Inorganic phosphate is an essential nutrient in terms of both cell function and skeletal mineralization. It is required for glycolysis, gluconeogenesis, and energy metabolism, as well as for the synthesis of DNA, RNA, membrane phospholipids, and a variety of phosphorylated intermediates. In addition, the phosphorylation of cellular proteins is a major mechanism by which cell function is controlled. Intracellular regulatory roles for the inorganic phosphate anion involve such diverse functions as control of aerobic metabolism, control of the O2 dissociation curve of hemoglobin in the intact red blood cell, and regulation of cellular calcium metabolism.
Phosphate is sufficiently abundant in the usual human diet. Thus phosphate deficiency is unlikely to develop except under unusual circumstances, such as extreme starvation or as a consequence of administration of a class of therapeutic agents known as phosphate binders that bind phosphate in the intestinal lumen and prevent its absorption. The major portion of ingested phosphate (65–75 percent) is absorbed in the small intestine, and hormonal regulation of this process plays only a minor role in normal phosphate homeostasis. Absorbed phosphate is either eliminated by the kidney, incorporated into organic forms in proliferating cells, or deposited as a component of bone mineral (hydroxyapatite). Bone deposition accounts for a much larger percentage of retained phosphate during the growth period. However, even in the growing organism, only a small percentage of absorbed phosphate is retained, with most of it being excreted in the urine.
Phosphate homeostasis and plasma phosphate concentration depend primarily on renal mechanisms that regulate tubular phosphate transport. In view of the central role of the kidney in phosphate homeostasis, it is not surprising that the mechanisms that determine tubular phosphate reabsorption are complex and are regulated by a multiplicity of factors (for reviews, see refs. 1–13). Three important determinants of renal phosphate handling are dietary phosphate intake, circulating parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23).
Five well-characterized renal phosphate wasting disorders will be discussed herein. Four—X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), and autosomal recessive hypophosphatemic rickets (ARHR)—are inherited, and the fifth—tumor-induced osteomalacia (TIO)—is acquired. The latter is included in the present discussion because of its possible relevance to our understanding of the pathogenesis of the inherited forms of hypophosphatemia and the regulation of renal phosphate handling.
Despite the fact that all five conditions are characterized by a renal phosphate leak [i.e., a reduced maximum tubular capacity for phosphate reabsorption per glomerular filtration rate (TmP/GFR)] and hypophosphatemia and are associated with rickets and/or osteomalacia, patients with HHRH require different therapeutic measures. In the ensuing discussion, a consideration of phosphate homeostasis and renal phosphate handling will be followed by a discussion of the pathogenic mechanisms involved in these conditions. The clinical features of each syndrome and its treatment will be presented. Studies in the Hyp murine homologue of XLH is also described because it ...