Recent advances in renal phosphate handling

Abstract

Phosphate is critical for the maintenance of skeletal integrity, is a necessary component of important biomolecules, and is central to signal transduction and cell metabolism. It is becoming clear that endocrine communication between the skeleton, kidney, and the intestine is involved in maintaining appropriate serum phosphate concentrations, and that the kidney is the primary site for minute-to-minute regulation of phosphate levels. The identification of genetic alterations in Mendelian disorders of hypophosphatemia and hyperphosphatemia has led to the isolation of novel genes and the identification of new roles for existing proteins--such as fibroblast growth factor 23 and its processing systems, the co-receptor alpha-klotho, and phosphate transporters--in the control of renal phosphate handling. Recent findings also indicate that fibroblast growth factor 23 has feedback mechanisms involving parathyroid hormone and vitamin D that control phosphate homeostasis. This Review will highlight genetic, in vitro and in vivo findings, and will discuss how these clinical and experimental discoveries have uncovered novel aspects of renal phosphate handling and opened new research and therapeutic avenues.

Figure 1. FGF23 regulatory systems in phosphate metabolism

FGF23 is produced in bone and secreted into the circulation, potentially in response to increased phosphate, 1,25(OH)₂D, and PTH. FGF23 acts in the kidney to decrease Npt2a and Npt2c expression and decrease 1,25(OH)₂D production, resulting in hypophosphatemia. Potentially, in a novel feedback loop FGF23 may reduce PTH mRNA and protein. (Red arrows indicate suppressive effects; green arrows indicate stimulatory effects).

Figure 2. The molecular and physiological consequences of genetic alterations in heritable hypo- and hyperphsophatemia

FGF23 is produced in osteoblasts and osteocytes (left). In hypophosphatemic disorders (outlined in red and red arrows), loss of PHEX and DMP1, in XLH and ARHR, respectively, are associated with a cell differentiation defect that causes elevated FGF23 by unknown mechanisms. The ADHR gain of function alterations in FGF23 result in a more stable full length protein. Circulating FGF23 (wild type or ADHR-mutant) signals through p-ERK1/2 in the renal DCT and down-regulates Npt2a, Npt2c, and the 1-α-hydroxylase, and increases the catabolic 24-hydroxylase in the proximal tubule through unknown mechanisms. This process leads to hypophosphatemia, osteomalacia, and fracture. In the hyperphosphatemic disorder TC (outlined in blue and blue arrows), loss of function mutations in FGF23 and GALNT3 result in incompletely glycosylated FGF23, which increases susceptibility to proteolysis and results in the secretion of inactive FGF23 fragments. Loss of FGF23 bioactivity results in the converse expression of the sodium-phosphate co-transporters and vitamin D metabolizing enzymes. The effect on serum biochemistries is hyperphosphatemia with elevated 1,25(OH)₂D, which leads to ectopic and vascular calcifications.