Structural brain alterations in frailty among end-stage renal disease patients

End-stage renal disease (ESRD) patients exhibit a high prevalence of multidimensional frailty, yet its neurobiological correlates remain unclear. This study investigated neuroimaging correlates of frailty in ESRD and explored whether neuroanatomical measures statistically accounted for cross-sectional associations of aging and uremic markers with frailty severity. We enrolled 89 ESRD patients and 53 healthy controls (HC) assessed using the Tilburg Frailty Indicator. 3D T1-weighted images were processed to quantify regional gray matter volumes, and T2-weighted fluid-attenuated inversion recovery (FLAIR) images were processed to quantify white matter hyperintensity (WMH) volumes. Among the ESRD patients, 36.0% were frail. Frailty correlated with advancing age, elevated blood urea nitrogen (BUN), and psychosocial deficits. The ESRD patients had widespread lower cerebral volume and greater WMH burden, and the frail ESRD patients exhibited a marked reduction in left inferior parietal volume (Cohen’s d = − 0.70, FDR- q = 0.030) compared to non-frail ESRD patients, with no significant WMH differences between the two groups. Cross-sectional mediation models showed a significant indirect association involving age, left inferior parietal volume, and frailty severity (ACME = 0.0246, P = 0.016), whereas the indirect association involving BUN was not statistically significant. These findings identify reduced left inferior parietal volume as a key neuroanatomical correlate that statistically accounted for the age-frailty association in ESRD, while BUN was associated with frailty independently of left inferior parietal volume, which does not support the supposition that BUN contributes to frailty via cerebral structural alterations.