Frailty in end-stage kidney disease: A multidimensional approach to risk stratification and personalized care

Literature search strategy

For this narrative review, we conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases from January 2015 to May 2025. Search terms included combinations of “frailty,” “end-stage kidney disease,” “chronic kidney disease,” “dialysis,” “hemodialysis (HD),” “peritoneal dialysis,” “kidney transplantation,” “assessment,” “outcomes,” and “interventions.” We prioritized peer-reviewed articles published in English, including systematic reviews, meta-analyses, randomized controlled trials (RCTs), observational studies, and relevant clinical practice guidelines. Additional articles were identified through reference lists of selected publications and recent nephrology conference proceedings.

Selection criteria

Articles were selected based on relevance to the following key domains: (1) Definition and pathophysiology of frailty in ESKD, (2) frailty assessment tools validated in kidney disease populations, (3) impact of frailty on clinical outcomes, (4) comparative studies of frailty across renal replacement modalities, (5) interventions targeting frailty in ESKD, and (6) implementation strategies for resource-limited settings. We prioritized studies with larger sample sizes, longer follow-up periods, and methodological rigor. Case reports and small case series were excluded unless they provided unique insights not available from larger studies.

Data extraction and synthesis

From each selected article, we extracted information on study design, population characteristics, frailty definition and assessment methods, key findings, and limitations. Data were synthesized narratively by thematic domain, with particular attention to consistency of findings across studies and applicability to clinical practice. Where available, we highlighted evidence specific to different ESKD subpopulations, including elderly patients, those with diabetes, and patients in low-resource settings.

Defining frailty in ESKD: controversies and consensus

The most widely used operational definition of frailty in nephrology research is the Fried Frailty phenotype (FFP), which identifies frailty based on the presence of three or more of five physical components: Slowness (measured by gait speed), weakness (measured by grip strength), unintentional weight loss, self-reported exhaustion, and low physical activity.^[1] Alternative conceptualizations include the deficit accumulation model (Frailty Index fi) and the clinical frailty scale (CFS).^[11,12]

A significant controversy in the field centers on whether generic frailty tools developed in geriatric populations are appropriate for ESKD patients, or whether kidney disease-specific adaptations are necessary. The Fried criteria, while extensively validated, may not fully capture the unique aspects of frailty in ESKD, such as dialysis-related fatigue, vascular access issues, and fluid shifts.^[13] Some researchers advocate for ESKD-specific tools that incorporate disease-specific elements, while others argue that maintaining standardized definitions enables cross-population comparisons.^[14]

Another area of debate concerns the dimensional structure of frailty in ESKD-whether it represents primarily a physical phenotype or a broader multidimensional construct encompassing cognitive, psychological, and social domains. The physical frailty phenotype dominates research in nephrology, but growing evidence suggests that cognitive impairment and psychological factors significantly contribute to adverse outcomes in this population.^[15]

It is important to distinguish frailty from related but distinct concepts such as comorbidity, disability, and sarcopenia. While these conditions frequently coexist with frailty in ESKD patients, frailty represents a unique physiologic state not fully explained by specific diseases, functional limitations, or muscle wasting alone.^[16]

Prevalence and risk factors

The prevalence of frailty in ESKD far exceeds that of the general population. While community-dwelling older adults exhibit frailty prevalence rates of approximately 2.8–10%, studies in ESKD populations report rates ranging from 20.9% in advanced chronic kidney disease (CKD) to 41–70% in dialysis-dependent patients.^[17,18] Joseph et al., found that 41% of CKD stage 5 patients met criteria for frailty, with similar prevalence between those on HD (43%) and those receiving pre-dialysis care (40%).^[19]

Certain subgroups demonstrate particularly high frailty burden. Among ESKD patients over 55 years of age, frailty prevalence reaches 82%, while diabetic ESKD patients show rates of approximately 75%.^[19] Other factors associated with increased frailty risk include female sex, lower socioeconomic status, and higher comorbidity burden.^[20,21]

Pathophysiologic mechanisms: An integrated model

The pathophysiology of frailty in ESKD involves complex interactions between kidney disease-specific factors and aging-related processes [Figure 1]. We propose an integrated conceptual model where uremia serves as the central driver, initiating and amplifying multiple pathophysiologic pathways that converge to produce the frailty phenotype:

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Figure 1:

Pathophysiology of frailty in end-stage kidney disease. PT: Physical therapy, OT: Occupational therapy.

