Age and Ageing 2022; 51: 1–5 This article has been co-published with permission in Clinical Kidney Journal, Nephrology Dialysis https://doi.org/10.1093/ageing/afac157 Transplantation, and Age and Ageing. © The Author(s) 2022. Published by Oxford University Press on behalf of the ERA and the British Geriatrics Society. All rights reserved. The articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article. For permissions, please e-mail journals.permissions@oup.com COMMENTARY Ageing meets kidney disease Alberto Ortiz1,2,3,† , Francesco Mattace-Raso4,† , María José Soler5,† , Denis Fouque6,† 1 Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain 2 RICORS2040, Madrid, Spain Downloaded from https://academic.oup.com/ageing/article/51/8/afac157/6609704 by guest on 28 July 2023 3 Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain 4 Division of Geriatric Medicine, Erasmus MC University Medical Center, Rotterdam, The Netherlands 5 Nephrology Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Nephrology and Kidney Transplant Research Group, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain 6 Department of Nephrology, Nutrition and Dialysis, Université de Lyon - Hospices Civils de Lyon, Lyon, France Correspondence to: Katy Ladbrook; E-mail aa@bgs.org.uk; Caroline Vinck; E-mail: caroline.vinck@era-online.org † All authors contributed equally to this work. Abstract Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health. The most used diagnostic criteria are a urinary albumin: creatinine ratio ≥30 mg/g or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Either of these diagnostic thresholds is associated with adverse health outcomes. GFR decreases with age and the prevalence of CKD is highest in older adults; moreover, the presence of CKD is associated with an increased risk of all-cause and cardiovascular death related to accelerated ageing in all age ranges, and the absolute increase in risk is highest for those aged >75 years. Indeed, premature death is a more common outcome than CKD progression to kidney failure requiring kidney replacement therapy. The progressive ageing of the world population contributes to the projection that CKD will become the second most common cause of death before the end of the century in countries with long life expectancy. The current collection of selected studies on kidney disease and ageing published in Age&Ageing, NDT and CKJ provides an overview of key topics, including cognitive decline, sarcopaenia, wasting and cardiovascular and non-cardiovascular morbidity and mortality, the management of kidney failure and gender differences in CKD progression. Keywords: ageing, chronic kidney disease, cognitive decline, haemodialysis, transplantation, sarcopaenia Introduction of uraemic toxins and altered homeostasis when GFR falls below 60 mL/min/1.73 m2 [2–4]. Indeed, GFR and Chronic kidney disease (CKD) is one of the fastest-growing UACR thresholds to define CKD were chosen because, causes of morbidity and mortality, expected to become the when persisting for >3 months, they are associated with an fifth most common global cause of death by 2040 and the increased risk of adverse outcomes including acute kidney second most common before the end of the 21st century injury (AKI), progression to kidney failure requiring kidney in countries with long life expectancy [1]. CKD has a replacement therapy, and all-cause mortality. Despite the bidirectional link with ageing (Fig. 1). The prevalence of clear implications of a CKD diagnosis for health, and CKD increases with age and CKD accelerates biological clear-cut diagnostic criteria, CKD remains an unrecognized ageing through a variety of mechanisms that include the condition, especially in older adults [5]. Moreover, recogni- early loss of additional kidney functions not assessed in tion of CKD is important for adequate drug prescription. routine clinical care, such as the production of the anti- Thus, in older adults, community prescriptions for quinine, ageing protein Klotho, when CKD is already present [e.g. the most commonly prescribed medication in the UK urinary albumin:creatinine ratio (UACR) ≥30 mg/g] but and USA to treat leg cramps, were associated with an global kidney function [i.e. estimated glomerular filtration increased risk of AKI [6]. Furthermore, the risk of AKI rate (eGFR)] is still normal, and later, the accumulation increased with advancing CKD stages, which conferred 1 A. Ortiz et al. Downloaded from https://academic.oup.com/ageing/article/51/8/afac157/6609704 by guest on 28 July 2023 Figure 1. Interaction between ageing and kidney disease. Chronological ageing is associated to a progressive decrease of multiple kidney functions, including glomerular filtration. While the age-associated decrease in eGFR has been considered ‘physiological’ by some, when it reaches the threshold values to diagnose chronic kidney disease (CKD), it is associated with adverse outcomes, including increased mortality, and should no longer be viewed as ‘physiological’, in the same manner that the age-associated development of hypertension is not considered ‘physiological’. Both ageing and CKD are risk factors for acute kidney injury (AKI) and AKI may accelerate CKD progression. Through multiple mechanisms, CKD accelerates biological ageing. the highest risk of AKI other than a prior history of AKI. Sarcopaenia, assessment of kidney function The current collection of selected manuscripts on kidney disease and ageing published in Age&Ageing, NDT and Older adults with CKD will present with a higher risk CKJ provides an overview of key