Treatment of chronic kidney disease in older populations

Abstract

As the world population ages, an expected increase in the prevalence of chronic kidney disease (CKD) among older individuals will pose a considerable challenge for health care systems in terms of resource allocation for disease management. Treatment strategies for older patients with CKD should ideally align with those applied to the general population, focusing on minimizing cardiovascular events and reducing the risk of progression to kidney failure. Emerging therapies, such as SGLT-2 inhibitors and GLP-1 receptor agonists, hold promise for the effective management of CKD in older individuals. In addition, non-pharmacological interventions such as nutritional and exercise therapies have a crucial role. These interventions enhance the effects of pharmacotherapy and, importantly, contribute to the maintenance of cognitive function and overall quality of life. Various factors beyond age and cognitive function must be taken into account when considering kidney replacement therapy for patients with kidney failure. Importantly, all treatment options, including dialysis, transplantation and conservative management approaches, should be tailored to the individual through patient-centred decision-making. The dynamic integration of digital technologies into medical practice has the potential to transform the management of CKD in the aging population.

Key points

• Aging is an important risk factor for chronic kidney disease (CKD); the expected increase in CKD prevalence with the aging population will likely pose a challenge to health care systems in terms of resource allocation and strategies for effective disease management.

• Structural and functional changes that occur in the kidney with aging are associated with a decline in kidney function from around 40 years of age; although these changes vary considerably between individuals, diseases such as hypertension and diabetes accelerate this decline.

• Older patients with CKD should be treated the same way as other members of the general population, with the goal of minimizing cardiovascular events and slowing progression to kidney failure; available evidence suggests that SGLT-2 inhibitors and GLP-1 receptor agonists may be effective in older populations and associated with a low risk of adverse events.

• Nutritional and exercise therapies are essential non-pharmacological treatments for older patients with CKD; these therapies not only enhance the effects of pharmacotherapies but may also help to maintain cognitive function and quality of life.

• Choice of kidney replacement therapy for patients with kidney failure should not solely depend on age or cognitive function; alongside dialysis and transplantation, conservative treatment options, including conservative kidney management, should be considered through patient-centred decision making.

• Digital technologies using wearable devices and virtual reality systems are expected to facilitate the treatment of CKD in older populations.

Introduction

In 2020, the global population over 60 years of age exceeded that of children under 5 years of age. By 2030, one in six people will be 60 or older, and the global population aged 60 or older will have increased from 1 billion in 2020 to 1.4 billion¹. This unprecedented rate of aging will require adaptations to health and social systems to manage the predicted increase in age-associated disease and disability. The aging process encompasses a wide range of changes, including biological, physiological, environmental, psychological, behavioural and social. These changes range from benign, such as greying hair, to more concerning increases in the risks of chronic diseases, frailty and disability². Critically, aging is expected to adversely affect kidney health and further increase the global prevalence of chronic kidney disease (CKD)^3,4.

The burden of CKD has been highlighted by the Global Burden of Disease study⁵, which showed that CKD contributes considerably to disability, reduced life expectancy and a substantial number of deaths each year. The impact of CKD is likely even more extensive than reported, as many regions lack adequate CKD screening and the true prevalence of CKD is unknown. Aging of the world’s population is expected to compound the burden of CKD. Indeed, aging is an important risk factor for CKD, exacerbated by the cumulative exposure to harmful substances over a lifetime. CKD is a complex disease to manage, and the expected increase in its prevalence among older adults will pose particular challenges for health care systems⁶.

In the USA, CKD affects nearly 40% of people aged 65 and older; moreover, the fastest-growing group of individuals initiating dialysis consists of those aged 75 and older⁴. A similar trend is seen in Canada, where more than half of patients initiating dialysis are over the age of 65 (ref. ⁷). In 2010, an estimated 2.6 million people worldwide were receiving kidney replacement therapy (KRT; dialysis or kidney transplantation)⁸. However, the number of individuals needing KRT in that same year was estimated to be 4.9–9.7 million, suggesting that >2.3 million people may have died because of a lack of access to KRT. This gap in access is particularly pronounced in low-income regions^9,10. The increasing prevalence of CKD with population aging will necessitate appropriate measures to prevent or slow progression to kidney failure and ensure provision of KRT to those who need it¹⁰. Here, we briefly review the causes of CKD in older individuals before focusing on the consequences of an increased CKD prevalence in aged populations and best practice principles for its management.

Changes in the kidney with aging

The morphology of the kidney undergoes considerable changes with age (Fig. 1). Despite these changes, it is important to note that aging per se does not necessarily lead to a decline in kidney function that is clinically problematic. Single-nephron glomerular filtration rate (GFR) can remain stable until at least 70 years of age¹¹. The absence of albuminuria in healthy aged individuals also suggests that underlying CKD or a kidney stressor, such as low nephron endowment at birth or a comorbid condition such as hypertension, may be responsible for the acceleration of kidney function decline in some individuals^11,12,13.

Fig. 1: Structural and morphological changes that occur in the kidney with aging.

a, Aging is associated with a decrease in the volume of the kidney cortex, which typically begins from around 30 years of age. By contrast, the volume of the medulla increases until about the age of 50, thus maintaining the overall kidney volume. Beyond this point, however, the medulla no longer increases in volume, and the overall kidney volume decreases. b, Kidney cysts also become more common with age, and the surface of the kidney becomes irregular owing to scarring from chronic ischaemia. c, The renal microvasculature, including the interlobular, arcuate and interlobar arteries, also undergoes age-related changes. These changes include intimal and medial thickening and luminal narrowing. Hyaline arteriolosclerosis can also be seen in the afferent arterioles. These changes in small arteries are associated with a decrease in renal blood flow. d, As chronic ischaemia progresses, secondary changes occur in the glomeruli, including thickening of the basement membrane, wrinkling of the capillary tufts and mild mesangial hyperplasia. At a more advanced age, the glomerulus collapses, the vessel’s lumen becomes occluded and constricted, and the surrounding Bowman’s capsule typically becomes filled with a matrix-like hyaline substance. e, Capillary rarefaction is also increasingly common with aging. Tubular atrophy leads to enlargement of the interstitial space and the development of fibrosis.

Structural changes

Kidney volume decreases progressively after 30 years of age, with a more notable decline observed after 50 years of age. Kidney weight, which is around 50 g at birth, increases to more than 400 g by the fourth decade of life before decreasing to <300 g, primarily as a consequence of reduced cortical volume^14,15,16, which is associated with nephron scarring^15,17 and a decline in the number of functional nephrons (Fig. 1a). In addition, aging can be associated with greater irregularity of the kidney surface due to scarring and the presence of cysts (Fig. 1b). Vascular conditions such as arteriosclerosis, medial hypertrophy and arteriolar hyalinosis also become more prevalent with age^15,18 (Fig. 1c) These vascular changes can lead to decreased renal blood flow and chronic ischaemic damage^18,19, characterized by cortical and juxtamedullary glomerulosclerosis¹⁵ (Fig. 1d). Although a decline in nephron number is initially associated with a compensatory increase in the filtration of the remaining nephrons, this compensatory capacity eventually diminishes, leading to impaired kidney function¹⁹. Tubulointerstitial changes include atrophy of the tubular epithelium, enlargement of the tubular lumen, thickening of the tubular basement membrane and tubulointerstitial fibrosis^15,19,20 (Fig. 1e).

Functional changes

Several studies have evaluated the rate of decline in kidney function through longitudinal measurements of creatinine clearance (CrCl). In the Baltimore Longitudinal Study of Aging²¹, the average rate of CrCl decline among 254 healthy individuals, excluding those with potential lesions in the kidneys and/or urinary tract, as well as those undergoing treatment with diuretics and/or antihypertensive drugs, was −0.75 ml/min per year across all age groups, corresponding to an average decrease in GFR of −0.58 ml/min per year. The annual decline in CrCl tended to increase with age²¹. However, considerable variability was noted in the rate of renal function decline. Whereas one-third of individuals showed no decline, some exhibited an increase in CrCl throughout the study period²¹. These findings indicate that renal function does not uniformly deteriorate with age in healthy individuals. Further analysis showed that both mean blood pressure and age independently affected kidney function decline.

