lozano t , Beatriz Mahillo c , María José Martínez v , Blanca Miranda w , Federico Oppenheimer o , Eduard Palou s , María José Pérez-Saez b , Lluis Peri m , Oscar Rodríguez k , Carlos Santiago x , Guadalupe Tabernero y , Domingo Hernández a , Beatriz Domínguez-Gil c , Julio Pascual b,∗ a Nephrology Department, Hospital Regional Universitario de Málaga, Spain b Nephrology Department, Hospital del Mar, Barcelona, Spain c National Transplant Organization, Madrid, Spain d Paediatric Nephrology Department, Hospital La Paz, Madrid, Spain e Nephrology Department, Hospital Universitario A Coruña, Spain f Nephrology Department, Hospital Universitario de Cruces, Bilbao, Spain g Nephrology Department, Hospital Universitario 12 Octubre, Spain h Nephrology Department, Hospital Universitario de Canarias, Spain i Nephrology Department, Fundacio Puigvert, Barcelona, Spain j Nephrology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain k RT Surgical Team, Fundació Puigvert, Barcelona, Spain l Cantabria High Court Magistrate, Spain m Urology Department, Hospital Clinic Universitari, Barcelona, Spain n Donation and Transplantation Coordination Department, Hospital Clinic Universitari, Barcelona, Spain o Nephrology and RT Department, Hospital Clinic Universitari, Barcelona, Spain p Hospital Psychology Unit, Hospital General Universitario de Alicante, Spain q Regional Transplantation Coordination, Seville, Spain r Nephrology Department, Hospital Universitario Virgen del Rocío, Seville, Spain ∗ Corresponding authors. E-mail addresses: miguel.frutos@gmail.com (M.Á. Frutos), julpascual@gmail.com (J. Pascual). 1 MAF, MC and MOV share the position of lead author. 2013-2514/© 2022 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Nefrología. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 6 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 s Immunology Department, Hospital Clinic i Universitari, Barcelona, Spain t Apheresis and Cell Therapy Unit, Haemotherapy and Haemostasis Department, Hospital Clinic Universitari, Barcelona, Spain u Nephrology Department, Hospital Universitari de Bellvitge, Barcelona, Spain v Paediatric Urology Department, Hospital Universitario La Paz, Madrid, Spain w Fundación Renal Iñigo Álvarez de Toledo, Madrid, Spain x Nephrology Department, Hospital General de Alicante, Spain y Nephrology Department, Hospital Universitario de Salamanca, Spain a r t i c l e i n f o a b s t r a c t Article history: This Guide for Living Donor Renal Transplantation (LDRT) has been prepared with the spon- Received 18 October 2021 sorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), Accepted 26 October 2021 and the Spanish National Transplant Organization (ONT). It updates evidence to offer the Available online 29 July 2022 best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes. Moreover, the role of living donors in the current RT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDRT, offer additional ways to treat renal patients with an incompatible donor. Good results in terms of patient and graft survival have expanded the range of circum- stances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations. This Guide does not forget that LDRT may lead to risk for the donor. Pre-donation evalua- tion has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors’ health. This aspect always has to be taken into account by LDRT programmes when evaluating potential donors. Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees. © 2022 Published by Elsevier España, S.L.U. on behalf of Sociedad Española de Nefrología. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Recomendaciones para el trasplante renal de donante vivo r e s u m e n Esta guía de recomendaciones para el TR de donante vivo (TRDV) es un documento elaborado con el patrocinio de la Sociedad Española de Nefrología, la Sociedad Española de Trasplantes y la Organización Nacional de Trasplantes que actualiza la calidad de la evidencia disponible para ofrecer el mejor tratamiento de la insuficiencia renal crónica cuando se disponga de un donante vivo potencial. El objetivo principal de esta guía es proporcionar a los profesionales con responsabilidad en los estudios previos del donante vivo y del receptor trasplantado, las mejores herramientas para tomar decisiones en beneficio del donante vivo y del receptor del trasplante. Además, en el contexto actual del TR, el donante vivo debe recuperar el protagonismo que alcanzó en un pasado reciente. Para ello, las nuevas modalidades de donación HLA y/o ABO incompatible, así como la donación cruzada disponibles en diversos centros con experiencia en TRDV, son oportunidades adicionales para el tratamiento de enfermos renales que tienen un donante incompatible. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 7 Los buenos resultados en supervivencia del paciente y del injerto están ampliando las circunstancias de aceptación de donantes vivos de riñón, incluyendo donantes de mayor edad y otros con algunos condicionantes que incluyen antecedentes o alteraciones límite que, cuando son evaluados con criterios objetivos, pueden aportar un numero adicional de trasplantes. No se ha obviado en esta guía que el TRDV puede representar algún riesgo para el que dona. Estos problemas que pueden aparecer a corto o largo plazo tienen que ser objeto principal de valoración previa a la donación y presentados al potencial donante para que en ejercicio de su autonomía los asuma o rechace. La experiencia acumulada en los últimos años ha permitido avanzar en el análisis de riesgos para preservar la salud de los donantes, aspecto que debe estar siempre presente en los responsables de programas de TRDV cuando se procede al estudio de idoneidad de un potencial donante. Finalmente, esta guía ha sido estructurada para facilitar la toma de decisiones con recomen- daciones y sugerencias ante incertidumbres derivadas de los resultados en los exhaustivos estudios predonación. Y todo ello, con el objetivo de que el consentimiento informado que debe certificar la calidad de los estudios y la información proporcionada a donante y receptor, alcancen las mayores garantías posibles. © 2022 Publicado por Elsevier España, S.L.U. en nombre de Sociedad Española de Nefrología. Este es un artículo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/). number of recommendations figure as suggestions with low Introduction, objectives and methodology or very low evidence quality (C, D), so that for reasons of sim- plicity and utility we decided to simply underline evidence In 2010 the Nefrología Journal published a supplement con- quality.5 Expert recommendations and suggestions that are taining the Recommendations of the Spanish Society for not graded (NG) have also been included when it was not pos- Nephrology (SEN) and the Spanish National Transplant Orga- sible to show any evidence, as well as in the case of legal nization (ONT) for living donor renal transplant (LDRT).1 Four requirements. year later our country achieved its record, with 423 LDRT. In any case, this LDRT update monograph should be highly LDRT is now a consolidated treatment, and it is the first useful for Clinicians working in the field of donation and trans- therapeutic option which should be offered to patients with plant, so that they are always able to find the best resources end stage renal disease (ESRD). This is so for paediatric as well and offer solutions to complex problems in their clinical prac- as adult cases in terms of survival and quality of life. tice. Now is therefore a good time to update the 10 year-old rec- The methodology followed for this update commenced ommendations document. This Project was undertaken under with the identification of the most recent and important the auspices of the SEN, the ONT and the Spanish Transplant developments in LDRT since the publication of the 2010 Rec- Society (SET), with the core aim of expanding the use of LDRT. ommendations. This is the case for paired RT; ABO and It includes all possible types of LDRT: paired donation, ABO HLA incompatible transplants; expanded criteria donors, and incompatible donation, donation for highly sensitized recipi- donor risk analysis. ents, altruistic donation and chain donation, etc. All of these The sections were distributed among the teams which had procedures complement deceased donor renal transplant (RT), published outstanding works in each specific field. The teams and together with direct LDRT they ensure the maximum were asked to undertake a systematic review of the bibliogra- number of transplants, regardless of their complexity. phy, with the aid of evidence already underlined in documents This document analyses donor safety several times. The published by the British Transplantation Society (BTS) and health risk for someone who donates one of their kidneys KDIGO2,3 before finishing with a study of the literature pub- must be minimized, carefully assessed and described to the lished in recent years. donor, so that they are able to decide completely indepen- The three coordinators also prepared a list of the minimum dently. Donor well-being is non-negotiable, and they are subjects to be covered in each section, to ensure that they were therefore recommended to follow a healthy lifestyle after completely up-to-date. Each manuscript was reviewed by a donating, with a life-long follow-up. group of Special Editors after it had been examined by the This document is not a Guide like those published in the coordinators. This group was composed of important RT clini- United Kingdom,2 North America3 or Europe.4 It is a hybrid cians in Spain, and they edited the documents before agreeing between a Review, an Update and a Clinical Practice Guide, the final versions with the authors. where Clinicians are able to find recommendations or the This process took 18 months, and those involved also had opinions of LDRT experts when the evidence is either weak to manage the work overload due to the Covid-19 pandemic. or non-existent. Unfortunately the majority of recommen- We would therefore like to offer our most sincere thanks to all dations in LDRT lack high-quality evidence, so that a large of the authors who helped to prepare this document. 8 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 for deceased donor recipients. Patient survival rates at 5 years The current situation of living donor renal (adjusted for age, sex and cause of primary renal disease) are transplantation in Spain and other countries 94.6% and 92.1%, respectively.14 American Registry data show very similar results to those of the European Registry.15 Living donor RT (LDRT) is the therapy which gives the best Different reasons have been suggested for the better results results in patients with end stage renal failure, in terms obtained with LDRT, including good living donor basal health, of patient and graft survival as well as quality of life.6 with less associated pathology than deceased donors.1 How- Ever since the first successful LDRT between humans took ever, no significant differences are found in mid-term survival place in 1954,7 advances in immunosuppression, the devel- or the incidence of acute rejection when the results of opment of minimally invasive surgical techniques for donor deceased donor RT are compared with those of standard nephrectomy, and agreement on how to evaluate, select living donors in patients with similar characteristics. Nev- and care for living donors8 mean that this treatment is ertheless, there is a significant difference in graft function now considered systematically for end stage renal failure delay.16 These differences in favour of living donation are sig- patients.2,9 nificant when the overall results of LDRT are compared with According to Global Observatory on Donation and Trans- those corresponding to deceased donors, without differentiat- plantation data, every year approximately 90,000 renal ing deceased donor type (brain death or asystole, and standard transplants are performed, of which approximately 40% come or expanded criteria).6,13,17 from living donors.10 Figure 1 shows renal transplantation (RT) On the other hand, LDRT is performed more often than activity per country in 2018, differentiating between deceased deceased donor transplantation before the patient com- donor and living donor procedures. When transplantation mences renal replacement therapy with dialysis 18 . It has activity is compared, countries with a lower human devel- to be underlined that long-term dialysis and its associ- opment index (HDI) are found to base their RT scheme on ated comorbidity have repeatedly been identified as factors living donors, although their rates per million of popula- which have a negative association with transplanted graft and tion (pmp hereunder) are lower than the rates in countries patient survival, regardless of chronic renal failure aetiology with a higher HDI, which perform RT from deceased as well 19,20 . as living donors.11 Nevertheless, major differences are also Based on current evidence, the better results achieved with found in LDRT pmp activity between countries at similar LDRT are therefore fundamentally due to transplant recipi- socioeconomic levels, as is the case within the European ent characteristics and degree of comorbidity, the delay until Union. transplantation and donor profile. Spain has a high rate of deceased donor transplantation and more than 3,000 RT procedures per year. LDRT here Changes in deceased donor profile and the waiting list is now a consolidated treatment option due to its bene- fits for patients, as well as the transplantation system as a Road and industrial safety laws have changed fundamentally whole, with low risk for donors. In this chapter we review in Spain over the last 20 years, and there has also been a the reasons which justify the LDRT scheme in our country, continuous improvement in medical care. These factors have covering important aspects of donor protection. We describe given rise to a fortunate decrease in the mortality of the popu- the situation of the scheme in Spain, together with the lation, although this has also caused a gradual fall in potential challenges which our system has to face in the current sce- donations due to brain death 21 . nario. Thanks to its transplant coordination network and medi- cal and surgical teams, our system has adapted to this new The need for living donor RT scenario. However, although this has increased the number of transplantations, it has also involved a substantial change in The LDRT scheme is needed for several reasons. Firstly, this donor profile. is due to the benefits it offers recipients in comparison with The changes in end-of-life care for critical patients have deceased donor RT. LDRT is also necessary if we are to progress continued, with the unprecedented development of con- towards transplantation self-sufficiency, as it would be hard trolled asystole donation programmes 16,22 . Successful organ to meet the needs for RT in our population given the gradual transplants from elderly and very elderly donors now occur change in the profile of deceased donors. Finally, the decision regularly, adapting to potential older donors with associated to implement this scheme is based on a substantial improve- comorbidities. The implementation of projects such as the ment in the procedure for donors. one for non-standard risk donors 23,24 and the preparation of clinical guides 25–28 to ensure appropriate evaluation of the Living donor RT results risk-benefit of transplanting organs from donors with differ- ent pathologies, have made it possible to gradually broaden LDRT is associated with better long-term results than the degree of acceptance and subsequent use of organs from deceased donor RT, regardless of the genetic relationship more complex donors. between the donor and recipient6,12 or whether it is a first or It is within this context that Spain achieved its highest ever second transplantation.13 European Registry of Renal Replace- rate of RT and the highest in the world, with 72.8 transplants ment Therapy data (ERA-EDTA) show a renal graft survival rate pmp in 2019 29 . Nevertheless, in spite of the fact that the trans- (adjusted for age, sex and cause of primary renal disease) of plantation waiting list shortens year after year, at the end of 86.7% at 5 years for living donor recipients, as opposed to 81.4% 2019 it still stood at 3.933 patients, so we are still a long way n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 9 Spain (3313) United States of America (22003) Netherlands (998) France (3567) United Kingdom (3642) Portugal (502) Czech Republic (508) Malta (19) Turkey (3874) Israel (401) Austria (414) Belgium (531) Canada (1706) Uruguay (161) Australia (1135) Sweden (448) Estonia (58) Norway (240) Croaa (183) Finland (238) Switzerland (352) Denmark (236) New Zealand (182) Belarus (356) Italy (2124) Ireland (167) Hun gary (335) Argenna (1475) Iceland (9) Saudi Arabia (1006) Lithuania (84) Brazil (5975) Latvia (53) Germany (2291) Slovakia (146) Slovenia (56) Poland (946) Mexico (3081) Colombia (864) Kuwait (70) Qatar (43) Cyprus (19) DD renal Tx pmp Cuba (173) Ecuador (249) Japan (1865) Syrian Arab Republic (251) LD renal Tx pmp Greece (141) Costa Rica (63) Panama (46) Thailand (668) Russian Federaon (1361) Romania (183) China (13029) Republic of North Macedonia (17) Mongolia (24) Bolivia (MulnaonalState of) (76) Guatemala (115) Sudan (273) Algeria (268) Paraguay (41) Ind ia (7936) El Salvador (34) Dominican Republic (54) Peru (157) Georgia (17) Armenia (12) Bulgaria (25) Republic of Moldova (13) Nicaragua (16) Malaysia (80) Venezuela (Bolivarian Republic of) (40) 0 10 20 30 40 50 60 70 80 Renal transplantaon procedures Figure 1 – Renal transplantations per million population (pmp) according to country, living (LD) versus deceased (DD). Year 2018. Source: Global Observatory on Donation and Transplantation. from becoming self-sufficient. When examining the negative segment may benefit more clearly from living renal donation, effect of the time spent in dialysis on post-transplantation sur- this therapy is suitable for patients in any age band. vival, we find that only 5% of ESRD patients were transplanted It has to be pointed out that the scarcity of young donors before starting treatment with dialysis 30 . also affects the availability of other organs, such as the pan- The increase in deceased donors has occurred due to the creas. Very briefly, diabetic patients compete against potential ongoing rise in the number of progressively older donors, young recipients for young kidneys. They all seek an appro- including those in controlled asystole. This makes it unlikely priate donor in terms of age, especially in the case of highly that young patients with end stage renal failure will be trans- sensitized patients. LDRT may help to resolve this situation by planted after only a short delay. Although this population occasionally offering the possibility of pancreas transplant. 10 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Improving living donor safety The public health system acquires a responsibility towards living donors, because of the complications they may develop Although the benefit of LDRT for patients is clear, this ther- over the short, medium or long-term. It is therefore obligatory apy could not be used without the sine qua non condition of to ensure living donors have continuous medical protection guaranteeing donor safety. Each chapter of this clinical guide and care to preserve their residual renal function (in the therefore takes into account the possible consequences for case of renal donors) while treating any possible complica- donors and their subsequent quality of life. tions deriving from donation. Within the European Union it is The standardization of the evaluation and care of living also obligatory to record information about each living donor donors 1,31 , as well as the use of increasingly less invasive in national registries designed to show their basal clinical nephrectomy techniques 32 , have the primordial aim of pro- and demographic characteristics and evolution, including any tecting donor health 1,8,9 . complications associated with the donation process. Apart Although performing a nephrectomy in a healthy indi- from recording this information, it is also obligatory for medi- vidual is not innocuous, the risk of immediate mortality cal workers to notify the National Biovigilance System 42 of any associated with living renal donation is estimated to stand adverse events (donation incidents that place a living donor at 0.03%, and this has not varied in the last 15 years 33 . The at risk, even if no harm was caused) and adverse reactions introduction of laparoscopic nephrectomy has led to a consid- (incidents that harmed a living donor). erable improvement in the immediate postoperative period, Determining the validity of the consent to donate is a basic and donors recover and recommence their social and profes- part of evaluating a living donor. A valid consent must be sional lives sooner. Although the probability of a living renal freely given, informed and clearly expressed. When evaluating donor developing renal disease over the long-term is lower a living donor it is fundamental to elucidate the underlying than the figure for the general population (where comorbid- reasons for the donation, and to evaluate the legitimacy of ity is a factor), it is still higher than it would have been if the relationship between the potential donor and the recipi- the donor had not been subjected to nephrectomy 34–37 . Age, ent. Information about the process should be broad in scope, African American, obesity and familial genetic diseases have structured and comprehensible. The possibility of discontin- been shown to be risk factors in long-term donor evolution. It uing the process at any time and without the need for any is therefore necessary to evaluate donor risk and take these explanation whatsoever should be expressed. The living donor factors into account, in the information supplied to donors advocate plays a fundamental role in determining the validity and recipients as well as in donor care after the procedure 9 . of consent: this professional is unconnected with the individu- als who are going to perform the harvesting and engraftation Donor protection of the organ, and they work to ensure the complete protec- tion of the person. In our country this role is fulfilled by the A LDRT scheme has to be based on the fundamental princi- intervention of an independent medical professional, while ple of complete protection of the living organ donor. The basic the Ethics Committee of the hospital in question also par- principles of this protection are contained in different interna- ticipates, and the potential donor has to appear before the tional legal documents: the WHO Guiding Principles on Human Examining Magistrate. This three-filter system established by Cell, Tissue and Organ Transplantation, the Council of Europe Con- our legislation is probably one of the strongest safeguards in vention on Human Rights and Biomedicine, as well as its Additional the world within this context. The donation procedure must be Protocol concerning Transplantation of Organs and Tissues of Human halted if situations which lead to suspicions of human traffick- Origin, and Directive 2010/53/EU of the European Parliament ing or other comparable scenarios are identified. The relevant and the Council, of 7 July 2010, on the Standards of Quality authorities should also be notified, to activate investigations and Safety of Human Organs intended for Transplantation 38–40 . and prosecute any possible crimes. In Spain these principles are expressed in Law 30/1979, of 27 The protection of living donors also involves the elimi- October, on organ harvesting and transplantation, and in Royal nation of disincentives against donating organs while alive. Decree 1723/2012, of 28 December, which governs the Activ- These include reimbursing any expenses incurred by the ities of Obtaining, Clinical Use and Territorial Coordination donor and compensation for loss of earnings due to the of Human Organs intended for Transplantation, establishing assessment, surgical operation and subsequent recuperation. Quality and Safety Requisites 41 . Apart from this national and Another example of measures to be applied would be pro- international legislative framework there are also national tection against loss of employment due to time off work for professional standards 1 , such as this Guide, and international diagnostic tests or the act of donation itself. ones, especially the KDIGO guides 9 . The protection of a living donor starts with the appropri- ate evaluation and selection of a potential candidate, based The evolution of living donor RT in Spain and how it on medical and psychosocial criteria 8 . Prospective donors compares with other countries should be subjected to an exhaustive standardized evalua- tion of their potential as such to assess the risk that donation In spite of the strong international consensus in favour of would involve for their state of health–as well as for the poten- LDRT, this treatment did not become widespread in Spain until tial recipient of the donated organ. Risk assessment covers the early years of the 21st century. This was partially because aspects of psychosocial as well as physical health, enabling of the success of the Spanish model of donation and trans- the identification of absolute or relative contraindications to plantation 43 , and partially because clinicians did not wish to donation. perform a nephrectomy on healthy individuals 44,45 . n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 11 LDRT absolute number LDRT pmp 10 450 09 9 08 400 Live donor renal transplantation (absolute N) 08 08 8 07 07 07 350 07 7 06 300 6 05 05 250 5 LDRT pmp 200 4 03 03 150 3 02 02 100 2 01 01 01 01 1 00 00 00 00 00 01 01 01 00 00 00 01 50 18 16 16 15 15 20 35 22 20 19 17 19 31 34 60 61 87 102 137 156 235 240312 361382 423 388 343332 293 335 0 0 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Figure 2 – Living donor renal transplantation in Spain. Absolute number of renal transplantations and rate per million population (pmp). Source: National Transplantation Organization. Given the agreement reached in the Amsterdam Forum, the in similar sociodemographic and economic circumstances, we international stance regarding donor protection and the good find a lower rate of activity than is the case in the Scandinavian results obtained with this therapy in major international reg- countries, the Netherlands, the United Kingdom, the United istries 8,33,46,47 , LDRT started to be advocated in different areas States (U.S.A.) or Canada 49 . A slight fall in recent years is a (transplantation teams, scientific societies, patient associa- striking finding in the U.S.A., although this has been analysed tions, regional transplantation coordination bodies and the by the system there and has now been reversed (Figure 3). ONT) 48 . Work was undertaken to raise awareness of this Nor has transplantation activity increased uniformly therapy among patients and their families: the benefits it throughout Spain. There are large differences between the offers patients, the type of assessment donors are subjected to numbers of LDRT procedures pmp performed in the different and the possible consequences of donation for them 1 . Major Autonomous Communities, leading to unequal access to this efforts were also made to train the clinicians involved in this therapeutic option (Figure 4). Several of the Communities with activity. the highest rates of LDRT pmp also have high rates of deceased The implementation of a national registry was fundamen- donor RT pmp. LDRT activity in Catalonia and Galicia is simi- tal in Spain to show the possible consequences of living lar to that registered in a country as active in this field as the donation. This registry includes data on the main clinical United Kingdom 49 . and epidemiological characteristics of living renal donors, the nephrectomy techniques used, their complication rates and Adapting the living donor RT scheme to new needs the possible clinical implications of renal donation over the short-, medium- and long-terms. This registry started working Standard LDRT takes place between a donor and recipient in 2010 and, thanks to the commitment of administrative bod- who are blood group and HLA compatible. One of the advan- ies and clinicians, it now contains information on 96% of living tages of living as opposed to deceased donation is that as it renal donors. It makes it possible to extract reliable conclu- often takes place between blood relatives, there is a higher sions, so that it is used to assess donor risk as well as supplying probability that donor and recipient will share a higher num- information they are given about the procedure. ber of antigens. Nevertheless, this fact has not prevented These measures have driven the emergence of new LDRT LDRT taking place between genetically unrelated individu- schemes and increased activity in existing ones. While 61 als, with excellent results 50 . This favours the increasing use LDRT were performed in 12 hospitals in 2004, more than 300 of transplantation between couples, friends and unrelated procedures in 33 accredited hospitals were performed in 2019, individuals, as occurs in paired and altruistic renal donation corresponding to an activity of 7.1 transplantations pmp 29 programmes 51 . (Figure 2). Although this is good news, it is important to reflect The increase in living donation has led to a rise in the that, in spite of the increase in activity, we are still a long way number of potential donor assessments which detect incom- from achieving the aim of preventing many patients from hav- patibility with the recipient. In fact, from 30% to 40% of ing to enter dialysis. When LDRT over recent years in Spain is potential donors who are evaluated are found to be incom- compared with the situation in other nearby countries or ones patible with their recipient. This may be due to blood group 12 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Figure 3 – Evolution of the rate of living donor renal transplantations per million population in different countries. Years: 2009-2018. Source: Global Observatory on Donation and Transplantation. incompatibility, the presence of hemagglutinins against the better knowledge of the process and its results, increasingly donor’s blood group, or the detection in the recipient of specific systematic information about this therapy and the overcom- antibodies against the HLA of their donor. Different strategies ing of technical obstacles against transplantations of this type. have been used to overcome incompatibility: some of them are Nevertheless, several challenges still have to be faced, and based on desensitizing the recipient so that direct incompat- these are described in the National Organ Donation and Trans- ible transplants can be used (ABO or HLA incompatible) 52–54 plantation Strategy for 2018-2022 58 . while others use donor interchange within a pool of incompat- Insufficient LDRT activity and the differences between hos- ible pairs, known as pooled or paired transplantation 51,55,56 . pitals and Autonomous Communities mean that a strategy of Both strategies have been used in Spain for more than 10 identifying and spreading good practices is necessary. This years, enabling LDRT for approximately 50 patients per year is so for the organization and development of living donor 29 who would otherwise have remained on the waiting list for information and assessment, as well as selection processes in a deceased donor. terms of immunology, nephrology, urology and psychosocial Adapting the LDRT scheme is not solely based on over- aspects. Good practices should also be identified and shared coming incompatibility, as it also involves broadening donor regarding the surgical procedure for the donor and their care acceptance criteria in terms of cardiovascular risk factors, as and follow-up. The ONT, the SEN and the SET have therefore well as donor and recipient age. Respecting the former, and led a benchmarking project which will produce specific rec- always with donor protection as the core aim, the number of ommendations to be adopted by hospitals and clinicians to donors with pharmacologically-controlled arterial hyperten- improve critical areas within the LDRT process. It is important sion (hypertension) has risen over recent years. This is also to always supply information about LDRT in ESRD consulta- the case for patients with obesity (defined as a BMI≥30 Kg/m2 ) tions. The position in charge of coordinating LDRT activity in (see sections 5, 7 and 8), and these donors now amount to 10% accredited hospitals should be identified, and ad hoc train- and 16% of live renal donors, respectively 57 . ing actions for the teams and clinicians who are able to Respecting age, according to Spanish Registry of Renal prescribe this renal replacement therapy have to be devel- Patients (REER) data, annual post-transplantation mortality is oped. lower than that of those patients of all age groups who remain Measures to protect living donors have to be improved in in dialysis 30 , so that LDRT is also an excellent option for the our country, including those which apply to social and work- oldest group of patients. In fact, in Spain 16% of LDRT recip- related factors that require reforms which are already being ients are above 60 years old, as are 21% of donors, with good prepared. The introduction of technical improvements in the post-donation evolution 57 . national paired RT, altruistic donation and incompatible donor schemes will also make it possible to increase the number Optimising the living donor RT scheme of patients who are able to benefit from LDRT with suitable post-transplantation results. The national LDRT scheme over recent years has gradually Finally, the need to reach clinicians in an effective way is improved in quantitative terms, with an increasing number of one of the reasons why the SEN, the SET and the ONT decided transplantations. It has also improved qualitatively, thanks to to prepare this LDRT recommendations document. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 13 TOTAL 44 21.57 7.12 CATALONIA 58 39.37 17.21 CANTABRIA 43 37.93 1.72 PRINCIPALITY OF 75 4.9 1.96 ASTURIAS BASQUE 34 34.55 8.18 COUNTRY 46.49 26.32 BALEARIC IS. 45 20.47 5.12 CANARY IS. 41 23.19 4.04 ANDALUSIA 54 5.34 7.63 ARAGON RT BD (p.m.p.) RT @ (p.m.p.) 33 18.96 13.38 GALICIA LDRT (p.m.p.) 39 17.27 7.51 MADRID 48 7.116.28 CASTILE Y LEON 44.8 12.2 2.8 VALENCIAN COMMUNITY 38.92 19.7 0.49 CASTILE-LA MANCHA 41 12.75 4.03 MURCIA 19.35 32.26 LA RIOJA 31 16.92 3.08 C. FORAL DE NAVARRA 25 8.49 2.83 EXTREMADURA 0 10 20 30 40 50 60 70 80 90 100 110 120 Figure 4 – Renal transplantations per million population (pmp) according to donor type and Autonomous Community. Spain 2019. Source: National Transplantation Organization. individuals with no ties, on condition that this takes place Regulations governing living donor RT in Spain voluntarily, altruistically and selflessly (NG). • The donor has to be legally of age, with full mental faculties • LDRT is governed in Spain by the 30/1979 Transplantation and a suitable state of health, which is to be accredited by Law, developed by Royal Decree 1723/2012 (Quality of evi- the relevant medical certificate issued by a doctor who is dence: NG). not involved in the donation process, and they should be • Our law permits living donor organ donation if this is com- fully informed of the consequences of their decision (NG). patible with life, and if the function of the organ may be • The donor must grant their consent expressly, freely and compensated for by the organism in a safe manner (NG). consciously before a judge, although before this takes place • Such donation requires the absence of any economic, they will have already signed a medical informed consent psychological or social conditioning factors, and that the document in which they state that they have been informed destination of the organ will be transplantation in a certain of the possible risks for their person and the advantages individual (NG). which are expected to arise from the engraftation of the • Although the regulations mention the possibility of dona- organ in the recipient (NG). tion between individuals related genetically, by kinship or • Hospitals which perform LDRT must be authorized for the close friendship, they do not exclude donation between harvesting as well as for the transplantation of the said 14 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 organ, which makes it necessary to meet the requisites The second principle expresses the purpose that has to demanded for the authorization of hospitals to obtain and guide the whole activity being regulated: organs may only transplant from cadaveric donors, so that framework proto- be collected and transplanted for therapeutic ends, thereby cols should be prepared to guarantee the quality and safety excluding purposes such as research or other equally legal of the procedure (NG). benefits. • Failure to comply with the requisites established in the The legal regime differs depending on whether the donor transplantation regulations may give rise to administrative is living or cadaveric: for living donors, the law demands com- responsibility due to the commission of an infraction (NG). pliance with a series of requisites which have the aim of • In the cases of organ harvesting without the free, informed guaranteeing the validity of the consent that the donor should and express consent of the living donor, or when a reward of give after receiving the necessary information. These are: any nature intervenes, an organ trafficking crime will have been committed and penal responsibility will be demanded a) That the donor must be of age. Royal Decree-law 9/2014, of (NG). 4 July, which establishes the quality and safety standards for donating, obtaining, evaluating, processing, preserv- Law 30/79, of 27 October, on the harvesting and ing, storing and distributing human cells and tissues, and transplantation of organs, and Royal Decree 1723/2012, passes the regulations governing their coordination and of 28 December. functioning for use in humans, permits obtaining cells and tissues from minors or individuals incapable of giving con- Law 30/79 on the harvesting and transplantation of organs. sent in the case of surgical residues or haematopoietic More than forty years have passed since Law 30/79 on the precursors, or other reproducible cells and tissues with a harvesting and transplantation of organs was passed, and it therapeutic indication that is or may be vital for the recipi- has only been modified once. The change was made by Law ent. Under these circumstances, consent will be granted by 26/2011, of 1 August, to adapt the regulation to the Interna- the individual who is the legal representative of the donor tional Convention on the Rights of Persons with Disability, and (article 7.1). which adds letter e) to article 4 in the subject of how individu- b) That the donor must be of sound mind. That the donor was als with disability are to be informed and how they are to give previously informed of the consequences - physical, spir- their consent. itual and psychological - of their decision, as well as the In spite of the passage of time, this regulation is still a eventual repercussions that the donation may have on their valid and secure instrument for governing the subject it cov- personal, family and professional life. Respecting cells and ers, giving the system a high level of reliability. The ethical tissues, the regulation requires a personal interview with and legal implications deriving from living donor organ dona- the donor, during which a structured questionnaire has to tion are unquestionable. Living donors are healthy people who be completed. According to article 7.1 of Royal Decree-law are subjected to a surgical operation that is not indicated to 9/2014, of 4 July, the information which the doctor who will improve their physical condition, but rather that of someone perform the harvesting or who is in charge of the same else who is sick. This intervention involves the donor losing a should offer the donor has to include the objective and major organ, harm which is legally permitted on the grounds nature of the means of obtaining the cells and tissues; its of the consent of the donor and the expected benefit for the consequences and risks; the analytical tests which will be recipient. However, this exception to the general rule of penal- performed; data recording and protection; and the thera- ising those who cause severe injuries is conditioned by the peutic purposes of the procedure. Likewise, the donor will need for strict compliance with certain requisites, to guaran- be informed of the protective measures applicable to them tee that consent is given freely and selflessly by the donor, and the expected benefits for the recipient of the use of after receiving exhaustive information on the risks and bene- the tissue or cell group collected. In the event of a “pos- fits involved. sible similar use” of the cells or tissue, the content of the The articles of the law establish the governing principles information offered will also have to include: i) the indica- of the activity and distinguish two different legal regimes, tion that the cells and tissues obtained will be available for depending on whether the organs in question are from a liv- allogenic use in other patients, if this is therapeutically indi- ing or cadaveric donor. Each specific regime is supervised cated, ii) information that is up-to-date, true and complete by the regulations that develop the law, complemented by on the state of scientific knowledge respecting therapeutic the directive governing the harvesting and use of human tis- or research use; iii) the processing and storage conditions sues. in authorized establishments, and iiii) any other question The basic principle is that of being free of charge, expressly associated with the therapeutic use of the cells and tissues forbidding any economic compensation for the donor due to obtained that was not medically indicated at the time they organ donation, while it is also prohibited for the recipient were obtained and when preservation of them commenced. to be subjected to any demand for payment or reward what- Likewise, they are to be informed of the benefits which the soever. This declaration is understood without prejudice to recipient is expected to obtain from the transplantation of adopting the necessary measures to ensure that donation will the donated organ. never be costly for the donor. It is therefore possible to com- c) That the donor is to grant their consent expressly, freely pensate donors for any economic losses incurred as the result and consciously. of the donation process, without violating the principle of d) If the donor were a person with disability that fulfils the being free of charge. requisites described in the above sections, the information n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 15 and consent document should be provided in suitable for- Royal Decree 1723/2012, of 28 December, which governs mats, following the rules set by the principle of design for the activities of obtaining and clinically using human all, so that they are accessible and comprehensible for their organs, and the territorial coordination of the human type of disability. organs destined for transplantation, establishing quality e) That the destination of the collected organ will be trans- and safety requisites. plantation into a selected person with the purpose of substantially improving their life expectation or conditions. This regulation replaces Royal Decree 2070/1999, of 30 Decem- f) That the anonymity of the recipient is guaranteed. ber, which had been in force since it repealed the Decree of 22 February 1980, which had been developed for the first time The legal regulation concludes by listing the requisites by Law 30/79. Throughout its existence the law has undergone which have to be met for the person in charge of the transplant these three regulatory developments, of which the modifica- to give their consent for the same, all of which are considered tion that occurred in 1999 was especially relevant in the field from the viewpoint of the recipient. The demand for this req- of cadaveric organ donation. The regulatory reforms have not uisite is modified by legal regulation - RD 1723/2012- as article altered the living donor donation regime, although this does 5 of the same stipulates that this limitation is not applicable to not mean that new forms of donation, such as altruistic dona- those directly involved in the transplantation of organs from a tion, are excluded from the scope of coverage of the current living donor between genetically related individuals or those regulation. related by kinship or close friendship: The Royal Decree that is currently in force incorporates in Spanish legal code Directive 2010/53/EU of the European a) That they should be fully aware of the type of intervention Parliament and Council, of 7 July 2010, on quality and safety that will be carried out, knowing the possible risks and fore- standards for human organs destined for transplant. The seeable advantages which, in physical and psychological Directive determines the minimum requisites that have to be terms, may derive from the transplantation. applied when donating, evaluating, characterising, obtaining, b) They should be informed when so required that necessary preserving, transporting and transplanting human organs, immunological, histocompatibility studies or any others with the purpose of guaranteeing high levels of quality and that may be necessary have been performed on the donor safety for the said organs. It also sets requisites for traceabil- and future recipient by a laboratory that is accredited by ity and the development of a system for the notification and the Ministry of Health, Social Policy and Equality. management of events and severe adverse reactions, estab- c) That the said information is supplied using appropriate for- lishing the minimum data that have to be recorded for the mats, following the rules set by the principle of design for evaluation of donors and organs. all, so that it is accessible and comprehensible for individ- Its outstanding ethical foundations include those which uals with disability. refer to the voluntary and free nature of donation, together d) That they express their consent to the performance of with consent, the protection of living donors and personal the transplantation in writing or another medium suitable data protection. For the first time it also introduces a list of for their disability when they are an adult who is legally administrative infractions due to failure to comply with the responsible for their actions, or by their legal representa- regulations governing the harvesting and transplantation of tives, parents or tutors if they are disabled, or in the case of organs. minors. If the recipient is a person with disability, their per- Observing the requisites and principles established in the sonal circumstances must be taken into account together Directive, RD 1723/2012 sets quality and safety requisites with their capacity to make the said specific decision, con- for activities connected with obtaining and clinically using sidering the supply of support for making these decisions. human organs, with the aim of guaranteeing a high level of In the case of persons with disability and the need for sup- human health protection and reducing the loss of available port in decision-making, they will freely decide once they organs as far as possible. have been supplied with the forms of supports and assis- Law 30/79 states that the purpose of the said activities tance necessitated by their specific circumstances. has to be therapeutic. That is, they should be guided by the sole purpose of favouring the health or conditions of life of The recipient is a patient and therefore this regulation has the recipient, without prejudice to any research that may to be completed with the stipulations of law 41/2002, which also be taking place. The exercise of these activities also has governs patient autonomy and their rights and obligations to respect the fundamental rights of persons and the eth- regarding information and clinical documentation. It must be ical postulates applied to clinical practice and biomedical understood that the minors referred to in article 6 of the law research. are under the age of 16 years. The age of maturity required to The principles of the regulation contained in the Royal be an organ donor and recipient will be covered in the section Decree are based on Law 30/79, which develops Organic Law corresponding to consent. 3/2018, of 5 December, on Personal Data Protection and the 16 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 guarantee of digital rights. They are also based on Directive - Free of charge: it is not possible for the donor or any other 2010/53/EU, which transposes them, and they are listed below: physical person or legal entity to receive any reward or eco- - Confidentiality: this principle prohibits the communica- nomic compensation whatsoever for donation. Nor will the tion of data that would make it possible to identify the donor recipient be subjected to any demand for any payment what- and recipient. The exception to this rule are those cases in soever for the transplanted organ, and nor is it possible to offer which an individual publicly, freely and voluntarily identifies or deliver any economic benefits or benefits of any other type herself as a donor or recipient. Even when this occurs, the in connection with the assignation of one or several organs principle should be respected that neither donors nor their for transplantation, and nor is it possible to request them or family members may know the identity of the recipient or accept such benefits. All advertising regarding the need for an their family members, and vice versa. organ or the availability of one is also prohibited, as is offering In general, any diffusion of information that may directly or seeking any type of reward or remuneration. connect obtaining an organ and its subsequent transplanta- The Royal Decree reproduces the exception for the com- tion is to be avoided. However, this restriction is not applicable pensation of economic losses when it indicates that the to the parties directly involved in the transplantation of organs performance of the medical procedures associated with from a living donor between individuals who are genetically obtaining an organ shall not, in any case, be at the expense related or connected by kinship or close friendship. Outside of the living donor. Living donors are not to be prevented from such cases, the principle of confidentiality should be respected receiving repayment of their expenses and compensation for even in the case of living donor organ transplantation. any reduction in income directly associated with the donation. Respecting this principle does not prevent taking preven- However, when the said repayment is applicable, it will neces- tive measures when the existence of an individual or collective sarily have to be made using the mechanisms which may be risk to health is suspected. supplied for this purpose by the competent authorities. - Personal data protection: information on human organ donors and recipients is to be recorded, processed and stored - Fairness: the selection of and access to possible recipients in the strictest confidentiality, according to the stipulations should be subject to criteria of fairness, guaranteeing equal- of data protection laws, in the General Health Law and in Law ity of opportunities for the therapy. 41/2002, of 14 November, which governs patient autonomy and - Adoption of the quality and safety measures which are rights and obligations in the field of information and clinical necessary to reduce the loss of organs, minimise possible documentation. risks and attempt to ensure the maximum possibilities of The individual in charge of the therapy will have to success for transplantation, improving the efficiency of the adopt the technical and organizational measures necessary process of obtaining and transplanting organs. to guarantee the security of the data in this special category, preventing their alteration, loss, processing or unauthorized Respecting the specific regulation of donation of this type, access. The individual in charge as well as the person in charge it is governed by article 8 in a form that is consistent with the of processing are obliged to keep professional secrecy, even regulation contained in law 30/79, but more completely devel- after their professional relationship has ceased. Infractions oped. Living donation is subject to the following requisites: in this area may be penalized by the Spanish Data Protection Agency, without prejudice to any criminal responsibility that 1. The harvesting should be of an organ or part of the same may be incurred (articles 197 and 198 of the Penal Code). whose absence is compatible with life and whose function According to article 9 of Organic Law 3/2018 on Personal can be compensated by the donor’s organism appropriately Data Protection and the guarantee of digital rights, by refer- and sufficiently safely. ence to article 9.2 of Regulation (EU) 2016/679, data processing 2. It will not be possible to harvest organs from minors, even in the field of health may be supported when this is required by with the consent of their parents or tutors. the management of healthcare, social, public and private sys- 3. Nor will it be possible to harvest - or, if applicable, to use - tems, or the execution of an insurance contract which covers organs from a living donor when: the affected party. - For any reason it may be considered that consent was - Limitation of Promotion and Publicity: the promotion of obtained due to an economic conditioning factor or one organ donation activity should take place in general terms, of any other type, social or psychological. underlining its altruistic, voluntary and selfless nature. It will - There are suspicions that the free consent of the donor has not be possible to advertise the donation of organs to benefit been altered. specific individuals or certain hospitals, institutions, founda- - Sufficient possibilities of transplant success are not tions or companies. expected. Deceitful advertising which leads to erroneous opinions on 4. The right to information should include the planned proce- obtaining human organs and using them clinically is expressly dure for the possible case in which after harvesting of the prohibited. organ it cannot be transplanted in the recipient for whom Without prejudice to the foregoing point, the competent it was intended. All information should be supplied to the authorities will promote the information and education of donor in appropriate formats, so that it is accessible and the population regarding donation and transplantation, the comprehensible for persons with disability. benefits these offer to those who need them, as well as the 5. It will be mandatory for the Ethics Committee of the trans- conditions, requisites and guarantees which apply to them. planting hospital to issue a report. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 17 Accreditation of the state of health and mental faculties of organ removal, according to the accepted standards in of the donor is a requisite demanded by Law 30/79. The this field and the best medical practices; Royal Decree stipulates that this accreditation should be by g) They must have framework programmes which guarantee a doctor other than the one who will perform the harvesting, the quality and safety of the whole process; after being supplied with the corresponding information. This h) They must have a confidential registry with restricted information will necessarily include the following aspects: a) access, with its corresponding alphanumerical codes, to inherent risks of the intervention, b) foreseeable physical and record the necessary data that makes it possible to ensure or psychological consequences, c) possible repercussions in traceability, as well as to link the traceability of the tissues their personal, family or professional life, and d) expected and cells obtained from donors; benefits of the transplantation and the potential risks for the i) They must keep a donor serum deposit during a period of recipient. The living donor should also be informed of the at least ten years, for the purpose of performing biological need for them to communicate their medical history, and they controls, if necessary; will be informed that they will be given medical care for their j) They must guarantee the availability of the appropriate recovery and will be clinically followed-up in connection with personnel, facilities and services for the restoration of the the harvesting of the organ. body of the deceased person, after removal; The above points will be accredited in a medical certificate k) They must comply with the requisites established for con- which describes the donor’s state of health, the information fidentiality and the protection of personal data, together that was supplied and the donor’s freely expressed response with the promotion, publicity and free nature of donations. and motivations and, if applicable, any sign of external pres- 1) They must have sufficient medical and nursing personnel sure on the same. This certificate will include the list of the with qualifications and accredited experience for correct names of the other clinicians who have helped the certifying donor assessment and selection and the performance of doctor in the tasks involved. the removal. 2) They must have sufficient facilities and materials nec- Authorized Hospitals. Competences of the Autonomous essary for the correct performance of organ removal, Regions. according to the accepted standards within this field and the best medical practices. Article 10 of the Royal Decree lists the general requisites which 3) They must have the medical services, including laborato- living donor organ removal hospitals have to fulfil, following ries and imaging techniques, which are necessary to ensure authorization by the competent authority of the Autonomous the proper preoperative study of donors and to treat any Community: complications which may arise in them. These medical ser- vices are to be staffed by qualified personnel and they are 1) It should be authorized as a deceased-donor organ removal to have appropriate facilities and equipment. hospital and as an organ transplantation hospital for which 4) They must have protocols which ensure appropriate donor living-donor organ removal authorization is requested. assessment and selection, communicating relevant infor- Article 11.2 RD 1723/2012.2. mation about the donor and recipient when harvesting and transplant are not performed in the same hospital, To be authorized, deceased-donor organ removal hospitals as well as protocols for the process of organ removal must fulfil at least the following requisites: and the immediate postoperative and long-term follow-up, together with other protocols or framework programmes a) They must have an organization and working regime which with the aim of ensuring the quality and safety of the whole makes it possible to ensure that organ removal is per- process. formed in a satisfactory manner; 5) They must have a confidential registry with restricted b) They must have a hospital transplantation coordina- access and its corresponding alphanumerical codes, to tion unit with the appropriate personnel and material record the necessary data that makes it possible to ensure resources; traceability. c) They must guarantee the availability of qualified medical 6) They must guarantee recording of information about living personnel and the technical means of verifying death; donors and their clinical follow-up, according to the stip- d) They must guarantee the availability of duly qualified med- ulations of article 31, without prejudice to the regulations ical and nursing personnel, as well as sufficient medical on the protection of personal data and statistical confiden- services and technical resources for the correct selection, tiality. Article 31, on information systems, establishes: evaluation, description and care of the donor; e) They must guarantee the availability of appropriate i. Without infringing the agreements that may be established medical services, including laboratories and imaging tech- with relevant professional and scientific associations or niques, to carry out the determinations that are considered the systems that may be implemented by the autonomous necessary at any time and which permit appropriate clini- communities for such purposes, and in cooperation with cal assessment of the donor. These services will be staffed the same, the National Transplant Organization will by qualified personnel and will have appropriate facilities develop and Maintain the state information systems that and equipment; will record and store the data relating to: a) Donors and f) They must guarantee the availability of the facilities and organs and their description; b) Organ traceability from materials which are necessary for the correct performance their donation to transplantation or rejection and vice 18 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 versa; c) The characteristics and movements of the patients to guarantee the viability and quality of the transplantation included in the waiting list for transplantation; d) The char- scheme. acteristics and follow-up data of transplanted patients; e) b) It must have a medical organization and working regime The characteristics and follow-up data of living donors; that are appropriate for performing the requested inter- f) Notification and measures used to manage events and vention. severe adverse reactions. c) It must have the corresponding medical and surgical unit ii. For each one of the above sections, the National Trans- with sufficient medical personnel and have proven experi- plant Organization will define, in cooperation with the ence in the type of transplantation in question. autonomous communities, the minimum data that will d) It must guarantee the availability of specialist doctors with have to be supplied to the state system for each donor, proven experience in the diagnosis and treatment of com- organ, patient in a waiting list or recipient. plications arising from the transplantation that is to be 7) They must comply with the established requisites regard- performed. ing confidentiality and personal data protection, promo- e) It must have a hospital transplantation coordination unit. tion and advertising and the free nature of donations. f) It must have the facilities and materials which are necessary for the appropriate performance of the trans- The procedure for obtaining medical authorization from plantation process, in the preoperative stage, during the the corresponding autonomous community, as well as renew- intervention and in the postoperative stage, according to ing or cancelling the same, without prejudice to the specific the accepted standards in this field and the best medical regulation in each one of the said communities, will follow practices. the instructions of article 11 of RD 1723/2012 on authoris- g) It must have the medical departments, including labo- ing hospitals to remove the organs of deceased donors. This ratories and imaging techniques, which are necessary to authorization must contain at least the following: a) the activ- guarantee the performance of the transplantation, appro- ity for which the hospital is authorized; b) The name(s) of the priate clinical follow-up of the recipient and the correct person(s) in charge of the removal process; c) The duration of treatment of the possible complications which practising the authorization, depending on the period during which it the type of transplantation in question requires. These will be in force as determined by the competent authority. medical services will have qualified staff and the appro- When the authorization expires it may be renewed after priate equipment and facilities. checking that the conditions which made it possible continue. h) It must have a pathological anatomy department with the In no case may it be understood to have been renewed auto- necessary human and technical resources for the study of matically. complications associated with transplantation and carry- Any form of substantial modification which occurs in the ing out possible post-mortem studies. conditions, structure, persons in charge or working of the hos- i) It must have a microbiology laboratory which is able to pital should be reported to the competent authority, and it may undertake checks of the infectious complications patients give rise to review of the medical authorization or even to the may suffer. cancellation of the same, even before the end of the period j) It must guarantee the availability of an immunology labo- during which it would be in force. ratory and a histocompatibility unit with the technical and The authorization will specify the person who, as well as human resources which are necessary to guarantee the cor- being in charge of the medical unit in which the transplant will rect performance of the immunological studies which are take place, has to approve each intervention, and this may be necessary for pre- and post-transplantation monitoring. revoked or suspended as a result of inspection and checks by k) It must have a Transplantation Commission and the pro- the competent authorities. tocols to ensure the appropriate selection of recipients, Respecting organ transplantation hospitals, article 19 of the the transplantation process and immediate and long-term Royal Decree stipulates, as well as the general requisites estab- postoperative follow-up, and to guarantee the quality and lished for the hospitals where organs are removed, that the safety of the whole therapeutic process, as well as other minimum specific requisites shown in appendix II will apply. quality and safety protocols. To carry out any transplantation of organs from a living donor l) It must have a confidential registry with its corresponding it will be indispensable that the hospital be authorized for the alphanumerical codes, with records of the transplantations transplantation of the corresponding organ from a deceased performed and the data that are necessary to guarantee donor, proving accredited experience in this intervention. traceability. Section 1 of article 18 of RD 1723/2012 states that human m) It must guarantee registration of the information that organ transplantation may only be performed in those hos- makes it possible to evaluate the transplantation activity pitals which hold the specific authorization of the competent undertaken in the hospital, as well as the results obtained, authority in their corresponding autonomous community. In according to the stipulations of article 31 and without section 2 it states that to be authorized, a human organ trans- prejudice to the regulations governing the protection of plantation hospital must fulfil at least the following general personal data and statistical confidentiality. requisites: n) At all times it should ensure that the actions and resources of the medical units involved in different types of trans- a) It must be authorized as a hospital for obtaining the organs plantation are appropriate for the state of the art in science, of deceased donors and accredited with sufficient activity using up-to-date diagnostic and therapeutic protocols. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 19 o) It must comply with the established requisites in the field The general medical age of majority -16 years- is not con- of confidentiality and personal data protection, promotion sidered to be sufficient by legislators to make decisions such as and advertising and the free nature of donations.