Background: α-Klotho is reported to have protective effects against kidney injury, and its renal expression is decreased in many experimental models of kidney disease. However, circulating α-klotho levels in human chronic kidney disease (CKD) and the relationship to progression are unknown. Study Design: Post hoc analysis of a prospective cohort study. Setting & Participants: 243 of 301 participants from a CKD cohort at our institution between January 2006 and December 2011 were eligible for the study. Predictor: Baseline α-klotho levels. Outcomes: Primary outcome was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease, or death. End-stage renal disease was defined as onset of treatment by renal replacement therapy. Measurements: Serum α-klotho and fibroblast growth factor 23 (FGF-23) were measured using enzyme-linked immunosorbent assay. Results: Lower serum α-klotho levels were associated with more severe CKD stage in the cross-sectional analysis of the baseline data (P for trend < 0.001). In the adjusted multivariable linear regression model, log(α-klotho) was associated independently with estimated glomerular filtration rate (β = 0.154; P = 0.001). Cox regression analysis showed that baseline α-klotho level independently predicted the composite outcome after adjustment for age, diabetes, blood pressure, estimated glomerular filtration rate, proteinuria, parathyroid hormone level, and FGF-23 level (HR per 10-pg/mL increase, 0.96; 95% CI, 0.94-0.98; P < 0.001). When patients were categorized into 2 groups according to baseline median α-klotho value, 43 (35.2%) patients with α-klotho levels ≤396.3 pg/mL reached the primary composite outcome compared with 19 (15.7%) with α-klotho levels >396.3 pg/mL (HR, 2.03; 95% CI, 1.07-3.85; P = 0.03). Limitations: Uncontrolled dietary phosphorus intake and use of frozen samples. Conclusions: This observational study showed that low circulating α-klotho levels were associated with adverse kidney disease outcome, suggesting that α-klotho is a novel biomarker for CKD progression. More data from larger prospective longitudinal studies are required to validate our findings.
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