Clinical Kidney Journal, 2022, vol. 15, no. 3, 372 –387 LEADING EUROPEAN NEPHROLOGY doi: 10.1093/ckj/sfab170 Advance Access Publication Date: 23 September 2021 Editorial Comment Clinical Kidney Journal Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 EDITORIAL COMMENT RICORS2040: the need for collaborative research in chronic kidney disease Alberto Ortiz on behalf of Asociación Información Enfermedades Renales Genéticas (AIRG-E), European Kidney Patients’ Federation (EKPF), Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Rin ~ ón (ALCER), ~ igo Álvarez de Toledo (FRIAT), Red de Investigación Renal Fundación Renal Ín (REDINREN), Resultados en Salud 2040 (RICORS2040), Sociedad Espan ~ ola de Nefrologı́a (SENEFRO) Council, Sociedad Espan ~ ola de Trasplante (SET) Council, Organización Nacional de Trasplantes (ONT) Correspondence to: Alberto Ortiz; E-mail: aortiz@fjd.es ABSTRACT Chronic kidney disease (CKD) is a silent and poorly known killer The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is ‘solved’ by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020–2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Received: 12.8.2021; Editorial decision: 23.8.2021 C The Author(s) 2021. Published by Oxford University Press on behalf of the ERA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://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 372 The need for collaborative research in CKD | 373 ~ ón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from Enfermedades del Rin becoming true. Keywords: accelerated ageing, burden of disease, chronic kidney disease, COVID-19, decade of the kidney, kidney failure, kidney transplantation, research funding CHRONIC KIDNEY DISEASE: AN EVOLVING Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 known to the wider public, non-nephrologists and healthcare CONCEPT IN NEED OF UPDATING authorities. Non-experts usually equate the burden of CKD with the burden of KRT for kidney failure. Despite care for KRT The Kidney Disease: Improving Global Outcomes consensus patients representing a disproportionate percentage of the defines chronic kidney disease (CKD) as abnormalities of kidney healthcare budget (the roughly 64 292 persons on KRT in Spain structure or function present for >3 months with implications consume 2.5–5.0% of the healthcare budget), the bulk of the for health [1]. Just one criterion identifying abnormal kidney health burden of CKD is not represented by KRT but by acceler- structure or function allows the diagnosis of CKD. Criteria in- ated ageing and premature death, as clearly quantified by clude a low glomerular filtration rate (GFR; <60 mL/min/1.73 m2) Global Burden of Disease (GBD) data discussed below [14]. or evidence of kidney damage such as pathological albuminuria However, there are no registries in Spain for persons with CKD [urinary albumin:creatinine ratio (UACR) 30 mg/g]; abnormal not on KRT as is the case for many other countries. urine sediment, histology or imaging; abnormalities due to tu- bular disorders or kidney transplantation. In clinical practice, this means that diagnosing CKD when GFR is 60 mL/min/ KRT: A SUCCESS STORY OR A STORY OF 1.73 m2 requires urinalysis or kidney imaging. A recent concep- FAILURE? tual manuscript summarized the key features of CKD for non- KRT has been hailed as one of the success stories of healthcare nephrologists, as there is ongoing confusion, even in high-qual- that allows survival when a vital organ has failed. ity journals, such as the New England Journal of Medicine [2]. Counterintuitively, this reflects only a partial view of the facts. A CKD diagnosis implies an increased risk of progressing to Rather, KRT should be considered a failure of CKD management, require kidney replacement therapy (KRT), of all-cause and car- as the expected remaining lifetime is severely reduced—by ~70% diovascular death and of acute kidney injury (AKI) [1, 3–5]. There (40 years less) and by 25% (15 years less) for a 20-year-old on dial- is a bidirectional relationship between CKD and AKI. CKD is the ysis or with a functioning kidney graft, respectively [15, 16]. The main risk factor for AKI and AKI may accelerate CKD [6]. AKI has absolute reduction in the expected remaining lifetime is less at a high mortality and increases the risk of death for >1 year after older ages, but the relative reduction in life expectancy remains the episode [6]. AKI is also common, as ~5% of hospitalized constant up to age 89 years (Figure 3A). The fact that the mortal- patients develop in-hospital AKI [7]. More recently, CKD has been ity of kidney failure remains high, up to 100-fold higher in identified as the most prevalent risk factor for lethal coronavirus patients on KRT than for similar-aged controls [5], is not well disease 2019 (COVID-19) and as the factor that most increased known by health authorities and may hinder funding for CKD re- the risk of death in COVID-19 after older age [8–10] (Figure 1). AKI search. Indeed, the 5-year survival of patients on dialysis is lower is also common in COVID-19 and a key risk factor for death [8]. than for all forms of cancer combined [17] (Figure 3B). Correct CKD diagnoses require indicating cause and G (GFR: G1–G5) and A (albuminuria: A1–A3) categories. Increasing CKD categories are associated with an increased risk of all-cause and THE MOST COMMON CAUSE OF CKD IS cardiovascular death, even in the elderly (Figure 2A and B). The UNKNOWN: THE NEED TO REDEFINE THE CKD G1 (GFR 90 mL/min/1.73 m2) and A1 (UACR <30 mg/g) catego- AETIOLOGY LANDSCAPE ries are not diagnostic of CKD by themselves. Persons in cate- gory G1A1 must fulfil an additional criterion to be diagnosed The most common cause of KRT in Spain is diabetes (25% of per- with CKD, such as imaging diagnostics of polycystic kidney dis- sons initiating KRT), followed by unknown (15%), ‘vascular’, glo- ease (PKD) [1, 2]. The autosomal dominant PKD paradigm illus- merulonephritis (14%) and inherited kidney disease [15, 16, 18]. trates the way to go: a diagnostic test (sonography) allows the The magnitude of the inherited category is difficult to assess as it diagnosis of CKD decades before patients fulfil any other crite- is usually divided into PKD and others. Others are usually dumped rion to diagnose CKD, including the most commonly used ones into a ‘miscellaneous’ category or misdiagnosed as glomerular or such as GFR and UACR thresholds [11]. Similar diagnostic tools interstitial CKD. Recent analysis of the Madrid and Catalonian KRT are needed for other forms of CKD, as by the time GFR falls to registries has disclosed that inherited kidney disease is as frequent 60 mL/min/1.73 m2, CKD has progressed unnoticed (potentially as glomerulonephritis [19]. Inherited kidney diseases are fre- over years and even decades) to destroy >50% of the functioning quently overlooked by physicians as illustrated by whole-exome kidney mass. Similarly, albuminuria as low as >2.5 mg/g is al- sequencing findings of monogenic kidney diseases in 9% of adult ready associated with an increased risk of premature death CKD and in 17–34% of those with CKD of unknown cause [20, 21]. (Figure 2B). Again, the current albuminuria threshold used to di- ‘Vascular’ mainly means hypertension, and it is labelled as agnose CKD is a late event. There is a clear margin for earlier di- hypertension in the European Renal Association–European agnosis and therapy of CKD. Additional future criteria to Dialysis and Transplant Association (ERA-EDTA) Registry [15, diagnose CKD may be envisioned, such as genetic tests disclos- 16, 18]. In clinical practice, hypertension is usually listed as a ing clearly pathogenic gene variants or urinary biomarkers be- cause when there is no other obvious aetiology, following expert yond UACR, including urinary peptidomics [12, 13]. recommendation [22]. This practice has been criticized, as it Kidney failure (end-stage kidney disease, G5, GFR <15 mL/ may replace an inadequate aetiologic workup, likely downplay- min/1.73 m2) is probably the only form of kidney disease well ing the incidence of other causes of CKD while falsely boosting 374 | A. Ortiz A B CKD 4.0 23% of global population 3.5 Adjusted HR for COVID-19 death at risk of severe COVID-19 3.0 2.5 Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 2.0 Other risk 1.5 factors 1.0 0.5 0 s nt ic ea y e 5 3 d) se n si og 1 y nc as G G io la lle ea di r ly 4– ns a p se KD tro ia ur d < ign ns is te G D td C on tra er ne se al KD al ar yp nc er no m an C he H (u th g al rg O dia gic ic ol s O te on o be ol hr at ia C em D H FIGURE 1: CKD is the most prevalent risk factor for severe COVID-19 and also the risk factor for severe COVID-19 that is associated with the highest risk of death, after old age. (A) CKD as a percentage of persons at risk of severe