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

## TL;DR

This paper reviews how FGF23, a hormone regulating phosphate and vitamin D, behaves differently in various kidney diseases and highlights its role in diagnosis and treatment.

## Contribution

The paper provides a detailed analysis of FGF23 regulation in AKI, CKD, and ADPKD, emphasizing disease-specific mechanisms and diagnostic potential.

## Key findings

- FGF23 is elevated in AKI due to inflammation and metabolic stress, while in CKD it's sustained due to phosphate retention and Klotho deficiency.
- ADPKD shows early FGF23 increases independent of GFR, possibly from ectopic production and tubular defects.
- FGF23 correlates with disease severity and outcomes in AKI, CKD, and ADPKD, offering diagnostic and therapeutic insights.

## 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.