Nephrol Dial Transplant (2019) 34: 1469–1480 doi: 10.1093/ndt/gfz089 Advance Access publication 14 June 2019 Nephrology and Public Policy Committee propositions to stimulate research collaboration in adults and children in SPECIAL REPORT Europe Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 Ziad A. Massy1,2, Fergus J. Caskey3, Patrik Finne4,5, Jerome Harambat6, Kitty J. Jager7, Evi Nagler8, Benedicte Stengel2, Mehmet Sukru Sever9, Raymond Vanholder10, Peter J. Blankestijn11, Annette Bruchfeld12, Giovambattista Capasso13, Danilo Fliser14, Denis Fouque15, Dimitrios Goumenos16, Maria Jose Soler17,18, Ivan Rychlı́k19, Goce Spasovski20, Kathryn Stevens21, Christoph Wanner22 and Carmine Zoccali23 1 Division of Nephrology, Ambroise Paré Hospital, APHP, Paris-Ile-de-France-West University (UVSQ), Boulogne-Billancourt, Paris, France, 2 INSERM U1018 Team5, Paris-Saclay University, Villejuif, France, 3Consultant Senior Lecturer, Population Health Sciences University of Bristol, UK, 4Finnish Registry for Kidney Diseases, Helsinki, Finland, 5Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 6Pediatric Nephrology Unit, Pellegrin-Enfants Hospital, Bordeaux University Hospital, and University of Bordeaux, INSERM, Team LEHA, Bordeaux, France, 7ERA-EDTA Registry, Department of Medical Informatics, Academic Medical Center, University of Amsterdam, Amsterdam Public Health research institute, Amsterdam, The Netherlands, 8European Renal Best Practice, London, UK, 9Department of Nephrology/Internal Medicine, Istanbul School of Medicine, Istanbul University, Millet Caddesi, Istanbul, Turkey, 10 Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Corneel Heymanslaan, Ghent, Belgium, 11Department of Nephrology, University Medical Center, Utrecht, The Netherlands, 12Department of Renal Medicine, CLINTEC, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden, 13Department of Medical Translational Sciences, University of “Luigi Vanvitelli” Naples and Biogem, Ariano Irpino, Italy, 14Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany, 15Department of Nephrology, Dialysis, Nutrition, Université de Lyon, CARMEN, Centre Hospitalier Lyon Sud, Pierre Bénite Cedex, France, 16Department of Nephrology, University Hospital of Patras, Patras, Greece, 17Department of Nephrology, Vall d’Hebron University Hospital, Barcelona, Spain, 18Departament of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain, 191st Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic, 20Department of Nephrology, Medical Faculty, University of Skopje, Skopje, Former Yugoslav, Republic of Macedonia, 21Glasgow Renal and Transplant Unit, Queen Elizabeth University Hospital, Glasgow, UK, 22Department of Medicine, Division of Nephrology, University Hospital, Wuerzburg, Germany and 23CNR-IFC, Ospedali Riuniti, Reggio Calabria, Italy Correspondence and offprint requests to: Ziad A. Massy; E-mail: ziad.massy@aphp.fr; Twitter handle: @denisfouque1 ABSTRACT Keywords: acute kidney injury, big data, cohorts, guidelines, The strengths and the limitations of research activities currently registry present in Europe are explored in order to outline how to pro- ceed in the near future. Epidemiological and clinical research INTRODUCTION and public policy in Europe are generally considered to be com- prehensive and successful, and the European Renal Association The goals of this article are to present the current state of the art – European Dialysis and Transplant Association (ERA-EDTA) of research in epidemiological and clinical nephrology in adults is playing a key role in the field of nephrology research. The and children in Europe. It also aims to specify the strengths and Nephrology and Public Policy Committee (NPPC) aims to im- the limitations currently present in Europe in order to explore prove the current situation and translation into public policy by how to proceed in the near future. To this end, the article will planning eight research topics to be supported in the coming also propose a research plan with a few hot topics to be facili- 5 years by ERA-EDTA. tated by the European Renal Association – European Dialysis C The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1469 data over long periods of time, through prospective cohorts (which look ahead in time) and retrospective cohorts (which look back in time). Over the past 15 years, there has been con- siderable development of cohort studies investigating kidney diseases worldwide, several of them set up in European coun- tries. This paragraph takes into consideration the available large cohorts, though not exhaustively, encouraging future research collaborations to enhance the scientific potential of the data. Table 1 lists examples of such studies, investigating CKD, end- stage kidney disease (ESKD) or, to a lesser extent, acute kidney injury (AKI) in the general population or in the clinical setting, initiated or funded by nephrology researchers in one or more European countries [2–23]. Whereas stand-alone cohort studies are a valuable resource Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 FIGURE 1: Roadmap for ongoing nephrology research for screening, for research, collaboration on innovative research topics may diagnosing, preventing and treating CKD. Although valuable registry further increase both their scientific quality and impact. Some data and cohort studies exist for defining the current burden of examples of areas where collaboration may provide added value CKD, novel studies are certainly needed for screening, diagnosing, include (i) the identification of determinants of outcome where preventing and treating this public health problem. Information that exposures or events are rare, and numbers in separate cohort may be gained from future research may be useful for establishing studies may be too small; (ii) the investigation of specific patient novel predictive biomarkers for screening and diagnosing CKD, and subgroups, such as those defined by age, a specific type of ne- thus be useful for creating/implementing guidelines and finally per- phropathy or an uncommon patient phenotype; (iii) the con- forming interventions for prevention and treatment of CKD. National societies, kidney foundations, ERA-EDTA and EKHA may current development and external validation of biomarkers or collaborate and support all parties involved in managing the prob- prediction models; and (iv) the comparison of prevention strat- lems encountered during the planning and the support of these egies, clinical practices, services and costs in kidney disease care. projects. Although several hurdles would need to be overcome re- garding different data definitions and discrepancies among in- and Transplant