COVID-19 on a global scale. Data from Clark et al. [10]. (B) Risk of death associated with pre-existent condi- tions in patients with COVID-19 in an adjusted analysis. Data from Williamson et al. [9]. Reproduced from ERA-EDTA Council and ERACODA Working Group [8]. hypertension as a cause (rather than as consequence) of CKD adding hypertension) followed by glomerulonephritis (19%), [23, 24]. Thus there is no relationship between the prevalence of diabetes (15%) and PKD (8%). This identifies a major issue in hypertension and hypertensive CKD in different countries [23]. CKD. A significant percentage of persons lack an aetiological In African Americans, hypertensive nephropathy has long been diagnosis, which precludes aetiology-targeted therapy and shown to represent a familial predisposition to CKD triggered by early prevention campaigns. Among the fastest-growing seg- different causes, i.e. it would be better classified as inherited ment of CKD patients (those 65 years of age), unknown and kidney disease accelerated by triggers such as human immuno- hypertension accounted for 43% of incident KRT patients, deficiency virus or severe acute respiratory syndrome coronavi- highlighting the need to define cause in the elderly. We pro- rus 2 (SARS-CoV-2) infection [25]. pose that accelerated kidney ageing may be a key contributor The ERA-EDTA Registry provides more elaborate data to CKD, including in the elderly, and are currently devising a (Spanish data are made public on websites but not regularly working definition for accelerated kidney ageing that spurs re- published in journals by themselves) and a European-wide search in this field. perspective [15, 16]. In ERA-EDTA Registry data for all coun- tries, the most common cause of incident KRT was unknown (27%, increasing to 39% if we add hypertension) followed by di- THE GROWING BURDEN OF CKD abetes (20%), glomerulonephritis (11%) and PKD (5%). For prev- Globally, ~850 million persons have CKD [26]. The GBD study alent KRT, the ranking is unknown (27%, increasing to 35% by has generated data on the global and local burden of CKD, while A B 140 140 Average all-cause mortality Average all-cause mortality > 75 years 120 120 rate/patient-years rate/patient-years 100 100 80 80 60 > 75 years 60 65–75 years 40 40 55–64 years 65–75 years 20 55–64 years 20 18–54 years 18–54 years 0 0 30 60 90 120 2.5 10 30 300 1000 eGFR (ml/min/1.73 m2) Urinary albumin:creatinine ratio (mg/g) FIGURE 2: CKD is associated with an increased risk of death even in the very elderly. All-cause mortality rate (absolute risk) for different (A) eGFR and (B) UACR values by age categories based on weighted average across cohorts, adjusted for covariates. A steeper slope at an older age indicates a higher absolute risk difference associ- ated with low eGFR as compared with younger age categories: the discontinuous green line represents the overlay of the risk for the very elderly on top of the risk line for the younger age range. Similar trends were observed for albuminuria. Conceptual representation of data presented in Hallan et al. [4]. In panel A, an increase in the risk of death observed in patients >55 years of age with higher eGFR values is not shown, as this is thought to be an artefact depending on lower muscle mass of patients who were sicker at baseline. The need for collaborative research in CKD | 375 A Expected remaining lifetimes of the general population B and of prevalent dialysis and kidney transplant patients 90 100 85–89 Transplant 85 80–84 Dialysis 80 90 Age of dialysis and kidney transplant patients 75–79 General population 75 70–74 80 70 65–69 65 Age of general population 60–64 70 Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 60 5-year survival (%) 55–59 55 60 50–54 50 45–49 45 50 40–44 40 35–39 40 35 30–34 30 25–29 30 –25% –15 years 25 20–24 –70% –40 years 20 20 15 0–19 10 10 5 0 0 0 10 20 30 40 50 60 70 80 90 ne ia s di is f c an uk is an ar a d ynx in l c m a ca a H ro er r sp lad d d r : l ca or U ing cer ea ca r in ca r os ela er er m ce an b e ce o Sk st nce ito od u on ph i U t: d dne hom te m al lys r o th Le alys ol d em gk Al ctu b nc la de on ru on Pr m nc nc er em nch ta no ly an Tr ry as can n Expected remaining lifetime (years) an ca te d re p g as rin ec y nt r Br s iv un e d f l ncr e n Ki r o Pa ce ou od P an m a -H la C r of on sp ce N ce an an an Tr C C FIGURE 3: Severely limited survival in persons on KRT. (A) Expected remaining lifetimes of the general population and of dialysis and kidney transplant patients in the ERA-EDTA Registry. Arrows and numbers depict relative and absolute reductions in life expectancy for young adults on KRT, either on dialysis (burgundy) or with a functioning kidney graft (orange) [15, 16]. (B) Percentage 5-year survival of KRT modalities (red bars) (haemodialysis, peritoneal dialysis, transplantation after deceased donation and transplantation after living donation) or after the diagnosis of cancer (blue bars). Only malignancies with an incidence >3% of all cancers are illustrated. Orange bar: all cancers aggregated. Based on 2016 data. Source: Vanholder et al. [17]. Spanish epidemiological studies provide information on the lo- will become the second leading cause of death, after cal prevalence of CKD and the epidemiology of KRT. Alzheimer’s, before the end of the century [29] (Figure 5A). This In 2017, 1.2 million people died from CKD globally and CKD is likely an underestimation, as the progressive change in the resulted in 35.8 million disability-adjusted life years (DALYs), age pyramid over the next few decades was not considered. most of them (>70%) not due to diabetic kidney disease (DKD), Spanish projections may also apply to other countries with long as well as in 7.3 million years lived with disability (YLD) and life expectancies. 28.5 million years of life lost (YLL) [27] (Figure 4A). Considerable The population of Spain is projected to peak in the present global variation was noted in CKD burden. Age-standardized decade and to become progressively older and decrease to ~23– CKD DALY rates varied >15-fold between countries, a variability 33 million by 2100 [30, 31]. The most recent estimate of the also evident within Spain and even within Spain autonomous number of persons with CKD dates from 2010, when 14% of communities [15, 27]. This illustrates the need for interregional Spanish adults (6.7 million) had CKD [32]. CKD was more com- collaborative research to identify and correct the drivers of a mon in men than in women and a majority of persons with higher burden in certain regions. CKD were in the 45- to 64-year age range. Projecting these num- The GBD projected that CKD will become the fifth greatest bers into the future in the absence of changes to the current global cause of death by 2040 [14] (Figure 4B). YLL due to CKD standard of care, assuming a constant prevalence of CKD within are expected to double by 2040, the fastest increase among ma- each age range and gender group and using World Health jor causes of death after Alzheimer’s. In contrast, the burden of Organization (WHO) population prediction estimates, results in other major causes of death is projected to decrease (e.g. ischae- at least 8.12 million persons with CKD by 2040 and 7.96 million mic heart disease 3.6% or stroke 10.7%). Interestingly, CKD by 2100, which will represent 18% and 24% of the Spanish popu- growth as a global cause of death outpaces diabetes, illustrating lation, respectively (Figure 5B and C). This is an underestima- the need to address non-diabetic causes of CKD and protect the tion, as progressive ageing of the population (persons 65 years kidneys in persons with diabetes. Spain GBD data identified of age are estimated to increase from 17% in 2010 to 32% by 2040 CKD as the eighth greatest cause of death, representing the larg- and 35% by 2100) will also occur within the same age range cate- est departure from official Instituto Nacional de Estadistica gory, and this would be associated with an increased prevalence (INE) data among causes of death in Spain. The INE underesti- of CKD within age categories. Additionally, by 2040, most per- mated the burden of CKD, likely due to low awareness of the sons with CKD will be 65 years old. condition [28, 29]. Spain’s GBD identified CKD as the second The prevalence of KRT in Spain is also increasing. It in- fastest-growing cause of death, the sixth fastest-growing cause creased 38% from 2007 to 2019 [985 to 1367 per million popula- of YLD and the seventh fastest-growing cause of DALYs among tion (pmp)] and the rate appears to be accelerating (it increased the top 25 causes for each category [28, 29]. Projecting into the 14% from 2007 to 2013 and 22% from 2013 to 2019). At this rate future, the recent rate of increase of CKD in Spain’s GBD, CKD