Fibroblast Growth Factor 23 and the Last Mile

Reduction in FGF23 Concentrations

Given that dietary phosphorus intake stimulates FGF23, the most common approach to reducing FGF23 has centered on using drugs to diminish gastrointestinal phosphorus absorption—via dietary phosphorus restriction, oral phosphorus binders, or inhibitors of sodium-proton exchange transporters or sodium-phosphorus cotransporter 2b in gut epithelial cells (5). In general, these approaches have had modest effects on reducing FGF23 concentrations in patients with CKD, with long-term concerns about adherence. Furthermore, no randomized, controlled trials have shown that reducing FGF23 through restriction of gastrointestinal phosphorus absorption improves meaningful clinical outcomes in CKD.

Calcimimetics are more effective in lowering FGF23, reducing FGF23 concentrations by approximately 30%–50% in patients with ESKD (6). Furthermore, in a post hoc analysis, a greater reduction in FGF23 concentrations in response to cinacalcet was strongly associated with lower mortality and cardiovascular disease events (particularly heart failure) in patients on hemodialysis (6). These data provide some evidence that a strategy of lowering FGF23 using calcimimetics may improve outcomes in patients with ESKD.

Given the efficacy of anti-FGF23 antibodies in reducing FGF23 concentrations and improving symptoms in individuals with phosphorus wasting disorders, a similar approach may be feasible in CKD. Enthusiasm for this needs to be counterbalanced by experimental data showing poor outcomes in animals with CKD exposed to anti-FGF23 antibodies due to the development of hyperphosphatemia and accelerated mortality when FGF23 concentrations were drastically reduced (7). In light of these data, it is likely that the use of anti-FGF23 antibodies may be most relevant for those with ESKD, and even then, those with little to no residual kidney function.

Inhibition of FGFR4

It is important to note that the classic effects of FGF23 in the kidney are mediated by binding to complexes of FGFR1 and Klotho, leading to activation of Ras/mitogen-activated protein kinase signaling (4). In contrast, the prohypertrophic effects of FGF23 on cardiomyocytes are mediated by binding of FGF23 to FGFR4, even in the absence of Klotho, which activates phospholipase Cγ/calcineurin/NF of activated T cells signaling. This is serendipitous in that it allows for a more targeted approach to inhibiting adverse effects of FGFR4 binding in the heart without at the same time blocking the FGFR1-specific effects of FGF23 in enhancing phosphaturia. The potential importance of this was demonstrated by studies showing that the adverse effects of elevated FGF23 on cardiac hypertrophy in animals with experimentally induced CKD were partially reversible through targeted blockade of FGF23 binding to FGFR4 without precipitating hyperphosphatemia (4).

In addition to cardiac hypertrophy, FGF23 binding to FGFR4 may promote cardiovascular disease by stimulating inflammation. In cultured hepatocytes, FGF23 induces secretion of inflammatory cytokines through binding to FGFR4. Additionally, injection of FGF23 in mice increased hepatic C-reactive protein (CRP) and IL-6 expression and raised serum CRP concentrations compared with mice injected with vehicle (8). Importantly, injection of anti-FGFR4 antibodies or cyclosporin A in 5/6-nephrectomized rats prevented the elevation of serum CRP compared with nephrectomized rats treated with vehicle, despite no differences in the degree of kidney function decline (8). These intriguing data suggest that blockade of FGFR4 or the calcineurin-dependent signaling pathway by which FGFR4 activation upregulates inflammatory cytokine secretion may be a novel therapy for reducing systemic inflammation in patients with CKD.

Treatment of Iron Deficiency

Iron plays a key role in regulating phosphorus metabolism (9). Experimental data have shown that iron deficiency increases FGF23 expression by stabilizing hypoxia-inducible factor 1α, which in turn, binds to a site in the Fgf23 promoter to induce transcription. The hypoxia-inducible factor 1α–induced increase in FGF23 expression is normally accompanied by increased cleavage of the intact FGF23 peptide into N- and C-terminal fragments of unclear physiologic significance, presumably to protect from developing systemic signs of excess FGF23. Thus, iron deficiency is typically characterized by high concentrations of C-terminal FGF23 (consisting of both C-terminal FGF23 fragments as well as the intact peptide) but normal or only slightly high intact FGF23. However, individuals with CKD have an impaired ability to cleave the intact FGF23 peptide, especially in ESKD, in which virtually all circulating FGF23 is the full-length peptide. Accordingly, iron deficiency may be a novel factor underlying excess intact FGF23 in patients with CKD, with attendant consequences such as cardiac hypertrophy and inflammation. Whether iron supplementation similarly lowers FGF23 in patients with CKD is an active area of investigation. Importantly, because the C-terminal FGF23 assay detects the intact peptide as well as circulating fragments, identifying individuals who might benefit from treatment of iron deficiency would require using FGF23 assays that detect the intact peptide exclusively.

Inhibition of the Renin-Angiotensin-Aldosterone System

FGF23 may also affect cardiovascular health via effects on the renin-angiotensin-aldosterone system. Elevated FGF23 was shown to increase the expression of renin-angiotensin-aldosterone system genes in cardiomyocytes (4). Furthermore, treatment with renin-angiotensin-aldosterone system inhibitors attenuated the effects of FGF23 on cardiomyocyte hypertrophy and fibrosis in in vitro models. This is important in that post hoc analyses of randomized controlled trials of angiotensin-converting enzyme inhibitors in the treatment of ischemic heart disease and heart failure showed that the benefit from treatment with an angiotensin-converting enzyme inhibitor was only observed in individuals with an elevated baseline FGF23 (10). Together, these data suggest that treatment with renin-angiotensin-aldosterone system inhibitors may attenuate the adverse effects of FGF23 on cardiac function.