key: cord-0769576-lgn5flop
authors: Ortiz, Alberto
title: RICORS2040: the need for collaborative research in chronic kidney disease
date: 2021-09-23
journal: Clin Kidney J
DOI: 10.1093/ckj/sfab170
sha: ace0aa8931a25ab8e07cbac4b0be61d92004b086
doc_id: 769576
cord_uid: lgn5flop

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.

The Kidney Disease: Improving Global Outcomes consensus defines chronic kidney disease (CKD) as abnormalities of kidney structure or function present for >3 months with implications for health [1] . Just one criterion identifying abnormal kidney structure or function allows the diagnosis of CKD. Criteria include a low glomerular filtration rate (GFR; <60 mL/min/1.73 m 2 ) or evidence of kidney damage such as pathological albuminuria [urinary albumin:creatinine ratio (UACR) !30 mg/g]; abnormal urine sediment, histology or imaging; abnormalities due to tubular disorders or kidney transplantation. In clinical practice, this means that diagnosing CKD when GFR is !60 mL/min/ 1.73 m 2 requires urinalysis or kidney imaging. A recent conceptual manuscript summarized the key features of CKD for nonnephrologists, as there is ongoing confusion, even in high-quality journals, such as the New England Journal of Medicine [2] .

A CKD diagnosis implies an increased risk of progressing to require kidney replacement therapy (KRT), of all-cause and cardiovascular death and of acute kidney injury (AKI) [1, [3] [4] [5] . There is a bidirectional relationship between CKD and AKI. CKD is the main risk factor for AKI and AKI may accelerate CKD [6] . AKI has a high mortality and increases the risk of death for >1 year after the episode [6] . AKI is also common, as~5% of hospitalized patients develop in-hospital AKI [7] . More recently, CKD has been identified as the most prevalent risk factor for lethal coronavirus disease 2019 and as the factor that most increased the risk of death in COVID-19 after older age [8] [9] [10] (Figure 1 ). AKI is also common in COVID-19 and a key risk factor for death [8] .

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 cardiovascular death, even in the elderly (Figure 2A and B). The G1 (GFR !90 mL/min/1.73 m 2 ) and A1 (UACR <30 mg/g) categories are not diagnostic of CKD by themselves. Persons in category G1A1 must fulfil an additional criterion to be diagnosed with CKD, such as imaging diagnostics of polycystic kidney disease (PKD) [1, 2] . The autosomal dominant PKD paradigm illustrates the way to go: a diagnostic test (sonography) allows the diagnosis of CKD decades before patients fulfil any other criterion to diagnose CKD, including the most commonly used ones such as GFR and UACR thresholds [11] . Similar diagnostic tools are needed for other forms of CKD, as by the time GFR falls to 60 mL/min/1.73 m 2 , CKD has progressed unnoticed (potentially over years and even decades) to destroy >50% of the functioning kidney mass. Similarly, albuminuria as low as >2.5 mg/g is already associated with an increased risk of premature death ( Figure 2B) . Again, the current albuminuria threshold used to diagnose CKD is a late event. There is a clear margin for earlier diagnosis and therapy of CKD. Additional future criteria to diagnose CKD may be envisioned, such as genetic tests disclosing clearly pathogenic gene variants or urinary biomarkers beyond UACR, including urinary peptidomics [12, 13] .

Kidney failure (end-stage kidney disease, G5, GFR <15 mL/ min/1.73 m 2 ) is probably the only form of kidney disease well known to the wider public, non-nephrologists and healthcare authorities. Non-experts usually equate the burden of CKD with the burden of KRT for kidney failure. Despite care for KRT patients representing a disproportionate percentage of the healthcare budget (the roughly 64 292 persons on KRT in Spain consume 2.5-5.0% of the healthcare budget), the bulk of the health burden of CKD is not represented by KRT but by accelerated ageing and premature death, as clearly quantified by Global Burden of Disease (GBD) data discussed below [14] . However, there are no registries in Spain for persons with CKD not on KRT as is the case for many other countries.

KRT has been hailed as one of the success stories of healthcare that allows survival when a vital organ has failed. Counterintuitively, this reflects only a partial view of the facts. Rather, KRT should be considered a failure of CKD management, as the expected remaining lifetime is severely reduced-by~70% (40 years less) and by 25% (15 years less) for a 20-year-old on dialysis or with a functioning kidney graft, respectively [15, 16] . The absolute reduction in the expected remaining lifetime is less at older ages, but the relative reduction in life expectancy remains constant up to age 89 years ( Figure 3A ). The fact that the mortality of kidney failure remains high, up to 100-fold higher in patients on KRT than for similar-aged controls [5] , is not well known by health authorities and may hinder funding for CKD research. Indeed, the 5-year survival of patients on dialysis is lower than for all forms of cancer combined [17] ( Figure 3B ).