* that of assigning previous instructions, as stipulated by arti- cle 11 of Law 41/2002, which also demands the age of majority The procedure to obtain authorization by the corre- to issue such instructions for the future. Nor may a decision sponding autonomous community will commence with an which affects the health and physical integrity of a healthy application that should contain at least the following data: a) person be made if it is not proven that they have reached a The type of transplantation to be performed. b) The list of doc- biological age at which sufficient maturity may be presumed tors who are in charge of the transplantation team, as well as to make relevant decisions. Article 156 of the Penal Code is the documentation which accredits their qualifications, and unequivocal on this point, when it confers on the consent c) A report with the detailed description of the human and of the donor that has been given in a manner that is valid, material resources and the protocols which the hospital has, free, conscious and expressly issued, the power to free the according to the requisites for undertaking the corresponding doctors who harvest an organ according to the stipulations of activity. the law from penal responsibility. Nevertheless, possible cases Without prejudice to the specific regulations of each are excepted when consent has been obtained in an irregular autonomous community, the authorization should contain at manner, or by means of price or reward, or when the signer is a least the following: a) the type of transplantation for which minor or completely lacks the aptitude necessary to give con- the hospital is authorized. b) The name(s) of the person(s) in sent, in which case the consent they give or that given by their charge of the transplantation team, and c) the duration of the legal representatives will not be valid. That is, the Penal Code authorization, according to the period it will be in force as only understands the harvesting of organs from a living donor determined by the competent authority. to be free of penal consequences when the said donor, being of It will be the responsibility of each autonomous community age, has consented to the harvesting in a valid, free, conscious to inspect or supervise transplantation coordination units, and express manner. Otherwise, and even when consent has organ removal hospitals and transplantation hospitals at reg- been given for the harvesting, the doctors will incur in the ular intervals. For this purpose, units and hospitals should crime defined in article 149 of the Penal Code, which punishes supply all of the information in the format and way which - with a prison sentence of from six to twelve years - those may be requested, in connection with the activity for which who cause another, by any means or procedure, to lose or lose they have been authorized. the use of a principal organ. The psychological requisite is covered by Law 30/79, which Informed consent. Exceptional donors: “competent” demands that the donor has full mental faculties, which must minors and “incompetent” adults. be accredited by the corresponding medical certificate. It also prohibits persons with a psychological deficiency or mental Informed consent by the donor. disease from donating, or those who for whatsoever other Law 30/79 as well as Royal Decree 1723/2012 both demand, if cause are unable to validly give their consent. donor consent is to be valid, that two requisites are fulfilled: This regulation should not be understood to be altered by biological and psychological. the legal modification introduced in Law 30/79 by Law 26/2011, For the first requisite the law states that the donor must of 1 August, on adapting the regulations to the International be of age, and this condition is confirmed by the Royal Decree Convention on the rights of Persons with Disability. The said when it prohibits the harvesting of organs from minors, even modification permits individuals with disability to become with the consent of their parents or tutors. A doubt may arise donors, but always on condition that they fulfil the requi- concerning the limit which has to be applied to determine sites of being of age and in full possession of their mental whether an individual is of age or a minor, as Law 41/2002 faculties. In such cases the information should be supplied to in article 9.4 excepts individuals over the age of 16 years from the donor in appropriate formats, so that it is accessible and consent by representation when their capacity has not been comprehensible for them, given the type of their disability. legally modified, except when they are not able intellectu- Consent is always given after the information which a ally or emotionally to comprehend the scope of the proposed donor must receive, following the general rule governing all intervention. The so-called medical majority - being of age to informed consent. Nevertheless, the information which has consent to any action in the field of healthcare - has been set to be supplied to a living donor is far more extensive than that at 16 years. which is required for any other medical act, precisely because Nevertheless, this is not the age of majority referred to by they are a healthy person who is not going to receive an inter- the regulation for the harvesting and transplantation of organs vention for their own benefit. The information on risks of all when it sets the conditions for the validity of the consent types, and the information on the expected benefits for the offered by a living donor. This age of majority coincides with recipient, must be exhaustive. In this respect RD 1723/2012 what is denominated the civil age of majority, which the Con- states that the information should cover the following points: stitution sets, in article 12, at 18 years. In the same way, the a) risks that are inherent in the intervention, b) foreseeable Civil Code states in article 315 that the age of majority com- physical or psychological consequences, c) repercussions that mences on the 18th birthday, counting the whole day of birth may arise in their personal, family or professional life, and for this purpose, and in article 322 it states that those over the d) the expected benefits of the transplantation and potential age of majority are capable of all acts in civil life “except for risks for the recipient. A living donor should also be informed the exceptions established in special cases by this Code. of the importance of communicating their personal medical 20 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 history, and they will be informed that they will be given “competent” minor under the age of 18 from donating, and medical assistance for their recovery and will be clinically they also prevent any “incompetent” individual above the age followed-up in connection with the harvesting of the organ. of majority from doing so when due to any reason they are The medical certificate accrediting the state of health of the unable to give their valid consent. donor should also refer to the information they were sup- plied with and their freely expressed response to this and Penalties for buying and selling organs. Detecting and their motivations and, if applicable, the presence of any sign reporting cases of illegality committed outside Spain. of external pressure applied to them. The consent given by the donor in a medical context should Penalties for buying and selling organs. be ratified by them before the legal authority. We will cover this Catalogue of administrative infractions.. Although buying or point under the corresponding heading. selling organs is a serious crime, the classification of this behaviour as a crime is not incompatible with the existence of Informed consent of the recipient a punitive administrative law. Penal law acts in this field as a Article six of Law 30/79 covers the consent given by the recip- form of extra protection of the legal goods which administra- ient, establishing requisites that do not differ from those tive law also protects. corresponding to any other informed consent within a med- Article 33 of the Royal Decree includes a list of infractions, ical context. It only specifies the type of information which giving the regulation the indispensable element of constraint has to be supplied, depending on the nature of the intended as a mechanism which sets out the consequences for the intervention. case of incompliance with its stipulations. The infractions are The regulation of the informed consent of the recipient defined by reference to the regulations, not only those in the by the law governing the harvesting and transplantation of Royal Decree, but also the circumstances described in Gen- organs must be understood to have been modified by the eral Health Law 14/1986, of 25 April, and General Public Health law governing patient autonomy. This is expressly stated in Law 33/2011, of 4 October, together with the circumstances article 17 of RD 1723/2012 when it affirms that the transplan- described in the law on personal data protection (Organic Law tation of human organs may only be carried out by hospitals 3/2018 on the Protection of Personal Data and guarantee of which have been authorized to do so, with the previous writ- digital rights). ten consent of the recipient or their legal representatives, as The Royal Decree classifies infractions according to their stipulated by article 9 of Law 41/2002, of 14 November. They severity, distinguishing between those that are very serious, must be informed beforehand of the risks and benefits which serious and slight. the intervention involves, as well as studies which are tech- The following are very serious infractions: nically appropriate for the type of transplantation in question in each case. 1) The performance of any activity governed by the Royal Decree without respecting the principle of confidentiality, Exceptional donors: “competent” minors and “incompetent” on condition that this can be demanded. adults 2) The performance of any activity governed by the Royal The terms “competence” or “incompetence” in reference to Decree without respecting the principles of a voluntary the capacity of persons to consent to a medical act are not nature, altruism, the absence of desire for profit or being in themselves legal concepts. We will examine which legal free of charge. concepts refer to the capacity of persons. 3) Advertising the need for or availability of an organ, offering Legal capacity or capacity in law involves the aptitude of a or requesting some type of reward or remuneration. subject for the full holding and exercise of rights. It is a person- 4) Obtaining organs from a living donor in the absence of com- ality attribute and in the abstract it is the same for everyone, pliance with any of the previous requisites established in so that the existence of a person is sufficient for its existence the Royal Decree, in particular those which refer to being to be asserted (Article 30 of Civil Law: personality is acquired of age, mental faculties, state of health and consent. at the moment of live birth, once entirely free of the maternal 5) Obtaining organs from a deceased donor in the absence womb). of any of the previous requisites established in the Royal The so-called capacity to exercise or the capacity to act is Decree, in particular those which refer to the study of the the aptitude of a subject for the exercise of their rights. Given will of the deceased respecting the donation of organs and its nature it is contingent and variable: it does not exist in the diagnosis and certification of death. all persons, and nor does it occur in all of them to the same 6) Obtaining or transplanting organs in a hospital that does degree, as it requires intelligence and will. Due to this the law not hold the necessary authorization from the competent sometimes refuses it and sometimes restricts it. authority. The definition of “competence” within a medical context 7) Failure to comply with the traceability requirements. implies the recognition of psychological aptitudes to make cer- 8) The transportation into or from Spain of organs without tain decisions. This concept must be completed with that of the necessary authorization, according to the stipulations the “capacity of discernment”, which expresses the psycholog- of article 15. ical aptitude that is necessary to reach a responsible decision 9) Obstructing or hindering the work of inspection. “here and now”. The special requisites and demands which the law imposes As may be seen, any activity involving the purchase or sale on the consent by living donors completely prevent a of living donor organs will fall under the definitions of the n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 21 forms of behaviour described in numbers 2, 4 and 5, with- declared that the sale of organs was contrary to the Universal out prejudice to its penal classification. Article 34 of the Royal Declaration of Human Rights, and it appealed to doctors not to Decree states respecting this that in the events in which infrac- perform transplants if they suspected that the organ involved tions may be crimes, the evidence for guilt will be passed to had been the object of a transaction. In the International Sum- the competent judicial authority and the punitive procedure mit Meeting on transplantation tourism and organ trafficking will not be followed until the judicial authority pronounces a held in May 2008, the representatives of 78 countries agreed firm sentence which terminates the procedure. If no crime is on the “Istanbul Declaration”, which states that the said prac- found to exist, the punitive process will continue on the basis tices violate the principles of equality, justice and respect for of the facts which the Courts have considered to be proven. human dignity, and that they should be eradicated. Although our Penal Code already covered these crimes under the head- Penalties and the punitive procedure. A financial penalty is ing of injuries–article 156, interpreted “sensu contrario”-, it established for all types of infractions. This is stipulated in was considered necessary to differentiate the treatment of the article 33 of the Royal Decree which refers, to determine the said activities, expressly classifying them. size of the amount, to the conditions set by article 58 of Law The legislator includes an authentic interpretation of what 33/2011, of 4 October, and article 36 of Law 14/1986, of 25 April. trafficking in third-party human organs should be understood Article 58 of Law 33/2011 states: to mean, including the illicit harvesting or removal of the same in the definition. This is defined as follows: 1) The commission of infractions in the field of public health will give rise to the imposition of the following penalties, 1) When organs have been removed without the free, without prejudice to those which may be established by informed and express consent of the living donor, in the the autonomous communities and local entities within the way and with the requisites demanded by law. scope of their competences: a) In the case of a very seri- 2) When in exchange for the harvesting or procurement, the ous infraction: a fine of from 60,001 euros to 600,000 euros, donor or a third party requests or receives a gift or reward although this sum may be surpassed until it amounts to five of any nature, or accepts an offer or promise, themselves or times the market value of the products or services involved by an intermediary, for their own benefit or that of a third in the infraction). In the case of serious infractions: a fine party. The reimbursement of expenses or compensation for of from 3,001 euros to 60,000 euros) In the case of slight loss of income due to the donation will not be understood infractions: a fine of up to 3,000 euros. These amounts may to be a gift or reward. be updated by the Government in accordance with regula- 3) Likewise penal sentences will be applied to those who, for tions. their own benefit or that of another: a) request or receive, 2) Without prejudice to the economic penalty that may apply, themselves or through an intermediary, a gift or reward of in the cases of very serious infractions the competent any nature, or who accept an offer or promise for proposing authority will be able to decide to temporarily close the or recruiting a donor or a recipient of organs; b) offer or establishments or departments involved for a maximum deliver, themselves or through an intermediary, a gift or period of five years. reward of any nature to medical personnel, civil servants or private individuals due to the exercise of their profession The punitive procedure will be the one established in article or position in public or private clinics, establishments or 60 of Law 33/2011, of 4 October, which refers to the stipulations surgeries, with the aim of undertaking or facilitating the of Law 39/2015, of 1 October, on the Common Administrative harvesting or illicit procurement or engraftation of illicitly Procedure of the Public Administrative Bodies. The initiation, collected organs. Likewise, so-called manifest intentions processing and resolution of punitive processes will corre- to provoke, conspire or commit this crime will be punished spond to the Administration that is competent due to the with a penalty reduced by one to two degrees territory and material, without prejudice to penal or civil responsibilities or those any other type that may apply. The definition of criminal behaviours covers the recipi- I) Classification of buying and selling organs. Article 156 A ent of the organ who consented to the transplantation while of the Penal Code. aware of its illicit origin. The penalty for the recipient is hard Article 156 A of the Penal Code (introduced by Organic Law to imagine theoretically, because very probably they will allege 5/2010, and reformed by Organic Law 1/2019, of 20 February, that a state of need exonerates them because the transplant which modified Organic Law 10/1995, of 23 November, of the was necessary for them to remain alive. This has to be under- Penal Code, to transpose European Union Directives in the stood without prejudice to the fact that their behaviour may be fields of finance and terrorism, and on how to proceed in considered to be necessary cooperation for illegal trafficking international questions) punishes those who in any way pro- in third-party human organs, under the possible supposition mote, favour, facilitate, advertise or carry out human organ that the necessary requisites for this were present. trafficking, setting different penalties depending on whether In any case, as the judge is able to impose a lesser sentence the organ is from a living or cadaveric donor, as penalties are due to the reduced reprehensibility of the behaviour of the greater in the former case. recipient due to their circumstances, this seems to exclude This classification has the purpose of responding to the the cause of exoneration which may be alleged. increasingly widespread phenomenon of buying and selling The outlines of the legal good protected by this criminal human organs, and the call by several international forums definition were drawn by the sentence of the Second Court to make it punishable. In 2004 the World Health Organization of the High Court on 27 October 2017. The High Court stated 22 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 that the crime of organ trafficking not only has the purpose of to report this to the Attorney General’s office or competent protecting the health or integrity of persons, but rather than court. The anachronism is clear after reading the second para- the object of protection goes beyond this; although it of course graph, which states: “if the person who omitted to report were has the purpose of protecting physical integrity, it also seeks Qualified in Medicine, Surgery or Pharmacy and it occurred in to protect the dignity of persons, preventing them from being connection with the exercise of their professional activities, treated like objects, like a container of organs which, because the fine may be no less than 125 pesetas nor higher than 250”. It of their bilateral or secondary nature may be objects of traf- adds “if the individual who commits the omission were a pub- ficking. It also adds that “the national transplantation system lic employee, their immediate superior will also be informed establishes an altruistic and supportive system for obtaining for the relevant administrative purposes”. and distributing organs for transplantation into patients who Although there is no doubt regarding the validity of the need them”. obligation to report, if this obligation is not obeyed then the There is therefore no justification whatsoever for access- doctor involved would not have committed the crime defined ing human organs by means other than those included in by article 408 of the Penal Code. This precept punishes the per- the national transplantation system, as such devious means son in authority or civil servant who, disobeying the obligation always lead to types of organ trafficking that offend against arising from their position, intentionally fails to prosecute the the dignity of vulnerable individuals. That there may be offers crimes they detect or those responsible for them. However, the of supposedly legitimate means for obtaining organs outside subjective scope of the crime cannot extend to cover medical the national transplantation system does not exonerate those personnel, because they are not civil servants with the obli- who use such means, in the knowledge that if they are unable gation to prosecute crimes. The crime does not in fact consist to access an organ in Spain, this is due to the permanent of not reporting to a legal body that a crime has supposedly imbalance between the offer and demand for organs, or to been committed, but rather in not prosecuting it; omitting the medical criteria which advise against transplantation if an necessary investigation. organ is available. The obligation to report a well-founded suspicion to the II) Detecting and reporting illegal acts committed outside medical administration that an organ trafficking crime has Spain. been committed is not countermanded by a supposed exercise The credibility of the national transplantation system as a of the right to professional secrecy. Thus professional secrecy part of the national health system is not reduced by the fact is not affected by informing the authority of a well-founded that someone has procured an organ illicitly and more espe- suspicion that a crime has been committed. Knowledge of the cially in a foreign country. A person who acts in this manner supposed crime arises from simple observation or the physi- does not do so because they believe the Spanish system to be cal examination of the patient, and it is not information about ineffective, but rather because they prefer to use mechanisms a pathological process that would be subject to the duty of that allow them faster access to an organ, even though the confidentiality. procedure to do so is illegal, affects the dignity and health of The most appropriate procedure for reporting would be to vulnerable people and is less safe for the recipient. inform the competent medical authority that medical assis- Trust in the national health system is maintained in these tance has been given to a person with a graft that had cases, and this leads to a demand for treatment in our country not been engrafted using legally approved channels, i.e., the after engraftation. In such situations it is first possible to ask national transplantation system. The medical authority will whether somebody who has broken the law to obtain an organ then, directly or by means of its legal departments, prepare outside the procedures established for this purpose should be the corresponding report for the attorney general or the exam- given medical care. Secondly, it may be asked whether the ining magistrate. doctor should report this to a medical authority or the legal or Another difficulty should be taken into account, apart the fiscal authority, due to the suspicion of human organ traffick- one which arises in the case of the recipient of an organ ing. that had been trafficked alleging exoneration due to a state Respecting the first question, all doctors are obliged to of need (which as we pointed out will not usually apply). duly treat a patient in the said situation. This obligation will This additional difficulty involves prosecuting someone in depend on whether the required medical care is included in Spain for a crime committed abroad, when organ trafficking the portfolio of services offered by their hospital, and whether is not defined as a crime in the country where it occurred. the appropriate resources for such care are available. If the The general principle of attributing jurisdiction to Spanish resources were lacking, it would always be possible to priori- courts is territoriality (Article 23.1 of the Organic Law of Judi- tise care for those who had received an organ transplant by cial Power), although some suppositions exist as exceptions, legal means. This is because the survival prognosis for the in which Spanish courts extend their jurisdiction to cover graft will be better. From a penal viewpoint, such a refusal to crimes committed abroad, by Spanish citizens or foreigners. offer medical care (article 196 of the Penal Code) will only con- These exceptions (principles of personality and the protection stitute a crime when this refusal leads to a serious risk for the of interests) generally require, unless an international treaty health of persons. creates an exemption from this requisite that the act commit- With regards to the obligation to report, this is imposed ted should be punishable at the place where it occurred. Thus by article 262 of the Criminal Justice Law which, in spite in the absence of a treaty, if the behaviour considered to be of the evident anachronism of its language, is still in force. criminal in Spain occurred in a country where organ traffick- According to this precept, “those who because of their posi- ing is not defined as a crime, then Spanish courts will not be tion, profession or trade learn of a public crime” are obliged able to prosecute it. There would be nothing to prosecute in the n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 23 country where it occurred because the behaviour in question Paired transplantation and altruistic donation. is not considered to be criminal. Confidentiality in indirect donations. Documentation and custody of the same Paired donation The imbalance between the need for organs and their avail- Article 32 of the Royal Decree governs the information sys- ability for transplantation explains the initiatives of the tems that have to be implemented for the registration and medical administration to try to increase the number of custody of certain data. These are data on: a) The donors and potential donors, deceased as well as living. Living donation the organs, and their description. b) The traceability of organs between unrelated individuals with no emotional ties is one of from donation until transplantation or rejection and vice these initiatives. However, it raises the following questions: is versa. c) The characteristics and movements of the patients it voluntary, altruistic and selfless, and if this is so, is it covered included in the transplantation waiting list. d) The charac- or not by our legal system? teristics and follow-up data of transplanted patients. e) The World Health Organization Resolution WHA 63.22, of 21 characteristics and follow-up data of living donors, and f) Noti- May 2010, established the main guidelines for organ transplan- fication and measures taken in the case of severe events and tation. Guiding principle 3 stipulates that in the donation of adverse reactions. organs from living donors, the donors must be related to the The National Transplant Organization has the function of recipients genetically, legally or emotionally. In our country, developing and maintaining the state information systems in article 5 of RD 1723/2012 refers, to exclude donor and recipi- which the said data are registered and stored, in cooperation ent from the general rule of confidentiality, to persons who are with the autonomous communities and without infringing genetically related or are related by kinship or close friendship. on the systems the latter may develop and the agreements The latter concept is equivalent to the emotional tie referred which may be entered into with the relevant professional and to by the World Health Organization, and it does not exclude scientific associations. donation to recipients united by emotional ties other than In cooperation with the autonomous communities, the close friendship. Nor can donation between persons who have National Transplant Organization will establish the minimum no ties be ruled out, because the said tie is solely mentioned data which will have to be supplied to the state system for by the Royal Decree for the purpose of introducing an excep- each donor, organ, waiting list patient or recipient. The state tion to the obligation of confidentiality respecting donor and information systems, which will have to permit regular sta- recipient identities. tistical analyses, will receive data from the hospitals where As we have warned, donation to unknown recipients may organs are obtained or transplanted, as appropriate, either arouse suspicions about the existence of some type of reward directly or through the available autonomous community sys- for the donor, who will lose one of their organs for the sole tems. The National Transplant Organization will establish, in purpose of substantially improving the life expectancy or cooperation with the autonomous communities, the proce- conditions of someone completely unknown to them. The def- dures that will make it possible for the state to compile the inition of altruism must be kept in mind, as it consists of information. diligently ensuring good for another even when this reduces With the data included in the systems, and without prej- your own welfare, as this is exactly the attitude that guides udice to other reports that may be prepared, the National living RT donors. To confirm the altruistic nature of the dona- Transplant Organization will prepare annual reports on the tion and eliminate all suspicion of spurious ends, investigation activity undertaken in hospitals where organs are obtained takes place to confirm the will of the donor to improve the and transplanted throughout national territory, including health or conditions of the recipient. This is achieved by the aggregated data on living and deceased donors, the number corresponding psychosocial reports on the donor, which will and type of organs obtained and those which were trans- accredit their true motivations and supply data on their pro- planted or rejected. These reports will never contain the fessional, economic and family circumstances. personal data of donors or recipients, and they will be supplied However, paired donation takes place precisely to help to the transplantation coordination network and the trans- someone with whom the donor has some form of emotional plantation teams, and they will be publically accessible. tie. This is why they donate, even if the recipient of their organ As well as permitting general use of the data in question, will be somebody they do not know. They agree to donate state information systems may also be used by hospital or an organ because they know that someone else is doing the autonomous community information systems for their own same for their close friend, and the second donor also knows data, when the corresponding autonomous community or that their action will achieve their initial purpose. Both donors hospital requires this. know that the person they wish to help by donating will Access to any of the data contained in the information receive an organ, if they donate for someone they do not know. systems will be restricted to authorized persons in hospitals, It should be made clear that this is not a determining fac- autonomous community coordination units or in the National tor for the donation - which would be expressly prohibited by Transplant Organization, and all of the systems at hospital, law, as we know - but rather a legally valid condition which autonomous community or state level will comply with the can be expressed as follows: “I donate because you donate” (a current regulations on personal data protection, confidential- condition), not “I donate so that you donate” (a determining ity and statistical secrecy. factor). 24 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 The objective here in terms of medical policy is also gov- not change the situation regarding any other living organ erned by the law, as the aim is to overcome the constant donation, without prejudice to the fact that in this case legal imbalance between the number of patients in the waiting list examination of the consent may require a broader foundation for a kidney and the number of donors. of proof. The legal validity of this donation makes it necessary The legal possibility of accepting donations by a living to verify, as well as the other requisites for living donation donor to a waiting list of recipients should be examined, even (age, capacity and information, etc.), that the first donor who though this considerably reduces (although it does not elimi- wishes to donate in favour of a close friend, still wishes to do nate) the risk of motivation by payment masked by the will to so in favour of a close friend of the second donor, and that donate. Obviously the beneficiary of such a donation would be the latter who wishes to donate in favour of someone close to unknown to the donor, preventing any type of economic trans- them still wishes to do so to benefit the person close to the action between them. A greater problem would arise in those first donor. Both donors are unable to donate their organs to cases when the selection of a recipient is reduced to a specific aid the person they know because the recipients are incompat- group with certain characteristics in terms of their age or clin- ible with them, although this is not the case for the recipients ical situation, etc., to improve the probability of a successful they do not know. transplantation. In such cases it seems that there could be an Paired renal donation is configured as simultaneous, based indication of who the possible recipient or a small group of on a previous desire to donate to improve the health and life the same could be, so that precautions should be maximized conditions of a known specific recipient. Given this, and that to ensure that any donor is purely altruistic and selfless. If the donor and known recipient are incompatible, the donor this were the case, we would reach the same conclusion as wishes to donate in favour of an unknown person so that that corresponding to paired renal donation. another donor does so for the individual they wish to help. The whole process has the structure of an exchange of pre- Confidentiality in non-directed donations vious accredited desires to donate, favouring those who were Article 5.2 of the Royal Decree establishes the general rule of unable to receive an organ from the person they knew even confidentiality that neither the donors nor their family mem- though they wanted to donate and had decided to do so. bers may know the identity of the recipient or their family As we pointed out above, this form of donation is fully cov- members and vice versa, preventing the diffusion of any infor- ered by our laws, and this legal protection also covers the case mation that may connect obtaining and then transplanting in which although the donor and the recipient they are close to an organ. Nevertheless, for reasons which derive from the liv- are not incompatible, the aim is to gain a real benefit from the ing donor organ transplantation technique itself, this general paired RT process (such as an age gain). The therapeutic pur- rule excepts “those who are directly involved in the trans- pose is to achieve a better result of transplantation, and this plantation of living donor organs between individuals who are would justify the choice of a paired RT as the correct therapy related genetically, by kinship or by close friendship”. Non- in this situation. directed donation is therefore an exception to the exception, so that it is therefore subject to the general rule of confiden- Purely altruistic donation tiality. Somebody who donates to someone who is totally unknown With the aim of preserving the confidentiality of the pairs to them with the sole purpose of improving their health or life in this process, the National Renal Donation Protocol created conditions, fulfils more completely than anyone else the legal a registry of donor-recipient pairs in the National Paired Renal demand that donation be voluntary, altruistic and selfless. Donation Programme. This registry complies with the require- The problem which may arise in donations of this type is ments of the personal data protection law, and its functions the same as the one covered in the section on paired donation. include giving each member of the pair a unique identifica- It consists of the suspicion that there is a hidden non-altruistic tion number. This number is used to preserve the anonymity motivation–usually economic in nature - that negates the of the pair when comparing before an examining magistrate. validity of the consent that has been given. Although trans- In this way, no information which permits identification of the actions involving your own organs is not included within the recipient will be shown in the document with which the donor definition contained in article 156 A of the Penal Code (which appears before the judge. Nor will it be possible for third par- understands organ trafficking to involve harvesting or illegally ties to identify the members of the other pair who will take obtaining human organs from others), the recipient’s actions part in the exchange, only their identification number in the may be understood to be included if a price is paid. It is true paired renal donation registry. The transplantation coordina- that organs donated in this way could never be accepted by tor of the hospital where the operation will take place in each the national transplantation system. case will give the judge an informative sheet supplied by the The procedures that may be established to guarantee National Transplant Organization, accrediting the identities of the altruistic motivation of the donor–psychosocial reports, the two donor-recipient pairs and their correspondence with structured questionnaires, investigation of their professional, the identification number. economic, personal and family circumstances, etc. - will be subject to their consent as part of the donation process, and Appearance in court the results should be presented to the examining magistrate, so that they can decide whether the consent given by the Law 30/79 refers to the development of regulations govern- donor to the said authority is free of any economic, social, ing the granting of donor consent, as well as determining psychological or other type of determining factor. This does the authority before which consent must be granted. In Royal n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 25 Decree 426/1980, of 22 February, and until RD 1723/2012 came out, or the delegated individual, describing the personal and into force, the regulations of the sector stipulated that con- familial circumstances of the donor, the purpose of the dona- sent had to be granted before a judge, and more specifically, tion, the medical centre where harvesting is to take place and the judge in charge of the Civil Registry. The second additional the identity of the doctor in charge of the transplant, all this Regulation of Law 20/2011, of 21 July, on the Civil Registry, accompanied by the medical certificate referring to the mental when it refers to the legal regime of the person In Charge of and physical health of the donor. the Central Civil Registry Office and the General Civil Registry The donor must give their express consent before the judge Offices, states that the posts of being in charge of Civil Reg- during the appearance that takes place in the voluntary juris- istries were to be filled by career civil servants in Subgroup diction proceedings (which require the intervention of a legal A1 who held a degree in Law or the university qualification body for the tutelage of rights and interests, without any con- which had replaced this, and the legal secretaries (now justice troversy or conflict which would have to take the form of administration lawyers). Thus the legislator ordered the Civil litigation) and which commences, following the explanations Registry to be more independent of the judicial system, turn- of the doctor who is to carry out the harvesting and in the ing it into an administrative organ which was no longer under presence of the doctor who accredits the physical and mental the control of a judge. In connection with the said legal project, health of the donor, the doctor in charge of the transplantation RD 1723/2012 tried to keep to the same line as the previous reg- and the person who has to approve the intervention, according ulations, stating that the authority before which donors had to the document which authorises the harvesting of organs in to give their consent was still a judicial authority. Neverthe- question. less, given the legal plan to make civil registries independent The document transferring the organ where the donor of the judiciary, the Royal Decree attributed the competence expresses their agreement will be issued by the Judge and to the examining magistrate. This also agrees with the project signed by the donor, the doctor who is to execute the harvest- for the Law of Voluntary Jurisdiction, which was being pro- ing and the others who are present. If any of the former doubt cessed at the time and is now in force (Law 15/2015, of 2 July, that consent was given expressly, freely, consciously and self- on Voluntary Jurisdiction). lessly, they may effectively oppose the donation. A copy of this The report issued by the General Council of Judicial Power transference document will be given to the donor. In no case on the project for Royal Decree 1723/2012 found in favour may organs be obtained without this document being signed of the maintenance of judicial intervention in case of liv- beforehand. ing donation, as it proved that the introduced reform is not To confirm that the consent of the donor is firm, the legisla- “less important, or a trivial question, as the legal modification tors set a period of at least twenty four hours from the moment which made the Civil Registry independent of the judiciary the organ transfer document is signed to the moment of har- involves, respecting the purposes of this report, the disappear- vesting, during which the donor is able to revoke their consent ance of the jurisdictional guarantee of the rights, in this case, at any time prior to the intervention without the need for any of the freedom of a living donor to give consent, and the aware- formality whatsoever. The said revocation may not give rise to ness of the same of the importance and repercussions of their compensation of any type. decision (definitively, that they have the information that is In any case and prior to the presentation of the request to necessary to freely give their consent), which had been con- appear before the court of first instance, the potential donor ferred by the Judge in charge of the Civil Registry, and which will have signed an informed consent document in which they cannot be substituted by the civil servant who is in charge of declare that they were sufficiently informed duly in advance the Civil Registry, according to the model established in Law of the proceedings to which they would be subjected, as well 20/2011”. as the risks, possible complications, expected benefits and It is true that the civil registries have not become indepen- alternatives, with the possibility of asking all of the questions dent of the judiciary. Royal Decree-law 16/2020, of 28 April, they considered to be appropriate and stating that all of their on the organizational and procedural measures to combat questions had been answered. COVID-19 within the context of the Legal Administration, Voluntary Jurisdiction Law 15/2015, of 2 July, considers the modifies the final tenth regulation of Law 20/2011, of 21 July, giving of consent for the donation of organs by a living donor on the Civil Registry, and stipulates that the same will come to be one of the acts in which a judge has to take part, for into force on 30 April 2021. the effective tutelage of their rights and interests under civil In any case the authority for giving consent is now defini- law. The publication of this regulation, apart from establishing tively held by the examining magistrate of the court of first the legal procedure to follow to formalise consent for dona- instance which exists in each judicial administrative area, tion, does not modify the legal regime created by Royal Decree with jurisdiction over the entire territory of the same and 1723/2012. with its seat in its capital, who is the authority on recogni- Articles 78, 79 and 80 (Chapter X under the heading “On the tion in civil law procedures, including procedures of voluntary harvesting of organs from living donors”) of this Law centre on jurisdiction. regulating this area, and they always consider that the judicial The procedure which must be followed to obtain living intervention has the sole aim of verifying that the consent of donor organs requires the presentation, before the court of the donor is given freely, voluntarily, selflessly and that is com- first instance of the locality where the harvesting or trans- plies with the other requisites of Law 30/79 and the resulting plantation is to take place, as selected by the promotor of the regulations. proceedings, of a request by the donor or a communication by The law stipulates that the request must be pre- the director of the medical centre where this will be carried sented before the judicial body by the donor or through 26 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 communication with the director of the medical centre, aim of benefiting family members, friends or even unknown describing the personal and familial circumstances of the individuals, and it underlines the philosophy of voluntary donor, the purpose of the donation, the medical centre where donation without payment through solidarity between the harvesting is to take place and the identity of the doctor in donor and recipient 63 . charge of the transplantation or harvesting, or the person Dignity is associated with the Kantian concept of intrin- who is delegated for this purpose. The said request or com- sic dignity or the special status of the human body, where munication must be accompanied by a medical certificate on dignity and price are mutually exclusive. To keep their dig- the mental and physical health of the donor. The appear- nity human beings must remain above any negotiable price. ance before the examining magistrate must be attended by the Thus any form of payment for parts of the body would vio- donor, the doctor who is to carry out the harvesting, the doc- late human dignity even if the donor herself does not feel tor who signed the health certificate and the doctor in charge degraded. The Oviedo Convention under the auspices of the of the transplantation or their delegate. The person who has Council of Europe 64 sought to guarantee dignity and iden- to authorise the intervention must also be present. The exam- tity without any type of discrimination, together with rights ining magistrate is to authorise the transfer document if they and freedoms that are fundamental in biological and medical consider that consent was expressly given freely, consciously interventions. and selflessly, and that the other requisites established by the The clinicians who take part in LDRT should therefore law governing the harvesting and transplantation of organs apply high ethical standards, so that their decisions will have also been fulfilled. As demanded by the said legislation, harmonise with good clinical practice, offering complete the Voluntary Jurisdiction Law orders that the transfer docu- transparency to medical workers and society 65 . ment describes the possibility of revoking consent at any time Living donation is considered to be included within the prior to the intervention. basic level of the ethical principle of beneficence, and the Both texts are completely consistent, as they have to be. ethical requisites which have to be examined include those One of them is for the medical sector and orders how it is to associated with autonomy and non-maleficence. Beneficence proceed, while the other is for the judge, informing them of the therefore describes actions that facilitate the well-being of legal procedure to be followed. Giving consent before the legal third parties. Maximising benefits while minimising risks is authority confers a double guarantee on living donor organ considered to be ethical. Autonomy is the right of individuals donation. On the one hand, consent has to be given before an to reach decisions independently. A decision is autonomous authority which is both external to and independent of the when it is made freely and without coercion. Finally, non- public health system. On the other hand, the fact that the maleficence restricts interventions that could cause prejudice organ transfer document is issued by a judge adds to secu- or harm, while attempting to ensure that the risk-benefit ratio rity, as this validates the checks on consent undertaken in the is correct. medical sector. The World Health Organization has established eleven guiding principles for the transplantation of human cells, tis- sues and organs, with the aim of providing an ordered, ethical Ethical aspects of living donor donation and RT and acceptable framework for donation and transplantation for therapeutic purposes. The majority of these principles are LDRT is considered to be a highly effective procedure for the applicable to live donors 66 . treatment of CRD. Nevertheless, due to its nature it is neces- The most important ethical considerations which may be sary to comply with legal and ethical norms which guarantee raised when studying potential living RT donors are: donor suitability and protection, while also governing the actions of those who intervene in the procedure 59 . Organ donation ethics is a dynamic discipline, as every sci- Analysis of donor autonomy entific advance creates a new ethical dilemma that requires new and better definitions 60 . Ethics starts by suggesting cri- • The safety and well-being of the candidate donor should teria or guidelines for action which subsequently, in some prevail over the potential benefit for the recipient, so that cases, are ordered and raised to the level of Law, as not all all of the clinicians who intervene in the study have the ethical approaches are expressed in law. Law is therefore coer- ethical duty to protect the best interests of the living donor cive, while the ethics which governs living donation would (Quality of evidence: NG). be classified within the imperfect obligations, as it will never • We recommend that the requisites for acceptance be speci- be possible to demand that somebody donates, as this deci- fied with the donor, together with the information that they sion is strictly personal and nobody may ever be placed under would wish to share with the recipient and the procedure in pressure in favour of or against donation 61 . case of unexpected results, whether or not they are relevant Several conflicts exist regarding living organ donation. The for the donation (B). key ethical dilemma lies in the fact that living donation • We suggest that the studies of the donor and recipi- inevitably involves physical harm, and it causes a potential ent should be carried out separately, although the teams health risk for a healthy individual 62 . Individual autonomy is involved have to be properly coordinated to guarantee good therefore especially important in their decision to donate. communication, without compromising donor and recipi- Altruism has formed the basis of organ donation from the ent independence (C). start, and it is justified as a selfless gift without any expec- • We suggest that professional support and confidentiality be tation of remuneration. Altruism in donation may have the offered when a potential donor decides not to donate and n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 27 expresses difficulties in communicating this decision to the Decisions in donor selection based on sex recipient (NG). • We suggest that the clinicians who are in charge of select- The decision to donate while alive is a voluntary act that ing donors minimise sex-based imbalances, ruling out the potential donors will evaluate finally after they have received possible coercion of women to donate (NG). complete information. Nevertheless, in the first meeting with the donor, the clinician who commences the study is to The professionals who take part in the decisions to select accredit their capacity and the reason which has led them the best of several possible donors should consider the ethical to decide to donate one of their kidneys. Although qualified need to minimise any possible sex-based imbalance. Although professionals will subsequently report on and accredit their many studies report that the majority of living renal donors mental state and capacity, the donor should be alone in this are women, the reasons for this disparity in the donation rates interview, in the absence of the recipient and even other fam- of men and women are still controversial 68 . According to the ily members. The chief benefit which donation will confer ONT 69 and the Amsterdam Forum 8 , 65% of living renal donors on the donor is psychological, based on the personal sat- are women, while 65% of the recipients were men 8 . These isfaction which arises from improving the health of a sick differences make it necessary to consider the sex of donors person by means of an altruistic donation. The absence of from an ethical standpoint before selecting one. In some cir- pressures which mask other motivations should be evalu- cumstances and due to cultural or social pressure, it would ated at first by means of open questions such as: “Could you seem that women have no other choice but to be selected let me know your main motivation for becoming a donor?”; “Do to donate. If this bias is suspected, the medical profession- you think that if you do not donate, the patient may die due to als and psychologists who evaluate the donor should rule out a lack of alternatives?”; “Do you think that your personal, finan- the existence of possible coercion due to sex. cial or social situation may have influenced your decision to become a donor?”; “Have you ever felt pressured by anyone to become a Analysis of altruism donor?”. In the first meeting the potential donor will be informed of We suggest that precautions be maximized under certain the alternative therapies which are available to the recipient, circumstances or when suspicions exist that there may be hid- as well as their survival estimations and waiting times. They den economic agreements or other spurious benefits, above all will be assured that commencing the study for becoming a in donors who are unrelated (NG). donor does not commit them to donating, as they are able to This evaluation is more complicated in the case of donors stop the process at any moment without any consequences at who are not genetically or legally related. According to World all. Health Organization estimations, 8% of the more than 100,000 In situations when LDRT is considered to be urgent (for transplantations performed every year in the world use organs example, a highly sensitized patient without vascular access) that have been illegally trafficked 70 . The Istanbul Declaration and study of the donor has to be completed within a short defines commercialising organ transplantation as “a practice time, the potential donor may be under pressure to a certain in which an organ is treated as a basic product, even buying it, degree to donate, thereby invalidating their consent. Due to selling it or using it to obtain another benefit71 . With the excep- this, emergency living donation should only be considered in tion of Iran, where payment is made and controlled by the exceptional circumstances, seeking other alternatives using a state for living donation to unrelated recipients, this practice deceased donor 67 . is universally rejected. Over and above its highly controversial Sometimes, if risks to the donor’s health are increased by ethical aspects 72 , this practice is said to reduce the growth the donation, this may be accepted on condition that the in donations from deceased donors 73 . Such agreements are consequences for their health are not unacceptable, and if clandestine and are denied in other countries, although sub- complete and verified information is expressly shown in the sequent disagreements or failures to fulfil conditions bring consent document. Nevertheless, a conflict may arise between to light acts of this type, in which intermediaries exploit the the autonomy of the donor who wishes to donate and the neediest individuals for profit. They also corrupt professionals absence of malice of the medical team, which wishes to pro- and clinics in countries with limited resources to investi- tect and exclude them. This dilemma may be resolved by gate and prosecute these illegal practices. Professionals who reference to the ranking of the principles, in which justice commence studying a living renal donor have to maximise and the absence of malice would be level 1 (the public sphere), precautions against certain circumstances which may mask while autonomy and beneficence would be level 2 (the private economic agreements or other specious benefits. In the case sphere) 61 . Public sphere ethical principles affect everybody in of donors who are unrelated, unemployed, immigrants or pris- the same way, and they take preference over private princi- oners, the first requirement is to accredit what forms the basis ples, which everyone manages according to their own ideals of the relationship of the donor and recipient. The next step is and life plan. for a multidisciplinary team to help evaluate what motivates Finally, all living donors will be informed at the start of the the donor, with the aim of reaching a decision. Such vulnerable study that if they find any difficulty in communicating their donors should be considered to be victims, as their decision decision not to donate, they will receive assistance from the to donate may be due to coercion, regardless of any promised transplantation team to do so. economic benefit or payment of any other type. 28 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 It is a crime to offer or accept an economic reward for donat- all of the European countries with paired and altruistic dona- ing an organ, and this should be reported if it is suspected. tion programmes have legally regulated anonymity 51 . It is also unacceptable in ethical terms when the reward is In a study of 414 donors and recipients who took place in intangible, as this undermines the principles of dignity, jus- non-directed and paired transplantation in Germany and Swe- tice and equality. Such practices enable the richest patients to den, where such programmes demand anonymity, 22% of the gain solutions for their health problems which are unattain- donors and 31% of the recipients expressed the desire to meet able for ordinary people. Internet has made it easier to buy and after the transplantation 77 . Other similar studies agree that sell kidneys from living donors. Although they are banned, it is more recipients than donors wish to meet the other party. not hard to find offers or requests for donation in exchange for Although donors and recipients are generally satisfied with economic rewards, and the authorities should prosecute these anonymity, they consider a strict policy of anonymity to be practices. Internet has also enabled the creation of web pages unnecessary. that have the purpose of finding unrelated living donors for Experts in bioethics are divided on this point. Breaking with direct transplantation. This is ethically inacceptable, unless anonymity may lead to psychological or economic pressures such donation is anonymous and controlled by medical pro- on the beneficiary of the donation, terminating in conflict. fessionals, as is the case in “Good Samaritan” paired donation Although such situations would be rare, they would cause programmes with altruistic donors 74 . Otherwise we would stress for donors and recipients. As well as being legally oblig- be turning these websites into what have been called beauty atory in Spain, keeping anonymity is an ethically acceptable contests, where recipients are evaluated on the basis of their practice, because it encourages altruism and prevents forms personal appearance and biography, which are irrelevant vari- of behaviour that could damage social perceptions of donation ables for organ assignation 75 . by living as well as deceased donors. Occasionally, some donors request to be studied without the recipient knowing. It is not good clinical practice to assume Accreditation of donor identity and their relationship with that all recipients will accept related LDRT, although many the recipient health professionals or family members believe this. The eth- ical principle of autonomy for the LDRT recipient may be In the case of genetically unrelated donors we suggest that relevant in specific cases, in which their refusal to receive a their relationship of kinship or the circumstances which certain kidney from a living donor would prevail. accredit the donor-recipient relationship be documented, to ensure that the donation complies with the law and ethical standards (NG). Procedure in the case of unforeseen results Exhaustive knowledge of the identity of the donor and their genetic or legal relationship with the recipient should be We recommend specifying the requisites for acceptance with the priority in the initial phases of the suitability study. The donors; the information they wish to share with the recipi- professionals who take part in the study of the donor (nephrol- ent, as well as the procedure in cases of unexpected results, ogists, urologists, psychologists/psychiatrists, nurses, social whether or not they are relevant for the donation (B). workers and transplantation coordinators, etc.) should inves- Potential donors will be informed of the procedure to be fol- tigate the identity of each donor and their relationship with lowed in the case of unexpected results that identify a highly the recipient in depth. To this end they will request all of improbable genetic relationship. HLA analysis during donor the documentation which permits accreditation of kinship assessment may reveal, for example, cases of misattributed relationships and, in the case of unrelated donors, the cir- paternity (0.25% - 0.50% of all living donors) and also, although cumstances which verify the intensity and duration of their to a lesser degree, cases of siblings and children born to ado- relationship and its nature, to guarantee that altruism is the lescent mothers who grew up believing that another relation main motivation for the donation. The Convention on Human in their family was their mother 78 . The way to handle such Rights and Biomedicine of the Council of Europe protocol on information is controversial, and there is no standard answer, the Transplantation of Human Organs and Tissues urges pro- so that each case has to be dealt with according to its own tection of the dignity and identity of donors and recipients, singular characteristics. guaranteeing individual rights and freedoms without discrim- In the same way, potential donors should be informed of ination to attain the maximum professional standards while the procedure to be followed in the case of unforeseen ana- minimising risks 76 . lytical findings (cases of HIV or HCV) the positive nature of which may have implications for the health of third persons, Anonymity who will have to learn of this circumstance so that they can be referred to specialists. Respecting the recipient, the donor It is obligatory in Spain to maintain anonymity in living donor will have to be informed of any previously unknown analytical transplantations involving paired donation and non-directed results (viral serology or specific antibodies) which may alter altruistic donors (NG). the survival of the transplanted organ. This regulation is not applicable to directed LDRT between individuals related genetically, by legal kinship or close friend- Risks analysis and information for the donor ship. Anonymity in Spain is obligatory for paired donation LDRT and in non-directed altruistic (Good Samaritan) dona- The donation of one kidney for transplantation involves tions which permit chain transplantations. Nevertheless, not accepting a degree of risk for the donor’s health that must be n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 29 minimum, known and accepted by the donor before harvest- donate. It therefore adopted a resolution in 2017 for the selec- ing (NG). tion, assessment, donation and follow-up of non-resident We suggest that the information for the potential donor on living donors, as it recognized that such individuals are espe- the risks and benefits of LDRT be given in at least two phases, cially vulnerable, so that they require extraordinary vigilance and in oral and written format (D). to ensure their protection and care after donating 85 . All donors are recommended to undergo a lifelong medical It is important to maintain close vigilance to ensure the follow-up (B). early detection of possible cases of human trafficking for the From an ethical viewpoint the professionals who assess purpose of organ harvesting for transplantation. This ques- donors must not forget that they have to work in favour of the tion may be particularly difficult to detect when assessing and donors’ interests. Nephrectomy of a kidney for transplantation accepting a non-resident living donor. and the consequences of this for the donor will never be free - Recipient and living donor who live outside Spain. Before of possible complications, and some may consider this risk they travel to Spain the hospital where the transplantation is to be ethically unacceptable. However, in LDRT it is accepted to take place should receive a detailed report which accredits that to attain the benefit of the transplant it is possible to the recipient and possible donor as suitable for transplan- accept a minimum or reasonable level of risk for the donor. tation and donation, respectively, according to Amsterdam Due to this, all living renal donors must receive precise infor- Forum criteria for living donation. The recipient is to supply mation as many times as is necessary about the risks of major clear proof of genetic or legal kinship. In exceptional cases it surgery and the restrictions or precautions that are involved will be possible to accept another type of emotional tie if this in living with a single kidney 79 . We suggest that this infor- is accredited with absolute certainty within the legal frame- mation be offered in at least two phases, in oral and written work in force in Spain. If a visa is required for entry into the format 80 . The general risks shared by all living renal donors country this must have a duration of at least six months. The will be described in the first phase, and in the second phase, medical reports on suitability, informed consent, approval by after the results of the tests on the donor’s state of health the Ethics Committee and the legal appearance are to be pre- have been received, the specific risks for the donor must be pared according to the legal requisites, and a translation is to described (CRD, hypertension, diabetes mellitus, preeclamp- be supplied when applicable. The recipient will have no access sia, etc.). These risks are covered in other chapters of this to deceased donor RT in Spain. The expenses deriving from the Guide. Tools such as the ESRD Risk Tool for Kidney Donor Can- procedure are payable by the recipient or secondarily by their didates” may aid objective work when evaluating each one of country of origin. these risks 81 . - Recipient resident in Spain and a non-resident living Additionally, donors must accept undergoing regular donor. All of the above safeguards will be applied regarding check-ups after nephrectomy to permit the early detection the medical report on the donor, which must be prepared in of cardiovascular and renal risk factors, among others, which the donor’s own country. In the specific case of living donor can be controlled by changes in lifestyle, dietary recommen- transplantation, the transplant will be linked to the care dations, pharmacological therapies or surgical procedures. associated with the donation process, as well as any possible The data on living renal donors lost to follow-up in Spain complications of the same 86 . This will therefore be applied to (2010-2017) are 18% and 13% in the fourth and sixth years, donors without social security or recipients who are covered respectively 69 ; some studies in other countries detect far by other regimes such as MUFACE. higher percentages 82 . Centres which are authorized for LDRT must have a spe- Post-donation follow-up for living renal donors is also an cific protocol for acceptance of the recipient of an organ from ethical obligation to protect their health. It is an indispensable a non-resident living donor. They should previously inform tool which uses the best scientific methodology to verify the the ONT through the autonomous community coordination risks of donation at different times, with the smallest possi- system of the dates on which the surgical operations are to ble distortions 83 . Living renal donor follow-up registries are take place, and comply with the protocol according to the included in a directive of the European Parliament 84 as well document “Living donor RT in non-resident recipients” 85,87 . as in our regulations. Signing the informed consent (IC) document Evaluation of non-resident living donors We recommend that the IC document should include the risks Donors with a genetic or emotional tie who do not live in the which are common to all donors, the particular risks for the same country as the recipient are especially vulnerable, so that donor in question and that it be signed by the latter without extraordinary vigilance is needed to ensure their protection the presence of the recipient, family members or persons who and care after donation (NG). could influence their decision (B). We suggest that donation by non-resident donors should Open questions are to be used in the signing of the IC not be accepted when no long-term medical follow-up can be document to confirm that the donor has understood the infor- guaranteed for them (NG). mation on nephrectomy and its risks, and that their decision The Committee of Ministers of the Council of Europe to donate is firm and without duress (NG). is aware that many countries accept donations from non- Donors are to be informed of their right to leave the study resident living donors with or without a genetic, legal or at any time, as well as the procedure to be followed if after emotional tie with the recipient and who arrive in the country the removal of a kidney it were not possible to engraft it in the legally (with a visa or other authorization) and who wish to recipient (NG). 