Jury still out on whether FGF23 is a direct contributor, a useful biomarker, or neither

Abstract

Fibroblast growth factor 23 (FGF23) is an endocrine hormone that is mainly produced by osteocytes. In patients with chronic kidney disease (CKD), circulating FGF23 levels increase as kidney function declines. This helps maintain normal phosphate balance by enhancing urinary phosphate excretion. As a trade-off, it suppresses biosynthesis of 1,25-dihydroxyvitamin D, favoring the early development of secondary hyperparathyroidism. Besides these canonical renal actions, FGF23 has been identified as an independent predictor of mortality, cardiovascular disease, and other adverse outcomes. 1 Gutiérrez O.M. Mannstadt M. Isakova T. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med. 2008; 359: 584-592 Crossref PubMed Scopus (1402) Google Scholar , 2 Chonchol M. Greene T. Zhang Y. et al. Low vitamin D and high fibroblast growth factor 23 serum levels associate with infectious and cardiac deaths in the HEMO study. J Am Soc Nephrol. 2016; 27: 227-237 Crossref PubMed Scopus (102) Google Scholar , 3 Komaba H. Fuller D.S. Taniguchi M. et al. Fibroblast growth factor 23 and mortality among prevalent hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. Kidney Int Rep. 2020; 5: 1956-1964 Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar , 4 Wolf M. Molnar M.Z. Amaral A.P. et al. Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality. J Am Soc Nephrol. 2011; 22: 956-966 Crossref PubMed Scopus (226) Google Scholar , 5 Marthi A. Donovan K. Haynes R. et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J Am Soc Nephrol. 2018; 29: 2015-2027 Crossref PubMed Scopus (106) Google Scholar Experimental data suggest a direct link between FGF23 and multiple organ injury, particularly cardiac hypertrophy, 6 Grabmer A. Amaral A.P. Schramm K. et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015; 22: 1020-1032 Abstract Full Text Full Text PDF Scopus (360) Google Scholar which provides biological plausibility to support the observational findings. Despite these seemingly compelling data, however, it remains unclear whether FGF23 has a causal role in adverse events and whether FGF23 serves as a useful predictor of poor outcomes or a reliable biomarker of disordered phosphate metabolism. In this article, we present various arguments that plead against the role of FGF23 as a causal actor in CKD-associated pathologies. Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23Kidney InternationalVol. 94Issue 1PreviewSeveral experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Full-Text PDF Open ArchiveThe elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease riskKidney InternationalVol. 94Issue 1PreviewHigh circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Full-Text PDF Open ArchiveRole of FGF23 in clinical outcomes of patients with chronic kidney diseaseKidney InternationalVol. 100Issue 5PreviewMutations and overexpression of the hormone fibroblast growth factor 23 (FGF23) were discovered 20 years ago as the cause of autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia, respectively. Subsequently, numerous studies first demonstrated the role of FGF23 in regulating phosphate and calcium homeostasis and second its involvement in inflammation, iron metabolism, and erythropoiesis.1 Moreover, a steadily increasing number of observational studies in patients with advanced stages of chronic kidney disease (CKD) showed associations of increased circulating FGF23 levels with intermediate and hard outcomes, including myocardial hypertrophy and dysfunction, cardiovascular events, and mortality. Full-Text PDF