Renal control of calcium, phosphate, and magnesium homeostasis

Abstract

Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.

Keywords: calcium; cell and transport physiology; channel; electrolytes; ion; renal physiology.

Figure 1.

Calcium, phosphate, and magnesium flux between body compartments. Calcium (A), phosphate (B), and magnesium (C) balance is a complex process involving bone, intestinal absorption of dietary calcium, phosphate, and magnesium, and renal excretion of calcium, phosphate, and magnesium.

Figure 2.

Intestinal pathways for calcium, phosphorus, and magnesium absorption. (A) Proposed pathways for calcium (Ca) absorption across the intestinal epithelium. Two routes exist for the absorption of Ca across the intestinal epithelium: the paracellular pathway and the transcellular route. (B) Proposed pathways for phosphorus (Pi) absorption across the intestinal epithelium. NaPi2b mediates active transcellular transport of Pi. A paracellular pathway is also believed to exist. (C) Proposed pathways for magnesium (Mg) absorption across the intestinal epithelium. Apical absorption is mediated by the TRPM6/TRPM7 channel, whereas basolateral exit occurs by an Mg exchanger that is yet to be fully defined. A paracellular pathway is also believed to exist. TRPM, transient receptor potential melastatin.

Figure 3.

Schematic illustration of the reabsorption of calcium, phosphorus, and magnesium by different segments of the nephron. (A) Calcium is filtered at the glomerulus, with the ultrafilterable fraction of plasma calcium entering the proximal tubule. Within the proximal convoluted tubule and the proximal straight tubule, 60%–70% of the filtered calcium has been reabsorbed. No reabsorption of calcium occurs within the thin segment of the loop of Henle. The cortical segments of the loop of Henle reabsorb about 20% of the initially filtered load of calcium. Approximately 10% of the filtered calcium is reabsorbed in the distal convoluted tubule, with another 3%–10% of filtered calcium reabsorbed in the connecting tubule. (B) The majority (approximately 85%) of phosphate reabsorption occurs in the proximal convoluted tubule. Approximately 10% of Pi reabsorption occurs in the loop of Henle, 3% occurs in the distal convoluted tubule, and 2% in the collecting duct via unidentified pathways. (C) Approximately 10%–30% of the filtered magnesium is absorbed in the proximal tubule, 40%–70% of filtered magnesium is absorbed in the thick ascending limb, and the remaining 5%–10% of magnesium is reabsorbed in the distal convoluted tubule. CD, collecting duct; DCT, distal convoluted tubule; PCT, proximal convoluted tubule.

Figure 4.

Model of calcium and magnesium absorption by the thick ascending limb of Henle. Calcium absorption proceeds through both an active, transcellular pathway and by a passive paracellular pathway. Only transport pathways relevant to calcium absorption are shown. Basal absorption is passive and is driven by the ambient electrochemical gradient for calcium. The apical Na⁺-K⁺-2Cl⁻ cotransporter and the renal outer medullary potassium K⁺ channel generate the “driving force” for paracellular cation transport. Calciotropic hormones, such as parathyroid hormone and calcitonin, stimulate active calcium absorption in cortical thick ascending limbs. Inhibition of Na-K-2Cl cotransport by loop diuretics or in Bartter’s syndrome decreases the transepithelial voltage, thus diminishing passive calcium absorption. In the model of magnesium absorption by thick ascending limb of Henle, 40%–70% of filtered magnesium is absorbed in the thick ascending limb by a paracellular pathway, mostly enhanced by lumen-positive transepithelial voltage. The apical Na-K-2Cl cotransporter mediates apical absorption of Na, K, and Cl. The apical renal outer medullary K channel mediates apical recycling of K back to the tubular lumen and generates lumen-positive voltage. Cl channel Kb mediates Cl exit through the basolateral membrane. Here Na,K-ATPase also mediates Na exit through the basolateral membrane and generates the Na gradient for Na absorption. The tight junction proteins claudin-16 and claudin-19 play a prominent role in magnesium absorption. The calcium-sensing receptor was also recently determined to regulate magnesium transport in this segment: upon stimulation, magnesium transport is decreased. CaSR, calcium-sensing receptor.

Figure 5.

