Alpha-Klotho, FGF-23, and Calcium-Phosphate Product Across Renal Function Strata in Chronic Heart Failure: Associations with Cardiac Remodeling and Six-Month Treatment Response

Abstract

Background: Renal dysfunction in chronic heart failure (CHF) is accompanied by disturbances in mineral metabolism and may promote vascular calcification. The alpha-Klotho/FGF-23 axis is a potential molecular link between declining renal filtration, phosphate handling, and adverse cardiovascular remodeling.

Objective: To evaluate circulating alpha-Klotho, fibroblast growth factor-23 (FGF-23), and the calcium-phosphate product (Ca×P) across cystatin C-based estimated glomerular filtration rate (eGFR) strata in patients with CHF, examine their associations with cardiac remodeling, and describe six-month biomarker changes during guideline-directed therapy with or without adjunctive sevelamer carbonate.

Methods: This clinical cohort included 120 patients with ischemic heart disease-related NYHA functional class II–III CHF. Patients were stratified by cystatin C-based eGFR into <60 mL/min/1.73 m² (n=55), 60–90 mL/min/1.73 m² (n=45), and >90 mL/min/1.73 m² (n=20). Serum alpha-Klotho, FGF-23, cystatin C, vitamin D, NT-proBNP, aldosterone, calcium, phosphorus, electrolytes, and echocardiographic parameters were assessed. Ca×P was calculated as a research surrogate of mineral-related calcification propensity. Fifteen patients in each of the two lower-eGFR strata received sevelamer carbonate in addition to standard CHF therapy; follow-up was performed at six months. Treatment allocation procedures were not described in the source dissertation.

Results: Alpha-Klotho decreased stepwise with renal impairment (0.52±0.02, 0.84±0.01, and 0.98±0.03 ng/mL across the <60, 60–90, and >90 eGFR strata, respectively; P<0.001), whereas FGF-23 increased markedly (404.9±17.2, 118.5±3.7, and 84.07±2.01 pg/mL; P<0.001). Ca×P was highest in the lowest-eGFR group (3.51±0.04 vs. 2.84±0.02 vs. 2.24±0.02 mmol²/L²; P<0.001). Alpha-Klotho correlated inversely with Ca×P in the eGFR <60 (r=−0.53, P<0.001) and 60–90 (r=−0.47, P<0.001) strata, but not significantly in the >90 stratum (r=−0.24, P>0.05). Lower eGFR was also accompanied by lower LVEF and higher left ventricular myocardial mass. At six months in the eGFR <60 stratum, the subgroup receiving sevelamer had numerically higher alpha-Klotho (0.68 vs. 0.61 ng/mL), lower Ca×P (3.02 vs. 3.27 mmol²/L²), lower FGF-23 (271.9 vs. 356.7 pg/mL), and higher vitamin D (37 vs. 33 ng/mL) than the standard-therapy subgroup. Direct between-subgroup significance tests were not reported.

Conclusion: The alpha-Klotho/FGF-23 axis is strongly altered as renal filtration declines in CHF and is accompanied by greater mineral-metabolism disturbance and adverse cardiac remodeling. The inverse relationship between alpha-Klotho and Ca×P was most evident in patients with impaired renal filtration. Exploratory six-month data suggest a potentially favorable mineral-metabolic profile with adjunctive sevelamer in the lowest-eGFR stratum, but randomized and independently validated studies are required.

Keywords:

Chronic heart failure, Alpha-Klotho, FGF-23, Cystatin C, Estimated glomerular filtration rate, Calcium-phosphate product, Cardiorenal syndrome, Vascular calcification, Sevelamer carbonate

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