The most common cause of KRT in Spain is diabetes (25% of persons initiating KRT), followed by unknown (15%), 'vascular', glomerulonephritis (14%) and inherited kidney disease [15, 16, 18] . The magnitude of the inherited category is difficult to assess as it is usually divided into PKD and others. Others are usually dumped into a 'miscellaneous' category or misdiagnosed as glomerular or interstitial CKD. Recent analysis of the Madrid and Catalonian KRT registries has disclosed that inherited kidney disease is as frequent as glomerulonephritis [19] . Inherited kidney diseases are frequently overlooked by physicians as illustrated by whole-exome sequencing findings of monogenic kidney diseases in 9% of adult CKD and in 17-34% of those with CKD of unknown cause [20, 21] .

'Vascular' mainly means hypertension, and it is labelled as hypertension in the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry [15, 16, 18] . In clinical practice, hypertension is usually listed as a cause when there is no other obvious aetiology, following expert recommendation [22] . This practice has been criticized, as it may replace an inadequate aetiologic workup, likely downplaying the incidence of other causes of CKD while falsely boosting hypertension as a cause (rather than as consequence) of CKD [23, 24] . Thus there is no relationship between the prevalence of hypertension and hypertensive CKD in different countries [23] . In African Americans, hypertensive nephropathy has long been shown to represent a familial predisposition to CKD triggered by different causes, i.e. it would be better classified as inherited kidney disease accelerated by triggers such as human immunodeficiency virus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection [25] .

The ERA-EDTA Registry provides more elaborate data (Spanish data are made public on websites but not regularly published in journals by themselves) and a European-wide perspective [15, 16] . In ERA-EDTA Registry data for all countries, the most common cause of incident KRT was unknown (27%, increasing to 39% if we add hypertension) followed by diabetes (20%), glomerulonephritis (11%) and PKD (5%). For prevalent KRT, the ranking is unknown (27%, increasing to 35% by adding hypertension) followed by glomerulonephritis (19%), diabetes (15%) and PKD (8%). This identifies a major issue in CKD. A significant percentage of persons lack an aetiological diagnosis, which precludes aetiology-targeted therapy and early prevention campaigns. Among the fastest-growing segment of CKD patients (those !65 years of age), unknown and hypertension accounted for 43% of incident KRT patients, highlighting the need to define cause in the elderly. We propose that accelerated kidney ageing may be a key contributor to CKD, including in the elderly, and are currently devising a working definition for accelerated kidney ageing that spurs research in this field.

Globally,~850 million persons have CKD [26] . The GBD study has generated data on the global and local burden of CKD, while CKD 23% of global population at risk of severe COVID-19

Adjusted HR for COVID-19 death Figure 4A ). Considerable global variation was noted in CKD burden. Age-standardized CKD DALY rates varied >15-fold between countries, a variability also evident within Spain and even within Spain autonomous communities [15, 27] . This illustrates the need for interregional collaborative research to identify and correct the drivers of a higher burden in certain regions.

The GBD projected that CKD will become the fifth greatest global cause of death by 2040 [14] ( Figure 4B ). YLL due to CKD are expected to double by 2040, the fastest increase among major causes of death after Alzheimer's. In contrast, the burden of other major causes of death is projected to decrease (e.g. ischaemic heart disease À3.6% or stroke À10.7%). Interestingly, CKD growth as a global cause of death outpaces diabetes, illustrating the need to address non-diabetic causes of CKD and protect the kidneys in persons with diabetes. Spain GBD data identified CKD as the eighth greatest cause of death, representing the largest departure from official Instituto Nacional de Estadistica (INE) data among causes of death in Spain. The INE underestimated the burden of CKD, likely due to low awareness of the condition [28, 29] . Spain's GBD identified CKD as the second fastest-growing cause of death, the sixth fastest-growing cause of YLD and the seventh fastest-growing cause of DALYs among the top 25 causes for each category [28, 29] . Projecting into the future, the recent rate of increase of CKD in Spain's GBD, CKD will become the second leading cause of death, after Alzheimer's, before the end of the century [29] ( Figure 5A ). This is likely an underestimation, as the progressive change in the age pyramid over the next few decades was not considered. Spanish projections may also apply to other countries with long life expectancies.

