CKD: The burden of disease invisible to research funders

Abstract

The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. A prevalent view is that for those in whom kidneys fail, the problem is "solved" by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and all-cause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10-100-fold higher than similar age peers, and life expectancy is shortened by around 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 global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 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 CIBER network research structure in Spain. Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too late.

Keywords: Accelerated aging; Burden of disease; COVID-19; Carga sanitaria de la enfermedad; Chronic kidney disease; Decade of the kidney; Enfermedad renal crónica; Envejecimiento acelerado; Fallo renal; Financiación de la investigación; Kidney failure; Kidney transplantation; La decada del Riñón; Research funding; Trasplante renal.

Fig. 1

Chronic kidney disease (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 in a global scale. Data from . (B) Risk of death associated with pre-existent conditions in patients with COVID-19 in an adjusted analysis. Data from . Reproduced from 1 and 9.

Fig. 2

Chronic kidney disease (CKD) is associated with an increased risk of death even in the very elderly. All-cause mortality rate (absolute risk) for different eGFR (A) and UACR (B) values by age categories based on weighted average across cohorts, adjusted for covariates. A steeper slope at 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 . In panel A, an increase in the risk of death observed in patients older than 55 years with higher eGFR values is not shown as this is thought to be an artifact depending on lower muscle mass of patients who were sicker at baseline. (C) The blind spot in CKD, as illustrated by autosomal dominant polycystic kidney disease. In ADPKD, CKD is present from birth, but using conventional criteria to diagnose CKD as low eGFR or pathological albuminuria, it can only be diagnosed 30–40 years later. However, there is a diagnostic test, sonography, that allows a much earlier diagnosis by demonstrating the presence of kidney cysts. Diagnostic tests should be developed that allow to diagnose CKD from other, non-ADPKD, causes decades earlier than current GFR or albuminuria criteria allow (figure from ref. 13). Reproduced from 1.

Fig. 3

Comorbidities diagnosed in a Swedish cohort of patients with chronic kidney disease (CKD), representing clinical conditions the treating physicians was aware of. Inclusion in the cohort required a researcher diagnosis of CKD based on the presence of two eGFR values below 60 ml/min/1.73 m² separated by at least 90 days as per KDIGO definition. Patients on kidney replacement therapy were excluded. Note that among persons included in the cohort because researchers retrospectively diagnosed CKD, the physician in charge diagnosed cancer or diabetes more commonly than CKD. Data from , figure from .

Fig. 4

Severely limited survival in persons on kidney replacement therapy (KRT). (A) Expected remaining lifetimes of the general population and of dialysis and kidney transplant patients in the European Renal Association (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)., . (B) Percent 5-year survival of KRT modalities (red bars) (hemodialysis, peritoneal dialysis, transplantation after deceased donation and transplantation after living donation) or after the diagnosis of cancer (blue bars). Only malignancies with an incidence over 3% of all cancers are illustrated. Orange bar: all cancers aggregated. Based on 2016 data. Source: 20. Reproduced from 1.

Fig. 5

Global burden of chronic kidney disease (CKD), according to the Global Burden of Disease (GDB) study. (A) 2017 global disability adjusted life years (DALYs), years lived with disability (YLD) and years of life lost (YLLs) due to CKD. (B) Major global causes of death in 2016 and predicted for 2040 according to the GBD study, ranked by YLLs. 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 his point we are unaware of the logo. Thus, the CIBER logo was used and the word “INFEC” was added. Reproduced from 1.

Fig. 6

CKD burden and epidemiology in Spain. (A) Projected numbers of annual deaths in Spain by cause. Alzheimer not shown but it is projected to become the first cause of death before the end of the century, well above the others. Past growth according to GBD 2016 Spain was projected into the future. The projection did not consider the progressive aging 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 World Health Organization (WHO) predictions., , Since the increasing mean age within each age category was not considered, this projection represents an underestimation., 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., , (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. In blue, estimates according to hypothesized exponential growth; in orange, estimates according to linear growth. The progressive aging of the population was not accounted for, potentially underestimating the results. (E) Increase in incidence and prevalence of KRT from 2013 to 2019 in Spain. Reproduced from 1.

Fig. 7

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 – 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: 20. Reproduced from 1.

Fig. 8

CKD as a local and systemic inflammatory disease leading to accelerated biological aging. (A) Albuminuria itself may trigger kidney inflammation as illustrated by the albumin overload model in mice: pathological albuminuria triggered interstitial macrophage (F4/80+ cells) infiltration (shown) while kidney function was preserved (not shown). Thus, albuminuria induces the loss of a key kidney function (production of the anti-inflammatory, anti-fibrosis and anti-aging protein Klotho) well before the kidney function assessed in routine clinical care (glomerular filtration rate) 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 circle reflects magnitude of albuminuria. Reproduced from 1.

Fig. 9

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 set 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 aging 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 named as the accelerated biological aging of CKD. Please note that aim 4 is focused on accelerated kidney aging as a cause of CKD and on kidney events, while aim 6 is focused on the impact of CKD on other organs and systems, that is, on accelerated biological aging 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. Reproduced from 1.