Association (ERA-EDTA) in the coming years cluded data, such collaboration may promote further use of through stimulating research collaboration and supporting data and biobanks and optimize scientific output. Notably, the grant applications to other funding bodies. Finally, it is hoped availability of large biobanks in carefully clinically phenotyped that there may be an improvement in screening, diagnosing, patients is a major strength and provides an opportunity to con- preventing and treating chronic kidney disease (CKD) duct collaborative research designed to uncover non-invasive (Figure 1). diagnostic tests or novel predictive markers of kidney disease This article is divided into several sections and written by the complications and to further improve the classification and following authors who are members of the Nephrology and prognostication of kidney diseases, notably based on large-scale Public Policy Committee (NPPC), an advisory group recently genomic and proteomic data. The identification of the best created to develop the Clinical Nephrology Governance Branch form of prevention, clinical and therapeutic practices would of the ERA-EDTA [1]: also be enhanced by developing collaborative outcome research in culturally close populations exposed to different environ- (i) Kidney disease cohorts in Europe (Kitty Jager, ments and socioeconomic backgrounds. A few cohorts also Benedicte Stengel and Ziad Massy); have access to patient-level claim data and hospitalization (ii) National kidney registries and the ERA-EDTA Registry records through record linkage with a health administrative (Patrik Finne); database, thus combining the benefit of well-defined patient (iii) European paediatric nephrology (Jerome Harambat); phenotypes with so-called big data. Whether and how such (iv) European Renal Best Practice (ERBP) (Evi Nagler); data can be used for international comparisons would be worth (v) Important topics related to the European Union (EU) testing. Such initiatives require funding to help build European priorities (Raymond Vanholder); nephrology research networks and infrastructures where data (vi) Important clinical research topics in Eastern (Mehmet from various countries can be analysed according to current Sukru Sever) and Western Europe (Fergus Caskey); European data protection rules. This may provide the opportu- and nity to train nephrologists in clinical epidemiology and include (vii) Summary and research proposals (Ziad Massy). the support of PhD students and post-doctoral researchers ana- lysing the collaborative databases. Based on these principles and KIDNEY DISEASE COHORTS IN EUROPE with the advantages of existing cohorts, the selection process for Cohort studies are important tools in medical research when it research projects to be supported by the ERA-EDTA may thus comes to investigating risk factors for disease occurrence in the strongly contribute to improve the scientific quality and scope population and factors related to prognosis in patients. These of clinical research in Europe and evidence-based nephrology studies follow large numbers of individuals and typically collect worldwide. 1470 Z.A. Massy et al. Table 1. Studies investigating CKD, ESKD or AKI in the general population or in the clinical setting, and initiated or funded by nephrology researchers in one or more European countries Cohort studies [Ref.] Country Target population Sample size General population and primary care cohorts Berlin Initiative Study [2] DE General population 2069 Esther Study [3] DE General population 9961 Gubbio Study [4] IT General population 5376 Prevention of Renal and Vascular End-stage Disease NL General population 8592 Study [5] The Renal Risk in Derby study [6] UK Primary care patients with CKD 1741 Stage 3 Uppsala Longitudinal Study of Adult Men [7] SE Men from the general population 2322 CKD cohorts (adults) Cardiovascular and Renal Outcome in CKD Stages 2– DE CKD Stages 2–4 444 4 Patients—The Fourth Homburg evaluation [8] Chronic Renal Impairment in Birmingham [9] UK CKD Stages 3–5 not on dialysis 382 Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 Multifactorial Approach and Superior Treatment NL CKD Stages 2–4 788 Efficacy in Renal Patients with the Aid of a Nurse Practitioner [10] Grampian Laboratory Outcomes, Morbidity and UK CKD Stages 3–5 not on dialysis 3414 Mortality Studies [10] Mild to Moderate Kidney Disease Study [12] DE, AU, IT Patients with primary kidney 227 disease NephroTest Study [13] FR CKD Stages 3–5 not on dialysis 2084 EQUAL study [14] DE, IT, SE, NL, UK CKD Stages 4–5 and aged >65 3500 (target) years The German Chronic Kidney Disease (GCKD) study DE CKD Stages 1–5 5217 [15] Chronic Renal Insufficiency Standards UK CKD Stages 3–5 not on dialysis 1325 Implementation Study [16] The Chronic Kidney Disease-Renal Epidemiology and FR CKD Stages 3–5 not on dialysis 3033 Information Network (CKD-REIN) cohort study [17] MERENA study [18] ES CKD Stages 3–4 1129 The Biobank of Nephrological Diseases in the NL CKD Stages 1–4 2200 Netherlands cohort: the String of Pearls Initiative [19] CKD cohorts (children) 4C-Study [20] TR, DE, FR, IT, PL, Children ages 6–17 years old— 688 UK, AU, RS, PT, CZ, GFR of 10–60 mL/min/1.73 m2 LT, CH AKI cohorts FINNAKI [21] FI ICU patients 2901 PREDICT [22] FR ICU patients 1200 OAKS [23] UK Adults undergoing gastrointesti- 6500 nal resection, liver resection or reversal of ileostomy or colostomy DE, Germany; IT, Italy; NL, the Netherlands; SE, Sweden; AU, Austria; FR, France; ES, Spain; TR, Turkey; PL, Poland; RS, Serbia; PT, Portugal; CZ, Czech Republic; LT, Lithuania; CH, Switzerland; FI, Finland; FINNAKI study, Finnish Acute Kidney Injury study; OAKS, Outcomes After Kidney injury in Surgery; GFR, glomerular filtration rate; ICU, intensive care unit. AKI and related metabolic disorders are increasingly recog- ERA-EDTA’s missions and objectives, additional proposals nized to represent significant causes of morbidity and mortality. should be presented such as the creation of a dedicated nephrol- Also, AKI is recognized as an important risk factor for CKD as ogy network for AKI at the European level to organize, coordi- well as ESKD [24]. With this in mind, the International Society nate and improve the practices, research and education in the of Nephrology (ISN) launched the 0by25 AKI initiative to pre- field of AKI [24]. vent all avoidable deaths from AKI across the world by 2025 [25]. This initiative seems more directed at developing coun- NATIONAL KIDNEY REGISTRIES AND THE tries than to European countries. The distinctive features of ERA-EDTA REGISTRY AKI in Europe are the ageing population, the association with multiple organ failure, the