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1. Protein-energy wasting: Affecting 20–50% of dialysis patients through inadequate nutrient intake, dialysis-related protein losses, metabolic acidosis, and inflammation-induced hypercatabolism.^[22] This pathway directly contributes to muscle wasting, weakness, and fatigue-core components of the frailty phenotype.

2. Chronic inflammation: ESKD creates a persistent pro-inflammatory state characterized by elevated levels of interleukin (IL-6), tumor necrosis factor-α, and C-reactive protein.^[23] This inflammatory milieu promotes muscle catabolism, anorexia, and endothelial dysfunction. Importantly, inflammation serves as a central mediator connecting multiple pathophysiologic pathways, amplifying the effects of protein-energy wasting, cardiovascular dysfunction, and cellular senescence.

3. Endocrine dysregulation: Kidney disease disrupts multiple endocrine pathways relevant to frailty pathogenesis, including resistance to anabolic hormones (insulin, insulin-like growth factor-1), vitamin D deficiency, secondary hyperparathyroidism, and dysregulated adipokine production.^[24] These endocrine abnormalities promote sarcopenia, bone fragility, and metabolic dysfunction.

4. Cardiovascular dysfunction: The high prevalence of cardiovascular disease in ESKD contributes to frailty through reduced cardiac output, impaired peripheral oxygen delivery, and exercise intolerance.^[25] Volume shifts during HD may further compromise hemodynamic stability, with intradialytic hypotension showing a significant association with frailty (P = 0.002).^[19]

5. Accelerated aging processes: ESKD is characterized by accelerated cellular senescence, telomere shortening, and epigenetic changes that mirror physiologic aging.^[4] These processes affect multiple organ systems and contribute to the global decrease in physiologic reserve that defines frailty.

Our integrated model proposes that these pathways do not operate in isolation but rather form a complex network of bidirectional interactions. For example, inflammation promotes protein-energy wasting, which further exacerbates inflammation; cardiovascular dysfunction limits physical activity, contributing to muscle deconditioning; and cellular senescence amplifies inflammatory processes. This network of interactions creates multiple self-reinforcing cycles that accelerate frailty progression in ESKD patients.

The model also highlights potential intervention targets at multiple levels: Nutritional support to address protein-energy wasting, anti-inflammatory strategies, hormone replacement, cardiovascular optimization, and senolytic approaches targeting cellular aging processes. The complexity of these interactions underscores the need for multimodal interventions addressing multiple pathways simultaneously.

Summary of assessment tools

Multiple validated instruments are available for frailty assessment in ESKD populations, each with distinct advantages and limitations. Performance-based tools like the Fried frailty phenotype (FFP) and short physical performance battery (SPPB) offer objective measurements but require equipment and time. Clinical judgment scales such as the clinical frailty scale (CFS) provide rapid assessment with minimal resources. Comprehensive instruments like the frailty index (FI) and Edmonton frail scale capture multidimensional aspects of frailty but demand more extensive evaluation. Self-report questionnaires like the Strength, Assistance with walking, Rising from a chair, Climbing stairs, and Falls (SARC-F) enable screening with minimal staff involvement. The choice of assessment tool should be guided by the clinical context, available resources, and intended purpose—either for research, comprehensive clinical evaluation, or rapid screening. Figure 2 provides a visual comparison of these major assessment tools, highlighting their key components, administration time, and resource requirements to facilitate selection of the most appropriate instrument for specific clinical settings.