The decline in kidney function associated with aging has been also investigated in cross-sectional studies. One study that used inulin clearance to measure GFR in 70 men, excluding hospitalized patients with renal disease, cerebrovascular disease, coronary artery disease or hypertension, found that the mean GFR of men in their 20s, was 122.8 ± 16.4 ml/min/1.73 m², but decreased after 40 years of age at a rate of 1 ml/min/1.73 m² per year, such that men in their 80s had a mean GFR of 65.3 ± 20.4 ml/min/1.73 m² (ref. ²²). In line with these findings, another study that examined the relationship between age and GFR assessed by iothalamate clearance in 1,057 potential kidney transplant donors reported a rate of GFR decline of −0.373 ml/min/1.73 m² per year up to the age of 45 years. Beyond 45 years of age, the rate of GFR decline increased to −0.753 ml/min/1.73 m² (ref. ²³).

Haemodynamic changes

The observed decline in GFR with age is intrinsically linked to haemodynamic changes within the renal parenchyma. A key observation is the decline in effective renal plasma flow with age, which declines by approximately 10% per decade after 30 years of age²⁴. Importantly, this decline in kidney function is more pronounced in the renal cortex, whereas blood flow in the medulla remains relatively well preserved. Tubular function also changes with age, leading to a decrease in sodium reabsorption and to lower plasma renin activity and aldosterone levels²⁵. Older adults also exhibit a decreased responsiveness to stimuli such as dehydration, along with a decreased ability to excrete sodium efficiently, resulting in increased nocturnal urine output²⁶. Although levels of atrial natriuretic peptide increase with age, responsiveness to this hormone decreases. In addition, aging is associated with a decreased ability to concentrate and dilute urine.

Molecular changes

Understanding the molecular mechanisms that underlie the complex age-related change in the kidney may lead to the development of new therapeutic interventions (Fig. 2). As described above, renal aging manifests clinically as a decrease in GFR, structurally attributed to a decrease in the number of functioning nephrons. Mechanistically, processes such as glomerulosclerosis, podocyte hypertrophy, interstitial fibrosis and tubular atrophy, and progressive microvascular rarefaction are involved²⁷, exacerbated by factors such as diabetes, obesity and hypertension. Risk factors for these processes include oxidative stress; decreased expression of anti-aging factors such as klotho and SIRT-1–PGC-1α signalling; activation of Wnt–β-catenin signalling; impairment of autophagy, DNA damage repair and mitochondrial function; epigenetic changes; and the development of cellular senescence^27,28. Collectively, these mechanisms contribute to the acceleration of renal aging, exacerbating the decline in kidney function beyond the natural aging process.

Fig. 2: Molecular changes in the aging kidney.

The alterations in the kidneys that accompany aging encompass processes such as glomerulosclerosis, hypertrophy of podocytes in the remaining glomeruli, interstitial fibrosis and tubular atrophy, and progressive microvascular rarefaction. The mechanisms that underlie the acceleration of aging are multifaceted, involving oxidative stress, diminished levels of anti-aging factors such as klotho and the Sirtuin-1–PGC1α signalling, defects in processes such as autophagy, DNA damage repair and mitochondrial function, epigenetic modifications, an increase in the number of senescent cells with a senescence-associated secretory phenotype (SASP), and activation of Wnt–β-catenin signalling. These processes diminish the regenerative capacity of the kidney, increase susceptibility to injury and contribute to a decline in kidney function. AKI, acute kidney injury; CKD, chronic kidney disease.

Frailty and CKD

Frailty disproportionately affects older adults. It is characterized by a reduced physiological capacity and an increased susceptibility to disease, leading to health complications such as falls, decreased quality of life (QoL), an increased need for health care services and mortality²⁹. Over 60 measures of frailty exist³⁰. The physical frailty phenotype (PFP) is a widely used tool in both nephrology and geriatrics²⁹. It consists of five indicators: decreased grip strength, decreased walking speed, unintentional weight loss, self-reported physical inactivity and self-reported exhaustion³¹, and has been reported to predict the likelihood of falls, hospitalization, and mortality among community-dwelling older adults³¹.

The risk of being classified as frail increases with decreasing GFR^32,33,34. Around 14% of patients with stage 1–4 CKD are classified as frail, as defined by the PFP — a prevalence that is more than twice that of older patients living in the community^32,35. The prevalence of frailty is even higher among patients on dialysis³⁶. Specifically, 71% of patients on dialysis over the age of 65 are classified as frail — a rate that is more than five times higher than that of the general population³⁷. At the time of kidney transplantation, 20% of patients are defined as frail, according to the PFP³⁸.

Frailty is associated with adverse outcomes in patients with CKD³⁹. Even in patients who are not on dialysis, frailty is associated with a higher risk of death or initiation of dialysis^35,40. Among patients on dialysis, frailty is a common issue and is associated with negative outcomes such as poor cognitive function⁴¹, increased risk of falls⁴², worse QoL⁴³, hospitalization^36,44,45 and death^36,46,47. The importance of measuring frailty in patients who are undergoing kidney transplantation is highlighted by the finding that frailty is associated with adverse outcomes in transplant recipients^{29,48,49,50,51,52}. For example, frailty at the time of transplantation increases the risk of complications such as delayed graft function, prolonged hospitalization, readmission, immunosuppression intolerance and death^{51,53,54,55,56,57,58,59}.

Pharmacokinetics

The pharmacokinetics of a drug is dependent on its absorption, distribution, metabolism and excretion. The presence of kidney dysfunction can alter the pharmacokinetics of many drugs. Unfortunately, assessments of drug pharmacokinetics in patients with CKD are generally limited to small studies that may not be representative of all patients, and often exclude patients on dialysis. Consequently, a fundamental understanding of pharmacokinetic principles is necessary to develop rational drug therapies for patients with kidney dysfunction⁶⁰.

For example, the blood concentration of hepatically metabolized drugs that are renally excreted may increase in patients with kidney dysfunction, increasing the risk of adverse effects. Accurate assessment of kidney function is therefore crucial in clinical settings. Ideally, kidney function should be assessed using measures of inulin clearance or CrCl, but in practice, creatinine-based estimated (e)GFR is often used. In older patients, the presence of sarcopenia can overestimate eGFR values, which may in turn result in medication overdosing⁶¹. Consequently, eGFR derived from cystatin C measurements and calculation of an individualized GFR that does not adjust for body surface area may be more relevant in these scenarios. Moreover, when prescribing medications, the selection of drugs that are either not renally excreted or have minimal renal excretion should be considered.

Treating CKD in older patients

CKD in older people should be diagnosed and treated as for other age groups, although some debate exists as to whether the diagnostic criteria for CKD should be the same as those used for young adults⁶². Low eGFR and high albuminuria are independently associated with mortality and progression to kidney failure, regardless of age^61,63,64. Thus, the primary goal of treatment in older patients with CKD should be to reduce the risk of cardiovascular events and prevent progression to kidney failure. Recognizing the paucity of randomized controlled trials (RCTs) specifically designed for older populations is essential. Consequentially, evidence regarding the efficacy and safety of treatments, particularly new medications, may not be directly applicable to older individuals.

In addition, frailty in older patients often requires modifications to treatment goals commonly prescribed for younger individuals with CKD. The presence of multiple comorbidities in older individuals requires a comprehensive, multidisciplinary approach to care and treatment⁶¹. Given the naturally shorter life expectancy of older CKD patients than of younger patients, the focus of treatment for very aged patients may shift from prolonging survival to improving QoL.

Pharmacological therapies

The conventional strategy for the management of non-dialysis-dependent CKD includes the control of blood pressure, blood glucose, lipids, anaemia, metabolic acidosis and bone–mineral metabolism. Here, we focus on established pharmacological therapies as well as emerging treatments for CKD.