advanced technology available for Most European countries have their own registries for dialysis patient care, the emerging area of onco-nephrology and the fi- and transplantation patients. Many of these registries are of nancial resources that allow care for almost all patients with high quality with a virtually complete coverage of the patient AKI [24]. Several cohort studies are presented in Table 1. Since population dating back many years. The national and regional the committee believes that the study of AKI should be part of registries have an important role in serving the local nephrology NPPC propositions to stimulate research 1471 communities by publishing annual reports and, for example, Many fairly large differences have been observed between coun- ensuring regional equality of nephrological care within a coun- tries and regions, for example, regarding incidence and preva- try. A central task of these local registries is data collection, lence of KRT and regarding outcomes. This indicates that which would be very difficult to organize in a centralized man- treatment policies are different. Efforts should be made to con- ner in Europe because it requires close collaboration with the tinue studying international differences and secular trends of nephrology units, preferably in the local language. On the other KRT in Europe, and to attempt to find the reasons behind, and hand, the decentralized data collection has led to heterogeneity the consequences of, these differences for patient outcomes. in the data sets between registries. Registry data are commonly used for observational studies, which have known limitations when comparing effectiveness of What data do the national registries provide and what treatments. There is a scarcity of high-quality evidence from should they provide to the ERA-EDTA Registry? randomized controlled trials (RCT) to guide treatment of dialy- Many of the national registries provide the ERA-EDTA sis and transplantation patients. The registry-based RCT is an Registry with a core dataset with individual patient data, which innovative type of trial that uses registry data to identify the enables international comparisons on essential epidemiological study subjects and to also collect outcome data [28]. For exam- Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 measures such as incidence and prevalence of kidney replace- ple, randomization protocols could be built into the database ment therapy (KRT) including kidney transplantation rates and systems of renal registries. When a new patient who fulfils pre- patient outcomes (ERA-EDTA Annual Report, please consult specified inclusion criteria is reported to the registry, he would www.era-edta-reg.org). Some registries provide aggregate data be randomized to an intervention arm and asked for consent. rather than individual patient data, which gives basic informa- The intervention must carefully be selected and should be safe tion about KRT in the country. and inexpensive, for example, comparing two compositions of In recent years, some registries have provided the ERA- dialysate. As the inclusion criteria are usually less stringent than EDTA Registry with an extended data set on clinical perfor- in conventional RCTs, the results may be more generalizable. mance indicators, such as blood pressure and various labora- As the follow-up data are obtained from registries, the cost is tory variables. So far these data have been used in a few research typically low. One successful example is a Swedish study on projects [26, 27], but have not been presented in annual bench- thrombus aspiration during myocardial infarction, which uti- marking reports. An aim for the future is that more countries lized a national registry to recruit and follow-up a large number could provide similar data on clinical performance indicators of patients at low cost [29]. Registry-based RCTs could be per- because this would enable comparison of achievements of treat- formed in some national renal registries in collaboration with ment targets between countries and initially. This could be the ERA-EDTA Registry with especially high-quality data, po- done in a representative sample of patients in order to enhance tentially providing very valuable information that could change feasibility. The collaboration of the ERA-EDTA Registry and treatment policies in nephrology. the national registries is clearly a necessary imperative to define Extension of the present national and regional registry data- the requested common parameters and explore the feasibility of bases to include patients in CKD Stages 4–5 at national levels is such collection. ongoing. It is of crucial importance to stimulate such registries to collect similar data and use the same definitions so that valid How can the ERA-EDTA Registry support the national comparisons can be made in the future. The ERA-EDTA registries? Registry could serve as a facilitator in this. The ERA-EDTA Registry is dependent on well-functioning national and regional registries, which the ERA-EDTA Registry EUROPEAN PAEDIATRIC NEPHROLOGY has supported, mainly by providing know-how. Since 2004, the Past and present situation Registry staff has organized almost 30 courses on clinical epide- miology and statistics in various parts of Europe. In addition, In the field of paediatric CKD, the European collaborative educational articles on epidemiological methods have been clinical research began 30 years ago with studies conducted by published in Nephrology Dialysis Transplantation, Kidney the ‘European Study Group for Nutritional Treatment of International and Nephron Clinical Practice (please consult Chronic Renal Failure in Childhood’ in 25 centres from 8 differ- www.era-edta-reg.org), and young researchers have been able ent countries. The research done by this group showed that a to visit the Registry office in Amsterdam to work on research low-protein diet did not affect growth and CKD progression, in projects. A central aim must be to continue and develop this contrast to proteinuria and blood pressure, which were strongly support to national registries as it helps improve the quality and associated with disease progression [30]. The network then ex- enhance the conformity of the registries. A large amount of data panded to cover a wider clinical research area, especially in car- is available in the national registries and it is important that this diorenal research. In 2009, the trial entitled ‘Effect of Strict are analysed and reported by knowledgeable persons. Blood Pressure Control and ACE Inhibition on the Progression of CRF in Paediatric Patients’ (ESCAPE) showed that strict How to get the most out of the