The population of Spain is projected to peak in the present decade and to become progressively older and decrease to~23-33 million by 2100 [30, 31] . The most recent estimate of the number of persons with CKD dates from 2010, when 14% of Spanish adults (6.7 million) had CKD [32] . CKD was more common in men than in women and a majority of persons with CKD were in the 45-to 64-year age range. Projecting these numbers into the future in the absence of changes to the current standard of care, assuming a constant prevalence of CKD within each age range and gender group and using World Health Organization (WHO) population prediction estimates, results in at least 8.12 million persons with CKD by 2040 and 7.96 million by 2100, which will represent 18% and 24% of the Spanish population, respectively ( Figure 5B and C). This is an underestimation, as progressive ageing of the population (persons !65 years of age are estimated to increase from 17% in 2010 to 32% by 2040 and 35% by 2100) will also occur within the same age range category, and this would be associated with an increased prevalence of CKD within age categories. Additionally, by 2040, most persons with CKD will be !65 years old.

The prevalence of KRT in Spain is also increasing. million by the end of the century, i.e.~1-4% of the projected population of Spain at that time ( Figure 5D ). The incidence of KRT also increased by 22% from 2013 to 2019 (125-152 pmp) [18] ( Figure 5E ). A majority of persons on KRT in Spain (55%) have a functioning kidney graft. Thus improving kidney and person outcomes in kidney graft recipients is a major aim in kidney research. As for CKD, KRT is also more common in men than in women. Therefore studies on CKD or KRT that do not split by gender may reflect the disease in men and studies addressing risk stratification, diagnosis and therapeutic approaches independently 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.

for men and women are required. Furthermore, there are large regional differences (range of incident KRT is 85-197 pmp and of prevalent KRT is 740-1567 pmp for different Spanish regions), which are also observed within regions (e.g. in Madrid, the range of incident KRT is 50-200 pmp and of prevalent KRT is 980-1700 pmp for different healthcare catchment areas). The causes of these differences are not fully understood, but it is critically important to define them in order to identify and target factors that generate CKD hotspots or benchmark potential healthcare contributors [33] .

The burden of CKD is also economic. The extrapolated annual cost of all CKD is at least as high as that for cancer or diabetes and estimated at >e140 billion annually in Europe and >$130 billion in the USA [17, 34] (Figure 6 ).

From 2022, the Instituto de Salud Carlos III (ISCIII, a Spanish government agency that funds health research) will fund the Redes 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] [31] [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] [31] [32] including non-transmissible immune system diseases, allergic diseases, multiple sclerosis and eye diseases. Thus RICORS2040 complies with guidance indicating that proposals should address one of the four thematic areas and may refer to one or more topics within a thematic area [35] .

CKD as a chronic inflammatory disease CKD can be characterized as a local inflammatory disease that becomes a systemic inflammatory disease as it progresses. Indeed, activation of the master regulator of inflammation [nuclear factor (NF)-jB], local expression of inflammatory cytokines and immune cell infiltrates are already observed in the early stages of CKD and can be triggered by albuminuria, hyperglycaemia and genetic defects, among others [36, 37] (Figure 7A ). Kidneys have multiple functions and GFR, which is usually estimated (not measured) in routine clinical care, is just one of them. There is increasing evidence that production of the antiageing and anti-inflammatory factor Klotho is a key function of kidney tubules that is lost very early in the course of CKD (GFR category G1, i.e. normal kidney function) partly in response to local inflammation and/or albuminuria [38] [39] [40] (Figure 7B ). Loss of anti-inflammatory molecules and accumulation of uraemic toxins leads to systemic inflammation, which is a key predictor of cardiovascular events and death in CKD, likely contributing to the accelerated biological ageing that characterizes CKD [41, 42] . The immune response also causes native kidney injury and is a leading cause of chronic graft injury.

We strongly believe that current research should be guided by future projections of disease burden rather than by past statistics. Predictions for the global impact of CKD are dire.

RICORS2040 derives its name from its aim to prove wrong the projections that CKD will become the fifth leading global cause of death by 2040. In this regard, RICORS2040 is fully aligned with the Decade of the Kidney concept first established by the American Association of Kidney Patients for 2020-2030, given the realization that CKD care lags other major causes of death in terms of current outcomes, predicted outcomes in the next decades and research funding [43] . This was followed by the Advancing American Kidney Health (AAKH) initiative of the USA government that is expected to become a catalyst for investment in kidney disease clinical trials and precision medicine [44] . The Decade of the Kidney is supported by the European Kidney Health Alliance (EKHA) and by patient associations across Europe that have launched a European movement for 2021-2030 [17, 43] . The RICORS2040 leadership is actively contributing to EKHA efforts.