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Figure 2:

Assessment tools for frailty in end-stage kidney disease. ESKD: End stage kidney disease, SARC-F: Strength, assistance with walking, rising from a chair, climbing stairs, and falls.

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Short physical performance battery (SPPB)

The SPPB assesses lower extremity function through gait speed, chair stand, and balance tests.^[34] SPPB scores correlate with frailty status and predict adverse outcomes in ESKD, with scores <7 associated with significantly higher mortality risk (HR 2.46, 95% CI 1.72–3.52).^[35]

Table 1 summarizes the comparative performance of major frailty assessment tools in ESKD populations.

Mortality

Frailty consistently demonstrates strong and independent associations with mortality in ESKD patients. Frail dialysis patients exhibit 2.6 times higher mortality risk compared to non-frail counterparts, even after adjustment for age, gender, comorbidity, and disability.^[5] This mortality differential persists across age groups, challenging the notion that frailty is merely a proxy for advanced age or comorbidity burden.

In the transplant population, frailty at the time of transplantation independently predicts post-transplant mortality. Frail kidney transplant recipients demonstrate higher 1-, 3-, and 5-year mortality compared to non-frail recipients.^[36] Particularly concerning is the finding that worsening frailty status while awaiting transplantation carries an especially poor prognosis.^[37]

Hospitalization

Frailty is strongly associated with increased hospitalization risk, extended hospital stays, and readmission rates in ESKD patients.^[38] Frail dialysis patients have 1.4 times higher risk of hospitalization, independent of age, gender, and comorbidity.^[14] Hospital utilization patterns differ between frail and non-frail ESKD patients, with frail individuals demonstrating not only more frequent admissions but also longer length of stay (mean difference 2.6 days, P < 0.001) and higher likelihood of discharge to skilled nursing facilities (odds ratio [OR] 2.65, 95% CI 1.89–3.71).^[27]

Transplant-specific outcomes

Frailty exerts significant influence on multiple transplant-related outcomes. On the waitlist, frail candidates demonstrate a lower likelihood of receiving transplantation, higher rates of waitlist inactivation, and a greater risk of removal due to deteriorating health.^[39] Post-transplant complications occur with greater frequency and severity in frail recipients, including delayed graft function (OR 1.94, 95% CI 1.13–3.36), post-operative complications, and longer hospital stays.^[40]

Despite these increased risks, frail ESKD patients may still derive a survival benefit from transplantation compared to remaining on dialysis.^[41] This finding underscores the need for individualized risk-benefit assessment rather than categorical exclusion of frail candidates from transplant consideration.

Other clinical outcomes

Frailty is strongly associated with increased fall risk in ESKD patients, with an adjusted relative risk of 3.09.^[42] This elevated fall risk translates to increased fracture incidence, with frail patients experiencing more frequent and severe fractures.^[43] Emerging evidence suggests associations between frailty and vascular access complications, cognitive impairment, and reduced quality of life.^[15,44,45]

Table 2 summarizes the impact of frailty on outcomes across renal replacement modalities.

HD

HD patients demonstrate among the highest prevalence of frailty in the ESKD population, with 43% meeting frailty criteria in recent studies.^[19] Several HD-specific factors demonstrate significant association with frailty, including intradialytic hypotension (P = 0.002) and edema (P < 0.001).^[19] Interestingly, the duration of dialysis therapy does not show a significant association with frailty prevalence (P = 0.838), suggesting that frailty development may be more closely related to patient-specific factors and comorbidities than to dialysis vintage.^[19]

Peritoneal dialysis (PD)

The prevalence of frailty in PD populations appears comparable to HD cohorts in most studies.^[46] PD presents unique considerations regarding frailty, including the home-based nature of therapy, eliminating transportation burden, but requiring sufficient manual dexterity, visual acuity, and cognitive function.^[45] Nutritional considerations are particularly relevant in frail patients, with peritoneal protein losses potentially exacerbating protein-energy wasting.^[47]

