Higher circulating levels of phosphate and fibroblast growth factor (FGF)-23 are associated with increased risk of cardiovascular disease in populations with or without chronic kidney disease
Higher phosphate concentrations induce vascular calcification and endothelial dysfunction in vitro and in animal models; observational studies in humans have corroborated these findings
Higher levels of FGF-23 might have direct hypertrophic effects on cardiac myocytes, which could explain their association with left ventricular hypertrophy and congestive heart failure in patients
Simultaneous control of FGF-23 and serum phosphate levels might be useful strategies to reduce cardiovascular disease in at-risk populations, including those with chronic kidney disease
Disturbances in phosphate homeostasis are common in patients with chronic kidney disease. As kidney function declines, circulating concentrations of phosphate and the phosphate-regulatory hormone, fibroblast growth factor (FGF)-23, rise progressively. Higher serum levels of phosphate and FGF-23 are associated with an increased risk of adverse outcomes, including all-cause mortality and cardiovascular events. The associations between higher FGF-23 levels and adverse cardiovascular outcomes are generally independent of serum phosphate levels, and might be strongest for congestive heart failure. Higher serum phosphate levels are also modestly associated with an increased risk of cardiovascular events even after accounting for FGF-23 levels. This observation suggests that FGF-23 and phosphate might promote distinct mechanisms of cardiovascular toxicity. Indeed, animal models implicate high serum phosphate as a mechanism of vascular calcification and endothelial dysfunction, whereas high levels of FGF-23 are implicated in left ventricular hypertrophy. These seemingly distinct, but perhaps additive, adverse effects of phosphate on the vasculature and FGF-23 on the heart suggest that future population-level and individual-level interventions will need to simultaneously target these molecules to reduce the risk of associated cardiovascular events.
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J.J.S. is supported by grant K23DK095949 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). M.W. is supported by grants R01DK076116, R01DK081374, R01DK094796, K24DK093723 and U01DK099930, all from the NIDDK.
M.W. declares that he has served as a consultant or received honoraria from Abbott, Amgen, Genzyme, Keryx Biopharmaceuticals, Lutipold Pharmaceuticals, Opko, Pfizer, Shire and Vifor Pharma. J.J.S. declares no competing interests.
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Scialla, J., Wolf, M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol 10, 268–278 (2014). https://doi.org/10.1038/nrneph.2014.49
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