Calcium Transport

Calcium homeostasis is maintained by the kidney excreting an amount of Ca2+ equal to that which is absorbed from the GI tract. Approximately 60% of plasma Ca2+ is ultrafilterable (that fraction not bound to albumin), including both ionized Ca2+ and Ca2+ complexed to anions such as phosphate, citrate, HC03~ and sulfate.

Once filtered, approximately 65% of Ca2+ is reabsorbed in the proximal tubule (Fig. 12). In the proximal tubule, Ca2+ reabsorption and Na + reabsorption are regulated in parallel, with tubule fluid to ultrafilterable Ca2+ concentrations ranging from 1.0 to 1.2. This observation suggests that the majority of Ca2+ absorption is passive. Consistent with this mode of transport, the proximal tubule has an extremely high passive paracellular permeability to Ca2+ that is equal to that of Na +. While there may be an additional transcellular active component of proximal tubule Ca2+ absorption, it is at best small in magnitude and of poorly defined physiologic significance. Increases in proximal tubule Na + and volume absorption increase luminal Ca2+ concentration which leads to more Ca2+ being passively absorbed. In addition, some of the ultrafilterable Ca2+ may be reabsorbed by solvent drag. Both of these mechanisms explain the tight coupling between the rates of Na+ and Ca2+ absorption in the proximal tubule.

Little Ca2+ absorption occurs in the thin limbs of the loop of Henle. Then, approximately 25% of filtered Ca2+ is reabsorbed in the thick ascending limb of the loop of Henle (Fig. 12). Once again, this appears to be mostly a passive

FIGURE 12. Ca2+ transport along the nephron. Numbers indicate percentage of filtered Ca2+ remaining in the luminal fluid. The majority of filtered Ca2+ is reabsorbed in the proximal tubule and the thick ascending limb. An important regulated fraction is reabsorbed in the distal convoluted tubule.

process, driven by the lumen-positive voltage. Thus, conditions which alter the rate of thick ascending limb NaCl absorption and the lumen-positive voltage will secondarily affect the rate of Ca2+ absorption. Thus, Na+ and Ca2+ absorption are indirectly coupled. In addition to this passive Ca2+ flux, studies examining the regulation of Ca2+ absorption by PTH have demonstrated a small transcellular Ca2+ absorptive flux in the thick ascending limb.

An additional 8% of filtered Ca2+, approximately 80% of the Ca2+ remaining after tubule fluid has passed the thick ascending limb, is reabsorbed in the "early" distal nephron, the distal convoluted tubule (Fig. 12). Although only a small fraction of filtered Ca2+ is reabsorbed in this segment, this segment is key to the tight regulation of renal Ca2+ excretion. It is also a tubule site where Ca2+ and Na + absorption can be dissociated. It is well established that the distal convoluted tubule mediates active Ca2+ absorption. At the beginning of the distal convoluted tubule, luminal Ca2+ concentration is approximately equal to 60% of ultrafilterable Ca2+ concentration, and this ratio falls to about 30% at the end of the distal tubule. Given the fact that this segment has a lumen negative voltage, the mechanism of Ca2+ absorption must be active.

The mechanism of distal convoluted tubule Ca2+ absorption is shown in Fig. 13. Ca2+ enters the cell from the luminal fluid most likely via a dihydro-pyridine-sensitive Ca2+ channel. Because cytoplasmic ionized Ca2+ concentra-

Voltage -10 mV

FIGURE 13. Ca2+ transport in the distal convoluted tubule. Ca2+ is reabsorbed from the luminal fluid across an apical membrane Ca2+ channel. Ca2+ then exits the basolateral membrane on either a Ca ATPase or a 3Na/Ca exchanger. Active transport mechanism; o, passive transporter; =, channel.

