Intestinal absorption is the primary site of regulation of total body calcium. Dietary calcium is passively absorbed in a concentration-dependent fashion throughout the small intestine and is actively transported in the duodenum and upper jejunum by mechanisms regulated by 1,25-dihydroxyvitamin D. The efficiency of calcium absorption is increased with reduced dietary intake, rapid growth during childhood, pregnancy, and lactation. Dietary magnesium is principally absorbed in
the jejunum and the ileum by both active and passive mechanisms. Magnesium absorption is enhanced during reduced dietary intake. Phosphate is absorbed in the duodenum and jejunum by passive processes and active mechanisms regulated by 1,25-dihydroxyvitamin D. Absorption of phosphate is impeded by the presence of polyvalent cations (e.g., Ca²⁺, Mg²⁺, and Al³⁺) in the intestinal lumen or by deficiency of vitamin D. A small proportion of calcium, magnesium, and phosphate is secreted in digestive juices and excreted via stool.

Approximately 60%-70% of total plasma calcium, chiefly in its ionized and complexed forms, is filtered by the kidneys, with less than 5% of filtered calcium being excreted in the urine. Most (˜70%) of filtered calcium is reabsorbed along with sodium and water in the proximal convoluted tubule (PCT) by a concentration-dependent mechanism. An additional 15%-20% of calcium is reabsorbed in the thick ascending limb of the loop of Henle (TALH). The action of the Na⁺-K⁺-2Cl⁻ cotransporter in the thick ascending limb creates a potential difference that favors voltage-dependent absorption of calcium. The remaining 10%-15% of filtered calcium is reabsorbed in the distal convoluted tubule (DCT) by active mechanisms that are poorly understood and that are regulated by parathyroid hormone (PTH) and cyclic AMP.

Approximately 70%-80% of plasma magnesium, in its ionized or complex forms, is filtered in the glomerulus. Approximately 3% of filtered magnesium is excreted in the urine, and 5%-15% is reabsorbed in the PCT by an undefined passive mechanism. The majority of filtered magnesium (60%-70%) is reabsorbed in the TALH as the consequence of a voltage-dependent gradient generated by action of the Na⁺-K⁺-2Cl⁻ cotransporter. The remaining 5%-10% of magnesium is reabsorbed in the DCT by an unknown mechanism that is stimulated by PTH (2).

As with calcium and magnesium, the ionized and complexed forms of phosphate are filtered in the glomerulus and accounts for ultrafiltration of 85%-90% of the total plasma phosphate. The amount of phosphate excreted in the urine ranges from 3% to 20% of the filtered load. Nearly 80% of the filtered phosphate is reabsorbed in the PCT through the action of sodium-phosphate (Na-P) cotransporters, which are regulated by PTH. An additional 5% of phosphate is reabsorbed in the DCT by an unknown active mechanism (3). Thus, the kidney is the major site of regulation of total body phosphorous.

Multiple factors can alter renal reabsorption or excretion of calcium, magnesium, and phosphate (1) (Table 108.1). Volume expansion, for example with a bolus saline infusion, leads to increased calcium, magnesium, and phosphate excretion primarily due to decreased proximal tubular reabsorption. Hypercalcemia decreases renal blood flow and glomerular filtration rate (GFR) and simultaneously increases excretion of calcium due to decreased reabsorption of calcium in the proximal tubule, loop of Henle, and DCT. The net effect of these two potentially opposing mechanisms is enhanced calcium excretion due to suppression of PTH release by elevated serum calcium levels. The effects of hypercalcemia on phosphate excretion are determined by the duration of the hypercalcemic state. During acute hypercalcemia, reduction in GFR, formation of calcium-phosphate-protein complexes (which prevents ultrafiltration of phosphate), and suppression of PTH release (which prevents phosphate reabsorption in the proximal tubule) contribute to decreased phosphate excretion. In contrast, during chronic hypercalcemia, phosphate excretion increases due to decreased reabsorption via unknown mechanisms. Hypocalcemia induces PTH secretion, which in turn reduces renal excretion of calcium by enhancing reabsorption in the DCT. Hypocalcemia contributes to reduced excretion of magnesium and phosphate by increasing magnesium absorption in the TALH and by increasing phosphate absorption by an unknown mechanism. Hypermagnesemia has no clear effect on calcium or phosphate excretion but increases magnesium excretion by reducing the fractional reabsorption of magnesium in the proximal tubule and inhibiting reabsorption in the loop of Henle. Conversely, during hypomagnesemia, magnesium excretion is decreased due to increased reabsorption in the loop of Henle by an unclear mechanism. Hyperphosphatemia induces PTH secretion, thereby reducing calcium excretion through increased uptake in the DCT. Hyperphosphatemia has no clear effect on magnesium excretion. Hypophosphatemia increases Na-P cotransporter-mediated reabsorption in the proximal tubule, thereby decreasing phosphate excretion.

Acid-base disturbances have significant effects on renal handling of calcium, magnesium, and phosphate. Both acute and chronic metabolic acidosis induce calciuria by inhibiting epithelial calcium channel type 1 (ECaC1)-mediated uptake of calcium in the distal tubule (4). On the other hand, metabolic alkalosis enhances conductance of calcium through the ECaC1, leading to reduced calcium excretion (4). Metabolic alkalosis reduces renal losses of magnesium by increasing absorption in the loop of Henle. Acute metabolic acidosis does not seem to have any significant effect on phosphate excretion, whereas chronic metabolic acidosis causes phosphaturia by reducing Na-P cotransporter expression at the tubular cell surface, resulting in decreased absorption in the proximal tubule (5). Respiratory acidosis enhances both calcium and phosphate excretion. Respiratory alkalosis decreases renal phosphate excretion but has no effect on calcium excretion. Respiratory acid-base disturbances do not appear to have any significant effect on magnesium excretion.

Multiple medications, in particular diuretics, have a major impact on renal excretion of calcium, magnesium, and phosphate. Thiazide diuretics decrease calcium excretion by enhanced calcium reabsorption in the DCT. In contrast, thiazide diuretics cause a modest increase in magnesium excretion via inhibition of the Na⁺-Cl⁻ cotransporter. Thiazides induce phosphaturia by inhibiting carbonic anhydrase. Loop diuretics augment calcium and magnesium excretion through inhibition of the Na⁺-K⁺-Cl⁻ cotransporter in the TALH, which reduces voltage-dependent absorption of both calcium and magnesium. Similar to thiazides, loop diuretics slightly enhance phosphate excretion through inhibition of carbonic anhydrase (6). Other medications such as aminoglycosides, cisplatin, and cyclosporine have been shown to increase magnesium excretion by inhibiting magnesium reabsorption in the loop of Henle (6). These medications generally do not affect calcium or phosphate excretion.

The plasma concentrations of calcium, phosphate, and, to a lesser degree, magnesium are precisely regulated by several hormones (Table 108.2). The key hormones in calcium regulation are PTH, 1,25-dihydroxyvitamin D, and calcitonin.