Heterogeneous regulation of fibroblast growth factor 23 in acute kidney injury, chronic kidney disease, and polycystic kidney disease: mechanisms, diagnostic utility, and clinical implications

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Abstract
Fibroblast Growth Factor 23 (FGF23) is a bone-derived hormone regulating phosphate and vitamin D metabolism, now recognized as a dynamic biomarker across acute and chronic kidney disorders. Elevated FGF23 is a hallmark of chronic kidney disease (CKD), but also rises acutely in acute kidney injury (AKI) and appears disproportionately high in autosomal dominant polycystic kidney disease (ADPKD), underscoring condition-specific regulation. This review explores the correlation and heterogeneity of FGF23 expression in AKI, CKD, and ADPKD, highlighting shared and divergent mechanisms and the diagnostic and therapeutic implications. We summarize FGF23 expression kinetics in each condition, elucidate known and proposed molecular drivers of its elevation, and discuss how FGF23 serves as a unifying yet disease-divergent marker in renal pathology. In AKI, inflammation, ischemia, and acute metabolic stress drive a rapid FGF23 surge, whereas in CKD, phosphate retention and Klotho deficiency promote a sustained, maladaptive FGF23 elevation. ADPKD shows early FGF23 increases independent of glomerular filtration rate (GFR), potentially due to ectopic production (liver and cysts) and unique tubular defects. Clinically, FGF23 has emerged as an indicator of disease severity and outcomes in these contexts: it can signal early AKI and predict progression, is a strong prognostic factor for mortality and cardiovascular complications in CKD, and correlates with cystic disease burden and kidney growth in ADPKD. We also examine FGF23’s systemic effects (notably on cardiovascular remodeling) and potential therapeutic targets, from modulating phosphate balance and iron metabolism to novel interventions in development. Understanding the nuanced regulation of FGF23 across acute injury, chronic degeneration, and genetic kidney disease provides insight into acute-chronic disease intersections and guides precision diagnostics and therapies for improved patient outcomes.

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