Renin–angiotensin–aldosterone system inhibitors

The use of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) in managing cardiovascular outcomes in older patients with CKD has been the focus of much research. The ANBP2 study demonstrated that among 65–84-year-old patients with hypertension, ACE inhibitors outperformed diuretics, resulting in fewer adverse events and notably improved cardiovascular outcomes, especially in men⁶⁵. The HYVET trial further underscored the benefits of the ACE-I, perindopril, showing a significant reduction in heart failure events in patients over 80 years of age⁶⁶. In the SCOPE trial, which included individuals aged 70–89 years with systolic blood pressure of 160–179 mmHg and diastolic blood pressure of 90–99 mmHg, the ARB candesartan mitigated the risk of cardiovascular events by 11% in comparison with the placebo group⁶⁷. The CHARM-Alternative trial further found that candesartan significantly lowered the risk of death from sudden cardiac events or heart failure exacerbation in patients with symptomatic heart failure, particularly among those over 65 years of age⁶⁸. Furthermore, the ARB, olmesartan, effectively lowered blood pressure and was equally well tolerated in patients over 75 years of age compared with patients aged 65–74 years⁶⁹. Although these studies have not focused on patients with CKD, they offer essential perspectives on the effects of renin–angiotensin–aldosterone system (RAAS) blockers on cardiovascular outcomes in populations aged over 65 years.

Findings from clinical trials also indicate that ACE-Is and ARBs may decelerate the progression of CKD; however, it is crucial to recognize that most studies that have investigated the effects of these agents on long-term kidney outcomes have excluded participants over 70 years of age and did not establish effectiveness in patients with CKD and low levels of proteinuria^{70,71,72,73,74}. These findings raise important considerations for clinical practice, especially because an absence of proteinuria and a slow decline in eGFR (<2 ml/min per year), which is common among older individuals, often indicates a more benign course of kidney disease⁷⁵.

In patients with mild-to-moderate CKD, ACE-Is and ARBs may slow the decline in eGFR, decrease proteinuria and slow disease progression⁷⁶. However, there is little evidence that these agents are beneficial in patients with advanced CKD⁷⁶. A 2022 study found that discontinuing ACE-I or ARB therapy in patients with stage 4 and 5 CKD, with an average age of 73.3 ± 1.8 years, led to a slight improvement in eGFR⁷⁷. Similarly, a large Swedish cohort study found a reduced need for KRT following the cessation of RAAS blockade⁷⁸. However, it is critical to recognize that stopping these therapies was associated with a higher risk of mortality and major adverse cardiovascular events (MACEs)⁷⁸.

Current guidelines do not provide specific advice on the continuation or discontinuation of RAAS blockers in patients with advanced CKD. The randomized, controlled STOP ACEi Trial, which explored the consequences of discontinuing RAAS blocker therapy in 411 patients with stage 4–5 CKD, found no significant difference in renal function or rates of dialysis initiation between the groups after 3 years of follow-up⁷⁶, although a trend towards a reduction in dialysis initiation was evident in patients who continued treatment (HR 1.28; 95% CI 0.99–1.65). These findings held, even when the analyses were restricted to patients aged 65 years and older⁷⁶.

The development of hyperkalaemia should be carefully monitored in patients receiving RAAS blockers, as their use has been linked to decreased aldosterone action at the distal nephron²⁵. Older patients are also at a high risk of acute kidney injury (AKI) due to hypovolaemia because of their low fluid volume and limited renal blood flow, secondary to arteriosclerosis and other risk factors⁷⁹. Although caution has been advised when using diuretics or NSAIDs concurrently with ACE-Is or ARBs owing to a potentially increased risk of AKI^80,81, observational studies have shown that discontinuing or reducing the dose of ACE-I or ARB therapy following an episode of AKI or hyperkalaemia can lead to worsening heart failure, increased hospitalizations and progression to kidney failure^71,82,83,84. Thus, the decision to discontinue ACE-I or ARB therapy should not be taken lightly and requires careful consideration.

SGLT2 inhibitors

Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower blood glucose levels by blocking the reabsorption of filtered glucose and thereby increasing the amount excreted in urine. A wealth of RCTs have underscored the multifaceted benefits of SGLT2 inhibitors on heart failure outcomes, cardiovascular events, mortality, albuminuria onset and progression of CKD, leading to their swift recognition as a vital treatment, not only for diabetes but also for cardiovascular diseases and CKD^{85,86,87,88,89,90}.

Scrutiny of the cardiovascular outcomes of SGLT2 inhibitor trials has revealed consistent benefits across age demographics. A post hoc analysis of the EMPA-REG OUTCOME trial indicated no significant difference in cardiovascular or renal outcomes with empagliflozin treatment in adults aged above or below 65 years of age⁹¹. This pattern of consistent efficacy across age groups was also evident in the DECLARE-TIMI trial, where reductions in cardiovascular death or hospitalization associated with dapagliflozin use in patients with heart failure were uniformly observed across different age categories, including in those aged under 65, between 65 and 75, and over 75 years of age⁹². The DAPA-HF study further corroborated this trend⁸⁵, and a subsequent meta-analysis that categorized patients by age demonstrated uniform cardiovascular benefits of SGLT2 inhibitors across younger (<65 years) and older (>65 years) cohorts, with hazard ratios indicating no significant differences between these age groups⁹³. The safety and efficacy of dapagliflozin in older populations with CKD, including those considered frail or aged over 75 years, was further investigated in a post hoc analysis of the DAPA-CKD study⁹⁴. Findings revealed that dapagliflozin consistently diminished the risk of a primary composite end point encompassing renal outcomes, cardiovascular events and all-cause mortality across all degrees of frailty (mild, moderate or severe, as determined by the Rockwood cumulative deficit model). Notably, participants in the dapagliflozin cohort also encountered fewer serious adverse events than those receiving placebo⁹⁴. Similarly, a post hoc analysis of the VERTIS CV study that assessed cardiovascular and renal outcomes in over 900 adults aged 75 or older demonstrated that the risk–benefit profile of ertugliflozin in older patients aligned with that observed in younger cohorts⁹⁵. Moreover, a 2024 study from Taiwan demonstrated that initiation of SGLT2 inhibitors in patients with type 2 diabetes mellitus (T2DM) and advanced CKD (eGFR <20 ml/min/1.73m²) was safe and associated with significantly reduced risks of dialysis initiation, heart failure hospitalization, acute myocardial infarction, diabetic ketoacidosis and AKI compared with no SGLT2 inhibitor use⁹⁶. Of note, patients aged 65 years or older accounted for 38.5% and 45.4% of the 23,854 and 23,792 non-users and SGLT2 inhibitor users included in the analyses, respectively. These findings highlight the potential for SGLT2 inhibitors to provide important cardiorenal benefits, even in those with very advanced pre-dialysis kidney disease.

It is important to note that SGLT2 inhibitors have been linked to various adverse events, including fluid loss and sarcopenia⁹⁷. Emerging research suggests that SGLT2 inhibitors might influence muscle metabolism by increasing glucagon levels and reducing insulin secretion, which could contribute to muscle wasting⁹⁸. Indeed, observational studies and meta-analyses of patients with T2DM have reported a decrease in skeletal muscle mass with the use of SGLT2 inhibitors^99,100. However, the effects of SGLT2 inhibitors on skeletal muscle mass and function in older adults, regardless of diabetes status, are unclear. One randomized, double-blind, placebo-controlled trial of older Japanese patients with T2DM reported a decrease in body weight among participants receiving empagliflozin, but crucially found no significant difference in muscle mass or strength, grip strength, or performance in the five times sit-to-stand test compared with those who received placebo¹⁰¹. These findings suggest that SGLT2 inhibitors might not detrimentally impact muscle mass or strength in older patients with T2DM. However, it is important to note the study’s limitations, including its small sample size of 129 individuals, the exclusion of patients with low body mass index and the exclusion of patients with eGFR <45 ml/min/1.73 m² (refs. ^97,101).

