An Overview of Frailty in Kidney Transplantation

Measurement, Management and Future Considerations

Meera N. Harhay; Maya K. Rao; Kenneth J. Woodside; Kirsten L. Johansen; Krista L. Lentine; Stefan G. Tullius; Ronald F. Parsons; Tarek Alhamad; Joseph Berger; XingXing S. Cheng; Jaqueline Lappin; Raymond Lynch; Sandesh Parajuli; Jane C. Tan; Dorry L. Segev; Bruce Kaplan; Jon Kobashigawa; Darshana M. Dadhania; Mara A. McAdams-DeMarco


Nephrol Dial Transplant. 2020;35(7):1099-1112. 

In This Article

Pretransplant Frailty: Prevalence, Risk Factors and Outcomes

Prevalence of Frailty in Populations With CKD and ESKD

People with CKD and ESKD have a high prevalence of frailty: there is 15–21% frailty prevalence in the CKD population versus 3–6% in the general population.[54,55] Among dialysis-dependent individuals, the prevalence of frailty is likely higher, ranging from 14 to 73%, and is common among those <40 years of age (63%).[16,56] These data suggest that the prevalence of frailty is high among all KT candidates, including pre-emptive candidates and younger candidates.

Individuals who are referred for KT evaluation are likely to be healthier than the overall population of individuals with ESKD, and those who are selected for KT waitlists may be healthier still. A large multicenter study identified 18% of individuals as frail at the time of initial evaluation, while only 12% of individuals were identified as being frail among those who were ultimately listed for KT.[57] Furthermore, frailty status may change considerably from the time of listing to the time of KT. For example, in a single-center study of 569 adult KT candidates, 22% of the cohort was more frail at the time of KT than at the time of KT evaluation, whereas 24% were less frail at KT.[58] Approximately 20% of KT recipients are frail at the time of KT,[59] and the frailty components most commonly observed in this population are weak grip strength (50%) and low physical activity (49%).[59] Given the dynamic nature of frailty, periodic reassessments of frailty may be warranted prior to the surgical stressor of KT.

Risk Factors and Correlates for Frailty

Many of the risk factors for frailty in potential KT candidates are not modifiable (Figure 2). For example, studies have consistently shown that KT candidates of advanced age and female sex are more likely to be frail than younger candidates and males, respectively.[57,60,61] However, other risk factors, such as obesity and low physical activity, might be modifiable. With respect to correlates of frailty, although higher comorbidity burden is also a risk factor for frailty among KT candidates, frailty can also occur in the setting of lower comorbidity burdens.[62] Diabetes and serum albumin concentration are also associated with frailty among prevalent dialysis patients[63] and individuals with CKD and ESKD who are frail are also more likely to have cognitive impairment and sarcopenia, or low muscle mass, than their nonfrail counterparts.[64,65]

Figure 2.

The continuum of frailty in kidney disease. The figure displays current knowledge on the risk factors, correlates and outcomes of frailty among individuals with kidney disease.

Among individuals with nondialysis-dependent CKD, the risk of frailty has an inverse relationship with CKD stage, as defined by cystatin-based glomerular filtration rate (GFR) calculations.[66] However, the association between CKD stage and frailty is attenuated when GFR is estimated using creatinine as opposed to cystatin C, a finding that is potentially explained by the relation of creatinine to muscle mass (i.e. lower serum creatinine may reflect sarcopenia). Therefore creatinine-based estimated GFR (eGFR) may overestimate actual GFR in frail people with sarcopenia, an important consideration given that waiting time for deceased donor KT (DDKT) cannot be accrued in the USA until individuals have eGFRs ≤20 mL/min/1.73 m2.

Among those who are dialysis-dependent, it is unclear whether dialysis itself improves or worsens frailty. Multiple studies have shown a decline in functional status in older adults who initiate dialysis.[67,68] In a longitudinal study that measured frailty in a dialysis cohort of 762 subjects, most subjects' scores changed from year to year.[63] However, improvement in frailty was as common as the worsening of frailty. With respect to modality of renal replacement therapy, several recent studies have suggested that frailty and functional impairments are similarly prevalent among patients with ESKD who receive hemodialysis, peritoneal dialysis and conservative care.[69–71] Studies are needed to determine whether dialysis treatment–related interventions (e.g. parenteral nutrition and duration of treatment) could improve frailty.

Outcomes of Frailty in Populations With Nondialysis-dependent CKD and Dialysis Dependence

Potential KT candidates with frailty are at high risk of multiple adverse health outcomes. In a cohort of 336 subjects with nondialysis-dependent CKD, the proportions of frail individuals who had impairment in at least one activity of daily living, instrumental activity of daily living and mobility were 15, 60 and 40%, respectively, compared with 5% (P = 0.009), 28% (P < 0.001) and 18% (P = 0.001), respectively, among those without frailty.[72] Frailty is also an independent risk factor for hospitalization[27,56,73] and doubles the risk of death among individuals with ESKD and KT.[19,27,54,56,72–74] Slow gait speed,[50,74] immobility[75] and poor physical function (PF)[76] have also been associated with a higher risk of death in both CKD and ESKD. In a study of 311 subjects with nondialysis-dependent CKD, the 6-min walk distance had the highest discriminative accuracy for 3-year mortality {area under the curve [AUC] 0.80 [95% confidence interval (CI) 0.70–0.90]}, followed by gait speed [AUC 0.78 (95% CI 0.70–0.86)] and timed up and go [AUC 0.74 (95% CI 0.64–0.84)]. Each of these physical performance tests had an AUC that was superior to commonly measured biomarkers of CKD, including eGFR, serum bicarbonate, hemoglobin, C-reactive protein and albumin.[74] Therefore, knowledge of frailty could inform shared decision-making about the risks and benefits of KT between potential KT candidates and their providers beyond the standard biomarkers that are commonly assessed and reviewed.

Frailty and Access to KT

Among individuals who are being evaluated for KT, frailty is associated with reduced access to the waiting list and higher waiting list mortality. In a study of 7078 individuals who were evaluated at three transplant centers between 2009 and 2018, frail individuals were almost half as likely as nonfrail individuals to be placed on a KT waiting list [hazard ratio (HR) 0.62 (95% CI 0.56–0.69)].[57] In another study of 128 individuals who were evaluated for KT, 30.4% of frail individuals were subsequently listed for KT, compared with 57.6% of nonfrail individuals.[77] Among those who are successfully wait-listed, frail KT candidates may be more likely to be inactive, less likely to receive KT[51] and more likely to die while wait-listed than nonfrail KT candidates.[61] Healthcare utilization might be another useful proxy for frailty in predicting waiting list outcomes: compared with listed KT candidates with no hospitalization days in the first year after listing, a study of 51,111 wait-listed individuals in the USA found that candidates with ≥15 hospitalized days had a >2-fold risk of subsequent waiting list mortality [HR 2.07 (95% CI 1.99–2.15)].[78]