CKD: The burden of disease invisible to research funders
CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. Criteria that by themselves diagnose CKD include 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. Diagnosing CKD implies assigning cause and G (GFR: G1 through G5) and A (albuminuria: A1 through A3) categories. 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 require to fulfill an additional criterion to be diagnosed of CKD, such as imaging diagnostic of polycystic kidney disease (PKD). , Persons with CKD are at an increased risk of progressing to require kidney replacement therapy (KRT), of all-cause and cardiovascular death, and of acute kidney injury (AKI). , , , There is a bidirectional relationship between CKD and AKI. CKD is the main risk factor for AKI and AKI may accelerate CKD. AKI has a high mortality and increases the risk of death for over a year after the episode. AKI is also common, as around 5% of hospitalized patients develop in-hospital AKI. More recently, CKD has been identified as the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19), and as the factor that most increased the risk of death in COVID-19 after older age , , ( ). AKI is also common in COVID-19 and a key risk factor for death. Increasing CKD categories are associated with increasing risk of all-cause and cardiovascular death, even in the elderly, thus questioning the concept of a “physiological” decrease in eGFR with age ( A, B). Albuminuria as low as > 2.5 mg/g is already associated with an increased risk of premature death ( B). Thus, the current albuminuria threshold used to diagnose CKD is a late event. Additionally, 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. This is the so-called blind spot in the diagnosis of CKD ( C). In this regard, there is clear margin for earlier diagnosis and therapy of CKD. The autosomal dominant PKD paradigm illustrates the way to go: a diagnostic test (sonography) allows the diagnosis of CKD decades before patients fulfill any other criterion to diagnose CKD. Similar diagnostic tools are needed for other forms of CKD. Additional future criteria to diagnose CKD may be include genetic tests disclosing clearly pathogenic gene variants or urinary biomarkers beyond UACR, such as urinary peptidomics or urinary Klotho. , , Kidney failure (end-stage kidney disease, G5, GFR < 15 ml/min/1.73 m 2 ) is 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 as the 64,000 persons on KRT in Spain consume 2.5–5.0% of the healthcare budget. However, the bulk of the health burden of CKD is not represented by KRT but by accelerated aging and premature death, as clearly quantified by Global Burden of Disease (GBD) data discussed below. Illustrating the lack of awareness of the CKD concept, in a recent report of a cohort of persons selected because they had CKD, as evidence for low eGFR for at least 3 months, CKD was only the sixth more common diagnoses after hypertension (82%), cardiovascular disease (39%), cancer (29%), diabetes (29%), heart failure (28%) ( ). , Thus, only 23% of participants in the CKD cohort had been diagnosed by their physicians as having CKD while the number should be 100%. 

KRT is one of the success stories of health care in the 20th century and allows survival following failure of a vital organ. However, KRT is a failure of CKD management that, if successful, should have prevented CKD progression this stage. Indeed, in persons on KRT expected remaining lifetimes are severely reduced – by around 70% (40 years less) and by 25% (15 years less) for a 20-year-old on dialysis or with a functioning kidney graft, respectively. , The absolute reduction in expected remaining lifetimes is milder at older ages, but the relative reduction in life expectancy remains constant up to age 89 years ( A). Annual mortality of persons on KRT is up to 100-fold higher than for similar aged controls. Indeed, the 5-year survival of patients on dialysis is lower than for all forms of cancer combined ( B). 

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. , , While PKD is the only inherited kidney disease usually reported by large registries, recent Madrid and Catalonian KRT registry data found all inherited kidney diseases combined as frequent as glomerulonephritis. Inherited kidney diseases are frequently overlooked by physicians. Indeed, whole exome sequencing found monogenic kidney diseases in 9% of adult CKD, and in 17–34% of those with CKD of unknown cause. , “Vascular” is labeled as hypertension in the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) Registry. , , In clinical practice, hypertension is usually listed as a cause when there is no other obvious etiology, following expert recommendation. This practice may replace an inadequate etiologic workup, downplaying the incidence of other causes of CKD while falsely boosting hypertension as cause (rather than as consequence) of CKD. , Thus, there is no relationship between prevalence of hypertension and of hypertensive CKD in different countries. In African Americans, hypertensive nephropathy is known to represent a familial predisposition to CKD triggered by different causes, including human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the 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%). , Thus, a significant percentage of persons lack an etiological diagnosis, which precludes etiology-targeted therapy and early prevention campaigns. Among the fastest growing segment of CKD patients (those aged ≥ 65 years), unknown and hypertension accounted for 43% of incident KRT patients, highlighting the need to define cause in the elderly. We propose that accelerated kidney aging may be a key contributor to CKD, including in the elderly, and are currently devising a working definition for accelerated kidney aging that spurs research in this field. 

