Fibroblast growth factor 23, Klotho, and phosphorus metabolism in chronic kidney disease

Abstract

Fibroblast growth factor 23 (FGF23) and Klotho have emerged as major hormonal regulators of phosphorus (P) and vitamin D metabolism. FGF23 is secreted by bone cells and acts in the kidneys to increase urinary P excretion and inhibit the synthesis of 1,25 dihydroxyvitamin D (1,25(OH)2D) and in the parathyroid glands to inhibit the synthesis and secretion of parathyroid hormone. Phosphorus excess stimulates FGF23 secretion, likely as an appropriate physiological adaptation to maintain normal P homeostasis by enhancing urinary P excretion and diminishing intestinal P absorption via lower 1,25(OH)2D. The FGF23 concentrations are elevated early in the course of chronic kidney disease (CKD) and may be a primary initiating factor for the development of secondary hyperparathyroidism in this setting. Klotho exists in two forms: a transmembrane form and a secreted form, each with distinct functions. The transmembrane form acts as the key co-factor needed for FGF23 to bind to and activate its cognate receptor in the kidneys and the parathyroid glands. The secreted form of Klotho has FGF23-independent effects on renal P and calcium handling, insulin sensitivity, and endothelial function. Disturbances in the expression of Klotho may play a role in the development of altered bone and mineral metabolism in early CKD. In addition, abnormal circulating concentrations of both FGF23 and Klotho have been linked to excess cardiovascular disease, suggesting that both play an important role in maintaining cardiovascular health.