Another prospective observational study evaluated the effects of empagliflozin on cognitive impairment in frail older patients aged over 65 with T2DM and heart failure with preserved ejection fraction. Despite the study’s brief, 1-month duration, improvements in cognitive function and 5-m walk speed were reported, indicating a possible advantage of empagliflozin in diminishing physical disability in this demographic¹⁰². Continuing efforts to gather real-world data, coupled with new evidence from high-quality RCTs, will be crucial to further understanding the benefits and mitigating any potential adverse effects of SGLT2 inhibitors on this vulnerable population.

GLP-1 receptor agonists

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are commonly used in the treatment of T2DM owing to their glucose-dependent stimulation of insulin¹⁰³. To date, seven injectable GLP-1RAs and one oral GLP-1RA have been evaluated in Cardiovascular Outcomes Trials. A 2021 meta-analysis that included eight trials involving 60,080 patients (median age 60–66 years) found that overall, GLP-1RAs reduced the risk of MACE by 14%, with no significant heterogeneity across different structural homologies or other examined subgroups; GLP-1RAs also reduced all-cause mortality by 12%, hospitalizations for heart failure by 11% and composite renal outcomes by 21%, with no increase in the risk of severe hypoglycaemia, retinopathy or pancreatic adverse effects¹⁰⁴. The randomized, controlled FLOW study directly compared the kidney and cardiovascular effects of weekly subcutaneous semaglutide with placebo in 3,533 patients adult patients with T2DM and CKD (mean age 66.6 ± 9.0 years; mean eGFR 47.0 ± 15.2)¹⁰⁵. After 3.4 years, semaglutide reduced the risk of major kidney events (kidney failure, ≥50% eGFR decline, kidney/CV death) by 24% compared with placebo (HR 0.76; 95% CI 0.66–0.88, P = 0.0003). It also lowered the risk of kidney outcomes (HR 0.79) and cardiovascular mortality (HR 0.71). eGFR decline slowed by 1.16 ml/min/1.73m² per year with semaglutide (P < 0.001). Serious adverse events were also less frequent with semaglutide (49.6% vs 53.8%)¹⁰⁵. These findings highlight the potential importance of GLP-1RAs in the treatment of CKD.

A post hoc analysis of the LEADER study — an RCT of liraglutide treatment in patients with T2DM and high cardiovascular risk of whom 66% were aged 60–74 years and 9% were aged ≥75 years — revealed that patients aged ≥75 years who received liraglutide experienced a 34% risk reduction in MACE and a 29% risk reduction in expanded MACE (defined as MACE, coronary revascularization, hospitalization for unstable angina pectoris or heart failure) compared with that of patients who received placebo. In addition, the risk of all-cause mortality in the liraglutide group was reduced by 35% in patients aged ≥75 years compared with a 6% reduction in patients aged 60–74 years¹⁰⁶. In a post hoc analysis of the SUSTAIN-6 trial, which randomly assigned 3,297 patients with T2DM — of whom 43% were aged 65 years or older — to receive semaglutide or placebo, found that once-weekly semaglutide treatment consistently reduced the risk of first occurrence of MACEs and components compared with placebo across all-age subgroups¹⁰⁷. These findings warrant a cautious interpretation for several reasons: the incidence of MACEs was relatively low in both the semaglutide (6.6%) and placebo (8.9%) groups, the follow-up duration was brief (2.1 years) and insufficient numbers of patients over 75 years of age did not permit subgroup analyses in this age group. Furthermore, the exploratory nature of these post hoc analyses hinders our ability to draw firm conclusions regarding the uniformity of clinical benefits in the very aged patient population¹⁰⁸. Despite these caveats, available data suggest that SGLT2 inhibitors and GLP-1RAs may be effective in reducing cardiovascular and renal endpoints, even when used in patients older than 65 years (Table 1).

Table 1 Effects of SGLT2 inhibitors and GLP-1RAs in older adults

Comparisons of SGLT-2is and GLP-1RAs

A number of studies have compared the efficacy of SGLT2 inhibitors and GLP-1RAs in managing T2DM. One US study that used propensity score matching of Medicare data to evaluate outcomes among 90,094 patients aged 66 years or older with T2DM who initiated treatment with either an SGLT2 inhibitor or a GLP-1RA found that patients treated with SGLT2 inhibitors had a similar risk of MACEs but a lower risk of hospitalizations for heart failure compared with those treated with GLP-1RAs. Importantly, the researchers observed a reduction of 7.1 AKI events per 1,000 person-years in the SGLT2 inhibitor cohort compared with the GLP-1RA cohort. However, the higher rates of diabetic ketoacidosis, leg amputations and genital tract infections observed in the SGLT2 inhibitor group warrant caution¹⁰⁹ (Fig. 3).

Fig. 3: Effectiveness and safety of SGLT2 inhibitors and GLP-1RAs in older adults with type 2 diabetes.

An analysis of Medicare data for 90,094 patients with type 2 diabetes mellitus aged ≥66 years old who received GLP-1 receptor agonists (GLP-1RA), or SGLT2 inhibitors (SGLT2-i) for a median follow-up of 6 months, demonstrated that the two drug classes were associated with a similar risk of major adverse cardiovascular events (MACE). However, SGLT2 inhibitors were associated with a lower risk of hospitalization for heart failure (HHF). Differences were also observed in the risk of secondary safety outcomes. AKI, acute kidney injury; DKA, diabetic ketoacidosis. The information presented in this table was compiled based on the findings from Patorno et al.¹⁰⁹.

Another study used Medicare data from 2013 to 2019 to evaluate the cardiovascular efficacy and safety of SGLT2 inhibitors, GLP-1RAs, and dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with T2DM, specifically examining the impact of varying levels of frailty using one-to-one propensity score matching stratified by frailty level. Compared with DPP-4 inhibitors, SGLT2 inhibitors and GLP-1RAs showed consistent benefits with a lower overall incidence rate of the primary cardiovascular effectiveness end point (a composite of acute myocardial infarction, ischaemic stroke, hospitalization for heart failure and all-cause mortality; hazard ratios of 0.72 for SGLT2 inhibitors versus DPP-4 inhibitors and 0.74 for GLP-1RAs versus DPP-4 inhibitors). Of note, absolute rate reductions were larger among frail participants and neither SGLT2 inhibitors nor GLP-1RAs were associated with an increased incidence of serious adverse events compared with that observed with DPP-4 inhibitors. Of note, the incidence rate difference (IRD) for the primary outcome between SGLT2 inhibitors and DPP-4 inhibitors was −6.74 for patients who were not considered to be frail and −27.24 for patients who were in a frail state (interaction P < 0.01). Similarly, a comparison of GLP-1RAs and DPP-4 inhibitors showed a large difference in the IRD, with an IRD of −7.02 for patients who were not considered to be frail and −25.88 for those who were frail (interaction P < 0.01)¹¹⁰.

In addition, a 2024 study reported on a two-cohort analysis comparing the effects of a combination of GLP-1RA and SGLT2 inhibitor versus single-agent use in patients with T2DM. Combination use of an SGLT2 inhibitor and a GLP-1RA had a 30% lower risk of major cardiovascular events and a 57% lower risk of serious renal events than use of a GLP-1RA alone. Also, compared with SGLT-2 inhibitors alone, combination therapy had a 29% lower risk of major cardiovascular events¹¹¹. Therefore, combination therapy may be actively considered in the future.