topics including cognitive of sarcopaenia and falls, which may be increased when decline, sarcopaenia, cardiovascular and non-cardiovascular both are present and there is interest in the contribution morbidity and mortality, management of kidney failure, and of physical activity to improve outcomes, including those gender differences in CKD progression, as older men with involving cognition. Among 3223 older participants in CKD G4 and G5 lost eGFR faster than women, whereas National Health and Nutrition Examination Survey 2011– diabetes was a key determinant of loss of eGFR specifically 14 [11], CKD G4–G5 was associated with lower objective in women [7]. cognitive function only in those with low physical activity. This cross-sectional association may reflect a lower kidney function than indicated by eGFR in persons with low Cognitive decline muscle mass which generates less creatinine. In this regard, The cumulative effect of shared cardiovascular risk factors eGFR has limitations and may be less reliable in older could both cause CKD and cognitive decline, the latter more persons as loss of muscle mass lowers serum creatinine. probably in later life. Within the framework of the White- In baseline data of the IMPROveFALL study, among hall II prospective population-based study which included 578 older participants, those with eGFR ≥90 mL/min 6050 older adults [8], kidney function increased the risk had lower handgrip strength than those with lower eGFR of incident dementia which was not attributable to stroke; [12]. They additionally had a smaller calf circumference. moreover, in the same study, a decline of the eGFR was also Overall, these data suggest that lower muscle mass may associated with the incidence of dementia even in partici- lead to overestimation of GFR (i.e. of kidney function), pants with eGFR ≥60 mL/min/1.73 m2 at baseline. These identifying an unmet need for biomarkers independent of findings were not confirmed in a smaller study (n = 1127 muscle mass to estimate kidney function in older persons. older adults); in this case, no association was reported in Despite the potential interference of higher muscle mass older adults with mild to moderately low eGFR [9]. Further with eGFR, in 1352 elderly men from the British Regional insight is provided by a prospective study of 250 CKD Heart Study, higher levels of objectively measured physical patients. Previous stroke, depression or anxiety, higher pro- activity were associated with reduced odds ratios (ORs) teinuria and prescription of psychotropic medications were for lower eGFR (<45 versus ≥45 mL/min/1.73 m2 ) after associated with an increased risk of cognitive impairment adjustment for covariates [13]. CKD is defined by an eGFR [10], emphasizing the need to add the albuminuria/protein- below 60 mL/min/1.73 m2 in adults, regardless of age, and uria dimension on top of eGFR for the full evaluation of the largest increase in absolute risk of death associated with CKD and associated risks. an eGFR-based diagnosis of CKD (i.e. an eGFR below 2 Ageing meets kidney disease 60 mL/min/1.73 m2 ) was found in persons ≥75-year-old coexisting conditions of older CKD patients increase the [14]. More recently, in the National Health Insurance risk of polypharmacy. In 1317 participants in the EQUAL Service (NHIS) database, the eGFR percentile showing cohort, polypharmacy (≥5 medications) was found in 91% minimum mortality was higher in the aged population: and hyperpolypharmacy (≥10) in 43% [21], respectively. 28th percentile (84 mL/min/1.73 m2 ) for middle-aged Cardiovascular medications were the most prescribed med- males and 63rd percentile (86 mL/min/1.73 m2 ) for elderly ications (mean 3.5 per person). However, there were inter- males; 42nd percentile (103 mL/min/1.73 m2 ) for middle- national differences: hyperpolypharmacy was more frequent aged females and 75th percentile (90 mL/min/1.73 m2 ) for in Germany (almost 3-fold higher than in the UK), the elderly females [15]. These findings support the current Netherlands (almost 2-fold higher) and Italy (around 50% eGFR thresholds to define CKD even in older people and higher), and less common in Poland. The impact of practice argue against considering that a lower eGFR threshold variation on outcomes should be studied. The UK also has in older people indicates a ‘physiological’ decrease in a less proactive approach in providing kidney replacement GFR. therapy than other Western European countries [22]. Inter- Downloaded from https://academic.oup.com/ageing/article/51/8/afac157/6609704 by guest on 28 July 2023 Among older haemodialysis patients, physical perfor- estingly, life expectancy at birth is similar in Germany and mance was poor and declined faster than in the healthy the UK, but higher in the Netherlands and Italy, and lower population. In 714 prevalent haemodialysis patients, only in Poland [23]. Unfortunately, key large European countries, a minority (15%) of patients maintained good physical such as Germany and Italy, do not contribute data to the condition; the remainder deteriorated or died [16]. Among ERA Registry. older patients (≥75 years) only 4% remained in good The optimal target systolic blood pressure (SBP) in CKD physical condition. In this very high-risk population (75– is also disputed, with wildly different recommendations from 95 years), a 12-week intradialytic lower limb exercise major guidelines [24]. Among 158 713 participants with programme improved the 5-times sit-to-stand (STS-5) test CKD3 and 6611 with CKD4 without diabetes or protein- and the Fried frailty scale [17]. Improvement