ERA-EDTA Registry blood pressure control under the 50th percentile slows down data in order to improve nephrology in Europe? CKD progression during the 5-year follow-up [31]. The initial The data provided to and held by the Registry are needed to antiproteinuric response to the angiotensin-converting enzyme produce information to guide decisions about KRT in Europe. inhibitor therapy was predictive of a long-term renal survival 1472 Z.A. Massy et al. despite the occurrence of proteinuria rebound in half of the Dialysis Working Group’ [39]. In addition, many European patients [32]. The ESCAPE Network now involves more than paediatric nephrology centres participate in the global 55 centres in 16 European countries and serves as a collabora- ‘International Paediatric Dialysis Network’ [40]. tive platform for major ongoing paediatric projects, such as the The main causes of CKD in children are Congenital ‘Cardiovascular Comorbidity in Children with Chronic kidney Anomalies of Kidney and Urinary Tract and hereditary ne- disease’ (4C) study [20, 33], the ‘HDF, Heart and Height’ (3H) phropathies. Continuous advances in cell and molecular biol- study [34] and the ‘Antibiotic Prophylaxis and Renal Damage ogy techniques have revolutionized the knowledge, diagnosis in Congenital Abnormalities of the Kidney and Urinary Tract’ and sometimes even prognosis of many inherited kidney dis- (PREDICT) trial [ClinicalTrials.gov. Antibiotic Prophylaxis eases. As the rarity of these diseases creates a barrier for clinical and Renal Damage In Congenital Abnormalities of the Kidney research, several European networks, registries, disease-specific and Urinary Tract (PREDICT). Accessed at: https://clinical databases and bio-repositories have been created to overcome trials.gov/ct2/show/NCT02021006]. The findings of these proj- this issue, with major clinical inputs in genetic counselling, phe- ects concerning the management of how to improve the out- notypic refinement or genotype–phenotype association, prog- come of CKD have often been translated into clinical practice nostic value and eventually mechanistic insights leading to Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 guidelines and implemented in routine clinical settings. therapeutic approaches [41–44]. Furthermore, the European ESKD in children is a specific and extremely challenging Rare Kidney Disease Reference Network, a consortium of 38 condition that requires large-scale, prospective and cohort stud- centres in 12 European countries, has been implemented to ies. In 2007, a new European registry of paediatric KRT, the promote dissemination of knowledge, research and healthcare European Society for Paediatric Nephrology (ESPN)/ of rare kidney diseases (ERKNet. The European Rare Kidney ERA-EDTA Registry, was launched. Since then, there has been Disease Reference Network. Accessed at: https://www.erknet. a progressive increase in the number of European countries org/index.php? id¼home). providing individual patient data to the Registry, with 38 coun- Future epidemiological and clinical research directions tries—the whole of Europe—currently participating, covering a general population of more than 100 million children 15 years There remain, however, many challenges and areas in which old. In recent years, the ESPN/ERA-EDTA Registry has suc- further epidemiological and clinical research is needed. There is cessfully provided epidemiological data on incidence, preva- an increasing emphasis on patient-centred outcome research in lence, patient characteristics, KRT modalities and mortality in kidney disease but this remains an understudied area of paedi- paediatric ESKD, along with relevant insights on cardiovascular atric nephrology (e.g. growth, pubertal development, fatigue, risk, anaemia, nutrition and growth, dialysis and transplanta- schooling, absenteeism, familial stress, quality of life and cogni- tion outcomes and rare kidney diseases [35]. The Registry has tive function). Accurate evaluation of social determinants of yielded several research findings directly relevant to patients, kidney health and integration of social aspects into clinical care physicians and healthcare policy makers. For instance, among to assist vulnerable families with broad social needs will repre- more than 6000 children who started dialysis in Europe in the sent an important step towards optimization of renal care and period between 2000 and 2013, the mortality rate was 28 deaths long-term outcomes for children with kidney diseases. per 1000 patients a year [36], more than 50 times higher than in There is unmet need for new drug developments and high- the general paediatric population without kidney disease. The quality clinical trials in paediatric nephrology research. Recently, mortality rate in Europe is approximately half that reported in the ‘connect4forchildren’ (C4C) initiative, a new paediatric mul- the USA by the United States Renal Data System (USRDS). tidisciplinary public–private consortium that includes academic Along with other international registries, the ESPN/ERA- and industry partners from 20 European countries, has been EDTA Registry provided information on the largest cohort of launched. This network, in which paediatric nephrology is repre- children starting chronic dialysis in the neonatal period to date sented, is a sustainable infrastructure created to facilitate the de- [37]. Given the medical and ethical challenges that arise from livery of multinational clinical trials in children. Finally, further studies are needed to improve patient out- this rare clinical situation, this study provided data of critical comes after transitioning from paediatric to adult care. This is a importance showing much improved survival rates. This study key issue that should include standardized outcome measures will thus help clinicians to provide reliable prognoses and and time intervals in order to evaluate successful transition pro- counselling to families. Another population-based Registry cesses during this high-risk period. This essential research will study on mortality of children on KRT in 32 European coun- require active collaboration between paediatric and adult neph- tries showed considerable variation in the country-specific mor- rologists and cohorts/registries that allow tracking lifelong tality rate and demonstrated that most of this variance could be psychosocial and medical outcomes of patients with kidney explained through disparities in public health expenditure, disease. which was inversely associated with mortality risk [38]. In con- trast to data for adult ESKD, increased healthcare spending pro- motes patient survival for the vulnerable population of children