Kidney transplantation

Approximately 20% of kidney transplant candidates meet criteria for frailty, lower than the dialysis population but substantially higher than age-matched individuals without kidney disease.^[38] Frailty at the time of transplantation independently predicts post-transplant complications and mortality, including delayed graft function, longer hospital stays, and higher long-term mortality.^[40]

Interestingly, frailty status may improve following successful transplantation in some patients. McAdams-DeMarco et al. reported that 33% of frail recipients no longer met frailty criteria 1-year post-transplant, suggesting partial reversibility of the frailty phenotype with improved kidney function.^[48]

Modality selection considerations

Modality selection for frail ESKD patients should consider multiple factors beyond frailty status alone, including social support, cognitive function, physical limitations, comorbidity profile, and patient preferences. The potential for prehabilitation to improve candidacy for preferred modalities represents an emerging area of interest.^[49]

Nutritional interventions

Nutritional deficiencies contribute significantly to frailty pathogenesis in ESKD through multiple mechanisms.^[22] While evidence from RCTs specifically targeting frail dialysis patients remains limited, several promising approaches have emerged:

1. Protein supplementation: Studies examining protein supplementation (20–30 g following dialysis sessions) have shown modest improvements in lean body mass (mean increase 1.1 kg, P = 0.03) and physical function measures.^[50] Whey protein appears particularly beneficial due to its high essential amino acid content and rapid absorption profile, with one trial demonstrating a 9% improvement in handgrip strength after 12 weeks of intradialytic supplementation (20 g thrice weekly).^[51]

2. Oral nutritional supplements: Energy-dense, protein-rich oral supplements (providing 400–600 kcal and 25–30 g protein daily) have demonstrated efficacy in improving nutritional parameters (serum albumin increase of 0.2–0.4 g/dL) and physical function in malnourished dialysis patients.^[52] However, long-term adherence remains problematic, with dropout rates of 30–45% in trials extending beyond 3 months.

3. Vitamin D supplementation: Observational studies show associations between vitamin D status and frailty severity in ESKD, though interventional data remain limited.^[53] One small RCT (n = 42) demonstrated that cholecalciferol supplementation (50,000 IU weekly for 8 weeks) improved physical performance measures in dialysis patients, but effects on overall frailty status were not assessed.^[54]

4. Individualized dietary counseling: Personalized nutritional intervention by renal dietitians has shown promise, with one trial demonstrating a 38% reduction in frailty progression when combined with exercise compared to standard care.^[55] However, resource limitations often restrict the availability of specialized dietetic services.

Critical limitations of the current evidence base include small sample sizes (most trials n < 100), short follow-up periods (typically 3–6 months), heterogeneous intervention protocols, and focus on surrogate endpoints rather than frailty status itself. In addition, most studies exclude severely frail patients, limiting generalizability to the highest-risk population.

Multimodal approaches

The multifactorial nature of frailty in ESKD suggests that multimodal interventions addressing multiple contributing factors simultaneously may yield superior outcomes compared to single-domain approaches.^[65] The frailty intervention through nutrition education and exercise studies demonstrates that combined nutritional education and exercise training more effectively prevent frailty progression than either intervention alone, with a 38% reduction in frailty incidence over 12 months compared to 15–20% with single-component interventions.^[55]

Comprehensive geriatric assessment followed by targeted intervention addressing identified deficits shows promise, with one trial in pre-dialysis CKD patients demonstrating a 33% reduction in frailty prevalence compared to standard care.^[66] However, such approaches require substantial resources and multidisciplinary expertise rarely available in routine nephrology practice.

The fundamental barriers to successful implementation of frailty interventions in ESKD include:

1. Complexity of the frailty syndrome: The multidimensional nature of frailty necessitates complex, multicomponent interventions that are challenging to implement and sustain in clinical practice.

