Higher cystatin C, but not creatinine, predicts frailty risk in individuals with normal kidney function

Objective This study investigates the associations of creatinine and cystatin C with frailty risk in individuals with normal kidney function, using data from the Health and Retirement Study (HRS) and the China Health and Retirement Longitudinal Study (CHARLS). Methods We used CKD-EPI to estimate glomerular filtration rate based on serum creatinine (eGFR scr ) and cystatin C (eGFR cysc ), respectively, and an eGFR ≥60 was considered "normal kidney function". Frailty was assessed using a frailty index derived from clinical and functional measures. Cox proportional hazards models were used to evaluate the associations of creatinine and cystatin C with incident frailty, adjusting for demographic, lifestyle, and clinical covariates. Results Creatinine levels showed no significant association with frailty risk in individuals with normal kidney function across both cohorts. In contrast, cystatin C levels were consistently and significantly associated with an increased risk of frailty in individuals with normal eGFR scr . For each 1-unit increase in cystatin C, the adjusted hazard ratios (HRs) were 2.05 (95% CI: 1.30–3.22) in HRS and 2.12 (95% CI: 1.60–2.82) in CHARLS. Quartile analyses revealed a dose-response relationship, with the highest quartile of cystatin C associated with significantly higher frailty risk compared to the lowest quartile (HRS: HR = 1.34, 95% CI: 1.02–1.76; CHARLS: HR = 1.70, 95% CI: 1.40–2.07). Conclusions Higher cystatin C levels, but not creatinine levels, were significantly associated with an increased risk of frailty among individuals with normal kidney function, suggesting that cystatin C may be a useful biomarker for early identification of frailty risk.