RICORS2040 is focused on preservation of native and graft kidney function and improving outcomes in persons with CKD by preventing systemic consequences of CKD, collectively grouped into the concept of accelerated biological ageing, including consequences of kidney transplantation and its therapy (Figure 8) , as a majority of persons on KRT in Spain have a kidney graft. Thus, preventing the need for KRT in men and women with native kidneys or kidney grafts and improving kidney and patient outcomes in kidney graft recipients are major aims of RICORS2040. Risk stratification and optimization of therapeutic approaches to improve quality of life and life expectancy in the dialysis population are also addressed.

There is mounting evidence that course and complications of 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 same metric and the same cut-off points to diagnose CKD and for risk stratification in men and women, even knowing that creatinine excretion differs and therefore the denominator for UACR differs for men and for women. RICORS2040 will address the factors behind the gender gap in CKD burden and aims to provide clinical guidance for both men and women and to identify information gaps that preclude a gender-conscious approach to the diagnosis, risk stratification and treatment of CKD.

RICORS2040 will also address the factors behind geographical differences in CKD burden as it incorporates multiple centres from all over Spain. Specifically, kidney research and care centres from 12 of the 17 Spanish regions (autonomous communities) encompassing 90% of the Spanish population are integrated into RICORS2040.

A key issue hampering the achievement of health outcome targets 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 or barriers to implementation. RICORS2040 will use continuous improvement approaches to generate, validate and improve clinical guidance documents for different causes of CKD as well as for assessing and slowing the progression of CKD and the associated accelerated biological ageing of organs and systems in men and women with native kidneys or with kidney grafts. Testing the implementation of clinical guidance documents in a large number of centres from different regional health systems under real-world conditions will allow identification and correction of most shortcomings and feasibility issues.

In summary, RICORS2040 is focused on decreasing the need for KRT by improving prevention, diagnosis and therapy for major causes of CKD (diabetic, glomerular, inherited and accelerated kidney ageing; the latter is a concept that RICORS2040 is developing) in native kidneys and of chronic allograft nephropathy as well as on improving outcomes of men and women with CKD by preventing, identifying and treating major consequences of CKD or its therapy that contribute to the burden of accelerated ageing and premature death (Table 1 ). This will be achieved through systematization of prior knowledge generated by its antecessor REDINREN and the international community into gender-conscious clinical guidance documents, novel research to address gaps of knowledge and monitoring of clinical guidance implementation to generate updated clinical guidance documents as output of RICORS2040. 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. [17, 46] . It is also aligned with the AAKH initiative, the American National Kidney Foundation and the American Society of Nephrology, which advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases [34, 44] . The long-term goal is to reduce the burden of kidney disease and improve the quality of life of persons living with kidney disease. Kidney research is in dire need of research funding support, and this would be best achieved through the collaboration of all major stakeholders, from patient and scientific organizations to pharmaceutical companies to international, national and public funders.

The ISCIII is the main funder of health research in Spain and has long fostered successful collaborative research structures through dedicated research centres [e.g. Spanish National Cancer Research Centre (CNIO) and Spanish National Cardiovascular Research Centre (CNIC)]. Additionally, the ISCIII currently funds research networks for most major predicted 2040 global causes of death [14] : ischaemic heart disease (CIBERCV), stroke (CIBERCV and from 2022, stroke RICORS), infection (CIBER from 2022) and chronic obstructive pulmonary disease. The ISCIII research networks also fund projected 2040 causes of death ranked below CKD (e.g. CIBERONC for cancer and CIBERDEM for diabetes). In fact, in 2022, CKD will become the only top-15 predicted worldwide cause of death that is not supported by the ISCIII CIBER programme ( Figure 4B ). This represents a major, correctable gap in Spain's health research funding structure since there is also no dedicated research centre for kidney research. In this environment, the success of RICORS2040 would be critical for the survival of collaborative kidney research in Spain, although the ultimate aim would not be survival, but expansion according to the projected global burden of CKD.

Supplementary data are available at ckj online.

This study was supported by REDINREN RD16/0009 by the Instituto de Salud Carlos III (ISCIII). APPENDIX Asociació n para la informació n y la investigació n de las enfermedades renales gené ticas (AIRG-E) Marta RogerPresidenta Víctor Martínez Jimé nezHospital Virgen de la Arrixaca de Murcia 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 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 

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