FIGURE 13. Ca2+ transport in the distal convoluted tubule. Ca2+ is reabsorbed from the luminal fluid across an apical membrane Ca2+ channel. Ca2+ then exits the basolateral membrane on either a Ca ATPase or a 3Na/Ca exchanger. Active transport mechanism; o, passive transporter; =, channel.

tion is 10 7 M, 4 orders of magnitude lower than that of extracellular fluid, and cell voltage negative compared to lumen, there is a large electrochemical gradient favoring passive Ca2+ entry. Within the distal convoluted tubule cell, low concentrations of free ionized Ca2+ must be maintained because high cell Ca2+ would complex ATP and other phosphorylated intermediates, events that would lead to cell death. To safeguard low cell [ Ca2+ ], apically reabsorbed Ca2+ in distal tubule cells is bound to Ca2+ binding proteins. One of these, calbindin-D28, has been localized in distal convoluted tubule cells. Ca2+ exits across the basolateral membrane by two mechanisms, a Ca ATPase, and a 3Na/Ca exchanger. The Ca ATPase has been well characterized and is of the P type ATPase type. The 3Na/Ca exchanger exchanges 3 Na+ for 1 Ca2+ ion. Although not totally settled, it appears that the Ca ATPase mediates the majority of Ca2+ efflux in these cells. Paracellular permeability to Ca2+ is very low in this segment. Only small amounts of filtered Ca2+, equivalent to 1 - 2%, are reabsorbed in the remaining downstream tubule segments (cortical and medullary collecting ducts).

Renal Ca2+ absorption is tightly regulated. Parathyroid hormone enhances Ca2+ absorption in the cortical thick ascending limb and in the distal convoluted tubule. These processes appear to be mediated by cellular increases in cAMP. PTH has been shown to lead to recruitment of dihydropyridine-sensitive Ca2+ channels to the apical membrane of the distal convoluted tubule cell. This process is associated with an increase in intracellular Ca2+ concentration.

Another important regulator of Ca2+ transport is effective arterial volume. In states of low effective arterial volume the kidney retains Ca2+, while in states of high effective arterial volume the kidney excretes Ca2+ at high rates. This effect is mostly attributable to changes of Ca2+ transport in the proximal tubule where decreases in effective arterial volume enhance Na + and water reabsorption and secondarily increase Ca2+ absorption. Changes in volume status may also modulate thick ascending limb Na + transport and voltage and secondarily affect Ca2+ absorption.

Last, changes in acid-base status regulate Ca2+ absorption. This effect is attributable to an effect of luminal pH on Ca2+ absorption in the distal convoluted tubule. Decreases in luminal pH inhibit apical membrane Ca2+ uptake leading to hypercalciuria, while increases in luminal pH have the opposite effect. Accordingly, metabolic acidosis often leads to hypercalciuria. Proximal renal tubule acidosis (RTA) is an exception in that distal nephron luminal pH is high as a consequence of diminished proximal HC03~ reabsorption. Alkalosis associated with high rates of distal delivery of HCO , is often associated with Ca2+ retention.

Diuretics have diverse effects on Ca2+ absorption. Carbonic anhydrase inhibitors have a minimal effect on Ca2+ absorption. Because they inhibit proximal tubule salt and water reabsorption, they inhibit proximal tubule Ca2+ reabsorption. However, this is counterbalanced by enhanced distal convoluted tubule Ca2+ reabsorption in response to enhanced distal HCO > delivery. Loop diuretics cause hypercalciuria by decreasing the lumen positive voltage in the thick ascending limb and secondarily inhibiting thick ascending limb Ca2+ absorption. However, if loop diuretics lead to decreased effective arterial volume, the expected hypercalciuria will be modest.

Thiazide diuretics cause renal Ca2+ retention and have been useful in the treatment of hypercalciuria. Part of this effect is related to a decreased effective arterial volume and increased proximal tubule Ca2+ reabsorption. However, there is also a direct effect of thiazide diuretics on the distal convoluted tubule. Two possible mechanisms have been proposed. By inhibiting apical membrane NaCl entry in the distal convoluted tubule there is a decrease in cell Na+ concentration which would enhance basolateral membrane Na+/Ca2+ exchange and lower intracellular Ca2+ concentration. As a consequence of a steeper transmembrane Ca2+ gradient, accelerated Ca2+ entry across the apical membrane would lead to enhancement of Ca2+ absorption. A second possible mechanism is that inhibition of apical membrane NaCl cotransport will also lower cell CI- concentration. Because the basolateral membrane of these cells has a large CI ~ conductance (Fig. 8), a decrease in cell CI ~ concentration will lead to cell hyperpolarization which again enhances passive Ca2+ entry across the apical membrane.

Amiloride also causes increased Ca2+ reabsorption. This effect occurs in the distal nephron and is likely due to cell hyperpolarization with secondary increases in apical Ca2+ entry.

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