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Chapter 36 discusses the homeostasis of potassium, calcium, and phosphate. Figure 36.18 illustrates the transport of phosphate (Pi) along the nephron, with the proximal tubule being the primary site of Pi reabsorption. Around 20% of the filtered Pi is excreted. In patients with chronic renal failure, the kidneys are unable to excrete Pi. Consequently, Pi accumulates in the body and plasma, resulting in an increase in plasma Pi concentration. The excess Pi binds with calcium ions (Ca++) and reduces the concentration of ionized calcium in the plasma. Furthermore, the accumulation of Pi inhibits the production of calcitriol, which leads to a reduction in calcium absorption by the intestine, further lowering plasma calcium levels. This decrease in plasma calcium triggers the secretion of parathyroid hormone (PTH) and the release of calcium from bones. These actions contribute to renal osteodystrophy, characterized by increased bone resorption and replacement with fibrous tissue, making the bones more prone to fractures. Chronic hyperparathyroidism, caused by the elevated PTH levels due to the decrease in plasma calcium, can result in metastatic calcifications where calcium and Pi precipitate in arteries, soft tissues, and organs. The deposition of calcium and Pi in the heart can lead to myocardial failure. To prevent and treat hyperparathyroidism and Pi retention, a low-phosphate diet or the use of a "phosphate binder" can be prescribed. A phosphate binder is a substance that forms insoluble Pi salts, rendering Pi unavailable for absorption by the intestine. Additionally, supplemental calcium and calcitriol may be administered to increase plasma calcium levels. Figure 36.19 depicts the cellular mechanisms involved in Pi reabsorption by the proximal tubule. The apical transport pathway contains two Na+/Pi symporters, one transporting three sodium ions (Na+) for each Pi (IIa) and the other transporting two Na+ for each Pi (IIc). The basolateral membrane facilitates the exit of Pi from the cell, but the exact mechanism is unknown. Fibroblast growth factor 23 (FGF-23) is a hormone secreted by osteocytes and osteoblasts. It increases renal Pi excretion and plays a role in regulating plasma Pi concentration. FGF-23 inhibits Pi reabsorption and calcitriol production by the proximal tubule. The secretion of FGF-23 is stimulated by sustained hyperphosphatemia, PTH, and calcitriol. Genetic mutations in the FGF23 gene can lead to various disorders, such as hypophosphatemia with low plasma calcitriol and rickets/osteomalacia in activating mutations, or hyperphosphatemia with high serum calcitriol and calcification of soft tissues in inactivating mutations. The regulation of urinary phosphate excretion is summarized in Table 36.3 and Figure 36.20. Increased plasma Pi levels reduce the reabsorption of Pi in the proximal tubule.

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CHAPTER 36 Potassium, Calcium, and Phosphate Homeostasis • Fig. 36.18 Pi transport along the nephron. Pi is reabsorbed primarily by the proximal tubule. Percentages refer to the amount of the filtered Pi reabsorbed by each nephron segment. Approximately 20% of the filtered Pi is excreted. CCD, cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.
In patients with chronic renal failure, the kidneys cannot excrete Pi. Because of continued Pi absorption by the intestinal tract, Pi accumulates in the body and plasma [Pi] rises. The excess Pi complexes with Ca++ and reduces the ionized plasma [Ca++]. Pi accumulation also decreases production of calcitriol. This response reduces Ca++ absorption by the intestine, an effect that further reduces plasma [Ca++]. This reduction in plasma [Ca++] increases PTH secretion and Ca++ release from bone. These actions result in renal osteodystrophy (i.e., increased bone resorption with replacement by fibrous tissue, which renders bone more susceptible to fracture). Chronic hyperparathyroidism (i.e., elevated PTH levels due the fall in plasma [Ca++]) during chronic renal failure can lead to metastatic calcifications in which Ca++ and Pi precipitate in arteries, soft tissues, and viscera. Deposition of Ca++ and Pi in the heart may cause myocardial failure. Prevention and treatment of hyperparathyroidism and Pi retention include a low-Pi diet or administration of a “phosphate binder” (i.e., an agent that forms insoluble Pi salts and thereby renders Pi unavailable for absorption by the intestinal tract) in the diet. Supplemental Ca++ and calcitriol are also prescribed to increase plasma [Ca++].
• Fig. 36.19 Cellular mechanisms of Pi reabsorption by the proximal tubule. The apical transport pathway contains two Na+/Pi symporters, one that transports three Na+for each Pi (IIa) and one that transports two Na+for each Pi (IIc). Pi leaves the cell across the basolateral membrane by an unknown mechanism. ATP, adenosine triphosphate. TubularfluidBloodPiPiK˜Na˜2Na˜Pi3Na˜ATPIIaIIc?
Fibroblast growth factor 23 (FGF-23) increases renal Pi excretion and thereby contributes to regulation of plasma [Pi] (see
Fig. 36.17 ). FGF-23 is secreted by osteocytes and osteoblasts and inhibits Pi reabsorption and calcitriol production by the proximal tubule. Secretion of FGF-23 is stimulated by sustained hyperphosphatemia, PTH, and calcitriol. Activating mutations in the FGF23 gene cause hypophosphatemia, low plasma calcitriol, and rickets/osteomalacia, whereas inactivating mutations cause hyperphosphatemia, high serum calcitriol, and calcification of soft tissue.
Regulation of Urinary Phosphate Excretion
Table 36.3
Fig. 36.20 ). Increased plasma Pi reduces
TABLE Summary of Hormones and Factors 36.3 Affecting Pi Reabsorption by Proximal Tubule