Chapter 7: Disorders of Phosphorus Balance: Hyperphosphatemia and Hypophosphatemia

INTRODUCTION

Approximately 80–85% of phosphorus in the body is contained in bone, 14% in cells and soft tissues, and 1% in the extracellular fluid. A very small fraction of the intracellular pool is inorganic and available for synthesis of high-energy phosphorus-containing molecules. Neutral phosphate balance is maintained with dietary intakes over a wide range from 800 to 1500 mg/day. Phosphorus homeostasis is dependent upon the interaction of three organ systems: the gastrointestinal (GI) tract, bone, and kidney. A general overview of phosphorus metabolism is shown in Figure 7–1.

Normal plasma phosphorus concentration is about 2.5–4.5 mg/dL. Approximately 85–90% of plasma phosphorus is freely filtered by the glomerulus. The small amount that is nonfilterable is due to protein binding. Normally, renal tubules reabsorb 80–97% of the filtered load so that only 3–20% of filtered phosphate appears in urine. The proximal convoluted tubule reabsorbs nearly 80% of filtered phosphate. Another 10% is reabsorbed in the distal convoluted tubule by unclear mechanisms. Phosphate reabsorption in the proximal tubule occurs by a transcellular route. Phosphate traverses the apical cell membrane via a Na⁺/PO₄ cotransporter (Figure 7–2). Energy for this process is supplied by the basolateral Na⁺/K⁺ ATPase, which maintains intracellular Na⁺ concentration low, thus providing a favorable gradient for inward Na⁺ movement. There is a variety of different sodium phosphate cotransporters expressed in kidney. Types IIa and IIc mediate the majority of phosphate transport in proximal tubule, while the role of PiT-2 is still being actively investigated. Parathyroid hormone (PTH) and fibroblast growth factor (FGF)-23 decrease transporter activity via an endocytic retrieval process whereby the proteins are removed from the luminal membrane and degraded in the lysosomal compartment. This leads to an increase in phosphorus excretion.

FGF-23 is a 251 amino acid protein secreted by osteocytes and osteoblasts in response to hyperphosphatemia, high phosphorus intake, and 1,25-dihydroxyvitamin D₃. It inhibits PTH synthesis and secretion and results in removal of sodium-phosphate cotransporters from the proximal tubular luminal membrane. It decreases 1,25-dihydroxyvitamin D₃ concentration due to downregulation of 1α-hydroxylase and upregulation of 24-hydroxylase. FGF-23 can be detected in the circulation of healthy people, indicating that it may play a role in normal phosphate homeostasis.

Several lines of evidence suggest that FGF-23 is important in the feedback regulation of 1,25-dihydroxyvitamin D₃ concentration. FGF-23 knockout mice have elevated 1,25-dihydroxyvitamin D₃ levels. When injected into animals, FGF-23 reduces 1,25-dihydroxyvitamin D₃ concentration within 3 hours (a result of a combination of decreased synthesis and increased degradation). This is followed several hours later by a decrease in ...