of growth, the number of persons on KRT will hit 0.23–1.00 376 | A. Ortiz A Global burden of CKD 28.5 million years of life lost 35.8 million (YLLs) disability-adjusted Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 life years (DALYs) 7.3 million years lived with disability (YLDs) B Global causes of death Collaborative Mean % change research network Leading causes 2016 Leading causes 2040 number of YLLs in Spain from 2022 1 Ischemic heart disease 1 Ischemic heart disease –3.6 (–43.1 to 40.9) 2 Stroke 2 Stroke –10.7 (–40.1 to 31.9) 3 Lower respiratory infections 3 Lower respiratory infections –24.8 (–47.9 to 3.4) 4 Diarrhoeal diseases 4 COPD 32.1 (–13.0 to 98.4) 5 Road injuries 5 Chronic kidney disease 100.3 (8.3 to 302.1) 6 Malaria 6 Alzheimer’s disease 131.2 (90.9 to 196.6) 7 Neonatal preterm birth 7 Diabetes 76.7 (10.3 to 228.8) 8 HIV/AIDS 8 Road injuries –18.3 (–31.7 to 8.5) 9 COPD 9 Lung cancer 20.7 (–9.0 to 60.5) 10 Neonatal encephalopathy 10 Diarrhoeal diseases –39.7 (–76.5 to 47.0) 11 Tuberculosis 11 Self-harm 7.8 (–15.2 to 41.9) 12 Congenital defects 12 HIV/AIDS –30.4 (–41.8 to –20.3) 13 Lung cancer 13 Liver cancer 69.6 (30.7 to 135.2) 14 Self-harm 14 Hypertensive heart disease 89.9 (6.3 to 358.7) 15 Diabetes 15 Colorectal cancer 59.1 (18.3 to 123.9) 16 Chronic kidney disease 16 Tuberculosis –40.0 (–52.8 to –19.7) 17 Other neonatal 17 Congenital defects –41.0 (–50.6 to –30.5) 18 Alzheimer’s disease 18 Neonatal preterm birth –57.0 (–66.4 to –48.9) FIGURE 4: Global burden of CKD, according to the GDB study. (A) 2017 global DALYs, YLD and YLL due to CKD [27]. (B) Major global causes of death in 2016 and predicted for 2040 according to the GBD study, ranked by YLL [14]. CKD is marked by empty rectangles. Logos to the right correspond to ISCIII-funded collaborative research net- works in Spain that will address each cause from 2022. At the time of this writing, the status of kidney research in 2022 is still unclear. An infectious disease CIBER will be created in 2022, but at this point we are unaware of the logo. Thus, the CIBER logo was used and the word ‘INFEC’ was added. million by the end of the century, i.e. ~1–4% of the projected outcomes in kidney graft recipients is a major aim in kidney re- population of Spain at that time (Figure 5D). The incidence of search. As for CKD, KRT is also more common in men than in KRT also increased by 22% from 2013 to 2019 (125–152 pmp) [18] women. Therefore studies on CKD or KRT that do not split by (Figure 5E). A majority of persons on KRT in Spain (55%) have a gender may reflect the disease in men and studies addressing risk functioning kidney graft. Thus improving kidney and person stratification, diagnosis and therapeutic approaches independently The need for collaborative research in CKD | 377 A Projected numbers of annual deaths in Spain by cause B Number of adult persons with CKD in Spain Ischemic heart disease Age (years) 100 000 Stroke 18–44 90 000 COPD 45–64 Lung cancer 9 000 000 ≥ 65 80 000 Colorectal cancer Number of annual deaths Lower respiratory infection 8 000 000 70 000 Chronic kidney disease 7 000 000 Number of persons 60 000 6 000 000 Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 50 000 5 000 000 40 000 4 000 000 30 000 3 000 000 20 000 2 000 000 10 000 1 000 000 0 0 2016 2026 2036 2046 2056 2066 2076 2086 2100 Men Women All Men Women All Men Women All 2010 2040 2100 C Percentage of adult Spanish D Number of persons on KRT in Spain E Spanish burden of CKD population with CKD Hypothesized 25 1 000 000 22% increase in exponential growth kidney replacement therapy Linear growth incidence and prevalence Percentage of adult population 20 800 000 2013–2019 in Spain Number of persons 15 600 000 10 400 000 5 200 000 0 0 2010 2040 2100 2019 2043 2104 FIGURE 5: CKD burden and epidemiology in Spain. (A) Projected numbers of annual deaths in Spain by cause. Alzheimer’s not shown but it is projected to become the lead- ing cause of death before the end of the century, well above the others. Past growth according to the GBD 2016 for Spain was projected into the future [29]. The projection did not consider the progressive ageing of the Spanish population. Thus it represents an underestimation of CKD-related deaths. (B) Number of adults with CKD in Spain, by gender and overall, according to the ERICA study from 2010 and projection into the future assuming the same prevalence of CKD by age category and considering changes in the Spanish population age pyramid according to the WHO predictions [30–32]. Since the increasing mean age within each age category was not considered, this projection represents an underestimation [30, 31]. For each selected year, data for men, women and all are shown. (C) Percentage of Spanish adults with CKD in the ERICA study (2010) and projection into the future [30–32]. (D) Number of prevalent persons on KRT in Spain in 2019 and projection into the future based on the 22% (12 000 persons) growth from 2013 to 2019 [18]. In blue, estimates according to hypothesized exponential growth; in orange, estimates according to linear growth. The progressive ageing of the population was not accounted for, potentially underestimating the results. (E) Increase in the incidence and prevalence of KRT from 2013 to 2019 in Spain. for men and women are required. Furthermore, there are large de Investigación Cooperativa Orientadas a Resultados en Salud regional differences (range of incident KRT is 85–197 pmp and of (RICORS; Cooperative Research Networks Focused on Results in prevalent KRT is 740–1567 pmp for different Spanish regions), Health) programme of network research. This will replace the which are also observed within regions (e.g. in Madrid, the prior ISCIII-funded programme of network research called RETICS range of incident KRT is 50–200 pmp and of prevalent KRT is (Network for Cooperative Research in Health). The Spanish kidney 980–1700 pmp for different healthcare catchment areas). The research community, represented by the research groups inte- causes of these differences are not fully understood, but it is grated into the Kidney Research Network RETIC (RETIC REDINREN) critically important to define them in order to identify and tar- and by several working groups of the Spanish Society of get factors that generate CKD hotspots or benchmark potential Nephrology [Sociedad Espan ~ ola de Nefrologı́a (SEN)], such as healthcare contributors [33]. GLOSEN (glomerular disease working group) and GEENDIAB (dia- The burden of CKD is also economic. The extrapolated an- betes working group), has submitted the RICORS2040 proposal to nual cost of all CKD is at least as high as that for cancer or dia- the RICORS call. RICORS2040 is supported by the Sociedad Espan ~ ola de Nefrologı́a (SENEFRO), the ERA-EDTA, Federación betes and estimated at >e140 billion annually in Europe and Nacional de Asociaciones para la Lucha Contra las Enfermedades >$130 billion in the USA [17, 34] (Figure 6). del Rin~ ón (Spanish Kidney Patients Association) and Organización Nacional de Trasplantes (ONT). RICORS2040 is focused on kidney THE RATIONALE FOR RICORS2040 diseases within one of the four thematic areas of the RICORS call: From 2022, the Instituto de Salud Carlos III (ISCIII, a Spanish gov- ‘inflammation and immunopathology of organs and systems’ [35]. ernment agency that funds health research) will fund the Redes This thematic area includes kidney diseases and also other topics, 378 | A. Ortiz RICORS2040 derives its name from its aim to prove wrong the 140 No dialysis/transplant projections that CKD will become the fifth leading global cause Early stage chronic of death by 2040. In this regard, RICORS2040 is fully aligned with kidney disease the Decade of the Kidney concept first established by the 120 American Association of Kidney Patients for 2020–2030, given the realization that CKD care lags other major causes of death Yearly cost (billions of euros) in terms of current outcomes, predicted outcomes in the next 100 decades and research funding [43]. This was followed by the Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Advancing American Kidney Health (AAKH) initiative of the No dialysis/transplant 80 USA government that is expected to become a catalyst for in- Advanced stage chronic kidney disease vestment in kidney disease clinical trials and precision medi- cine [44]. The Decade of the Kidney is supported by the 60 European Kidney Health Alliance (EKHA) and by patient associa- tions across Europe that have launched a European movement for 2021–2030 [17, 43]. The RICORS2040 leadership is actively 40 contributing to EKHA efforts. Transplantation 20 Emphasis on prevention Dialysis RICORS2040 is focused on preservation of native and graft kid- ney function and improving outcomes in persons with CKD by 0 Cancer