ERBP on KRT. Other relevant European collaborative efforts in paedi- Clinical practice guidelines are designed to aid medical atric ESKD include the ‘Cooperative European Paediatric Renal decision-making with the aim of improving care. In theory, TransplAnt Initiative’ registry, a multinational paediatric kid- their primary relevance and their quality rely on the rigour of ney transplantation network [38], and the ‘European Paediatric the underlying development process. During the past decade, NPPC propositions to stimulate research 1473 Table 2. EKHA actions clinical practice guidelines per se does not ensure their use in daily renal practice [50]. Several factors related to knowledge, Organization of an Annual European Kidney Forum in the European Parliament attitude and behaviour affect their uptake. While ERBP has Participation in the European Commission Conference on chronic invested much effort in producing and disseminating trustwor- diseases (2014) thy guidelines over the years, little is known about their imple- Participation at the ASN 2015 Kidney Week stakeholder meeting to mentation in practice and any resulting changes in the quality present EKHA as a possible model for collaboration across US or outcomes of care. kidney organizations Participation in the European Commission Conference on food International and European cohorts and registries with cen- product improvement (2016) tre-level data could offer an opportunity for monitoring the Contribution to the event ‘Improving organ donation and transplant downstream effects of guideline implementation on a national, across the EU: A cross-condition campaign’ (2016) European and international scale. Meaningful initiatives would Successful advocacy towards EU support of ‘The Effect of Differing require informed determination of quality indicators, covering Kidney Disease Treatment Modalities and Organ Donation and Transplantation Practices on Health Expenditure and Patient structure, process and outcome [51, 52]. Such indicators may Outcomes’ project (2017–19) overlap with existing quality of care measures, already captured Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 Organization of multi-country survey on patient information (2017) by existing datasets. One key future goal may require inclusion Contribution to EU Health Policy Platform (2017) of new indicators as part of prospectively collected datasets in Development of a European Commission Thematic Network on the Employment of Patients with Chronic Diseases different cohorts and particularly in the ERA-EDTA Registry. Collaboration with the EU Joint Action CHRODIS on prevention and To this end, the QUality European STudies initiative [53]— treatment of chronic diseases taken over by the Registry almost 15 years ago—may be revital- Co-drafting of position statements calling for EU action on risk factors ized. For any such exercises to be informative, long-term in- (salt, trans fatty acids, tobacco) volvement of experts in implementation science will be needed. Participation in the drafting of a position statement of the European ADPKD Federation Moreover, the promotion for a further and close collaboration Participation in the drafting of the EU Roadmap for Action on Food between the two ERA-EDTA entities, the ERBP experts and the Product Improvement ERA-EDTA Registry staff, should become a key goal in the Development of a thematic network on Improving Organ Donation future. and Transplantation in the EU for the EU Health policy Platform, resulting in practical recommendations on how to proceed for the European Commission (2019) IMPORTANT TOPICS RELATED TO THE EU ADPKD, autosomal dominant polycystic kidney disease; CHRODIS, Chronic Diseases PRIORITIES platform. Actions of European kidney health alliance (EKHA) in the last few years ERBP has substantially contributed to raising the standards for The constantly rising number of patients with CKD and guideline developments in nephrology [45]. For every guideline, ESKD throughout Europe [54] consumes a considerable por- an extensive scoping process ensures overlap with other guide- tion of healthcare budgets [55]. To maintain high-quality care, line bodies is avoided and important questions are addressed a coordinated European approach is needed, which implies or- [46]. Decision-making is based on core outcomes that are criti- ganizational, educational and clinical action, as well as research cally important to all stakeholders, including patients, their planning. clinicians and policymakers [46]. Evidence is comprehensively The EKHA (http://ekha.eu/) unites all key European stake- collected and critically appraised using Cochrane systematic re- holders in kidney care (patients, nurses, foundations and physi- view methodology [47]. Results are subsequently fed into an cians), and proposes solutions at the EU policy level for the evidence-to-statement framework using grading of recommen- challenges posed by CKD, given that both the European dations assessment, development and evaluation methodology, Commission (EC) and European Parliament play vital roles in which requires guideline developers to carefully consider the assisting national governments via a top-down approach. anticipated effects of the options being considered, the certainty EKHA’s work at the EU level is complemented by its contacts of the evidence for those effects and the costs and feasibility of with kidney stakeholder groups at a national level. options [48]. Patient involvement is encouraged throughout the With these aims in mind, in 2015, EKHA published its development process and every step is executed transparently Recommendations for Sustainable Kidney Care (http://www.re with clear documentation of judgements made. Guidelines are nal.org/news-item/2015/05/26/ekha-recommendations-for-sus primarily published in Nephrology Dialysis Transplantation, tainable-kidney-care#sthash.331yWFTZ.dpbs), which are cen- but co-publication has occurred, depending on the topic [49], tred around four main goals: (i) early detection and prevention to reach a wider audience. National societies are involved in of CKD and its progression; (ii) patient education and free translating short versions of the guidelines into various lan- choice of treatment; (iii) increasing access to transplantation; guages, and dissemination is supported through presentations and (iv) treatment reimbursement strategies. during national and international conferences. From 2016 on, EKHA undertook various initiatives to reach In order for guideline development efforts to have signifi- these aims (Table 2) and also organized yearly stakeholder for a cance, guideline recommendations must be correctly imple- in