RICORS2040: the need for collaborative research in chronic kidney disease

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 Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true.

Keywords: COVID-19; accelerated ageing; burden of disease; chronic kidney disease; decade of the kidney; kidney failure; kidney transplantation; research funding.

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 conditions 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].

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 associated 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.

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].

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 networks 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.

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 leading 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.

FIGURE 6:

The economic burden of CKD. Comparison of aggregated annual 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/categories G1–G2 in native or transplant kidneys, in light blue), more advanced stages of CKD (stages/categories G3–G5 not on dialysis in native or transplant kidneys), transplantation and dialysis (dark blue). Source: Vanholder et al. [17].

FIGURE 7:

CKD as a local and systemic inflammatory disease leading to accelerated biological ageing. (A) Albuminuria itself may trigger kidney inflammation as illustrated 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 cytokines 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 itself, 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].

FIGURE 8:

RICORS2040 concept and overall structure and research aims. RICORS2040 aims at improving kidney and person outcomes in both men and women with CKD. There are two sets of aims. The first set aims at improving 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 (diabetes, glomerular, inherited/genetic) will be addressed and the accelerated kidney 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 kidneys, chronic allograft dysfunction will also be explored. The second set aims to improve person outcomes by optimizing the diagnosis and management of the consequences of CKD (or of kidney transplantation therapy) on other organs and systems, what we have collectively called the accelerated biological ageing of CKD. Please note that Aim 4 is focused on accelerated kidney ageing as a cause of CKD and on kidney events, while Aim 6 is focused on the 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 taken to identify and optimize the management of gender-related issues and provide clinical guidance with specific information for men and for women.