30 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 The instructions in this step must be followed exactly. The The healthcare ethics committee (HEC) in living donation wording of the IC document varies widely from one hospi- tal to another. Now may be the time to standardise a specific The function of the Healthcare Ethics Committee is to pro- national informed consent document that includes the pecu- tect the rights of donors and, in the case of conflict, to help liarities associated with nephrectomy for LDRT. A copy of this decision-making (NG). must be given to the donor and recipient. This initiative agrees We suggest that the medical reports arising from the study with the opinions of professionals involved in transplanta- of the donor and recipient be sent to the Healthcare Ethics tion in transplanting hospitals in Spain and other European Committee, as well as all of the information which is consid- countries 47 . ered to be relevant for risks and motivation analysis (C). The act of signing the informed consent document (IC) RD 1723/2012 covers intervention by the Healthcare Ethics is considered optimum when it takes place in the presence Committee in the evaluation of a living donor: “In any case, of professionals who have taken part in the study of the before proceeding to obtain the organ, it will be necessary to donor and a surgeon who is a member of the donation or have a report by the corresponding Ethics Committee”. To this transplantation team. In this session all of the analytical and end the professionals who have studied the donor and recipi- radiological tests will be discussed, together with reports by ent will send a request to the Healthcare Ethics Committee for other specialities and any other result which may affect the its report, accompanied by the clinical reports on the donor donor’s safety or the success of the transplantation. Now will and recipient which contain a detailed clinical history and the be the time to offer all of the additional explanations that tests used to assess their state of health. These will be accom- the donor may require. Before signing, the medical team will panied by the donor’s mental health report and the informed use open questions to confirm that the donor has compre- consent documents of the donor and recipient. The Healthcare hended the information, is aware of the nephrectomy process Ethics Committee has the function of protecting the rights of and its intrinsic risks, and that their decision is firm and was donors and, in case of conflict, to help decision-making. Its made without any duress whatsoever. The donor will also be mission is not to evaluate the suitability of the procedure, but informed that they are free at any time to revoke their con- rather to ensure that the donor is properly informed of the sent, and it is therefore advisable for the recipient to be absent probabilities of success and the risks which they accept. In during this step. some cases they may request an interview with the donor The IC document for the donor is to include at least the to confirm the degree to which they are informed and the following: absence of coercion. The Healthcare Ethics Committee will issue a document - The risks of the surgical procedure (type of surgery, anaes- on the suitability of the living donation, or it may request thesia, transfusions, infections, further surgery, mortality). an additional report or consideration in connection with the - The risks deriving from the nephrectomy such as the possi- guarantees for the donor. This report will never substitute bility of CRD, hypertension or cardiac pathology. the responsibility of those who control the process of living - The individualized risks for the donor studied, due to bor- donation and transplantation. derline analytical results, pre-existing disease or family In North American hospitals LDRT programmes have been history. In young women with the potential to become preg- introduced recently which include the so-called “independent nant, risks of gestational hypertension or preeclampsia will living donor advocate”. This individual is independent of the be reported. transplantation team and is not involved in the study of the - Actions in case the collected kidney cannot be engrafted in donor and recipient. Their mission is to ensure that the donor the recipient. The donor must decide at the moment of sign- and recipient have all of the relevant information about the ing the IC if the kidney should be transplanted to another donation process and that they have understood it properly, person or re-engrafted in the donor. ruling out the possibility of coercion or commercialization - The right to withdraw their IC at any time prior to surgery. as far as possible and defending the donor’s rights 88 . One - Quantification of the risk or possibility that the kidney will hospital in our country which is very active in LDRT has an not function in the recipient or that it will cease working independent professional who is unconnected with the trans- prematurely. plantation team, who accredits the correctness of the whole - Commitment to medical follow-up after donation. process prior to the LDRT procedure. Nevertheless, for the majority of hospitals the authors consider that the Health- The IC document for the recipient is to include at least the care Ethics Committee included in Spanish law perfectly fulfil following: the role of this independent advocate and that therefore there would be no need to involve other professionals for the same - The risks of the surgical procedure (anaesthesia, transfu- purpose. sions, infections, further surgery, mortality). - The risks that the transplanted kidney will not function (thrombosis, rejection) or will cease to work prematurely. Information in living renal donation - The adverse effects of immunosuppressant medication. - The risks of catching diseases that were not detected in The chief aim of the information given to potential living renal the donor due to the window period or the impossibility of donors is to obtain their consent for donation. Obtaining this diagnosis. consent is more of a process than it is an event. The RT scheme - The recurrence of the original renal disease. is responsible for establishing that potential donors are able n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 31 to understand the relevant information, that they are suitably The best shared decisions are those which have a suffi- informed about the risks and benefits of the donation and the ciently scientific basis for their efficacy and safety, while being alternative therapies available to the recipient, and that they as suitable as possible for the values, preferences and aims understand this information and act voluntarily. of the patient. The tools which can aid this decision-making In the Spanish guidelines published in 2010 1 , this sec- are instruments that help the patient to obtain informa- tion about information gave general recommendations and tion and answers to their key questions about what they reviewed the literature available to date while centring on should do or what they have to know to reach a decision. when to supply information and the nature of the information These tools can come in a wide range of formats: pamphlets, to be supplied 89 . This section now contains recommendations information sheets, videos, on-line applications or interactive to ensure that the process is suitable. Sections 2 (legal aspects) websites, etc. The information supplied should be expressed and 3 (ethical aspects), are also relevant here, together with appropriately and effectively, high quality and in an easy-to- sections 5 to 8 and 17, on the physical and psychosocial risks understand clear format 90,91 . for the donor. When a patient reaches stage 4 CRD, with an estimated The lack of randomized studies or systematic reviews jus- glomerular filtration rate (eGFR) below 30 ml/min, the first step tifies the fact that all of the recommendations under this should be their assessment as a possible candidate for LDRT heading are “ungraded”. 92 . Parallel to this option, it is also necessary to select one form of dialysis or the other (peritoneal or haemodialysis), in case it is impossible to carry out transplantation before dialysis is Information about types of renal replacement therapy required. The ideal context for this process of information and selection of RRT type is during consultation for ESRD, where • Selection of the type of renal replacement therapy is a apart from this process a series of increasingly standardized shared decision-making process by the patient and the activities are also implemented, in a way that could be for- medical team (Quality of evidence: NG) mally accredited (Table 1). • All patients who are considered candidates for receiving a The webpage set up by the Departament de Salut of the RT should be offered the possibility of receiving a kidney Generalitat de Catalunya contains a detailed set of tools for from a living donor (NG). use in a joint decision for the treatment of ESRD 91 (Table 2). • All patients who are considered candidates for receiving a Whether online or personally, the different options have to be RT should be informed that the best option is transplanta- compared, and it would be advisable to detect patients’ pref- tion before they need treatment by dialysis (NG). erences by means of a test. This space would allow patients to reflect and use the results in conversation with their clinician. The decision-making process for the type of renal replace- Shared decision-making ensures that patients know more ment therapy (RRT) to be used is completely covered by the and are better informed, with greater awareness of their own concept of shared decisions, with at least two parties: the values and better able to perceive risks and advantages: they patient and the medical team of clinicians, the nephrologist are able to decide without negatively affecting their health 93 . and a nephrology nurse. The clinicians will supply scientific There is currently debate about the relevance of using evidence on the diagnosis, aetiology, prognosis and different quantitative methods to select the type of RRT to be used, to therapeutic options, including conservative treatment with- calculate the risk of mortality or the probability of survival. out dialysis or a RT. The patient will describe their values, their Calculators of this type are widely used in the Anglo-Saxon social, family and economic circumstances and their worries world, while they are used less often in Spain. One of the and preferences. Both parties will eventually reach an agree- best is iChoose Kidney, which was developed in the Emory ment on the best options to be selected. (Atlanta, U.S.A.) transplantation programme 94 . This calcula- This selection of a RRT, within the context of an unstop- tor was found to be useful in a randomized trial 95 , and it was pable flow of information associated with the increasingly validated in Ontario, Canada 96 . It includes age, sex, race, time explicit right of patients to independently decide on every in dialysis and the most important comorbidities. The Cana- aspect that affects their health, implies the complete aban- dian validation of this calculator, which included 0,520 patients donment of the classical paternalistic model. In this new in dialysis and 4,505 transplanted patients, was able to predict deliberative model the patient decides, while medical profes- mortality at 3 years. An example shown in the publication 96 , sionals pay respectful sensitive attention to their individual is that a 70 year-old women of African American, with more preferences, needs and values, before agreeing to the deci- than one year in dialysis, hypertensive and diabetic, has a risk sion of the true protagonist in this process. When choosing of mortality at 3 years of 27% in dialysis and 11% if she receives a RRT this deliberative model is far more suitable than the a transplant. If the kidney comes from a living donor the risk purely technical and informative alternative, in which the clin- is 6%, and if the donor is deceased it stands at 12%. ician simply functions as an advisor. In the deliberative model Apart from the different strategies developed by each hos- which this Guide proposes, the patient enters a trusting rela- pital or ESRD unit to properly process the shared decision tionship with the clinician and nurses that is based on this on the type of RRT to be used, other specific strategies have active two-way exchange of information, to reach the best been developed to help the specific decision involved in LDRT shared decision. The clinician guarantees that the information (Table 3) 97 . The materials which aid the decision (book- is appropriate, comprehensible and easy to access, especially lets, videos, online material, text messages and calculators, the information about therapies and their advantages and etc.) centre on general education about the process involved risks. in renal disease and transplantation. They are more or less 32 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 1 – Patient route map in the end-stage renal disease unit of the Hospital del Mar, Barcelona. General assessment and evaluation by nursing. Decision-making process on renal replacement therapy (living or deceased donor renal transplantation, haemodialysis or peritoneal dialysis). Referral to the appropriate specific department (haemodialysis or peritoneal dialysis); if the patient is a transplantation candidate, referral to the specific living donor surgery or inclusion in the deceased donor transplantation list, if applicable. Patients who are not candidates for renal replacement therapy will be evaluated immediately to increase their comfort and treat any complications, referring them to their primary care centre with a report for palliative care, if applicable. An analytical study, a comorbidity study, screening for tumours and viral markers (HIV, B-C virus), and regular follow-up procedures. Vaccination against virus B and others. Surveys on quality of life and degree of dependency. Signing of their specific consent for the selected technique. adapted to patients in general or culturally sensitive aspects, RT programmes should develop the process by which can- and they are aimed at potential donors as well as poten- didate donors are informed 100 . The use of standardized tial recipients. The strategy in which each unit prepares its checklists has been suggested, to ensure that all of the rel- own materials is more widespread in Spain, essentially pam- evant information is supplied 101 . In the United States, the phlets or small explanatory books which in a series of chapters Organ Procurement and Transplantation Network has developed explain different aspects associated with the process of dona- a list to ensure the suitability of the process 102 , as well as tion, describing advantages and drawbacks, risks for the donor a document for potential donors in language that is easy to and recipient, and the results that can be expected. The ques- understand 103 . tions which any material for potential renal donors should This information should be communicated in each RT answer are shown in Table 4. Booklets can never completely scheme in the most favourable environment in each case; replace a conversation which lasts for as long as a potential the most frequent and appropriate circumstances for this are donor may require, in which they are able to raise any ques- consultation in the case of ESRD, consultation before trans- tions 98 . plantation or transplantation coordination, where patients are All CRD patients should be considered and assessed for RT, referred after a general visit to nephrology or dialysis units. except for those with an absolute contraindication, because It often happens that the possibility of living donation is RT offers a higher quality and longer life than dialysis 3,4 . raised in the context of the selection of a RRT in a nephrol- Patients who receive an early RT from a living or deceased ogy consultation. This leads to a specific visit and analysis donor have better personal and graft survival than is the of this type of transplant with specialized nephrologists. It is case for those who had already started dialysis 99 . Thus an therefore essential that the nephrologists who are in charge early RT should be offered to all of the patients who have the of CRD patients always keep in mind the possibility of treat- possibility of a living renal donor. Patients and their family ing them with the best available therapy, which is living will be informed of this option in the decision-making pro- donor RT, if possible prior to the need for dialysis. The cess in cases of ESRD, and they will be given informative best time to present this possibility and check whether booklets and referred for a first pre-transplantation consul- potential donors are available is when the potential recip- tation. ient is in stage 4 CRD, with an eGFR of from 16 ml/min to The European guides recommend that patients with 30 ml/min. gradual deterioration of renal function and an eGFR A range of printed material may be used to offer this <15 ml/min/1.73 m2 should be assessed for inclusion in the information systematically, facilitating the presentation and waiting list for a preventive or early RT 3,4 . The patients discussion of the basic concepts with the patient or poten- who are considered to be potential candidates for RT will be tial donors. From the first, potential donors should receive referred to start assessment when their GF is <20 ml/min, once clear information on the details of the assessment process. the possibility of a living donor RT has been examined. The language used has to aid communication and the mutual understanding of a potential candidate and the clinicians 104,105 . The climate in which this exchange takes place should The basic information required for potential renal donors permit questions of all types, adapting to the particularities of to give their consent the candidate 105,106 . The information which has to be supplied is included in • The information given to the donor will be standardized many guides and declarations 1,2,104,107,108 . Some regulations and will include details about the assessment process and stipulate a minimum content that should be present in the acceptance; the risks, benefits and evolution that can be informed consent process 107 . Table 5 shows the information expected in the donor’s health; alternative therapies for the that should be supplied to the potential donor. recipient; how personal health data are used and donor sup- The most common worry expressed by renal donors prior to port personnel (NG). donating is the possibility of suffering renal failure themselves Table 2 – Shared decision-making tool and material for selecting a renal replacement therapy [Modified from Ref 89]. What are the treatment options? RENAL TRANSPLANTATION PERITONEAL DIALYSIS HAEMODIALYSIS What does it consist of? A kidney from a deceased or living Blood is filtered and cleaned Blood is filtered and cleaned donor is implanted through a natural membrane through a an external circuit in the abdomen with a machine What is needed? A good general state of health, with no A thin flexible tube inside the Access in a vein or a created medical or surgical contraindications abdomen fistula (minor surgery) or a catheter n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Is surgery required? Yes Yes, to position the catheter Yes, to make the fistula Does it hurt? Discomfort in the wound after surgery No Injections in the fistula in each session Where is it performed? In hospital, but only while admitted, At home or anywhere clean In hospital or a haemodialysis afterwards you are seen as an and suitable centre outpatient Who does it? An expert surgeon You yourself A medical professional; sometimes yourself at home How often? Once if there is no acute or chronic Every 3-4 hours during the day Three times a week during rejection. Follow-up visits are needed or during 8-10 hours at night 4 hours in a care centre; flexible for life at home Does it involve restrictions in Less than the other treatments Few Yes liquid intake and diet? Does it have side effects? Surgical complications and the Risk of infection of the catheter Tiredness, risk of low arterial therapies to prevent rejection: orifice or in the abdomen pressure after the session, infections and tumours (peritonitis) infections What are the long-term Better than the other therapies Good; better than Good results? haemodialysis over the short term, but the same over the long-term How long may it work? Half work from 10-12 years, some Several years Several years more, some less. A new transplantation is possible 33 34 Table 3 – Summary and short description of the tools that are available to aid decision-making in living donor renal transplantation (LDRT). Decision Aid Type Of Tool Short Description Comprehensive educational decision-making aids PREPARED: Patients’ readiness to make decisions about kidney Booklet, video, website Knowledge. Economic aspects. Video testimonies by patients, family disease members and professionals, describing concerns La gran pregunta, el gran don (“The big question, the great gift”) Printed material Material for renal patients and their families, as well as potential donors, centring on LDRT and their assessment process Specific or culturally sensitive instruments Living ACTS: Opciones en trasplante (“Transplant options”) DVD and book This has the special purpose of overcoming communication barriers about LDRT in the Afro-American community n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Infórmate (about living donor renal donation for Latin Website Culturally adapted information in English and Spanish for patients and Americans) families Decision aids for potential recipients Tu ruta al trasplante (“Your route to transplant”) Messages adapted and A programme that generate personalized education based on the personalised by computer analysis of a specific recipient, advantages and disadvantages of LDRT Explora el trasplanteCasa Text messages Educational material about the advantages of LDRT (“Explore transplantation home”) Mi entrenador de trasplante iOS application This offers predictions for a specific patient and their survival after (“My transplantation trainer”) different therapeutic options. It promotes consideration of LDRT. iChoose Kidney Smartphone app Transplantation vs dialysis Decision aids for donor education Live Donor Champion In person Training for a potential representative or “advocate” of potential living renal donors DONOR Facebook A platform for renal patients which allows them to share their experiences. By answering a series of questions, a narrated history is created that is easy to share Calculadora de riesgo de enfermedad renal avanzada para Website This shows the risk of reaching the stage of needing renal replacement candidatos a donante renal (“End-stage renal disease risk therapy 15 years after donating a kidney calculator for renal donor candidates”) Decision aids for professionals and providers Living donor KDPI Website To determine the recipient risk in case of a range of living donors, according to their characteristics, and comparing this with a potential deceased donor n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 35 renal donor candidate and is now a patient. One such finding Table 4 – Questions which any material supplied to a potential renal donor should answer. may be that a previously accepted family relationship (such as paternity) is ruled out, or that a new previously unknown What is end-stage chronic renal disease? What is living donation? relationship is discovered 78 . There is no agreement on the Who can be a living donor? appropriate behaviour in these cases. At an early stage it is Who cannot be a living donor? advisable to warn that such a discovery may occur. The RT What can the potential recipient do? scheme should establish an information protocol for such What risks are involved in living donation for the donor? cases, regarding when and how to inform the interested par- What should we expect of the transplantation? ties 78,114–117 . What type of assessment is used for the donor-recipient pair? Renal donor candidates should receive information on the What are the risks for the donor? What are the risks for the recipient? surgical, medical and psychosocial risks involved (sections 5- 7 and 17), including the necessary individualization and the inevitable degree of uncertainty and lack of evidence in the in the future, together with the recovery process, its duration majority of cases. For example, the risk of mortality 3 months and possible complications 100,109,110 . after donating is estimated to stand at 0.03%, and no pro- Potential renal donors have to know that they will only file has been established of donors who are at increased risk 118–120 . be able to donate once in their life, and they should also be aware of the alternative renal replacement therapies available The surgeon who carries out nephrectomy on a renal donor to any potential recipient. When incompatibility due to blood has a particular responsibility to ensure that they understand group or HLA sensitization is detected, the donor should be the potential short and long-term risks. The surgeon is usu- informed of the range of options that may be available, such ally a urologist in Spain, and they will have their own process as ABO-incompatible RT, paired RT 111–113 or HLA desensiti- for informing the donor, centring on the nephrectomy itself, zation, which in general usually require a specific informed which is usually performed laparoscopically. The urologist will consent. explain the purpose of the surgery and describe the tech- The assessment process for a potential renal donor nique they will use and the risks associated with it, obtaining involves the risk of discovering previously hidden pathologies the donor’s informed consent. On the other hand, potential and diseases, and these may even require diagnosis and ther- donors should also receive information on the circumstances apy. All findings and the decision about what to do should that may arise while they live with a single kidney. These will be shared with the individual who has now ceased to be a include exceptional risks such as severe injuries or medical Table 5 – Information that a potential renal donor must be given in the process of obtaining their consent. [Modified from Ref. 91]. Type of information Information that must be given to a potential donor Personal health data of the Personal information about the health of the candidate donor is confidential potential donor The transplantation scheme will supply the recipient with confidential information about the donor with the permission of the latter: immunological compatibility and relevant medical characteristics for the future of the graft. Risks of positive findings in the Possible diseases that require study and treatment assessment Possible transmissible diseases that have to be reported to the authorities Possible ruling out of family relationships that were previously assumed, or findings of new family relationships that were previously unknown Risks of donation Physical, medical, surgical, psychological and social risks of renal donation, over the short- and long-term Alternative therapies for the Information about dialysis techniques and deceased donor renal transplantation, and the potential recipient comparative results respecting living donor renal transplantation. Personal health data of the The personal information about the health of the candidate to receive the renal transplantation is potential recipient confidential The transplantation scheme will give confidential information about the potential recipient to the donor if the donor gives permission for this, on condition that these findings are relevant in the donation decision-making process. Processes involved in the It is possible that some procedures will require specific informed consent evaluation of a potential donor, It is necessary to insist that the donation is completely free of reward donation and follow-up The possibility of deciding not to donate at any moment in the process should be described After the assessment process there are two final possibilities which are subject to the decision of the transplantation team and communicated to the candidate: that they are suitable for donation or they are not. In the latter case the reasons why they were rejected should be explained to the candidate who was ruled out. The whole process of hospitalization, nephrectomy, postoperative recuperation, discharge from hospital and subsequent short- and long term follow-up should be explained The social, medial and economic advantages arising from the donation should be described, including priority for deceased donor transplantation if the donor develops chronic end-stage renal disease 36 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 6 – Potential risks accepted by the recipient of a renal transplantation that the potential renal donor should be aware of in the process of obtaining their consent [Modified from Ref. 89]. The kidney Surgery Drugs Unmet expectations Never functioning (5%) Complications associated with Need for drugs every day for Not leaving hospital: follow-up anaesthesia (<1%) life for life Functioning much less than Complications with They cause side effects such as A transplant will often not expected (10%) haemorrhaging (3%-5%) diabetes or hypertension function lifelong, there is chronic rejection and a return to dialysis (50%) Dialysis sessions are necessary A urinary fistula, lymph or blood Chronic administration is The original disease may until it functions (25%) appear around the kidney or associated with infections and “reproduce” in the renal infection of the wound (5%-8%) malign tumours transplant Rejection and other situations A blood transfusion may be Doubts about whether it would require a biopsy (15%) necessary (20%) not have been better to remain in dialysis problems involving lithiasis or infections that may compro- may have on their professional performance and the length mise the working of their remaining kidney. It can be con- of time they will be temporarily off work, under normal cir- firmed that over the long-term there is no significant tendency cumstances as well as in case of complications. On the other for GF to gradually decrease in any age group 121 , and that the hand, the donor should also be told that it is illegal to obtain incidence of hypertension does not increase over time 122 . any material benefit (economic or any other type) as a reward A question that young women who are potential donors ask for the donation. is about the possibility of gestation. An increase in gestational The informing clinician should tell the renal donor that hypertension and preeclampsia has been described in renal they are able to decide not to donate at any time during donors in comparison with their general non-donor health the process, and that regardless of the reason for this, they control group. Nevertheless, these findings are not associated will continue to have the full support of the transplanta- with any extra complications for the mother or foetus 123 . Spe- tion scheme. On the other hand, the majority of programmes cial attention should be paid to checks of arterial pressure, reserve the right to accept or refuse a potential renal donor, weight gain and proteinuria, although these are generally the so that the latter should be informed of this in detail, together same as those recommended for all pregnant women 124 . with the reason for the decision 131 . In general, it is assumed Although it may be advisable to use transparent quantita- that a transplantation scheme which rejects a donor due to tive tools in the process of informing potential donors about unacceptable risk for their or the recipient’s health should the long-terms risks involved 125 , calculations of this type are seek a second opinion from another scheme if the potential highly limited and we have no exact means of estimating the donor requests this. risk that could be attributed to renal donation. Even though no The renal donor should be informed of the risks and bene- official regulation exists on this point, potential donors should fits which the recipient of the kidney will experience, including be told that in the unlikely event of their developing ESRD, among others: 1) that the therapy is not definitive, and that they would be given maximum priority to receive a kidney gradual loss of renal function over the years often occurs, due transplantation 126,127 . above all to the development of chronic forms of rejection, 2) With the same degree of emphasis that is used to inform that there is a possibility of around 5% that the graft will be them of the risks involved, the transplant scheme should lost at an early stage because of acute rejection, primary fail- inform renal donation candidates of the potential benefits of ure of the graft, thrombosis or infectious complications. This their donation. The difficulty of measuring this benefit is not aspect is covered in greater detail in Table 6 89 . very different from the above-mentioned difficulty of measur- The essential point of the process is to hold a suitable ing the risk 128 . interview in a completely trusting and frank atmosphere, The donor should be informed about the estimated sur- without the potential recipient or any of their family being vival of the kidney as well as the recipient at 1, 5 and 10 years, present. A persistent doubt or ambivalence will normally after LDRT as well as a deceased donor RT or treatment using lead to a refusal to donate, and in this case as well as in different dialysis techniques. This information should prefer- that of a clear negation, the scheme should respectfully and entially be based on the results of the renal donation scheme confidentially support the decision and the individual who in question. Although in the U.S.A. potential donors should be had been a potential donor and finally decided not to proceed told about the survival of the kidney and recipient one year 132 . Although it often used to be employed in the past, it after RT 107 , there is no such obligation in Spain. is unadvisable to use a “medical alibi”, or justification of the Donor candidates should know that the potential recipient decision not to donate for the potential recipient by giving a will not be informed of any aspect of their health without their false medical reason to justify the choice. It would seem to express consent 129,130 . Equally, the donor will not be informed be better to state that “this donor is unsuitable” in general, of anything about the recipient without the consent of the lat- without giving a false reason 133 . The transplantation scheme ter 2,107 . The potential donor should also know the economic should help the donor to communicate this if they wish. On and social implications of their donation, the impact that it the other hand, in some cases the potential recipient will not n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 37 accept a voluntary renal donation, and in this context conflict haemostasis, HBV, HCV and HIV serologies and microal- reduction procedures should also be in place, permitting a buminuria/creatinine and sporadic sediment in urine. refusal without any other consequences. Social information and the media Preliminary approach to the viability of donation • Informing society about living donor transplantation should • The process of studying a potential renal donor permits a stimulate promotion of the same (NG). very wide range of approaches which depend on the donor’s • Attending to the media and proactive information should characteristics, the urgency of the study and local facilities be priorities (NG). and waiting times for examinations (NG). • The first step consists of the screening of a potential The scientific evidence in favour of LDRT, especially when renal donor to rule out unviable cases with a minimum it takes place before the need for dialysis, should stimulate of inconvenience for the donor and resource consumption. its promotion in educational spaces for all types of healthcare This screening should therefore include: a review of the professionals, including those who work in primary care 134 . pre-transplantation study of the recipient, donor-recipient On the other hand, dialysis therapy providers should be fully compatibility (ABO group, crossmatch test) and evaluation aware of the advantages of transplantation, especially from a of the potential donor, with basic analysis and estimation living donor, so that they will be able to educate the patients of their GF rate (NG). they treat regarding this. Agreements should be reached at all levels of society, The process of studying a potential renal donor permits a the media and even religious organizations to promote and very wide range of approaches which depend on the donor’s drive LDRT. Technological advances should therefore be used characteristics, the urgency of the study and local facilities to spread a wide range of educational and training tools and waiting times for examinations. Studies may take place throughout society. This educational work should be even simultaneously from the first in very clear cases, above all more intense where there is a low educational level in dif- if the aim is to reach a swift conclusion. The order in which ferent communities and regions, to overcome economic and examinations take place should also be varied depending on social concerns. the case; for example, in donors with specific pathologies Attending to the media has always been a priority for the that require approval by other specialists, no in-depth studies ONT, as it is for regional and hospital transplantation coor- should be undertaken until their approval has been obtained. dinators. They are all aware that information given to the The first step has to consist of the screening of a potential media will directly affect the whole of society. All medical renal donor within the context of the initial consideration of professionals involved in the donation and transplantation of the donor-recipient pair, using hardly invasive and immedi- organs should cooperate all of the time with the media, always ate basic examination techniques that will make it possible being available to answer their requests and questions, while to decide whether the donation is possible. The aim here is attempting to quell the possible negative effects of a poorly to rule out unviable cases with minimum inconvenience for expressed news item as quickly as possible. Medical profes- the donor and resource consumption. This also gives the donor sionals should maintain what is known in communication time to confirm their decision. No written informed consent is theory as “proactive communication”. Journalists welcome required for this first step, simply the verbal acceptance of the this attitude, and it leads to personalized daily attention. The potential donor. Written consent will be required later, when continuous publication of positive news has helped to cre- invasive examinations take place, as well as the final consent ate the good image enjoyed by transplantation in our country, to nephrectomy. where it is considered to be not only normal, but also and This first screening should include three fundamental above all a basic service of our healthcare system. In the aspects: social imagination transplantation is associated by Spanish citizens with life, and this perception surely aids the donation 1) Review of the pre-transplantation study of the recipient: of organs in general, and donation by living individuals in par- confirm the indication for transplantation, that the pre- ticular. Basic communication principles such as the need to transplantation study is appropriate and complete, and use clear, concise and well-argued messages, coherent argu- assessment of the risk and prognosis. ments, properly explained complexities, the tone of messages 2) Donor-recipient compatibility: determination or repetition and of course the most suitable techniques to express them of the ABO group in blood bank, donor HLA typing (and of are of key importance for the system to work. the recipient, if they are not included in the deceased donor As the ex-director of the ONT, Rafael Matesanz, writes: “You list) and the first crossmatch test. This makes it possible to should always attend to journalists when they call, in the best consider the possibility of directed transplant if there is possible way and regardless of where they are calling from. ABO compatibility and a negative crossmatch test; other- And you have to do so as quickly as possible, because journal- wise, it makes it possible to offer the option of a paired RT ists usually don’t have the luxury of being able to wait. That or a desensitization procedure. way we will be able to prevent lots of misunderstandings that 3) Assessment of the potential donor, with anamnesis and may end up as malicious rumours, while on the other hand physical examination, basic analysis with serum crea- we’ll have the opportunity of spreading a positive image of tinine and eGFR, glycaemia, liver function, haemogram, the process.” 135 38 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Time off work, economic costs, life insurance policies and the donor over the short, medium and long-term are very low, applying for loans and that the possibilities of success in the recipient are high. The transmission of diseases from the donor to the recipient • Extracting a kidney for donation should be included as a should also be prevented, especially infectious and/or neo- specific cause which justifies the declaration of temporary plastic ones. It is very important to confirm that a potential incapacity to work, with the resulting financial support from donor and the recipient are free of hereditary diseases. It is the social security system (NG). also necessary to ensure that the donor and recipient have a • The direct accredited costs incurred by a donor due to dona- good level of immunological compatibility. This compatibility tion should be repayable, and their medical care should be and the metabolic study of the donor are described in other guaranteed for life (NG). chapters. This chapter describes how the study of the donor • The change in the health circumstances of an individual should proceed, and the main findings which may contraindi- because they have donated cannot give rise to penalizations cate donation. in contracting or renewing insurance policies or loans of any type (NG). General analysis and Radiology Kidney donation leads to problems at work in a certain Although it is not the same in all hospitals, the majority rec- number of cases. Donors have to miss a lot of workdays due ommend a study protocol similar to the one shown below 9,101,137,138 : to medical tests and the postoperative period. It is possible that they may even lose their job due to the consideration that interventions of this type are “voluntary”. Restrictive interpre- Haematological analysis tation of the General Social Security Law (art. 128) prevents - Haemogram, coagulation study, iron metabolism. recognition of temporary incapacity to work with the right to - Biochemistry (glucose, HbA1c, urea, creatinine, CRD- economic support, as the donor is considered to be neither EPI, sodium, potassium, calcium, phosphorus, uric acid, sick nor to have suffered an industrial accident. Many donors venous gasometry, hepatic biochemistry, proteinogram, therefore take a holiday or unpaid leave during the donation total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyc- process. erides, reactive C protein). This lack of work-related protection for living donors has - Serological studies: to be resolved, and the harvesting of an organ for donation • Human immunodeficiency virus (HIV). PCR-HIV before should be included as a specific cause which justifies the surgery. declaration of temporary incapacity to work and the result- • Hepatitis B: HBV-surface antigen (HBsAg), HBVcAc (HBcAc ing economic support from the social security system during IgM/IgG), HBV-surface antibody (HBsAc), PCR-HBV in plasma the harvesting and subsequent recovery of the donor, includ- if HBcAc positive. ing the impossibility of dismissing the individual during the • Hepatitis C (ELISA). Evaluate RNA-HCV in some cases. donation process. Although the current regulation governing • Cytomegalovirus (CMV IgG/IgM). temporary incapacity already permits this form of interpre- • Epstein-Barr virus (EBV IgG/IgM) tation, it would be advisable for Spanish law to include this • Toxoplasma. explicitly. • Syphilis: RPR (Rapid Plasma Reagin)-FTA. A more ambitious and encouraging initiative could take the • Coronavirus. Screening for SARS-CoV-2. form of social and work-related protection similar to the cur- • Human T- lymphotropic virus-HTLV I-II. rent system for pregnancy and birth, with a similar amount - PSA (men >40 years). of leave to that granted to parents. This measure would affect - Pregnancy test, if applicable. about 400 people per year, a very low figure. Resolving this - Oral glucose overload test, if applicable. problem would encourage people to donate kidneys while alive. The direct and accredited costs incurred by donors due to Urine analysis their donation should be repaid, and they should be guaran- teed life-long healthcare. Nevertheless, no economic reward - Elemental, twice. can be set, as this is prohibited by current law. - Albumin/creatinine ratio, proteins/creatinine ratio The change in their health circumstances which someone - Creatinine clearance, calciuria and proteinuria in a 24 hr. may undergo due to having donated a kidney should not lead sample to penalties when they take out or renew an insurance policy - Urine culture. or any type of loan. 136 . Tuberculin skin test (PPD) To be considered depending on risk assessment based on Assessment, clinical history and specific tests endemic geographical areas: for living renal donors - Trypanosoma cruzi The study of a renal donor is a complex process in which many - Strongyloides specialists take part. This study should ensure that the physi- - Rapid detection test for malaria (RDT) using antigen detec- cal and psychological health of the donor is suitable, that their tors and antibody determination using indirect immunoflu- donation is conscious, voluntary and selfless, that the risks for orescence (IIF) against the same n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 39 - Schistosomiasis • Study using 99Tc DTPA is suggested when there is a size - Coccidiomycosis, histoplasmosis difference between both kidneys greater than 10% (C). - Ebola • The donor GFR measured before donation should be suf- - Zika ficient so that afterwards the foreseeable GFR will remain - Western Nile Virus within values that are acceptable for their age and sex dur- ing the rest of their life (B). • We suggest that the decision to accept a candidate with Radiological tests renal function below the required threshold or who has - Thoracic radiography (posteroanterior and lateral) additional risk factors for progression to chronic renal fail- - Abdominal CT-angiography. This will inform us of any pos- ure should be made on an individual basis (D). sible alterations in individual organs, detecting vascular • We suggest that the donor be informed and that the problems, lithiasis and tumours, offering a description of informed consent document should contain a statement both kidneys that will contribute definitively to the selec- of the slight increase in the risk of suffering chronic renal tion of the one to be nephrectomized. It will also permit the failure during their lifetime (D). characterization of the renal excretory system. Anomalies • We recommend that all donors should be followed up for detected by CT-angiography are usually the first cause of life, with especial attention to renal function, proteinuria rejection. and arterial blood pressure (B). Evaluation of GF 9,101,137,138 Cardiovascular and pulmonary studies Donor renal function must not be evaluated using only plas- • We suggest that donor studies should include stress tests matic creatinine. This is of limited value when it seems to be such as the myocardial SPECT test or MR imaging with dobu- normal, although if it is known previously and it is equal to tamine in the case of an abnormal ECG or echocardiogram, 1.5 mg/dl or higher, this may help to rule out donation. In gen- individuals older than 60 years or multiple risk factors (C). eral standardized GFR estimation equations for body surface and creatinine clearance in urine over 24 hours are recom- The cardiovascular study has the aim of detecting mended. It is necessary to collect urine in the absence of fever, significant cardiac pathologies which would constitute a con- menstruation, urinary infections and previous heavy phys- traindication due to increased risk for the donor: ischemic ical exercise. It is also important for the intake of proteins heart disease, heart failure, cardiac valve pathologies, left ven- in the diet to be at least 1 g/kg weight, as a low protein diet tricular hypertrophy or significant arrhythmia. After finishing may reduce creatinine clearance by up to 10 ml/min 140 . The this study and having been selected, donors do not seem possibility of incomplete or excessive urine collection should to suffer any increase in cardiovascular risk after donation 139 . always be taken into account. For this we base ourselves on the excretion of creatinine (which should be within the range Together with the detailed anamnesis, physical examina- from 15 mg/kg - 25 mg/kg). This should be determined on two tion, thoracic radiography and the ECG, age or other potential occasions to minimise errors. donor risk factors such as hypertension, heart murmurs, Estimating the GFR using formulas validated by interna- stress dyspnoea or end stage age lead us to use echocardio- tional standards is accepted in the initial study and should graphy, Holter (to rule out arrhythmia) and stress tests such be repeated later (9,137). The most widely used standards are as the myocardial SPECT or MR imaging with dobutamine in Cockroft-Gault, MDRD and CRD-EPI. These formulas have not the case of an abnormal ECG or echocardiogram, age over 60 been validated for this specific population of renal donors. years or multiple risk factors: age >45 years in men/>55 years Nevertheless, it has been communicated that average Cr clear- in women, smoking, dyslipidaemia, hypertension or a family ance and MDRD give a good approximation to GF measured history) 137 . If the case so requires, the cardiologist will request by 125-iothamalate 141 . It is currently thought that CRD-EPI other donor assessment tests. may offer a better fit with measured GF than other formulas Respiratory function tests would be indicated in the case of in patients with normal function 142 . chronic lung disease or heavy smoking. There is an increased The KDIGO and British guides recommend subsequent risk for donors in the case of forced expiratory volume in 1 sec- checks and the evaluation of renal function using more “exact” ond (FEV1) or forced vital capacity (FVC) <70%, or a FEV1/FVC methods, such as measuring GF using exogenic markers such ratio of <65% 138 . as 125 iothalamate, 51 Cr-EDTA, iohexol or 99 Tc-DTPA (9,137). These tests are even more important, if this is possible, in the Evaluation of donor renal function presence of borderline renal function as measured by other formulas. • We recommend that the initial study should include the If it is not feasible to measure GF it is recommended that estimation of GF using validated formulas (Quality of evi- at least Cystatin C be determined, using eGFR in these cases dence: B). as determined by formulas based on creatinine or Cystatin C. • We recommend that the measurement of glomerular fil- However, these techniques are only necessary in cases where tration should be confirmed by means of more precise creatinine clearance is close to the limit. Study using 99 Tc exogenous markers, such as 125- iothalamate, 51 Cr-EDTA, DTPA is recommended when the difference in size between iohexol or Tc-DTPA, especially in patients with borderline both kidneys is greater than 10%. This has the additional renal function (B). advantage of estimating the functioning of both kidneys sepa- 40 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Proteinuria Table 7 – Minimum glomerular filtration rate for the acceptance of a living renal donor. • We recommend that the excretion of protein in urine should Age (years) Minimum glomerular filtration be quantified for all potential living donors (B). rate (ml/min/1.73 m2 ) • We recommend that donors with less than 30 mg/day excre- Men Women tion of albumin in urine or with an albumin/creatinine ratio 20-29 90 90 lower than 30 mg/g be accepted as candidates. Individualise 30-50 80 80 cases from 30 mg/day - 300 mg/day (30 mg/g - 300 mg/g) and 55 80 75 contraindicate those with higher levels of albuminuria (A). 60 76 70 • We suggest that the risk of CRD and cardiovascular risk run 65 71 64 70 67 59 parallel to an increase in albuminuria or proteinuria (C). 75 63 54 80 58 49 The excretion of protein in urine should be measured in all potential living donors 137 . Although it is preferable to determine donor albuminuria rather than total protein- rately 137 . If vascular or urological anomalies are detected that uria, the majority of hospitals measure both. We recommend do not contradict donation, the best kidney must be kept for testing the albumin/creatinine ratio in a urine sample, and the donor. confirming this with total albuminuria in 24 hour urine or an To support these guidelines the Organ Procurement and albumin/creatinine in 24 hour urine coefficient. Excretion of Transplantation Network (OPTN) developed an online GF calcu- less than 30 mg/day albumin in urine or an albumin/creatinine lator, to calculate GF and compare it with the measured GF ratio lower than 30 mg/g is considered to be acceptable. It is 143 . This tool was validated by a study of candidate donors 144 , advisable to individualise cases from 30 mg/day - 300 mg/day which suggests that calculated GF may be sufficiently accurate (30-300 mg/g) and to contraindicate the ones with higher albu- for decision-making, without the need to measure it directly. minuria 9 . An acceptable alternative is the protein/creatinine Nevertheless, the use of eGFR alone is not recognized by the ratio in a urine sample. In this case it is recommended policy of the OPTN, although a strategy of detection with eGFR that it be below 50 mg/mmol. The values that would clearly followed by confirmation by 24 hour creatinine clearance or contraindicate donation would be albumin >300 mg/day, measured GF may be sufficient and comply with the estab- an albumin/creatinine ratio >300 mg/g (>30 mg/mmol), a lished norms. protein/creatinine ratio > 500 mg/g (50 mg/mmol) or protein The donor’s GFR measured prior to donation should be >500 mg/day 9,137,143 . sufficient so that, after donation, their foreseeable GFR will The significance of moderate albuminuria or protein- remain within acceptable values for their age and sex during uria (albumin/creatinine 3-30 mg/mmol, protein/creatinine the rest of their life 137 . British guides offer a table as guidance 15-50 mg/mmol, albumin 30-300 mg/day or protein from on this point (Table 7). 150 mg/day - 500 mg/day) in living renal donors has yet to be In general, rates of GF > 90 ml/min/1.73m2 are considered determined. We do know that the risk of CRD and cardiovas- to be optimum for donation, with the recommendation for cular risk run parallel to the increase in albumin or protein, individual evaluation when rates are from 60-90 ml/min/1.73 so that these may be relative contraindications against dona- m2 . If they are below 60, donation is generally considered to tion 101,137 . However, each hospital may have its own different be contraindicated. The decision to accept a candidate whose acceptance threshold. In the United States, a survey on the renal functioning is below the required threshold or who has protein threshold set by different hospitals for the acceptance other additional risk factors for progression to chronic renal or rejection of a living renal donor found that 37% defined this failure should be individualized and based on the probabil- as protein < 150 mg/day, and 44% set it lower than 300 mg/day ity that they will develop chronic renal failure during their or even higher 145 . expected lifespan 137 . The necessary renal functioning for the future recipient Microhaematuria should also be taken into account. This has to be compared with the donor’s calculated renal functioning for the purpose • We recommend that erythrocytes in urine be determined at of deciding whether or not it will be sufficient. This decision is least twice in all donors (B). highly important in directed donation as well as when undi- • We recommend that further studies should take place of rected donation is possible. donors with persistent microhaematuria on two or more The donor will have a risk of terminal renal failure after occasions (A). donation which is no higher than that of the general popu- • We recommend that a renal biopsy should be taken if micro- lation 33 . Nevertheless, there will be a slightly increased risk haematuria probably has a glomerular origin, to rule out the of this occurring during their lifetime 35,37 . A potential donor existence of glomerular pathologies (B). should be aware of this aspect and they should have consented • We recommend that a genetic specialist should be con- to it 9 . sulted in case of the suspicion of hereditary renal disease Finally, it should be added that the donor should be (B). followed up during their whole life, paying especial atten- • We recommend that cystoscopy should be performed tion to their renal function, proteinuria and arterial blood patients over the age of 40 years with microhaematuria that pressure 8 . has an unknown cause (B). n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 41 All donors should be subjected to at least two determi- should perfectly understand the risks which donation involves nations of erythrocytes in urine during the study 137 . If a in this case. In the U.S.A. the majority of hospitals will accept donor has persistent microhaematuria, (>3 erythrocytes/field a donor with a history of lithiasis if at the current time they or 5 erythrocytes x 106 /l) on two or more occasions, this have no lithiasis and their metabolic urine study is normal should be studied to determine the cause (dysmorphic ery- 145 . Independently of whether or not they donate, a potential throcytes, urine culture, urine cytology, cystoscopy, a renal donor with a history of lithiasis should follow the usual criteria biopsy, study of lithiasis) 137 . If the probable cause is glomeru- to prevent the relapse of lithiasis. lar (dysmorphic erythrocytes) a renal biopsy will be considered Renal lithiasis may be considered to be an absolute con- to rule out the existence of glomerular pathologies (IgA/IgM traindication in certain situations with a high risk of relapse, or nephropathy, Alport’s syndrome, thin basement membrane), a renal lesion such as nephrocalcinosis, if it is bilateral, recur- medullary sponge kidney and significant glomerulosclerosis ring or with a probability of doing so with associated disorders 146 . If a hereditary renal disease is suspected, a geneticist could (hypercalciuria, hyperphosphatemia, hypocitraturia, hyper- examine the possible alternative of creating a panel of heredi- uricaemia, hyperuricosuria, cystinuria, hyperoxaluria, distal tary diseases that could lead us to a diagnosis without the need tubular acidosis, recurring urine infections, sarcoidosis or for a renal biopsy 147 . Glomerular pathology would contraindi- inflammatory intestinal disease) 138,149 . The metabolic abnor- cate donation in general, except for thin basement membrane malities of a donor should always be discussed with an expert disease 101,137 . In any case, the absolute absence of risk for in lithiasis, especially if no clear metabolic cause for lithiasis developing ESRD in donors with basement membrane disease has been found 137 . It is generally accepted that, in the absence cannot be guaranteed, so that it is suggested that such donors of a major metabolic anomaly, potential donors with a limited be more than 40 years old at the moment of donation. If no history of renal lithiasis or slight current lithiasis may be con- cause is found, in patients who are more than 40 years old sidered for donation. It is necessary to fully communicate the it would be recommendable to perform a cystoscopy to rule risks to the donor and recipient, together with an appropriate out bladder pathology. It is possible that renal donors with follow-up of the donor over time 137 . microhaematuria are at greater risk of gradual renal function If there is unilateral lithiasis and donation is accepted, deterioration 148 . the kidney affected by the lithiasis should be subjected to The decision whether to accept a potential donor will nephrectomy (while attempting to extract the calculus dur- depend on the cause, reversibility and/or risk of progression ing the operation), so that the donor is left with a lithiasis-free in their case. kidney 137 . Leukocyturia Detection of tumours in the donor • We suggest that donation should be contraindicated in case of persistent leukocyturia in the absence of urine infection • A carefully prepared clinical history is recommended, or prostatitis (C). together with a detailed physical examination, to find any undetected neoplasia prior to renal donation, especially Donation will be considered to be contraindicated when when the donor is more than 50 years old (B). leukocyturia is persistent in the absence of urine infection or • We recommend that potential donors with a minimum risk prostatitis. If it is not explained by an infection, a renal biopsy of low stage tumour transmission (<1%) be accepted after may be required to rule out interstitial nephritis or chronic careful assessment and discussion (B). pyelonephritis (which exclude donation).3 • We suggest that kidneys from donors with a T1a renal Urinary tuberculosis which contraindicates donation must tumour may be accepted after performing tumorectomy always be ruled out by at least three mycobacteria cultures. during the harvesting (D). We suggest that donation should be rejected in the case of Renal lithiasis bilateral angiomyolipoma. In cases that are unilateral and • We suggest that specialists should be consulted if lithiasis or larger than 4 cm the affected kidney can be collected for associated metabolic alterations are present, informing the tumour exeresis ex vivo. If they are unilateral and less than donor and recipient of the risks and appropriate follow-up 4 cm in size they do not contraindicate donation, and if they (C). are less than 1 cm in size, the kidney with angiomyolipoma • We suggest that in donors with unilateral lithiasis who are may be left in the donor or given to the recipient (C). accepted the affected kidney should be nephrectomized, so that the donor keeps the kidney that is free of lithiasis (C). The possibility that a potential donor may be a carrier of tumours that could be transmitted to the recipient must be The existence of renal lithiasis should be ruled out in all ruled out. The study should take place according to the guides potential renal donors. The clinical history (chronology and used in each country. A painstaking clinical history and composition of the calculi) and the CT-angiography performed detailed physical examination are essential, especially for during the study are important for this 9 . If there is a clinical donors above the age of 50 years 137 . They should be comple- history then the cause of the lithiasis should be determined mented by general analysis, thoracic X-ray, CT-angiography, and a metabolic study of 24 hour urine should be undertaken. digital rectal examination and PSA in men aged over 50 years, Acceptance of the donor will depend on the probability of the blood in stool, colonoscopy or cystoscopy if applicable and a lithiasis recurring in their remaining kidney, and the donor gynaecological study (examination, cytology, gynaecological 42 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 ultrasound imaging, mammography). Specific studies may haemolytic - uremic syndrome. Potential donors who are car- also be used depending on the findings of the preliminary riers of the same disease as the recipient must not be accepted study or personal or family background; for example: a as donors. dermatological examination if there is a family history of melanoma or a high number of nevi 138 . The risk of transmitting infectious diseases 155 In general, if an active malign process is detected during the study of a donor, or if they have a history of this, it usually • Tests to detect transmissible infections should be applied rule out donation 150 . Donation is rejected if there is a previ- to all potential living donors (B). ous diagnosis of haematological, gastrointestinal, testicular, • We recommend that if a potentially transmissible infectious melanoma, lung, breast or urinary cancer with certain excep- disease is found, the medical team and recipient should tions, coriocarcinoma or monoclonal gammopathy 9 . Only accept or reject the suitability of the donation after receiving potential donors with a minimum risk of transmission (<1%) detailed information about the risks that would be involved may be considered if they have low stage tumours and after (B). careful evaluation and discussion 9,137,138 ), including basocel- • Positivity for HIV or HTLV (human T lymphotropic virus) is lular skin tumours, in situ colon or cervix carcinoma, kidneys considered to be an absolute contraindication against living which carry a Bosniak II-III cyst, or even a T1a renal tumour donation (B). after tumorectomy 151,152 . • We recommend that the donor and recipient be informed Radiological study by CT with contrast, ultrasound scan or of the risk of post-transplant primo infection in the case of MR imaging usually make it possible to distinguish between a CMV+ donor and CMV- recipient, and the risk of lympho- benign lesions such as angiomyolipoma and malign ones such proliferative disease in the case of an EBV+ donor and EBV- as clear cell renal carcinoma. The help of an experienced radi- recipient (B). ologist is required for this 137 . Bilateral angiomyolipomas contraindicate donation. In The tests to detect transmissible infections which should unilateral cases that are larger than 4 cm some groups con- be applied to all living donors were described above 156,157 . We sider what is known as therapeutic donation, performing recommend that these tests should be applied shortly before exeresis of the angiomyolipoma during the nephrectomy ex the transplant for the highest risk diseases, so that window vivo. Unilateral cases that are smaller than 4 cm do not usually periods can be ruled out. Especially for HIV, HBV and HCV it contraindicate donation. If cases are unilateral and smaller is preferable that the relevant tests be applied in the month than 1 cm, it is considered that the kidney with the angiomy- before donation 9 . Some active or latent infections will not olipoma may either remain in the donor or be given to the be a contraindication if it is possible to treat the donor for recipient 137 . them effectively. It is important to undertake a correct anam- nesis of the risk factors for latent diseases in the donor, with Hereditary renal diseases or those with a familial special emphasis on factors involving their social behaviour, component addictions, professional risks, geographical risks or exposure to animals. The criteria for accepting transmissible diseases • We recommend that a detailed clinical history should be in the donor vary from country to country 26,27 and they have prepared for all potential RT recipients, with especially changed rapidly over recent years. When the donor has a detailed content on any family history of renal disease. It potentially transmissible disease, the fully informed medical is indispensable to exclude hereditary renal disease from team and recipient will reach a decision on whether it is pos- potential donors (A). sible to accept the risks of transmission 9,137 . All potential RT recipients should have a detailed history Hepatitis B virus (HBV) of renal disease in their family and, when possible, the diag- Positivity for HbsAg or the presence of viral DNA in the blood noses of the same. This will help to detect familial risks in contraindicates donation to HBsAg negative patients. Posi- potential living donors. At the same time, all donors should tivity for HBcAc-IgM, which indicates recent infection, and be questioned about their personal or family history of hered- isolated positivity for HbcAc make it necessary to rule out itary diseases. If the disease of the recipient is due to a active replication by DNA or viral mutations. Positivity for hereditary renal disease, it is indispensable to rule this out HBcAc-IgG with/without positive HbsAc and negative viral in the donor, using radiological examinations, renal biopsy DNA implies a very slight (although not zero) risk of transmis- or genetic studies if they are necessary 9,137,138 . Autosomal sion. Although this makes donation acceptable, the recipient dominant polycystic renal disease stands out among the most should be naturally immunized or immunized by effective important diseases. Classically certain criteria were used to vaccination 9,138 (NG). diagnose this and differentiate it from simple isolated cysts 153 . In case of doubt a genetic diagnosis will help us to be Hepatitis C virus (HCV) sure that the donor will not suffer the disease in the future The presence of HCV antibodies has classically been a con- 154 . Other hereditary diseases or ones with a familial compo- traindication against renal donation, due to the risk of nent that should be ruled out in donors are Alport’s syndrome, transmission to the recipient as well as the risk for the donor thin basement membrane disease, glomerular pathologies of glomerulopathy. From 2013 the recommendation has been with increased familial involvement (IgA, membranous, focal to determine RNA-HCV in the study of renal donors 158 . The and segmentary, membranoproliferative), LES and atypical appearance of new direct antiviral treatments against HCV n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 43 and their high degree of efficacy have changed the scenario. donor, as well as any journeys they have made to countries For example, kidneys from positive deceased donors are now where the risk is present 137 . The majority of transplanting being transplanted into negative recipients who will receive hospitals include at least the PPD test in the study of the trans- intensive treatment for their viral load, or direct antiretroviral plant donor and recipient. Others only include it if there is a treatment, if they give their consent 159,160 . This situation may certain degree of prevalence of tuberculosis in the local pop- extend to LDRT if the donor receives treatment beforehand ulation. If the PPD test is positive, active TBC should be ruled (NG). out (as this would be a contraindication) by clinical exami- nation and imaging tests (thoracic X-ray or CT, IV urography) Human immunodeficiency virus (HIV) and microbiological tests (mycobacteria culture in sputum The detection of HIV or HTLV (human T lymphotropic virus) and urine, or an interferon-gamma release assay, IGRA) 138,166 . is considered to be an absolute contraindication against living Latent TBC is not a contraindication, and the recommenda- donation 137 . Nevertheless, in South Africa there is experience tion is to treat it before donation (9 months isoniazid or 3 of transplantation from HIV+ donors to HIV+ recipients after months rifampicin). Post-transplantation prophylaxis should informed consent, with good results 161 . be considered in the recipient (NG). Cytomegalovirus (CMV) Syphilis The donor and recipient should both be tested serologically All donors are initially given a RPR test. Positivity for RPR before transplantation to discover their degree of immunity should be completed with Treponema tests. Although the against CMV. In living donor programmes serological states presence of latent syphilis does not contraindicate donation, against CMV do not contraindicate donation, and nor are the donor should receive appropriate treatment (3 weekly IM they a normal donor selection criterion. However, this status doses of 2.4 million benzacine-benzylpenicillin). If there is should be determined to discover whether it is necessary to considered to be