Fibroblast Growth Factor-23 and Cardiovascular Disease in Patients With Chronic Kidney Disease

Chronic kidney disease (CKD) is deemed one of the most potent factors that significantly increase the risk of cardiovascular morbidity and mortality. Yet, the magnitude of this excess risk cannot be explained solely by traditional cardiovascular risk factors, suggesting the presence of non hemodynamic, endocrine, and metabolic mechanisms linking renal dysfunction to cardiac disease. Fibroblast growth factor-23 (FGF-23), a bone-derived regulator of phosphate and vitamin D metabolism, rises early in CKD and has emerged as a key mediator of the cardiorenal-osteoendocrine axis. While physiological FGF-23 signaling through α-Klotho–dependent FGF receptor-1c (FGFR1c) maintains mineral homeostasis, pathological elevations in CKD promote Klotho-independent FGFR4 activation in the myocardium, leading to hypertrophy, fibrosis, diastolic dysfunction, and electrophysiological remodeling. Several cohort studies consistently demonstrate that elevated FGF-23 independently predicts left ventricular hypertrophy, heart failure, especially with preserved ejection fraction, atrial fibrillation, and mortality across CKD and even non-CKD populations, supporting its role as a biomarker of cardiovascular risk. However, clinical implementation is limited by assay heterogeneity, absence of standardized thresholds, and lack of definitive evidence that FGF-23-lowering interventions improve outcomes. This review examines FGF-23 physiology, mechanisms of pathological cardiac signaling in CKD, current clinical evidence, and current and emerging therapeutic strategies targeting the FGF-2–Klotho–FGFR axis.