Hypoxia-inducible factor prolyl hydroxylase inhibitors

Approximately 15% of individuals >64 years of age and 30% of those >85 years of age are anaemic¹¹². Anaemia is also a common complication of CKD, affecting 8.4% of patients with stage 1 CKD and 53.4% of those with stage 5 CKD¹¹³. Anaemia is associated with an increased risk of cardiovascular events¹¹⁴ and mortality, and a decrease in QoL and functional capacity¹¹⁵. Management of anaemia is critical, not only because of its high prevalence and impact on systemic status but also because it is a treatable condition. However, despite observational studies consistently demonstrating a strong, inverse association between haemoglobin (Hb) levels and risk of mortality among patients on dialysis, interventional studies that have used recombinant human erythropoietin to raise Hb levels to near normal (>130 g/l) have reported increased mortality and cardiovascular events¹¹⁶, questioning whether anaemia does in fact directly contribute to the increased risk of mortality among patients with CKD¹¹⁷.

The efficacy of hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in improving Hb levels among patients with renal anaemia is well supported by clinical trial data^116,118. These small-molecule compounds are administered orally and offer advantages over other approaches; however, unresolved concerns about their long-term safety require further investigation¹¹⁸. For instance, detailed analyses of cardiovascular outcomes with HIF-PHI use in anaemic patients with CKD are needed as is assessment of potential cancer risks^118,119. In addition, the need for precise dosing to mitigate potential drug–drug interactions adds another layer of complexity to the care of patients with CKD, given that these patients are often older and have multiple comorbidities and extensive medication regimens¹¹⁶. Given these considerations and the perspective that any new treatment should surpass the current standard of care in terms of safety and efficacy¹¹⁶, it remains unclear whether HIF-PHIs will be universally beneficial in older patients with CKD.

Statins

High LDL cholesterol is a risk factor for coronary artery disease in adults, including older individuals^120,121. One large clinical trial in patients aged 70–82 years¹²² reported that statin use was associated with a 15% reduction in the risk of the primary end point (a composite of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke). However, a subgroup analysis showed no benefit of statin use in patients at a high risk of developing vascular disease but with no evidence of existing vascular disease (that is, primary prevention). More robust data are therefore needed determine whether statin therapy should be recommended for primary prevention in older individuals.

There is a paucity of studies on the effects of lipid-lowering therapies on kidney function decline in older patients with CKD. A review of studies in the database of controlled clinical trials in the Rosuvastatin Clinical Development Program reported an increase in eGFR from baseline with rosuvastatin that was largely comparable in subgroups aged <65 and >65 years of age¹²³. Based on available evidence, it seems that statin use should not be actively recommended at this time for CKD patients over 75 years of age without a history of coronary artery disease.

Polypharmacy

Polypharmacy, defined as the simultaneous use of five or more medications, can increase the risk of adverse drug events, increase the likelihood of medication errors, and pose challenges to medication adherence¹²⁴. The entity is particularly concerning when the negative effects of managing multiple medications outweigh their therapeutic benefits. Current estimates suggest that >200,000 people die annually in the USA owing to polypharmacy-related complications, and an additional 2.2 million people experience drug-related problems.

Polypharmacy is common in patients with CKD, with research showing that more than 70% of CKD patients are prescribed five or more medications¹²⁵. This trend is exacerbated in patients with stage 5 CKD on dialysis, who typically manage an average of 10–12 medications. The association between polypharmacy and frailty must also be acknowledged, as demonstrated by cross-sectional studies^126,127,128. Longitudinal studies of community-dwelling older adults have also found that frail individuals tend to have higher rates of polypharmacy-related complications¹²⁹. Conversely, other longitudinal studies have documented a high rate of frailty-associated complications among patients with polypharmacy^130,131,132, suggesting that polypharmacy itself may also contribute to an increased risk of frailty.

The process of deprescribing medicines is aimed at reducing polypharmacy and the use of potentially inappropriate medications in situations where the potential harms outweigh the benefits^125,133. A single-centre study of 240 outpatient haemodialysis (HD) patients demonstrated that use of a deprescribing tool for specific medications effectively reduced polypharmacy without compromising patient safety and satisfaction¹³⁴.

Drugs to be used with caution

The combination therapy of an NSAID, a diuretic, and an ACEI or ARB has been described as a ‘triple whammy’^135,136 and linked to an increased risk of AKI, particularly in older patients or those with pre-existing renal impairment¹³⁷. A 2013 case–control study reported that the risk of developing AKI increases 1.82-fold within 30 days of initiating triple therapy, suggesting that particular attention is needed during the early period of initiation of the regimen⁸¹. Subsequent studies have shown that the prevalence of AKI in hospitalized patients receiving this triple therapy regimen ranges from 0.9% to 22.0%, depending on the clinical setting and patient demographics^137,138.

Numerous case–control and cohort studies have reported an association between proton pump inhibitor (PPI) use and AKI, with one meta-analysis reporting a risk ratio of 1.44 (95% CI 1.08–1.91)¹³⁹. Of note, the median age of patients with PPI-associated AKI is 74–75 years^140,141. Moreover, a significant association between PPIs and CKD has also been reported¹³⁹.

However, it should be noted that case–control and cohort studies are observational and do not prove causality. PPI users are more likely than non-users to have comorbidities, which may not be accounted for in retrospective studies. PPIs are important therapies for the treatment of gastro-oesophageal reflux disease and they should be used in patients who need them. However, the decision to start and continue PPI use should be made in the light of various risks, including kidney disease, and the balance of risks and benefits should be considered. The importance of deprescribing is particularly relevant for medications such as NSAIDs and PPIs¹²⁵. Although we can expect to see more CKD drugs in the future, it is equally important that efforts be made to avoid adverse drug–drug reactions to improve patient outcomes.

Non-pharmacological therapies

The inclusion of non-pharmacological interventions in CKD management can complement pharmacological interventions. Non-pharmacological interventions may also aid the management of frailty and cognitive decline.

Exercise

Compared with older individuals with normal kidney function, older patients with CKD exhibit greater frailty and reduced lower extremity function^35,142. Both kidney function and activities of daily life are independently associated with mortality risk in older patients with CKD¹⁴³. Thus, exercise has been posited as a potentially beneficial intervention to enhance physical function, activities of daily life and QoL, and potentially prolong life expectancy for older patients with CKD. Historically, exercise research in the CKD population primarily focused on individuals undergoing HD and kidney transplant recipients. However, studies over the past decade have increasingly included patients with earlier stage CKD, although an insufficient number of these have focused on the older population¹⁴⁴.

Exercise interventions in patients with non-dialysis-dependent CKD have typically involved aerobic and resistance training. Small-scale RCTs have demonstrated that resistance training can improve muscle strength and mass without negatively affecting kidney function^{145,146,147,148}. Similarly, programmes that combine aerobic and resistance exercise have demonstrated improvements in muscle strength, mass and exercise tolerance, again without detrimental effects on kidney health^{149,150,151,152,153,154}. Moreover, a study of 6,363 patients with CKD stages 3–5 (mean age of 70 years) conducted in China reported that walking as a primary form of exercise was associated with lower mortality (2.7 versus 5.4 per 100 person-years) and reduced KRT initiation (22 versus 32.9 per 100 person-years) compared with that of individuals who did not engage with walking over a mean follow-up of 1.3 years¹⁵⁵. These findings are in line with those from the LIFE trial, an RCT across eight academic centres in the USA that aimed to assess the impact of exercise on CKD progression among community-dwelling individuals aged 70–89 years at enrolment. Participants were sedentary, exhibited low physical performance scores, were able to walk 400 m without assistance, and showed no signs of cognitive impairment. Those in the intervention group participated in moderate-intensity physical activity for 2 years and exhibited a slower decline in eGFR than participants in the control, ‘health education’ group, with a mean difference in eGFR of 0.96 ml/min/1.73 m² over the 2 years¹⁵⁶.

These findings and others support the recognition of exercise as a legitimate, non-pharmacological intervention for older patients with CKD. Ideally, exercise regimens should be tailored to individual patients following a comprehensive cardiovascular risk assessment. Furthermore, a multidisciplinary approach and ongoing encouragement are essential to optimize the therapeutic advantages of exercise for these patients. However, further research is needed to identify approaches to overcoming barriers to exercise.