Globally, around 850 million persons have CKD. In 2017, 1.2 million people died from CKD globally and CKD resulted in 35.8 million disability adjusted life years (DALYs), most of them (>70%) not due to diabetic kidney disease, as well as in 7.3 million years lived with disability (YLD) and 28.5 million years of life lost (YLLs) (30) ( A). However, there are large geographical differences in CKD burden. Age-standardized CKD DALY rates varied more than 15-fold between countries, a variability also evident within Spain and even within Spain autonomous communities. , This illustrates the need for identification and correction of the drivers of a higher burden in certain regions. GBD projected that CKD will become the 5th global cause of death by 2040 ( B). YLLs due to CKD are expected to double by 2040, the fastest increase among major causes of death, after Alzheimer. By contrast, the burden of other major causes of death (e.g. ischemic heart disease −3.6% or stroke −10.7%) is already decreasing. CKD growth as a cause of death outpaces diabetes and research is needed in diabetes-independent causes of CKD. Spain GBD data identified CKD as the 8th cause of death. However, official Instituto Nacional de Estadistica (INE) data underestimated the burden of CKD, likely due to low awareness of the condition. , Spain GBD identified CKD as the 2nd fastest growing cause of death, the 6th fastest growing cause of YLD and the 7th fastest growing cause of DALYs among the top 25 causes for each category. , Projecting into the future the recent rate of increase of CKD in Spain GBD, CKD will become the 2nd cause of death, after Alzheimer, before the end of the century ( A). 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 expectancy. The population of Spain will become progressively older and decrease to around 23–33 million by 2100. , In 2010, 14% of Spanish adults (6.7 million) had CKD. CKD was more common in men than in women and in those aged 45–64-years. 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 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 ( B, C). This is an underestimation, as progressive aging of the population (persons aged 65 years or more 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, that we did not consider. Additionally, by 2040, most persons with CKD will be 65-year-old or older. The prevalence of KRT in Spain is also increasing. It increased 38% from 2007 to 2019 (985–1367 pmp) and the rate appears to be accelerating (it increased 14% from 2007 to 2013 and 22% from 2013 to 2019). At this rate of growth, the number of persons on KRT will hit 0.23–1.00 million by the end of the century, i.e. around 1–4% of the projected population of Spain at that time ( D). The incidence of KRT also increased by 22% from 2013 to 2019 (125–152 pmp) ( E). 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. Thus, 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 men and for women are required. Furthermore, there are large regional differences (range of incident KRT 85–197 pmp and of prevalent KRT 740–1567 pmp for different Spanish regions), which are also observed within regions (e.g. in Madrid, range of incident KRT 50–200 pmp and of prevalent KRT 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. The burden of CKD is also economical. The extrapolated annual cost of all CKD is at least as high as that for cancer or diabetes and estimated at over 140 billion euros annually in Europe and over 130 billion dollars in the United States , ( ). 