Diabetes Chronic kidney preventing systemic consequences of CKD, collectively grouped disease into the concept of accelerated biological ageing, including con- sequences of kidney transplantation and its therapy (Figure 8), FIGURE 6: The economic burden of CKD. Comparison of aggregated annual as a majority of persons on KRT in Spain have a kidney graft. healthcare costs for Europe of cancer (yellow), diabetes mellitus (red) and CKD (different shades of blue). Costs of CKD are a composite of early CKD (stages/cat- Thus, preventing the need for KRT in men and women with na- egories G1–G2 in native or transplant kidneys, in light blue), more advanced tive kidneys or kidney grafts and improving kidney and patient stages of CKD (stages/categories G3–G5 not on dialysis in native or transplant outcomes in kidney graft recipients are major aims of kidneys), transplantation and dialysis (dark blue). Source: Vanholder et al. [17]. RICORS2040. Risk stratification and optimization of therapeutic approaches to improve quality of life and life expectancy in the including non-transmissible immune system diseases, allergic dialysis population are also addressed. diseases, multiple sclerosis and eye diseases. Thus RICORS2040 complies with guidance indicating that proposals should address Men and women one of the four thematic areas and may refer to one or more topics There is mounting evidence that course and complications of within a thematic area [35]. CKD are not the same in men and women and even the cut-off points to define CKD may differ [45]. However, we still use the CKD as a chronic inflammatory disease same metric and the same cut-off points to diagnose CKD and CKD can be characterized as a local inflammatory disease that for risk stratification in men and women, even knowing that cre- becomes a systemic inflammatory disease as it progresses. atinine excretion differs and therefore the denominator for UACR Indeed, activation of the master regulator of inflammation [nu- differs for men and for women. RICORS2040 will address the fac- clear factor (NF)-jB], local expression of inflammatory cytokines tors behind the gender gap in CKD burden and aims to provide and immune cell infiltrates are already observed in the early clinical guidance for both men and women and to identify infor- stages of CKD and can be triggered by albuminuria, hypergly- mation gaps that preclude a gender-conscious approach to the caemia and genetic defects, among others [36, 37] (Figure 7A). diagnosis, risk stratification and treatment of CKD. Kidneys have multiple functions and GFR, which is usually esti- mated (not measured) in routine clinical care, is just one of Addressing regional inequality them. There is increasing evidence that production of the anti- RICORS2040 will also address the factors behind geographical ageing and anti-inflammatory factor Klotho is a key function of differences in CKD burden as it incorporates multiple centres kidney tubules that is lost very early in the course of CKD (GFR from all over Spain. Specifically, kidney research and care category G1, i.e. normal kidney function) partly in response to centres from 12 of the 17 Spanish regions (autonomous commu- local inflammation and/or albuminuria [38–40] (Figure 7B). Loss nities) encompassing 90% of the Spanish population are inte- of anti-inflammatory molecules and accumulation of uraemic grated into RICORS2040. toxins leads to systemic inflammation, which is a key predictor of cardiovascular events and death in CKD, likely contributing Clinical guidance should be implemented to the accelerated biological ageing that characterizes CKD [41, 42]. The immune response also causes native kidney injury and A key issue hampering the achievement of health outcome tar- is a leading cause of chronic graft injury. gets is the poor implementation of clinical guidance documents. In this regard, clinical guidance documents are rarely validated in real-world clinical practice to assess potential shortcomings Current versus future burden: the decade of the kidney or barriers to implementation. RICORS2040 will use continuous We strongly believe that current research should be guided by improvement approaches to generate, validate and improve future projections of disease burden rather than by past statis- clinical guidance documents for different causes of CKD as well tics. Predictions for the global impact of CKD are dire. as for assessing and slowing the progression of CKD and the The need for collaborative research in CKD | 379 A C 3.0 Control Albumin overload UACR (mg/g) > 6000 2.5 4500–6000 2500–4500 F4/80 1500–2500 Urinary Klotho protein 500–1500 Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 2.0 (arbitrary units) < 500 50 μm 50 μm 1.5 B 1.0 GFR category G1–2 G1–2 G3–5 G3–5 Albuminuria category A1–2 A3 A1–2 A3 0.5 Klotho (130 KDa) 0 0 20 40 60 80 100 120 140 eGFR (ml/min/1.73 m2) FIGURE 7: CKD as a local and systemic inflammatory disease leading to accelerated biological ageing. (A) Albuminuria itself may trigger kidney inflammation as illus- trated by the albumin overload model in mice: pathological albuminuria triggered interstitial macrophage (F4/80-positive cells) infiltration (data shown) while kidney function was preserved (data not shown) [37]. Thus albuminuria induces the loss of a key kidney function (production of the anti-inflammatory, anti-fibrosis and anti- ageing protein Klotho) well before the kidney function assessed in routine clinical care (GFR) is lost. (B) Decreased urinary Klotho in persons with CKD G1/G2 (i.e. higher eGFR levels that per se are not diagnostic of CKD) with pathological albuminuria (consistent with cell culture and in vivo preclinical models in which inflammatory cyto- kines or albumin/albuminuria decreased tubular cell Klotho production by healthy tubular cells) and also in persons with CKD G3–5 (i.e. reduced eGFR, diagnostic, by it- self, of CKD). In CKD G3–5 the decrease in Klotho is likely the consequence, in part, of decreased tubular cell mass. (C) Decreased urinary Klotho in persons with pathological albuminuria and preserved eGFR and also in persons with decreased eGFR irrespective of albuminuria. Vertical axis reflects urinary Klotho, horizontal axis reflects eGFR and diameter of circles reflects the magnitude of albuminuria [37]. RICORS2040 concept: a holistic approach to CKD In summary, RICORS2040 is focused on decreasing the need Improve kidney outcomes in Improve person outcomes in for KRT by improving prevention, diagnosis and therapy for ma- men and women with CKD men and women with CKD jor causes of CKD (diabetic, glomerular, inherited and acceler- 1 Diabetic kidney disease ated kidney ageing; the latter is a concept that RICORS2040 is 2 Glomerular Native kidneys developing) in native kidneys and of chronic allograft nephropa- 3 Inherited 6 Accelerated biological aging thy as well as on improving outcomes of men and women with 4 Accelerated kidney aging CKD by preventing, identifying and treating major consequen- Kidney allografts 5 Chronic allograft dysfunction ces of CKD or its therapy that contribute to the burden of accel- Causes of kidney disease Consequences of kidney disease erated ageing and premature death (Table 1). This will be achieved through systematization of prior knowledge generated FIGURE 8: RICORS2040 concept and overall structure and research aims. by its antecessor REDINREN and the international community RICORS2040 aims at improving kidney and person outcomes in both men and into gender-conscious clinical guidance documents, novel re- women with CKD. There are two sets of aims. The first set aims at improving search to address gaps of knowledge and monitoring of clinical the diagnosis and management of the most common causes of CKD to prevent or delay CKD progression. For this, the main causes of native kidney CKD (diabe- guidance implementation to generate updated clinical guidance tes, glomerular, inherited/genetic) will be addressed and the accelerated kidney documents as output of RICORS2040. ageing concept will be explored as a final common pathway of CKD progression and as a potential cause of CKD in persons in whom no other cause is identified. Since the life expectancy of kidney allografts is markedly shorter than for native RICORS2040 WITHIN THE WIDER MOVEMENT kidneys, chronic allograft dysfunction will also be explored. The second set TOWARDS ADDRESSING THE PLIGHT OF aims to improve person outcomes by optimizing the diagnosis and manage- ment of the consequences of CKD (or of kidney transplantation therapy) on PERSONS WITH KIDNEY DISEASE other organs and systems, what we have collectively called the accelerated bio- RICORS2040 addresses CKD, the predicted fifth leading global logical ageing of CKD. Please note that Aim 4 is focused on accelerated kidney