Nutritional therapy

The European Society for Clinical Nutrition and Metabolism and The National Resource Center on Nutrition and Aging recommend that healthy adults aged ≥65 years have a daily protein intake of 1.0–1.2 g/kg body weight. A higher protein intake of 1.2–1.5 g/kg per day is recommended for individuals who are malnourished or at risk of malnutrition^157,158,159. However, patients with CKD are typically encouraged to maintain a low-protein diet. A re-analysis of the MDRD trial showed that a low-protein diet (0.58 g/kg per day) combined with low phosphorus intake reduced the risk of GFR decline by 10% over 3 years compared with a higher-protein (1.3 g/kg per day) diet^160,161. Findings from small RCTs and a 2018 meta-analysis also suggest that low-protein diets may have renoprotective effects in patients with CKD^63,162.

Both animal and clinical studies have associated low dietary protein with reduced intraglomerular pressure and vasoconstriction-induced damage in glomerular afferent arterioles. By contrast, high-protein diets may lead to glomerular hyperfiltration and worsen CKD progression¹⁶³. However, low-protein diets risk contributing to sarcopenia and protein-energy wasting (PEW), especially in older patients with CKD^164,165. A large-scale, observational, multicentre, prospective study that evaluated the effect of dietary protein intake on CKD progression and the risk of PEW in 1,572 patients with non-dialysis-dependent CKD reported that dietary protein intake was not a major determinant of CKD progression, defined as a greater than 50% decrease in eGFR, doubling of serum creatinine or initiation of dialysis. Rather, the findings suggested that an association between reduced dietary protein and PEW may be a more important predictor of CKD progression¹⁶⁶. These findings, together with an appreciation of the need for sufficient protein consumption to counteract age-related muscle catabolism^167,168, highlight the importance of ensuring adequate protein intake to prevent PEW.

Of note, the risk of death is a more important concern than the risk of progression to kidney failure in older patients. For example, a large cohort study of ~200,000 patients with stage G3 to G5 CKD in the USA reported that the risk of death over a mean follow-up of 3.2 years was consistently higher than that of kidney failure, especially in those older than 85 years of age¹⁶⁹. Similarly, a cohort study of 461 patients with stage G3 to G5 CKD in Japan with a mean follow-up of 3.2 years reported that age was a decisive factor in mortality. None of the patients aged >65 years who had stage G3 CKD and no urinary protein at baseline progressed to kidney failure during follow-up¹⁷⁰. Based on these findings, a uniform approach to protein restriction in older CKD patients must be reconsidered, albeit with consideration of eGFR and the extent of urinary protein.

One way to harness the potential renoprotective benefits of a low-protein diet while minimizing the risk of PEW might be through dietary supplementation with essential amino acids^{171,172,173,174}. Combined supplementation with keto acid analogues and essential amino acids has been reported to stabilize or improve serum albumin levels, decrease proteinuria, reduce the progression of CKD (including in patients in their 60s), with only slight changes in lean body mass and fat mass over time^{173,174,175,176,177,178}. An RCT of non-diabetic, uraemic patients over 70 years of age with a GFR of 5–7 ml/min reported that adherence to an ultra-low protein diet (0.3 g/kg per day protein) supplemented with keto acid analogues, essential amino acids and vitamins delayed initiation of dialysis by approximately 11 months, with no effect on mortality¹⁷⁹. Meta-analyses published in the past few years have also reported the efficacy and safety of low-protein-supplemented diets^180,181. Of note, any low-protein diet must still provide adequate energy intake, and reducing animal protein intake in favour of a diet rich in plant-based proteins should be considered as a potential approach to maintaining healthy blood pressure and body mass index, while lowering levels of triglycerides and inflammatory markers^{165,182,183,184,185}.

Thus, available evidence underscores the importance of a nuanced approach to dietary management in older patients with CKD. Balanced nutritional strategies might support overall health and delay disease progression; however, individual nutritional needs and the potential limitations of such diets must also be considered.

Dialysis

As described earlier, the global aging population is expected to contribute to the increasing number of patients with kidney failure. According to the United States Renal Data System (USRDS) annual report, the number of newly registered cases of kidney failure in the USA rose 37.8% from 2001 to 2019, to 134,837, although the adjusted incidence rate fell 8.9%¹⁸⁶. In 2021, incidence rates of kidney failure per million population (pmp) were 12 (for individuals aged 0–17 years), 115 (for those aged 18–44 years), 593 (for those aged 45–64 years), 1,219 (for those aged 65–74 years) and 1,581 (for those aged 75 years or older)¹⁸⁶. Additionally, in 2021, the number of patients initiating dialysis therapy was 746 (for those aged 0−17 years), 14,992 (for those aged 18–44 years), 47,801 (for those aged 45–64 years), 36,329 (for those aged 65–74 years) and 31,194 (for those aged 75 years or older)¹⁸⁶. In Asia, the impact of an aging population on KRT incidence is particularly notable in countries such as Japan and Taiwan. In Japan, among the 25,785 men and 11,254 women who started dialysis therapy in 2022, 72.4% of men and 77.8% of women were over 65 years old¹⁸⁷. In Taiwan, KRT incidence rates pmp were 97 (for those aged 20–44 years), 530 (for those aged 45–64 years), 1,583 (for those aged 65–74 years) and 2,858 (for those aged 75 years or older)⁶¹. The higher rates of kidney failure and KRT among older ages suggest that the aging population is driving the increases⁶¹. These findings contrast with those of an Australian study that reported a sharp decrease in the rate of dialysis with advancing age, such that only 4% of patients with kidney failure aged 85 and older received KRT¹⁸⁸. In line with those findings, 2014 data from Japan showed that 22.1% of female patients with kidney failure aged 85–89 years and >60% of male and female patients over 90 years of age, died without initiating dialysis therapy¹⁸⁹. These findings suggest that practices for the initiation of dialysis in older individuals vary widely, and highlight a need to carefully weigh the benefits and potential impact of dialysis at the level of the individual patient.

Although dialysis can prolong life for many individuals, its initiation can be physically and psychologically straining. Many individuals find the transition to dialysis daunting and anxiety inducing^190,191. The adverse effects of dialysis, including drops in blood pressure, muscle cramps and reduced urine output, can be distressing. Fatigue and decreased social engagement due to thrice-weekly dialysis sessions can further contribute to diminished well-being¹⁹² and QoL¹⁹³. Older patients, particularly those starting dialysis at age 80 or older, also often experience a swift loss of independence¹⁹⁴. Thus, care is needed to avoid physical and psychological harm.

The circumstances under which dialysis is discontinued also requires careful consideration. According to USRDS data, discontinuation of dialysis accounted for 16.1% of all deaths among patients with kidney failure in 2021, rendering discontinuation the third most common cause of death among patients on dialysis, after cardiovascular and infectious diseases¹⁹⁵. A meta-analysis of studies from six countries reported an increase in mortality preceded by dialysis withdrawal from 3 per 1,000 patients per year in 1966 to 48.6 per 1,000 patients per year in 2010 (ref. ¹⁹⁶). These statistics potentially reflect the increased recognition of the value of palliative care and a growing recognition of the need to balance the benefits of dialysis with considerations of patient welfare and QoL.

Dialysis and life expectancy

Older patients on dialysis often have a shorter life expectancy than younger individuals, primarily due to a higher prevalence of comorbidities, such as cardiovascular disease and multiorgan failure^197,198. The Dialysis Outcomes and Practice Patterns Study, has shown that the high mortality of patients within 3–6 months of HD initiation is predominantly driven by patients aged 65 and older (with 40 deaths per 100 person-years)¹⁹⁹. Similarly, 2017 USRDS data reported a mortality rate among patients aged 65 and above of 30%²⁰⁰. Moreover, the adjusted mortality of patients on dialysis over 75 years of age is four-fold higher than that of an age-matched, non-dialysis population²⁰¹, and the rates of hospitalization, intensive care and deaths in the intensive care unit are much higher than those of non-dialysis patients with similar life-threatening diseases such as cancer and congestive heart failure^190,202.