risk of transmission to the recipient, it is apply prophylaxis if the donor is positive and the recipient is preferable to administer prophylactic treatment (2.5 MU of negative, or in other situations with excess immunosuppres- a single IM dose of benzacine-benzylpenicillin or 100 mg/day sion 162 . Some guides consider the need to inform the donor oral doxycycline during 14 days or 1 g azithromycin in a single and recipient of the post-transplantation risk in the case of a oral dose) 167 . positive donor and negative recipient 137 . Emerging infectious diseases. Parasites Epstein-Barr virus (EBV) Donors from zones that are endemic for other emerging dis- The serological status of the donor and recipient against EBV eases or which have endemic parasites and donors who have should be determined prior to transplantation. The presence lived in them should be investigated for them. We recommend of antibodies against EBV means that there was a previous that the infectious diseases department provide support dur- infection which is possibly in a latent phase and may be trans- ing this consultation. The main such diseases are malaria, mitted to the recipient. Although this does not contraindicate Chagas, toxoplasmosis, Schistosomiasis and Strongyloidosis. donation, when the recipient is negative they will be at greater After study of the donor, donation may be considered fol- risk of developing a disease caused by EBV, which may run lowing effective treatment of the disease 137,138,168–170 . When from a trivial viremia, the symptoms of infectious mononucle- in the previous 28 days the donor has visited a zone where osis or a post-transplantation lymphoproliferative disease 163 . the Ebola virus or Zika virus is endemic, donation should be The latter situation is seen more often in the case of recipients deferred for a prudent time to ensure that the donor has not of paediatric age. The British guides recommend informing been infected 9 (NG). about this risk when the donor is EBV+ and the recipient is EBV- 137 . Urinary tract infections All potential donors should be tested with a urine culture. Other herpes viruses It is relatively common to find asymptomatic bacteriuria in The need to screen for herpesvirus 6 and 7 (HHV 6 and 7) women. If the donor is a man with bacteriuria or if there (which is almost universal) and herpesvirus 8 (HHV 8) (with is a family history of urinary tract infections, then it is rec- a highly variable prevalence depending on geographical area) ommendable to perform a radiological study (CT, urography, has not been clearly established. HHV8 may be transmitted voiding cystourethrography) to rule out renal cortical lesions by transplantation, and it has been associated with increased or other urinary tract anomalies, while such studies some- risk of Kaposi’s sarcoma 164,165 . times include a cystoscopy or urodynamic study 137,138 . Lower urinary tract infections in women, even recurring ones, do not West Nile Virus contraindicate donation, although repeated pyelonephritis This virus has spread to certain regions where it was not does. Donor urine must be sterile at the moment of donation. autochthonous. It should be screened for in donors from regions at risk by PCR, as serological study is complex 166 . Prion diseases Donation is contraindicated when there is a personal or family Tuberculosis history of Creutzfeldt-Jakob disease. There is currently no effec- It is calculated that 30% of world population have been tive diagnostic test. Transmission due to a transplanted organ is infected by Mycobacterium Tuberculosis. It is very important exceptional. Genetic advice may be required regarding the familial to show the country of origin in the clinical history of the component. The risk factors are blood transfusions after 1980, dura 44 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 mater grafts or treatments with pituitary hormone or gonadotrophin Professionals with knowledge and experience of transplan- 137 . tation should take part in the assessment process and the evaluation and follow-up of donors and recipients. It is there- SARS-CoV-2 fore appropriate to include a psychologist in multidisciplinary The 2020 pandemic makes screening for this indispensable for transplantation teams, who will focus on care for transplanted the donor and recipient. The guidelines for this are constantly patients, assessing and following up donors, as well as provid- evolving, so that it is advisable to consult the recommenda- ing emotional support for team members. tions of the ONT at any specific moment. The transmission of The psychological and social assessment of living donors this disease from a deceased donor is exceptional. should take into account all of the variables which may influ- ence their perception of the donation process. Haematological diseases of the donor The members of the psychological assessment team for living renal donors are listed in Table 8, as follows: • An exhaustive study of the donor is recommended if they have anaemia (A). Living donor psychological assessment protocol Many hospitals already systematically perform hypercoag- • We suggest that psychological assessment should be based ulability studies of all donors. In spite of this, such studies are on a clinical interview and psychometric evaluation (Quality considered to be obligatory only if there is a history of throm- of evidence: C). bosis. A previous incident of pulmonary thromboembolism • We suggest that psychological assessment should be or deep vein thrombosis may constitute a contraindication undertaken by psychologists or psychiatrists with clinical against donation (NG). In women who are carriers of V-Leiden experience and who do not take part in care of the recipient factor the preoperative suspension of contraceptives or hor- (NG). mone replacement therapy would be indicated. • We suggest that the contents of the psychological assess- In the case of anaemia an exhaustive study prior to ment protocol should be uniform, regardless of donor type donation is indispensable 137 . This is also the case when a (NG). haemoglobinopathy is detected. • We suggest that psychologists should be included in the multidisciplinary transplantation teams (NG). Psychological evaluation of living renal donors Psychological assessment should include mental health evaluation of the donor, as well as their comprehension of Living renal donation is a complex process which includes eth- the risks and circumstances of donation. The relationship ical, psychological, social and physical aspects. It takes place between the potential donor and patient should be analysed, with the expectation that the risk for the donor will be com- together with the motivation to donate and coping strategies pensated by the psychosocial benefits (quality of life, social for surgery and possible complications, among other factors and psychological well-being, body image and self-perception) 174–178 . A wide range of methods and criteria exist for psy- and the improvement in health for the recipient 171 . chological assessment; in some cases formal criteria are used, Additionally, the physical and mental health of the donor while others use semi-structured clinical interviews 173,179,180 . must be accredited and certified by a qualified doctor. This We therefore suggest that an interview and psychometric eval- is a legal requirement in Spain for donation and transplanta- uation should be used, so that sufficient data are available tion between people with an emotional relationship and also for the generation of a final report. Psychosocial assessment between people who do not know each other, on condition that should be performed by psychologists or psychiatrists with donation is altruistic and selfless 172 . The ONT is decidedly in clinical experience and suitable qualifications, as well as men- favour of encouraging living donation, for which the proto- tal health expertise. We also recommend that they should not cols governing the study of living donors have to be updated, take part in care of the recipient, to reduce conflicts of inter- including those on psychological evaluation 58,172 . est in their assessment of the donor candidate. Psychosocial A unified protocol is suggested for the psychological evalu- assessment should take place in the absence of the recipient, ation of a living renal donor. This protocol combines a personal family members or any other individuals who may influence interview and a psychometric evaluation, thereby facilitating the donor’s decision, regardless of their type of relationship their informed consent and ensuring that donors’ psycholog- with the recipient. ical health is appropriate 173,174 . For altruistic renal donation the Spanish National protocol indicates that the assessment which takes place will make Living donor selection and acceptance criteria it possible to: “a) express the whole complexity and depth involved in the experience of altruistic donation, b) evaluate • We recommend not to proceed with the living donation their mental health, quality of life and the psychosocial sit- process in case of severe clinical or personality disorders, uation in which they live, and c) understand the underlying as well as acute phase disorders and situations of stress, motivation for the donation” 58,172 . In the case of the altruistic vulnerability, personal defencelessness or serious addictive or Good Samaritan donor, the fact that motivation plays an disorders (B). important role here should be taken into account, so that this • We recommend contraindicating donation in altruistic or will require a more exhaustive evaluation. Good Samaritan candidate donors if they have a notable n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 45 Table 8 – Items in the psychological assessment interview for a living renal donor. Exploring the donor Information they have about donation and transplantation Relación con el receptor Comprensión de posibles riesgos y complicaciones del procedimiento Comprobar que es competente y libre de tomar la decisión de forma voluntaria Explorar posibles conductas de riesgo (tatuajes, promiscuidad sexual, adiccione) Motivación que le lleva a tomar la decisión Expectativas post intervención Entrevista sociodemográfica Apoyo social y familiar Estado de pareja e hijos Nivel académico Actividad laboral y situación económica Antecedentes clínicos (intervenciones terapéuticas, enfermedades y trastornos psicológicos) Creencias religiosas Hábitos saludables Consumo de tabaco, alcohol, drogas u otras sustancias Valoración cognitiva Comprobación capacidades cognitivas que confirmen madurez y capacidad volitiva Valoración emocional Valorar posible afectación emocional que pueda influir en el proceso: Desórdenes emocionales (ansiedad, depresión, etc.) Impulsividad Estresores habituales Explorar posible ideación suicida (previa o actual) Existencia o no de abuso sexual (previo o mantenido) Valoración de estrategias de afrontamiento Comprobar estrategias de afrontamiento del donante, si son o no adaptativas y pueden ayudarle en la post-intervención ante posibles complicaciones or exaggerated predisposition to arouse the admiration of of coping strategies, resilience and available emotional others or be the centre of attention (B). support (NG). • We recommend that altruistic or Good Samaritan donors In general, the main psychosocial contraindications for should be subjected to a more exhaustive evaluation, living donation would include severe psychiatric problems with a careful assessment of their motivation as the most or substance abuse, the presence of major financial stresses important criterion (B). that may have a coercive effect on the decision to donate, or which may worsen significantly as a result of donation, and In the psychological interview with a potential donor all any medical complication, evidence that the potential donor of the areas that could compromise the intervention in some has experienced pressure or the undue pressure of other way should be taken into account. These include not only individuals to donate, restricted understanding or capacity the medical area, but also social, economic and professional, to understand the risks and benefits for the renal donor emotional, cognitive and familial factors. It is essential to or transplant candidate, or ambivalence about whether to ensure that the donor is aware of possible negative effects proceed with the donation 172,181 . that may arise due to the donation 174,175 . At the start of the The following contraindications should also be taken into interview it is advisable to check the knowledge of the donor account for good Samaritan donors candidates: a) An unreal- about donation, in order to give comprehensive additional istic opinion that transplantation involves no risk of rejection information about the procedure, possible risks, benefits, or failures; b) Donor confusion about who is responsible in results and post-donation follow-up, etc. During the assess- case of transplantation failure; c) Seeking monetary reward; d) ment some additional aspects should be assessed, such as Desire for media attention; e) Use of donation as a palliative that the donation is selfless and seeks no economic interest, for a psychological problem or another underlying disease; f) publicity or any type of personal promotion in all cases, and Donor willingness to decide on the type of recipient (regard- most especially for Good Samaritan donors. This latter type ing gender, age, race or ethnic group, and g) Desire to meet the of donation is anonymous in Spain by national law 172 . The recipient and become involved in their life 182 . interview should cover a list of subjects including mental health history, drug abuse, that the donor is able to under- The psychological interview stand the risks, social support, motivation and voluntary nature and the donor recipient relationship, etc. 183 . During • We suggest that the psychological interview should elicit the initial phase of the interview factors in connection with motivation and post-donation expectations, sociodemo- the information held by the donor about the procedure, risks graphic aspects and background. It should include cognitive and possible complications will be explored. In connection evaluation, emotional evaluation and the evaluation with post-intervention expectations, it is necessary to verify 46 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 whether the donor has taken into account that, although ones 187,188 . This questionnaire offers a dimensional vision rare, they may suffer renal complications that may threaten of the normal-abnormality continuum in psychopathology, their health to the extent that they need renal replacement making it especially interesting for the evaluation of a col- therapy. All of the above points will give us information about lective (consisting of potential donors) who in principle are the motivation which leads to donation, and this is especially not considered to have any psychological pathologies at all important for Good Samaritan donations. 189–190 , and it has been used to evaluate living renal donors The interview will focus on the sociodemographic data that 191,192 . are necessary for all psychological assessments and especially those which are relevant for organ donation, such as healthy Donor follow-up habits and possible substance consumption. The cognitive assessment will evaluate the intellectual • We suggest that living donors should be followed up psy- capacity and maturity of the donor to ensure that they under- chologically using interviews, especially those in whom stand the significance and possible consequences of their pathological personality traits had been detected (NG). actions. The aim here is to maximise precautions to ensure • We suggest that recipients should be followed up psycho- that the process of giving consent is free, without any family, logically to improve the survival of the organ and patient professional or economic pressures 184 . (NG). The emotional assessment will explore the possible exis- tence of emotional disorders which affect their free decision In the same way that follow-up of living donors is recom- to donate, such as anxiety, depressive or impulse control mended over the short, medium and long-term to prevent or disorders, etc. This assessment will be confirmed in the psy- treat risk factors that could compromise their health in gen- chometric evaluation. Whether the decision is a mature one eral and their renal function in particular 193 , follow-up of the and the result of proper reflection will also be taken into recipient should also be standardized to cover possible psy- account, or whether on the contrary it was due to a thought- chological complications that may arise after transplantation. less act that may have been the consequence of a momentary Respecting this, high levels of anxiety and depression have impulsive action. Lastly the normal coping strategies used by been detected in the immediate post-transplantation period the donor will be taken into account, as these may be pre- 194 . dictors of good post-intervention well-being. The capacity of According to the Altruistic Renal Donation Protocol of the the donor to practically resolve problems will therefore be ONT, it would be advisable for candidates who had been explored, together with their capacity to control their emo- accepted for donation to receive appropriate psychological tions and manage stressful situations, taking into account the assistance from the moment they are included in the scheme. fact that donating an organ is intrinsically stressful. Adap- This would aid the emotional expression and management of tive coping strategies such as active confrontation, planning, any possible anxiety and suffering caused during the donation impulse control, positive reinterpretation and the search for process, with the aim of preventing future emotional com- social support may all be considered. On the contrary, nega- plications and the development of psychological disorders tion, avoiding concentrating on their own negative emotions triggered after donation 172 . Identifying which donors could and addictive forms of behaviour would all be considered potentially have the greatest post-transplantation psychologi- strategies that fail to adapt, and they would therefore be pre- cal problems could help to limit the follow-up of such cases 192 , dictors of poorer post-intervention welfare 185 . reducing the probability of subsequent complications emerg- ing 195 . Psychometric assessment • We suggest that psychometric assessment based on the use Living renal donors with borderline alterations: of an objective test should be used, making it possible to acceptance and rejection criteria. evaluate clinical personality traits (C). • We suggest that the Millon MCMI Questionnaire (which The experience accumulated in thousands of donors over is now in its IV edition) should be used for psychometric recent decades makes it possible to evaluate the results and assessment (NG). procedures of donation to date. Solid recommendations have • We suggest that the evaluator should be familiar with this therefore be established for the acceptance of living renal test and have sufficient experience in applying it (NG). donors who will experience a favourable post-donation result. However, when we examine borderline cases of donation there Aside from the results of the interview, it is always advis- are far fewer examples of experience, and the results are not able not to reach a diagnosis or take important decisions for homogeneous. This means that the said limits are inherently patients without the support of objective data which comple- a field of uncertainty where research is needed, and here the ment clinical judgement or diagnostic impression 186 . onset of new data may move the limits in one direction or We propose using the Millon MCMI Questionnaire for this another. purpose, because it is able to identify the presence of severe In donation, as is the case in almost all biological phenom- clinical syndromes such as clinical personality traits and ena, the risk associated with a certain variable does not follow severe personality pathologies. It supplies information and a a discontinuous pattern but is rather a continuum. This makes nomenclature which better fit ICD and DSM diagnostic crite- it necessary to arbitrarily set the limit at a certain point that ria, as medical personnel in general are more used to these will be more of a transition zone than a clear borderline. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 47 Limits to donation based on donor GF The aim in both cases is that the GFR after donation will not compromise the prognosis for the donor during their • All donors should at least fulfil the GFR thresholds set for whole life expectancy, with zero or minimum impact on the their age and sex (Table 7). The thresholds are valid under long-term health of the donor. It is therefore necessary to appropriate conditions of post-donation compensation and know the expected donor GFR following donation, and the preservation of renal function (Quality of evidence: B). threshold GFR below which an excess of morbimortality is • We recommend that the GFR should be ≥ 90 ml/min/1.73 m2 detected. in donors < 30 years old; and that the GFR is ≥ 80 ml/min/1.73 m2 in donors aged from 30 to 45 years. The absence of Fall in the GFR after renal donation additional risk factors should be confirmed in both cases Donors lose approximately 50% of their renal mass in dona- (C). tion, although this loss under optimum conditions is followed • The use of the Grams et al. risk calculator [21] is not by a period of compensation which leads to a GFR 12 months recommended for young candidates as it may seriously after donation of approximately 70% of the baseline GFR (60- under-estimate the risk of end-stage CRD (ESRD) (B). 75%) 206,207 . A recent analysis of more than 21,000 donors in • In donors > 45 years old with a GFR higher than the mini- the American registry found that eGFR at two years after dona- mum rates which are required, but with other risk factors, tion was 68.7% of the eGFR before donation, equivalent to an it is recommended to estimate the risk of ESRD using the absolute fall of 31.2 ml/min/1.73 m2 208 . Grams et al. risk calculator tool [21] (C). Consequentially, depending on the GFR accepted pre- • We suggest that donors with a GFR < 70 ml/min/1.73 m2 donation, a large percentage of donors with a normal GFR should not be accepted, except for elderly donors and after pre-donation may fall to a GFR <60 ml/min/1.73 m2 post- a careful assessment (C). donation. Using the current classification of the KDIGO they would therefore be considered to be within the CRD category. The GFR is now accepted to be the best renal function indi- In spite of the fact that serious differences exist regarding cator, in healthy individuals as well as in patients with CRD. the importance of a low GFR in donors, several studies have In spite of this, there is no clear agreement on what the GFR found when following up donors that there is an increase in should be in any specific individual or how the GFR should the prevalence of several complications associated with CRD, be adjusted to the changes that occur with age. Much of the including hypertension, preeclampsia, hyperuricaemia, gout literature to date accepts that the average GFR for a young and hyperparathyroidism (122,123,209,210). Even more impor- Caucasian male is 125 ml/min/1.73 m2 196,197 . Nevertheless, tantly, several recent studies showed small increases in the more recent studies based largely on populations of healthy long-term risk of end-stage CRD (ESRD) in donors 35,37 . donors show lower GF rates for the same average individual, at Regarding the expected fall in the GFR that occurs with around 107 ml/min/1.73 m2 198–200 (Figure 5). In the same way, ageing, long series of donors confirm that, under appropriate we have evidence that the GFR falls physiologically after a cer- selection conditions, the loss of GFR with age is even less in tain age, although the speed of this fall and its cause are also donors than it is in the healthy general population. the subjects of intense debate 201–203 . The study of potential A long period of stabilization or even positive compensa- healthy donors has shown that there is a constant drop in the tion of the GFR after donation is described in the follow-up of GFR after the age of 40-45 years, amounting to approximately donors, and this period may last for years 211 . This compen- 0.9 ml/min/1.73 m2 per year 198,199 . These data, obtained from sation process seems to be limited by several risk factors such studies of the general population as well as candidate donors, as age, male sex or obesity 212 . Several studies show lower GFR have even been used to create a new proposal for the estima- compensation in elderly donors during the earliest phases, as tion of the GFR and its normal intervals as an alternative to well as over the longer term 213,214 . This may be linked to a dif- the staging currently used for CRD in the KDIGO guides, so ferent capacity and speed in the compensation mechanisms that the classification of CRD and its staging based on GFR that are associated with ageing. Similarly, although the mech- thresholds uses limits which are adjusted to the age of the anisms involved are less obvious, slower compensation and specific individual 204 . less capacity to compensate the GFR have been described in These circumstances are important when evaluating a can- donors who are related to the recipient 211,213 . didate donor and, in fact and in consonance with them, there Determining pre-donation functional renal reserve has not are now two different approaches in evaluating acceptable or been shown to date to offer an added value in predicting the borderline GFR for donation. The first approach is suggested post-donation GFR, so that this determination is restricted to by the KDIGO, and it is the result of classifying CRD in GFR the field of research 215 . intervals independently of the individual’s age. It states that a donor is suitable if their GFR ≥ 90 ml/min/1.73 m2 (9). The The GFR attained in the recipient. second approach is proposed by the Guides of the British The GFR prior to donation is closely linked to the GFR obtained Transplantation Society, BTS, and it accepts the concept that in the recipient, and it is essential for appropriate survival a physiological fall occurs in the GFR with ageing. It proposes of the graft. The GFR is in fact the most important charac- GFR thresholds that are acceptable for donation in the nor- teristic in predicting renal function in the recipients of living malcy ranges defined for each interval of donor age (Figure 6) donor RT 216 . Moreover, the development of ESRD in the donor 2 . The use of one approach or the other has important conse- is a risk factor that is independent of the pre-donation GFR quences in the classification of candidates as suitable or not for recipient death-censored loss of the graft 217 . A study of for donation 205 . 275 kidney recipients whose donors developed ESRD showed 48 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Figure 5 – Pre-donation glomerular filtration rates (mL/min/1.73m2 ) measured (United Kingdom, UK) 215 or estimated rates (Spain, United States, US) 200,237 per age group. The population figures in the United Kingdom correspond to the average of those published for men and women. The figures shown in the population of donors in the United States (US) correspond to representative values for the said population per age group. The figures for the Spanish population correspond to the average in donors of the Spanish Registry of Living Donor Renal Transplantation 2010-2017. that their censored graft loss and mortality rate increased in for each donor, and this is important for decision-making and comparison with a control group of LDRT recipients, adjusted even for selection among different donors. for all of the relevant confusion factors in the donor, recipi- ent and transplant, and independently of the donor-recipient Individualization of donor CRD risk relationship 218 . This work shows that there may be subclini- Concerns about the long-term consequences of donation cal renal disease prior to donation, or that there are factors have underlined the concept of focussing donor assessment which predispose to CRD that are not detected in the rou- on their future risk of developing ESRD. KDIGO recommenda- tine examination of candidate donors. Detailed analyses of tions include individual estimation of the future risk of ESRD pre-implantation biopsies of living donor grafts may eluci- after donation, as the central axis of a new donor assessment date this question. A review of almost 3000 donor - recipient framework 9 . This approach differs from the previous one, in pairs has shown that the presence of subclinical lesions in the which donation was either accepted or rejected depending pre-implantation biopsy is associated, independently of the on whether the donor fulfilled a series of health and renal clinical variables corresponding to the donor and recipient, function criteria, rather than an attempt to quantify their with patient death-censored graft survival 219 . Other compo- overall risk. nents of renal function in the donor, as well as GFR, have been The risk of ESRD should first be calculated without tak- correlated with recipient GFR 220 . ing donation into account, adjusting for the demographic The final GFR in the recipient will be the result of vari- and clinical characteristics of the candidate, including their ables associated with the donor as well as with the donor - GFR. A calculator has been developed which makes it possi- recipient pairing. Several attempts have been made to com- ble to estimate the risk of ESRD and dialysis at 15 years and bine all of these variables to develop predictive models of renal throughout the life expectancy of an individual (http://www. functioning or living donor graft survival 221,222 . Although they transplantmodels.com/esrdrisk/). This calculator is based on have limitations, these models offer an individualized score a meta-analysis of several cohorts of individuals in the general n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 49 Figure 6 – Graph and table showing the minimum estimated glomerular filtration rates (eGFR) for donation to be accepted, according to candidate age for men (-•-), women (- -), and both sexes (-•-) proposed by the latest British Transplantation Society Guides 2 , comparing them with the limiting threshold per age group proposed for the definition of chronic renal disease by Delayane et al. 203 . Table 9 – Variables associated with the future risk of ESRD and corresponding Hazard Ratios (ref. 237). Characteristic Hazard ratio (95% CI) Race (black vs Caucasian) NA Sex NA Age NA eGFR CKD-EPI < 60 mL/min/1.73m2 6.61 (4.87–8.96) 60-89 mL/min/1.73m2 1.63 (1.53–1.74) 90-119 mL/min/1.73m2 1.02 (0.85–1.23) > 120 mL/min/1.73m2 0.79 (0.56–1.10) Systolic arterial pressure Per increases of 20 mmHg above 120 mmHg 1.42 (1.27–1.58) Antihypertensive therapy (Yes vs No) 1.35 (1.01 - 1.82) Non-insulin dependent DM (Yes vs No) 3.01 (1.91–4.74) BMI Per increase of 5 points above > 30 Kg/m2 1.16 (1.04–1.29) Smoking Ex-smoker 1.45 (1.23 - 1.71) Active smoker 1.76 (1.29 - 2.41) Albumin coefficient/Cr in urine (mg/g) Per 10 times increase over levels of 4 mg/g 2.94 (0.99–8.75) Cr, creatinine; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; CI, confidence interval; BMI, body mass index; NA, not available population of the U.S.A. Almost 5 million individuals were factor is the coefficient between the expected risk of ESRD then selected with a low risk profile for CRD according to after 15 years in the general population analysed by Grams clinical and analytical variables. Multiple variables were con- et al. stratified according to race and sex, and the observed sidered, and finally 10 were selected which had been found to risk after 15 years in the series of more than 96,000 donors in be predictive of the said risk, and these were included in the the American registry 35,125 . calculator 125 (Table 9). This process has several limitations. Firstly, some variables The second step consists of calculating the risk of ESRD are excluded from the calculation of an individual’s future that can be attributed to donation, and this risk will be added risk of ESRD. The absence of the risk factor which arises from to the basal risk of the donor. This risk is not clearly defined, the relationship between the donor and recipient is espe- and estimations of it cover a very wide range (35,37,125). The cially important, as the genetic component may have a highly KDIGO suggest calculating the final risk of ESRD after dona- important specific weight in the overall risk of ESRD for the tion by multiplying the basal risk by a factor of from 3.5 to 5.3, candidate 2,37,223,224 . Secondly, it should be taken into account depending on the sex and race of the donor 125 . This multiplier that the attribution of basal risk to each donor profile will be 50 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 strongly distorted by the follow-up time of the general pop- (http://www.transplantmodels.com/esrdrisk/). Use of this tool ulation included in the Grams et al. meta-analysis (average shows that a broad range of GFR figures may be considered follow-up time 4-16 years), as this was used to build the risk valid for donation, depending on donor age and other char- calculation tool 125 . Uncertainty in calculating the basal long- acteristics. However, given the importance of basal GFR in term risk of ESRD therefore increases considerably in young determining the results and future of the donor, these Clin- donors, or in other words, the younger a donor is (with a longer ical Guides offer no specific advice on the borderline GFR that life expectancy), the lower the predictive value of a normal is acceptable in each case. result at the moment of donation will be 225 . The BTS guides, which were published soon after the There are also major uncertainties regarding calculation of KDIGO, accept two principles questioned by the KDIGO as the risk fraction that can be attributed to donation. Different valid: 1) Using GFR data measured in potential British donors studies give slightly different figures, from an excess of 27 to 230,231 , they set a standard GFR for young adult men that is 41 cases of ESRD at 15 years for every 10,000 donors 35,37 . More- lower than the historical level of 120 ml/min/1.73 m2 ; and over, there are insufficient data to know with any exactitude 2) they take into account the ageing-related physiological how the risk fraction will change depending on the demo- decrease in GFR, leading to different ranges of normality graphic and clinical characteristics of the candidate. Lastly, we for each donor age cohort 2 . They thereby set minimum have to consider that the future risk of ESRD does not seem GFR thresholds for donation, so that the renal function of to be lineal over time, as it is likely to rise exponentially more the donor remains within normal limits during their life- than 10 years after donation 223 . time. As a result of these limitations, several publications have Interpreting the BTS guides requires some clarifications: raised doubts about the process proposed by the KDIGO for the calculation of the individual risk of a specific donor 47,226–228 . 1) The thresholds for each age group, differentiated accord- Due to all of these considerations, it is obvious that the risk ing to sex, predict that the GFR will remain within normal calculation tool proposed should only be used on condition limits while the donor ages, on condition that it runs in that its inherent limitations are clearly understood, together an “ideal” GFR decline curve. Existing data on the evolu- with the fact that it may give rise to serious under-estimations tion of the GFR after donation show that the fall in the of long-term risk. This method of donor assessment should be GFR is no greater than the physiological fall in the healthy used as just one of different tools, in a process that requires a population, and it may even be less. However, we have to global and multidisciplinary clinical vision, one which has to remember that these data correspond essentially to Cau- take into account multiple factors as well as the quantitative casian series of donors with an average age of around 45 estimations of risk. years, who are not hypertensive or diabetic and with nor- Massie et al. recently published a donor ESRD risk esti- mal albuminuria 33,211,232,233 . mation calculation tool 229 . This tool, which is also available The minimum threshold is set at 80 ml/min/1.73 m2 for in internet (http://www.transplantmodels.com/donesrd/), female donors aged from 30 to 50 years and men aged includes fewer variables than the one published by Grams 30 to 55. The limit is set at 90 ml/min/1.73 m2 for donors et al. For example, it does not include certain highly important under the age of 30 years, and this is the same minimum risk factors, such as albuminuria or high blood pressure, while figure recommended by the KDIGO. If these thresholds it does nevertheless include a family history of CRD, which is are accepted then it has to be taken into account that lacking from Grams’ calculation tool. In any case, both risk the post-donation GFR in donors aged from 30 to 45 calculation tools would need external validation, and this has years may even fall below the normal range. The BTS yet to be done. guides contain no clear justification for this decision, which implicitly assumes that the accumulated experi- Analysis of the recommendations in the main Clinical Guides ence over recent decades, accepting donors with a GFR The KDIGO guides recommend the standard GFR for a >80 ml/min/1.73 m2 , has been followed by very slight candidate donor of ≥ 90 ml/min/1.73 m2 , while a GFR increases in the absolute risk of ESRD over the long- <60 ml/min/1.73 m2 should exclude donation 9 . These limits term 35,37 . differ from the ones that were accepted previously, which set 2) The BTS have selected the figure of 75% of basal renal the optimum limit at a GFR ≥80 ml/min/1.73 m2 , and they were function as the degree to which renal function is com- not set using evidence-based medicine, as they were based pensated by the remaining kidney, which is in the upper on studies in non-donors. Long-term studies of large series of range of observations 206,207,231 . Due to this, post-donation donors, with an average age of 40-50 years and a measured GFR estimations of GFR and its long-term evolution may not ≥ 80 ml/min/1.73 m2 , showed that there is very little increased extrapolate to very elderly donors or those with comorbidi- risk of ESRD in these populations 35,37 . ties. Although the selection of this new standard may be correct 3) Like the KDIGO, the BTS recognise the possibility of donat- when assessing the youngest donors, its significance in older ing with basal GFR figures at from 60 ml/min/1.73 m2 to donors is unclear. This lack of clarity is due to the relationship 70 ml/min/1.73 m2 , while the BTS even do so when rates are between ageing and a falling normal GFR 201,202,204 . lower than 60 ml/min/1.73 m2 . In both cases, GFR thresh- For a GFR of from 60 to 90 ml/min/1.73 m2 the KDIGO rec- olds that are so distant from standard advisable GFR and ommend evaluating the long-term risk of ESRD based on the previously published experience lack supporting evidence, health and demographic characteristics of each candidate. and they should only be accepted in exceptional cases in They offer an online risk calculation tool for this purpose experienced hospitals. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 51 Donor age as a limit to donation Age is an independent risk factor in for ESRD in donors, with the exception of African Americans 37,224,229 . This fact • We suggest that donation by young people, especially those may be due to the higher risk of developing hypertension who are under 30 years old, should be restricted to can- and DM after donation in the African American population, didates who have a GFR of at least the average for their so that the longer life expectancy in young and intermedi- age group, without any additional risk factors and a strictly ate age donors would increase the long-term risk of ESRD 224 . normal result of evaluation of their health status (C). • We recommend that advanced age alone should not con- traindicate donation, although such candidates are subject Minor urinary alterations and their impact on donation to more perioperative risks (A). • We suggest that hypertension, one of the risk factors for The term “minor” urinary alterations does not always corre- CRD, may have less impact in elderly donors, due to their late with their importance for an individual’s renal prognosis, reduced life expectancy (C). so that the term “minor” is only applicable when it refers to • We recommend that donor-recipient pairs should be lower grade urinary alterations that are close to normality. informed that when donors are elderly, especially when they are older than 60 years, the renal function attained Proteinuria and Albuminuria in the recipient and probably the long-term survival of the graft may be reduced (B). • We recommend that donor proteinuria should be evaluated by measuring the excretion of albumin in urine, not solely Increasing numbers of elderly donors have been accepted by measuring total proteinuria in urine. In spite of this, both in recent decades, and more than 30% of LDRT donors are now determinations are necessary when evaluating a candidate older than 50 234 . This tendency reflects the change in the (A). perceived long-term risk of ESRD for donors, as this affects • We recommend that the amount of albuminuria be included younger candidates to a greater extent. in the estimation of the future risk of cardiovascular dis- We now recognise that all donors have an increased risk ease and ESRD in donors (http://www.transplantmodels. of ESRD. This risk is very small in absolute terms, and it com/esrdrisk/) (B). arises over the very long-term after donation (one or several • Albuminuria of less than 30 mg/day permits unrestricted decades), and it seems to increase exponentially with time donation (B). after donation 223,229,235 . Analysis of the donors who have • Albuminuria levels of from 30 to 100 mg/day are a relative reached a stage of ESRD shows that the majority of these contraindication against donation. Accepting a donor in this patients took more than 10-15 years to arrive at this point, range of albuminuria may be considered in elderly candi- and they donated when they were young. Donation when dates when no other risks are present (D). young is therefore a risk factor of the first order for donors • We suggest that albuminuria from 100 to 300 mg/day may to reach stages of ESRD 235–238 . Only 2% of the donors in be accepted in exceptional cases, when there are no other the American UNOS registry were younger than 35 years old comorbidities. (D). 223 . Young patients have a very long time of exposure to the risk Increased protein excretion in urine is a strong renal dis- of new diseases such as hypertension and DM, which usually ease marker, and it sometimes appears earlier than the fall debut after the age of 45 years. These diseases are difficult to in the GFR. Albuminuria signals an increase in glomerular predict, but may affect their future risk of CRD 223 . We also permeability, while the elimination of low molecular weight know that hypertension and/or DM cause practically 50% of proteins reflects a failure in tubular reabsorption. Although the cases of ESRD in donors, a situation that occurs several both may be associated with different forms of renal dis- decades after donation 238 . All these factors reduce the predic- ease, the determination of albuminuria is a better marker in tive power of a normal evaluation result in young candidates evaluating renal disease. All of the methodological aspects in when they donate, and it may lead to an under-estimate of the connection with the determination of proteinuria or albumin- risk 225 . On the other hand, there is less available evidence for uria are described in section 5. how young donors will evolve than there is for intermediate- Independently of the GFR, in the general population albu- age donors 223 . minuria higher than standard normal levels is associated with All these factors are inversely applicable for elderly donors. an increased risk of CRD, cardiovascular disease and mortal- Although the latter are exposed to higher risk during nephrec- ity 243–260 . Albuminuria also predicts the progression of CRD tomy and the immediate post-donation period, older donors and cardiovascular events in patients with CRD, cardiovascu- with CRD risk factors such as hypertension and DM are less lar disease or diabetes 0,61 . Although albuminuria of 30 mg/day likely to be exposed to them for long enough to lead to ESRD is usually considered to be the limit of normality, ranges above 239 . In spite of this, age may be a clear limiting factor for 5 mg/day already show an increased risk that is proportional donation. According to the detailed analyses in other sec- to the rise in albuminuria 217,247 . A meta-analysis of almost tions of these recommendations, advanced age is a risk factor 5 million individuals in the U.S.A., selected for their low risk for surgical complications during donation, recovery and the of CRD and with an average follow-up of from 4 to 16 years, development of hypertension after donation 240,241 . Donors found that for each 10-time rise of albuminuria, a 3-times older than 50 should therefore be subjected to exhaustive car- increase in the risk of ESRD is detected. Although this finding diorespiratory evaluation 242 . did not attain statistical significance, the projected incidence 52 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 of ESRD at 15 years showed that the increase in albuminuria defining and determining microhaematuria and the diagnos- was associated with a higher risk in all age groups indepen- tic sequence after finding it are described in section 5. dently of sex 125 . Orthostatic proteinuria is an exception, given Microhaematuria may have many causes. Firstly, micro- that it has a benign prognosis and must not be considered a haematuria associated with intense exercise, sexual activity, contraindication for donation 247 . menstrual contamination, or injury should be excluded 248,249 . In spite of all the above considerations, we lack solid evi- The most frequent causes of microhaematuria include a non- dence that would allow us to set a clear limit that excludes malign urinary aetiology such as urinary infection, prostatic donation. This is because there is practically no published hypertrophy or urolithiasis. There are also many other less fre- experience of the long-term evolution of donors with different quent causes, such as systemic diseases, infectious diseases, levels of proteinuria or albuminuria. urothelial neoplasia or primary glomerulopathy 249–251 . The The KDIGO and BTS guides set a level of albuminuria majority of cases are therefore due to benign causes and are <30 mg/day, or a ratio of albumin/creatinine in urine <30 mg/g potentially reversible. Donation will be permissible once the as a suitable limit for accepting a donor. However, they also underlying cause and associated factors have been resolved. recognise that there are individuals within this range who In fewer cases microhaematuria is due to a pathology which have normal albuminuria, and others with a slightly raised affects the health of the donor or the safety of donation, level for their age and sex. At the other extreme, albumin- making it a contradiction against donation. After the relevant uria higher than 300 mg/day for the BTS guides, or higher than study and once other causes have been ruled out, the study of 100 mg/day for the KDIGO, are a contraindication. Donation microhaematuria for the purpose of enabling donation must is relatively contraindicated between both extremes, and the conclude by indicating a renal biopsy. In such cases the pres- decision to accept a donor should be taken on an individ- ence of different histological findings may raise doubts about ual basis, according to their demographic characteristics and whether to accept the donation. health. According to current recommendations these “inter- In an individual with persistent microhaematuria, any mediate” albuminuria values (30 mg/day - 300 mg/day) are pathological entity detected in a renal biopsy will be a sufficient to establish a diagnosis of CRD, so that even admit- contraindication against donation. This includes IgA glomeru- ting the weakness of the available evidence, donation is not lopathy, regardless of its clinical or histological expression. advisable. The current KDIGO guides justify accepting these Only thin basement membrane disease (TBMD) will give rise to donors because the projected risk of ESRD in elderly individ- a doubt regarding the acceptance of a potential donor 173,180 . uals with albuminuria levels from 30 mg/day to 100 mg/day is This entity, which had only been defined using histological very low, on condition that a reduced GFR and other comor- criteria, now corresponds in genetic terms with autosomal bidities are ruled out 125 . dominant Alport’s syndrome (ADAS) 252 . These patients only have a pathogenic variant of the COL4A3 or COL4A4 gene, and its possible clinical presentation varies widely, from isolated Microhaematuria microhaematuria to the development of ESRD, generally over • We recommend that after ruling out the most common the age of 40 years 253 . The BTS guides consider the possibility causes, a renal biopsy should be indicated if isolated per- of donation by patients with persistent isolated microhaema- sistent microhaematuria is found in the study of a living turia due to TBMD 2 . This is based on the fact that there are donor (B). precedents for donations under these circumstances when • Any pathological entity detected in a renal biopsy is a there was awareness of donor TBMD and when there was not, contraindication against donation, including IgA glomeru- and no adverse events have been reported in the follow-up lopathy. Only TBMD would require a different decision (B). of either type of donor 146,148 . Nevertheless, even when this • Candidates with TBMD face an increased risk of ESRD. Dona- decision is based on rigorous genetic evaluation and family tion may be considered in individuals older than 40 or 50 history, it does not exclude the risk of developing ESRD. Only years, after clinical, histological and genetic evaluation and individuals with a complete genetic, histological and clinical after they have received detailed information on the risks evaluation who are older than 40 to 50 years may be considered and uncertainties associated with donation (D). as donors, with especial emphasis on detailed information about the risks and uncertainties associated with donation. The presence of microhaematuria or non-visible persis- TBMD should be differentiated in Alport-carrier patients with tent haematuria is defined by the presence in microscopic a heredity linked to chromosome X, who have a significant risk evaluation of urinary sediment of more than 2-5 erythrocytes of ESRD, at 12% before they are 40 years old and increasing to per microscope field in at least 2 separate determinations. 30% and 40% at 60 and 80 years old, respectively 253 , so that Lower degrees of haematuria, i.e., the presence of erythro- these candidates are not considered to be acceptable donors. cytes in urine in any degree (1-3 erythrocytes per microscope Donation in women who are Alport’s syndrome carriers with field) are considered to be irrelevant in the general popula- heredity linked to chromosome X has been followed by the tion. Nevertheless, the few available studies prove that the development of CRD, proteinuria and hypertension in more histological examination of such cases shows a significant than 50% of cases 254 . presence of underlying nephropathy 146,148 . Therefore, and In exceptional cases, and after extensive study which even recognising that the indication for biopsy is weaker, the includes all of the relevant complementary examina- study of a donor candidate with detectable haematuria does tions, including renal biopsy with electron microscopy and not substantially differ from that of a candidate with persis- immunofluorescence studies, donation may be accepted from tent isolated microhaematuria. The methodological aspects of individuals with isolated microhaematuria as the sole finding. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 53 It is fundamental in these cases to exclude any family history associated with increased levels of uric acid and perhaps of renal disease, with a targeted genetic study in the case of the a higher risk of gout (C). slightest doubt. Several experiences support the acceptance of these donors. One recent study which targeted the general A fall in the GFR is accompanied by a reduction in the excre- young population (16 to 25 years old), with an average of 22 tion of uric acid and a subsequent increase of uric acid in the years of follow-up, found a small excess long-term risk of ESRD blood, while the risk of gout also rises 264 . Within the context associated with the presence of isolated microhaematuria in of the fall in the GFR which occurs after donor nephrectomy, individuals with less than 200 mg/day proteinuria and normal an 8% increase has been observed in uric acid levels 6 months range creatinine levels. The majority of the ESRD cases cor- after donation in donors compared to healthy controls, and responded to the development of primary glomerular disease this increase persists 36 months after nephrectomy 210 . If we 255 . Taking into account that these patients were not subjected compare donors pre- and post-donation, uric acid was found to such an exhaustive or extensive evaluation process as the to have increased by 20% 7 years after nephrectomy and more one proposed, it is possible that this evaluation would detected episodes of gout were detected, although at a low absolute fre- the individuals with underlying renal pathology, thereby elim- quency 209 . African American, male and older donors are the inating the excess risk detected in this study. This occurred in most likely to suffer gout after renal donation 265 . A recent a Dutch study including renal biopsy of a series of 49 patients Japanese retrospective study found that donors with higher with persistent isolated microhaematuria. The 20 patients uric acid levels before donation were at greater risk of devel- with normal histology showed no worsening of renal function- oping suboptimum compensatory renal hypertrophy 266 . ing or developing proteinuria over the 11 years of follow-up As well as the risk of gout, high levels of uric acid have been 256 . associated with increased cardiovascular risk and the risk of developing CRD in the general population 209,267 . These data have not been confirmed in cohorts of renal donors. Dyslipidaemia Of the recently published guides, only the 2017 KDIGO make recommendation about renal donor hyperuricaemia 204 . • We suggest that donation should not be contraindicated if As the development of hyperuricaemia and gout after dona- dyslipidaemia is an isolated finding (C). tion seems to be strongly associated with sociodemographic • We suggest that dyslipidaemia should be taken into account factors 265 , donors should be assessed on an individual basis, when estimating the overall cardiovascular risk of a donor asking about possible episodes of gout and informing them (C). about the potential risk of hyperuricaemia and/or gout after donation. The prevalence of dyslipidaemia in the general Span- ish population stands at 30%–51%, making it one of the most prevalent cardiovascular risk factors, surpassed only Smoking by hypertension in some studies 258 . Additionally, within dyslipidaemia, hypertriglyceridemia and low levels of HDL • We suggest that the impact of smoking on whether cholesterol form part of the diagnosis of metabolic syn- candidate donors are accepted should be individualized, drome 259 . Few studies have analysed the possible association depending on the overall risk of the candidate (C). between pre-donation lipid levels and the results after • Smoking cessation is recommended before donation as well nephrectomy. One study in México found that metabolic syn- as during donor follow-up (C). drome had a negative impact, leading to a lower GFR at 5 years, • Potential donors should be properly informed of the risks although none of the components of metabolic syndrome associated with smoking and having smoked (NG). that were analysed (abdominal perimeter, fasting glycaemia, hypertriglyceridemia, HDL cholesterol levels or hypertension) Tobacco consumption is a major but modifiable cardiovas- had any impact alone on post-donation renal functioning. cular risk factor, with a prevalence in Spain of 39% among In an Israeli study donors were found to be at higher risk adults aged from 35-64 years 268 . As well as its widely known of metabolic syndrome than the control group 261 . However, cardiovascular and carcinogenic risks, smoking may also no studies analyse the influence of dyslipidaemia as an iso- cause direct renal damage by promoting atherosclerosis and lated prognostic factor for renal donors. A meta-analysis in the microvascular damage in tissues, and it has been associated general population found no association between LDL choles- with the appearance of CRD 269 . The aforesaid meta-analysis terol levels and the development of ESRD 125 . All of the guides on risk factors for developing ESRD in the general population consulted (2,4,9,262,263) recommend the determination of the after 15 years showed that active smokers had a 76% increase lipid profile in the study of live donors, although none of them in risk, while ex-smokers too had a 45% increased risk 125 . sets a limit for non-acceptance. There is little literature on the risk for smoking donors after nephrectomy. An American study found a risk of mortality at Hyperuricaemia and gout 12 years to be 5 times higher in donors who were smokers than it was in non-smokers 120 . • We suggest that hyperuricaemia or a history of gout in a No guide recommends contraindicating donation for donor are not a contraindication against donation (C). smokers 2,4,9,262,263 . They do recommend undertaking res- • We suggest that candidates with a history of hyperuri- piratory function tests to rule out structural pulmonary caemia and/or gout should be informed that donation is pathologies 2 and, depending on the accumulated packs per 54 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 year index, it may also be necessary to use low radiation tho- a potential limitation. Nevertheless, the majority of potential racic scan imaging to rule out lung neoplasia 263 . donors are in older age groups, and there is limited scientific evidence on long-term donor health. Decisions about donation Alcohol consumption and addiction to other drugs by these populations are therefore controversial. The major- ity of studies suggest that living renal donors have a minimum • The overall and psychosocial assessment of donor can- life-long risk of developing ESRD. However, the long-term com- didates should specifically examine their consumption of plications and psychological and physiological after-effects of alcohol and other drugs (NG). donation are still unclear, due to the lack of optimum donor • We suggest that all donors should be encouraged to reduce follow-up after RT. their alcohol consumption to the recommended levels for Optimising the selection of these donors should guaran- the general population (D). tee the safety and efficacy of this replacement therapy. The detection of risk factors for the development of ESRD is of There is no evidence or recommendation whatsoever crucial importance in this assessment. The increase in these regarding the evaluation of alcohol consumption and/or risk factors in potential donors has led to the broadening of addiction to other drugs in potential renal donors 2,4,9,262,263 . the selection criteria for them, modifying absolute and rel- The advice to reduce consumption or to consume alcohol ative contraindications, so that individualized assessment is in “moderation” seems to be insufficient to correctly assess necessary. The identification of these risk factors makes it pos- donor risk, as alcohol consumption may be associated with sible to set donor selection and exclusion criteria, as well as the development of hypertension or gout, for example 204 . recommending specific changes in their lifestyle. Moreover, addiction in itself should be included within the psychological assessment of donors. Obesity The European guides examined “alcohol consumption” in depth 4 . The authors concluded that a reduction in alco- • We suggest that the body mass index (BMI) should be used hol consumption should not only be recommended but also for the clinical evaluation of overweight and obese subjects encouraged and sought. The target was to reduce consump- (Quality of evidence: C). tion to below 60 grams per day in men and 40 grams per day • We suggest that individuals with a BMI > 35 kg/m2 should be in women, according to World Health Organization criteria 270 . advised against renal donation (C). Although extrapolation from renal recipients to donors should • We recommend that living donor renal donation should be not be the norm, it would seem recommendable to at least contraindicated in obese patients with a second risk factor evaluate donor alcohol consumption, over and above a simple (B). question such as: “Do you drink?” Alcohol consumption preva- • We recommend that obesity (BMI > 30 kg/m2 ) should be con- lence in the previous 30 days stands at 60% in adults in Spain, sidered a relative contraindication against donation, and and up to 25% of men aged from 55-64 years consume it daily that this should be evaluated on an individual basis to detect 264 . It is therefore necessary to assess alcohol consumption the presence of other cardiovascular risk factors such as more precisely in our renal donor candidates, so that we can glucose intolerance, hypertension and proteinuria (B). offer suitable information and detect possible alcohol depen- • We recommend that obese donors should be advised on dency disorders. Excessive consumption can also be identified the increased risk of perioperative morbidity and the lack using indirect signs, such as altered liver function in analysis of data on long-term safety (B). or ultrasound scan imaging. • Donors with a BMI >27 kg/m2 should be informed that they On the other hand, there is no evidence or any recommen- may be at higher long-term risk of developing CRD and that dation on assessing donors for sporadic drug consumption. In therefore, they should lose weight prior to donating and fact, the majority of guides contextualise drug consumption keep to a healthy weight afterwards (C). within their donor assessment in terms of infectious diseases. Within this scenario, psychological assessment is the most Being overweight or obese is a public health problem due to important means of ruling out problems with addiction, so its high rate of prevalence in the general population, as a result that the decision whether to accept a donor is based on their of a sedentary lifestyle and overeating. National Health Insti- complete psychological and medical evaluation. tutes define obesity as a BMI ≥ 30 kg/m2 . Although historically living donors were free of pathologies, the selection criteria for marginal donors have been gradually broadened 271 . Cur- Metabolic evaluation and healthy lifestyles rently more than 25% of living donors are obese at the moment before and after living renal donation of donation, as opposed to 8% in the 1970s, and up to 43% are overweight. The prevalence of ESRD is increasing worldwide as the result Obesity is an independent risk factor for ESRD in the of a higher prevalence of comorbidities such as hyperten- general population. It may cause functional and structural sion, DM and obesity. These comorbidities are generally changes at renal level, such as glomerular hyperfiltration, contraindications against accepting living donors because of glomerulomegalia and focal segmental glomerulosclero- the long-term risk of developing ESRD and increasing post- sis lesions. The risk of ESRD increases in patients with transplantation morbimortality, particularly in elderly donors. a solitary kidney, who develop compensatory glomerular Likewise, metabolic syndrome, which affects 30% of the gen- hyperfiltration. Patients with a BMI >30 kg/m2 at the moment eral population, is a prelude to these comorbidities and may be of nephrectomy are therefore at higher risk of developing n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 55 proteinuria and renal failure 10 years afterwards, due to under treatment, when measurement in the surgery reasons other than renal donation 272 . shows raised blood pressure >140/90 mmHg or normal- Obesity is associated with a higher risk of hypertension, raised > 130/85 mmHg (C). DM, CRD, metabolic syndrome and cardiovascular disease • Eligible donors with controlled hyperten- in the general population, and this is also the case in living sion < 140/90 mmHg with one or two antihypertensive donors. Although BMI is a useful tool in the identification drugs, without evidence of organic harm that could be due of overweight and obese patients, there is no established to hypertension. Consider excluding donors with controlled agreement on what constitutes a safe BMI for donors, and hypertension but also with other associated risk factors, there are several different recommendations 2–4 . The long- such as obesity, smoking or advanced age (C). term impact of obesity on donors is therefore uncertain, • We suggest that potential donors with a blood pres- and it is hard to find the limit that would predict a higher sure > 140/90 mmHg who are under antihypertensive treat- post-donation risk, so that candidates could be excluded ment or signs of organic lesion should be excluded (C). during the pre-donation assessment, or lifestyle strategies • We suggest that blood pressure and other modifiable risk could be implemented to modify this factor. factors should be monitored annually after donation (C). Obesity in living renal donors does not seem to affect their long-term health, except for a more complicated wound and a In the general population, the prevalence of hyperten- longer time in surgery. There are no differences in the GFR sion in adults is estimated to stand at 30%-45%, reaching in comparison with non-obese donors in the years follow- 60% in individuals over the age of 60 278 . Hypertension is a ing donation 213,273 . However, the long-term impact may be relative contraindication for living renal donation, and indi- negative. In a national study in the U.S.A., obesity alone (with- vidual assessment is necessary to determine whether there out hypertension or DM) was associated with a higher rate are any other associated comorbidities. The most recent clini- of CRD and mortality in comparison with non-obese donors cal guides set an arterial blood pressure of >140/90 mmHg with 271 . They also developed DM and hypertension more often and one or two antihypertensive drugs or evidence of organic dam- earlier than donors who were not obese after donating 274,275 , age induced by hypertension as contraindications for living although this risk was not aggravated by the nephrectomy 276 . renal donation. Nevertheless, the definition of hypertension The above findings have important implications for the may undergo slight variations over time 279 . selection of living donors in terms of the BMI cut-off points A meta-analysis that included 48 studies in 28 countries set previously as contraindications for donation. It therefore with 5,145 living renal donors found an average weighted varies from a BMI of 30 kg/m2 to 35 kg/m2 , depending on the increase in systolic blood pressure of 6 mm Hg, while the dias- hospital. Being overweight may lead to a high risk of ESRD in tolic increase was 4 mm Hg, which is higher than what would the long-term in comparison with a normal BMI, so that poten- be foreseen in normal ageing 122 . Donor may be at greater short tial donors who are obese or overweight should be advised to - to long-term risk of developing hypertension 280–284 . The lose weight before donation. Moreover, a lower BMI is associ- associated risk factors are age, male sex, African-American ated with an improvement in other cardiovascular risk factors ethnicity, a family history of hypertension, BMI and higher over the short-term. Donors with normal BMI at the time of systolic and diastolic blood pressure. Nevertheless, given that donation underwent significant weight loss prior to donation these risk factors are similar to those in the general population and kept a healthy bodyweight afterwards; donors with a BMI of the Framingham cohort, it may be inferred that the effect ≥25 kg/m2 at the moment of donation underwent a signifi- of nephrectomy neither modifies nor increases the risk 283 . cant weight gain during 1 year after the donation, suggesting Donors with pre-existing hypertension maintain a higher the need to improve weight control efforts among obese renal blood pressure beforehand and two months after donation donors and those with excess weight before and after donation than their controls. They are similar at 5 years, and no dif- to reduce their risk of advanced CRD 277 . ferences in renal function or proteinuria have been found 285 . To summarise, obese potential donors should be evaluated Although the majority of hospitals exclude patients with on an individual basis to detect other risk factors associated hypertension as renal donor candidates, they usually base this with CRD, such as glucose intolerance, hypertension and per- on blood pressure measured in a clinical examination, and sistent proteinuria. Potential donors with metabolic syndrome this does not reflect their real blood pressure. In a study of 178 should be evaluated individually, given the reversible nature donors, 63 of them had hypertension when measured in the of the alterations. Post-donation evaluation and follow-up to surgery, but two thirds of these were found to correspond to control weight, as well as to underline the importance of daily “white coat hypertension”, as when ambulatory blood pres- physical exercise and coordination with nutritionists for indi- sure monitoring (ABPM) was used, these patients were found vidualized healthy diet programmes should be an objective in to be eligible for donation. On the contrary, of the 115 indi- living donor RT programmes, to minimise cardiovascular risks viduals found to be normotensive in clinical measurement, and to improve long-term renal survival. 