Calcium Balance

Calcium is the most abundant ion in the body but 99% of it is in the skeleton and does not participate in the regulation of the plasma Ca2+ concentration.

Typical adults ingest about 600 to 1500 mg of calcium daily; however, the gastrointestinal tract absorbs only 150-200 mg/day. This rate of absorption is regulated largely by the most active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol [1,25(OH)2D3; see Chapter 43], in response to the demands for the maintenance of the normal ECF calcium concentration and the remodeling of bone. The plasma Ca2+ concentration is also closely regulated by PTH, which controls the release of Ca2+ from bone, as discussed in Chapter 43. Nevertheless, the kidney is essential in regulating the final output of Ca2+ to match the daily intake and to maintain a constant total body Ca2+.

Although the normal plasma Ca2+ concentration is about 8-10 mg/dL (2.1-2.6 mmol/L), -40% of this Ca2+ is bound to plasma proteins and cannot be filtered at the glomerulus. Thus, the rate of Ca2+ filtration is one-half the usual product: GFR • PCa, giving a daily filtration rate of —9 g of Ca2+ per day for a GFR of 180 L/day. However, typically only 0.5-1.0% of this amount is excreted, indicating substantial reabsorption along the nephron.

The major regions of the nephron responsible for reabsorbing Ca2+ are shown schematically in Fig. 5. Reabsorption in the proximal tubule is mostly passive, although some active transport may be involved. In this region, the rate of Ca2+ reabsorption is proportional to that of Na+. Therefore, a proximal diuretic such as acetazolamide and osmotic diuresis increases Ca2+ excretion. Approximately 30% of the filtered load of Ca2+ is reabsorbed in the loop of Henle. This reabsorption occurs primarily in the thick ascending limb of the loop of Henle and, again, is proportional to the rate of Na+ reabsorption. Most if not all of this reabsorption is passive and is driven by the lumen-positive voltage.

Approximately 8% of the filtered load of Ca2+ is reabsorbed in the late distal convoluted tubule and the connecting tubule. Active Ca2+ reabsorption by these regions of the nephron is the primary target of factors that regulate the final excretion of Ca2+. The most important factor that changes the Ca2+ reabsorptive rate is the plasma Ca2+ concentration. As it rises, reabsorption decreases and vice versa. The late distal convoluted tubule and the connecting tubule also express receptors for the hormones PTH, 1,25(OH)2D3, and calcitonin. Parathyroid hormone and 1,25(OH)2D3 increase Ca2+ reabsorption in this region of the nephron. High plasma levels of calcitonin inhibit Ca2+ reabsorption, but the regulatory significance of calcitonin in Ca2+ reabsorption is doubtful (see also Chapter 43).

Ca2+ reabsorption is stimulated in metabolic alkalo-sis and by volume contraction, whereas it is inhibited by phosphate depletion, metabolic acidosis, or ECF

Calcium Nephron
FIGURE 5 Calcium reabsorption along the nephron. Reabsorption in the proximal tubule and the loop of Henle is passive, and proportional to the reabsorption of Na+ and water. Reabsorption by CNT cells in the late distal convoluted tubule and connecting tubule is active and is hormonally regulated.

volume expansion. Diuretics also increase Ca + excretion, presumably because of increased distal tubular flow and a decreased opportunity to reabsorb Ca2+ because of that more rapid flow.

The reabsorption of Ca2+ in the proximal tubule and the loop of Henle is passive and involves the paracellular diffusion of Ca2+ down its electrochemical potential gradient from the lumen to the interstitial fluid. A favorable concentration gradient for Ca2+ diffusion is produced as water reabsorption in the proximal tubule and the descending limb of the loop of Henle causes the Ca2+ concentration in the tubular fluid to rise. The lumen-positive transepithelial voltage in the late proximal tubule and in the thick ascending limb of the loop of Henle also contributes to a favorable electrochemical potential gradient for Ca2+ reabsorption. Nevertheless, the passive reabsorption of Ca2+ also requires that the junctional complexes be quite permeable to Ca2+. Because of a high permeability, the factional reabsorption of Ca2+ in the proximal tubule (~60% of the amount filtered) and the loop of Henle (~30%) approximates that for Na+. In addition, because the favorable electrochemical potential gradient for passive Ca2+ reabsorption is dependent on Na+ and water reabsorption in the proximal tubule and the loop of Henle, those factors that alter Na+ reabsorption in these segments produce parallel changes in Ca2+ reabsorption.

Ca2+ is actively reabsorbed by CNT cells in the late distal convoluted tubule and connecting tubule. Specific Ca2+ channels mediate Ca2+ transport across the luminal membrane of these cells as shown in Fig. 6. Because the intracellular Ca2+ concentration in these cells is very low (on the order of 100 nmol/L, or 100 • 10"6 mmol/L), Ca2+ entering from the lumen must be transported out of the cell across the basolateral membrane at the same rate to maintain that low intracellular concentration. The mechanisms responsible for active Ca2+ transport across the basolateral membrane (Fig. 6), include an active Ca2+-ATPase

FIGURE 6 Active Ca2+ reabsorption by CNT cells in the late distal convoluted tubule and connecting tubule. Ca2+ enters CNT cells passively down its electrochemical potential gradient through Ca2+-selective channels. The very low intracellular concentration of ionized Ca2+ is maintained by active transport out of the cell across the basolateral membrane. There are two active transport mechanisms: a Na+-Ca2+ exchanger by which the active transport of 1 Ca2+ out of the cell is energetically coupled to the entry of 3 Na+, and a Ca2+-ATPase. Despite the high transcellular flux of Ca2+ in these cells, the intracellular Ca2+ concentration remains low due to the presence of the Ca2+-binding protein calbindin-D28K (labeled Calb. in the illustration), which also facilitates the diffusion of Ca2+ across the cell.

FIGURE 6 Active Ca2+ reabsorption by CNT cells in the late distal convoluted tubule and connecting tubule. Ca2+ enters CNT cells passively down its electrochemical potential gradient through Ca2+-selective channels. The very low intracellular concentration of ionized Ca2+ is maintained by active transport out of the cell across the basolateral membrane. There are two active transport mechanisms: a Na+-Ca2+ exchanger by which the active transport of 1 Ca2+ out of the cell is energetically coupled to the entry of 3 Na+, and a Ca2+-ATPase. Despite the high transcellular flux of Ca2+ in these cells, the intracellular Ca2+ concentration remains low due to the presence of the Ca2+-binding protein calbindin-D28K (labeled Calb. in the illustration), which also facilitates the diffusion of Ca2+ across the cell.

that uses energy from ATP hydrolysis to extrude Ca2+ from the cell and an electrogenic Na+-Ca2+ exchange mechanism that uses the energy available from the entry of three Na+ ions for each Ca2+ ion driven out of the cell. CNT cells also express a Ca2+ binding protein called calbindin-D28K, which also helps to maintain a low intracellular Ca2+ concentration and enables more rapid diffusional equilibration of Ca2+ within the cell. The CNT cells appear to be specifically differentiated to control the reabsorption and hence the final excretion of Ca2+. They are the only cells along the nephron that express the Ca2+-specific channel, and they also express both active Ca2+ transporters, the three related hormone receptors, and calbindin.

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