the European Parliament on these topics, in order to stream- mented. Unfortunately, merely developing and disseminating line activities, draw the attention of European and national 1474 Z.A. Massy et al. Table 3. Preliminary results of the patient information questionnaire: per- and that action should be undertaken to increase by country the centage of patients perceiving that they did not receive enough informa- types of donations that occur less [59]. tion about a given approach Future actions of the EKHA Kidney Replacement or FR NL SP GR SL LI Conservative Therapies Between 2009 and 2015 the EC ran an Action Plan to stimu- Peritoneal dialysis 40 13 36 56 51 41 late transplant activities throughout Europe. The plan was par- Home haemodialysis 56 50 48 74 79 65 tially successful, but more work remains to be done. EKHA Overnight haemodialysis 70 50 60 78 71 68 suggests that a second EU Action Plan could further boost Kidney transplantation 15 17 35 44 30 14 European transplant activity, benefitting from the experience Conservative care 77 64 70 56 90 33 accumulated during the first programme. EKHA intends to be- Data are presented as percentage of total responders per country; FR: France; NL: the come one of the catalysers for this, drawing from the EKHA Netherlands; SP: Spain; GR: Greece; SL: Slovenia; Li: Lithuania. Data are preliminary and need more detailed analysis. ‘gift of life’ campaign launched in 2018 and the EC Thematic Network on transplantation, which will be developed by EKHA starting in 2019 (https://www.eurekalert.org/pub_releases/ Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 policy makers to these themes and include the involvement of 2018-12/e-epo121718.php). Members of European Parliament to advance kidney-related The reimbursement of KRT is a matter of concern. There matters. are substantial discrepancies in reimbursement of dialysis Prevention is one of the cornerstones of good outcomes and among Member States. The strategies that are least expensive to quality of life, but it is underused. Current CKD cohorts and the health system (transplantation and home dialysis) are coun- population-based cohorts will play a key role in identifying terintuitively underrepresented throughout Europe. An addi- modifiable risk factors for disease onset and progression, as well tional matter of concern is the appearance of insufficiently as the best clinical practices. They also have the potential to evidenced but costly therapies for rare kidney disorders. All point out barriers for successful implementation of primary these factors need further research to guide policy action. and secondary prevention strategies. However, on average in Although the EU has funded several research projects where Member States, only 3% of the health budget is spent on pre- kidney disease was the main or an ancillary focus, it is time for a vention. If part of healthcare financing were shifted from ther- more coordinated action, in analogy with the ‘Kidney apy to prevention, this would have a positive impact on total Innovation Accelerator (KidneyX)’ project run by the US health expenditure [55]. CKD is linked to many other non- Department of Health and Human Services, in collaboration communicable diseases (NCDs), including diabetes mellitus, with the American Society of Nephrology (http://www.kidneyx. hypertension, cardiovascular disease, cancer and liver disease org/). [55, 56]. Modifiable measures to reduce incidence of these The approach outlined by several Dutch stakeholder groups NCDs are often related to lifestyle, diet and environment. Since (‘Combating Kidney Disease—Nierziekte de baas’) may be the same risk factors are common to many chronic diseases, taken as an example for the development of an action plan out- they require broader action than from the kidney community line (https://www.nierstichting.nl/media/filer_public/14/ef/14e alone. In this context, EKHA also has a leading role in the f1c2a-73f9-40f6-b833-afbc940dbd41/onderzoeksagenda_nierzi European Chronic Diseases Alliance, an umbrella consortium ekte_de_baas_-_gezamenlijke_agenda_oi_2017.pdf). This fra- representing 11 chronic disease organizations (http://www.alli mework has four major foci: the much neglected prevention ancechronicdiseases.org/home/). and quality of life aspects of kidney disease, and the innovatory Not all renal replacement strategies are available to all valid fields of personalized and regenerative medicine. This research candidates in all EU countries, and many patients are not well framework strives for more sustainable and less costly solutions, informed about their options, especially regarding home dialy- while also considering the scarcity of evidence-based and sis (both home haemodialysis and peritoneal dialysis), trans- health-economic analyses in nephrology [60, 61]. plantation and comprehensive conservative (palliative) care Personalized medicine covers not only tailored treatment for [57]. EKHA confirmed this shortcoming via a recent survey specific disorders or mechanisms (e.g. the multiple diverging among patients from several European countries (Table 3). factors at play in kidney fibrosis and progression of CKD) or In addition, the Effect of Differing Kidney Disease targeted drug administration depending on the individual sen- Treatment Modalities and Organ Donation and Transplanta- sitivity, but also, as health illiteracy is frequent among CKD tion Practices on Health Expenditure and Patient Outcomes patients [62], education (with specific approaches and attention project, advocated by EKHA at EU level and funded by the for the less educated or low income groups as well as ethnic Third Health Programme of the EU, started to assess KRT op- minorities). tion availability and patient information at the beginning of Regenerative medicine programmes focus on bioartificial 2017 [58]. Although Europe is one of the leading continents in organs (the combination of polymers and cells), organoids and transplantation [59], the differences in transplant rate and stem cells [63]. Research might also be guided towards often number of KRT patients living with a functioning transplant neglected but troublesome problems for patients, such as itch- among countries suggests that there is room for improvement ing, cognitive dysfunction or pain, focusing on patient-centred [59]. Likewise, the differences across Europe between living and outcomes, such as those defined by the Standardised Outcomes deceased donation show that few countries are strong in both, in Nephrology (SONG) initiative (http://songinitiative.org/). NPPC propositions to stimulate research 1475 Programmes supporting KRT strategies, which favour better • creating registers of patients willing to be contacted about quality of life, are encouraged with focus on projects promoting clinical trials relevant to them; and improving transplantation and home therapies. EKHA will • providing educational courses that train investigators to target the hot topics that should be supported in the future by design and execute trials; nephrologists according to the EU needs and will work in col- • funding clinical trial fellowships to attach research leaders of laboration with ERA-EDTA to reach these goals. the future to developing projects to help grow the expertise; • improving the management/presentation/discussion of trial results at the ERA-EDTA annual conference; IMPORTANT CLINICAL RESEARCH TOPICS • arranging standalone workshops to examine specific IN EUROPE topics such as end-point design; Western Europe • interfacing with regulatory agencies, research funders, in- dustry and patients to design and deliver trials that are Beyond registries and cohort studies, there are broadly needed to inform clinical practice; speaking three types of health services research—clinical trials, • fostering closer working with other specialities to reduce big data and qualitative (exploratory) research. While there is a Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 working in a condition-specific silo—some of the future great deal of interesting and important qualitative research go- drugs for kidney diseases are likely to come from develop- ing on to explore ‘why’ things happen using non-numeric data ments in oncology; in Western Europe, qualitative research groups in nephrology • creating a culture of offering patients RCT where evidence in Western Europe and indeed globally are less well established is lacking (similar to oncology); and than in other research areas. Furthermore, results tend to be • using the ERBP to encourage inclusion in clinical trials, more hypothesis/logic generating and more context-specific for example, avoiding expert recommendations when a than from other research areas. The committee therefore agreed clinical trial could be done. that the potential for qualitative research to be world leading, It was felt that the ISN had successfully established a clinical practice changing and with high impact is less clear at the mo- trials infrastructure Advancing Clinical Trials (ACT), and those ment, and for that reason prefers focusing on existing strengths lessons could be learned from that while avoiding duplication. and opportunities in clinical trials and big data research. The conclusions below are based on responses to the follow- Big data. Traditionally, Scandinavian countries and those ing questions from four to six experts in each of these two re- with nationalized healthcare systems provide an excellent op- search areas in Western Europe: portunity to use routine health and social care records to de- Q1. In what way do you think the region covered by ERA-EDTA is in a scribe associations between practices and outcomes in general, unique position to lead the world in (clinical trials/big data research) un-selected, populations. There are also, however, some poten- (e.g. existing healthcare infrastructure, information governance and tially useful general population-level linked datasets in Spain, existing research networks)? Q2. Can you give 2–3 examples of world-leading (clinical trials/big data France and Switzerland. The new general data protection regu- research) conducted in the region covered by the ERA-EDTA in the last lation makes the rules clearer and more consistent and makes it 5 years? less difficult to establish a lawful basis for academics to process Q3. What do you think would be the key 2–3 things that the ERA-EDTA personal data for clinical research. There is also heterogeneity could do to promote world-leading (clinical trials/big data research) in Europe? in clinical practice within Western Europe that provides an ex- cellent opportunity to use observational data to explore the con- sistency of associations and even the causal nature of Clinical trials. A number of major, practice-changing, inves- relationships. tigator-initiated trials have been led by researchers in Western It should also be recognized that big data research extends Europe in recent years. These have been in the areas of vasculi- far beyond linking health and social care records for research; it tis, membranous glomerulopathy, renal vascular disease and can include data from scans, free text and wearable devices, ge- cholesterol lowering, and demonstrate that it is possible to cre- nomics, proteomics, metabolomics and exposomics. ate a network of renal units across Europe to recruit sufficient Both types of big data research can involve the use of prior numbers to trials. On the contrary, respondents raised concerns hypotheses and statistical models or agnostic approaches such about Western Europe’s ability to recruit to trials and especially as machine learning and artificial intelligence. There is certainly industry-led trials. world-leading statistical expertise in Western Europe with con- Existing collaborations and cultural similarities, along with siderable potential to apply novel methods of analysis to ne- the harmonized regulatory process, should facilitate delivery of phrology if interesting research questions and datasets can be large trials across the continent. It was felt that the role of the presented to them. There is less of a track record of machine ERA-EDTA should be ‘concertation’, that is, bringing academ- learning and artificial intelligence in nephrology in Western ics and other partners together to define the best questions, Europe, but the methodological expertise undoubtedly exists. methodology and clinical trial processes. This could be achieved It was felt that the ERA-EDTA could support the develop- in a number of ways: ment of world-leading big data research in a number of ways: • establishing a network of centres willing to do clinical tri- • establishing a network of researchers with awareness of als and provide methodological support; and access to routine healthcare databases in different 1476 Z.A. Massy et al. Table 4. Research plan with eight hot topics to stimulate research collaboration and grant applications in Europe (i) To conduct collaborative research designed to uncover non-invasive diagnostic tests or new predictive markers for kidney disease complications, aimed to further improve the classification and prognosis of kidney diseases based on large-scale omics data using available European patient cohorts (ii) To review the feasibility and relevance of the development of CKD Stages 4–5 registries based on on-going