cause of death by 2040. Currently there is no confirmed funded ageing as a cause of CKD and on kidney events, while Aim 6 is focused on the research network on CKD for 2022 in Spain, as the current RETIC impact of CKD on other organs and systems, i.e. on accelerated biological ageing of diverse organs and systems occurring as a consequence of CKD. Care will be REDINREN expires in 2021. RICORS2040 will build upon knowl- taken to identify and optimize the management of gender-related issues and edge, resources and collaborations developed by REDINREN. provide clinical guidance with specific information for men and for women. RICORS2040 is aligned with a major international movement to improve the outcomes of persons with kidney disease through investment in kidney research. In this regard, RICORS2040 fol- associated accelerated biological ageing of organs and systems lows the plea of Vanholder et al. representing major European in men and women with native kidneys or with kidney grafts. scientific and patient associations, nephrology professionals, Testing the implementation of clinical guidance documents in a patients and their families, caregivers and kidney health advo- large number of centres from different regional health systems cacy organizations to draw the attention of authorities to real- under real-world conditions will allow identification and correc- ize changes in understanding, research and treatment of tion of most shortcomings and feasibility issues. kidney disease during the Decade of the Kidney (2020–2030) 380 | A. Ortiz Table 1. Aims of RICORS2040 The general aim of RICORS2040 is to improve kidney and person outcomes in men and women with CKD or at high risk of CKD. The name derives from the aim to prove wrong the dire predictions regarding the global burden of CKD by 2040, which closely reflects those for Spain: the GBD collaboration predicts that CKD will become the fifth leading global cause of death by 2040. Specific aims: 1. Improve kidney outcomes in men and women with diabetes or DKD Improve risk stratification in DKD to foster precision nephrology Evaluate novel strategies for kidney protection through therapeutic drug repositioning Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Develop, evaluate and update the Spanish Clinical Practice Guideline for detection and management of DKD 2. Improve kidney outcomes in men and women with primary glomerular disease Improve risk stratification in glomerular disease to foster precision nephrology Evaluate novel kidney protective approaches in primary glomerular disease Develop, evaluate and update clinical guidance documents 3. Improve kidney outcomes in men and women with inherited kidney disease Increase awareness of inherited kidney disease with special focus on glomerular and tubular kidney disease Improve risk stratification in inherited glomerular disease to foster precision nephrology Identify genetic predictors of CKD progression Develop, evaluate and update clinical guidance documents 4. Define accelerated kidney ageing as a cause of CKD and slow the loss of GFR in men and women Develop a working definition of accelerated kidney ageing Develop tools to predict and assess rapid CKD progression Test novel therapeutic approaches to kidney protection Develop, evaluate and update clinical guidance documents 5. Improve kidney allograft outcomes and improve the outcomes in men and women with a functioning kidney graft Improve the outcome of chronic allograft nephropathy, decreasing graft loss Limit the negative impact of immunosuppressive therapies on comorbidities and life-threatening complications Develop, evaluate and update clinical guidance documents for precision immunosuppression 6. Improve the outcomes of men and women with CKD by targeting the accelerated biological ageing that is a consequence of CKD Develop novel risk stratification tools for cardiovascular disease and CKD–mineral and bone disorder (MBD) to foster precision nephrology. Improve the recognition and outcome of frailty Evaluate the long-term safety and efficacy of SARS-CoV-2 vaccines in persons with advanced CKD Develop, evaluate and update clinical guidance documents on key consequences of CKD, such as cardiovascular disease, CKD-MBD, frailty and susceptibility to severe SARS-CoV-2 infection [17, 46]. It is also aligned with the AAKH initiative, the research. In this environment, the success of RICORS2040 would be American National Kidney Foundation and the American critical for the survival of collaborative kidney research in Spain, al- Society of Nephrology, which advocate for increased funding though the ultimate aim would not be survival, but expansion for the National Institute of Diabetes and Digestive and Kidney according to the projected global burden of CKD. Diseases [34, 44]. The long-term goal is to reduce the burden of kidney disease and improve the quality of life of persons living SUPPLEMENTARY DATA with kidney disease. Kidney research is in dire need of re- search funding support, and this would be best achieved Supplementary data are available at ckj online. through the collaboration of all major stakeholders, from pa- tient and scientific organizations to pharmaceutical compa- FUNDING nies to international, national and public funders. This study was supported by REDINREN RD16/0009 by the MAJOR SHORTCOMINGS IN SPAIN’S HEALTH Instituto de Salud Carlos III (ISCIII). RESEARCH FUNDING STRUCTURE The ISCIII is the main funder of health research in Spain and has CONFLICT OF INTEREST STATEMENT long fostered successful collaborative research structures through Authors are members of scientific and patient associations with dedicated research centres [e.g. Spanish National Cancer Research an interest in improving the outcomes and quality of life of per- Centre (CNIO) and Spanish National Cardiovascular Research sons with kidney disease. A.O. is Editor in Chief for Clinical Centre (CNIC)]. Additionally, the ISCIII currently funds research Kidney Journal, Maria Jose Soler is Associate Editor and Editor in networks for most major predicted 2040 global causes of death [14]: Chief elect for Clinical Kidney Journal and Roser Torra and Jose ischaemic heart disease (CIBERCV), stroke (CIBERCV and from 2022, Maria Cruzado are Associate Editors for Clinical Kidney Journal. stroke RICORS), infection (CIBER from 2022) and chronic obstructive pulmonary disease. The ISCIII research networks also fund pro- jected 2040 causes of death ranked below CKD (e.g. CIBERONC for APPENDIX cancer and CIBERDEM for diabetes). In fact, in 2022, CKD will be- Asociación para la información y la investigación de las enfer- come the only top-15 predicted worldwide cause of death that is medades renales genéticas (AIRG-E) not supported by the ISCIII CIBER programme (Figure 4B). This rep- Marta RogerPresidenta resents a major, correctable gap in Spain’s health research funding Vı́ctor Martı́nez JiménezHospital Virgen de la Arrixaca de structure since there is also no dedicated research centre for kidney Murcia The need for collaborative research in CKD | 381 José Carlos Rodrı́guez PerezHospital Universitario de Gran Javier Bricen ~ o DelgadoAsociación Espan ~ ola de Cirugı́a. Canaria Dr. Negrin Hospital Universitario Reina Sofı́a de Córdoba Mónica FurlanoFundació Puigvert Marta Bodro MarimontGrupo de Estudio de la Infección en el Laia Sans AtxerParc De Salut Mar Trasplante (GESITRA)/Sociedad Espan ~ ola de Enfermedades Federación Europea de Pacientes Renales (EKPF) Infecciosas y Microbiologı́a Clı́nica (SEIMC). Hospital Clinic de Daniel Gallego Zurro Barcelona Asociación para la lucha Contra las Enfermedades Renales Marı́a O. Valentı́n Mun ~ ozOrganización Nacional de (ALCER): Trasplantes (ONT) Carlos Marı́a Romeo Casabona José Miguel Pérez VillaresSociedad Espan ~ ola de Medicina Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Daniel Gallego Zurro Intensiva Critica y Unidades Coronarias (SEMICYUC). Hospital Clemente Gómez Gómez Universitario Virgen de las Nieves Pilar Pérez Bermúdez Ángel Salvatierra VelázquezGrupo de Trasplante de Pulmón Manuel Arellano Armisen de la Sociedad Espan ~ ola de Neumologı́a y Cirugı́a Torácica Santiago Albaladejo López (SEPAR). Hospital Universitario Reina Sofı́a de Córdoba Inmaculada Gutiérrez Porras Luis Almenar BonetSección Trasplante Cardı́aco de la Josefa Gómez Ruiz Sociedad Espan ~ ola de Cardiologı́a. Hospital Universitario y José Manuel Martin Orgaz Politécnico de la Fe de Valencia Marta Moreno Barón Miguel Ángel Gómez BravoSociedad Andaluza de Sociedad Espan ~ ola de Nefrologı́a (SENEFRO) council: Trasplantes. Hospital Virgen del Rocı́o Patricia de Sequera OrtizHospital Universitario Infanta Francesc J. Moreso MateosSociedad Catalana de Trasplantes. Leonor Hospital Universitario Vall dHebrón Gabriel de Arriba de