17% were found to have masked hypertension in the ABPM, and they were excluded from donation. The individuals with Arterial hypertension masked hypertension were older, male and had a somewhat higher clinical blood pressure than the individuals with sus- • We suggest that arterial blood pressure should be measured tained normotension 286 . ABPM better reflected the real blood at least twice, separated by an interval (C). pressure than measurements in the surgery. Several studies • We suggest that arterial blood pressure should be mea- have pointed to the value of ABPM in renal donors when clin- sured in the following cases: donors with hypertension ical measurement of blood pressure is in the hypertensive 56 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 range. 30%-60% of potential donors who had hypertension during clinical assessment were found to be normotensive when studied using ABPM 287 . Eligible hypertensive donors should therefore be appro- priately monitored using by ABPM and have no evidence of hypertension-induced organic harm. In the same way as for the general population, it is probable that a rise in blood pressure in living renal donors will increase their cardiovascu- lar risk and the risk of CRD. The first therapeutic step would be to administer renin angiotensin system blockers. The donors without pre-existing hypertension should be informed that donation may accelerate the increase in blood pressure respecting what would be expected with normal ageing, and that it is necessary to monitor blood pressure regularly. Figure 7 – Possible mechanisms which lead to hyperfiltration, progressive renal disease and proteinuria in Diabetes mellitus and metabolic syndrome potential living renal donors who have metabolic syndrome prior to donation. GFR: Glomerular Filtration Rate. Adapted • We recommend that basal glycaemia and glycated from Hernández D 305 . haemoglobin (HbA1c) should be determined in all donors (B). • We recommend that an oral overload glucose test should be performed if there is a history of gestational diabetes, a first- Up to 70% of prediabetic individuals (basal glucose from degree family history of type 2 diabetes, impaired fasting 100 mg/dl to 125 mg/dl, or an altered OGTT) will develop type glycaemia, overweight, hypertension or dyslipidaemia (B). 2 DM 295,296 . The proportion of donors with glucose intoler- • Donors with type 1 DM should be excluded (D). ance has increased from 7% to 22% over the past two decades 297 , and studies carried out with donors of this type show good • Donors with type 2 DM should generally be excluded, although they may be considered under special circum- outcomes, without differences in the GFR or albuminuria after stances (C). 10 years of follow-up in comparison with non-prediabetics 298 . A study of 93 donors with HbA1c and OGTT distributed • In cases with pre-diabetes or metabolic syndrome the deci- sion should be taken on an individual basis (D). them in three groups: high risk of DM (HbA1c and OGTT in the • Recommendations for a healthy lifestyle (C). prediabetic range), low risk (one of both parameters altered) • Follow-up after donation to monitor CV risk factors (C). and the control group (with both parameters normal). After an average follow-up time of 76 months, a high percentage There has been a major increase in the prevalence of DM of the high risk group developed DM, in comparison with the over recent decades 288,289 . Potential renal donors should have low risk group and the control group (31.3% vs 6.5% vs 0%). a determination of basal glycaemia and glycated haemoglobin They showed no higher risk of hypertension or microalbu- (HbA1c), In those ones with a first-degree family history of type minuria, and the prediabetic donors had a similar GFR to the 2 diabetes, a history of gestational diabetes, impaired fast- control group. The conclusion was that although HbA1c iden- ing glycaemia (IFG), obesity, hypertension or dyslipidaemia, tifies prediabetic donors at risk of progressing to DM, with an Oral Glucose Tolerance Test (OGTT) should be performed. careful selection these donors would not be at higher risk of Maintained hyperglycaemia triggers a series of haemody- renal function deterioration 299 . namic and structural changes which, when they coincide with Notwithstanding all of the above, these results should be a genetic basis and converge with other factors such as obe- interpreted with caution since there is no long-term follow- sity or hypertension, may lead to the appearance of diabetic up. A study of 2954 living renal donors found that after an nephropathy 290,291 . If this is combined with hyperfiltration average follow-up time of almost 18 years, 154 had developed due to reduction in the nephron mass after nephrectomy, the type 2 DM. During the first decade, they had no increased risk risk of developing diabetic nephropathy in renal donors with of CRD after developing diabetes, although this was not the diabetes may be considerable. The presence of type 1 DM has case for increased albuminuria 300 . In a later publication this therefore classically been considered to be an exclusion crite- same group presented the outcomes of these diabetic donors, rion for renal donation. Nevertheless, in type 2 DM and under and over the longer term they showed faster deterioration of certain circumstances, especially if there are no other fac- the GFR than the non-diabetic control group if they also had tors such as hypertension or overweight, donation may be hypertension and proteinuria 301 . considered 292 . In a series of 225 donors, the 14 diabetics at Several risk indexes have been prepared for the general the moment of donation were compared with the 211 non- population to estimate the probability of developing type 2 diabetics over an average follow-up time of about 4 years. DM, but their predictive capacity varies widely as they exclude There were no differences in renal function or albuminuria major risk factors. In practice, basal fasting glucose and the between both groups 293 . Another series found no differences OGTT are the standard recommended tests for the diagnosis of in survival over the long-term, and none of the diabetic donors type 2 DM, in renal patients too. Figure 7 shows a flow diagram had advanced CRD 294 . that may help to detect type 2 DM before renal donation. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 57 Figure 8 – Flow diagram for the detection of diabetes mellitus before living donation. OGTT: Oral Glucose Tolerance Test; AOGTT: Altered Oral Glucose Tolerance Test; AFG: Altered Fasting Glucose. DM: Diabetes Mellitus. Adapted from Hernández D et al. 305 . Metabolic syndrome arises when at least three of the fol- In potential donors with type 2 DM, prediabetes or lowing circumstances coincide: abdominal perimeter (waist metabolic syndrome, changes should be recommended in circumference) >102 cm in men and >88 cm in women, fast- lifestyle, diet, weight loss and physical exercise. The aim ing serum triglycerides ≥150 mg/dl, HDL-cholesterol <40 mg/dl would be to prevent progression to diabetes and reduce CV in men and <50 mg/dl in women, systolic blood pressure risk and the risk of progression to CRD 308 . ≥130 mmHg and/or diastolic ≥ 85 mmHg or taking antihy- The benefits of weight reduction to slow the development pertensive drugs and fasting glucose ≥100 mg/dl or taking of diabetes have been clearly proven, at least in the short- hypoglycaemiant drugs. This syndrome has a prevalence in term 309–311 . However, this benefit is not usually maintained Spain of 25%, and it is associated with CV morbimortality, over time, above all because the partial or total recovery of the diabetes and renal damage 302–304 . The high prevalence of weight that had been lost is very common over the long-term metabolic syndrome, its comorbidities and its negative conse- 312 . quences, make it necessary to undertake an exhaustive search Physical exercise has also been shown to be effective in for this entity in potential renal donors 305 . Metabolic syn- slowing the progression to diabetes 50 . The ADA recommends drome and each one of its components are independently at least 150 minutes/week of moderate to vigorous physical associated with a higher risk of CRD 306 . However, it is less activity, or shorter periods (at least 75 minutes/week) of vigor- clear whether the presence of metabolic syndrome in a donor ous intensity exercise to prevent or delay the appearance of is associated with worse renal function after donation. In this type 2 DM in high risk populations and/or those with predia- respect, an interesting study analyses the association between betes 313 . Intermittent high intensity training and continuous the syndrome, renal function and histological damage in liv- moderate intensity training have a similar positive effect on ing renal donors. Of a total of 410 donors, 12% had metabolic functional capacity and cardiometabolic markers in individu- syndrome at the time of donation; the pre-implantation renal als with prediabetes or type 2 DM 314–315 . biopsies of the donors with metabolic syndrome showed more histological signs of chronicity, and this finding was associ- ated with slower recovery of the GFR after donation 307 . One group of renal donors with metabolic syndrome reached a GFR Compatibility and incompatibility in living <70 ml/min in a shorter period of time (an average of 5 years vs donor RT 12 years) 260 . Theoretically, in individuals with metabolic syn- drome who are subjected to nephrectomy for living donation, Compatibility barriers insulin resistance and the fall in renal mass may predispose their remaining kidney to hyperfiltration, with proteinuria and • An ABO blood group and HLA compatible transplant offers progressive renal disease (Figure 8). the best opportunity of success (Quality of evidence: A). 58 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 • Incompatibility in ABO blood group and the HLA system are the most important barrier for the survival of a solid organ independent. Donor and recipient may be HLA identical and transplant lies in the potential immunological “incompatibil- ABO incompatible (NG). ity” with the donor, which may trigger the loss of the graft • We recommend that blood group should be determined at 317 . an early stage in the study of a potential RT donor-recipient All of the molecules which are present in the donor pair so that expectations can be properly managed and but absent in the recipient are able to cause a potential transplant options can be discussed (B). immune response. Nevertheless, the barriers identified in • ABO blood group incompatibility is not an absolute con- clinical practice which clearly generate incompatibility and traindication for transplant, and it can be resolved by paired possible rejection are: RT or a desensitizing treatment (A). • To evaluate the transplant options for an ABO incompatible • Blood group incompatibility, due to the presence of antibod- pair it is essential to quantify the isoagglutinins (ABO anti- ies which are naturally present in any individual older than bodies) in the recipient, preferably using donor erythrocytes 4 months. (B). • Incompatibility in the Human Leukocyte Antigen (HLA) sys- tem, due to the presence of antibodies acquired by previous HLA should be typed using molecular biology methodolo- contact with HLA antigens. gies (B). More than one third of potential RT recipients have devel- • We recommend that HLA should be typed at allelic level (2 oped anti-HLA antibodies that may hinder compatibility 318 . fields) and in the 11 loci HLA, that is: HLA-A, B, C, DRB1, Incompatibility in both of these systems is independent. The DRB3/4/5, DQA1, DQB1, DPA1 and DPB1, in the recipient as gene involved in the definition of the ABO blood group is well as in the possible donors (B). located in the long arm of chromosome 9, and the genes which • High resolution HLA typing makes it possible to interpret encode the HLA antigens are located in the short arm of chro- whether the recipient has donor-specific antibodies (DSA), mosome 6. This explains the fact that two brothers may be detected using the new techniques for studying anti-HLA HLA identical and nevertheless also ABO incompatible. antibodies (NG). However, it is possible to transplant a non-compatible • The new solid phase techniques have higher sensitivity to organ but with different levels of HLA mismatches between detect anti-HLA antibodies in comparison with the classic the donor and recipient. The probability of rejection is asso- cellular techniques (A). ciated with the number of HLA loci mismatches between • The moment for studying histocompatibility should be the donor and the recipient, Greater match between them is decided on the basis of the characteristics of the recipient related to the increase in graft survival 319 . and the potential donors to prevent unnecessary examina- tions, guiding the expectations of the donor and recipient Compatibility barriers due to ABO blood group (NG). 360 different blood groups have been recognized on the sur- face of human erythrocytes 320 . Nevertheless, only one of the We recommend that a detailed clinical immunological his- blood group systems described has been shown to be signifi- tory of the recipient should be prepared, and this should be cant for RT: the ABO. shared with the histocompatibility laboratory, including their potentially sensitizing events and the relationship between Characteristics of the A, B, O antigens. The ABO group is one the recipient and potential donors (NG). of the simplest blood groups in terms of its structure, as a It is important to show whether the potential donor is the single monosaccharide at the end of a chain of three or four father of the descendants of a female recipient or whether monosaccharides determines whether it is specifically A, B the donor is the son of a female recipient, given the risk of or O. However, it is also the most important blood group sys- sensitization during pregnancies. tem, which was why it was the first group to be described by Changes should be shown in immunosuppression if the Landsteiner in 1901 321 . It consists of chains of 4 or 5 monosac- recipient still carries a dysfunctioning graft. charides on the surface of erythrocytes, usually conjugated We recommend that a crossmatch test should always be with polypeptides to form glycoproteins or with a type of lipid performed between the donor and recipient (A). (ceramides) to form glycosphingolipids. The majority of ABO A virtual crossmatch test will give us an initial approximate antigens are found in the glycoproteins of the erythrocyte cell idea of donor and recipient compatibility (NG). membrane. A cell-based crossmatch test should be performed before The oligosaccharides which determine the A, B or AB transplantation, with cytotoxicity techniques and flow cytom- specificity of the group are synthesized in stages. Over a etry between the donor and recipient (NG). basic chain of three monosaccharides (fucose, galactose and The histocompatibility laboratory or a trained professional N-acetyl galactosamine (NAcGlc)) known as antigen H, if a in this field should interpret the test data and advise the clin- certain glucosyltransferase is inherited then an additional ical team on the risk for the donor-recipient pair (NG). monosaccharide is added. Individuals who inherit the NAcGlc Human RT became a reality in the 1950s after performing glucosyltransferase add one NAcGlc to substance H. This 4 the procedures on identical monozygotic twins as donor and monosaccharide structure is known as blood group A. Not all recipient 316 . The required technical and surgical advances of the NAcGlc glucosyltransferases display the same efficiency had occurred decades earlier. This underlines the fact that in transforming substance H into antigen A. One form that is n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 59 expressed by approximately 80% of A individuals transforms It is easier to read and reproducible, and it even permits about 85% of substance H into A (of 1,000,000 antigens per ery- automatic reading and interpretation. To detect blood group throcyte). These are group A1 individuals. The remaining 20% antigens there are 6 or 8 column cards in the market, depend- of A individuals have a NAcGlc glucosyltransferase that only ing on the manufacturer, each one of which is able to detect a transforms 15% of substance H into antigen A (about 200,000 specific antigen (A, B, AB, RhD), while one of them is used as antigens) and they are known as group A2 322 . the control of the agglutination reaction. Automatic devices The individuals who inherit galactose transferase add a now exist in the market which dispense, incubate and cen- molecule of galactose and the structure is that of group B. trifuge, before reading and interpreting the results. Those individuals who inherit both glucosyltransferases are the AB group. In individuals who inherit glucosyltransferase ABO antibodies: isoagglutinins. The visibility, importance and genes that produce non-functional enzymes, substance H is relevance of the ABO blood group is due to the fact that all not modified and they are blood group O. The correct term is individuals have antibodies against the antigen that they lack, the letter “O” and not the number zero 323 . unlike the other 357 antigens in which antibodies are only generated when the individual has come into contact with Expression of the A, B, O antigens. As well as in the erythro- human erythrocytes (transfusion or pregnancy, and they are cytes, the ABO is expressed in many other tissues within the negative for the antigen in question). The reason why the anti- organism, and it is also found as a soluble glycoprotein in bod- bodies are present lies in the fact that ABO antigens are also ily secretions. Within the kidneys antigens are expressed in present in vegetables and many Gram negative aerobic bacte- the vascular endothelium (arteries, glomerular capillaries and ria 327 . After 2 or 4 months of life humans develop antibodies peritubular) and in the distal tubular epithelium. On the con- against antigen A or/and B, depending on their group. These trary, it is not found in the proximal tubule or in the mesangial antibodies are known as isoagglutinins because the erythro- cells 324 . cytes agglutinate when human plasma/serum is confronted The intensity of group ABO antigen expression in the ery- by incompatible erythrocytes. This was how they were dis- throcytes and tissues varies in parallel 324 . Thus individuals covered by Landsteiner. in group A1 have greater antigen expression (in the tissues Unlike other immune responses in humans, in which IgM and erythrocytes) than those in group A2. An additional fac- antibodies are generated after an initial exposure, followed tor affects ABO antigen intensity of expression, the secretor by IgG antibodies and the disappearance of the IgM ones, in gene. The secretor gene makes it possible for antigen H to also the case of the ABO the majority of individuals have a signifi- be found in bodily secretions, and it makes A and B antigen cant amount of IgM isoagglutinins in circulation during most expression more intense. To detect whether an individual is of their life. It has been suggested that their continued pres- a secretor or not it is necessary study if they carry the gene ence may be due to continuous exposure to ABO antigens in (FUT2) using molecular biology or by determining if the indi- Gran negative bacilli that are present in the intestinal flora. vidual is a carrier of the Lewis blood group (Le) b in their IgM antibodies are responsible for the agglutination of erythrocytes. Only individuals who have the secretor gene will incompatible erythrocytes due to their pentameric structure, be Le b positive. which permits the aggregation of several erythrocytes. They These differences in the intensity of ABO antigen expres- are also effective complement activators, able to bring about sion are of practical importance in the field of renal the lethal consequences observed in cases of transfusion of transplantation. In the case of A2 group and non-secretor ABO incompatible erythrocytes or when an ABO incompatible donors, due to the low presence of A antigens in their kidneys kidney is transplanted, with almost instantaneous graft loss grafts to O recipients have been undertaken, without previous 328 . conditioning 325 . Nevertheless, the majority of ABO isoagglutinins in circula- tion are IgG, Unlike IgM, IgG are monomeric and do not cause A, B, O antigen study techniques. The techniques currently direct agglutination. For this to occur it is necessary to add a used to differentiate blood groups in human erythrocytes are second antibody against human IgG, which is known as the based on haemagglutination reactions between erythrocyte indirect antiglobulin test (IAT). Not all IgG subclasses are able antigens and antibodies which are read and interpreted man- to activate the complement, only subclasses IgG3 and IgG1 ually or automatically. have significant activity 329 . The significant change in recent years is the support where these techniques are applied. At first, erythrocyte aggrega- tion reactions took place in a test tube, and they were read Anti-ABO antibody study techniques. Given that isoagglutinins and interpreted manually by agitating the centrifuged tube are able to agglutinate erythrocytes, the main technique used against an illuminated background. However, at the end of due to its ease and availability is haemagglutination. The first the 1980s the French scientist Yves Lapierre developed a new method used for detection was tube agglutination. To detect technique and commercialized it to detect erythrocyte agglu- the IgM the dilution of erythrocytes is added and the plasma to tination 326 . be tested is centrifuged and read. If it is wished to measure IgG Column agglutination technology (CAT) is based on plas- an additional stage is necessary: after adding the dilution of tic microcolumns that are full of acrylamide or glass gel erythrocytes, the plasma and a low ionic strength solution to microspheres which retain the erythrocyte agglutinates. In favour fixation of the IgG, it is incubated for 15 minutes. After comparison with the traditional technique in glass tubes, this centrifuging it is washed 3 times and the anti-human IgG is technique gives a reaction that is stable once it has occurred. added, it is centrifuged and read. Given that these techniques 60 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 are routinely used for transfusions, they have the advantage endothelium, B cells and dendritic cells. Their physiological that they are available in the majority of hospitals 24/7. function is to present extracellular antigens (e.g., bacteria) Column agglutination techniques have now replaced tube to CD4+ T helper lymphocytes. T helper lymphocytes may techniques, as is the case for blood group study. For IgM the also express HLA-II molecules in their membranes after solution of erythrocytes and the plasma to be tested is dis- being activated. pensed, centrifuged and read, while for IgG the same process is used but in a microcolumn which contains the human anti One of the main characteristics of the HLA system genes Ig-G, so that it only has to be incubated, centrifuged and read. is its complex polymorphism. As they differ between individ- The introduction of automation has also simplified the exe- uals, allogenic HLA molecules are recognized as foreign, and cution of the technique even further, and as the reading is the cells which express them are attacked in a similar way also automatic this reduces the variability of interpretation, to cells infected by a virus. The antigenicity of HLA system making it possible to store the reaction pattern for subsequent molecules is conditioned by the fact that each individual has revision, if necessary. several types of HLA antigens with multiple possible different In the field of ABO-incompatible renal transplanta- alleles, due to their expression in the cell membrane and their tion quantification is more important than the detec- peculiar function as a molecule which presents peptides to tion of isoagglutinins. Another technique commonly used lymphocytes. in immunohaematology to quantify them is dilution. The aim of the majority of the techniques used in the his- Successive dilutions are made of the plasma stream tocompatibility laboratory is to: (1,1/2,1/4,1/8,1/16,1/32/,1/64,/128, etc.) with a buffer solution, and they are confronted with erythrocytes. In general in • Evaluate the incompatibilities that the recipient will detect immunohaematology the inverse of the last dilution to give in the donor cells. This consists of typing the HLA system a positive reaction is reported as the titre (for example, in the recipient and the donor. titre 8 if the last positivity occurs in 1/8 dilution. How- • Identify the presence in a recipient of alloantibodies against ever, in our experience, given the frequent administration of polymorphisms in the possible donors. As well as detecting endovenous immunoglobulins in pre-transplantation desen- them, it is possible to characterise these antibodies at the sitization, treatments in the case of incompatible ABO which level of their target (HLA-I, HLA-II or non-HLA), the type of in the columns usually give a weak positivity that hinders immunoglobulin (IgG, IgG subclasses, IgM) or their capacity readings, we use the final dilution that gave a reaction pat- to fix complement. tern of +2 as the titre. (The intensity of positive reactions is • Identify whether the recipient alloantibodies will react graded in 4 levels, +1, +2, +3 and +4, depending on how the against the polymorphisms expressed in the proposed erythrocytes are distributed along the column). donor. This is analysed by applying the crossmatch test. Another important aspect for consideration in titration of the isoagglutinins is the question of the erythrocytes to be HLA typing studies. To evaluate HLA compatibility it is essen- used in the test. Given the direct correlation between expres- tial to typify the HLA of the recipient and all of the possible sion in tissues and in the erythrocytes of individuals, it is donors. The majority of laboratories undertake HLA typing recommended to always use the erythrocytes of the donor for studies using Molecular Biology techniques based on PCR the follow-up of titration pre- and post-transplantation in a (Polymerase Chain Reaction). Depending on the type of tech- recipient of an ABO incompatible kidney. nique used it is possible to achieve a low or antigen level of typing resolution (1 field, example A*02) or a high or allelic Compatibility barriers due to the HLA system level of resolution (2 fields or more, example A*02:01). There Characteristics of the HLA system. Transplantation success are multiple types of PCR for HLA typing: depends on avoiding the allogenic response of the recipient to the differences in the major histocompatibility antigens • PCR-SSO (Sequence Specific Oligonucleotide probes): the most expressed in the transplanted organ, i.e., the incompatibili- polymorphic exons in each HLA locus are amplified generi- ties in the HLA system. The immunological alloresponse will cally before hybridising the amplified product with specific be more intense when the difference between the donor and DNA probes for the polymorphic positions. The Luminex recipient HLA typing is greater. platform is used now, in which the probes are attached to HLA system antigens are molecules which are expressed microspheres in suspension. in the cell membrane, and they are classified in 2 types: • PCR-SSP (Sequence Specific Primers): this is based on the use of specific primers for a certain region of DNA present only • Class I HLA molecules formed of a single polypeptide chain in a specific allele or group of alleles. This enables the use (bound to Beta2-microglobulin) and codified by 3 gene loci of PCR that will only be positive for each one of the alleles (HLA-A, B, C). They express in the membrane of all cells and or group of alleles. their physiological function is to present intracellular anti- • PCR-SBT: this is direct nucleotide sequencing of the gene gens (peptides) (e.g., virus) to cytotoxic CD8+ T lymphocytes. to be analysed. Amplification takes place using specific • Class II HLA molecules are heterodimeric proteins anchored primers for the most polymorphic regions of the gene (exons to the cell surface by their two chains (␣ and ␤). There 2,3 and 4 in class I HLA and exon 2, and sometimes 3, in class are also 3 types of HLA-II molecules (DR, DP, DQ) which II HLA) before performing the sequencing reaction and elec- are codified in the gene loci DRA1, DRB1, DRB3/4/5, DPA1, trophoresis of these reactions in an automatic sequencer. DPB1, DQA1 and DQB1. They are expressed in monocytes, The complete nucleotide sequence of the amplified region n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 61 is compared with the sequences of all of the HLA alleles of it is possible to study their level of recipient/donor compatibil- the corresponding locus, to thereby determine which alleles ity. Several studies have shown that eplet-level compatibility are present in a certain individual. is clinically relevant 332 , as HLA mismatches in renal trans- • Real time PCR: specific primers and probes are used with no plants which are compatible at eplet level have been found to need for any post-PCR processing. A fluorescent substance have practically the same survival rate as those in recipients identifies the presence or absence of the amplified products. transplanted from zero-mismatched donors according to con- Analysing the positive and negative reaction patterns gives ventional criteria (at antigen level). Although recipient/donor the HLA typing. compatibility is not now routinely evaluated using eplets, it is • Second generation or Next Generation Sequencing (NGS): this possible that in the near future this will be a part of clinical consists of clonal, massive and parallel sequencing which practice. permits a large number of sequences of each nucleotide in each test. Although several platforms exist, they all use Anti-HLA antibodies: antibody determination techniques. Anti- technology that includes amplification of the DNA template HLA alloantibodies may be determined by using cells that (HLA genes), the preparation of libraries, cluster generation, express HLA molecules on their surface as the target, or sequencing and data analysis. This technique is highly pro- by using “artificial” systems which present HLA molecules ductive and permits complete gene sequencing, reducing attached to a solid phase support. the number of ambiguities in the assignation of the results. The main cellular technique that has been used to deter- mine alloantibodies is microlymphocytotoxicity or complement- Classically, in candidate patients for RT and their donors, dependent cytotoxicity (CDC): this technique is based on the HLA typing was performed in the A, B and DRB1 loci at antigen cytolytic effect of the complement on lymphocytes when level (1 field). The association between HLA incompatibilities a (serum) antigen-antibody reaction takes place on their and renal graft survival has been widely proven in deceased surface. This study is performed using a panel of cells from dif- donor RT. In the case of living donor transplantation the risk ferent donors 30–60 who are carriers of different HLA antigens. of graft failure has also been observed to increase by 44% It detects the presence in serum of complement-activating for each mismatch in adult recipients who received a first cytotoxic antibodies, chiefly IgG1, IgG3 and IgM. Variations of transplant from a related living donor, and it increases twice this technique exist, such as incubation of the cells and serum if mismatches are 6/6, taking transplanted patients with 0 with human anti-IgG. This variant, which is used the most incompatibilities as the benchmarks. These differences are often in the U.S.A., increases sensitivity and detects IgM, IgG1, even more marked if the organ is from an unrelated donor 319 . IgG3, IgG2 and IgG4 immunoglobulins. HLA typing at allele level is advisable (2 fields) and in the Specificity is assigned by mathematical correlation 11 HLA loci (HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1 between the presence of a certain antigen in the lymphocytes and DPB1), in the recipient as well as in potential donors and positive and negative reactions of the serum. The CDC (EFI European Federation for Immunogenetics. Standards for his- test thereby provides three types of information: tocompatibility testing. http://www.efiweb.eu/). Not all of the techniques listed above permit high resolution or allele level • Whether or not the recipient has alloantibodies. typing. This is why second generation or NGS technology is • The percentage of reactivity or PRA (Panel Reactive Anti- becoming predominant in the majority of HLA typing labora- body). This represents the percentage of the general tories, as it makes it possible to study all of the HLA genes in population (represented in the panel) with whom the high resolution relatively easily and highly productively. High patient is incompatible. This enables prediction of the prob- resolution HLA typing of the recipient/donor pair makes it pos- ability of a positive lymphocyte crossmatch test. sible to evaluate their compatibility more precisely, thereby • In some cases it identifies the antigens which the alloan- gaining better knowledge of the probability of long-term graft tibodies are reacting against. In recipients with multiple survival. alloantibodies, determining acceptable antigens using cyto- High resolution HLA typing also makes it possible to deter- toxicity techniques lacks precision because each cell mine whether the recipient has donor specific antibodies expresses several alleles. Donors with these antigens have (DSA) using the new anti-HLA antibody study techniques, if a very high probability of a positive crossmatch test using there are antibodies against certain alleles but not all of them cytotoxicity. in a single antigen group (such as A*02:01 positive, A*02:03 neg- ative). Typing all of the HLA genes also makes it possible to The use of serological techniques such as CDC to detect determine, if the recipient has anti HLA-C or HLA-DQ or DP anti-HLA alloantibodies is decreasing. They are being replaced antibodies, if they are DSAs or not 330 . by more sensitive solid phase methods which are able to iden- Another advantage of high resolution HLA typing is that tify specific antibodies more quickly and simply. it enables the evaluation of recipient/donor compatibility in The crossmatch test consists of confronting the cells of a terms of the epitopes that may be recognized by specific specific donor with recipient serum to detect the presence of antibodies, rather than being based on antigen/allele incom- preformed alloantibodies against the donor. In clinical prac- patibilities. These epitopes are determined by polymorphic tice this is performed using two techniques: amino acids on HLA molecule surfaces, and it is possible to determine HLA compatibility at this structural level. The poly- A) Crossmatch cytotoxicity lymphocyte test or “Crossmatch-CDC” morphic residues that can be recognized by antibodies have (CDCCM) between the recipient and donor: Based on the CDC been entitled “eplets” and, by using the HLAMatchmaker 331 , technique, the recipient serum(s) are incubated with donor 62 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 lymphocytes in the presence of complement. A positive The most widespread solid phase techniques based on reaction is visualized with the aid of a vital colouring agent, Luminex technology are: which penetrate through the cell membrane if it has been made permeable by the complement. It detects IgG1, IgG3 A) Screening Bead arrays: each microsphere contains natu- and IgM antibodies. The reaction is quantified according to ral class I or II HLA molecules from multiple individuals. the percentage of dead cells, so that the cellular viability of They make it possible to identify the existence or not (pos- the basal sample is essential. This crossmatch test may be itive/negative) of alloantibodies against class I or II HLA, performed using total lymphocytes or cell subpopulations. although they cannot determine their specificity. Some kits If the subpopulations of T and B lymphocytes are sepa- also detect the presence of anti-MICA antibodies. These rated it is possible to differentiate the anti HLA-I antibodies tests are more sensitive than antibody detection using from the anti-HLA-II antibodies. It is possible to treat using cytotoxicity (CDC) 334,335 . DTT (which destroys the IgM) to differentiate IgM lympho- B) Microspheres with isolated antigens, or Single Antigen toxic antibodies (generally autoantibodies) from IgG type Bead arrays: each microsphere is coated with a single class I ones. To discover the approximate “quantity” of anti-HLA or class II HLA allele obtained using genetic recombination, alloantibodies in the recipient it is possible to detect the so that they are recombinant antigens. This permits the cytotoxicity of the serum at different dilutions (from 1/1 direct identification of antibody specificity. This is highly to 1/512). This analysis is of interest if recipient desensi- useful, especially in hypersensitized patients, as it enables tization is intended. Crossmatch by cytotoxicity predicts a the identification of those antigens that may be consid- high risk of hyperacute rejection, so positivity contraindi- ered acceptable even though they are mismatches, i.e., the cates RT. It has a high positive predictive value (PPV) for alleles against which the recipient has no alloantibodies. graft loss (80%) 2 . Based on the positive specificities it is possible to estimate B) Flow cytometry crossmatch lymphocyte test between the recipient a calculated PRA or PRAc, which has the same significance and donor (FCCM): the binding of the recipient serum anti- as the classic PRA by CDC. bodies to the donor lymphocyte membrane is identified using a human anti-immunoglobulin (generally a Fab2- There is no single shared criterion among different lab- anti-IgG) marked with a fluorochrome that is detectable oratories defining the level of antibodies (MFI or Median by flow cytometry. To identify the lymphocyte subtypes Fluorescence Intensity) which is relevant and which are irrel- against which the serum reacts, monoclonal antibodies evant 336 . Moreover, the cut-off differs depending on the kit marked with other fluorochromes are used. Anti-CD3 is used. Each laboratory therefore has to set its own MFI cut-off usually used to identify the T lymphocytes, and anti- CD19 to define positivity/negativity. It is important to differentiate is used to identify the B lymphocytes. The (inactivated) T between a positive result according to kit manufacturer crite- cells only express HLA-I, while the B cells express HLA-I ria and positive within the clinical context of establishing an and HLA-II. Thus the anti-HLA-I antibodies will react with acceptable risk of suffering antibody-mediated rejection. the T and B cells, while the anti-HLA-II antibodies will only Comparing the positive alloantibody specificities and the recognise the B lymphocytes. This also makes it possi- HLA typing of a specific donor makes it possible to obtain ble to rule out IgM autoantibodies. Positivity is generally the result of what is known as the Virtual Crossmatch, which calculated based on the Change in the Mid Channel of predicts the result of the cell-based crossmatch. The Virtual Fluorescence = [Mid Channel of the problem serum]–[Mid Crossmatch has a high Negative Predictive Value in compar- Channel of the negative control]. The positivity cut-off has ison with the cytotoxicity crossmatch, although its Positive to be set in each laboratory. The usual cut-off values may be Predictive Value is lower (that is, it detects antibodies that different for T (CD3 + ) lymphocytes and for B (CD19 + ) lym- are undetectable by cytotoxicity) 325 . It has to be taken into phocytes. The cytometry crossmatch indicates an increase account that a positive solid phase virtual crossmatch indi- in the risk of losing the graft within one year which is low cates increased risk of antibody-mediated rejection (which for the first transplantation (10%), although it is higher for varies according to the study from 5% to 55%) 337,338 although second or consecutive transplants (30%) 333 . it does not necessarily contraindicate transplantation. Solid phase methods have the advantage that they do not Solid phase techniques are based on the union to a “solid detect antibodies against non-HLA antigens. Nevertheless, phase” of purified HLA antigens from multiple individual cells there is a theoretical possibility that in the process of obtaining and joined to a plastic surface. ELISA plates can be used (less and joining to the solid phase the HLA molecules may suf- often), or a set of polystyrene microspheres or “bead arrays” fer conformational changes which interfere with the union to (more commonly). These polystyrene microspheres coated some alloantibodies, or which give rise to non-specific reac- with HLA molecules have an internal fluorescent marker that tions. are be identified by cytometry (Luminex). The reaction is Variants of the standard technique which permit the deter- revealed with a secondary antibody, generally human anti-IgG, mination of complement-fixing anti-HLA antibodies have marked with fluorochrome, so that they detect IgG alloan- become more relevant over recent years. There are therefore tibodies if they are complement activators (IgG1, IgG3) or if commercial methods to determine whether antibodies fix C1q they do not activate it (often IgG2, IgG4). No IgM antibodies or C3d. Determination of the capacity of anti-HLA alloanti- are detected (unless an anti-IgM is used as a secondary anti- bodies to fix complement may be indicated in patients with body), and nor are those against non-HLA antigens (such as acute early antibody-mediated rejection, to determine which autoantibodies). treatment will be the most appropriate 339,340 . n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 63 Other variants of the technique enable the identification techniques) or calculated PRA (PRAc) (using solid phase tech- of IgM antibodies or the study of the different IgG subclasses niques - Luminex® ). The PRA will inform us about the possi- (IgG1, IgG2, IgG3 and IgG4). Although IgG3 and IgG1 are known bility of access to transplantation for a specific recipient, and it to be able to activate complement, while IgG2 and IgG4 do not, will be a necessary step in the study of a donor-recipient pair. the role of each one of these subclasses in the development of The immunological study of the recipient and their rejection has not yet been sufficiently elucidated to use these immunological follow-up are beyond the scope of this chap- determinations in clinical practice. ter. The most up-to-date recommendations for study of the recipients are those published in the latest KDIGO Guides on Planned study of the donor-recipient pair the assessment and management of RT recipients and those of the STAR project 263,341 . Recipient HLA sensitization evaluation It is fundamental within the study for LDRT to carry out a detailed immunological clinical history of the donor and the HLA typing and compatibility intended recipient in the initial assessment. We recommend The recipient and all potential donors should be typed using that this history should include: molecular biology techniques. Serological methods are not A) Potential sensitizing events in the recipient 329 recommended, as they do not offer sufficient resolution to The following HLA-sensitising events should be included assign potential antibodies which are directed against a spe- in the clinical history: cific allele. HLA allele typing (two digits) is currently recommended for - Pregnancies (including gestation to term and abortions) at least HLA-A, -B, -C, -DR and -DQ loci 137 . The most recent - Transfusions KDIGO guides recommend typing the loci that enable correct - Previous transplantations interpretation of the recipient’s HLA antibodies (for example, - Tissue implants (ventricular assistance devices, biological in recipients with antibodies against HLA-DP, it is recom- valves mended that this locus should be typed in the recipient and their potential donors) 329 . However, it is best to type 11 loci: Some consensus documents also recommend giving HLA-A, B, C; HLA-DRB1,3, 4, 5; DQB1, DQA1; DPB1 and DPA1 detailed information about inflammatory events which may (9). This information will be essential for the correct interpre- reactivate the pre-existing alloimmune memory, such as: tation of the level of D/R compatibility and HLA antibodies major surgery, severe infections or recent vaccination 263 . It analysis, preformed as well as de novo after transplantation. is also relevant to include information on treatments with The number of incompatibilities (mismatches) between biological agents which may generate false positives when donor and recipient may be relevant, especially if there is more cellular techniques are used (anti-CD20 antibodies, anti-IL6, than one potential donor, or in young recipients with a high etc.) probability of needing a new renal graft in their lifetime. It is B) The relationship between a recipient and the potential also a risk factor for the de novo development of donor spe- donors cific antibodies, and it therefore affects the development of It is useful to know the relationship between the recipient antibody-mediated rejection and graft survival 333 . and donor, to offer an initial approximation of the level of com- patibility, and it may also be an essential decision-making tool - HLA matching at antigen/allele level. - The level of HLA com- when there are several potential donors, or when recipients patibility between donor and recipient is expressed in the have a high level of HLA sensitization. number of HLA specificities for each donor locus that are The following data are of especial interest in clinical prac- absent in the recipient. Advances in HLA typing have led to tice: improvements in the analysis of D/R matching, which used to be determined in the HLA-A, -B and -DR loci at antigen Siblings: the possibility of an identical D/R HLA pair. This level, as HLA matching is now measured in 11 loci at allele is associated with longer graft survival. This is especially level. interesting for highly sensitized recipients (e.g., in case of - HLA compatibility at epitope level. - The introduction of re-transplantation). molecular typing techniques and knowledge of the three- Parents/children: they will share at least one haplotype. dimensional structure of a HLA molecule has enabled the A woman whose donor is the father of her children: there is a identification of antibody recognition patterns at the level possibility of HLA incompatibility due to recipient exposure of how amino acids are arranged within these molecules. to donor HLA antigens during pregnancies. This HLA compatibility is based on the fact that each HLA molecule is structurally unique, and that there cannot be This information should be shared with Histocompatibil- an immunological response to self-proteins 342,343 . Differ- ity laboratories to ensure correct interpretation of the results ent software systems have been developed based on these of the immunological study.c) Study of anti-HLA antibodies principles, to establish the compatibility between donor and (“PRA” report) recipient at epitope level. The first to be developed was HLA- Study of a RT recipient includes the determination of Matchmaker 16 , which is a software algorithm to calculate HLA antibodies. HLA antibody detection techniques allow the number of mismatched eplets between the donor and us to measure the level of recipient sensitization: a panel recipient. Other algorithms were subsequently developed, of cytotoxic antibodies or PRA CDC (using lymphotoxicity such as Pirche-II 31 or HLA-Emma 344 . 64 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 These programmes are not currently in routine use in His- A male recipient without sensitizing events. - In the first tocompatibility Laboratories to examine HLA mismatching at stage of the study we will be able to estimate that the VCM epitope level for live donor transplantation. with the donor is negative. We will therefore perform recipi- ent and donor HLA typing, as well as the cell-based CM at more Compatibility studies between a recipient and potential advanced stages. Only when there is more than one potential donors donor will we consider typing the recipient and the potential As well as discovering the level of HLA compatibility between donors in an initial phase, to discover the level of compati- donor and recipient, the immunological study of a pair bility between the recipient and potential donors, as this will for LDRT includes pre-transplantation crossmatch tests to be a relevant tool when deciding which donor to accept. In the confirm the absence or presence of specific anti-donor alloan- final stage of the study we will perform crossmatch tests using tibodies. CDC and flow cytometry, together with typing if this had not The virtual compatibility test [virtual crossmatch (VCM)] been carried out beforehand. is defined as immunological evaluation based on the alloan- Recipient with sensitizing events. - We initially propose tibody profile of the recipient compared with donor HLA performing a VCM test to evaluate compatibility and immuno- antigens. This virtual VCM is increasingly important and logical risk. For this purpose we will type the donor and accepted within transplantation programmes, and it allows recipient as well as the study of HLA antibodies in the recipi- us to take the first steps in an immunological approach to the ent’s sera. study of live donor transplantation. Nevertheless, given that If the VCM is positive with preformed antibodies against LDRT is planned, applying only the virtual compatibility test the donor’s HLA which have a very high MFI and the cell-based is not recommended 331 . crossmatch test is positive, direct transplantation without The recommendation for LDRT study is always to perform desensitizing treatment will be ruled out due to the high risk of a direct compatibility study with a cell-based crossmatch test, early antibody-mediated rejection. We would suggest a paired using CDC (CDCCM) techniques and/or flow cytometry (FCCM), transplantation, given the low possibility of achieving HLA before transplantation. The recommendation is to perform a desensitization. If the MFI of the DSA is low, we would consider final crossmatch test 14 days before the planned date of trans- HLA desensitization strategies and/or inclusion in a paired RT plantation 28 . scheme. There are no recommendations on which type of cross- If the VCM test is negative, we will be able to wait until a match test (CDCCM vs FCCM) should be used in the study for final phase before performing a cell-based CM test. a LDRT. The KDIGO guides recommend using a flow cytom- etry or cytotoxicity crossmatch test, without preferring one Estimation of immunological risk [Figure 10]. The results of or the other 263 . The British guides recommend using a flow the different techniques used will allow us to estimate the cytometry crossmatch test in recipients with preformed anti- immunological risk between the recipient and the intended bodies against class I HLA (using donor T lymphocytes) and/or donor. This is essential to accept a potential donor, to decide class II (with donor T and B lymphocytes), as well as perform- the immunosuppression strategy for the recipient and even to ing a CDC crossmatch test with T and B lymphocytes with estimate outcomes 263 . Figure 10 shows the level of immuno- untreated recipient serum and serum treated with DTT that logical risk according to virtual and cell-based compatibility will give us more information for appropriate classification of test results. the immunological risk 137 . Recipients with a positive CDC crossmatch test and/or Nor are there any studies that measure the number of cytometry together with a positive virtual crossmatch test are crossmatch tests that should be carried out in a pair. New at very high risk of developing hyperacute rejection (above compatibility studies should be performed if the recipient has all in patients with a positive CDC crossmatch test) 317 and experienced any sensitizing event or if there is discordancy acute early antibody-mediated rejection 345 . Direct RT is not between test results. Given that LDRT is a planned procedure, advisable in these cases, and the approach is to include the it seems reasonable to perform a cell-based crossmatch test donor/recipient pair in paired RT programmes. using cytotoxicity and flow cytometry techniques to ensure a If the virtual crossmatch test is positive but the CDC correct approach for the immunological risk, given that both and flow cytometry crossmatch tests are negative, then the tests supply complementary information 338 . immunological risk is high 346 and we should consider desen- Although it is infrequent (<20%) discordant results may sitization strategies to overcome the HLA incompatibility arise between both types of crossmatch tests. It is funda- barrier in patients with antibodies against the donor who have mental that these tests are correctly interpreted by HLA medium to low MFI levels 347 . Nevertheless, if the MFI of these laboratories and transplantation teams to determine the level antibodies is very high, with little probability of success in of immunological risk 337 (Table 10). desensitization to achieve relatively safe levels to perform a direct RT, then we can decide on paired el RT. Practical procedure for the study of a LDRT candidate pair Potential RT recipients who have negative virtual and cell- based crossmatch tests will be candidates for direct RT with Immunological study tests and schedule [Figure 9] a high level of immunological risk (in patients with a high When we start the immunological study of a donor/recipient level of sensitization and high PRAc) or a standard level pair, the first thing to do is to study the immunological history of risk (recipients with a low PRAc). We should take into of the recipient and their level of sensitization. Based on this account that there is a potential latent immunological mem- information, we can classify them as: ory response in recipients who have previously received a n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 65 Table 10 – Interpretation of possible discordant results between both types of crossmatch test by HLA Laboratories together with transplantation teams, as this is fundamental to determine immunological risk. Virtual crossmatch test Physical crossmatch test Interpretation - - Concordant + + Concordant - + Discordant: - Consider false positive*,a - Cutoff MFI high - Specific antibody or allele not tested in SAB - Non-HLA antibodies + - Discordant: - Low level of HLA Ab - Antibodies against denatured antigens - Viability of donor cells ∗ consider treating with pronase 340 a Recipients who have been treated with anti-CD20 drugs (usually used to desensitize due to ABO or HLA incompatibility) Figure 9 – Representation of the immunological study for living donor renal transplantation. transplant, when there are HLA mismatches between the anti-HLA antibodies, we suggest using this workflow for the donor and the recipient, or in female recipients who have pre- recipient together with the potential living donors to achieve viously been pregnant, when the donor is the father of their a RT from the living donor who is the best option in terms of children 341 . Careful monitoring or close vigilance after trans- quality. It is also an opportunity to evaluate the risk in detail, plantation in this type of recipients will allow us to anticipate making it possible to fully plan the transplantation and the the development of this potential response, which would lead corresponding treatment. to an antibody-mediated rejection. The immunological risk To summarise, it is essential to have a good characteri- will be very low in the case of HLA-identical siblings. zation of the immunological risk and the opportunities for the recipient, through a good immunological history. Indi- viduals with a high level of HLA sensitization would benefit Recommendations for the management of HLA from the possibility of donation by a HLA-identical sibling, incompatibility (Figure 11) even if they were ABO incompatible, because as we will see in the specific chapters, ABO desensitization treatment is more The new techniques used to detect anti-HLA antibodies effective than HLA desensitization. If they have no identi- are more sensitive, and it is increasingly common to find cal siblings, the possibility of having a higher level of HLA living donor and recipient pairs who are HLA incompati- compatibility (a lower level of incompatibility) would lie in ble, especially in individuals with a very high cPRA, which genetically related family members. If although no compatible makes it very difficult to find a compatible donor 348 . For living donor is found there is the wish to donate, the intensity such individuals, and also for any potential recipient with 66 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Figure 10 – Degrees of immunological risk in candidates pairs for living donor renal transplantation. Figure 11 – Working algorithm showing recipients and potential living donors to achieve renal transplantation with a living donor as the best option. of donor-specific anti-HLA antibodies in the recipient should in living donors is now the technique of choice in the majority be evaluated and the options of paired RT or HLA desensitiza- of transplantation hospitals 349 . Laparoscopy has given rise tion should be considered. It is sometimes possible to study to a revolution in LDRT, as it has made donation far more a potential living donor while the patient is included in the attractive due to its few complications, short hospitalization, deceased donor waiting list, to increase transplant options for shorter convalescence and better cosmetic results 32 . Inno- a sensitized patient. vations such as LESS (laparoendoscopic single side Surgery), surgery through natural orifices, retroperitoneoscopy and robotic surgery are currently carried out in several hospitals. Living donor nephrectomy Open surgery using a mini-incision is still practiced in some centres. Surgical innovation and increased experience in trans- The concept of minimally invasive living donor nephrectomy plantation hospitals have increased the number of organs has been developed over the last 20 years. Due to the increased available for transplantation. Donors with a complex vascular experience in laparoscopic surgery, laparoscopic nephrectomy n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 67 pedicle, lithiasis and non-standard risks are now considered Kidneys with multiple pedicles are now accepted in the valid. majority of hospitals, and they have been shown to give good This guide describes the recommendations for donor selec- functional results 354,355 . In cases where there are multiple tion and planning the nephrectomy, applied in different arteries it is preferable to obtain a single anastomotic opening special donor situations. It will also make recommendations by bench surgery on the graft whenever this is possible. for different surgical techniques and their possible complica- When the arteries have similar calibres they should be joined tions. laterolaterally in a “shotgun barrel”. When the arteries have different calibres, the smaller ones are anastomosed to the Donor selection and planning surgery larger one (terminolaterally) using discontinuous or continu- ous stitches in Prolene 7/0 (Figure 12A). If the anatomy makes • Left nephrectomy is usually preferred in live donors, this necessary, it is possible to do independent anastomoses. although right nephrectomy may also be performed, with In those cases where the renal artery has been sectioned after similar complications (Quality of evidence: NG). the bifurcation, so that we have short vessels, the hypogastric • Living donor nephrectomy when there are multiple vessels artery and its branches in the recipient may be used to obtain or anatomical alterations should take place in more experi- a viable vessel (Figure 12B). enced hospitals (NG). When there are upper polar vessels, these can be elimi- • We recommend that donors with widespread atheromato- nated when they are small (<2 mm) as they do not represent a sis or fibromuscular dysplasia of both renal arteries should significant loss of renal function. This is more controversial for be rejected (NG). the lower polar vessels, as these irrigate the urethra and ligat- ing them may cause urinary tract ischemia. To avoid this tract Once the viability of donation has been confirmed on the ischemia an anastomosis can be done between the urethra of basis of medical workout, the donor should be physically the donor and the recipient’s one. examined and the results of their angiotomography should In the case of multiple veins, one of them can be ligated be thoroughly reviewed. It is important to know the surgical if they are of different diameters. When the veins are simi- history of the donor, to prevent possible complications during lar we should anastomose them to each other, ensuring good the operation. Donor weight and more specifically their physi- venous drainage. As older donors are now accepted athero- cal examination will be important when selecting the surgical matosis at the level of the renal artery ostium is frequently technique. If the aim is to perform a transvaginal nephrec- observed. When this atheromatous plaque is large and bilat- tomy, a digital vaginal examination should be performed prior eral, the donor should be rejected (Figure 12C). If these plaques to the surgery to confirm good elasticity that will permit the are unilateral, the kidney can be collected while taking special safe harvesting of the organ. In the case of a LESS nephrec- precautions during the harvest. It is important to place clips tomy the donor should be thin and without a history of major with sufficient separation to border the plaque. abdominal surgery (because it may have created adherences). Fibromuscular dysplasia may affect the renal arteries. This The anatomical evaluation of donors should include consists of a heterogeneous group of changes in the arter- angiotomography with arterial, venous and nephrographic ies that are neither atherosclerotic nor inflammatory, and phases to identify any possible alterations in the urinary tract, they cause a certain degree of stenosis, occlusion or vascu- and/or the vessels. This exploration has a sensitivity/precision lar aneurisms which may restrict the renal flow. Donors will of over 95% in the detection of renal veins and arteries 350,351 . be rejected if they have bilateral involvement. They may be The radiologists will be in charge of supplying exact anatom- accepted if the dysplasia is unilateral, with replacement of the ical information, based on their own experience. affected area in bench surgery using a cadaveric tissue graft If both kidneys are similar, it is preferred to collect the left (Figure 12D). one as it has a longer vein, making it easier to engraft. The Renal artery aneurisms are rare, and they generally affect laparoscopic harvesting of a right kidney is not a contraindica- the arterial division. They are at risk of rupture when they are tion nowadays, and it accounts for 15%-20% of nephrectomies larger than 1.5 cm and not calcified. Nephrectomy in a donor in the majority of series. A higher rate of graft thrombosis in with an aneurismatic artery is therapeutic. The affected kid- right living donor nephrectomies was described in the past. ney may be repaired in bench surgery using a cadaveric tissue Several subsequent studies have shown similar results for graft or the internal iliac of the recipient (Figure 12E). organs from both sides (2D) 352 . To facilitate renal transplan- tation with short veins, a transposition of the iliac vein in the Lithiasis recipient may be performed, as this reduces the space between veins in the anastomosis 353 . • Accepting donors with a history or presence of lithiasis should be based on the risk of its recurring after donation Variants and vascular alterations (NG). During the study of a living donor we may find differ- • After donation they should follow the specific guidelines set ent situations that have to be evaluated separately, while for the general population to prevent recurrence (NG). also taking into account the characteristics of the recipi- • It is safe and reproducible to extract lithiasis in bench ent. One such situation consists of complex bilateral renal surgery (NG). pedicles (multiple arteries and veins, fibromuscular dyspla- sia of the intima, calcifications in the arterial ostium and even In 5% of donors angiotomography shows the presence aneurisms). of asymptomatic lithiasis 356 . These donors are currently 68 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Figure 12 – A: Shotgun barrel anastomosis and terminolateral anastomosis in a kidney from a living donor. B: Use of the hypogastric artery to obtain a single artery. C: Atheroma plaques in the ostium. D: Fibromuscular dysplasia of the unilateral intima. Bench surgery repair with a cadaveric graft. E: Repair of arterial aneurism by means of cadaveric arterial graft in bench surgery. F: Exeresis of a tumour in bench surgery. considered to be valid in certain circumstances. The clinical • We recommend that the donor and recipient should be sub- history of the donor must be taken into account, as well as jected to regular oncological check-ups (NG). whether they have suffered renal colic previously or have been treated for lithiasis. These donors are accepted on As donors are becoming older we find incidental small the basis of the risk of the lithiasis recurring 357 and their renal masses 359 . These tumours of less than 4 centimetres awareness of the post-donation consequences. Donors who in size are usually of low risk and with low metastatic poten- are younger than 40 years old have a high risk of recurrence, tial. The treatment of choice is partial nephrectomy, which as do those with a family history of renal lithiasis and those has been found to give the same oncological results as in the who have suffered frequent lithiasis episodes. If they have no general population 360 . Those kidneys (non-standard risk) are history of lithiasis and it is unilateral, with a correct metabolic considered to be valid for transplantation on condition that study, then these donors may be considered to be valid. They they are suitable for the recipient and that the patient and should be followed-up according to the lithiasis management donor accept the risk 150,361,362 . guides to prevent recurrence. The tumour will be resected in bench surgery and a pre- Once they have been accepted it is necessary to decide operative biopsy will be used to detect the margins and which kidney to harvest, with different options. If unilateral characteristics of the tumour. A histological analysis of the microlithiasis is detected, we will be able to harvest either tumour prior to transplantation should be done to obtain kidney without the need to treat the said lithiasis. There is information on the aggressivity (grade) of the tumour, and take minimum risk of future problems for the donor as well as the the final decision whether to transplant (if it is low grade) or recipient. If single small unilateral lithiasis (<1 cm) is detected, not (Figure 12F) 151,152,363 . the kidney will be collected after extracorporeal lithotrity, or removed using ureteroscopy in bench surgery 358 . Surgical technique Renal tumours • The kidneys of a donor with an incidental low grade • Laparoscopic nephrectomy of a living donor is the technique renal tumour smaller than 4 cm may be accepted after of choice as it causes less postoperative pain and results tumorectomy, informing the donor and recipient of the risk in a shorter hospitalization and convalescence than open (NG). surgery (NG). n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 69 • Living donor nephrectomy by lumbotomy may be indicated of blood. Additionally, laparoscopy led to less postoperative when the donor has had multiple abdominal interventions pain and shorter hospitalization and convalescence 371–374 . and intra-abdominal adherences (B). A variation on pure laparoscopic surgery is hand-assisted • Living donor nephrectomy using a mini-incision is a valid laparoscopic nephrectomy, which was developed to shorten option for donation (NG). the learning curve for pure laparoscopic surgery. It consists • LESS or transvaginal living donor nephrectomy should be of the insertion of the non-dominant hand of the surgeon performed in experienced hospitals (NG). during the whole operation, to facilitate the surgical manoeu- • Robot-assisted living donor nephrectomy gives similar vres and increase safety. Randomized trials which compared results to laparoscopic techniques, although it is more pure laparoscopy with this hand-assisted variant in living expensive (NG). donor nephrectomy found no significant differences between them in terms of complications, conversion rate or length of The experience of the surgeon should be taken into account hospitalization, with less warm ischemia in the case of hand- when selecting a surgical technique, to minimise compli- assisted surgery 375,376 . cations and obtain a good quality organ. Traditionally the surgical technique of choice for living donor nephrectomy was Living donor nephrectomy by retro-peritoneoscopy open surgery through a lumbotomy, which was associated This technique was developed to avoid invading the peri- with a high rate of morbidity and a high risk of eventration. toneum and reduce possible complications at this level. The Increased experience in laparoscopic surgery means that this retroperitoneal approach involves performing surgery in a technique is now used in the majority of hospitals with good small space with an anatomical vision different from the one results for donors and recipients, minimising complications we are used to, which would be the transperitoneal view, 364,365 . Due to this, laparoscopic nephrectomy of the donor is increasing the difficulty of this approach. The possible dis- now the technique of choice 366 . advantages associated with this technique are the risk of All of the minimally invasive techniques require that the causing pneumomediastinum, pneumothorax, pneumoperi- donor be in lateral decubitus, with 3 or more