experiences at national level and explore if and how these can be brought together for quality assurance and research at the European level (iii) To plan a successful transition process from paediatric to adult care of CKD by active collaboration between paediatric and adult nephrologists and cohorts/registries (iv) To reinforce the collaboration between the ERBP experts and ERA-EDTA Registry staff in order to extend the number of indicators to include the thresholds of the ERBP recommendations as part of prospectively collected datasets stemming from different national or regional cohorts and from the ERA-EDTA Registry and to adapt those as new recommendations are published (v) To continue supporting EKHA with its established links with the EU, allowing it to target key nephrological topics prioritized by patients and professionals, such as better quality of life in KRT patients and improving kidney transplantation and home treatment modalities, which also include regenerative and personalized medicine (vi) To support the development of world-leading big data research in a number of ways including the creation of data networks and the development of educational programmes Downloaded from https://academic.oup.com/ndt/article/34/9/1469/5512198 by guest on 11 February 2022 (vii) To help the Eastern European nephrology community to optimize patient care and patient-oriented research in their countries by increasing public awareness, encouraging/supporting clinical nephrology and epidemiology studies and improving training in nephrology (viii) To create a European network of kidney units in order to extend our understanding of AKI progression and complications, including transition of AKI to CKD countries to facilitate international studies that validate Latvia, Lithuania, Montenegro, Serbia, Former Yugoslav findings and mine heterogeneity; Republic of Macedonia (FYROM), Georgia, Armenia, • arranging standalone workshops that bring together Azerbajan and Turkey] are also classified as being a part nephrologists and methodologists to examine specific of Eastern Europe. To the best of our knowledge, exten- topics; sive epidemiologic data on the prevalence of CKD stage • facilitating the training of the future big data researchers in Eastern Europe in the ERA-EDTA Registry are avail- through this network and statistical/epidemiological able only on CKD Stages 5D and 5T [64]. Only limited training courses that take things beyond the introductory data are available on the prevalence of CKD Stages 3–5 level; not yet on dialysis, which was considered to be higher • encouraging the adoption of information standards as than in Western Europe [65]. Although there are no part of renal IT systems to improve data quality for clini- comparative trials, it may be speculated, or largely cal care and research; accepted, that this part of Europe may differ from the • educating the public, policy makers and funders on the western part in: importance of kidney disease and in particular the per- • limited funds for both healthcare services and projects; sonal and societal burden of ESKD, which often gets over- • less public awareness about chronic diseases, which also looked due to its infrequent occurrence; means less attention paid to CKD; • dedicating a session at the ERA-EDTA conference to • difficult cooperation with health care authorities; innovations in big data analysis; • country-specific health problems (i.e. Balkan nephropa- • working out recommendations for which parameters thy, more frequent obesity and diabetes, possibly worse would be essential to be included in kidney big databases; control of diabetes and hypertension, air pollution and and deviations from recommended diet); • stimulating health-economically oriented kidney research • low transplantation rates in many, but not all, of these (nephrology traditionally being not being keen to investe countries [59]; and in this area, whereas nephrology is consuming propor- • targets/feasibility of these targets. tionally large chunks of health care budgets). Since all of the above-mentioned difficulties have potential Eastern Europe negative effects on various aspects (identification, prevention The problems cited below and suggestions for solutions and treatment) of CKD, actions to be taken may or should tar- improvements to these problems are not specific to the Eastern get to improve each of these items. Some of these actions are European countries. However, these problems may be more more easily achievable (i.e. increasing public awareness, prominent in this region of Europe. encouraging-supporting studies on clinical nephrology and epi- • Unique features of nephrological problems in Eastern demiology, improving nephrology training), whereas others are Europe. Overall, Eastern Europe includes 10 countries more difficult to achieve (i.e. limited funds and lower standards (Belarus, Bulgaria, Czech Republic, Hungary, Moldova, for healthcare and problematic cooperation with authorities). Poland, Romania, the Russian Federation, Slovakia and Suggestions by ERA-EDTA and/or EKHA may help contribute Ukraine). According to some other sources, additional to convincing authorities to make changes, at least in some countries [Albania, Bosnia-Herzegovina, Croatia, Estonia, countries. NPPC propositions to stimulate research 1477 Target population. Since CKD is very frequent (mostly af- Stevens reports personal fees from Vifor Pharma, grants from fecting 13–15% of the population of the whole country) and a Alexion, Vifor Pharma, Chiesi, LNC Medical, personal fees major cause of morbidity and mortality in addition to having a from Alexion, outside the submitted work. Dr Bruchfeld reports huge economic burden, it should be very well understood by: grants from Astra-Zeneca, honoraria from Chemocentryx, • healthcare authorities; MSD/Merck, participation in a company sponsored speaker’s • the public; and bureau for AbbVie, MSD/Merck, Sanofi-Genzyme, outside the • medical professionals, including general practitioners and submitted work. The other authors have no financial interest to specialists with a high probability of seeing CKD patients declare relevant to this work. (i.e. general internists, cardiologists, diabetologists, endo- crinologists, urologists, oncologists, hepatologists, vascu- REFERENCES lar and cardiac surgeons and neurologists). 1. Zoccali C, Arici M, Blankestijn PJ et al. The ERA-EDTA today and tomor- row: a progress document by the ERA-EDTA Council. Nephrol Dial Thus, the first step should be increasing awareness, and con- Transplant 2018; 33: 1077–1082 vincing these parties of the importance of CKD. 2. 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