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

Area of Science:

• Nephrology
• Cardiovascular Medicine
• Endocrinology

Background:

• Klotho deficiency is implicated in chronic kidney disease (CKD) pathogenesis via fibroblast growth factor-23 (FGF23)-dependent and -independent pathways.
• The relationship between circulating Klotho levels and clinical outcomes in CKD patients remains unclear.

Purpose of the Study:

• To investigate the association between plasma Klotho levels and clinical outcomes in a large cohort of CKD patients.
• To determine if Klotho deficiency confounds the relationship between FGF23 and adverse outcomes in CKD.

Main Methods:

• A prospective observational study involving 1,088 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with an estimated glomerular filtration rate (eGFR) between 20-70mL/min/1.73m².
• Plasma Klotho levels were measured at the year-1 study visit and divided into six groups.
• Cox proportional hazards regression and subdistribution hazards models were used to assess 5-year risks of mortality, heart failure hospitalization, atherosclerotic cardiovascular events, and kidney disease progression, adjusting for multiple confounders including FGF23.

Main Results:

• No significant differences in survival, heart failure hospitalization, atherosclerotic cardiovascular events, or CKD progression were observed between the highest and lowest Klotho groups.
• Fibroblast growth factor-23 (FGF23) levels were significantly associated with mortality and heart failure hospitalization independently of Klotho levels.

Conclusions:

• In this CKD cohort, circulating Klotho levels were not associated with major adverse clinical outcomes.
• Klotho deficiency did not appear to confound the association between FGF23 and mortality or heart failure hospitalization.
• Potential residual confounding or limitations of single-time point Klotho measurement warrant consideration.