trocars in place cardium or air embolism 377 . through the abdominal cavity. The path for renal harvest- One benefit of this technique is that it avoids contact ing will vary depending on the technique used, and it may with the intestine, and it may be positive for donors with be a periumbilical incision, a pfannestiel, in the iliac fossa or previous surgical operations. A meta-analysis undertaken to transvaginal. compare living donor nephrectomy using laparoscopy and Live donor nephrectomy by lumbotomy is not considered hand-assisted retroperitoneal technique, no differences were a technique of choice, as it requires a larger incision and found in terms of blood loss, hospitalization or graft survival. therefore involves more postoperative pain and longer hos- On the other hand, the retroperitoneal technique took less pitalization. Living donor nephrectomy through a lumbotomy time and caused less warm ischemia 377 . Retroperitoneoscopy may be considered in certain circumstances, when the donor has recently been suggested as the treatment of choice in has had multiple abdominal interventions and has intra- cases of right renal donors 378 . abdominal adherences. Different techniques have been developed as alternatives, using an anterior mini-incision, in the side, subcostal or pos- Robot-assisted living donor nephrectomy terior, giving simple access to the kidney 367 . Randomized It is possible to perform robot-assisted living donor nephrec- studies which compared surgery using a mini-incision with tomy. Robotic surgery permits more subtle movements, with classical open surgery and laparoscopic surgery found that greater mobility than conventional laparoscopy, although it surgery takes longer with the mini-incision than it does with is more expensive. A meta-analysis which compared robotic classical lumbotomy, although it causes less morbidity in the surgery with laparoscopy found shorter operations, less warm donor (with less need for analgesics and a faster recovery). In ischemia and less bleeding with conventional laparoscopy. comparison with laparoscopic surgery, donors require more Nevertheless, there was less postoperative pain with robotic analgesia and recovery time is longer. No significant differ- surgery. No differences were found between both techniques ences were found in terms of the functional results of the graft in terms of the duration of hospitalization or creatinine levels 379 . between any of the three techniques 368,369 . The micro-incision technique makes it possible to perform a nephrectomy with low morbidity and good functional results, so that it is a good Living donor nephrectomy through a single incision (LESS) alternative in certain circumstances when laparoscopy is still Surgery using the LESS technique involves making a small not viable 370 . incision to insert several laparoscopic instruments to perform intraabdominal surgery, giving the same surgical results as Laparoscopic living donor nephrectomy conventional laparoscopy but with less morbidity and better Laparoscopic living donor nephrectomy is the technique of cosmetic results 380–386 . This is an attractive alternative, as choice due to its advantages in comparison with open surgery. surgery takes place through a single incision through which Several systematic reviews which compare the open tech- the organ is collected. nique with laparoscopy conclude that the results in terms of Two randomized clinical trials 387,388 and cohort stud- donor safety and graft functioning are similar. It should be ies 389–391 , compared LESS with conventional laparoscopy, underlined that these works found open nephrectomy to have without finding differences in terms of complications or con- a shorter surgical procedure time, it also involved greater loss version to open surgery. Although the LESS technique was 70 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 associated with less bleeding, it was also linked to longer sur- • We do not recommend routinely administering throm- gical time. boembolic prophylaxis to all recipients using low molecular weight heparin (C). Assisted living donor transvaginal laparoscopic nephrectomy • We recommend that single dose antibiotic prophylaxis The assisted transvaginal approach permits assisted laparo- should be administered (A). scopic living donor nephrectomy through a transvaginal • We recommend that the lymph glands should be ligated or opening through which the kidney is collected. This tech- coagulated to prevent the appearance of lymphocele. (A). nique gives better cosmetic results and reduces morbidity, as • We recommend that the kidney should be kept cold during it reduces abdominal scarring 392 . There are no studies that surgery, wrapping it in a gauze containing crushed ice, or compare this technique to conventional laparoscopy. placing it in two gauzes with ice above and below the kidney (B). Clipping systems • We recommend that the shortest possible length of ure- A controversial aspect of living donor laparoscopic nephrec- thra should be used for anastomosis in the bladder, while tomy is the type of clipping system used on the renal artery. keeping the periurethral fat to ensure good irrigation (B). There are two types of clip: staples and clips 393 . Metal staples • We recommend that a Lich Gregoire-type extravesical re- were used at first, and these were not free of mechanical prob- engraftation should be used in a double J (A). lems (stapler malfunction), causing a shortening of the graft • We recommend that a prophylactic mesh should be used artery due to its width, and they are expensive. To overcome in obese and diabetic patients, and/or patients treated with these difficulties Hemo-o-lok-type clips came into use more mTOR inhibitors (A). than two decades ago. These are simpler to apply and make it possible to obtain an artery that is a few millimetres longer, as Surgical technique there is no need to clip the proximal part. In spite of this, some Recipient surgery commences when the surgeon receives the cases of haemorrhage have been described which caused the kidney recently collected from the donor. The renal artery is death of the donor, due to slippage of the Hem-o-loks 394 , and located on a table prepared for bench surgery and perfusion is neither the FDA nor the manufacturer recommend them 395 . started 399 . This perfusion continues until clear fluid emerges They are now generally used in radical nephrectomy and also from the renal vein and approximately 500 cc-1000 cc has in living donor nephrectomy, and they are completely safe to passed through. Bench surgery then commences, in which the use when they are properly located, with a two-millimetre following steps should be followed in order: separation between both Hem-o-loks at a distance of a few Freeing the perirenal fat to check that the correct perfu- millimetres from the section in the artery. sion of the graft, verifying the absence of traumatic or tumoral macroscopic lesions. Dissection of the artery and vein until an appropriate Recipient surgery in living donor KT length for anastomosis is achieved. The artery will have no aorta patch so that its ostium will be smaller. In the case LDKT surgery is technically highly complex, and it includes the of double or triple arteries the surgeon will have to decide creation of vascular and urinary tract anastomoses. It is under- whether to create an anastomosis between them and how: taken by dedicated KT surgical teams. In Spain, KT is an area terminolateral, laterolateral or separately. of recognized expertise within the scheme of the Urology spe- Vascular surgery techniques may be used in special cases, ciality. Although in the majority of hospitals which perform using the saphena or a segment of internal iliac of the patient LDRT it is carried out using open surgery (the “gold standard”), 400,401 . The right renal vein is usually short, although it is suf- laparoscopy has also been explored experimentally 396 , and ficiently long for anastomosis. If the renal vein is too short, there are now groups which have published their experience there are reconstruction techniques using the saphena vein using robotic kidney transplant (RKT) 397 . In spite of this, EAU and gonadal vein to achieve an optimum length 402,403 . Trans- (European Association of Urology) Guidelines do not routinely position of the artery and iliac vein is a manoeuvre that may recommend these techniques due to lack of evidence in this be useful to facilitate venous anastomosis 353 . field 398 . The recipient is catheterized in a sterile field, and previ- In this section we will describe the open or robotic sur- ously will have received thromboembolic prophylaxis with low gical technique used in the recipient, before analyzing the molecular weight heparin if they are a patient at risk, and a results and complications. Finally, we will analyze procedures single dose of antibiotic prophylaxis according to the specific in special situations, such as transplantation into complex protocol of each hospital 404 . recipients: 3rd - 4th transplantations, patients with arterioscle- A perirectal incision in the right iliac fossa is generally used. rosis and RT in patients with urinary tract disorders. The peritoneum is dissected and separated from the retroperi- toneal structures medially and cranially until the iliac vessels Conventional open surgery are identified, before creating the appropriate space to make the transplantation. • If a right kidney is used with a very short vein, we rec- The iliac vessels are then dissected and freed in the zone ommend that bench surgery should be used to create an where the anastomoses will be performed. A point must be optimum length renal vein by reconstruction and length- chosen where the vessels are not bent. The anastomosis ening techniques with saphena and gonadal vein (Quality should be made away from zones with vascular calcifications of evidence: B). and atheroma plaques so that the anastomosis is not made n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 71 on them, preventing possible arterial dissection. We recom- • We recommend that lymphoceles should be treated by mend ligating or coagulating the lymph glands during these inserting a percutaneous drainage. If the lymphocele is manoeuvres to prevent the postoperative appearance of lym- large and symptomatic then laparoscopic marsupialization phoceles. After placing a clamp on the vein of the recipient would be indicated (B). to isolate it from circulation the venotomy is performed, the • We recommend that initial low volume urine leakage recipient vein is irrigated with heparin and a venous termino- should be treated conservatively, with a urethral catheter lateral anastomosis is made using continuous monofilament and nephrostomy, or a double J catheter (B). 5/0 or 6/0 suture. A clamp is placed on the artery and the arte- • We recommend that if conservative treatment of the urine riotomy is performed. The recipient and donor intima should leak fails or the leak is massive and very early, then surgical be examined before starting the anastomosis to ensure that treatment should be selected: re-implantation or urethral there is no break. The terminolateral arterial anastomosis is anastomosis to the native urethra (B). then made using continuous 6/0 or 7/0 monofilament or single stitches. When engrafting a LD kidney the arterial anastomo- We recommend that in case of urethral stenosis >3 cm sis is the most delicate moment of surgery, as the artery has or the failure of minimally invasive treatment then re- no patch and it may sometimes be very narrow calibre. implantation surgery or urethral-urethrethrotomy should be The whole operation takes place while keeping the kidney used (B). chilled in ice. It may be wrapped in one gauze that contains In spite of the good results which are now achieved 406,407 , ice, or by placing it in two gauzes with ice above and below LDRT is not free of surgical complications. The most frequent it. complications are (Table 11): Renal perfusion commences once both anastomoses have Haemorrhage (0.2%-25%): this usually takes the form of been completed. In LDRT the kidney usually immediately an asymptomatic haematoma which does not require any takes on a pink colour. If this does not occur then the vein action. Larger haematomas which may compromise vessels, and artery are inspected by touch, and the anaesthesiolo- with haemodynamic instability and when computed tomog- gist is asked to check that the arterial pressure parameters raphy (TC) shows active bleeding will require revision surgery 398,408 . are correct. Likewise, if there is any doubt an intraopera- tive Doppler ultrasound scan can be performed. The urethral Arterial thrombosis (0.5%-3.5%): this is usually the result re-implantation is then performed. The shortest possible of a technical error in making the anastomosis, although length of urethra should be used, keeping the periurethral atherosclerosis, rupture of the intima, acute rejection, com- fat to ensure good vascular irrigation in the urethra and pression caused by haematomas or lymphoceles, hypercoag- thereby reduce the probability of postoperative urethral steno- ulability states, severe hypotension and immunosuppression sis and urinary fistulas. An extravesical Lich Gregoire-type may also participate. This manifests in anuria and worsening re-implantation is usually performed, leaving a catheter in of renal function. It is diagnosed by Doppler ultrasound scan. double J 405 . Immediate surgical exploration is usually recommended, At the end of surgery a drainage is put into place and the although there is little probability of finding a viable graft. wound is closed. Given that it is possible that an incisional If this occurs then the arterial anastomosis is disassembled hernia will appear after the operation or during follow-up, to extract the coagulate before perfusing the kidney and re- it is recommended that a prophylactic mesh should be put anastomosing it 398,409 . into place in the cases with the highest risk: patients who Venous thrombosis (0.5%-4%): this is one of the most are obese, diabetic or in treatment with an mTOR inhibitor important causes of graft loss during the first month. It may (imTOR). be caused by technical errors, difficulties during surgery, or The drainage will be removed on the 2nd -3rd day depend- a state of hypercoagulability in the recipient. Doppler ultra- ing on the volume drained, and the bladder catheter will be sound scan will show the absence of venous flow, with an withdrawn in 5-7 days. abnormal arterial signal. Surgical exploration is recommend- able even though the graft is lost in the majority of occasions. If the graft is viable venotomy may be performed with thrombec- Surgical complications tomy after clamping the iliac vein. Alternatively, the graft may be taken out to extract the coagulation, after which it is per- • Immediate surgical exploration is recommended in case of fused and re-engrafted 398,410 . an arterial thrombosis, and that depending on macroscopic Arterial stenosis (1%-25%): This is usually late-occurring. appearance, consider disassembling the arterial anastomo- Risk factors are donor arterial atherosclerosis, donor artery sis, extracting the coagulation, perfusing the kidney and trauma during harvesting, the absence of an aorta patch, performing a re-anastomosis (B). suture technique (with single stitches or continuous suture) • Surgical exploration is recommended immediately in case and iliac artery lesion during transplantation. Arterial steno- of the diagnosis of a venous thrombosis. If the graft is viable sis may also be suspected in case of hypertension refractory a venotomy may be performed with thrombectomy (B). to medical treatment, or an increase in creatinine. It is diag- • We recommend that significant stenosis of the renal artery nosed by Doppler ultrasound scan and in case of doubt with should be treated with angioplasty and the insertion of a angiotomography or magnetic resonance imaging technique. vascular stent. In the case of a very recent transplant, a Stenosis above 50% is usually associated with worsening renal long stenosis or failed angioplasty, surgical treatment can function. If there is stenosis <50% without clinical or analyti- be used (B). cal repercussion close monitoring is another option. If there is 72 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 11 – The main postoperative complications in renal transplantation. Complication (%) Symptoms Diagnostic technique Treatment 398,408 Haemorrhage (0.2-25) Haematoma CT Revision surgery if active bleeding. Arterial thrombosis (0.5-3.5)398,409 Raised creatinine Doppler ultrasound scan Immediate surgery. Anuria Venous thrombosis (0.5-4)398,410 Pain Doppler ultrasound scan Immediate surgery. Raised creatinine Anuria Arterial stenosis (1-25)398,411 Raised creatinine Doppler ultrasound scan <50% asymptomatic: observation Refractory AHT CT-Angiography >50%: stent, surgery Lymphocele (1-26)398,412 Pain Ultrasound scan Percutaneous drainage Raised creatinine CT Marsupialization Fever, infection Urinary leakage (0-9.3)398,413 Increase drainage volume Increased creatinine in Low volume: Nephrostomy, double J drainage liquid High volume: Surgery CT Pyelography Urethral stenosis (0.6-10.5)398,414,415 Dilated urinary tract Nephrostomy <3 cm. Percutaneous dilation Raised creatinine Anterograde Pyelography >3 cm. Surgery Haematuria (1-34)398 Haematuria Clinical Vesical washing Endoscopic examination Wound infection (4)398 Pain, exudate, infection Clinical Topical dressings Antibiotics Eventration (4)398 Opening of wound Clinical Repair with mesh Breakage of aponeurosis significant stenosis >50% the first line treatment will be angio- treatment then surgery will be indicated: re-implantation, plasty with the insertion of a vascular stent. In the case of very pyelovesicostomy, re-implantation with a psoic bladder or recent transplantation, very long stenosis or failed angioplasty Boari Flap or urethral-ureterostomy 398,414,415 . then surgical treatment may be used 398,411 . Haematuria (1%-34%): this is usually caused by bleeding of Lymphocele (1%-26%): simply puncturing and emptying the vessel that accompanies the urethra. Careful haemostasis this relapses in 95% of cases and adds the risk of infection. during re-implantation prevents this complication. Continu- Placing a percutaneous drainage may resolve the problem in ous vesical washing usually resolves this problem. In the case 50% of cases. If the lymphocele is large and symptomatic then of major bleeding the patient will be taken to the operating laparoscopic marsupialization will be indicated 398,412 . theatre to remove coagulations and coagulate the bleeding Urinary leakage (0%-9.3%): urinary leakage may be urethral vessels 398 . or vesical. Failure of the re-implantation suture or urethral Surgical wound infection (4%): the most frequent predic- necrosis are the most common causes. Advanced recipient tive factors for this are: obesity, age > 60 years, anaemia, age, acute rejection and vesical anomalies have also been hypoalbuminemia and prolonged surgery. Topical daily dress- associated with this complication. The suspicion arises when ings and antibiotics if there is associated cellulitis resolve the the drainage volume increases and the liquid has increased infection 398 . creatinine. If the leakage is initial and low in volume it may Eventration (4%): this occurs more often in patients who are be treated conservatively (with urethral catheterization or obese, diabetic or have a history of haematoma, graft rejection, nephrostomy and double J catheter). If conservative treatment repeated surgery and use of imTOR. Repair of the hernia with fails or leakage is massive and very initial, surgical treatment the placement of a mesh will be the usual treatment 398 . is advisable, with re-implantation or urethral anastomosis to the native urethra 398,413 . Robotic KT Urethral stenosis (0.6%-10.5%): early cases of stenosis (in the first 3 months after surgery) are considered to be due to • Robotic KT gives good results over the medium term and in defects in techniques or ischemic problems. If stenosis occurs the near future may be an alternative to open surgery (NG). late (>6 months after surgery) then infections, fibrosis, vas- • RKT is restricted to selected recipients as it has a higher rate cular disease or rejection may participate. Diagnosis will be of retarded graft functioning and arterial thrombosis, and it based on the presence of urinary tract dilation and renal func- cannot be used in patients with advanced atherosclerosis tion alteration. The first step will be to place a nephrostomy (NG). catheter and perform an antegrade pyelography. Stenosis <3 cm may be treated using percutaneous dilation or incision. In 2015 two hospitals carried out the first completely This conservative treatment resolves the problem in 50% of robotic transplants in Europe, and since then many experi- cases, with the best results in stenosis of less than 1 cm. In ences in specialized hospitals and multicentre series have the case of stenosis >3 cm or failure of minimally invasive been published 416,417 . Robotic KT is an alternative to open n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 73 surgery, and it is feasible, reproducible, safe and has surgi- A relevant percentage of recipients will require a second cal advantages when performing vascular anastomoses and KT. This KT takes place in the free iliac fossa, usually the one urethral re-implantation. This is partly due to the increase in on the left side, and technically it is no more difficult. Re- vision and great freedom of movements offered by the robot. transplanted patients are known to evolve better than those It has also been suggested that this technique may reduce who return to dialysis, in a similar way to patients trans- complications, the length of hospitalization and postoperative planted for the first time. pain, while giving better cosmetic results than open surgery Few series show the results of 3rd and 4th transplantations. 418,419 . The 3rd or 4th transplantation involves a re-transplantation RKT involves complex surgery with multiple steps, and it in an occupied renal fossa that had been operated previ- requires the complete domination of robotic surgery. Surgi- ously, implying increased technical difficulty: longer surgical cal time should not be excessively prolonged, and proper fluid time, an increase in bleeding and a second warm ischemia, management is essential, with appropriate intra-abdominal increasing the risk of an arterial or venous lesion due to pressures. This makes it possible to prevent the potential post-surgical adherences and a higher risk of repeat surgery. reduction in renal flow and pneumoperitoneum, as well as Depending on the location and size of the malfunctioning prolonged surgery 420–422 . Some groups have described good graft the transplantation may take place into more distal iliac results during the first year of development 423–426 . vessels or in the common iliac and iliac-cava sector. For a 3rd or 4th transplantation it is usually necessary to perform a transplantectomy that may be carried out before or during Surgical technique engraftation (in the majority of cases). Some authors perform The patient is placed in Trendelenburg 20◦ -30◦ position and the 3rd or 4th intraperitoneal transplantation in the medial line sterile catheterization is performed. Five ports are introduced, using more proximal vessels, and they thereby more away one of them for the camera, and the arms of the robot from the occupied renal fossa 427 . Likewise, if both iliac fos- are connected. Transperitoneal surgery then commences by sae are occupied, then an orthopaedic transplant may be preparing the iliac vessels and the bladder for subsequent re- indicated 428 . The 3rd or 4th transplants are a valid option implantation. A peritoneal flap is created in this first phase with acceptable results, although they are usually a surgical to retroperitonealize the kidney at the end of the proce- and medical challenge due to the high rate of complications dure. Covered in a gauze with ice the kidney is inserted 429,430 . into the patient through a periumbilical 6 cm incision that will be covered by a device (Gelpoint). The Gelpoint makes Recipients with severe arteriosclerosis it possible to insert ice around the kidney during surgery, • We suggest that an aortofemoral prosthesis should be con- and also to insert the trocar of the camera through it. After sidered in recipients with very severe arteriosclerosis 6 - 12 clamping the iliac vein with bulldogs, a venotomy is made months before transplantation, or an orthotopic transplant together with a terminolateral continuous venous anasto- (C). mosis with Goretex-6/0. The manoeuvre is repeated with the artery, making a continuous terminolateral anastomosis with Severe arteriosclerosis and peripheral vascular pathology 6/0 Gore-Tex. The extravesical re-implantation is made fol- are risk factors associated with graft loss, and they also hin- lowing the Lich-Gregoire technique, and finally the kidney der surgery. It is also known that patients with chronic renal is retroperitonealized and fixed, thereby reducing the risk of failure have thicker sclerotic plaques than the general popu- pedicle torsion. lations, as well as thicker intima and media, especially after Finally, a hypogastric drainage is put into place and the long periods of dialysis. periumbilical wound is closed. The drainage will be removed The detection of patients with vascular problems com- on the 2nd or 3rd day, depending on volume, and the vesical mences when they are outpatients. Patients with intermittent catheter will be removed after 5-7 days. claudication and without pedal pulses should be evaluated by the vascular surgeon. Pre-transplantation CT-angiography will Complications with RKT be of key importance when evaluating potential surgical dif- In spite of its good results, drawbacks have also been found ficulties 431 . In patients with calcifications the surgeon seeks with this technique, such as the impossibility of using it in a segment of artery that is free of them and makes the trans- patients with severe atherosclerosis, its higher-than-expected plantation. If any difficulty in placing the proximal and distal rate of retarded graft functioning and the development of arte- clamps for the anastomosis is foreseen, it will be possible to rial thromboses, even in selected patients. Early complications use an arterial angioplasty balloon introduced percutaneously do not seem to be any greater than those with conventional to occlude the circulation proximal and distal to the zone engraftation techniques 397 . selected for anastomosis. In spite of proceeding with precaution, sometimes when Re-transplanted recipients making the arteriotomy a certain degree of displacement of the intima may be noticed. In these cases it is necessary to • We recommend that the free iliac fossa should be used for affix it with a stitch to prevent arterial dissection during reper- second transplantations, usually the one on the left side (B). fusion. In very severe cases it may be necessary to make an • We recommend that transplantectomy should be per- endarterectomy, fixing the distal intima to the wall 431 . formed for a 3rd or 4th transplantation, either before or Sometimes the common iliac and external vessels are com- simultaneously with the engraftation (B). pletely occupied by calcifications. There are two options in 74 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 these cases: to use an aortofemoral prosthesis, or to make the derivation should be taken into account when making the an orthotopic transplantation. A vascular prosthesis is usually engraft 398 . put into place from 6 to 12 months before the transplantation, and the arterial anastomosis will be made over this prosthesis. Although it is possible to make the aortofemoral by-pass and Immunosuppression in LDKT the transplantation during the same procedure, this involves long surgery and risk 431 . It may be indicated in LD trans- The majority of studies in the field of KT immunosuppression plantations when the vascular and urology teams know each have included deceased and living donors without differen- other and have prepared for the surgery. Orthotopic transplan- tiating between the results, and very little specific research tation is another option in the case of diffuse calcifications has been undertaken on LDRT recipients. There is insufficient 428 . evidence to indicate whether the origin of the graft in terms of donor type modifies the risk of acute rejection or loss due to immunological reasons 433 . Based on current knowledge Recipients with problems in the bladder and urinary tracts immunosuppressant therapy during induction and mainte- • We recommend that patients with the suspicion of nance should therefore be based on similar criteria in living functional vesical problems should be subjected to a pre- and deceased donor KT. transplantation urodynamic study (B). Selection of immunosuppressant therapy during induc- • In the case of bladders with high pressure where vesical tion as well as maintenance will chiefly depend on the risk augmentation is indicated, it is recommended that this pro- that the recipient will develop acute rejection (immunological cedure should be carried out prior to transplantation (B). risk). The KDIGO guides consider patients with one or more of the following characteristics to be at high risk of suffering The main urological alterations which cause renal failure acute rejection 434 : one or more HLA antigen incompatibil- are vesicoureteral reflux, urethral valves, a neurogenic bladder ity, young or old recipients, Afro-American ethnicity (in the 10%-37% and Prune Belly syndrome. The majority are there- U.S.A.), more than 0% PRA, presence of DSA, ABO incompat- fore anomalies which appear at paediatric age, and patients ibility, retarded graft functioning or more than 24 hours cold will usually be transplanted before adult age 432 . ischemia. Patients who do not have any of these factors are On the other hand, up to 20% of adult patients who are considered to be at low immunological risk. candidates for RT will have urinary tract anomalies. The following patients will be at risk of having urinary tract Immunosuppression induction therapy in LDRT anomalies: those with a neurogenic bladder, myelomeningo- cele, spina bifida, spinal trauma, multiple sclerosis, central Induction therapy in patients at low immunological risk nervous system degenerative diseases, cerebral vascular acci- • We suggest that induction and maintenance immunosup- dent, dysfunctional bladder, bladder with fibrosis (due to pressant therapy should be selected on the basis of similar radiotherapy, tuberculosis, vesical tumour), urethral steno- criteria for LDKT and deceased donors, as there is no evi- sis, urinary derivations and infravesical obstruction 432 . The dence that the origin of the graft modifies the risk of acute pre-transplantation study of these patients should include rejection or loss of the graft (Quality of evidence: C). a good interrogation, physical examination and evaluation • We recommend that induction therapy should be combined studying vesical capacity, accommodation and emptying. with conventional immunosuppressant drugs, as the for- The following studies will be indicated for this evaluation: mer is only superior to therapy with conventional drugs in 1) retrograde and urinary urethrogram, offering informa- reducing renal graft rejection and graft failure (A). tion that is basically about the anatomy of the urethra, • We recommend that basiliximab should be used for induc- vesical capacity and the presence of reflux, and 2) a tion in LDRT recipients at low immunological risk, due to its urodynamic study to give information about the filling better efficacy and safety profile (B). phase (vesical capacity and accommodation), the empty- • We suggest that induction therapy with lymphocyte- ing phase (detrusor contraction and infravesical obstruction) depleting agents or interleukin-receptor antagonists should 432 . not be used in HLA-identical LDRT recipients (C). Depending on the result of these examinations a post- • We suggest that at least one dose of intraoperative steroids transplantation strategy can be prepared, which may run from should be administered, even in LDRT between twins with- observation to self-catheterization or surgery to remove an out induction therapy (D). obstruction. In the case of high-pressure bladders that require vesical augmentation, this will preferentially be carried out Given that the risk of graft loss is especially high in the prior to transplantation 432 . first months after transplantation [3] induction therapies using In RT with an augmented bladder re-implantation will be biological agents have been developed. There is insufficient attempted in the vesical part, making a submucosal tunnel or evidence to suggest that using biological agents as induction a Lich Gregoire-type re-implantation. In continent reservoirs therapy is superior to using standard triple immunosup- using colon a submucosal tunnel will be made. In patients with pressant therapy in terms of patient or graft survival and an ileal conduit, the kidney will be engrafted inverted, so that long-term renal function. Nevertheless, a large number of the urethra is proximal and close to the urinary derivation. controlled trials and meta-analyses across the whole spec- Bricker-type re-implantation will be used in these cases. In trum of immunological risk suggest that the combination patients with a Mitrofanof to the navel the arrangement of of induction therapy and conventional immunosuppres- n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 75 sant agents is better than therapy solely with conventional to add any benefit in the prevention of acute rejection in the agents in reducing rejection and failure of the renal graft first six months 473 , although this has been observed in high 435–438 . immunological-risk patients 474 . Higher mortality was shown The efficacy of induction with basiliximab 439 in patients to exist at three years 475 , principally cardiovascular in origin, with low immunological risk was tested in a Cochrane sys- and this may be due to the antiatherogenic effect which may tematic review of 71 controlled studies and 10,537 patients 440 be induced by Rituximab-depleted B cells 476 . Its most proven and in systematic reviews. Compared to a placebo, lIL-2 recep- use is in ABO-incompatible transplantation, based on a sys- tor antagonists reduced the rates of rejection and graft loss tematic review of 45 studies which show results comparable at one year, although they did not modify long-term patient to splenectomy 477 . and graft survival; compared with other mono- and polyclonal Studies undertaken in high immunological-risk LDRT antibodies they were found to have a better safety profile 441 . recipients also describe the superiority of thymoglobulin Thus in spite of the variable results obtained respecting their over anti-L2 antibodies and placebo 456,478,479 . Nevertheless, efficacy with thymoglobulin 442–449 and alentuzumab 450,451 , in patients in which thymoglobulin is considered to be thymoglobulin is associated with an increased risk of adverse unadvisable (due to severe leukopenia or plateletopenia, for effects such as leukopenia, thrombocytopenia, CMV infection example) substitution with basiliximab may be considered in and infection-associated mortality 452–454 . Alentuzumab has a combination with tacrolimus, mycophenolate and corticoids higher rate of acute late rejection 453 , it is not available in many 459 . hospitals, and it has been associated with the risk of inducing Although the optimum dose of thymoglobulin has not autoimmune diseases such as thrombocytopenia and autoim- been established, to ensure sufficient efficacy in the preven- mune thyroid diseases 455,456 . tion of acute rejection and reduce the risk of infections or When the evidence in low immunological-risk recipients lymphomas, the total dose may be from a total of 3 mg/kg of living renal donors is analysed specifically, although thy- to 6 mg/kg, administering 2 mg/kg on the first three days or moglobulin seems to be beneficial in some cohort studies, 1 mg/kg -1.5 mg/kg during five to seven days 480–484 . when it was compared with basiliximab 457,458 , two recent prospective studies showed similar results with both of them Maintenance immunosuppressant treatment in LDKT 459,460 , with a higher rate of infections by the BK virus in the recipients thymoglobulin group 459 . A reasonable exception to the use of induction therapy Initial maintenance immunosuppression in high risk patients would apply to recipients with an especially low immuno- • We recommend that triple immunosuppressant mainte- logical risk, such as those who receive a renal transplant nance therapy should be used during the first year after from HLA-identical living relative. When the donor and recip- transplantation (A). ient are identical twins good results have been reported after • We recommend that maintenance immunosuppression interruption of immunosuppressant therapy 461 , although this should consist of a combination of a calcineurin inhibitor treatment is maintained in many patients 462 ; in any case, it is (cyclosporine or tacrolimus), an antimetabolite (mycophe- recommended to administer at least one intraoperative dose nolate mofetil or enteric-coated mycophenolate sodium) of steroids to prevent the risk of immune response activation and glucocorticoids (A). induced by ischemia-reperfusion 463 . Several studies also sug- • We recommend that tacrolimus should be used rather than gest that it is also possible to avoid the use induction therapy other calcineurin inhibitors, including cyclosporine (B). when donor and recipient are HLA-identical but not twins, • We suggest that cyclosporine should be used when neces- although there are no prospective trials which would show sary to prevent the side-effects of tacrolimus (C). the best immunosuppressant strategy 464–466 . • We recommend that mycophenolate should be used rather than other antimetabolic agents such as azathioprine (B). Induction therapy in high immunological risk patients • We recommend that mycophenolate should not be used • We recommend that thymoglobulin induction should be in women who intend to become pregnant because of its used in high immunological risk LDKT recipients (A). teratogenicity (B). • We recommend that basiliximab should be used as induc- • We recommend that azathioprine should be used as an tion therapy in high immunological risk recipients when the alternative to mycophenolate in women who intend to use of thymoglobulin is not advisable (B). become pregnant (C). At a general level there is substantial evidence that rab- The most widely used immunosuppressant therapy bit antithymocytic globulin (ATG) is superior to placebo, IL-2 regimes combine several drugs with different mecha- receptor antibodies and horse antilymphocytic immunoglob- nism of action, to optimise efficacy and minimise side ulin (Atgam® ) in patients at high immunological risk effects. Most hospitals combine a calcineurin inhibitor 439,445,467–470 . Alemtuzumab is similar to thymoglobulin in (cyclosporine–CsA- or tacrolimus), an antimetabolite the prevention of early acute rejection, but it obtains worse (mycophenolate mofetil–MMF- or enteric-coated mycopheno- results in the rate of late acute rejection 450 , patient and graft late sodium -MPHS-), and glucocorticoids, chiefly prednisone survival and the development of chronic graft nephropathy 485–487 . Some time after transplantation, in case of toxicity 450,468,471,472 . Its lack of availability and the possibility of its or due to the appearance of a neoplasia, mammalian target being associated with the appearance of autoimmune dis- of rapamycin–mTOR are used, such as rapamycin/sirolimus eases has restricted its use 452,453 . Rituximab does not seem or everolimus. However, from the first some hospitals use 76 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 a combination of a calcineurin inhibitor and an imTOR. should be eliminated in renal transplantation between Belatacept may be used as the patient progresses in case of identical twins (D). toxicity or poor adherence to treatment 486–488 . • We suggest that the monozygotic nature of the donor- The effectiveness of triple immunosuppressant mainte- recipient twin relationship should be verified before nance therapy in preventing acute rejection and preserving deciding to minimise immunosuppression therapy (C). graft survival has been shown by several randomized con- • We suggest that calcineurin inhibitor drugs should not be trolled trials and meta-analyses 448,487,489–490 , as confirmed by used in long-term maintenance, keeping MMF and/or corti- the KDIGO guides 434 . Several studies have proved the bene- coids, in HLA-identical LDRT recipients who are not twins fit of combinations which use mycophenolate in comparison (C). with those that include an imTOR 491,492 . Use of the latter has • We suggest that corticoids should not be completely sus- been associated with early complications after transplanta- pended in low immunological risk non-HLA identical LDKT tion, such as delayed graft functioning, problems with scarring recipients, as this may be associated with a higher risk of and increased incidence of lymphoceles. rejection (C). Of the calcineurin inhibitors, tacrolimus is clearly preferred over cyclosporine 493 , even though patient and graft survival There is no agreement on the need for maintenance are similar, because with tacrolimus the rates of acute rejec- immunosuppression in transplantation between identical tion are lower 487,494,495 , and graft renal function seems to be twins, in which genetics suggests there will be no recipient better with tacrolimus at 1 and 2 years 455 . There are some immune response. Registry studies show that immunosup- differences in their adverse effects 488,496,497 , so that to avoid pression is maintained in from 1/3 to 2/3 of patients, and the side effects of tacrolimus it has sometimes been replaced that patient or graft survival is similar in those who maintain by cyclosporine in a reasonably safe way 498 , or by belatacept immunosuppression and those who suspend it 461,462 . In any or an imTOR, although there is little evidence in favour of use case, the monozygotic nature of the twins should be verified the latter. before deciding to minimise immunosuppression therapy, as There is little evidence that delaying the introduction of a 25% of non-monozygotic twins may be HLA-identical, 516 and calcineurin inhibitor reduces the incidence of retarded graft the existence of different phenotypes between twins should function 448,499 . The KDIGO guides recommend not waiting not rule out the possibility of their being monozygotic, because until the graft starts working to administer the calcineurin their degree of similarity is influenced by other factors 517 . inhibitor 434 . The most widespread tendency in the literature when min- Of the antimetabolite agents, although some cohort stud- imising immunosuppression is to eliminate the corticoids and ies found milder gastrointestinal effects with MPHS than they calcineurin inhibitors to prevent nephrotoxicity 433 . did with MMF 500,501 , clinical trials show that both agents are Reduced immunosuppression has also been suggested similar in terms of efficacy and safety 502,503 . The 2009 KDIGO in Caucasian patients who receive a living donor graft guides recommend them over azathioprine 434 as they are bet- from a HLA-identical non-twin relation 465,466,518,519 , chiefly ter to prevent acute rejection and have a better side-effects based on monotherapy with mycophenolate and the sus- profile 504 . pension of corticoids. In these patients a greater graft loss Although persistent diarrhea may lead to the interruption due to chronic nephropathy has even been observed since of mycophenolate, reducing or suspending this drug has been calcineurín inhibitors came into use 464 . Nevertheless, sus- associated with a higher risk of graft rejection and failure pending tacrolimus and continuing with everolimus and 505,506 . It is contraindicated during pregnancy as it is terato- corticoids does not seem to be acceptable, as this has been genic, and in women who want to become pregnant it is associated with a high rate of rejection 520 . preferable to use azathioprine, which seems to affect neither Finally, in patients with low immunological risk where fertility nor pregnancy 507 . there is no donor-recipient HLA-identity, the use of induction Respecting the glucocorticoids, in the field of KT there therapy has been suggested, together with the suspension of is no agreement on the optimum dose or the mainte- prednisone during the first week after induction. This would nance regime, which are set by each hospital depending on have the purpose of avoiding its adverse effects 434 , but no patient characteristics 508–512 . However, Organ Procurement good quality trials are available which evaluate the long-term and Transplantation Network/Scientific Registry of Transplant effect of this suspension, and some studies describe a possi- Recipients (OPTN/SRTR) data show that glucocorticoids are ble association with a higher probability of graft rejection and not suspended in the majority of patients during the first year loss 521 . 513 . Suspending them in comparison with continuing at aza- thioprine, MMF or MPHS 514 and be linked with an increased risk of a recurrence of glomerulonephritis 515 . Alternative drugs for maintenance immunosuppression Initial maintenance immunosuppression in low-risk patients • We suggest that imTOR should substitute calcineurin • We suggest that it is possible to suspend maintenance inhibitors when patients cannot receive the latter (C). immunosuppression during the first year after renal trans- • We recommend that belatacept should be given to patients plantation between identical twins (C). who cannot receive calcineurin inhibitors (B). • We suggest that, if it is decided to minimise immunosup- • We suggest that belatacept should be restricted in patients pression, that corticoids and/or calcineurin inhibitor drugs with positive Epstein-Barr virus serology (C). n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 77 Some trials suggest that the imTOR give better renal func- Europe in general has a policy of giving priority to paediatric tion at one or two years, although they do not improve graft transplantation over dialysis 540,541 . survival 522,523 . It also offers less long-term risk of malignity 524 . Other studies associate the imTOR with increased risk of Advantages of living donation for paediatric recipients death due to a cardiovascular or infectious cause 524 , dyslipi- daemia, lymphoceles, medullar toxicity 522 and acute rejection • We recommend that LDKT in childhood is the option which 524 . Although it seems to be safe when used as an alternative gives the best results in terms of survival in the treatment in patients who react to cyclosporine as toxic 525 , administer- of CRD (B). ing it instead of tacrolimus is associated with an increase in the rejection rate 526 , which has also been confirmed in LDRT The widespread belief that RT is the best renal replace- 527,528 . ment therapy in children and should be the first choice means Although Belatacept is associated with better long-term that the ideal donor has to be found. In general related graft functioning than cyclosporine, it has a higher rate LDKT, especially from parents to children, is normal practice of acute rejection and lymphoproliferative disorders after in transplantation programmes worldwide, and it is almost transplantation, especially in patients with previous negative exclusive in some countries in comparison with deceased serology for EBV 529–531 . In comparison with tacrolimus it has a donor transplantation. In terms of efficacy, the ONT describes higher acute rejection rate with a variable effect on long-term LDRT as “the therapy which offers the best survival results in the renal functioning 532,533 , although it is an alternative in case treatment of chronic renal failure” 542 . Its use in children is jus- of toxicity with calcineurin inhibitors 534,535 . tified by two needs; firstly there are too few deceased infant donor organs to meet existing paediatric demand, and there is also no preferential option for deceased adult donor RT, and secondly it is necessary to ensure the best results over the Living donor paediatric recipients short to medium terms. Living donation must be supported by an organizational system which guarantees the absence Demographic aspects of paediatric KT of coercion or economic reward for donors, although these problems do not arise in donation by parents to their children. • We recommend that related LDKT should be the renal The existence of a good national system to govern living replacement therapy of choice in children, and it is recom- donor programmes also makes paediatric paired RT possible, mended that it should be considered at an early stage, to when due to donor-recipient incompatibility transplantation avoid the transitory stage of dialysis (Quality of evidence: is impossible with the selected pair. In these cases donor- B). recipient pairs can be matched within a single hospital or within a strict national scheme which enables simul- KT is the ideal universally accepted treatment for ESRD taneous transplantations 543,544 . Apart from immunological in children, with countless advantages over other alternative compatibility, other advantages of living donation are that renal replacement therapies such as haemodialysis in hospi- transplantation can be planned to take place at the best tal or at home, or peritoneal dialysis. Paediatric nephrologists moment for the recipient, and donor-specific desensitization agree that early KT should take place to avoid the transi- can take place for recipients with anti-HLA or another type of tory phase of dialysis; this makes it possible to minimise the antibodies. Finally, it ensures better graft survival in children impact of renal disease while reducing institutional as well as with anatomical vascular or urological difficulties that would community healthcare costs. It also has countless social and make re-transplantation option far more complex or even familial advantages. It is exceptional for a child to be defini- impossible. The main contraindication against living donation tively excluded form a KT scheme, and when this does occur is the potential risk for the donor, or the risk of relapse of the for medical, surgical or psychosocial reasons, it is always tem- primary disease in the graft. porary. In spite of the above considerations, early KT is only Paediatric recipients of LDKT achieved in our context in 40% of patients, and overall LDKT represents 20%-30% of all paediatric transplantations 29 . • We suggest that the recipient should be informed about the Different registries show a worldwide tendency for KT transplantation process in a way that is suitable for their to be the most widespread paediatric therapy. Nevertheless, age, obtaining their informed consent and taking their opin- this varies between countries due to differences in per ion and desires into account (NG). capita income and national policy respecting preference for • The greatest difficulties in paediatric transplantations arise donation to children 536 . Thus with little variation between at the age limits of the same (new-born babies and adoles- countries, the average incidence in Europe of replacement cents), which are intrinsically special risk groups (NG) renal therapy in children stands at 6 new patients per year per million inhabitants younger than 14 years 537 . However, the Potential paediatric LDKT recipients should be treated in a rate of RT varies quite widely: in the Scandinavian countries, paediatric hospital by specialists who are aware of all of the France, Austria and Spain more than 85% of their population specific aspects associated with the primary disease as well under 14 years old and in renal replacement therapy have as those intrinsic to infancy. The latter are physical (growth, received a RT, and this datum is harder to obtain in registries development and maturing) as well as psychosocial factors that do not include the whole national population 538,539 . which are fundamental for the transplantation process 78 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 (socioeconomic status, degree of dependency, adherence to the major risk of graft loss, KT should not be performed therapies, etc.). Paediatric recipients should also be informed in recipients who weigh less than 6 Kg. Finally, perform- in a way suitable for their age about the transplantation ing KT in very small recipients requires a multidisciplinary process, so that they are able to give their informed consent, team that includes highly experienced surgeons and/or urolo- while taking their opinions and desires into account. gists, anaesthetists, nephrologists, intensive care specialists, The extreme paediatric ages (new-born babies and adoles- nutritionists and wide-ranging support by other paediatric cents) are a priori the ones which give rise to the greatest specialists. For technical reasons this type of transplantation difficulties when carrying out a transplantation, and they are should be performed in paediatric referral hospitals. groups at special risk 545–547 . Adolescent LDKT recipients Very young recipients of living donor transplantation • We suggest that a multidisciplinary approach should be • LDKT in extremely small recipients (in terms of their age or used in patients aged from 13 to 18 years, chiefly in the weight has a higher rate of primary graft failure, chiefly due process of supplying information before and after KT, to to vascular factors (arterial and venous thrombosis) (A). reduce the risk of non-adherence to treatment (D). • We recommend delaying transplantation until the recipient is two years old or 10Kg (B). The paediatric population from 12 to 18 years old who • It is exceptionally possible to perform a KT in recipients are candidate RT recipients are also going through the grad- weighing from 6 to 10 Kg in experienced hospitals, after ual process of becoming independent and responsible; this careful study of the balance between risks and benefits (D). makes this population especially vulnerable to non-adherence to therapy and a permanent risk of rejection 553,554 . Registry Children under the age of 2 years suffer the highest rate data also show an increase of graft loss due to non-adherence of morbimortality in all forms of renal replacement therapy to therapy, reaching a maximum at from 13 to 21 years old, 545,548 . Commencing replacement therapy during the first year after which it falls 555 . of life is associated with a mortality-independent relative risk Establishing a temporary contraindication against LDKT in 3 to 6 times higher than other age groups 545,548 . an adolescent who does not adhere to treatment would seem In the paediatric population starting replacement therapy to be obvious. Nevertheless, prolonged treatment with dialy- with RT has better results over the short to medium term than sis does not seem to mitigate the subsequent risk of failure to dialysis. However, this finding has not been completely cor- comply with therapy 556 . In such cases the process of inform- roborated in children under the age of two years 548,549 . RT is ing the patient before, during and after transplantation and not used universally for children under the age of 2 years and the support of social workers and psychologists who specialise most especially those under the age of 1 year; 99% of these in adolescents is useful in preventing a lack of adherence to patients start treatment with dialysis, especially peritoneal therapy 555,556 . dialysis 545,548–550 . Given that the highest percentage of graft losses occurs dur- Commencing RT programmes in extremely small recip- ing the transfer process, it is fundamental to ensure a smooth ients is associated with a higher number of vascular transition to adult units for these recipients. complications, especially arterial and venous thrombosis, as well as primary graft failure. These complications are espe- KT from an adult donor to a very young recipient cially frequent when the donor too is very young, and many (donor-recipient disassociation) programmes reject such young donors for small recipients 551 . • Living donation by a parent to a very young baby involves Surgical considerations and perioperative and postopera- a reduction in blood volume of from 33% to 50%, and the tive management are fundamental when performing a KT in surgical approach and perioperative management are fun- a patient less than 2 years old or less than 10 Kg in weight damental (B). 536,550,552–554 . In these patients a suitable policy of haemody- namic monitoring and supply of colloid and crystalloid fluids KT from an adult donor to a very small recipient is a habit- are associated with good results, preventing early graft loss ual practice which requires initial higher pressure perfusion, due to technical causes such as vascular thrombosis, lack and it may lead to a 33% to 50% reduction in blood volume, so of primary function or acute tubular necrosis 550–554 . The that surgical, perioperative and anaesthesia management are few experiences when recipient weight is lower than 6 kilo- fundamental 550,557,558 . grammes are generally negative 551–552 . Surgical approach: an adult kidney for a paediatric recip- We can therefore definitively consider recipients over 2 ient, and most especially if it is for a very small child, will years old and 10 Kg in weight to be suitable for RT; until then, involve a size discrepancy between the donated kidney and the best replacement therapy is peritoneal dialysis, and RT the abdominal cavity of the recipient. This may lead to com- should be postponed until the above weight and/or age have promise of the space, hindering the creation of the vascular been reached, if circumstances make this possible. Excep- anastomoses and closure of the abdomen after positioning tionally (in case of peritoneal or vascular access failure or the graft, with compartmental syndrome. The extraperitoneal other types of risk) it will be possible to perform a RT in approach using Gibson’s incision is the procedure of choice recipients weighing from 6 to 10 Kg in experienced hospi- in RT to babies, for living as well as deceased donors. Never- tals, after carefully balancing the risks and benefits. Given theless, doubts may arise when the recipient is very small or n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 79 has abdominal problems of another type. An intraperitoneal as the graft survives for a shorter time, even though this approach is recommended when the recipient weighs less survival time is longer than that of any graft from a deceased than 15 kilos, with the advantage of offering a larger surgi- donor, including young ones (D). cal field and wider exposure of the major vessels, although it also has the disadvantage of possible intestinal obstruction A tendency has been observed in international registries 559 . In any case, the approach should be selected on the basis over recent years for more renal transplants to be used from of the conditions of the recipient and the experience in each donors over the age of 50 years for paediatric RT 560 . Although hospital. survival at 5 years is less than that corresponding to young Vascular anastomosis: the size discrepancy is also found LDRT, it is better than that of any graft from a deceased donor, between the renal hilus vessels and those of the recipient, including young ones 554,557,561–563 . Long-term graft survival so that the best locations for anastomosis should be selected becomes poorer to the degree that donor age increases over on the basis of this disparity. The arterial anastomosis may 50 years 554,557,563 . be terminolateral in the aorta, in the common iliac or in the external iliac, and terminoterminal to the internal iliac. When the recipient weighs less than 20 kilogrammes we recommend Complex vascular anomalies in LDKT and paediatric making the anastomosis in the aorta and inferior vena cava recipients 558 . If they weigh from 20 kg-30 kg, the recommend site is the iliac artery and common iliac vein. When the graft has a dou- • Occlusive thrombosis of the inferior cava vein and mid ble artery, if both are separated then both anastomoses are aortic syndrome require planning of the transplantation independent, but if they are close, they will be joined in bench which includes selection of the optimum donor and plan- surgery, suturing the accessory artery to the main artery. ning of the surgical approach, which has to be adapted to Abdominal wall closure: closure of the abdominal cav- the anatomy of the recipient (D). ity after transplantation may be compromised and require delayed closure in 48 or 72 hours. When the disassociation Of the vascular anomalies which compromise transplan- between the donor and recipient is very striking, closure of the tation into a paediatric recipient, occlusive thrombosis of wall may cause an increase in abdominal pressure which may the inferior cava vein is one of the most challenging situa- collapse the inferior cava and hinder the venous return from tions, and although rare, it is the most frequent such anomaly the graft. This may progress until thrombosis occurs (compart- 564–566 . The other complex vascular anomaly is mid aortic syn- mental syndrome). In these cases positioning a Gore-Tex sheet drome, which is usually progressive during infancy but tends sutured to the edges of the wound may prevent this complica- to stabilise during puberty, so that transplantation should be tion, permitting the gradual closure of the wall on subsequent delayed as far as possible or may not even be feasible. Planning days 558,559 . This gradual closure of the surgical wound edges a transplantation should include the selection of an optimum will take place under Doppler ultrasound scan monitoring. donor and plan the surgical approach, deciding on the best Perioperative management: to maintain correct perfusion anatomical site for anastomosis based on recipient anatomy. pressure and reduce the risk of vascular thrombosis, peri- All KT candidates must be subjected to previous vascu- operative management should include the administration of lar evaluation by iliac-cava Doppler ultrasound scan. Those intravenous fluids (crystalloids and/or colloids) and inotropic patients with a suspicion of venous thrombosis or arterial drugs, together with correct haemodynamic monitoring 552 : anomalies should also be subjected to other more specific imaging tests such as CT-angiography, magnetic resonance • Monitoring central venous pressure with a central venous angiography or transjugular retrograde venography to per- catheter (12-18 cm H2 O) and direct monitoring of arterial mit planning of the surgery. It is also important to determine pressure. whether any risk factors for hypercoagulability are present. • Due to the risk of retarded graft functioning, the average In inferior cava vein thrombosis the veins which are col- arterial pressure obtained after 10 minutes of graft reperfu- lateral to the thrombosis should be avoided as venous graft sion should not be lower than the pressure when the clamps drainage may be compromised, favouring the thrombosis. Pos- were removed. sible vascular structure are: the ovarian vein, the left renal • The ratio between the average arterial pressure and weight vein, the superior or inferior mesenteric vein, the portal vein should be greater than 4.3 in patients who weigh from 13 to or even deeper veins such as the lumbar veins. As the first 21 Kg (56–90 mmHg), and ideally greater than 2.5 in patients option, and on condition that it is thrombus-free, we should who weigh more than 22 Kg. use the infrahepatic cava vein, placing the graft in orthotopic position on the left side 565 , performing left nephrectomy and What is the age limit for a living donor to a paediatric using the native renal vein for the anastomosis to the renal recipient? vein of the graft, with anastomosis of the renal artery of the graft directly to the aorta. If the renal vein of the donor is • Although graft survival 5 years after LDKT from a donor short, a lengthening procedure may be used; either with the over the age of 50 years is less than that of transplants cava of the donor or with a segment of gonadal vein 564,565 . from young living donors, it is better than any graft from The urethra will be re-engrafted using modified Lich-Gregoir a deceased donor, including young ones (B). technique if we have sufficient length, or by means of urethra- • We suggest that living donors over the age of 50 years should ureterostomy between the donor urethra and the native one, be assessed on an individual basis for a paediatric recipient, if the first is too short 558,559,567 . 