la FuenteHospital Universitario de Manuel Muro AmadorSociedad Espan~ ola de Guadalajara Inmunologı́aMurcia.Hospital Virgen de la Arrixaca Borja Quiroga GiliHospital Universitario de la Princesa Auxiliadora Mazuecos BlancaSociedad Espan ~ ola de Gema Fernández FresnedoHospital Universitario Marqués de Nefrologı́a. Hospital del Mar Valdecilla José A. Pons Min ~ anoSociedad Espan ~ ola de Trasplante Sagrario Soriano CabreraHospital Universitario Reina Sofı́a de Hepático. Hospital Virgen de la Arrixaca Córdoba Amado Andrés BelmonteSociedad Madrilen ~ a de Trasplantes. Javier Pérez ContrerasHospital General Universitario de Alicante Hospital 12 de Octubre Miquel Blasco PelicanoHospital Clinic de Barcelona Amparo Solé JoverSociedad Valenciana de Trasplante. Auxiliadora Mazuecos BlancaHospital Puerta del Mar Hospital Universitario y Politécnico de La Fe Mariano Rodrı́guez PortilloHospital Universitario Reina Sofı́a Daniel Casanova RituertoEuropean Union of Medical de Córdoba Specialists (UEMS) Committe Board. Hospital Universitario J. Emilio Sánchez ÁlvarezHospital Universitario de Cabuen ~ es Marqués de Valdecilla Marı́a José Soler RomeoHospital Universitario General Vall Fernando Pardo Sánchez UEMS Committe Board. Clı́nica d’Hebrón Universidad de Navarra. Manuel Gorostidi PérezHospital Universitario Central de Fundación Renal Ín~ igo Álvarez de Toledo: Asturias Marı́a Dolores Arenas MD PhD Marian Goicoechea DiezhandinoHospital General Roberto Martin Hernández MD Universitario Gregorio Maran ~ ón Blanca Miranda Serrano MD PhD Sociedad Espan ~ ola de Trasplante (SET) council, RICORS2040/REDINREN: Domingo Hernández MarreroTrasplante Renal. Hospital Alberto Ortiz ArduanFundación Instituto de Investigación Regional Universitario de Málaga Sanitaria Fundación Jiménez Dı́az Constantino Fondevila CampoTrasplante Hepático. Hospital Ana B SanzFundación Instituto de Investigación Sanitaria Clinic de Barcelona Fundación Jiménez Dı́az EduardoMin ~ ambres Garcı́aCoordinación Trasplantes. Adrian M RamosFundación Instituto de Investigación Hospital Universitario Marqués de Valdecilla Sanitaria Fundación Jiménez Dı́az DoloresGarcı́a- Cosı́o CarmonaTrasplante Cardiaco. Hospital Gina Córdoba-DavidFundación Instituto de Investigación 12 de Octubre Sanitaria Fundación Jiménez Dı́az Armando Torres Ramı́rezTrasplante Renal. Hospital Jorge Garcı́a-JiménezFundación Instituto de Investigación Universitario de Canarias Sanitaria Fundación Jiménez Dı́az Luis Mun ~ oz BellvisCirugı́a HBP. Complejo Asistencial Miguel Fontecha-Barriuso Fundación Instituto de Universitario de Salamanca Investigación Sanitaria Fundación Jiménez Dı́az Marina Berenguer HaymTrasplante Hepático. Hospital Juan Guerrero-MauvecinFundación Instituto de Investigación Universitario y Politécnico de la Fe Sanitaria Fundación Jiménez Dı́az Manuel Barrera GómezTrasplante Hepático. Hospital Ana M. Lopez-Dı́azFundación Instituto de Investigación Universitario Nuestra Sen ~ ora de la Candelaria Sanitaria Fundación Jiménez Dı́az José Manuel Cifrián Martı́nezGrupo de Trasplante Pulmonar. Marı́a Dolores Sánchez-Nin ~ oFundación Instituto de Hospital Universitario Marqués de Valdecilla Investigación Sanitaria Fundación Jiménez Dı́az Josep Marı́a Cruzado GarritTrasplante Renal. Hospital Lara Valin ~ o-RivasFundación Instituto de Investigación Universitario de Bellvitge Sanitaria Fundación Jiménez Dı́az Rafael San Juan GarridoEspecialidad en Enfermedades Leticia CuarentalFundación Instituto de Investigación Infecciosas. Hospital 12 de Octubre Sanitaria Fundación Jiménez Dı́az 382 | A. Ortiz Marta RibagordaFundación Instituto de Investigación ~ eiroHospital Clı́nic de Barcelona Gastón Julio Pin Sanitaria Fundación Jiménez Dı́az Carlos Martı́nez SalgadoFundación Instituto de Estudios de Aranzazu Pintor-ChocanoFundación Instituto de Ciencias de la Salud de Castilla y León (IECSCYL). Institute of Investigación Sanitaria Fundación Jiménez Dı́az Biomedical Research of Salamanca (IBSAL) Chiara FaveroFundación Instituto de Investigación Sanitaria Ana I. Morales Martı́nInstitute of Biomedical Research of Fundación Jiménez Dı́az Salamanca (IBSAL) Gloria Alvarez-LlamasFundación Instituto de Investigación Francisco J.López HernándezInstitute of Biomedical Research Sanitaria Fundación Jiménez Dı́az of Salamanca (IBSAL) Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Martı́n Cleary CatalinaFundación Jiménez Dı́az Nélida Eleno BalboaInstitute of Biomedical Research of Beatriz Fernández-FernándezFundación Jiménez Dı́az Salamanca (IBSAL) Marı́a Vanessa Pérez-GómezFundación Jiménez Dı́az Marta Prieto VicenteInstitute of Biomedical Research of Emma Raquel Alegre de MontanerFundación Jiménez Dı́az Salamanca (IBSAL) Raúl Fernández PradoFundación Jiménez Dı́az Isabel Fuentes CalvoInstitute of Biomedical Research of Jorge Rojas RiveraFundación Jiménez Dı́az Salamanca (IBSAL) Ana Marı́a Ramos VerdeFundación Jiménez Dı́az Laura Ramudo GonzálezInstitute of Biomedical Research of Sergio Luis-LimaFundación Instituto de Investigación Salamanca (IBSAL) Sanitaria Fundación Jiménez Dı́az Laura Vicente VicenteInstitute of Biomedical Research of Jinny Sánchez-Rodrı́guezFundación Instituto de Investigación Salamanca (IBSAL) Sanitaria Fundación Jiménez Dı́az Sandra M. Sancho Martı́nezInstitute of Biomedical Research Soledad Pizarro SánchezHospital Universitario Rey Juan Carlos of Salamanca (IBSAL) Marta Ruiz OrtegaUniversidad Autónoma de Madrid Alfredo G. Casanova PasoInstitute of Biomedical Research of Emilio González ParraFundación Instituto de Investigación Salamanca (IBSAL) Sanitaria Fundación Jiménez Dı́az Moisés Pescador GarrielInstitute of Biomedical Research of Sandra Rayego MateosUniversidad Autónoma de Madrid Salamanca (IBSAL) Pablo Javier Cannata OrtizFundación Instituto de Juan José Vaquero LópezUniversidad de Alcalá Investigación Sanitaria Fundación Jiménez Dı́az Ana Marı́a Cuadro PalaciosUniversidad de Alcalá Laura Márquez ExpósitoUniversidad Autónoma de Madrid David Sucunza SaénzUniversidad de Alcalá Antonio Tejera-Mun ~ ozFundación Instituto de Investigación Patricia Garcı́a Garcı́aUniversidad de Alcalá Sanitaria Fundación Jiménez Dı́az ~ a BonillaUniversidad de Alcalá José Luis Acen Vanessa MarchantUniversidad Autónoma de Madrid Manuel A. Fernández Rodrı́guezUniversidad de Alcalá Lucia Tejedor-SantamariaFundación Instituto de Alberto Domingo GalánUniversidad de Alcalá Investigación Sanitaria Fundación Jiménez Dı́az Estı́baliz Merino MarcosUniversidad de Alcalá Matilde Alique AgilarUniversidad de Alcalá de Henares Javier Carreras Pérez-AradrosUniversidad de Alcalá Fritz DiekmannFundación Privada Clı́nic. Hospital Clı́nic de Rubén Manzano San JoséUniversidad de Alcalá Barcelona. Institut D’investigacions Biomèdiques August Pi I Francisco Maqueda ZelayaUniversidad de Alcalá Sunyer (IDIBAPS) Ester Sans PanadésUniversidad de Alcalá Beatriz Bayes GenisHospital Clı́nic de Barcelona Álvaro González MolinaUniversidad de Alcalá Federico Oppenheimer SalinasHospital Clı́nic de Barcelona. Julia Atarejos SalidoUniversidad de Alcalá Institut D’investigacions Biomèdiques August Pi I Sunyer Roser Torra BalcellsFundació Puigvert (IDIBAPS) Elisabet Ars CriachFundació Puigvert Marı́a José Ramı́rez BajoFundació Privada Clı́nic Montserrat Dı́az EncarnaciónFundació Puigvert Elisenda Ban ~ on ManeusFundació Privada Clı́nic. Institut Lluis Guirado PerichFundació Puigvert D’investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) Monica FurlanoFundació Puigvert Marta Arias GuillenHospital Clı́nic de Barcelona Cristina Canal GirolFundació Puigvert Jordi Rovira JuárezInstitut D’investigacions Biomèdiques Yolanda Arce TerrobaFundació Puigvert August Pi I Sunyer (IDIBAPS) Marc Pybus OliverasFundació Puigvert Marta Lazo Rodrı́guezFundació Privada Clı́nic Laia Ejarque VilaFundació Puigvert Ignacio Revuelta VicenteHospital Clı́nic de Barcelona. Institut Nuria Serra Caban ~ asFundació Puigvert D’investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) Carme Facundo MolasFundació Puigvert Josep Miquel Blasco PelicanoHospital Clı́nic de Barcelona Irene Silva TorresFundació Puigvert Luis Fernando Quintana PorrasHospital Clı́nic de Barcelona. Santiago Lamas PelaezCentro de Biologı́a Molecular Severo Ochoa Institut D’investigacions Biomèdiques August Pi I Sunyer Carlos Rey SerraCentro de Biologı́a Molecular Severo Ochoa (IDIBAPS) Carolina Castillo TorresHospital Prı́ncipe de Asturias Pedro Ventura Abreu AguiarHospital Clı́nic de Barcelona. Jessica Paola Tituan ~ a FajardoCentro de Biologı́a Molecular Institut D’investigacions Biomèdiques August Pi I Sunyer Severo Ochoa (IDIBAPS) José Ignacio Herrero LahuertaCentro de Biologı́a Molecular Marc Xipell FontInstitut D’investigacions Biomèdiques Severo Ochoa August Pi I Sunyer (IDIBAPS) Verónica Miguel HerranzCentro de Biologı́a Molecular Severo Alicia