Nonlinear Associations between Glomerular Function and Frailty: A National Study Comparing Glomerular Function Using Cystatin C-Based and Creatinine-Based Estimated Glomerular Filtration Rate in Chinese Middle-Aged and Older Adults

BACKGROUND: Frailty and chronic kidney disease (CKD) are common, interrelated conditions in ageing populations, yet the association between kidney function and frailty remains incompletely characterized, particularly when estimated using different estimated glomerular filtration rate (eGFR) equations. METHODS: We analyzed 17,864 participants aged ≥45 years from the 2011 and 2015 waves of the China Health and Retirement Longitudinal Study (CHARLS). Frailty was defined primarily by the deficit-accumulation frailty index, with the Fried physical frailty phenotype applied in a prespecified sensitivity analysis. Kidney function was estimated using the CKD-EPI creatinine (eGFRcr), cystatin C (eGFRcys), and combined creatinine-cystatin C (eGFRcr-cys) equations. Multivariable logistic regression, restricted cubic splines, and threshold effect models were used to assess linear and nonlinear associations, with adjusted predicted probabilities derived to quantify absolute risk. RESULTS: Overall, 10.0% of participants were frail and 38.6% prefrail. Lower eGFR was independently associated with higher odds of frailty across all three equations, with the strongest and most consistent associations observed for eGFRcys (eGFRcys: <30 vs. ≥90 mL/min/1.73 m2; odds ratios [OR]: 4.39; 95% confidence interval [CI]: 2.32-8.32; p for trend <0.001), corresponding to an adjusted absolute risk difference of 18.9 percentage points. eGFRcr-cys showed similar but attenuated associations, whereas eGFRcr was associated with frailty only at severely reduced levels (<30 mL/min/1.73 m2). Nonlinear relationships were evident for eGFRcys and eGFRcr-cys, with inflection points at 58.78 and 51.65 mL/min/1.73 m2, respectively. Sensitivity analyses using the Fried phenotype and a model excluding laboratory parameters yielded directionally consistent results. CONCLUSION: Cystatin C-based eGFR was more strongly and consistently associated with frailty than creatinine-based estimates in middle-aged and older Chinese adults, with associations emerging at earlier stages of kidney dysfunction. Incorporating eGFRcys into kidney function assessment in this population may aid the identification of individuals at increased risk of frailty, pending confirmation in longitudinal and interventional studies.