Despite these adverse outcomes, it is important to note that the benefits of KRT can extend beyond the prolongation of life and, in some cases, enable patients to maintain a more fulfilling life. Therefore, withholding KRT solely on the basis of age is ethically indefensible and detrimental to the preservation of human dignity.

Survival data concerning older patients receiving KRT in low-income and middle-income countries are limited. In a cohort study of patients who initiated KRT (primarily HD) in South Africa between 2013 and 2018 (of whom 1,866 (20.1%) were aged 65 years or older), overall 1-year survival was 86.4%, which is comparable with that of countries such as the UK (79%) and the USA (81%)²⁰³. However, survival was inversely associated with age. Compared with patients aged 65–69 years, those aged 80–84 years had a 72% higher risk of mortality (HR 1.72; 95% CI 1.14–2.60), and the risk was increased further for those aged 85 years or older (HR 2.42; 1.41–4.14)²⁰³.

Haemodialysis versus peritoneal dialysis

When comparing outcomes associated with HD versus PD use in older patients it is important to understand the global variations in the prevalence of these modalities (Table 2). HD is the predominant form of dialysis worldwide. An estimated 323 individuals pmp receive maintenance dialysis, compared with 21 pmp worldwide for PD; however, these numbers vary widely between countries and regions, largely because of regional income levels and government policies^204,205.

Table 2 Comparison of haemodialysis and peritoneal dialysis

PD is often favoured in general over HD for its ability to preserve residual renal function and because it is less physically taxing²⁰⁶. A study that analysed 7,771 patients undergoing HD and PD from six countries found that patients on PD reported a lower disease burden score than patients on HD when assessed using the Kidney Disease Quality of Life questionnaire, with the burden remaining stable over 12 months. Notably, these favourable outcomes with PD were particularly evident in older adults^192,207.

PD is typically administered as a home-based treatment²⁰⁸, which is often considered an advantage for older patients. However, three observational cohort studies that focused on patients aged 60 years and older found no significant difference in QoL between patients on PD and those on HD. These findings suggest that the choice of dialysis modality might not substantially affect overall QoL of older individuals^209,210,211; however, the conclusions that can be drawn from these studies are limited by their observational and prospective nature.

No RCTs have directly compared survival outcomes between HD and PD in older patients. According to USRDS data, 5-year survival rates for individuals aged 75 years or older in the 2017 cohort were not significantly different (21.5% for HD and 20.5% for PD)¹⁸⁶. However, two meta-analyses of studies on older patients (defined as ≥56 years and ≥60 years, respectively) reported higher mortality with PD than with HD (HR 1.10, 95% CI 1.01–1.20 and HR 1.17, 95% CI 1.10–1.25, respectively). Both studies urged that caution should be exercised with regard to the long-term use of PD in older patients with kidney failure; however, neither study claimed the superiority of one modality over the other^212,213. A further study that examined the risk factors associated with early mortality after dialysis initiation (n = 1,580 patients, median age of patients on PD 66.3 years compared with 67.3 years for patients on HD; follow-up 12 months or until renal transplantation)²¹⁴ found that the short-term outcomes of PD and in-centre HD were similar among patients who had free choice of treatment. Thus, available comparative data on PD and HD are not entirely clear, highlighting the need for a balanced approach when selecting an appropriate dialysis modality for older patients that considers patient-specific health status and individual preferences.

Dialysis and cognitive function

CKD is an independent risk factor for cognitive dysfunction²¹⁵. Cognitive changes in the setting of CKD can reduce the ability of a patient to make autonomous medical decisions and can influence advance care planning, including the introduction of dialysis¹⁹². A Canadian cohort study of 385 patients with CKD stages 4 and 5 (mean age 68 years), reported that 61% of patients had undiagnosed cognitive impairment²¹⁶. Dialysis Outcomes and Practice Patterns Study findings have reported that rates of dialysis initiation among patients with dementia in European countries are lower than those of Japan and the USA²¹⁷. Although the reasons for these differences are unclear, one contributing factor could be differences in the way the medical team engage with patients who may be unable to make informed decisions about dialysis treatment.

A pressing need exists to identify strategies to prevent cognitive decline and support decision making in patients with cognitive impairment. The FINGER study demonstrated that lifestyle interventions markedly improved cognitive function in participants at risk of dementia²¹⁸. Active treatment of hypertension is recommended to reduce the risk of developing dementia in individuals aged 45–65 years and in those aged >65 years without dementia. In addition, interventions targeting other risk factors, such as increased access to education in childhood, regular exercise, maintained social engagement, reducing smoking, and managing hearing loss, depression, diabetes and obesity, might have the potential to delay or prevent one-third of dementia cases. These interventions might also have benefits for patients with CKD²¹⁹. These considerations are particularly relevant for older patients with CKD, and suggest that the proactive implementation of such interventions may bolster efforts to prevent dementia.

Patients with kidney failure often have reduced cerebral oxygen supply as a consequence of anaemia, despite increased cerebral perfusion at rest²²⁰. Moreover, HD-associated changes in blood pressure, serum osmolality and acid–base balance pose additional challenges for cerebral blood flow regulation²²⁰, prompting the suggestion that HD itself may detrimentally affect cognitive function. In support of this proposal, findings from observational studies^221,222 and meta-analyses^223,224 indicate that cognitive decline is less prevalent among patients undergoing PD compared with those receiving HD, although treatment selection bias must again be considered as a confounder. In addition to the effect of dialysis modalities on cognitive status, the impact of CKD-specific pathologies, such as uraemia-associated oxidative stress on vascular reactivity, cerebrovascular dysregulation and the development of dementia, requires further investigation^220,225.

Transplantation

Currently, over 90,000 people are on the waiting list for a kidney transplant in the USA. Notably, ~26% of waiting list candidates are over 65 years of age²²⁶. Available evidence indicates that kidney transplantation can provide an additional 4 years of life for recipients over 60 years of age^227,228. Transplantation offers significant advantages over dialysis even in older patients (Box 1), and it is therefore imperative that the accessibility of kidney transplantation is increased across all age groups.

Further research into the feasibility of using organs from older living donors and the evaluation of outcomes with organs from older deceased donors is needed²²⁶. In 2014, only 2.8% of living kidney donors in the USA were 65 years of age or older²²⁹. A comparison of long-term outcomes of 167 living kidney donors reported that donors aged 60 years or older at the time of donation had a higher risk of hypertension over 20 years of follow-up than donors who were younger than 60 at the time of donation; however, surgery could be performed safely, and the long-term risk of kidney failure was shown to be low and comparable with that of donors younger than 60 years²³⁰. This finding suggests that under appropriate selection criteria, kidney transplantation from donors over the age of 60 is safe and may help to expand the donor pool.

For older kidney transplant candidates who do not have a viable living donor, non-standard deceased donor organs should be considered because transplantation with a non-standard deceased donor kidney provides a significant survival advantage over dialysis, even in older recipients²³¹. As described earlier, frailty should be assessed in patients who are undergoing kidney transplantation, as frailty is associated with adverse outcomes in transplant recipients^{29,48,49,50,51,52}. Of note, research has also shown that patients may become frail during the first month after kidney transplantation. However, by 3 months post-transplantation, frailty has been shown to improve compared with pre-transplantation measures; it is also noteworthy that frailty may be reduced after kidney transplantation^29,232. A collaborative approach is therefore needed when considering transplantation for older patients with kidney failure. The involvement of older patients and their families in the decision-making process enables a thorough evaluation of the risks and potential outcomes associated with various transplant options, ensuring that these decisions are in harmony with the patient’s personal values and goals²²⁶.

Box 1 Benefits of kidney transplantation in older patients

• Extended life expectancy compared with remaining on dialysis.

• Improved survival rates over dialysis, particularly for patients over 60 years of age.