Model of calcium and magnesium absorption by distal convoluted tubules. Calcium entry across the plasma membrane proceeds through calcium channels with basolateral exit occurring through a combination of the plasma membrane ATPase and Na⁺-Ca⁺ exchanger. Calcium absorption is entirely transcellular. Calciotropic hormones such as parathyroid hormone and calcitonin stimulate calcium absorption. Calcitriol [1,25(OH)₂D] stimulates calcium absorption through the activation of nuclear transcription factors. Inhibition of the apical NaCl cotransporter by thiazide diuretics or in Gitelman’s syndrome indirectly stimulates calcium absorption. In the model of magnesium absorption by distal convoluted tubules, approximately 5%–10% of magnesium is reabsorbed in the distal convoluted tubule mainly by active transcellular transport mediated by TRPM6. The absorbed magnesium is then extruded via a recently identified magnesium/sodium exchanger across the basolateral membrane. The apical K channel Kv1.1 potentiates TRPM6-mediated magnesium absorption by establishing favorable luminal potential. In addition, the basolateral K channel Kir4.1 and the γ-subunit of Na,K-ATPase also regulate magnesium reabsorption.

Figure 6.

Model of phosphate reabsorption in the renal proximal tubule. Pi is reabsorbed via three sodium phosphate cotransporters: Npt2a, Npt2c and PiT-2. In humans, Npt2a and Npt2c are believed to play the most important role in phosphate reabsorption. The sodium phosphate cotransporters, which are positioned in the apical membrane of renal proximal tubule cells, use energy derived from the movement of sodium down its gradient to move Pi from the filtrate to the cell interior. The amount of phosphate reabsorbed is dependent on the abundance of the sodium phosphate cotransporters in the apical brush border membrane and hormones such as parathyroid hormone and fibroblast growth factor-23 decrease Pi reabsorption by decreasing the abundance of the sodium phosphate cotransporters in the brush border. Movement of phosphate from the interior of renal proximal tubular cells to the peritubular capillaries occurs via an unknown transporter.

Figure 7.

Schematic of PTH-induced homeostatic mechanisms to correct hyperphosphatemia as GFR falls. As GFR falls, serum phosphorus levels increase, which stimulates release of PTH from the parathyroid glands. This in turn decreases the brush border abundance of Npt2a and Npt2c in the renal proximal tubule, leading to increased urinary excretion of phosphorus. PTH, parathyroid hormone.

Figure 8.

Schematic of the role of FGF23 in reducing hyperphosphatemia as GFR falls. As GFR falls, serum phosphorus levels increase, leading to increased FGF23 secretion from bone. FGF23 binds Klotho, a required cofactor, and the FGF23/Klotho complex binds and activates FGFR1c, leading to decreased renal tubular expression of Npt2a and Npt2c. In addition, activation of FGFR1c by the FGF23/Klotho complex results in decreased 1α-hydroxylase activity and increased 24α-hydroxylase activity, which leads to decreased levels of 1,25(OH)₂D and decreased Pi absorption from the gut. FGF23, fibroblast growth factor-23; FGFR1c, FGF23 receptor 1c.

Figure 9.

Pathogenesis of secondary hyperparathyroidism in CKD. Progressive loss of renal mass impairs renal phosphate excretion, which causes an increase in serum phosphorus. Abnormalities in serum phosphorus homeostasis stimulate FGF23 from bone. Higher serum FGF23 levels in addition to decreased renal mass cause a quantitative decrease in synthesis of 1,25(OH)₂D. High serum FGF23 levels decrease the activity of the 1α-hydroxylase enzyme. 1,25(OH)₂D deficiency decreases intestinal absorption of calcium, leading to hypocalcemia, which is augmented by the direct effect of hyperphosphatemia. Hypocalcemia and hyperphosphatemia stimulate PTH release and synthesis. The lack of 1,25(OH)₂D, which would ordinarily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the increased PTH production to continue. Current therapeutic methods used to decrease PTH release in CKD include correction of hyperphosphatemia, maintenance of normal serum calcium levels, administration of 1,25(OH)₂D analogs orally or intravenously, and administration of a CaSR agonist (e.g., cinacalcet).