persisted uria, SBP 140–169 mmHg had little additional predictive 12 weeks after completing the programme, suggesting value while <120 mmHg was associated with increased that intermittent exercise programmes in resource-limited mortality [25], cautioning against recent Kidney Disease: settings may also be beneficial. Improving Global Outcomes (KDIGO) guidelines on SBP targets. Cardiovascular diseases An increased risk of cardiovascular and non-cardiovascular Management of kidney function death is also an integral part of the CKD definition. Loss of Klotho bioactivity is thought to drive the accelerated car- Three main options are available for patients with kidney diovascular ageing phenotype of CKD. Additionally, among failure (i.e. eGFR <15 mL/min/1.73 m2 ): kidney trans- 2185 participants with CKD in the NEFRONA study, a plantation from either a living or cadaveric donor, dialysis combination of three Single nucleotide polymorphisms in (haemodialysis or peritoneal dialysis) or conservative treat- the KL gene was associated with an increased risk for non- ment [26]. The decision-making process for the modality cardiovascular death, in line with a potential impact of of kidney replacement therapy (kidney transplantation or Klotho deficiency on accelerated ageing beyond the cardio- dialysis) in older adults merits specific consideration [27]. vascular system [18]. However, older patients may switch their choice of ther- Regarding cardiovascular disease, there is still debate as apy over time, mainly between dialysis and conservative to the optimal approach to improve outcomes in patients treatment [28]. A prediction tool of 2-year mortality was with CKD, especially those undergoing dialysis, since they developed to provide older (>70 years) advanced CKD are usually excluded from clinical trials. Moreover, CKD patients with individualized prognosis estimates for both patients have an increased risk of multiple forms of cardiovas- dialysis and conservative care, although it would need exter- cular disease. In CKD-REIN, both atheromatous (coronary nal validation in other CKD populations before widespread artery disease, peripheral artery disease and stroke) and non- use to inform treatment decision-making [29]. In this regard, atheromatous (heart failure, cardiac arrhythmia and valvular a smooth transition to dialysis may improve early outcomes heart disease) cardiovascular disease were highly prevalent after dialysis initiation among old and frail adults [30]. and more frequent in older patients, peaking at 43% at 75– Kidney transplantation also presents age-related issues. The 84 years and at 56% at ≥85 years, respectively [19]. Among short- and medium-term graft and recipient survival were 3033 adults with CKD Stages 3 and 4, older age (≥65 years) similar for kidneys from older donors after circulatory death was not associated with the underuse of antithrombotic and for older brain death donors, which is the conventional drugs (antiplatelet agents in coronary artery disease or oral cadaveric kidney donor [31]. anticoagulants in atrial fibrillation) but was associated with less use of renin-angiotensin system blockers, β-blockers and Funding: A.O. research is funded by Instituto de Salud lipid-lowering therapy, especially in patients >75–85 years Carlos III (ISCIII) RICORS program to RICORS2040 with coronary artery disease [20]. However, the multiple (RD21/0005/0001), FEDER funds. M.J.S. research is 3 A. Ortiz et al. funded by Instituto de Salud Carlos III (ISCIII) RICORS 9. Grasing M, Kennedy K, Sarnak MJ et al. Mild to mod- program to RICORS2040 (RD21/0005/0016), FEDER erate decrease in eGFR and cognitive decline in older funds and Marató TV3. adults. Nephrol Dial Transplant 2021; gfab226, https://doi.o rg/10.1093/ndt/gfab226 Conflict of interest statement: A.O. has received grants 10. Tollitt J, Odudu A, Montaldi D et al. Cognitive impairment from Sanofi and consultancy or speaker fees or travel in patients with moderate to severe chronic kidney disease: support from Advicciene, Astellas, Astrazeneca, Amicus, the Salford kidney cohort study. Clin Kidney J 2021; 14: Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi- 1639–1648 Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, 11. Chu NM, Hong J, Harasemiw O et al. Chronic kidney dis- Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk and Vifor ease, physical activity and cognitive function in older adults— Fresenius Medical Care Renal Pharma, and is Director results from the National Health and Nutrition Examina- tion Survey (2011–2014). Nephrol Dial Transplant 2018; of the Catedra Mundipharma-UAM of diabetic kidney gfab338, https://doi.org/10.1093/ndt/gfab338 disease and the Catedra Astrazeneca-UAM of chronic 12. Lisanne Tap, Nicole DA Boyé, Klaas A Hartholt et al. Asso- kidney disease and electrolytes. A.O. was the Editor-in- ciation of estimated glomerular filtration rate with muscle Downloaded from https://academic.oup.com/ageing/article/51/8/afac157/6609704 by guest on 28 July 2023 Chief for CKJ (up to 21 May 2022). M.J.S. has received function in older persons who have fallen. Age Ageing 2018; grants from Boehringer and consultancy or speaker fees 47: 269–274 or travel support AstraZeneca, Novo-Nordsik, Esteve, 13. Tessa J Parsons, Claudio Sartini, Sarah Ash et al. Objectively Vifor, Bayer, Mundipharma, Fresenius Medical Care Renal measured physical activity and kidney function in older men; a Pharma, Boehringer, Ingelheim Lilly, Jansen, ICU Medical, cross-sectional population-based study. 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