Klotho and Clinical Outcomes in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Rationale & Objective Klotho deficiency may affect clinical outcomes in chronic kidney disease (CKD) through fibroblast growth factor-23 (FGF23)-dependent and independent pathways. However, the association between circulating Klotho and clinical outcomes in CKD remains unresolved and was the focus of this study. Study Design Prospective observational study. Setting & Participants 1088 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rate (eGFR) 20-70 ml/min/1.73m2. Exposure Plasma Klotho level at the year-1 study visit. Outcomes 5-year risks of all-cause mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and a composite kidney endpoint comprised of a sustained 50% decline in eGFR, dialysis, kidney transplantation, or eGFR <15 ml/min/1.73 m2. Analytical Approach We divided Klotho into six groups to account for its non-normal distribution. We used Cox proportional hazards regression and subdistribution hazards models to compare survival and clinical outcomes, respectively, between Klotho groups. We sequentially adjusted for demographics, kidney function, cardiovascular risk factors, sample age, and FGF23. Results Mean eGFR was 42 ml/min/1.73m2, and median Klotho was 0.31 ng/ml (interquartile range 0.10-3.27 ng/ml). When compared to the lowest Klotho group, survival (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.32-1.89), heart failure hospitalization (HR 1.10, 95% CI 0.38-3.17), atherosclerotic cardiovascular events (HR 1.19, 95% CI 0.57-2.52), and CKD progression (HR 1.05, 95% CI 0.58-1.91) did not differ in the high Klotho group. In contrast, FGF23 was significantly associated with mortality and heart failure hospitalization independent of Klotho levels. Limitations Despite adjustments, we cannot exclude potential influence of residual confounding or sample storage on the results. A single measurement of plasma Klotho may not capture Klotho patterns over time. Conclusions In a large, diverse, well-characterized CKD cohort, Klotho was not associated with clinical outcomes, and Klotho deficiency did not confound the association of FGF23 with mortality or heart failure hospitalization.