80 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 During the postoperative phase anticoagulation should be immediately after a complete cure, without having to wait the used with heparin, followed by platelet antiaggregation, as traditional 1 - 2 years 567 . well as ensuring venous permeability by Doppler ultrasound scan immediately after the operation and magnetic resonance Intellectual retardation and the paediatric recipient imaging and/or vascular tomography 3 months after the trans- plantation. • LDKT is not contraindicated in recipients with a severe intel- lectual deficit, as there are no differences in graft survival between them and other patients. The final decision will be Complex urological anomalies and treating them in LDRT based on agreement between the transplantation team and and paediatric recipient the parents (NG). • We recommend pre-transplantation urological evaluation The decision to perform a RT in a paediatric recipient using cystourethrography to identify anomalies and treat with severe psychomotor retardation is always difficult, and them before engraftation (B). it should be adopted by all of the members of the mul- tidisciplinary transplantation teams and the parents, who Patients with a neuropathic bladder, posterior urethral are responsible for the patient’s independence 572 . Given valves, complex urological malformations and urological that patient and graft survival are similar to those for other problems associated with anorectal malformation, such as patients, the fact that a severe intellectual deficit does not cloacal fistula are common in KT candidates. These anoma- contraindicate receiving a RT is perfectly valid 573 . Absolute lies may endanger graft survival, due basically to the vesical contraindications derive from the association between psy- dysfunction which accompanies them. Pre-transplantation chomotor retardation and other concomitant situations which urological evaluation is therefore a requisite for a LDKT, allow- in themselves are each a complete restriction 571–576 . ing us to identify problems and duly treat them prior to engraftation 568 . Cystourethrography will be the first test used Obesity and the paediatric recipient in this evaluation. If there is a suspicion of vesical dysfunction we will per- • We suggest that LDKT should be delayed in recipients with form a urodynamic study to confirm whether the bladder a BMI higher than 35 Kg/m2 due to the increased risk of graft is dysfunctional and identify the type of problem (hyper- loss, stimulating weight loss by means of habits that modify reflexia, low accommodation or myogenic failure). High grade their lifestyle (D). urethral vesical reflux in native kidneys favours repeated post- transplantation infections and should be treated, surgically or Data from the European registry indicate that Spanish chil- endoscopically, before transplantation 558,559,567,568 . dren who receive KT are often overweight and obese 577 , due Correction of vesical dysfunction will require specific in part to the changing Western lifestyle. Certain hereditary treatments prior to transplantation, such as the use of anti- pathologies such as Prader-Willi or Bardet-Biedl syndromes cholinergic drugs and/or intermittent catheterization, the are associated with renal failure subsidiary to replacement injection of botulinum toxin, vesical augmentation or conti- therapy and specific problems with obesity which have to be nent urinary diversion. evaluated, defined and treated before transplantation. Vesical hypoplasia or urethral agenesis and atresia require Potential recipients should be assessed before transplan- reconstruction of the urinary tract before transplantation, tation in nutrition units, changing their diet and stimulating constructing a neobladder from a colon or ileal segment, and physical activity and sport. Recipients with a BMI > 35 Kg/m2 a Mitrofanoff-type drainage tract 564,569,570 . are at increased risk of graft loss ten years after transplan- tation 578 , so that they should be encouraged to lose weight. The decision to perform a RT in an obese paediatric recipient Cancer in the paediatric recipient should be based on team decisions. • The time during which LDKT is contraindicated in a malign ABO incompatible living donor RT and paediatric process should be evaluated jointly with Oncology depend- recipients ing on the type, grade and extension of the tumour (D). • Although it is ideal for a paediatric recipient to receive an There is no evidence or agreement on how long the wait- isogroup donation, ABO incompatible LDRT in a group O ing time should be before receiving a transplantation after or B paediatric recipient with low isoagglutinin levels is an the complete cure of a neoplasia. The most advisable strategy option that can be considered (C). is currently therefore to evaluate the risk of relapse together with oncologists, according to the type, grade and spread of Although there is no evidence which specifically supports the malign process, deciding the necessary waiting time on the paediatric indication, ABO incompatible LDRT in a group an individual basis 571 . Modern genetic studies are now very O and B paediatric recipient with low isoagglutinin levels useful aids in distinguishing between different biological sub- against the potential donor, and using plasmatic exchanges, types and thereby help in decision-making. immunoabsorption or rituximab, it is a reasonable option in Wilms’ tumour is an exceptional case, as the transplan- cases with large increases in waiting list time 579–581 . In recent tation candidate may be considered to be a valid recipient years it has been found that patients with low isoagglutinin n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 81 titres (<16) can receive an ABO incompatible transplantation although LDRT may strengthen positive emotions between without the need for plasma exchanges 582 , although there the donor and recipient, it may also lead to tensions and is no evidence to indicate which isoagglutinin levels permit anxiety, above all in adolescent recipients 594 . transplantation without previous treatment 583–586 . Aspects of surgery and the harvesting: the main limita- tion of LDKT for paediatric recipients is the size discrepancy Living donor RT in highly sensitized paediatric recipients between donor and recipient vessels. To guarantee a suitable flow to the kidney the recipient artery for the anastomosis The presence of preformed anti-HLA antibodies drastically should be twice the width of the renal artery of the donor, worsens the result of RT in children as well as in adults 562,563 . or at the least the same size 595 . In children who weigh less Although desensitization programmes give good results over than 15 kilogrammes it is often necessary to wait for a time the short to medium terms, the long-term prognosis is still before being able to perform the transplant with assurance disappointing. Several countries have developed national or of success. The presence of vascular anomalies or multiple international programmes with the aim of prioritizing trans- pedicles increases the risk of graft thrombosis; thus when plantation in these patients by using a virtual crossmatch there is a double artery and it is close to the main artery, 587–591 . the accessory artery anastomosis to the main one should be LDRT in highly sensitized children is no different from the terminolateral, with a single anastomosis in the recipient. If situation in adults, and it would be the therapy of choice if both arteries are a certain distance apart it will be necessary the potential donor had no antigen prohibited by recipient to make the anastomoses separately. There is no established antibodies. Otherwise, a child with the presence of a titre limit on the maximum number of arteries over which a kid- above 98% against the panel could be included in the national ney should be rejected. The surgeon’s criterion and experience scheme of highly sensitized patients 591 , while those patients will decide if a transplant is possible. Renal angiotomography with preformed antibodies but with a lower titre could be reconstruction in three dimensions, including the excretory included in the deceased donor waiting list, while evaluating phase, is the method of choice for evaluation of the arterial and the possibility of paired LDRT or even using a specific desen- venous anatomy and the parenchymal and collector system of sitization protocol, depending on the patient’s situation and a potential living donor 596 . how long they have spent in dialysis 592,593 . The left kidney is usually collected, as if they are both equally suitable this usually facilitates the vascular anas- Absolute contraindications in paediatric recipients tomoses, while otherwise the rule is that the best kidney should be left in the donor. Laparoscopic nephrectomy is There are few absolute contraindications against perform- preferred over open surgery for renal harvesting from a liv- ing a RT in the paediatric age 567,573–576 : malign neoplasia in ing donor 597 , as it causes less donor morbidity and has the previous 12 months, pulmonary disease which requires similar functional results. The greatest problem is that it continuous oxygen therapy, irreversible heart failure, active is harder to obtain renal vessels of an appropriate length, infection, a refusal to complete the normal vaccination sched- above all the renal vein, and this occurs more often with the ule or inappropriate social support for post-transplantation right kidney. A hand-assisted laparoscopic approach improves treatment. traction on the kidney and obtains a more suitable vessel length. Positioning the graft inverted in the recipient may also Considerations on choice of a live donor for children facilitate the vascular anastomoses in a graft with short ves- sels. Laparoscopic harvesting has less morbidity than open nephrectomy for the donor, and the functional results of the graft are the same (B). LDKT with HLA incompatibility Age and social aspects: 90% of living donations in child- hood are made by the parents, and the factors limiting age KT is the best therapeutic option for chronic renal failure are described in a previous section. The selection of one or 598 , and LDKT offers better results than those made from a the other parent if they are equally compatible and healthy deceased donor 599 , nevertheless, the number of LDKT has is their own choice after they have been informed of their fallen in Spain in recent years 600 . level of compatibility. All of the psychosocial and economic The number of recipients who have been highly sensi- factors which influence donation should also be taken into tized by pregnancy, transfusions or previous transplants is account 594 . In living donation for a paediatric recipient now increasing in Spain 601,602 . This tendency is similar to other family donors or donors with emotional ties are also the reported trend in countries such as the U.S.A. 15 , while accepted: compatibility must be taken into account, and the it is less pronounced than is the case in Korea 603 or the advantages must be weighed in comparison with a deceased United Kingdom 604 . The definition of a sensitized patient is donor transplantation 563,593 . Although donation by a young not precise, although the presence of antibodies against the sibling (under the age of 25 years) is not contraindicated, donor is considered to be a risk factor for the development of this requires a far more exhaustive evaluation to prove antibody-mediated rejection, making transplantation unad- their maturity. Sometimes we find single-parent families visable 317 . Less than 30 years ago candidates with more than without any social support, and these situations would lead 50% PRA were considered to be hypersensitized 605 . Currently us to advise against LDRT. In any case, it is fundamental to in the U.S.A. figures above cPRA > 80% are defined as highly offer psychological support before and after donation, and sensitized, while >99% is defined as very sensitized 606 ; the 82 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 corresponding figure in Eurotransplant is 85% 607 and in other formation of new ones by blocking B-cell proliferation and countries it stands at around 80% 608–610 . In Spain there is preventing recognition and an immune response by means a national scheme for hypersensitized patients which sets a of immunosuppressant therapy. There are several desensiti- minimum level of 98% cPRA for inclusion 602 . zation protocols, and in general they are based on the use of The transplantation options for highly sensitized patients rituximab, IVIG and apheresis techniques (2,611) New drugs vary, depending on the availability or not of a living donor. If have been added in recent years, including eculizumab and there is no incompatibility then transplantation will proceed. imlifidase, and these reduce the incidence of acute rejection. If on the contrary there is incompatibility between the donor A conditioning regime is shown in Figure 13.a) B-cell depletion and recipient then the options include inclusion in the waiting agents lists for paired donation, desensitization therapy or inclu- The most widely used regime at the present time con- sion in specific deceased donor waiting lists. Desensitization sists of using rituximab for one month prior to commencing protocols have been designed in the last two decades based apheresis. It functions 2-3 after infusion, with a peak at on treatment with intravenous immunoglobulin (IVIG), differ- from 2 to 4 weeks, and this effect may be maintained for ent apheresis techniques and B lymphocyte depletion agents up to 12 months 612 . The dose used in the majority of pro- or plasma cells. Recently new desensitization methods have tocols is 375 mg/m2 body surface, and premedication with emerged, including complement blocking agents, or Imlifidase paracetamol, steroids and antihistamines to prevent adverse (endopeptidase) which is capable of cleaving G immunoglob- secondary reactions. Some authors use bortezomib, a plasma- ulins, that are able to reduce the incidence of acute rejection, cell depletion agent, with different results 611 , although with although the mid-term prognosis is unknown 348 . a high incidence of side effects 613 .b) Immunosuppression Immunosuppression starts one or two weeks prior to trans- Desensitization for HLA-incompatible LDKT plantation, with tacrolimus (0.15 mg/kg to achieve levels of 8-12 ng/ml in the first month), MMF at a dose of 1 g every • We suggest that transplantation candidates with more than 12 hours or 720 mg every 12 hours of MPHS and 20 mg/day 80%-85% of cPRA antibodies against potential donors should prednisone 614 .c) Apheresis be considered sensitized (Quality of evidence: C). In patients with no vascular access (pre-dialysis or peri- • We suggest that LDKT candidates and their donors should toneal), it is necessary to catheterize a central vein (preferably be informed of the different options for HLA-incompatible the internal jugular vein) 615 for apheresis with or without dial- transplantation (paired, desensitization or specific lists with ysis. If the technique of centrifugal plasma exchange is used preference for a deceased donor) (C). then this can be applied using a peripheral vein. The apheresis • The decision to perform an HLA-incompatible trans- techniques used are PPF or plasma exchange, double filtration plantation by using a desensitization protocol should PPF and immunoadsorption (IA). The advantage of IA over PPF be considered depending on the characteristics of the is that it does not remove plasma, so that plasma proteins recipient, the donor and time in the waiting list, in including albumin and coagulation factors are not lost in the comparison with the increased risk of antibody-mediated exchange, so that replacement is not required, as it is with PPF 616 . The drawback is that it filters IgG 3 less efficiently and it acute rejection and other complications due to over- immunosuppression. (NG). is also more expensive; both techniques are usually combined 617 . The volume of plasma used in the exchange tends to vary • We recommend a desensitization protocol which includes rituximab, IVIG and apheresis techniques (immunoadsorp- at from 1 to 2.5 volumes per session, while the number of ses- tion or plasma exchange) (B). sions varies and generally depends on the degree to which • We recommend adding anti-CD20, as it increases the prob- the patient is sensitized. When the crossmatch tests with the ability of accessing a transplantation (A). donor for CDC and CF are negative and the NFI of the donor- • We do not recommend substituting rituximab with borte- specific antibody or antibodies falls below 1000 the patient is zomib, due to its toxicity and poorer results (B). considered to be desensitized and transplantation takes place 614,618 .d) Immunoglobulins • As there are no studies which compare different IVIG preparations (non-specific or CMV hyperimmune) it is not After each apheresis session in which some antibodies possible to recommend one or the other (NG). have been removed, IVIG is administered with the aim of neu- • The inclusion of eculizumab in the usual desensitization tralising the antibodies and modulating the immune response 619 . IVIG reduces the incidence of acute rejection and graft loss protocols reduces the incidence of short-term antibody- mediated acute rejection (B). in sensitized patients 620,621 . Two versions are marketed, non- • Imlifidase makes it possible to transform a highly positive specific IVIG and hyperimmune IVIG CMV. There are no studies crossmatch tests into a negative one in 6 hours (C). which compare the efficacy of both versions. One study com- • We suggest that LDKT HLA-incompatible candidates who pared historical series of candidates treated with high doses are not suitable for desensitization should be included in of IVIG or low doses plus PPF, and the results of the latter specific deceased donor transplant lists for highly sensitized group with PPF were better 622 . Non-specific IVIG is used in candidates (C). doses of 500 mg/kg weight - 2000 mg/kg weight 623 , with a maximum dose of 150 g, and a larger volume is required for 1.1.1. Desensitization protocol administration. Anti-ABO isoagglutinins are usually included Desensitization consists of removing pre-existing antibodies in its presentations, and premedication is required to prevent from the body using apheresis techniques, blocking exist- adverse reactions 624 . CMV-specific IVIG is used in a 100 mg/kg ing ones or their actions by using IVIG, preventing the dose 625–627 , so that the volume administered is considerably n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 83 Figure 13 – The most widespread form of desensitization. Rituximab commences 31 days before the planned date for transplantation. From 7 to 14 days before transplantation the patient is admitted to hospital and PPHS or IA commences until the crossmatch is negative. 100 mg/kg of CMV specific Igs is infused after each session of PPHS/IA. Immunosuppression also commences with tacrolimus, mycophenolic acid derivates and prednisone. Prophylaxis is given after transplantation, with valganciclovir, septrin, itraconazole or inhaled amphotericin. Basiliximab or thymoglobulin is given for induction, and PPHS takes place on days +3,+5 and +8. (Ref: 614). smaller. It is highly purified and has CMV and Epstein Barr comparison with previously used desensitization protocols, virus neutralising antibodies, so that it may offer beneficial although we do not have enough information about its use results in terms of the short-term prevention of opportunistic in clinical practice 634 . infections 628 . In economic terms the results seem to favour Other drugs are under development 635 , and these may using non-specific IVIG, although no cost-effectiveness stud- improve current results. These drugs include the administra- ies have been performed.e) Eculizumab tion of a complement C1 fraction inhibitor (C1Inh) although it Eculizumab is a humanized monoclonal antibody against is still in phase I/II 636 .h) Induction the C5 fraction of the complement, preventing it from cleaving Once successful desensitization is considered to have been and blocking the opsonizing and inflammatory capacity of C5a achieved then the transplantation takes place. Induction and the formation of membrane attack complex C5b-9 629 . Use therapy with basiliximab or thymoglobulin is administered, of Eculizumab during 4- 9 weeks is associated with a reduction depending on the protocol and groups 614 . Some protocols in the incidence of antibody-mediated acute rejection 630,631 , include the use of alemtuzumab instead of thymoglobulin although an increase in the MFI of the DSA has been detected, 623,637 .i) Prophylaxis together with a higher frequency of transplantation glomeru- The aim of desensitization protocols is to reduce the lopathy. This drug is tolerated well, although patients have to immune response, so that opportunist infections may be vaccinated beforehand against meningococcus, pneumo- increase. In spite of this the prophylaxis does not differ very coccus and haemophilus.f) Imlifidase. much from what is used in transplantations without desen- Imlifidase (endopeptidase) is a drug collected from Strep- sitization: cotrimoxazol during 3-6 months and valganciclovir tococcus pyogenes, and it functions like scissors, cutting the during from 3 to 6 months, basically in seropositive donors bonds which join the different chains of the immunoglobu- and CMV seronegative recipients. Antifungal prophylaxis will lins, turning a positive crossmatch test into a negative one in follow local practice; some hospitals use oral itraconazole or 6 hours. Data from the first international studies show that it is inhaled amphotericin during 3-4 months 614 . possible to transplant into sensitized patients with a reduced Patients who receive eculizumab should be vaccinated incidence of rejection in comparison with the usual protocols against meningococcus, haemophilus and pneumococcus, and 632,633 .g) Others. they should receive oral penicillin until at least one month Tocilizumab is a monoclonal antibody against the IL-6 after treatment has ended, as recommended for patients with receptor, and in initial studies it improved the results in aHUS 638,639 . 84 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 also includes the use of rituximab and IVIG. Patient and graft Results survival are 100% and 96% at the 6th month, respectively, with a 27% incidence of antibody-mediated rejection 632,633 . Adding • The incidence of antibody-mediated acute rejection is high eculizumab to the usual desensitization protocol makes it pos- in patients who receive a transplantation after desensitiza- sible to reduce this rejection rate to 12%-15% in the first year, tion (B). with renal survival higher than 90% 630,654 . • Survival is lower in patients transplanted after desensitiza- In an experience of the Mayo Clinic in patients with DSA tion than it is in patients with a compatible LDKT (B). MFI >1000 and negative CF, 75% with LDRT, shows a 0% • Survival is higher in HLA-incompatible patients trans- incidence of antibody-mediated rejection. The incidence of planted after desensitization than it is when they remain chronic antibody-mediated rejection was 17% and patient sur- in dialysis and are transplanted afterwards, or when they vival was 96.3%, while graft survival (death censored) was 86% remain in dialysis and the waiting list (B). after an average follow-up of 4 years 637 . These patients were not subjected to desensitization, so that the authors consider Probability of transplantation that certain patients could benefit from a transplantation, especially one from a living donor, rather than remaining in A retrospective multicentre study of hospitals in the U.S.A. the waiting list for a donor with a completely negative cross- found that the results in terms of transplanted patient sur- match test (negative DSA, MFI < 1000). vival after desensitization are better than those corresponding It is possible to apply desensitization protocols in deceased to patients who remain in dialysis before transplantation, donor RT with IA in the immediate postoperative period. If and those who remain in dialysis and do not receive a the crossmatch test was positive pre-IA but negative post-IA, transplantation 640 . Other studies do not find these differ- the patient was transplanted. 101 patients were transplanted ences between the groups of those who were transplanted or with this protocol, 27 of them were CDC positive pre-IA in the waiting list 604 . This may be explained by differences and negative post-IA. The incidence of antibody-mediated in definitions, desensitization, the method used to select the rejection stood at 41%. Death censored renal survival was control group, the population and mortality in dialysis, which worse in the patients with DSA than in the controls without is higher in the U.S.A. than it is in Europe 49 . In waiting list DSA 656 . patients with high cPRA, this is an independent risk factor for Some authors have reported the results of a combination mortality in transplantation candidates 641,642 . of desensitization and paired LDRT, with a small number of The probability of accessing transplantation after desen- patients, although they were able to transplant candidates sitization varies from 37% to 96%, depending on the with 100% cPRA 657,658 . protocol used, the level of sensitization and group experience Table 12 shows a summary of the latest publications on the 611,614,622,623,630,643–649 . A review found that the probability of results of desensitization. transplant was 90.7% when PPF was used, 95.5% when IA was used, 73% with the use of high dose IVIG without apheresis Complications and cost of desensitization and 30.8% with bortezomib 611 . The most experienced group with desensitization is probably the Cedairs Sinai group, Los • Desensitization protocols may expose patients to a higher Angeles. Vo et al. have transplanted 45/56 (80%) of the waiting incidence of infections and other adverse effects (NG). list patients with PRA >80% with a living donor using desen- • The costs of HLA-incompatible LDRT are higher than those sitization, as opposed to only 2% per year in the waiting list for a HLA-compatible donor, although it is cost-effective in without desensitization. They were unable to transplant 9/56 comparison with remaining in dialysis (NG). (16%) of the candidates 623 . There is little information on the frequency of transplantation in patients where desensitiza- The number of infectious complications (CMV, BK, urinary tion had failed. infection) is slightly higher in the group of sensitized patients When bortezomib is used, the probability of transplanta- than it is in those who are not sensitized. Few data exist on tion varies from 43% to 84% 613,650,651 . It was necessary to the incidence of EBV, and it is even possible that IVIG has a suspend bortezomib due to adverse effects associated with protective effect 603,614,632,640,643,646,655,659–664 (Table 13). bortezomib in 11.5% of patients, and in 15.4% without associ- Other complications have been reported in connection with ation with bortezomib. desensitization protocols that are especially linked to the use of apheresis techniques and other medications 639 . Survival and rejection HLA-incompatible LDRT is more expensive than a compat- ible RT, due to the use of B cell depletion agents, apheresis, In successive series patient survival is higher than 90% at 1- IVIG, induction, immunosuppressant medication and the time 5 years and 80% at 8 years, while graft survival is higher than spent in hospital 665 . Although its total cost is higher, LDRT is 90% at one year and from 60%-70% at 5-8 years, in spite of high cost-effective in comparison with remaining in dialysis 623,666 . acute rejection rates 611,614,618,623,630,637,643,646,652–655 . The costs of additional medication such as eculizumab have Recent publications show the results of using endopepti- not been evaluated. dases (Imlifidase) in 46 patients, the majority with a deceased donor (n = 39), although patients who had received a LDRT Conclusions were also included (n = 7). 85% of patients had a positive cross- To summarise, desensitization now makes it possible for 70- match test, DSA in 93% of cases and cPRA >97%. The protocol 90% of the patients who commence the protocols to access Table 12 – Summary of living donor desensitization protocols. Author YEAR N◦ . (follow-up) AAMR (%) ATMR (%) PAT. S (%) RENAL S (%) Method 1 Stegall (Mayo Clinic) 2006 61 (12) 37 93 82 CDC Magee (Boston)2 2008 28 (22) 39 42 96 89 CDC/FC Thielke (Illinois-Chicago)3 2009 51 (23) 24 43 91 81 CDC Rogers 2011 10 (12) 0 30 90 90 CDC/FC/Luminex (Adelaida-Australia)4 Montgomery (Baltimore)5 2011 211 (96) 86 Morath (IA) (Heidelberg. 2012 10 (19) 30 20 100 90 CDC/Luminex Germany)6 Vo (Cedairs Sinai- L.A.)7 2013 46 (48) 22 29 96 92 CDC/FC/Luminex Kute (BORT) (India)8 2011 29 (10) 10 24 100 88 CDC/FC Riella (Boston)9 2014 39 (60) 61 23 84 86 CDC/FC/Luminex E. De Sousa-Amorin 2015 24 (37) 41 21 86 CDC/FC/Luminex (Hospital Clinic)10 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Okada (Japan)11 2019 15 (48) 60 93.3 85.6 CDC/FC/Luminex Jordan (IdeS) (LA + Lund 2018 35 (6) 25 100 94% CDC/FC/Luminex +Paris)12 Winstedl (IMLIFIDASE) 2019 46 (6) 27 100 93.5 CDC/FC/Luminex ESOT 201913 Marks (Eculi vs PP + Igs)14 2019 102 (36) 11,8vs29,4 98 vs 98 91.8 vs 78.5 CDC/FC/Luminex Fernandez (A Coruña)15 2017 23 (43) 8,6 8,6 91.8 85 CDC/FC/Luminex Kim (Korea)16 2019 17 (37) 47 100 85 CDC/FC/Luminex N (FOLLOW-UP): No. of patients included and (months of follow-up). AAMR: acute antibody-mediated rejection. ATMR: acute T-cell mediated rejection. PAT. S: patient survival. RENAL S.: graft survival, Method: Methodology used to measure sensitization: CDC Antibody-mediated cytotoxicity, FC: flow cytometry, Luminex Stegall MD. Am J. Transplant. 2006; 6: p. 346-341. Magee C. Transplantation. 2008; 86: p. 92-103. Thielke JJ. Transplantation. 2009; 87: p. 268-273. Rogers NM. Transplant Int. 2011; 24: p. 21-29. Montgomery, RA. Am J. Transplant 2010; 10: 449–457 Morath C. Transplant Internat. 2012; 25: p. 506-517. Vo AA. Transplantation. 2013; 95: p. 852-858. Kute VB. Saudi J Kidney Dis Transpl. 2011; 22(4): p. 662-669. Riella LV. Transplantation 2014; 97: 1247-1252. De Sousa-Amorim E. Transplant Proc. 2015; 47: 2332e2335. Okada D. Transplant Internat. 2018; 31: 1008-1017. Jordan S. NEJM. 2017; 377: 442-453. Winstedt L. Transplant Int. 2019; 32(S2): 62. Marks WH. Am J. Transplant. 2019; 19: 2876-2888. Fernández C. Nefrologia. 2017; 37(6): 638-645. Kim DG. BMC Nephrology. 2019; 20: 456. 85 86 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 13 – Main infections after desensitization. Autor CMV (%) Urinarias (%) BK (%) 1 Khwaji (L.A.) 15 vs. 10 34 vs. 31 10,6 vs. 5,5 Jeong (Korea)2 5,3 10,5 De Sousa (H Clinic)3 13 85 4,3 Morath (Heidelberg)4 10 20 20 Thielke (Illinois)5 7 4,9 Niederhaus (Wisconsin)6 15 0 vs. 5,6 21 Okada (Japón)7 20 vs. 11 0 vs. 1,6 Jordan (USA + Suecia)8 0 0 Fernández (A Coruña)9 26 33 4 Toyoda (L.A.)10 16 vs. 25 EBV: 2,9 vs. 11,3 11,2 vs. 13 Amrouche (Necker)11 9 75 10 Kim (Corea)12 64,7 vs. 48,7 vs. 13,9 23,5 vs. 51,5. 7,7 0 vs. 5,1 vs. 6,6 Kahwaji J. Transplantation. 2011; 91: 225-230. Favor de considerar que si las referencias al pie de la tabla son las mismas que las numeradas en la tabla no se ve la necesidad de duplicarlas aquí. --> Jeong JC. Medicine. 2016; 95(5): e2635. De Sousa-Amorim E. Transplant Proc. 2015; 47: 2332e2335. Morath C. Transplant Internat. 2012; 25: 506-517. Thielke JJ. Transplantation. 2009; 87: 268-273. Niederhaus SV. Transplantation. 2011; 92: 1-17. Okada D. Transplant Internat. 2018; 31: 1008-1017. Jordan S. NEJM. 2017; 377: 442-453. Fernández C. Nefrologia. 2017; 37(6): 638-645. Toyoda M. J Immunol Res. 2017; 2017:5672523. Amrouche L. Transplantation. 2017; 101:2440-2448. Kim DG. BMC Nephrology. 2019; 20: 456. transplantation, with high patient and renal survival, in the paired donation list, the acceptance of A2 groups for O spite of an increase in the incidence of antibody-mediated recipients, the reduction in the unacceptable donor threshold rejection, which may be reduced by using Imlifidase or and transnational programmes all increase the possibilities. eculizumab. Another option could be to desensitize patients to try to reduce The possibility of a highly sensitized recipient accessing a their cPRA and have more options for transplantation. The HLA-compatible transplant by means of paired transplanted results with Imlifidase are hopeful, with the aim of achieving would be an excellent option. Nevertheless, the probabilities desensitization that is 100% effective. of transplantation are low, especially for those with a cPRA of 97% or more 667 . Specific RT programmes for hypersensi- tized patients at a national level make it possible to transplant Living donor with ABO incompatibility many patients who cannot find any possibility of accessing paired transplantation and who also cannot be desensitized. Of the different options for renal replacement therapy, LDKT The possibility of using this option falls considerably when the offers the highest patient and graft survival rates, a better cPRA is above 99.9%. long-term quality of life and lower economic cost 669 . In the Deciding on one option or the other basically depends on donor-recipient selection process, blood group incompatibil- weighing up the particular situation of a candidate and their ity (ABOi) has traditionally been considered to be an absolute donor in terms of blood group and cPRA, as this will influence contraindication for donation. However, it has been known for the time spent in the paired donor scheme waiting list, or the a number of years that transplantation from an ABOi donor special deceased donor list. With desensitization there is a gives excellent results. Unlike HLA incompatibility, in an ABOi higher probability of transplantation within less time, in spite transplantation (once the desensitization process has been of a high incidence of rejection. The British guides contain a successfully completed) clinical evolution is similar to that of simulator where depending on the blood group of the donor ABO-compatible transplantation (ABOc). and recipient, the state of sensitization and age, the proba- bility of a paired transplantation is calculated depending on the level of HLA sensitization and ABO group, with predicted The effectiveness of ABO-incompatible LDRT survival (2). Software has recently been developed to aid the management of a paired donation 668 . • We recommend ABOi LDKT as it gives results that are Finally, desensitization is not possible in a considerable per- comparable to those achieved by ABOc LDKT (Quality of centage of patients due to their high cPRA or MFI. Moreover, evidence: B). due to their high cPRA it is hard to find a suitable donor in • We suggest that the option of ABOi transplantation should the lists for paired RT or even in the deceased donor lists with be considered in hospitals that perform LDKT to increase specific programmes. The inclusion of compatible donors in the opportunities for transplantation (NG). n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 87 The rule that donation should be avoided in case of blood administration of IVIG, which may have an immunomodulat- group incompatibility has been abandoned and successfully ing effect, as well as making it possible to restore the protective surpassed 670 . Poor initial results 671 meant that this option antibodies lost in apheresis. Nevertheless, these preparations was side-lined until the 1990s, when different groups, espe- also contain isoagglutinins, which may be a confusion factor cially in Japan 672,673 reported excellent results in series with when interpreting how titres evolve during treatment 686,695 . a large number of patients. This led to its use by groups in To centre on the different apheresis techniques, many the U.S.A. 674,675 , France 676 and Sweden 677,678 . In Spain the different forms have emerged in recent years (53,683,696- first ABOi LDRT took place in 2006, in the Hospital Clínic, 701). Basically there are three techniques, each with its own Barcelona, and the good initial results were confirmed by versions: plasma exchange, specific immunoadsorption and other groups 679–683 . The Hospital Universitario in A Coruña non-specific immunoadsorption. When we are dealing with 684 soon tried this option, followed by several other hospitals low titres, any technique will be effective. To effectively reduce 685 . high titres, no technique has been proven to be any more effective than the others, although some authors state that What do we need to study to carry out an specific immunoadsorption would be the best. Economic costs ABO-incompatible LDRT? should be taken into account as well as efficacy, together with logistic aspects and side effects, especially in connec- • We suggest that ABOi transplantation should be considered tion alterations in coagulation factors, reactions of intolerance an alternative when there is no ABO-compatible donor (D). the risk of infections 688,698,699 . The immunoadsorption tech- • We suggest monitoring titres of the IgG and IgM isoag- niques are tolerated the best, making it possible to treat a glutinins. The importance of the role of both types of greater volume of plasma in each session without altering immunoglobulin in transplantation is controversial (D). the coagulation factors. An interesting logistic aspect is the possibility of simultaneously carrying out haemodialysis and The initial acceptance criteria are the same as for an ABOc apheresis. LDKT (9), to which we add the possibility of determining Respecting the blocking of isoagglutinin production, antibodies against A or B incompatible antibodies, known as splenectomy was used in the first Japanese experiences 671,672 . isoagglutinins. The titre of IgG and IgM isoagglutinins should The chief drawback with this, apart from possible surgical be the same or less than 1/8 for transplantation to take place. and complications and infections, was the need for routine The next requirement will therefore be to apply one of the vaccination against encapsulated bacteria over an indefinite apheresis treatments used to reduce the isoagglutinin con- period of time. Replacing splenectomy with treatment using centration, if necessary (it always is necessary, except for very rituximab not only proved to be more effective and safer, as low basal titres <1/8). Normally from 3 to 5 apheresis sessions its effect reduces after a few months. Although it is not sup- are required to reduce the titres to a safe level for transplanta- ported by any clinical trials, it is now the treatment of choice tion. If the basal titres are very high (>1/512) this increases the 676,678,682,684,697,698,702–704 . However, there is no agreement on risk that the apheresis treatment will not achieve an effec- the number or size of doses, how many days it should com- tive reduction in the same, so that donation is ruled out. mence before the start of desensitization or other aspects of This gives rise to an enormous economical and emotional administration criteria. Some groups consider a single dose cost 686,689 , so that many hospitals recommend or contraindi- given 3-4 weeks prior to transplantation to be sufficient; oth- cate desensitization treatment when the basal titres are very ers prefer two doses, the first 3-4 weeks before transplantation high (9,686,687). There is no agreement on whether a low titre and the second immediately beforehand, seeking to com- is simultaneously necessary for both Immunoglobulins (IgM bine the immediate and deferred pharmacological effects and IgG) 690,691 , or if this is necessary for only one of them. 678,682,684,692 . Opinions also differ regarding the size of the dose. Some groups believe that it is crucial to reduce the IgG titre, At first the same dose as the one used in lymphoma treatment while others hold the contrary opinion. On the other hand, was given, 375 mg/m2 once or twice 473 , but after studies were highly experienced hospitals accept transplanting patients published indicating that a lower dose was enough to remove with higher titres (1/32) at the moment of RT 692,693 . CD19-positive B lymphocytes from circulation guidelines were When the incompatible blood group of the donor is A2, established that varied from 50 mg to 400 mg 678,705–707 . Sev- given the low antigen expressivity some hospitals do not for- eral meta-analyses associate the excessively prolonged use of mally consider this to be an ABO incompatibility if the titres this drug (but not the size of the dose) with higher mortal- are low, and they go on to transplant directly as if the donor ity due to infections 697,698,700,701,708,709 . Thus these findings were ABO-compatible 694 . and the improved efficiency of apheresis techniques have led some groups to decide against systematically administering How should isoagglutinins be measured? rituximab, and they now only give it in certain cases 710,711 . Bortezomid would be included among the other therapeu- This aspect is described in detail in section 9. tic options for blocking isoagglutinin synthesis. It has been trialled as a desensitization therapy in ABOi LDRT in cases Desensitization techniques (Table 14) refractory to rituximab or to substitute it 680,712 . Eculizumab has also been trialled for usefulness, and it was able to prevent Desensitization for an ABOi RT requires two essential actions: antibody-mediated rejection in four patients with no aphere- eliminate isoagglutinins from the circulation and inhibit their sis treatment 713,714 . There is interest in knowing the possible synthesis. The treatment can be complemented with the efficacy of Imlifidase, which is capable of cleaving all circulat- 88 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 14 – Sensitization techniques and their objectives. Technique Variants Objectives Remarks Evidence quality Plasma exchange Single filtration To reduce circulating Possible complications with B Double filtration isoagglutinins post-transplantation haemorrhage due to alterations in the coagulation system Immunoadsorption Specific To reduce circulating Specific immunoadsorption is B Non-specific isoagglutinins more efficient in reducing IgM titres Immunoglobulins Low doses Replacing immunoglobulins Administered at high doses it may C High doses and a possible contain isoagglutinins that immunomodulatory effect interfere with the titration result Splenectomy Depletion of B cells This is no longer routinely C practiced Rituximab Conventional Depletion of B cells There is no agreement on dose or C doses vs. low frequency of administration doses ing IgG in two steps and a few minutes after single dose. A groups only do this if there is renal dysfunctioning or a biopsy limiting factor would be its lack of efficacy against IgM anti- shows signs of rejection other than C4d deposits. Some hospi- bodies. tals prefer to include one or two apheresis sessions in their Finally, many hospitals routinely use IVIG. This would protocol, in the attempt to prevent a rebound in the titres have two uses: it restores the immunoglobulins eliminated or even to prevent antibody-mediated rejection. It should not by apheresis, for which administration at low doses of be forgotten that this rejection may arise even if the patient 100 mg/kg - 200 mg/kg would be sufficient, or it could be has not yet shown a rise in titres 680–682 . On the contrary, given at high doses (1 g/kg - 2 g/kg) to achieve a multifactorial other hospitals consider that post-transplantation apheresis immunomodulating effect, most especially providing anti- sessions only cause problems (with haemorrhaging, logisti- idiotype antibodies which would facilitate the phenomenon of cal problems and unnecessary expense) without any benefits accommodation 715 . Three factors arise against the systematic 672,684,698,719 . use of IVIG: it is unnecessary to replace idiotype antibodies Is patient and graft survival the same as with ABOc LDRT? when specific IA is used; its efficacy has yet to be proven, The published results of series of hospitals report similar so that it may constitute an unnecessary cost, and finally results or slight differences in patient and graft survival (C). its isoagglutinin content may distort the results of titration Meta-analyses or analyses of registries are able to detect 677,682,683,690,695 . poorer patient and graft survival due to infections in the first How do the isoagglutinins behave after transplantation? Is year of evolution (B). it correct to monitor titres and no intervene while they remain We recommend closely monitoring complications with low? infections in ABOi recipients due to certain experiences that We suggest practicing one or two apheresis sessions after have reported increases in mortality secondary to infections transplantation as the protocol, although as no clear recom- (B). mendations exist, other groups prefer to wait for a possible The meta-analyses that report the results of patient sur- rise in the titres (C). vival after receiving an ABOi LDRT do so by comparing this Isoagglutinins must be at a safe level before practicing an with the results of ABOc transplantation. The majority show ABOi LDRT. Anti-A or B antibodies may bounce back after that there are no differences, or that any differences are small transplantation to levels even higher than they were at the 53,696,697,703,704 and that they disappear over the long-term. start of desensitization therapy 687,706 . This potential rebound Even when the potential increased risk of complications due may lead to an early rejection, although in the majority of to infection caused by desensitization therapy is taken into cases when an increase in titres is detected without any account, ABOi LDRT would be better in any case than deceased alteration in graft functioning, biopsy of the same shows the donor RT or remaining in dialysis 720 . On the other hand, nor absence of immunological damage except for the usual pres- was it found to have higher mortality when it was compared ence of C4d deposits 716,717 . A low level of isoagglutinins in the to paired donation 721 . peripheral blood may indicate that most of them have been In terms of graft survival, many groups have reported sim- absorbed by the graft, so that circulating anti-A or B antibod- ilar results over the short to medium term and even over ies would have less avidity for donor antigens, reducing their the long-term 682,692,693,700,708,722 . Other series found poorer pathological involvement 718 . results, and data from meta-analyses and registry studies In any case, after transplantation some groups believe underline shorter graft survival than in ABOc LDRT at one, it to be necessary to recommence apheresis sessions if the 3 and 5 years, although there were no long-term differences isoagglutinin titres increase during the first two weeks. Other 53,697,703,704,722 . n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 89 Although ABOi transplantation is considered to be a plasma membrane had occurred, with regional changes in reasonably safe procedure, the use of powerful immunosup- platelet aggregation and neutrophil recruitment, this intrin- pressant drugs, and especially rituximab, is associated with sic resistance against cytotoxicity would be lost and graft increased infections 700,708,709 . Several series report a higher thrombosis could occur in the first hours 718 . It is therefore rec- frequency of viral infections 723,724 as well as pneumonia, uri- ommended to administer prophylactic anticoagulation during nary infections and infections of the surgical wound 724,725 . the first week. Not all of the series agree with these findings, and moderat- What role would the complement and C4d deposit in trans- ing the use of rituximab as suggested by Japanese groups has plant biopsy? been accompanied by a significant fall in infection by CMV 693 . The systematic presence of C4d in protocol biopsy stains in Moreover, with this moderation and other anti-infection pro- ABOi transplantations is well-known, although its exact sig- phylactic measures, rates of urinary infection and pneumonia nificance is not known, although it tends to be understood have recently been reported that are comparable with those as an accommodation phenomenon 713,730,731 . Patients with corresponding to ABOc transplantation 698,723 . an ABOi transplantation with C4d deposit but no other histo- Unlike infections, the incidence of tumours does not seem logical abnormalities do not usually develop glomerulopathy to increase in ABOi transplantations, although it is true that of the transplant or chronic graft dysfunction. In fact, when there is not so much literature on this subject 726,727 . they have a persistent diffuse C4d deposit they have less What occurs with acute rejection? chronic damage after the first year. Pharmacological blockage The incidence of acute rejection, and particularly antibody- of complement activation may be of interest to prevent or treat mediated acute rejection, is higher in meta-analyses of ABOi humoral rejection, as well as to prevent thrombotic microan- transplantations, although many hospitals report comparable giopathy phenomena associated with endothelial damage. results (B). There are few experiences, which nevertheless were success- The initial Japanese series reported a significant incidence ful, in the prophylactic use of eculizumab in transplantations of graft loss due to hyperacute or accelerated rejection, and of this type. in fact this may be the main or perhaps the only differ- ence between ABOi and ABOc transplantations. This would be due to the swift development of acute rejection medi- ated by antibodies against A or B incompatible antigens. On Paired kidney transplantation and altruistic the contrary, the initial Swedish series described a very low donors rejection rate, cellular as well as humoral, which it attributed to the important amount of immunosuppressant medication LDKT proposes interchanging donors in different donor- administered. Other works underline a higher incidence of recipient pairs, which due to biological incompatibility or mild cellular rejection 679,728,729 . another reason decide not to transplant directly but rather Accommodation and rejection mechanisms to create new donor-recipient pairs for direct transplanta- A phenomenon involving possible immunological accom- tion. modation in a situation of ABO incompatibility arises in Biological incompatibility between donor and recipient is almost all ABOi transplantations: the presence of high titres a barrier for LDKT. 35% of patients are estimated to be incom- of isoagglutinins, AB antigen expression in the endothelium patible with their potential live donor 732 , due to blood group and C4d positivity in peritubular capillaries, in the absence of incompatibility (ABOi) or the existence of preformed anti- other signs of rejection and with conserved renal function (B). bodies in the recipient against the HLA system antigens of Early losses due to accelerated rejection are rare and are their potential donor, giving rise to a positive crossmatch test usually accompanied by thrombotic microangiopathy (C). (HLAi). The possible options for treatment therefore include We suggest that prophylactic anticoagulation should be (9): searching for another living donor; including the pair in a administered in the first weeks after transplantation, due paired RT scheme; considering an incompatible transplanta- to the susceptibility of the ABOi endothelium to thrombotic tion with desensitization; or remaining in the waiting list for phenomena in the case of any immunological or non- a deceased donor. immunological insult (C). Paired LDRT was suggested by Rapaport in 1986 733 , and The most intriguing aspect of rejection mediated by anti- for this the author considered it to be fundamental to guar- bodies against ABO antigens is that it rarely appears after 2 - antee the anonymity of the members of the new pairs which 3 weeks post-transplantation, in spite of isoagglutinins being were formed. Subsequently Park’s group 734 carried out the detected, even at high titres, and signs in protocol biopsies that first paired donation between two recipients with incom- the complement had activated. Several different mechanisms patible donors in South Korea, in 1991. Switzerland (1999) may intervene in accommodation, and they may affect anti- and the U.S.A. (2000), designed paired LDKT programmes body synthesis, exposure to antigens and the development of at hospital level. The Netherlands started the first national active protection measures. To establish accommodation it is scheme in 2004, followed by the United Kingdom [2007], necessary to overcome the first phase successfully, in which Canada [2009] 735–738 and Spain [2009] 543 . The Spanish scheme, the complement together with the initial damage caused by which led to 203 transplantations from 2009 to 2018, is now the antibodies would activate a repair and protection response the second in terms of activity, after the United Kingdom against the cytotoxicity which over the long-term will favour 51 . the acquisition of activate cellular and tissue protection mech- The results obtained have increased the number of trans- anisms 64 . If in the first phase ultrastructural alteration of the plantations 15,51,667,739–743 with similar results in graft and 90 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 patient survival to those of direct compatible LDRT 744,745 , and “hard to match”, and a working protocol which describes the better results than direct HLA-incompatible LDRT 6,54,746,747 . procedures for registering pairs, creating pairs (or matching- run) and the procedure which leads to transplantation. Foundations of the paired KT scheme in Spain Exchange options within the scheme (figure 14): We recommend the option of paired KT over HLA- incompatible transplantation due to the improved survival it An exchange of donors between donor-recipient pairs previ- achieves, so that this information should be given to paired ously registered in a database, to form cycles of two and three with HLA incompatibility (Quality of evidence: B). KT. Patients with very few transplantation options (blood group The donors and recipients in these cycles form new pairs O and highly sensitized) should receive an explanation of the which are “more” compatible in immunological terms or, if possibility of adding treatments such as desensitization to they were compatible beforehand, ones who are more suitable paired RT cruzado, to increase their possibilities of transplan- in anthropometric terms or age. Thus for a cycle to be formed tation (NG). it has to be bidirectional. That is, all of the donors in the cycle The main aim of the Spanish paired transplantation 543 should be compatible with the recipient selected for them. It is to increase the possibilities of LDKT in those cases with- is a legal imperative that the members of the new pairs must out donor-recipient compatibility, due to ABOi blood group not know each other 41 . or a positive crossmatch test, as well as other circumstances The transplantation procedures are executed simultane- in which, although transplantation within the pair is not ously, to minimise the risk of one or several recipients not impossible, there is a real benefit associated with a paired receiving a transplant after the nephrectomy of their incom- RT procedure (such as a reduced difference in donor-recipient patible donor. age or donor anthropometric characteristics that better fit the The inclusion of an altruistic donor in the scheme, thereby needs of the recipient). commencing a KT chain. Compatibility in this option is one The regulation which established the procedure for way, that is, it is only necessary for the donor to be compatible paired transplantations was developed and published by with the next recipient in the chain, facilitating the creation the ONT in 2009, in collaboration with a multidisciplinary of the latter 749 . committee of experts in different aspects of the living In this case it is not necessary to carry out all of the trans- donor KT procedure: nephrologists, immunologists, urolo- plantations at the same time, as if an unexpected event occurs gists, transplantation coordinators and experts in bioethics which causes a recipient in the chain to not receive their and lawyers. corresponding RT, their donor will still not have made their Once the scheme was under way a continuous improve- donation. Being able to create the transplantation chain in ment mechanism was established, based on the creation of several phases also makes it possible to add links, increas- a workgroup and a scientific committee (whose members are ing the number of transplantations. This option is known as a drawn from the workgroup). The workgroup is composed of transplantation chain with a bridging donor. The final link in the individuals in charge of the scheme in the ONT and in the chain is a patient in the waiting list of the hospital which each participating hospital. It is convened by the ONT once a evaluated the altruistic donor 750 . year to analyse the results of the scheme and establish modifi- Given that transplantation chains are characterized and cations in different areas to achieve continuous improvement. differentiated by including an altruistic (Good Samaritan) The functions of the scientific committee include evaluating donor, they are described in a specific chapter. complex cases, as well as drawing up suggestions for improve- ments. The scheme has thereby gradually improved, by including Participating hospitals new hospitals, unifying clinical and immunological crite- ria, updating registry information, expanding donor typing, Hospitals that wish to take part in a paired RT scheme must including chains of altruistic donors, creating a compatibility have the necessary infrastructure and the agreement of all algorithm, the recent inclusion of the possibility of performing the clinical departments involved to fulfil the conditions of ABOi transplantation in the scheme for potential recipients the scheme. The transplantation teams must also have expe- with HLA sensitization, the priority score, the search for renal rience in the LDRT procedure. This point is of vital importance, transport schemes which reduce times and are sustainable, as donors will be exchanged between different hospitals and and the broadening of pairs and HLA diversity by making the there must be trust in how all of them will work. scheme international. In fact, three international paired trans- Due to the above reasons, the national paired renal dona- plantations have now been performed, between Spain and tion protocol sets the following requisites: Italy and between Spain and Portugal 748 . There is a criterion which sets the minimum amount of The scheme contains 3 elements: the requisites which activity. This currently stands at having carried out 15 LDRT transplanting hospitals have to fulfil to take part, the com- in the three years prior to joining the scheme. puting tool which contains the donor and recipient database, Minimally invasive techniques must be used for nephrec- a selection algorithm for possible exchanges, and a tool for tomy 32 . optimising detected cycles, to maximise the number of trans- The conditions set by the scheme for carrying out diagnos- plantations and increase the options for recipients who are tic tests (such as broadening donor typing) must be accepted. n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 91 Figure 14 – Exchange options in the Spanish paired renal transplantation scheme. An individual in charge of the scheme must be designated donors are registered and kept updated, as required for match- at hospital level. ing: Participation in the scheme must be approved by the cor- A patient may be registered with more than one donor. A responding health authority 543 . recipients may form a pair for exchange with as many donors The scheme currently has 26 participating hospitals and as they supply, which increases their chances of finding a 19 histocompatibility laboratories (one of which is the refer- match 752,754 . From 2009 to 2018 656 donor-recipient pairs ence laboratory for two Madrid laboratories and 6 others in joined the Spanish scheme for paired renal donation (557 Catalonia) in 12 autonomous communities. This is an impor- recipients with a donor, 36 recipients with two donors and tant datum, given that countries such as the Netherlands base 9 patients with more than two donors). some of the success of their scheme on the existence of a cen- There is no upper or lower age limit for the inclusion of a tral histocompatibility laboratory 751 . In spite of the increased recipient. The donor has to comply with the requisites estab- difficulty of managing immunologically complex patients in lished by Spanish law respecting minimum age (≥18 years) different laboratories, Spain has obtained excellent results. and there is no upper age limit, on condition that the donor The English scheme is organized in a similar way to the one has been considered to be suitable by the participating hos- in Spain, with 20 different histocompatibility laboratories and pital. The donors and recipients registered in the scheme 23 transplanting hospitals, and the United Kingdom scheme have a similar average age, at 50 years and 46.3 years, respec- is now one which has performed the highest number of paired tively. RT in Europe 51 . The scheme permits patients to register with their poten- Hospitals which are not members of the scheme may tial a priori biologically compatible and incompatible donors, include donor-recipient pairs through hospitals which are although they must also wish to make an exchange, to find a members. Autonomous Community Transplantation Coordi- younger donor, or one of a more suitable size, improve HLA nators establish agreements and procedures for this 543 . compatibility or for simply altruistic reasons 755,756 . The rea- Thus all renal patients with a potential incompatible donor sons for inclusion in the scheme were ABOi in 43% of cases, (or a compatible one, but who could benefit from an exchange) the presence of DSA in 51%, ABO and HLA incompatibility will therefore have the opportunity of taking part in the in 4% and 12 pairs were compatible, amounting to 2% of the programme, thereby guaranteeing fair access to it. This oppor- registered pairs. tunity for patients and their potential donors involves the right The database permits the registration of altruistic donors which all of them have to be properly informed about the to build a transplantation chain 51 . paired LDRT Scheme 2,9 . The application automatically associates a numerical code with each registered donor and patient, which will allow the members of the new pairs formed to remain anonymous, Computer tool without the process losing traceability. It contains a compatibility algorithm, which searches for This online application can only be accessed by hospitals all of the possible options for exchange within the donor- which are members of the scheme and the personnel in recipient pool, forming cycles of 2 or 3 transplantations and charge of the scheme in the ONT, by entering their user name chains which commence with an altruistic donor. There are and password, to comply with the data protection law. The two rules: search for possible exchanges may be carried out manually, ABO compatibility and HLA compatibility: using a virtual although the number of pairs and their complexity makes it crossmatch test, it selects those recipients who do not have recommendable to use the system automatically to gain good preformed antibodies against the different HLA antigens of results. This computer tool includes 543,752,753 : the donor (for class I HLA as well as class II) 736,740,746 . A database of donor-recipient pairs, where the demo- Exclusively HLA compatibility, in this case permitting ABOi graphic and clinical data of the patients and their possible RT 697,757 . 92 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 A selection tool for the detected cycles to maximise the The participation of pairs in the paired donation scheme number of transplantations and increase the options of the requires signing a specific consent form (B). recipients who have most difficulties in finding a compatible Donors should be informed about the regulations govern- donor, such as those with group O and/or highly sensitized ing the confidentiality and anonymity of the procedure, when patients 543 . To this end the system has: it is paired as well as in the form of a chain or by direct altruistic A score which takes into account level of immunization donor, ensuring that the donor accepts this before continuing (cPRA), blood group, time in dialysis, donor and recipient age, (NG). the length of time a recipient has been included in the scheme The donor should be informed of the risks and benefits and, in case of a draw, geographical distribution. Given the which arise from transporting the kidney instead of the donor exceptional nature of a compatible pair and that this increases travelling, and the possibility of the kidney being transplanted the options for transplantation, these are given priority 51 . into another person (NG). An optimization model, which attempts to maximize: The donor and recipient have to sign a specific consent The number of transplantations carried out. form 2,9,543 to participate in the scheme, which means that Transplantations into patients with difficulties to find a they have understood the responsibilities they have towards compatible donor. the other pairs if they are selected in a transplantation cycle or The cycles selected, which involves obtaining more chain. For this they must be been previously informed about two-transplantation cycles than it does those with three the risks and benefits of LDRT, the options offered by this transplantations (on condition that the total number of trans- scheme, the procedure respecting the deceased donor wait- plantations is maximized) ing list, the obligation to keep maintain the anonymity of the The number of robust cycles. When cycles involving three members of the new pairs which are formed, the probability transplantation cycles are selected, if we have to choose of success of the transplantation according to their character- between two cycles that share one or two pairs and have the istics (blood group and level of immunization, etc.), and the same score, the one that can be shortened to a two-transplant possibility, if applicable, of receiving desensitization therapy cycle will always be selected (which facilitates its eventual together with paired transplantation, to increase the chances execution) 752 . of success of the transplantation, as well as the possibility of The compatibility algorithm and the selection tool are an unexpected event occurring (see the section on transporta- always applied together, seeking an optimum set of possible tion logistics). Therefore: combinations. Two programming models are currently used The information supplied to a transplantation candidate in Europe for this 752 : and their potential incompatible living donor must include Construction of a compatibility graph, assigning as score the scientific evidence for the results of a compatible trans- (known as weight) to each one of the members of a pair, plantation, incompatible transplantation, and the results of based on criteria set by the programme (age and level of both in comparison with remaining in the waiting list. Group immunization, etc.) This is the model used by the Spanish O recipients, highly sensitized patients or those with both con- scheme. ditions must be informed of the lower probability of receiving Formulation of the different exchanges using integral pro- a transplantation in this scheme (9). The recipient must be gramming. informed that if they are in the deceased donor waiting list they will be able to remain in both waiting lists, but that Action protocol they will leave the deceased donor waiting list if they are selected for paired transplantation. The information supplied Before including donor-recipient pairs in the paired transplan- to each pair must always be comprehensible and accessi- tation scheme and continuing with the pairing dynamic, the ble. pairs have to be informed of how the scheme works and other ABOi and/or HLAi donors and their recipient must be aspects of it. informed of the existence of the paired transplantation scheme, as well as the different options for treatment which Information for the pairs exist, the risks of each option and their probabilities of success We recommend the option of paired KT rather than HLA- 2,9 . incompatible transplantation due to its better survival, so that Donors must know that a compatible transplantation has a this information should be given to the pairs in which direct higher probability of success than direct HLAi transplantation, transplantation will not be possible (B). with higher short- and long-term risk, if one is suggested for The recipient and their potential live donor should be them 2,6 . given information about the paired scheme, with the exist- If a pair is compatible and decides on inclusion in the ing scientific evidence for the same as well as comparison paired transplantation scheme to obtain other benefits such as with other therapeutic options. The probability of receiving a reducing the age differences with their living donor, improv- paired transplantation should also be explained, depending on ing HLA compatibility or a more suitable weight, they must their characteristics (blood group and level of immunization) receive all of the relevant information to decide on their inclu- (NG). sion. The donor and recipient in a compatible pair who could Paired transplantation benefit from a paired transplantation should receive all of the We recommend registering the donor-recipient pair in the available information on the same to decide whether to par- paired RT scheme only after the end of the clinical study and ticipate (NG). when the immunological screening is complete (B). n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 93 We recommend that the individual in charge of the paired deceased donor waiting list while the paired transplantation RT scheme in each participating hospital should review and procedure continues. If the cycle or chain fails, then they will update the information corresponding to the registered pairs become active against in the waiting list 543 . before creating each pair (B). We recommend describing the possible factors that may Results of paired transplantation rounds limit donor acceptance (surgical complexity, age, etc.) at the moment when a pair is included in the paired RT scheme (B). Once the possible combinations have been selected the ONT We suggest that patients should be excluded from the issues a report on the results for the hospitals which are deceased donor waiting list when they are selected in a paired involved, using a secure information exchange space. After transplantation cycle. Meanwhile they can be active in both this moment the individuals in charge of each one of the cycles waiting lists (NG). at hospital level will evaluate the information received (age, As a general rule, the scheme plans to perform three rounds blood group and HLA typing), sharing the clinical reports of of paired transplantations per year, that is, one every four the donors and agreeing on the execution of crossmatch tests months, so that the transplantation teams have enough time with immunology laboratories. to review and update their pairs. It is possible to create an A 7 day deadline is set for sharing the clinical reports, plus extra round under special circumstances, such as that of an 15 days more to carry out the crossmatch test. As a general altruistic donor whose study has finalized. rule, this test will take place in the histocompatibility labo- In the Netherlands or the United Kingdom rounds of ratory of the hospital which registered the recipient, so that paired transplantations are created quarterly, and in the UNOS the donor and recipient hospital laboratories will agree on a scheme they are made weekly 51 . Nevertheless, there is no evi- date and means of sending the samples. This test will be take dence that a higher number of rounds gives rise to a higher the form of complement mediated cytotoxicity and/or flow number of transplantations. The number and characteris- cytometry. tics of the registered pairs determine the number of possible Some patients are immunized to such a high level that it exchanges 758,759 . In fact, the number of exchanges detected is improbable that they will find a donor for whom they lack increased in Spain when the number of active pairs increased. DSA. In these cases a combined strategy of desensitization and The average number of active pairs for each round of paired paired transplantation may be used. That is, the transplanta- transplantations in Spain was 120 over the past 6 years, with tion team may, after considering this with the immunology 60% of new pairs in each round. department and agreeing it with the recipient, decide not to Three weeks before each round the ONT sends out an email register in the database the DSA which the patient has at showing the specific date of the round, so that hospitals can low titres. If they are selected for exchange with a compati- include new donor-recipient pairs and update the registered ble donor who has one or several of the unregistered DSA in information. A donor-recipient pair cannot be included until the application, then desensitization and transplantation may their study has finished and immunological screening is com- take place. 55,761,762 . plete and has been updated, to ensure that if they are selected, If the results of the crossmatch tests in the same cycle are it will be possible to follow the steps in the process within the negative, the hospitals will share angiotomography images of set times. Otherwise potential cycles with a high risk of not the renal anatomy of the donors and agree the date for trans- being able to perform the transplantations would be created, plantation. with negative consequences for the selected patients and for As is the case in any directed LDRT, the ethics committee the working of the Scheme 756,760 . A similar recommendation should evaluate the procedure, and the donors will have to was published in the latest edition of the British LDRT guide 2 . give their express consent to donation before the examining It is also necessary that the information is kept up-to-date, magistrate of the court corresponding to the town in which to prevent the detection of cycles which are then found to be the nephrectomy or transplantation will take place 41 . impossible to implement, due for example to the appearance In the 9 years this scheme has been working, in Spain a of new unregistered donor-specific antibodies, or the medical total of 29 rounds of paired transplantations and 203 trans- contraindication of a recipient or donor to continue with the plantations have been carried out, distributed in 42 cycles procedure 746,760 . In fact, 50% of the reasons why a transplanta- of 2 transplantations, 27 cycles of 3 transplantations and 14 tion cycle is not implemented can be avoided by reviewing the chains of transplantations that commenced with an altruistic registered information (for example, the registered DSA), giv- donor 763 (Figure 15). 32.8% of the patients were transplanted ing information on possible restrictions for the acceptance of a in this scheme, unequally distributed according to donor and donor for specific patients (for example, not accepting a donor recipient blood group. The highest probability corresponded aged over 70 years for a recipient aged under 40) and if the sta- to those pairs in which the donor was group B and the recip- tus of donors and recipients is updated before each round (to ient was group A (Table 15). Altruistic donation made 43 detect possible medical contraindications in the donor as well transplantations possible, so that without this, the rate of as in the recipient). transplantations within the scheme would have been 26.1%. Patients can be active in the deceased donor waiting list and in the list of the paired transplantation scheme Transplantation logistics at the same time, thereby increasing their possibilities of transplantation. However, patients should be excluded from We recommend performing donor nephrectomy in their own the deceased donor waiting list when they are selected for a hospital and transporting the kidney to the recipient’s hospital cycle or chain, and they will be temporarily excluded from the for transplantation (B). 