FGF-23: More than a regulator of renal phosphate handling?

Abstract

Fibroblast growth factor 23 (FGF-23) is likely to be the most important regulator of phosphate homeostasis, which mediates its functions through FGF receptors and the coreceptor Klotho. Besides reducing expression of the sodium-phosphate cotransporters NPT2a and NPT2c in the proximal tubules, FGF-23 inhibits the renal 1α-hydroxylase and stimulates the 24-hydroxylase, and it appears to reduce parathyroid hormone (PTH) secretion in short-term studies. FGF-23 synthesis and secretion by osteocytes and osteoblasts is upregulated through 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and through an increased dietary phosphate intake. FGF-23 levels are elevated or inappropriately normal in patients with tumor-induced osteomalacia and several inherited hypophosphatemic disorders, but the most significant increases are found in patients with chronic kidney disease (CKD). During the early stages of CKD, increased FGF-23 production enhances urinary phosphate excretion and thus prevents the development of hyperphosphatemia, reduces the circulating levels of 1,25(OH)(2)D(3), and therefore contributes to the development of secondary hyperparathyroidism. In patients with end-stage renal disease (ESRD), FGF-23 levels can be extremely high and were shown to be predictors of bone mineralization, left ventricular hypertrophy, vascular calcification, and mortality. It remains to be determined, however, whether FGF-23 represents simply a sensitive biomarker of an abnormal phosphate homeostasis or has, independent of serum phosphate levels, potentially negative "off-target" effects. Nonetheless, reducing the production and/or the biologic activity of FGF-23 may be an important therapeutic goal for this patient population.

Fig. 1

Regulation of phosphate homeostasis in health and chronic kidney disease (CKD). (A) FGF-23, one of the most important regulators of phosphate homeostasis, is produced by osteocytes and osteoblasts in response to 1,25(OH)₂D₃ and when the dietary intake of phosphate is increased. PHEX, DMP1, and ENPP1 are most likely upstream regulators of FGF23 synthesis because inherited human disorders that are caused by a lack of these proteins are associated with increased FGF-23 levels and increased urinary phosphate excretion. Phosphate is absorbed in the gut from the diet, stored in the skeleton, and excreted by the kidneys. The sodium-dependent phosphate cotransporter NPT2b contributes significantly to the absorption of dietary phosphate, which is enhanced by 1,25(OH)₂D₃. FGF-23 activates different FGF receptors when associated with the coreceptor Klotho and it increases renal phosphate clearance by reducing expression of the sodium-dependent phosphate cotransporters NPT2a and NPT2c in the proximal renal tubules. It furthermore suppresses the renal 1α-hydroxylase and stimulates the 24-hydroxylase activity (not shown) and thus reduces 1,25(OH)₂D₃ levels through two different mechanisms. FGF-23 also may act on the parathyroid glands to decrease PTH production (dashed line). PTH activates the PTH/PTHrP receptor (PTHR1) and thereby increases renal phosphate clearance and 1,25(OH)₂D₃ synthesis. (Modified with permission from ref. (77).) (B) As renal function declines (CKD stages 2 to 4), FGF-23 levels increase, thereby enhancing renal phosphate clearance to help maintain serum phosphate levels within the normal range. Elevated FGF-23 levels, however, reduce 1,25(OH)₂D₃ levels and thus contribute to the development of secondary hyperparathyroidism. (C) In patients with end-stage renal disease (CKD stage 5) treated by dialysis, FGF-23 levels can be dramatically elevated and thus may have “off-target” effects in different tissues.