What is the role of fibroblast growth factor 23 (FGF23) in chronic kidney disease (CKD)?

FGF23's Role in Chronic Kidney Disease

FGF23 is a bone-derived hormone that rises early in CKD to maintain phosphate balance by promoting urinary phosphate excretion and suppressing vitamin D activation, but this compensatory mechanism becomes maladaptive, driving secondary hyperparathyroidism, bone disease, vascular calcification, and increased mortality. 1

Primary Physiologic Functions

FGF23 functions as a critical regulator in the complex feedback system controlling mineral metabolism:

• FGF23 promotes phosphaturia by acting on the kidney (in the presence of FGF receptor 1 and its coreceptor Klotho) to increase urinary phosphate excretion, preventing early hyperphosphatemia despite declining kidney function 2
• FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the kidney, which reduces intestinal phosphate absorption as an additional mechanism to control phosphate balance 3, 2
• FGF23, PTH, and 1,25(OH)₂D form an integrated multi-tissue feedback system that normally regulates blood phosphate and calcium levels, but this system becomes progressively dysregulated as CKD advances 1

Temporal Dynamics in CKD Progression

FGF23 elevation represents one of the earliest detectable hormonal abnormalities in CKD:

• FGF23 levels increase in the very early stages of CKD, even before elevations in blood urea nitrogen and creatinine, making it an early and sensitive marker for kidney injury 4, 5
• FGF23 rises progressively with CKD stage advancement to compensate for persistent phosphate retention, with exponentially elevated levels in late-stage disease 3, 5
• In early CKD, increased FGF23 production by bone does not appear responsible for rising levels, but trabecular osteocytes become the primary source of FGF23 production in late-stage disease 5

Pathogenic Consequences

The compensatory rise in FGF23 triggers a cascade of maladaptive changes:

Mineral Metabolism Disruption

• Elevated FGF23 directly suppresses renal production of 1,25-dihydroxyvitamin D, resulting in progressive decline of calcitriol levels with CKD advancement 6, 7
• Reduced 1,25(OH)₂D levels lead to decreased intestinal calcium absorption and hypocalcemia, which stimulates compensatory PTH secretion and drives secondary hyperparathyroidism 3, 2
• FGF23 may directly act on the parathyroid gland to mediate PTH secretion in the presence of Klotho as a cofactor, though this mechanism requires further confirmation in CKD patients 3

Bone Disease

• Increased FGF23 levels are associated with mortality and vascular calcification in CKD patients, though the direct pathological role remains under investigation 1
• FGF23 neutralization improves bone quality and osseointegration of titanium implants in experimental CKD models, indicating FGF23 is a key factor in CKD-related bone diseases 1
• Bone metabolism is regulated by the complex interplay of PTH, FGF23, and 1,25(OH)₂D, and complications from CKD interrupt the balance of these factors, impacting bone structural integrity and resulting in CKD-mineral and bone disorder 1

Cardiovascular Complications

• FGF23 is independently associated with cardiovascular disease and mortality in CKD patients, suggesting chronically elevated levels may directly contribute to adverse outcomes 2, 7
• FGF23 is associated with vascular dysfunction, atherosclerosis, and left ventricular hypertrophy in the CKD population 2
• Excess FGF23 levels have been independently linked with cardiovascular disease and mortality, raising concerns that the compensatory mechanism becomes directly harmful over time 7

Clinical Implications and Controversies

Despite its clear pathophysiologic importance, routine FGF23 measurement remains controversial:

• The 2025 KDIGO conference identified "the clinical relevance and applicability of measuring FGF23" as a key knowledge gap requiring further research 1
• KDIGO research priorities include assessing the effect of novel therapies to lower FGF23 in CKD G3-G4 and blocking FGF23 in CKD G5D on cardiovascular outcomes 1
• FGF23 can predict mortality and future development of refractory hyperparathyroidism in dialysis patients, where levels are markedly elevated in response to hyperphosphatemia and active vitamin D treatment 3

Treatment Considerations

Understanding FGF23's role influences therapeutic decision-making:

• Treatment with activated vitamin D compounds stimulates FGF23, raising important questions about optimal use of these agents in managing CKD-MBD 7
• Certain intravenous iron preparations increase intact FGF23 through mechanisms related to the carbohydrate shell, while ferric citrate (functioning as a phosphate binder) can lower both c-terminal and intact FGF23 levels 1
• Iron deficiency, ESA administration, and inflammation increase FGF23 levels by simultaneously increasing FGF23 transcription and cleavage, with different effects depending on CKD presence and severity 1

Common Pitfalls

Clinicians should recognize these important caveats:

• FGF23 levels must be interpreted in the context of phosphate, calcium, PTH, and vitamin D status, not as an isolated value, since these parameters form an integrated regulatory system 1
• The direct pathological role of FGF23 versus its function as a biomarker remains unclear, and whether FGF23 is a therapeutic target or simply a marker of disease severity continues to be debated 1
• Different FGF23 assays (intact versus c-terminal) may yield different clinical information, and the relative amounts of circulating forms are impacted by iron status, inflammation, ESA use, CKD presence, and iron formulation administered 1