94 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Figure 15 – Number of 2 transplantation rounds, 3 transplantation rounds and chains initiated by an altruistic donor. Spain 2009-2019 763 . Table 15 – Percentage of patients transplanted in the scheme according to blood group and average calculated PRA (PRAc), with Interquartile Range (RIC). Spain 2009-2018. GS N transplanted/N Median PRAc (RIC) of included those included D0-R0 26/111 (23.4%) 88 (56-99) D0-RA 47/77 (54.5%) 79 (11-94) D0-RB 9/22 (40.9%) 88 (51-98) D0-RAB 3/9 (33.3%) 100 (92-100) DA-R0 42/194 (21.6%) 0 (0-54) DA-RA 19/77 (24.7%) 86 (44-99) DA-RB 20/42 (47.6%) 0 (0-48) DA-RAB 2/12 (16.7%) 97 (90-99) DB-R0 15/48 (31.3%) 0 (0-70) DB-RA 16/24 (66.7%) 0 (0-36) DB-RB 2/12 (16.7%) 75 (34-92) DB-RAB 1/5 (20%) 96 (89-100) DAB-R0 3/11 (27.3%) 56 (0-99) DAB-RA 4/9 (44%) 56 (0-99) DAB-RB 0/4 48 (0-98) Although the scheme includes the possibility of the donor recipient’s hospital if they wish, while also explaining that the travelling to the hospital where the recipient of their kidney results of renal transportation are excellent 9 . will receive it, the recommended option is for nephrectomy As a general rule, the means of transport to be used is to take place in the donor’s hospital and for the kidney to the one which makes it possible to keep the duration of be transported. Nephrectomy in their own hospital permits ischemia below 8 hours in a cost-effective way 543 . Transport, the donor to be in contact with their family and allows them if necessary, may be terrestrial (in an ambulance, hired car or to remain in known surroundings, being cared for by the high-speed train) or by air (in a private or commercial flight). professionals who have studied them, all of which reduces The ONT has specific agreements that permit the transporta- the stress for the donor and their family. Moreover, if the tion of a graft in the aircraft cabin, looked after by the crew, at donor does not travel to the hospital where the recipient is, no cost to the healthcare system. it will be easier to maintain their anonymity. In Spain, 97% of The procedure also stipulates that the nephrectomies from paired transplantations have involved transporting the kid- all of the donors in the same cycle without an altruistic donor ney (using an ambulance for this, or a high-speed train or will take place simultaneously, except in exceptional cases. aircraft) with an average time in cold ischemia of 5.6 (2.8) This condition was established to minimise the risk that one hours. recipient in a cycle would not receive a kidney after their orig- Although renal transport necessarily involves the kidneys inal donor had been nephrectomized. being transplanted after a time in cold ischemia, it has been In any case, the scheme provides for different scenarios of found that cold ischemia times <12 hrs. do not affect the unexpected events: incidence of retarded renal function or graft and patient sur- The kidneys in one cycle have been collected and one vival over the mid-term 744,745,764 . The KDIGO guides suggest engraftation cannot take place: the kidney will be transplanted informing donors that they have the option of travelling to the into a patient in the waiting list of the hospital where the n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 95 nephrectomy took place and the hospital will return one kid- However, altruistic renal donors are especially relevant ney to the recipient’s hospital. The recipient who has not been when they are included as complements in Domino Renal transplanted will subsequently receive priority in the waiting Paired Donation (DRPD) 649 . This is why different coun- list. tries, such as South Korea 769 , the United States 749 , Canada If the unexpected event (during donor nephrectomy, bench 769,770,771 , the United Kingdom 772 , the Netherlands 773 and surgery, transport or other circumstances) invalidates one of Spain have developed altruistic renal donation schemes with the kidneys, the other transplantations will take place as excellent results 49 . planned. This circumstance will be considered an adverse To centre on European countries, and more specifically on event and the biovigilance system will be notified (the coor- those which have obtained the best results, altruistic dona- dinators of the autonomous communities involved will be tion rates in the past 6 years have accounted for from 8% to informed) and the case will be investigated, to discover the ori- 12% of total living donor activity in the United Kingdom and gin of the fault and establish preventive measures. In this case the Netherlands, respectively, while this percentage in Spain the recipient who has not been transplanted will subsequently accounted for less than 1% 774,775 . Nevertheless, it should be receive priority in the local waiting list. underlined that the Spanish scheme has been able to multi- In the case of an altruistic donor chain with a bridging ply the benefits of altruistic renal donation, obtaining a rate donor who does not proceed with the donation after this has of efficacy for each altruistic donation of 3 transplantations, already taken place in part of the chain (due to a change of as well as including long chains through the use of bridging mind or a health problem while waiting, etc.) the recipient donors. From 2010 to 2018 14 chains started by an altruistic who is left without having received a transplant will receive donor have taken place in Spain: 6 with two links, 3 with three, a deceased donor kidney from the hospital of the bridging 4 with four and 1 with six links, adding 43 transplantations to donor. the paired renal donation scheme, increasing its efficacy from 27% to 33%. Altruistic donors Action protocol All altruistic donors should be assessed using the same criteria as any other living renal donor, and the exploration of their The protocol for the evaluation of a potential altruistic renal motivations, expectations and social and family support will donor was published by the ONT in 2010, conjointly with a all be especially relevant (NG). multidisciplinary committee of experts in different aspects It is recommendable that all altruistic donors should initi- of living donor RT procedures: nephrologists, immunolo- ate transplantation chains, as this offers the greatest benefit in gists, urologists, transplantation coordinators and experts in terms of the number of transplantations. Nevertheless, they bioethics and law 172 . should be informed of the possibility of donating directly to the waiting list (B). The terms “altruistic donor”, “Good Samaritan” or “non- Evaluation of altruistic donors directed donor” are used to refer to those individuals who donate an organ to somebody they do not know who needs All altruistic donors should be evaluated following the same a transplant. In this document we refer to them as “Altruistic criteria as any other living renal donor (9), as described in the Donors” 172 . corresponding section of these recommendations. In Spain, after being fully informed altruistic donors may Some national guides, such as the one for the United decide to donate in two different ways: Kingdom, emphasise the need for all altruistic donors to be By donating an organ to someone in their local waiting list assessed by a qualified mental health evaluation professional (anonymously to someone they do not know). In some coun- prior to donation (2). Nevertheless, in Spain this is a requisite tries such as the United Kingdom they firstly seek a compatible sine qua non for all renal donors 41 . recipient among those with national priority, and if one can- The peculiarity of the Spanish scheme lies in the fact that not be found, by default all altruistic donors then initiate a the assessment of each altruistic candidate donor is divided chain of transplantations 2 . into three consecutive phases, all of which have to be passed in In paired renal donation the final recipient at the end of order to continue with the process. All three phases are coordi- the chain is also selected from the local waiting list. However, nated by the ONT, except for in Catalonia where this function the expected benefit in terms of the number of intermediate is performed by the Organització Catalana de Trasplantaments transplantations performed is greater. The KDIGO guides rec- (OCATT) 172 : ommend informing altruistic donors of the greater benefit in An initial semi-structured interview in the ONT/OCATT number of transplantations when they start a chain 9 . or in a hospital with experience in paired LDRT. This has two aims, firstly to inform the candidate about the National and international data process and, above all, to gather data on their sociode- mographic, motivational and health variables, before finally Altruistic renal donation is increasingly accepted as a strategy referring the candidate to the authorized hospital(s) in to overcome the lack of organs for transplantation 765,766 . From their Autonomous Community, if they pass this initial 11% to 54% of people in the world are estimated to be prepared triage. to make a living renal donation to patients with ESRD with The first hospital assessment, in a hospital that is experi- whom they have no previous tie 767,768 . enced in evaluating living renal donors. This assessment has 96 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 the purpose of ruling out clinical contraindications for dona- That participation in the scheme requires their tion. specific informed consent 9,172,543 , for which they must The second hospital assessment, which will take place have been previously informed and have understood all of in a hospital that is authorized in the Paired LDRT Scheme. the specific questions described in this section. This has the aim of ruling out surgical and psychological con- Recommend a period of time after the first interview, traindications, as well as ones in connection with their social encouraging them to think about all of the additional infor- and work-related support. mation they have received and to reflect on their final decision. This is considered to be good practice, and in Spain donors are able to take the time they need, although in the Specific considerations to be taken into account during majority of cases an answer is received in less than one assessment month (2). We recommend exploring the underlying motivation, which Expectations has to stem from altruistic eagerness (B). We suggest informing potential young donors that they In the case of altruistic donors, there are particular consid- could consider donating at a later stage of their life (NG). erations in connection with their lack of any ties with the We suggest waiting for a reasonable time after the first recipient, and this question has to be examined meticulously interview, encouraging the candidate to reflect and consider during the assessment process 743 . They have to be prepared the information that they have received (NG). for possible situations such as having no information after The whole process must guarantee (ethically and legally) donation about how the recipient is progressing, or hearing that the donation is selfless and that the candidate donor that the transplantation had not succeeded. Although no spe- seeks no economic benefit, publicity or personal promotion. cific data exist in Spain, in other countries it has been observed In case of suspicion, it is especially important to examine the that donors need to know that the recipient is doing well 776 . altruistic past of the potential donor, as well as their family The candidate should be informed about the hypothetical support (which should be strong) and their economic situation possibility that in the future they may need the kidney that (which should be sound) 172 . they currently wish to donate, for somebody important and close to them: a child, their partner or a brother, etc. or that they may need it themselves 172 . Information Motivation Apart from the information which all living renal donors should receive, in their first contacts with the donation net- The study of altruistic donors has removed many pre-existing work potential altruistic donors should also be informed of the doubts about their motivations 777 . Nevertheless, to prevent following points: any future problems in the mental health of altruistic donors, That for the process of study and assessment they will their underlying motivation has to be studied, verifying that it have to travel to a hospital with experience in paired renal stems from altruistic eagerness and that it results from their donation, and that this may be some distance away from positive aspects rather than any motivation based above all where they live. Nevertheless, the convenience for a poten- on psychopathological tendencies. It will therefore be useful tial donor will always be taken into consideration when there to explore the altruistic actions of the individual in the past are several options 172 172 . Some questions that may help to explore this facet are The regulation governing the confidentiality and shown in Table 16. anonymity of the procedure, ensuring that the donor accepts As is the case in Spain, in other countries donors have been this before continuing 9,41 found to be essentially motivated by a desire to help others, The risks/benefits of transporting the kidney and the safety and that they think that they will only experience minimum mechanisms in place to ensure that an collected kidney is drawbacks. transplanted, even though adverse events may occur 9 That they will not be able to select a specific date for Age donation, although all necessary efforts will be made to respects the time periods which the candidate says are Another subject that is discussed in the field of altruistic dona- preferable. 2,172 tion is the age of the donor, particularly in the case of young Table 16 – Questions to explore the motivation and altruistic history of a potential donor. Do you consider yourself to have been altruistic in your life? If so, could you tell me about it? Have you ever known anyone who had a renal disease and needed a transplantation? What did you feel? How did the idea arise of donating a kidney to somebody you do not know? How long have you been thinking about doing this? If you were asked what had led you to contact us, could you describe it? n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 97 adults. The majority of concerns here arise in connection with whether the youngest donors are more likely to regret their Analysis of the risks for living renal donors decision. Although there is no evidence to suggest that this over the medium and long-terms is the case, it may be useful to include questions for younger donors about why they wish to donate now, and whether they Cardiovascular risks for renal donors could consider doing so at a later stage (2). The long-term post-donation risk of hypertension is higher than it is for an equally healthy population which has not Family and social support undergone nephrectomy (Quality of evidence: B). The risk of mortality due to any cause and of cardiovascu- Another aspect where altruistic and conventional donors lar events over the long-term does not differ from that of the seem to differ consists of their social support and the percep- healthy control population (B). tion that they need help and attention. Some altruistic donors We recommend informing donors of the risks of renal and do not tell their loved ones about their decision, as they do cardiovascular disease associated with obesity, actively rec- not feel that they are sufficiently understood by those close to ommending changes in their lifestyle together with weight them. Nevertheless, a lack of social support could finally lead control (B). to the donation not occurring (2). This is why it is important to Preventing cardiovascular risk factors during post- identify their relationship with their family at an early stage, donation follow-up will contribute to maintaining the health and it is recommendable to encourage them to let their loved of the donor over the long-term (NG). ones know about their decision. This will allow them to gain Knowing the potential risks over the medium and long- their help during convalescence after nephrectomy, prevent- term for a potential donor and informing them accordingly is ing them from abandoning the process once it has begun due fundamental in guiding their decision-making and the process to pressure from those close to them. 754 of study and selection by the transplantation team. Studies with a long-term follow-up and a large number of cases (given Registration the scarcity of expected events) are necessary to know the long-term risks that can be attributed to renal donation. On After approval by the hospital ethics committee, the individual the other hand, donors are a rigorously selected group in very in charge of the scheme in the hospital informs the ONT of the good health. The control population will therefore have to be altruistic donors whose assessment has ended, and they are comparable, not only in terms of demographic factors but also registered in the paired renal donation database 172 . medically, to prevent under- or over-estimation of the risks in donors 778 . Renal assignation of an altruistic donor Most of studies are retrospective, observational and based on single centre or national registries. 95% of them are obser- If the donor has decided to donate directly to the waiting list, vational and half of them had short follow-up times (≤1 year), the hospital which assessed them will select one of its recipi- and most of them refer to results in connection with the GFR, ents, based on the waiting list recipient selection criteria. arterial pressure and peri-surgical complications 779 . If the donor has decided to initiate a chain of transplanta- Four studies analysed mortality and cardiovascular events tions the procedure will be similar to the one established for over the long-term with a prolonged follow-up and a represen- paired renal donation, as described above, with the following tative sample size. They use a selection of individuals with differences: similar health criteria to the donors. Three of these studies The other hospitals taking part will have to be informed found no increase in mortality or cardiovascular events in at least 15 days beforehand that a new extraordinary round the donors 120,780,781 . Although the remaining study contra- of paired donations will take place, due to the entry of a new dicts the other three 37 , it has two limitations: (a) the control altruistic donor into the scheme (if it is to take place outside population is almost 10 years younger on average than the the established three annual rounds). The purpose of this is donor population, indicating a distortion in pairing and a clear so that the other hospitals will be able to add new pairs which advantage for the controls (as age is a factor that is associ- have been completely studied, so that they can benefit from ated with mortality), and (b) there was a large percentage of this option. cases without information on variables such as their BMI or Inform the hospital which brings the altruistic donor that smoking, and the analyses were performed with and without it has to select a recipient from its waiting list for the end of data imputation. The results for cardiovascular mortality vary the chain. depending on whether cases with or without imputation are There is no limit to the number of links in altruistic donor used, weakening the final result. A systematic review found no chains. For chains involving more than four pairs, or in those evidence which suggest an increase in the risk of overall mor- when the starting times agreed with the altruistic donor are tality, cardiovascular disease or hypertension in living donors delayed, one of the donors may be proposed as a bridge, so compared with non-donor populations 782 . Based on current that the chain will go forwards in several phases. This option information there is no evidence of any greater risk of mortal- should be considered from the start in the hospitals involved, ity and cardiovascular events over the long-term in donors. so that they are able to agree on it with the affected donors. Nevertheless, further studies are required with a follow-up It is recommendable that the different phases should not be longer than 20 years to analyse the impact of donation over more than one or two weeks apart. the very long-term. In any case, the absolute risk of mortality 98 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 and cardiovascular events is very lower, lower than or similar mechanisms in the remaining kidney, which was previously to that of the general population 33,783,784 and healthy controls healthy, that are unconnected with glomerular hypertension, 120,780–782 . but rather are benign mechanisms such as a possible increase Both of the analyses which included a large number of in the filtration surface or glomerular plasma flow 794,795 . donors and controls show a risk of hypertension that is sig- The majority of donors therefore show a compensatory rising nificantly higher in the donors after follow-up periods of 6 785 curve of their GFR which remains during several years after and 11 years 786 . In the first analysis, the appearance of hyper- donation 207,257 . tension in the control group was associated with a greater In patients with CRD, falls in the GFR are associated with than expected annual fall in filtration, while in the donors an increase in cardiovascular risk 796–798 . The presence of it was associated with a halt in the foreseen rising curve albuminuria, on the other hand, amplifies this association. for filtration after donation. In a series of 3,700 renal donors In any case, a patient with CRD cannot be compared with a who were normotensive before donation, after an average of donor. 16 years follow-up 25% had developed hypertension 787 . The In the Framingham cohorts or NHANES I, moderate falls associated factors were higher BMI, smoking, dyslipidaemia, in the GFR were not associated with increased risk of car- familial history and older age. With current evidence, the risk diovascular disease 799,800 . In the PREVEND group 801 , in the of hypertension over the long-term in donors is higher it is absence of proteinuria, an eGFR of 30-59 ml/min/1.73m2 was compared with an equally healthy population that has not also not associated with an increased risk of cardiovascular been nephrectomized. Once again, long-term donor follow-up disease. However, other studies 243,802–805 found an association is fundamental for early detection and treatment of hyperten- between eGFR <60-75 ml/min and cardiovascular mortality, sion if it arises. especially if it was also associated with the presence of The prevalence of obesity has increased over recent albuminuria. The discrepancy between these results may be decades in the general population. This has led to an increase explained by differences in the risk factors for renal and car- in the percentage of potential donors with a BMI ≥30 Kg/m2 diovascular disease in the different cohorts. Once again, due who are assessed in LDRT schemes. Obesity is associated in to its heterogeneous nature the general population would not the general population with an increased risk of diabetes, be comparable with donors. metabolic syndrome, hypertension, ESRD and mortality 788 . To isolate the impact of nephrectomy on cardiovascular Several authors have also observed an increased risk of hyper- risk in donor studies with a prolonged follow-up would be tension, diabetes or ESRD when following up obese renal necessary, with a representative sample size and a paired con- donors 274,789–791 . The clinical guides contraindicate donation trol population that is comparable with the donors not only when BMI ≥35 Kg/m2 , although there is no agreement on mod- in terms of demographic factors but also in morbidity and erately obese patients with a BMI ≥ 30 Kg/m2 , and the British cardiovascular risk factors. That is, equally healthy popula- Guide and the KDIGO Guide suggest that the decision whether tions as the donors but without having been nephrectomized. to accept a donor or not should be individualized in each hos- Studies of healthy subjects who have been nephrectomized pital, depending on other associated risk factors for the donor due to other causes are useful in analysing this problem. in question 2,9 . Narkun-Burgess et al. 806 compared mortality after 45 years Few studies have analysed the possible implications of of follow-up in two groups of soldiers after the Second World obesity for donor mortality over the long-term. Recently, and War. The first group was composed of 62 veterans who had lost although the level of absolute risk was low, an increase in mor- a kidney as a war wound, and the second group was composed tality over the long-term has been described in donors with a of soldiers who had not suffered nephrectomy. The authors BMI ≥30 Kg/m2 271 . This datum underlines the need to insist on found no differences between the survival rates in both the importance of sufficient weight loss in potential donors, groups after almost five decades of follow-up. Recent stud- and during the subsequent follow-up, with lifestyle change ies found no differences in survival or cardiovascular events programmes if necessary. between donors and healthy selected controls 120,780–782 , and the discrepancy of the Norwegian study 37 may be due to the limitations described above. With the available evidence it The impact of the fall in the GFR after donation on cannot be said that the reduction in the filtration rate observed long-term mortality after donation is associated with an increase in mortality or cardiovascular disease. The fall in the GFR observed after nephrectomy is not associ- Finally, when evaluating how a fall in the GFR influences ated with an increase in mortality or cardiovascular disease donor cardiovascular risk and mortality, other factors should (B). be mentioned which may determine their long-term evolu- After elective nephrectomy the GFR in donors falls by 20%- tion. On the one hand, the initial assessment and selection 30% in comparison with the pre-donation rate, and up to 15% studies play a fundamental role here. It is necessary to know of donors have a GFR < 60 ml/min in the post-nephrectomy the exact basal GFR of the donor because among other fac- follow-up 792,793 . It is important to underline that the grad- tors, renal function after donation will be determined by this. ual fall in the GFR which characterises CRD and the loss The formulas used to estimate renal function have a margin of renal function following donation are not comparable. of error of ±30% 807 . When using formulas to select poten- The donor is a healthy subject whose nephron mass has tial candidates, some may donate when their filtration rates fallen suddenly due to the effect of the nephrectomy. This are non-optimum 205,808 , so that they would form a subgroup leads to the development of compensatory hyperfiltration at risk of developing renal and cardiovascular disease in the n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 99 future. On the other hand, it is possible that there is a group of paired according to donor characteristics. Although we are donors with less renal capacity (due to low weight at birth or able to inform potential female donors of fertile age about the prematurity) or a genetic predisposition the additional risk of risk of preeclampsia and gestational hypertension, the abso- which was not analysed at the moment of selection 809 . These lute risk of this is low and it is not associated with an increase donors may have a higher risk of hypertension and albumin- in preterm births. uria during follow-up 810,811 , especially if situations of greater demand are added, such as weight gain or metabolic syn- KT in renal donors drome after donation. Finally a very long follow-up and the correction of additional cardiovascular risk factors may influ- According to American registry data more than 150,000 indi- ence their evolution 47 . In fact, although the cases of ESRD viduals had made a renal donation while alive. Their incidence diagnosed in donors during the first decade have been said of ESRD was 10-30 events per 10,000 donors in 15 years 35,229 , to be due to immunological or genetic factors, in subsequent and their risk varied depending on their age, sex, race and time decades factors such as hypertension and diabetes are the post-donation 224 . predominant causes 812 . Many transplantation schemes have established policies which give priority in the waiting list to previous renal donors The risk of preeclampsia in donors with ESRD who do not wish or cannot select an anticipated LDRT. In the U.S.A. from 1996 and in the Netherlands from We suggest informing female donors of fertile age of the 2011 they have been assigned priority to minimise their time increased risk of gestational hypertension and preeclamp- in dialysis 127,819 . Other countries which give priority to these sia in pregnancies after donation, and that here is no cases are Sweden, Norway, Belgium, Luxembourg, Austria, evidence of other adverse results for mother or foetus Croatia and Slovenia. In Spain each transplanting hospital is (C). responsible for following up its living donors; if necessary they It is important to inform potential female donors of fertile are able to establish policies which give priority to certain age about the risks associated with a future pregnancy. Eight cases. relevant studies have been published to date which include Given the scarcity of ESRD cases in each LDRT scheme, almost one thousand pregnancies after renal donation in 800 there is very little bibliography on how these patients progress donors (the majority of whom were Caucasian). before and after transplantation. Multicentre registries are Three single centre studies 813–815 in the 1980s and 1990s essential to gain an understanding of the problem as a whole. included a small number of cases, without controls and based All efforts are directed towards ensuring that affected donors on surveys. None of these studies found a higher risk of dete- progress well, but if they develop ESRD it is the responsibility rioration of the GFR, proteinuria or maintained hypertension of the transplantation hospital to return them the therapeu- associated with donor pregnancy. In 2009, a Norwegian study tic benefit which they had created for the scheme in the compared the complications of pregnant women after dona- past. tion with two unpaired control groups: pregnant women prior to donation and pregnant women selected at random from a Mortality due to any cause registry of births in the general population 816 . The percent- age of preeclampsia in the post-donation pregnant women Early mortality deriving from renal donation is very low, and was significantly higher than it was in the donors prior to it is lower than the level corresponding to similar elective pro- nephrectomy and the registry control group (5.7% vs 2.6% cedures (B) vs 3.1%; p = 0.026). The small number of events made multi- The long-term mortality rate due to neoplasia in donors is variate analysis impossible. A North American study found no different from the rate in a comparable control population similar results, although without a non-donor control group (B). 124 . A Canadian study of female renal donors who had been According to American registry data mortality in the first pregnant compared their evolution with healthy non-donor three months after nephrectomy stands at 0.03% 118,120,820 . women who were similar in age and access to social and This is lower than the rate corresponding to other sur- health services 123 . There were higher rates of both preeclamp- gical procedures, such as laparoscopic cholecystectomy or sia and gestational hypertension in the donors than they nephrectomy for other reasons, although it is higher than were in the control group (11% (15/131) vs. 5% (38/788), OR 2.4 the estimated risk of peri-partum mortality 820 . The most p < 0.01). There were no differences in the incidence of Cae- frequent causes of death are haemorrhage, cardiovascular sarean births, prematurity or low birth weight and perinatal events and pulmonary thromboembolism. After this time, or maternal mortality. Once again the low number of events mortality in the first year is comparable to that of healthy restricted multivariate analysis. Finally, two more recent stud- controls 120 . Apart from the studies described above on sur- ies, one in an Asian population 817 and the other based on a vival and cardiovascular risk, two recent publications found North American registry 818 compare post-donation pregnan- no differences in terms of mortality between donors and cies with control group of the general population, and they healthy controls after average follow-ups of 8 years 821 and found no significant differences in terms of adverse maternal- 11 years 822 . Neoplasias were the most common cause of foetal results. death in the follow-up of each of the groups in both of these Further studies are needed to establish definitive recom- recent studies. Several registry studies confirm this finding mendations. The studies published to date show a small 784,823,824 . However, the lack of a control population makes number of events, and they lack a control group that was it impossible to draw conclusions regarding risks. None of 100 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 these publications permits the conclusion that donors are of recipient morbimortality, as this benefit also includes the at higher risk of mortality due to neoplasia than is the case economic repercussions for healthcare systems 829 . for the general population. Nevertheless, the importance of Rarely do we have to choose between a LDKT that is “subop- extensively ruling out neoplasia before donation has to be timum” or “ideal” for a potential recipient. The alternative to a underlined, and this should include recent urological and LDKT from a donor of any age is to remain in dialysis, waiting gynaecological examinations, while also ruling out malignity for a suitable organ from a deceased donor. The annual mortal- in suspicious skin lesions before continuing with the pro- ity rate for patients in dialysis in Spain stands at 15%-16%, and cess. it is far higher in elderly patients, a significant percentage of whom die while they remain in the waiting list 830 . To compli- cate this situation even more, comorbidity may increase over Results of LDKT in standard and special time in patients who are receiving dialysis 831 , and the higher situations their degree of comorbidity, the more likely it is that they will be excluded from the KT list 832 . The recipients of LDKT have longer survival than those who Moreover, a long time spent in the waiting list may increase receive a kidney transplant from deceased donors. This may the possibilities of receiving blood transfusions due to the be explained by many factors; it avoids the renal lesion appearance of additional complications. This may give rise associated with brain death, the donors are in good health to a higher risk of sensitization against a possible graft due and have little comorbidity, cold ischemia times are very to the formation of anti-HLA antibodies, thereby prolonging short and the surgical conditions for the recipient are opti- the waiting time even more and permitting the emergence of mum because it is a planned elective procedure. Moreover, comorbidities 833,834 . with this type of donation early transplantation is often The duration of dialysis prior to transplantation is still an attempted, or the time spent by recipients in dialysis is min- important and potentially modifiable factor in long-term sur- imised. vival after transplantation. Unfortunately, young recipients United Kingdom data show that 10 years after transplanta- may take some time before accessing a RT due to the scarcity tion, 75% of the adults who received their first KT from a brain of younger donors. 56% of the patients included in the waiting dead donor from 1998-2000 are alive. This compares with the list in the United Kingdom in 2011-12 received a transplant survival of 90% of patients who received their first LDRT dur- after 3 years, 6% had been eliminated from the waiting list ing the same period. There was therefore a 20% improvement and 5% had died while awaiting a donor 825 . This situation in patient survival at 10 years after living donation versus often arises, with long waits before transplantation. Mortality deceased donation for those who were transplanted during while waiting is another important matter when considering this period 825 . a potential living donor among transplantation options. Transplantation versus dialysis Expanded living donor KT criteria We recommend KT due to its lower mortality rate in compari- We recommend LDKT even when donors are over the age of 69 son with overall patient survival in the waiting list, regardless years, as it is a beneficial alternative to remaining in dialysis of the type of transplantation. These differences are detectable or to spending more time in the deceased donor waiting list after the third month post -RT (Quality of evidence: B). (B). We recommend shortening the time spent in dialysis prior Graft survival is shorter in recipients with living donors to transplantation, as this is a factor that can be modified, and older than 70 years than it is in recipients with standard it strongly influences long-term survival after transplantation donors, although patient survival is similar (B). (B). We suggest that donor renal function may be more impor- We suggest that LDKT should always be considered as tant than age in the results of LDKT, although this is not the first option for patients with CRD, and above all in confirmed by all studies (C). unfavourable clinical situations (young patients, ones with a We suggest that donors should not be excluded solely high comorbidity, a high level of surgical complexity or highly on the grounds of age. Older donors should be accepted or sensitized patients) who have fewer possibilities of accessing rejected after an exhaustive medical assessment (NG). a deceased donor renal transplant (C). The persistent disparity between the number of patients Patients with ESRD have significantly higher mortality than waiting for a RT and the available organs in the group of the general population and those with a functioning renal deceased donors, together with increasing knowledge and graft 826 . To centre on patients who are KT candidates, longitu- familiarity with the results of LDKT for donors and recipients, dinal studies have shown that the overall mortality of patients has led the transplantation community to consider candidate in the waiting list is significantly higher than mortality in donors who would have been ruled out in the past due to transplanted patients, independently of the type of trans- their demographic characteristics or intrinsic medical prob- plantation. These differences may be detected after the third lems. month post -KT 827 . The most frequent causes of mortality The areas of uncertainty associated with the short- and during the first year of replacement therapy are cardiovascu- long-term results for medically complex living donors should lar disease, followed by infectious complications 828 . There is be considered depending on the cause of this clinical situa- not only a clear benefit in comparison with dialysis in terms tion (age, hypertension, obesity, DM, lithiasis or oncological n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 101 problems) as described in other chapters in these recommen- unacceptably high, although they may be acceptable for an dations. elective KT, optimizing harvesting from an optimum donor, In terms of results for the recipient, several alternative with a team to manage any special difficulties, commencing options should be considered: the probability of receiving immunosuppression before transplantation and minimising a transplantation from a deceased donor using standard or any delay in graft functioning (NG). expanded criteria, the result of the said transplantation, the We suggest that the acceptance or rejection of LDKT in morbidity and potential risk of mortality while waiting for high-risk patients should be based on the opinions of expert a suitable organ from a deceased donor, the suitability/risks multidisciplinary teams. A lack of data makes it impossible to associated with emergency rather than elective surgery, the make clear recommendations for highly complex recipients result that can be expected with such an organ from a living (NG). donor in comparison with the foreseeable life expectancy of The success of a KT scheme cannot be judged solely on the same, etc. the basis of recipient and graft survival in patients with ESRD. The literature is sufficiently conclusive in supporting LDKT There may be errors in data interpretation, and it is more from older donors for at least one cohort of patients. Renal probable that a scheme which takes no risks will give results function gradually falls with age, and the renal function of corresponding to excellent recipient survival. This policy may an older living donor may be reduced 835 . Several single potentially be associated with unfair lack of access to trans- centre or registry studies show poorer results in terms of plantation for patients who are highly complicated in surgical renal survival after LDKT as donor age increases 560,836,837 . terms, or at immunological risk and subject to a higher risk In comparison with the recipients of grafts from standard of death in the waiting list. It is not easy to measure the dif- donors, graft survival falls in recipients whose living donors ficulty certain populations have in accessing transplantation 841 . were ≥70 years old, although patient survival was simi- lar. Renal transplantation recipients from older donors had To ensure terminological uniformity, a high risk recipient better graft and patient survival than did recipients with is one with a significantly higher risk of death, compli- expanded criteria donors 560 (Table 17). In general, it seems cation or graft failure due to pre-existing comorbidity or to be beneficial to use older LDRT donors, equivalent to wait- their immunological status. Statistically, this is equivalent to ing for a deceased renal donor 560 . Estimation of the GFR poorer results for the graft and patient survival. There are has been shown to be an important factor in transplanted no robust scoring systems for this risk evaluation. Although renal function 216 , and it has been suggested that donor renal it is probable that models will soon be developed 842 , it is function may be more decisive than their age for the final known that with the uncertainty of current predictive tools results, although this has not been confirmed by all studies there is still dependence on the clinical judgement of the 838 . transplantation professionals who are involved. The recent Older donors are more likely than younger ones to be British guidelines, and solely as a recommendation with a excluded from donation due to problems discovered during low level of evidence (C2), state that in cases where the their medical assessment. Nevertheless, each case should be probability of post-transplantation survival is less than two considered individually, and if an older donor is considered years, the option of LDRT should not be considered LDRT suitable after a rigorous medical assessment, and if their renal (2). function is normal after correction for age and sex, there is no LDKT may offer opportunities to individuals whose peri- evidence that they should be excluded from donation solely operative risks for an emergency procedure are considered due to their age 839,840 . In a similar way to age, the advisabil- to be unacceptably high, as they may be suitable for elective ity of assuming that a live donor kidney will have “non-ideal” transplantation. The advantages include: recipient optimiza- survival in the recipient (due to comorbidities, renal function tion, resolving and controlling their active health problems or HLA compatibility . . .) must also be considered on an indi- beforehand, the ad integrum availability of all of the person- vidual basis for each particular recipient. nel in the multidisciplinary team (surgeons, anaesthetists, intensive care specialists, nephrologists, immunologists and High risk recipients nursing staff, etc.), with the administration of immuno- suppressant drugs prior to transplantation and a high We suggest that “high risk” recipients should not be auto- quality organ with very low risk of retarded graft function- matically excluded, to prevent unfairness in access to KT. ing. Although the results in terms of survival may be statisti- The key question is whether, although these patients can cally “worse” due to their associated comorbidities, each case expect a relatively worse transplantation outcome in compar- should be assessed individually after the relevant studies ison with standard risk patients, their result may be better (NG). than it would be if they remain in dialysis. The persistence of We suggest that, with some exceptions, patients accepted cardiovascular disease, pulmonary disease, obesity, diabetes o for deceased donor RT are also suitable for a LDKT (C). hypertension will affect the survival of renal patients whether We suggest that the LDKT option should not be considered they receive a transplantation or are dependent on dialysis when it is estimated that post-transplantation survival will 843 . be not reach two years, or when there is a high probability of Another group of patients who may be considered complex renal disease relapse in the graft (C). is composed of those at high immunological risk and sen- LDKT may offer opportunities to patients whose perioper- sitized. LDRT recipients with HLA incompatibility are often ative risks for an emergency procedure are considered to be excluded from survival analysis in the results of LDRT as 102 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Table 17 – Survival of renal graft and patient adjusted for donor sex and race, and the age, sex, race, renal disease aetiology and HLA of the recipient (Ref 560). LDRT: living donor renal transplantation. eGFR: estimated glomerular filtration rate. Graft survival at 10 years Patient survival at 10 years Donor group (reference = standard donor) LDRT <60 years 0.73 (0.71-0.74), p < 0.001 0.70 (0.69-0.72), p < 0.001 LDRT 60-64 years 1 (0.91-1.11), p = 0.99 0.82 (0.76-0.89), p < 0.001 LDRT 65-69 years 1.2 (1.02-1.41), p = 0.03 0.98 (0.86-1.11), p = 0.74 LDRT >70 years 1.73 (1.29-2.31), p < 0.001 1.08 (0.86-1.36), p = 0.52 Expanded criteria donor 1.83 (1.78-1.88), p < 0.001 1.32 (1.29-1.35), p < 0.001 Donor group (reference = LDRT < 60 years) LDRT 60-64 years 1.41 (1.25-1.59), p < 0.001 1.15 (1.03-1.28), p = 0.01 LDRT 65-69 years 1.67 (1.36-2.05), p < 0.001 1.39 (1.18-1.64), p < 0.001 LDRT >70 years 2.18 (1.50-3.17), p < 0.001 1.54 (1.14-2.08), p = 0.01 Donor group (reference = eGFR >150) eGFR: 120-149 ml/min/1,73 m2 0.99 (0.76-1.29), p = 0.96 1.12 (0.85-1.47), p = 0.41 eGFR: 90-119 ml/min/1,73 m2 1.08 (0.84-1.39), p = 0.52 1.08 (0.84-1.4), p = 0.55 eGFR: 60-89 ml/min/1,73 m2 1.16 (0.9-1.48), p = 0.25 1.07 (0.83-1.38), p = 0.61 eGFR: <60 ml/min/1,73 m2 1.32 (1.01-1.71), p = 0.04 1.09 (0.84-1.43), p = 0.51 their rates of survival are not as good as those for compat- ible transplantations without antibodies. However, for some Coordination of the living kidney donation patients transplantation in these circumstances is the only process way they will achieve independence from dialysis. The recom- mendation is to establish a specific scheme to select a donor All of the successive phases of the LDKT process have to be against whom the recipient does not produce antibodies. This perfectly coordinated to ensure its success, while always guar- objective can be achieved in LDKT by paired exchange strate- anteeing the complete protection of the living donor, the basic gies. Patients with DSA should only receive a transplantation element of all LDRT Schemes 2,3,8,27,42,64,844,845 . The different if these measures cannot be applied and after desensitiza- international standards agree in guaranteeing the principle tion programmes. The presence of DSA that can be detected of non-commercialization and the absence of practices which using techniques other than complement-dependent cyto- would be compatible with human or organ trafficking. The toxicity is considered to be a risk factor in itself but not a process should emphasise the need for free, informed and contraindication 101 . In the case of HLA incompatibility, the express consent to be obtained. It is also necessary to evaluate use of desensitization techniques in ABOi RT offers similar a range of medical, family, social, professional and economic long-term results to ABOc RT 53 . aspects to ensure the well-being of the donor over the short- The donor and the recipients should be informed of the and long-term, minimizing the risks associated with the dona- possible risks and results. Although this is also the case for tion. living donation transplantation in general, it is particularly The LDKT process is regulated in Spain by Law 30/1979, of important for highly complex recipients, where the risk of 27 October, on the donation and transplantation of organs 846 an adverse result is higher than it is in cases of standard and Royal Decree 1723/2012, of 28 December, which governs transplantation. It is proves impossible to reach an agreement the activities of obtaining organs, clinically using them and within a particular transplantation hospital due to differences the territorial coordination of the human organs for trans- of opinion on the degree of risk, the option of referral to plantation, establishing quality and safety requisites 41 . Our another hospital for a second opinion should be discussed regulatory framework emphasises respect for the basic prin- with the potential recipient and donor. ciples described above, and it standardises several aspects of Although we unify the inclusion criteria of our protocols, the process, including; i) the medical and psychosocial assess- clinical practice will surely eventually lead us to differences ment of the potential donor by a doctor other than the ones in who we include. Nevertheless, this would not be a problem who will harvest and transplant the organ; ii) evaluation of and it would be corrected by the patient’s freedom to request the procedure by an Ethics Committee; and iii) the donor second or third opinions about the advisability of a LDRT. It is has to appear before the Court appearance. Compliance with important that the decision to transplant into high-risk recipi- these legal requirements and managing the different logistical ents should not be influenced by the sometimes unwarranted aspects of the process requires coordination work which may concern about the possible results. It is very difficult to set be undertaken by one or more professionals with different standards for results in this LDRT group, given the hetero- profiles and origins. geneous nature of the patients and the differences between According to the document TR de donante vivo en España. the definitions of what constitutes high risk between different Análisis de Situación y Hoja de Ruta (“Living Donor RT in Spain. units. Situation Analysis and Route Map”), prepared by the ONT, n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 103 the SEN and the SET, of the 33 Spanish hospitals with a gather all of the opinions that make it possible to discuss LDKT scheme, the Transplantation Coordinator (TC) is in the case in a multidisciplinary way before it is approved or charge of coordinating the process in 10 of them, chiefly rejected: urology, anaesthesia, psychology or psychiatry and in transplanting hospitals with little activity 847,848 . In 15 of other specialities (vascular surgery, cardiology, oncology and the 19 hospitals that have no specifically designated profes- haematology, etc.). sional for this coordination work, the TC supports different stages of the process. More specifically, they work together Offer the donor a free space where they can express their with the transplantation teams in the logistic aspects of the doubts and resolve questions process, support the healthcare Ethics Committee (EC) and take part as a guarantor of the protection of the donor who It is advisable to offer a potential donor an interview with- is independent of the transplantation team, as required by out the presence of the recipient, to give them a space where Spanish law and as recommended internationally–the “donor they can express themselves freely, revealing their worries advocate” 88 . and doubts. In this interview the donation process has to be The professional in charge of coordinating LDKT has to explained once again, clarifying and resolving any questions coordinate their work with the RT team, and this justifies their in a way that will allow them to give their valid informed inclusion in the multidisciplinary LDKT group, on condition consent. The importance of the EC should also be explained, that their independence is ensured, together with their role of together with the legal obligation to appearance in Court, to guarantor of the rights of the donor 3,27 . ratify that the organ is donated freely, without economic or any other form of coercion, and that they have been duly Coordination of living donor RT informed. As this interview with the donor is in private, it is important Healthcare coverage by the National Health System or pri- to verify that the donor fulfils the recommended requisites vate insurers must be guaranteed for the direct costs of in the Council of Europe Guide to safety and quality assurance pre-transplantation assessment and the medical and surgi- for organs, tissues and cells 27 and the ones in these Rec- cal interventions in the LDKT process. It must be ensured that ommendations, including the evaluation of risk factors and the donation will be economically neutral for the donor, facil- behaviours to minimise the possibility of transmitting infec- itating reimbursement of the direct and indirect costs of the tious diseases–and diseases of other types - to the recipient. same. (Quality of evidence: B) Although this task should be carried out by the doctor in For foreign living donors, the relationship between the charge of assessing the state of health of the donor, it is impor- donor and recipient must be verified, and the former must tant that an independent professional should also do so. The comply with the legal requisites to enter and remain in the latter should, in a coordinated way with the transplantation country during the LDKT process. (B) team, indicate precautionary measures to the donor, inform- The logistics of the process should be organised in such a ing them of the risks which certain forms of behaviour involve way that evaluation of the viability and compatibility of the for the recipient. donor and recipient takes place in the most effective and fluid way possible, always offering complete information, particu- Review of the documentation and the relationship of the larly to the donor, about the risks they are accepting and the living donor with the potential recipient (Table 1) expected benefits of the LDKT. As well as collaborating with the nephrologists of the Documentation has to be requested which accredits the LDKT scheme by informing patients, professionals in the identity of the potential donor and recipients, and which dialysis units and ESRD units of the hospital and oth- guarantees the relationship between them, although it is the ers for which the transplanting hospital is the referral responsibility of the Examining Magistrate to verify the verac- hospital, the individual in charge of coordinating the ity of this documentation. LDKT process may also collaborate in the following 10 This fact is particularly important in the cases of live phases: donors who are not genetically or emotionally related, as well as when the donor (and/or the recipient) are foreigners, Initial assessment by the nephrologist who is responsible either individuals from another country who have travelled for the living donor specifically for the transplantation, or foreign residents in Spain. In such cases, some groups propose that, prior to com- The process commences with the interview by the respon- mencing the tests in the studies of the health of the donor sible nephrologist and the potential donor. This permits an and recipient, an interview should be held to exhaustively initial evaluation of the feasibility of the process and factors review the documentation which proves the tie between them in connection with the protection of the donor. According to and ensure that both the donor and the recipient are autho- Royal Decree 1723/2012, of 28 December 41 , it is necessary to rised to legally stay in Spain. It is also suggested that the verify that the principles of voluntary donation, altruism, con- EC should be consulted first to evaluate the advisability of fidentiality, the absence of a desire for profit and freedom interviewing the donor before continuing with the assessment from charge have been fulfilled. The laboratory tests should process. then be requested, HLA and the imaging tests described in Foreign donors (and/or recipients) who live outside Spain other sections of this document. Visits to the other profes- are recommended to count on a known and trusted medical sionals involved in the scheme also have to be arranged, to team in a referral hospital, so that they are able to perform 104 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 where a clinical route or similar pathway has been imple- Table 18 – Documentation to prove the tie between donor and recipient. mented) slows down procedures because they have to be done over and above the normal daily work for the professionals Spanish nationality DNI (National Identity Card) involved. Medical insurance (social security, private, etc.) Proof of the tie with the recipient (libro de familia (official Collaboration in decision-making and the socioeconomic, family record booklet), civil registry, historic municipal familial, social and professional evaluation of a donor registration, photographs, shared bank accounts, testimonies by friends or family members) If the donor has children who are minors or their children’s To ensure that donors are completely protected, the interview family lives abroad or does not live with the donor, some seeks to discover the nature of their decision-making process groups suggest that the partner or family should be aware of and their family and social context, as well as their economic the donation process and professional situation: Foreigners: As well as the four documents listed above, we The decision to donate: suggest The documents which prove the tie should be translated into Spanish, English or a comprehensible Latin-based language. • How they obtained the information on how to become a Any translation must be by an official translator. It is donor recommendable to consult the respective Embassy or • Motivations to be a donor Consulate, to verify the validity of the documents which • Feelings they have experienced prove the tie. • Whether they have asked people they know about their Valid passport, preferably one with future validity of at least 6 decision months • Pressures that may have influenced their decision Visa or legal residence permit which covers the donation and transplantation process period • Implications and consequences at every level Family situation: • The individuals in their close family the basic tests in their country of origin which are necessary • Family conflicts to assess the suitability of the donor, thereby avoiding unnec- • Individuals who would care for them after post-donation essary travel and expense for the donor if the donation is discharge from hospital contraindicated. The tests involved may include at least blood • How they have planned for the well-being of those who are group, viral serology and renal function and ultrasound scan. dependent on them in case of any complication arising, par- In this case only donors genetically or emotionally related to ticularly if there are children or family members who live the recipient should be accepted, for direct transplantation as abroad who are economically dependent on the donor well as for participation in the Paired KT Scheme of the ONT • Professional and economic situation 543 . A legal stipulation is that living donors must be supplied with medical treatment for their recovery, as well as life-long Profession and employment: follow-up. It is therefore indispensable to ensure medical cov- erage in their country of origin, to guarantee medical care • type of contract, the effects of their decision on their work, for the donor after the donation process. They must also be the possibility of time off work. followed-up encouraging healthy lifestyle habits to help them preserve their health. The above recommendations are con- Economic repercussions: tained in a Government Resolution on the principles for the selection, assessment, donation and follow-up of non-resident living • Measures they have adopted organ donors 85 . • Their social situation and family and social support. Table 18 describes the documentation used to prove the relationship between the donor and recipient, and we sug- The multidisciplinary team will therefore be able to check gest reviewing this based on the origin of the donor and/or with the donor and guide them regarding possible reimburse- recipient. ment for the direct and indirect costs deriving from their donation, such as travelling expenses, allowances, lodgings, Coordination of the general study of a living donor and the childcare and time off work, to prevent the donation hav- necessary tests in each specific case ing a negative economic impact. These aspects are especially important when the donor lives abroad. The National Health Appropriately coordinating all of the studies, depending on System in Spain or the recipient’s private insurance policy the needs of the patient, makes it possible to perform them covers the costs deriving from pre-transplantation assess- in a short period of time. It also permits monitoring the ment and medical and surgical procedures. In the case of studies of a living donor, verifying that nothing relevant is private donations, care must be taken to ensure that these lacking and speeding them up. As the Living Donor Route costs are paid for by the recipient. Foreign living donors in Map and Situation Analysis Document (Documento de análisis particular, and most especially if they require treatment that de situación y hoja de ruta del Donante Vivo) 847 states, the lack was unconnected to the donation process (such as if a pre- of an individual in charge of this aspect (except in hospitals viously unknown neoplasia is detected), then it important to n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 105 inform the donor that such costs are not covered by the health- recipient, as prepared by the nephrologist in charge of the care coverage of the recipient (2,85,848). It is advisable to check process, as well as the mental state report prepared by the that the donor has someone who will be able to care for them, psychologist or psychiatrist and the social, familial and pro- at least during the first days after discharge from hospital (2). fessional evaluation of the donor, which may be supplied by the LDKT coordinator. The nephrologist, the coordinator and Participation in the Informed Consent procedure other professionals who are considered relevant will attend the EC meeting. After deliberation, the EC will prepare the The nature of a valid consent process (free, informed and report which authorises the donation. express) was described in the living donation Ethics Chap- The LDKT process coordinator will be able to manage the ter in this document. The LDKT coordinator has to verify that appearance in Court, agreeing the day and time for this with the donor understands the information given and that all of the Judge, together with the presentation of the documenta- their questions have been answered. Acting as the guaran- tion and the ratification of the consent. The donor, the doctor tor of the donor’s rights, the coordinator has to verify that in charge of the process and the surgeon in charge of the their consent is granted expressly, freely, consciously and self- harvesting and transplantation must all go to the Court. All lessly. They have to clarify that this decision is reversible, of them will have to show their identification national card so that at any time the potential donor may withdraw from or passport (if the donor is foreign). In the case of a living the process without giving any explanation and without any donor who does not speak any of the official languages of repercussion whatsoever. In all cases, and in particular for Spain, they must be accompanied in the Court by an indepen- unrelated and altruistic donors, there must be verification that dent interpreter who has no ties with the donor, the process they are under no external pressure and that there no other coordinator or the transplantation team, after approval by the circumstance which suggests that there is an economic, social, Judge. psychological or any other type of conditioning factor. The following relevant documents must be given to the court: Arranging the multidisciplinary meeting to accept a living donor • The application to appear before the Court, signed by the donor. Depending on the level of LDKT activity, it is recommendable • Certification of the donor’s state of health, signed by a doctor to schedule a regular meeting to discuss all of the cases once who is independent of the living donor study process. they have been assessed as possible living donors and before • Copy of the consent document or the authorization for liv- they are presented to the EC for evaluation. This meeting ing donor renal donation should be multidisciplinary, with all of the professionals who • The EC Report are assessing the suitability of the living donor candidates in terms of the physical and mental health. This assessment will In the case of a donor in the National Paired KT Scheme, include nephrology, urology, anaesthesiology, nursing, radiol- the Judge will be given a copy of the codes generated by the ogy, immunology, haematology, social work, psychology and scheme. The Judge will also be given a copy of the Paired KT psychiatry. The LDKT coordinator will be able to take part Authorization Document - generated by the ONT, and which in this meeting by offering their opinion as the donor advo- contains the information on the pairs taking part - signed by cate, offering information on the relationship between the the donor. donor and recipient, and explaining their social, familial and In the Court, the Judge will verify the donor’s free decision, professional situation. An overall clinical evaluation of the and before the Judge those attending will sign the Certificate donor and recipient will determine whether they fulfil the of Consent for the Donation of human organs between living criteria set by each transplantation group, and the decision individuals. The Court will give a copy for the donor’s history is taken if to approve the case as a living donor for a spe- and another copy for the donor him/herself. cific recipient, or if they will enter the National Paired Renal Transplantation Scheme. It is advisable to prepare the Min- LDKT report for the competent authorities and the utes of this meeting to be appended to the clinical history of Registry. the donor. In the case of a foreign live donor, prior to donation the Coordination of the legal process: theEC and appearing Autonomous Community Transplantation Coordination before the Court authority and the ONT must be informed, sending informa- tion which verifies the tie, passports and medical coverage LDKT is facilitated by a specific professional who coordinates of the donor and recipient. In the case of a living donor for the ethical-legal process. In turn they have to guarantee that paired KT, the KT unit has to inform the ONT that the donor the hospital where the process of donation, harvesting and and recipient have accepted to participate in the program. transplantation will take place has been expressly authorised The Codes of the National Paired KT Scheme are obtained for the harvesting of living donor organs by the corresponding from the ONT web portal 543 , together with a table showing Autonomous Community health authority. the hospitals and donors involved in each paired donation We recommend that the EC should meet regularly, espe- and the ONT Paired Donation Scheme Authorization Docu- cially in hospitals with a high level of transplantation activity. ment, which the donor has to sign. In turn, on the day after The EC should receive the medical reports on the donor and the donation, the Autonomous Community Transplantation 106 n e f r o l o g i a. 2 0 2 2;4 2(S 2):5–132 Coordination authority will be informed and it will be regis- tered in the National and Autonomous systems of the Living Acknowledgements Donor Registry and, in the case of a foreign donor, it will be possible to also inform the respective Registry in the donor’s This study was partially supported by grants from the Insti- country of origin. tuto de Salud Carlos III, co-financed by the European Regional Development Fund–ERDF (Redinren RD16/0009) and grants ICI14/00016 and PI17/02043) of the Spanish Government Min- Renal transport management in the paired living donor istry of the Economy and Competitiveness. These institutions scheme did not take part in designing the study or the gathering, anal- ysis and interpretation of data or writing the manuscript. We The transport and/or reception of the kidney to and from the would like to thank Silvia Musquera for the drawings in Figure hospitals involved has to be organised by the National Paired 12. KT Scheme 543 . The packaging, preservation and transporta- tion have to be verified according to ONT specifications 849,850 and Royal Decree 1723/2012, of 28 December 41 . An internal document of the hospital of origin will be appended, making references it possible to identify the donor (ONT Paired Code, hospital clinical history, etc.), the side of the kidney, the macroscopic appearance of the organ, the type of harvesting procedure 1. Guías S. Recomendaciones de la Sociedad Española de used, warm ischemia times and the time of renal perfusion Nefrología “SEN” y de la Organización Nacional de Trasplantes “ONT” sobre trasplante renal donante vivo. and the solution in which the organ is preserved. 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