Phosphate and FGF-23

Abstract

Fibroblast growth factor (FGF)-23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)₂D₃) levels. It is secreted by osteocytes and osteoblasts in response to oral phosphate loading or increased serum 1,25(OH)₂D₃ levels. In human chronic kidney disease (CKD), plasma FGF-23 appears to be a sensitive biomarker of abnormal renal phosphate handling, as FGF-23 levels increase during early stages of kidney malfunction. In humans and animals with CKD, elevated FGF-23 levels increase fractional phosphate excretion, reduce serum phosphate levels, and reduce 1α-hydroxylase activity, which reduces 1,25(OH)₂D₃ formation thereby increasing parathyroid hormone (PTH) secretion. FGF-23 thus has a key adaptive role in maintaining normophosphatemia. Plasma FGF-23 continues to increase as CKD progresses, increasing by orders of magnitude in end-stage renal disease. At the same time, responsiveness to FGF-23 declines as the number of intact nephrons declines, which is associated with reduced expression of Klotho, the co-receptor required for FGF-23 signaling. In late CKD, FGF-23 cannot reduce serum phosphate levels, and abnormally high plasma FGF-23 concentrations appear to exert unwarranted off-target effects, including left ventricular hypertrophy, faster CKD progression, and premature mortality. Lowering serum phosphate levels through the use of oral phosphate binders and/or long-acting PTH agents may reduce FGF-23 levels in early CKD stages, thereby limiting off-target effects, which may improve patient outcomes.

Figure 1

Spectrum of serum fibroblast growth factor (FGF)-23 levels in early chronic kidney disease and end-stage renal disease (ESRD) as compared with the normal condition and with different disorders affecting FGF-23. ADHR, autosomal dominant hypophosphatemic rickets; ARHP, autosomal recessive hypophosphatemia; TIO, tumor-induced osteomalacia; XLH, X-linked hypophosphatemia. Adapted with permission from Isakova et al.

Figure 2

Mortality in patients with end-stage renal disease (ESRD) receiving hemodialysis in relationship to quartiles of serum fibroblast growth factor (FGF)-23 concentration at initiation of dialysis. R, reference. Reproduced with permission from Gutiérrez et al. Copyright The Massachusetts Medical Society.

Figure 3

‘Trade-off hypothesis' revisited. Involvement of fibroblast growth factor (FGF)-23 in end-stage renal disease (ESRD) pathology, reflecting potentially adverse effects of increased secretion of this phosphaturic hormone, which helps normalize phosphate homeostasis but contributes to the development of secondary hyperparathyroidism. PTH, parathyroid hormone.