Circulating α-Klotho Levels in CKD and Relationship to Progression

Background: alpha-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 alpha-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 alpha-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 alpha-klotho and fibroblast growth factor 23 (FGF-23) were measured using enzyme-linked immunosorbent assay. Results: Lower serum alpha-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(alpha-klotho) was associated independently with estimated glomerular filtration rate (beta = 0.154; P = 0.001). Cox regression analysis showed that baseline alpha-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 alpha-klotho value, 43 (35.2%) patients with alpha-klotho levels <= 396.3 pg/mL reached the primary composite outcome compared with 19 (15.7%) with alpha-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 alpha-klotho levels were associated with adverse kidney disease outcome, suggesting that alpha-klotho is a novel biomarker for CKD progression. More data from larger prospective longitudinal studies are required to validate our findings. (c) 2013 by the National Kidney Foundation, Inc.