Molina AndujarHospital Clı́nic de Barcelona Ochoa David CucchiariHospital Clı́nic de Barcelona. Institut Mariano Rodriguez PortilloHospital Reina Sofı́a D’investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) Alejandro Martin MaloHospital Reina Sofı́a Enrique Montagud MarrahHospital Clı́nic de Barcelona Sagrario Soriano CabreraHospital Reina Sofı́a Josep MCampistol Plana Hospital Clı́nic de Barcelona. Institut Juan Rafael Mun ~ oz Castan ~ edaInstituto Maimonides de D’investigacions Biomèdiques August Pi I Sunyer (IDIBAPS) Investigación Biomédica de Córdoba (IMIBIC) The need for collaborative research in CKD | 383 Marı́a Encarnación Rodrı́guez OrtizInstituto Maimonides de Mercedes CabelloHospital Regional Universitario de Malaga/ Investigación Biomédica de Córdoba (IMIBIC) IBIMA Julio Manuel Martı́nez MorenoInstituto Maimonides de Abelardo CaballeroHospital Regional Universitario de Malaga/ Investigación Biomédica de Córdoba (IMIBIC) IBIMA Ana Isabel Raya BermúdezInstituto Maimonides de Myriam LeónHospital Regional Universitario de Malaga/ Investigación Biomédica de Córdoba (IMIBIC) IBIMA Rafael Santamarı́a OlmoHospital Reina Sofı́a Pedro RuizHospital Regional Universitario de Malaga/IBIMA Fátima Guerrero PavónInstituto Maimonides de Investigación Juana AlonsoHospital Regional Universitario de Malaga/ Biomédica de Córdoba (IMIBIC) IBIMA Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Cayetana Moyano PeregrinHospital Reina Sofı́a Juan Navarro-GonzálezHospital Nuestra Sra. Candelaria, Escolástico Aguilera TejeroInstituto Maimonides de Tenerife Investigación Biomédica de Córdoba (IMIBIC) Marı́a Del Carmen Mora-FernándezHospital Universitario Ignacio Lopez VillalbaInstituto Maimonides de Investigación Nuestra Sen ~ ora de Candelaria Biomédica de Córdoba (IMIBIC) Javier Donate-CorreaHospital Universitario Nuestra Sen ~ ora Andrés Carmona Mun~ ozInstituto Maimonides de de Candelaria Investigación Biomédica de Córdoba (IMIBIC) Ernesto Martı́n-Nun ~ ezHospital Universitario Nuestra Sen ~ ora Marı́a Victoria Pendon Ruiz De MierHospital Reina Sofı́a de Candelaria Carmen Marı́a Pineda MartosInstituto Maimonides de Nayra Pérez DelgadoHospital Universitario Nuestra Sen ~ ora de Investigación Biomédica de Córdoba (IMIBIC) Candelaria Rodrigo López BaltanasInstituto Maimonides de Secundino Gigarrán-GuldrisHospital Da Costa, Burela Investigación Biomédica de Córdoba (IMIBIC) José Carlos Rodrı́guez PérezHospital Universitario Dr. Negrı́n Cristian Rodelo HaadHospital Reina Sofı́a José Luis Górriz TeruelHospital Clı́nico Universitario de Marcella Franquesa BartoloméFundación Instituto Valencia Investigación Germans Trias I Pujol Alberto Martı́nez CastelaoHospital Universitario Bellvitge, Ricardo Lauzurica ValdemorosHospital Germans Trias I Pujol Hospitalec, Barcelona Francisco Enrique Borras SerresFundación Instituto José Manuel Valdivielso RevillaInstituto de Investigación Investigación Germans Trias I Pujol Biomédica de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Maruja Navarro Dı́azHospital Germans Trias I Pujol Cristina Martı́nez Martı́nezInstituto de Investigación Francisco Javier Juega Marin ~ oHospital Germans Trias I Pujol Biomédica de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Laura Can ~ as SoleHospital Germans Trias I Pujol Milica Bozic StanojevicInstituto de Investigación Biomédica Maria Isabel Troya SaboridoHospital Germans Trias I Pujol de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Jordi Soler MajoralHospital Germans Trias I Pujol Eva Castro BoqueInstituto de Investigación Biomédica de Marina López Martı́nezHospital Germans Trias I Pujol Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Emilio Rodrigo CalabiaUniversity Hospital Marqués de Marı́a Nuria Sans RosellInstituto de Investigación Biomédica Valdecilla/IDIVAL, University of Cantabria de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Juan Carlos Ruiz San MillánUniversity Hospital Marqués de Virtudes Maria De LamoInstituto de Investigación Biomédica Valdecilla/IDIVAL, University of Cantabria de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Marcos López-HoyosUniversity Hospital Marqués de Juan Miguel Dı́az TocadosInstituto de Investigación Valdecilla/IDIVAL, University of Cantabria Biomédica de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Adalberto Benito-HernándezUniversity Hospital Marqués de Alicia Garcia CarrascoInstituto de Investigación Biomédica de Valdecilla/IDIVAL, University of Cantabria Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Gema Fernández FresnedoUniversity Hospital Marqués de Marcelino Bermúdez LópezInstituto de Investigación Valdecilla/IDIVAL, University of Cantabria Biomédica de Lleida. Fundación Dr. Pifarre (IRBLLEIDA) David San SegundoUniversity Hospital Marqués de Maite Caus EnriquezInstituto de Investigación Biomédica de Valdecilla/IDIVAL, University of Cantabria Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Rosalı́a ValeroUniversity Hospital Marqués de Valdecilla/ Ana Martinez BardajiInstituto de Investigación Biomédica de IDIVAL, University of Cantabria Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Eliécer Coto Garcı́aHospital Universitario Central de Asturias Nuria Dolade MasotInstituto de Investigación Biomédica de Juan Gómez De OnaHospital Universitario Central de Asturias Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Elias Cuesta LlavonaHospital Universitario Central de Aurora Pérez GómezInstituto de Investigación Biomédica de Asturias Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Fernando Santos Rodrı́guezHospital Universitario Central de Auria Eritja SanjuanInstituto de Investigación Biomédica de Asturias Lleida. Fundación Dr. Pifarre (IRBLLEIDA) Rebeca Lorca GutiérrezHospital Universitario Central de Antonio Osuna OrtegaHospital Universitario Virgen de las Asturias Nieves de Granada Helena Gil Pen ~ aHospital Universitario Central de Asturias Rosemary Wangensteen FuentesUniversidad de Jaén Manuel Gorostidi PérezHospital Universitario Central de Maria del Carmen De Gracia GuindoHospital Universitario Asturias Virgen de las Nieves de Granada Domingo Hernández MarreroInstituto de Investigación Maria del Carmen Ruiz FuentesHospital Universitario Virgen Biomédica de Málaga (IBIMA) de las Nieves de Granada Verónica LópezHospital Regional Universitario de Malaga/ Francisco O’Valle RavassaUniversidad de Granada IBIMA Mercedes Caba MolinaHospital Universitario San Cecilio Eugenia SolaHospital Regional Universitario de Malaga/IBIMA César Luis Ramı́rez TortosaHospital Universitario San Cecilio 384 | A. Ortiz Raimundo Garcı́a Del Moral GarridoUniversidad de Granada José Luis Fernández Martı́nHospital Universitario Central de Marı́a José Soler RomeoFundación Instituto de Investigación Asturias. Instituto de Investigación Sanitaria del Principado de Valle de Hebrón Asturias Conxita Jacobs-CacháVall D’Hebron Research Institute (VHIR) Natalia Carrillo LópezInstituto de Investigación Sanitaria del Oriol Bestard MatamorosVall D’Hebron Research Institute Principado de Asturias (VHIR) Sara Panizo Garcı́aInstituto de Investigación Sanitaria del Francesc Moreso MateosVall D’Hebron Research Institute Principado de Asturias (VHIR) Cristina Alonso MontesInstituto de Investigación Sanitaria Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Marı́a Antonia Emilia MeneghiniVall D’Hebron Research del Principado de Asturias Institute (VHIR) Minerva Rodrı́guez Garcı́aHospital Universitario Central de Joana Sellares RoigHospital Universitari Vall DHebron Asturias. Instituto de Investigación Sanitaria del Principado de Irina Torres BetsabéHospital Universitari Vall DHebron Asturias Carlos López LarreaHospital Universitario Central de ~ igo Lozano Martı́nez LuengasHospital de Cabuen In ~ es Asturias. Instituto de Investigación Sanitaria del Principado de Emilio Sánchez ÁlvarezHospital de Cabuen ~ es Asturias Laura Martı́nez AriasInstituto de Investigación Sanitaria del Beatriz Suarez ÁlvarezInstituto de Investigación Sanitaria del Principado de Asturias Principado de Asturias Beatriz Martı́n CarroInstituto de Investigación Sanitaria del Marı́a del Carmen Dı́az CorteHospital Universitario Central de Principado de Asturias Asturias. Instituto de Investigación Sanitaria del Principado de Julia Martı́n VirgalaInstituto de Investigación Sanitaria del Asturias Principado de Asturias Raúl R Rodrigues-DiezInstituto de Investigación Sanitaria del Miguel Garcı́a GonzálezComplejo Hospitalario de Santiago de Principado de Asturias Compostela (CHUS). Instituto de Investigación Sanitaria (IDIS) Antonio López VázquezHospital Universitario Central de José Marı́a Lamas BarreiroComplejo Hospitalario Asturias. Instituto de Investigación Sanitaria del Principado de Universitario de Vigo Asturias Miguel Pérez FontanComplejo Hospitalario Universitario A