2. Resource constraints: Effective interventions typically require specialized personnel, equipment, and time commitments beyond what is available in many clinical settings.

3. Reimbursement structures: Current payment models rarely support preventive interventions targeting frailty, creating financial disincentives for implementation.

4. Care fragmentation: Frailty management requires coordination across multiple specialties and settings, which is challenging in siloed healthcare systems.

5. Evidence limitations: Most intervention studies have methodological limitations, including small sample sizes, short follow-up periods, and selected populations, creating uncertainty about real-world effectiveness.

Table 3 summarizes evidence-based interventions for frailty in ESKD, including the magnitude of effects and implementation considerations.

Challenges in low-resource settings

Low-resource settings face substantial constraints that may impede frailty assessment and management, including equipment limitations, workforce shortages, financial barriers, and infrastructure challenges.^[7] Equipment limitations include a lack of specialized tools, such as dynamometers for grip strength measurement and standardized walkways for gait speed assessment. Workforce shortages refer to insufficient numbers of healthcare professionals with appropriate training in geriatric assessment and frailty management, particularly in settings where nephrologist-to-patient ratios may exceed 1:200.^[67] Beyond resource limitations, healthcare system factors such as fragmented care, acute care focus, knowledge gaps, and absence of context-specific guidelines further complicate implementation.^[68]

Simplified assessment tools

Despite these challenges, several frailty assessment approaches demonstrate feasibility and utility in resource-limited settings. The CFS has emerged as a particularly valuable tool, requiring no specialized equipment, minimal training, and typically less than one minute to administer.^[28] Self-administered questionnaires such as SARC-F and the frail scale offer another approach to frailty screening with minimal staff involvement.^[31]

Implementation strategies

Successful implementation of frailty assessment and management in low-resource settings requires pragmatic strategies addressing local constraints. These include integration with existing workflows (dialysis initiation, routine clinic visits), task-shifting approaches (nursing staff training, community health worker involvement), and prioritization strategies focusing on high-risk populations.^[7]

Figure 3 presents an implementation flowchart for clinical practice.

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Figure 3:

Implementation flowchart for frailty assessment and management in end-stage kidney disease. MIS:, MoCA: Montreal Cognitive Assessment, Mini-Mental State Examination, CFS: Clinical frailty scale.

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Clinical implications

Frailty assessment provides valuable prognostic information that can inform multiple aspects of ESKD management. For dialysis patients, frailty status may guide decisions regarding vascular access type, dialysis prescription, and advanced care planning.^[5] In the transplant setting, frailty evaluation contributes to comprehensive candidate assessment without serving as an absolute contraindication.^[36]

The heterogeneity of frailty presentation in ESKD necessitates individualized intervention strategies. Comprehensive assessment identifying specific deficits across physical, cognitive, nutritional, and psychosocial domains enables targeted approaches addressing modifiable contributors to frailty.^[66] Emerging evidence suggests that earlier intervention, ideally before severe frailty is established, yields greater benefit than attempting to reverse advanced frailty.^[65] This finding underscores the importance of frailty staging, with the CFS providing gradations from mild (CFS 5) to moderate (CFS 6) to severe frailty (CFS 7–8), each stage requiring progressively more intensive intervention approaches.^[69]

Research implications

Despite significant advances in understanding frailty in ESKD, several knowledge gaps require attention in future research, including standardized assessment approaches, intervention effectiveness in rigorous trials, biological mechanisms, implementation science, and economic evaluation.

Policy implications

The substantial burden of frailty in ESKD and its strong association with adverse outcomes have important implications for healthcare policy, including incorporation of frailty assessment into quality metrics, reimbursement policies supporting comprehensive geriatric assessment, workforce development combining nephrology and geriatrics expertise, and resource allocation decisions in limited-resource settings.