From 2022, the Instituto de Salud Carlos III (ISCIII, Spain Government Agency that funds health research) will fund the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS, Cooperative Research Networks Focused on Results in Health) program of network research. This will replace the prior ISCIII-funded program of network research termed RETICS. The Spanish kidney research community, represented by the research groups integrated into the Kidney Research Network RETIC (RETIC RED de INvestigación RENal, REDINREN) and by several working groups of the Spanish Society of Nephrology (Sociedad Española de Nefrología, SEN), such as GLOSEN (glomerular disease working group) and GEENDIAB (diabetes working group), has submitted the RICORS2040 proposal to the RICORS call. RICORS2040 is supported by SENEFRO, the ERA-EDTA, ALCER (Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón, Spanish Kidney Patients Association) and ONT. RICORS2040 is focused on kidney diseases within one of the four thematic areas of the RICORS call: “Inflammation and immunopathology of organs and systems”. This thematic area includes kidney diseases and also non-transmissible immune system diseases, allergic diseases, multiple sclerosis and eye diseases. CKD as a chronic inflammatory disease . CKD is a local inflammatory disease that becomes a systemic inflammatory disease as it progresses. Activation of the master regulator of inflammation (NFκB), local expression of inflammatory cytokines and immune cell infiltrates are already observed in early stages of CKD and can be triggered by albuminuria, hyperglycemia and genetic defects, among others , ( A). Kidneys have multiple functions and GFR is just one of them. There is increasing evidence that production of the antiaging 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, that is, normal “kidney function”) partly in response to local inflammation and/or albuminuria , , ( B). Loss of anti-inflammatory molecules and accumulation of uremic toxins leads to systemic inflammation, which is a key predictor of cardiovascular events and death in CKD, likely contributing to the accelerated biological aging that characterizes CKD. , Current versus future burden: The decade of the kidney . Current research should be guided by future projections of disease burden rather than by past statistics. RICORS2040 derives its name from its aim to prove wrong projections that CKD will become the 5th global cause of death by 2040. Emphasis on prevention . RICORS2040 is focused on preservation of native and graft kidney function and in improving outcomes in persons with CKD by preventing systemic consequences of CKD, collectively grouped into the concept of accelerated biological aging, including consequences of kidney transplantation and its therapy ( ), as a majority of persons on KRT in Spain carry a kidney graft. Thus, preventing the need for KRT in men and women with native kidneys or kidney grafts and improving kidney and person 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. Men and women . There is mounting evidence that CKD course and complications are not the same in men and women and even that the cut-off points to define CKD may differ. 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 thus, 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. Addressing regional inequality . RICORS2040 will also address the factors behind geographical differences in CKD burden as it incorporates multiple centers from all over Spain. Specifically, kidney research and care centers from 12 of the 17 Spanish regions (Autonomous communities) encompassing 90% of the Spanish populations, are integrated into RICORS2040. Clinical guidance should be implemented . A key issue hampering the achievement of health outcome targets in 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 of the associated accelerated biological aging of organs and systems in men and women with native kidneys or with kidney grafts. Testing the implementation of clinical guidance documents in a high number of centers from different regional health systems under real world conditions will allow to identify and correct 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, accelerated kidney aging, the latter 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 aging and premature death ( ). 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. 

Despite CKD being the 5th predicted global cause of death by 2040, there is no confirmed Spanish research network on CKD from 2022 on. This is in contrast to a wider global movement to increase awareness of the health burden of CKD, summarized in the Decade of the Kidney (2020–2030) strategy in Europe and the US promoted by the American Association of Kidney Patients (AAKP) and adopted by the Advancing American Kidney Health (AAKH) initiative of the United States Government, the European Kidney Health Alliance (EKHA) and by patient associations across Europe. , , , , Moreover, even if RICORS2040 is funded, CKD lacks dedicated research centers (e.g. Spanish National Cancer Research Center, CNIO and Spanish National Cardiovascular Research Center, CNIC) or well-funded ISCIII CIBER research networks that fund research on all other major predicted 2040 global causes of death, except CKD : ischemic heart disease (CIBERCV), stroke (CIBERCV and from 2022, stroke RICORS), infection (CIBER from 2022) and chronic obstructive pulmonary disease (CiberRes). ISCIII research networks also fund projected 2040 causes of death ranked below CKD (e.g. CIBERONC for cancer and CIBERDEM for diabetes) ( B). This represents a major, correctable gap in Spain's health research funding structure. Note added in press: On October 13 2021, it was made public that RICORS2040 would be funded by ISCIII starting 2022. 

REDINREN RD16/0009. 

On October 13 2021, it was made public that RICORS2040 would be funded by ISCIII starting 2022. 

Authors are members of scientific and patient association with an interest in improving the outcomes and quality of life of persons with kidney disease. Alberto Ortiz is Editor in Chief for Clinical Kidney Journal, Maria Jose Soler is Associate Editor and Editor in Chief elect for Clinical Kidney Journal and Roser Torra and Jose Maria Cruzado are Associate Editors for Clinical Kidney Journal. 

