Clinical Note

Calcium and Phosphate Balance in Renal Failure

Renal failure patients, among their other problems, also suffer from hyperparathyroidism and a resulting reabsorption of bone that leads to osteoporosis and increased risk of fractures. The reasons for the hyperparathyroidism are not completely known. According to one hypothesis, the decreased clearance of phosphate as GFR falls leads to a small increase in its plasma concentration, causing a fall in the plasma Ca2+ concentration and the secretion of PTH. Elevated levels of PTH help the kidneys to maintain phosphate balance by decreasing phosphate reabsorption in the proximal tubule (see Chapter 26), but they also cause the bone pathology.

An additional or alternate possibility is that phosphate retention as well as the reduction in renal mass would diminish 1,25(OH)2D3 production. (The kidney is the primary site where dietary vitamin D is converted to the highly active calcitriol form; see Chapter 43.) The fall in calcitriol decreases its normal tonic inhibition of PTH secretion, leading to increased PTH secretion. It has been found that when patients on hemodialysis are given calcitriol intravenously, plasma PTH levels are markedly reduced.

The usual mode of therapy for the phospha-temia and hyperparathyroidism of renal failure is to have the patient eat a low-phosphate diet and to administer phosphate binding agents such as calcium carbonate to reduce intestinal absorption of phosphate.

approach the filtered load with excessive magnesium intake, and it can even exceed the filtered load in the extreme. Alternatively, filtered Mg2+ can be reabsorbed almost completely in states of Mg2+ depletion. Presumably, these changes in renal handling occur because of hormonal influences, but these mechanisms are at present unknown.

The proximal tubule passively reabsorbs a far smaller fraction of Mg2+ (only 20-30%) than of Na+, K+, or Ca2+. Although the Mg2+ concentration in the tubular fluid of the proximal tubule and the descending limb of the loop of Henle rises considerably as fluid is reabsorbed, its reabsorption is limited due to the low Mg2+ permeability of the junctional complexes in these segments of the nephron. However, about two-thirds of the filtered Mg2+ is reabsorbed passively in the thick ascending limb of the loop of Henle. The elevated luminal concentration of Mg2+ and the lumen-positive voltage in these segments provide a large driving force for this passive reabsorption, but it would not occur if it were not for the presence of a protein called paracellin in the junctional complexes of the thick ascending limb. It appears that paracellin mediates the facilitated diffusion of Mg2+, and to a lesser extent Ca2+, and it is the first known example of such a transporter in the junctional complexes. Paracellin was discovered serendipitously through research on a rare congenital defect that causes hypomagnesemia due to excessive urinary Mg2+ excretion. Genomic analysis of a kindred that exhibited this trait revealed a linked gene mutation. Antibodies that were raised to the protein coded by the normal gene revealed that it was localized exclusively to the junctional complexes between thick ascending limb cells, leading to its name paracellin. There seems to be some competition between Mg2+ and Ca2+ for this transporter, but because of its limited reabsorption in the more proximal regions of the nephron, the absence of paracellin has a greater effect on Mg2+ than Ca2+ excretion. A small amount of the filtered Mg2+ is also reabsorbed in the distal convolution, the connecting tubule and collecting duct by mechanisms that have not been identified but appear to be passive.

Suggested Readings

Friedman PA. Renal calcium metabolism. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1749-1790. Hoenderop JG, Nilius B, Bindels RGM. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol 2002;64:529-549.

Malnic G, Muto S, Giebisch G. Regulation of renal potassium excretion. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1575-1614. Quamme GA, DeRouffignac CP. Renal magnesium handling. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1711-1730.

Rosa, RM, Epstein FH. Extrarenal potassium metabolism. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 2, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1551-1574.

Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders, 5th ed. New York: McGraw-Hill, 2001, pp 372-403. Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredle D, Milford D, Sanjad S, Lifton RP. Paracellin-1, a renal tight junction protein required for paracellular Mg2+ reabsorption. Science 1999;285:103-106.

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