• Potential to adapt surgical care and immunosuppressive treatment to suit older patients.

• Transplants from older donors, including those aged 60 and above, are often viable.

• Options are available to use non-standard deceased donor organs, thereby increasing the donor pool.

Conservative kidney management

Some patients with kidney failure — particularly those whose survival and QoL do not improve with dialysis — may choose to forego or discontinue dialysis as part of their end-of-life care. In such cases, a holistic approach known as conservative kidney management (CKM) becomes crucial. CKM is a patient-centred strategy aimed at minimizing complications, managing symptoms and facilitating advance care planning to achieve the treatment goals and wishes of the patient. As well as providing psychological and social support to the patient, CKM is also aimed at educating, involving and supporting the patient’s family and caregivers²³³ (Fig. 4).

Fig. 4: Conservative kidney management CKD treatment.

As chronic kidney disease (CKD) progresses, decisions regarding conservative kidney management (CKM) should be centred on the needs and wishes of the patient. The success of CKM hinges on a collaborative decision-making process through the engagement of a multidisciplinary health care team. It is important to recognize that the expected lifespan of patients opting for CKM varies substantially and is largely dependent on the patient’s remaining kidney function. Assessing a patient’s distress necessitates a comprehensive approach that accounts for physical, psychological, social, and spiritual dimensions. Owing to the potential for rapid symptom progression, vigilant daily assessment and management are imperative. Patients may decide to discontinue dialysis treatment after initially choosing it. In these scenarios, the emphasis on patient-centred shared decision making remains of paramount importance. This principle equally applies to the family members involved. The involvement of a broad spectrum of professionals, including but not limited to health care providers and social workers, is anticipated in this process. To foster the development and progress of CKM it is essential to establish a system for aggregating data on the patient undergoing CKM to facilitate the generation of scientific data, and aid our understanding of medical, ethical and social issues. Additionally, insights obtained from continued research should feed into consensus guidelines that are integrated into clinical practice, fostering a cycle of continuous enhancement and application.

A 2021 systematic review found that although CKM was associated with shorter survival among patients with stage 5 CKD than among patients on dialysis, the survival benefit of dialysis was lost in patients older than 80 years of age and in older patients with comorbidities. Moreover, CKM was associated with benefits over dialysis in terms of QoL, symptom burden, hospitalization rates and place of death²³⁴. Of note, predicted outcomes associated with discontinuation of dialysis differ substantially from those associated with adherence to CKM. Therefore, CKM should be implemented as soon as a decision to withhold or discontinue dialysis has been made, rather than leaving patients without care. CKM may also be considered as a treatment option for patients with stage 5 CKD; the decision to implement a CKM approach rather than initiate dialysis should involve shared decision making, patient-centred care and active management of symptoms, and be aimed at improving QoL through advance care planning^235,236. The palliative care component of CKM includes approaches to addressing physical distress — including pain, fatigue and sleep disturbance, uraemic pruritus, nausea and vomiting, restless legs syndrome, dyspnoea, constipation, and oedema; and psychological distress — including depression, anxiety and delirium, as well as anger, irritability and loneliness. This approach requires consideration of whether the causes of these symptoms can be remedied, and it is important to collaborate with psychiatrists and psychosomatic physicians to ensure that psychiatric symptoms are managed appropriately. Social distress can be triggered by issues at home or work, or by issues relating to finances, relationships or legacy, or by spiritual pain. Such distress should be addressed in collaboration with social workers and relevant individuals. The patient’s family and/or caregivers should be involved throughout the care pathway, including diagnosis, initiation and maintenance of dialysis if relevant, consideration and implementation of CKM, and end-of-life care.

A systematic review of cohort studies that documented the survival, QoL, and use of health care resources in 5,102 patients with advanced CKD who decided to forgo maintenance dialysis (5–99% men; mean age range 60–87 years)²³⁷ found that only 12 of the 41 studies described patients in formal, conservative care programs with dedicated staff and clinicians trained in palliative care²³⁸. The remaining studies described patients in the usual nephrology care setting or did not specify a conservative care approach. 34 of the studies (3,754 patients) provided data on median survival, which ranged from 1 month to 41 months for patients with a baseline mean eGFR of 7–19 ml/min/1.73 m². Younger cohorts aged 70–79 years had a median survival of 7–41 months, whereas cohorts aged 80 years or older had a shorter median survival of 1–37 months, despite overlapping eGFR ranges. Patients managed in dedicated care pathways had a median survival of 1–27 months, compared with 1–39 months for those in usual nephrology care settings. Eight studies (500 patients) that described QoL during follow-up from 8 to 24 months found that mental well-being improved with time, whereas physical and overall QoL remained stable until late in the disease course. 14 studies (1,709 patients) provided information on end-of-life care, demonstrating wide variation in rates of hospice enrolment (20–76%), final-month hospitalization (57–76%), in-hospital death (27–68%) and home death (12–71%). One study found that 47% of decedents received intensive procedures such as surgery or mechanical ventilation in the final month, whereas another large study reported that only 4% of patients received intensive measures such as mechanical ventilation.

These findings highlight the variability in CKM uptake and in patient outcomes and emphasize the need to further develop and promote best practices in CKM, while recognizing the variation in health care delivery systems worldwide. Furthermore, CKM should be recognized as a viable treatment option, not only for patients with non-dialysis-dependent CKD or those on dialysis but also for transplant recipients with declining graft function²³⁹. In Asia, Taiwan has developed palliative care guidelines for kidney failure²⁴⁰. Japan has also now published a guide based on the recommendations of a public research group to aid decision-making processes for initiating and discontinuing dialysis, as well as a methodology for palliative care²⁴¹.

Digital medicine

The growing health care needs of the aging population might not be adequately addressed by traditional clinic-based approaches. Digital technologies are expected to enable convenient and continuous telemedicine, and may facilitate the more effective management of CKD²⁴². For example, technologies for wearable sensors have advanced rapidly, enabling the measurement of physical and chemical signals, such as physical activity, blood glucose and blood pressure²⁴³. Continuous, real-time monitoring of these and other parameters may enable more rapid feedback and adjustment of interventions.

Other technologies, such as virtual reality, may be used by patients to enhance overall fitness through exergaming (that is, the merging of exercise with video gaming) as well as to aid specific treatment programmes, such as cardiac or neurological rehabilitation, or to manage musculoskeletal disorders²⁴⁴. However, the integration of digital technology into management programs for older adults with CKD presents several challenges, including gaps in digital literacy, concerns over privacy and security, and issues with the performance of devices. Therefore, although digital technologies offer considerable potential for CKD management, it is crucial to address barriers to their use to ensure their effectiveness and accessibility for the older population²⁴².

Conclusions

Managing CKD within an expanding population of older patients is complex but is of utmost importance given the expected increase in CKD prevalence. The intricacies of age-related changes in kidney function, combined with various comorbidities and distinctive needs of the older population, call for a comprehensive treatment approach. Vital components of this approach encompass innovative pharmacological treatments with established efficacy and safety, such as SGLT2 inhibitors and GLP-1RAs, along with non-pharmacological interventions such as dietary adjustments and exercise therapy. The limited evidence supporting these treatments in older patients primarily stems from the scarcity of high-quality RCTs conducted in this population. Potential solutions to this lack of data must be explored through the design of RCTs with rigorous ethical considerations and real-world data analysis.

As in the management of younger patients, older patients who progress to kidney failure require a thorough evaluation of all potential treatment options, including HD, PD, kidney transplantation and CKM. It is critical to honour the patient’s autonomy and tailor each treatment plan to the individual, considering both the physical impact of the treatment and their social circumstances. Therefore, a blend of medical advancements and a compassionate, holistic approach to health care is essential. The development of new therapies and the extensive integration of digital technology into medical care hold promise in providing fundamental treatments for age-related diseases. These areas are of great scientific interest and have great potential to provide considerable benefits from advances in research.