Segundo González Rodrı́guezUniversidad de Oviedo Corun ~a José Ramón Vidal Castin~ eiraHospital Universitario Central de Alfonso Otero GonzálezComplejo Hospitalario Universitario Asturias. Instituto de Investigación Sanitaria del Principado de de Ourense Asturias Luz Marı́a Cuin ~ a BarjaComplejo Hospitalario de Pontevedra Cristina Martı́n Martı́nInstituto de Investigación Sanitaria del Alejandro Sánchez BarreiroUniversidad de Santiago de Principado de Asturias Compostela Marı́a Laura Saiz ÁlvarezInstituto de Investigación Sanitaria Beatriz Pazos AriasPoliclı́nico Vigo S.A. del Principado de Asturias Ángel Alonso HernándezComplejo Hospitalario Universitario Viviana Corte IglesiasInstituto de Investigación Sanitaria del A Corun ~a Principado de Asturias Marı́a Pardo PérezInstituto de Investigación Sanitaria de Jesús Martı́nez BorraHospital Universitario Central de Santiago de Compostela (IDIS) Asturias. Instituto de Investigación Sanitaria del Principado de ~ o VarelaHospital Lucus Augusti Jesús Calvin Asturias Jorge Amigo LechugaFundación Pública Gallega de Medicina Marı́a Auxiliadora Bajo RubioHospital Universitario La Paz Genómica Gloria Del Peso GilsanzHospital Universitario La Paz Cándido Dı́az Rodrı́guezHospital Clı́nico Universitario de Manuel López CabreraCentro de Biologı́a Molecular Severo Santiago Ochoa Marı́a Garcı́a MuriasInstituto de Investigación Sanitaria de José Antonio Jiménez HeffernanHospital Universitario La Santiago de Compostela (IDIS) Princesa Ana Marı́a Barcia de la IglesiaInstituto de Investigación Marta Ossorio GonzálezHospital Universitario La Paz Sanitaria de Santiago de Compostela (IDIS) Olga Costero GonzálezHospital Universitario La Paz Pablo Bouza Pin ~ eiroComplejo Hospitalario A. Marcide-Novoa Marı́a Elena González Garcı́aHospital Universitario La Paz Santos Carlos Jiménez Martı́nHospital Universitario La Paz Álvaro Gil GonzálezUniversidad de Santiago de Compostela Pilar Sandoval CorreaCentro de Biologı́a Molecular Severo Adrian Cordido EijoInstituto de Investigación Sanitaria de Ochoa Santiago de Compostela (IDIS) Sara Afonso RamosHospital Universitario La Paz Noa Carrera CachazaInstituto de Investigación Sanitaria de Marı́a López OlivaHospital Universitario La Paz Santiago de Compostela (IDIS) Begon ~ a Rivas BecerraHospital Universitario La Paz Marta Vizoso GonzálezInstituto de Investigación Sanitaria de Cristina Vega CabreraHospital Universitario La Paz Santiago de Compostela (IDIS) Guadalupe Tirma González MateoCentro de Biologı́a Josep Maria Cruzado GarritHospital de Bellvitge Molecular Severo Ochoa Núria Lloberas BlanchFundación Idibell Rafael Sánchez VillanuevaHospital Universitario La Paz Ana Maria Sola Martı́nezFundación Idibell Laura Álvarez Garcı́aHospital Universitario La Paz Miguel Hueso ValHospital de Bellvitge Jorge B Cannata Andı́aHospital Universitario Central de Juliana BordignonDraibeHospital de Bellvitge Asturias. Instituto de Investigación Sanitaria del Principado de Edoardo MelilliHospital de Bellvitge Asturias Anna Manonelles MonteroHospital de Bellvitge Manuel Naves Dı́azHospital Universitario Central de Asturias. Núria Montero PérezHospital de Bellvitge Instituto de Investigación Sanitaria del Principado de Asturias Xavier Fulladosa OliverasHospital de Bellvitge The need for collaborative research in CKD | 385 Marta Crespo BarrioInstituto Hospital del Mar de Patricia Delgado MallenHospital Universitario de Canarias Investigaciones Médicas (FIMIM) Alejandra Álvarez GonzálezHospital Universitario de Julio Pascual SantosInstituto Hospital del Mar de Canarias Investigaciones Médicas (FIMIM) Ana Marı́a González RinneHospital Universitario de Canarias Clara Barrios BarreraInstituto Hospital del Mar de Rosa Miquel Rodrı́guezHospital Universitario de Canarias Investigaciones Médicas (FIMIM) Sara Estupin ~ an TorresHospital Universitario de Canarias Marı́a José Pérez SáezInstituto Hospital del Mar de Diego Álvarez SosaHospital Universitario de Canarias Investigaciones Médicas (FIMIM) Beatriz Escamilla CabreraHospital Universitario de Canarias Nayara Zamora Rodrı́guezHospital Universitario de Canarias Downloaded from https://academic.oup.com/ckj/article/15/3/372/6374449 by Fundacio Biblioteca Josep Laporte user on 04 December 2023 Marı́a Dolores Redondo PachónInstituto Hospital del Mar de Investigaciones Médicas (FIMIM) Arminda Farin ~ a HernándezHospital Universitario de Canarias Carlos Arias CabralesInstituto Hospital del Mar de Marı́a José Rodrı́guez GamboaHospital Universitario de Investigaciones Médicas (FIMIM) Canarias Anna Buxeda PorrasInstituto Hospital del Mar de Cobo Caso, Maria de Los AngelesHospital Universitario de Investigaciones Médicas (FIMIM) Canarias Eva Rodrı́guez Garcı́aInstituto Hospital del Mar de PerezTamajon, Maria LourdesHospital Universitario de Investigaciones Médicas (FIMIM) Canarias Laia Sans AtxerInstituto Hospital del Mar de Investigaciones Rufino Hernandez, MargaritaHospital Universitario de Médicas (FIMIM) Canarias Vanesa Palau GonzálezInstituto Hospital del Mar de Garcia Rebollo, Maria SagrarioHospital Universitario de Investigaciones Médicas (FIMIM) Canarias Laura Llinàs MallolInstituto Hospital del Mar de Delgado Mallen, PatriciaHospital Universitario de Canarias Investigaciones Médicas (FIMIM) AlvarezGonzalez, AlejandraHospital Universitario de Marta Riera OlivaInstituto Hospital del Mar de Canarias Investigaciones Médicas (FIMIM) Gonzalez Rinne, Ana MariaHospital Universitario de Canarias Diego Rodrı́guez PuyolFundación Investigación Biomédica. Miquel Rodriguez, RosaHospital Universitario de Canarias Hospital Prı́ncipe de Asturias Estupin ~ an Torres, SaraHospital Universitario de Canarias Marı́a Piedad Ruiz TorresUniversidad de Alcalá Alvarez Sosa, DiegoHospital Universitario de Canarias Susana López OngilFundación Investigación Biomédica. Escamilla Cabrera, BeatrizHospital Universitario de Canarias Hospital Prı́ncipe de Asturias Zamora Rodiguez, NayaraHospital Universitario de Canarias Laura Calleros BasilioUniversidad de Alcalá Farin~ a Hernandez, ArmindaHospital Universitario de Gemma Olmos CenteneraUniversidad de Alcalá Canarias Patricia Martı́nez de MiguelHospital Universitario Prı́ncipe de Rodriguez Gamboa, MariaJoseHospital Universitario de Asturias Canarias Loreto Fernández Rodrı́guezHospital Universitario Prı́ncipe de Marı́a Laura Garcı́a BermejoInstituto Ramón y Cajal de Asturias Investigación Sanitaria (IRYCIS) Hanane Bouarich NadahHospital Universitario Prı́ncipe de Milagros Fernández LucasHospital Ramón y Cajal Asturias Elisa Conde MorenoInstituto Ramón y Cajal de Investigación Marı́a Pérez FernándezHospital Universitario Prı́ncipe de Sanitaria (IRYCIS) Asturias Laura Salinas Mun ~ ozInstituto Ramón y Cajal de Investigación Manuel Rafael Ramı́rez ChamondUniversidad de Alcalá Sanitaria (IRYCIS) Patricia Sequera OrtizHospital Universitario Infanta Leonor Silvia Serrano HuertasInstituto Ramón y Cajal de Nuria Garcı́a FernándezInstituto de Investigación Sanitaria de Investigación Sanitaria (IRYCIS) Navarra (IDISNA), Esperanza Macarena Rodrı́guez SerranoInstituto Ramón y Alberto Benito BoillosUniversidad de Navarra Cajal de Investigación Sanitaria (IRYCIS) Nerea Varo CenarruzabeitiaUniversidad de Navarra Miren Edurne Ramos Mun ~ ozInstituto Ramón y Cajal de Marı́a Asunción Fernández SearaUniversidad de Navarra Investigación Sanitaria (IRYCIS) Inés Dı́az Dorronsoro,Universidad de Navarra Lorena Crespo ToroInstituto Ramón y Cajal de Investigación Paloma Martin MorenoClı́nica Universidad de Navarra Sanitaria (IRYCIS) Francisco Javier LavillaClı́nica Universidad de Navarra Carolina Pilar Blanco AgudoInstituto Ramón y Cajal de Armando TorresHospital Universitario de Canarias. Investigación Sanitaria (IRYCIS) Universidad de La Laguna Cristina Galeano ÁlvarezInstituto Ramón y Cajal de Domingo Marrero MirandaHospital Universitario de Canarias Investigación Sanitaria (IRYCIS) Aurelio Pastor Rodrı́guez HernándezHospital Universitario de José PortolesFundación Investigación Biomédica Hospital Canarias Puerta de Hierro Eduardo De Bonis RedondoHospital Universitario de Canarias Marı́a MarquésFundación Investigación Biomédica Hospital Esteban PorriniUniversidad de La Laguna Puerta de Hierro Marı́a de los Ángeles Cobo CasoHospital Universitario de Esther RubioFundación Investigación Biomédica Hospital Canarias Puerta de Hierro Marı́a Lourdes Pérez TamajónHospital Universitario de Beatriz Sánchez-SobrinoFundación Investigación Biomédica Canarias Hospital Puerta de Hierro Margarita Rufino HernándezHospital Universitario de Estefanya Garcı́a-MenéndezFundación Investigación Canarias Biomédica Hospital Puerta de Hierro Marı́a Sagrario Garcı́a RebolloHospital Universitario de Alberto Lázaro FernándezUniversidad Complutense de Canarias Madrid 386 | A. 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