Binding of Plasma Proteins and Formation of Calcium-Anion Complexes Influence the Filtration and Reabsorption of Calcium

Whole-body calcium balance-as well as the hormonal control of free, ionized plasma calcium (Ca2+) levels-is the subject of Chapter 51. The total concentration of calcium in plasma is normally 2.2 to 2.7 mM (8.8-10.6 mg/dl). Table 35-5 summarizes the forms of total calcium in the plasma. Some 40% binds to plasma proteins, mainly albumin, and constitutes the nonfilterable fraction. The filterable portion, approximately 60% of total plasma calcium, consists of two moieties. The first, approximately 15% of the total, complexes with small anions such as carbonate, citrate, phosphate, and sulfate. The second, approximately 45% of total calcium, is the ionized Ca2+ that one may measure with Ca2+ -sensitive electrodes or dyes. It is the concentration of this free, ionized calcium that the body tightly regulates; plasma [Ca2+ ] normally is 1.0 to 1.3 mM (4.0-5.2 mg/dl). Table 35-5. COMPONENTS OF TOTAL PLASMA CALCIUM mg/dl Ionized Ca2+ Diffusible calcium complexes Nondiffusible (protein-bound) calcium Total calcium mM 4.7 1.2 1.4 0.3 3.9 1.0 10.0 2.5 % OF TOTAL ∼45% ∼15% ∼40% 100

The distribution among the various forms of total calcium is not fixed. Because H + competes with Ca2+ for binding to anionic sites on proteins or small molecules, acidosis generally increases plasma [Ca2+ ]. Thus, the decrease in luminal pH that occurs along the nephron (p. 850) makes additional Ca2+ available for recovery. In addition, Ca2+ binding to proteins in the plasma depends on the concentration of proteins, particularly albumin. A change in the level of the anions with which Ca2+ can form complexes also affects the distribution of different calcium entities. Tubule cells probably reabsorb Ca-anion complexes poorly. However, because the concentration of these anions declines along the nephron owing to anion reabsorption, free Ca2+ becomes available for transport.
The Proximal Tubule Reabsorbs a Large Fraction of Filtered Ca 2+, with the Thick Ascending Limb and Distal Convoluted Tubule Reabsorbing Smaller Amounts

The kidney reabsorbs approximately 99.5% of the filtered load of calcium, principally at the proximal tubule, the thick ascending limb, and the distal convoluted tubule (Fig. 35-16A). PROXIMAL TUBULE. The proximal tubule reabsorbs approximately 65% of the filtered Ca2+, a process that is not subject to hormonal control. A small part of the Ca2+ reabsorbed by the proximal tubule (∼20% of the 65%) moves via the transcellular route that we will discuss in the next section. However, most proximal tubule Ca2+ reabsorption (∼80% of the ∼65%) occurs via the paraellular route (Fig. 35-16B). The evidence for a large component of paracellular Ca2+ transport is the high Ca2+ permeability of the tubule, as well as the sensitivity of net Ca2+ transport to changes in the transepithelial electrochemical gradient for Ca2+. For example, imposing a lumen-negative transepithelial voltage induces Ca2+ secretion, whereas a lumen-positive voltage induces reabsorption. Because the S2 and S3 segments of the proximal tubule normally have a small lumen-positive voltage, it is not surprising that they are responsible for reabsorbing a large fraction of filtered Ca2+ by the paraellular route. In addition to Ca2+ diffusion through tight junctions, proximal Ca2+ reabsorption parallels that of Na+ and water, implying participation of solvent drag (p. 469). THICK ASCENDING LIMB. The thick ascending limb (TAL) reabsorbs approximately 25% of the filtered Ca2+ (Fig. 35-16C). Under normal conditions, about half of the Ca2+ reabsorption in the TAL occurs passively via a paracellular route,

protein kinase C. PKC. PTH. the numbered yellow boxes indicate the fraction of the filtered load that various nephron segments reabsorb. the distal convoluted tubule (DCT) is a major regulatory site for Ca2+ excretion. it is not surprising that hormones such as AVP.driven by the lumen-positive voltage. DISTAL CONVOLUTED TUBULE. page 807 page 808 Figure 35-16 Calcium handling by the kidney. cyclic adenosine monophosphate. Thus. cAMP. hydroxyeicosatetraenoic acid. which PTH stimulates. parathyroid hormone. FACTORS AFFECTING Ca2+ REABSORPTION ALONG THE NEPHRON SITE Proximal tubule Thick ascending limb Distal convoluted tubule INCREASE REABSORPTION Volume contraction PTH Calcitonin PTH Vitamin D AVP Alkalosis Thiazide diuretics Amiloride DECREASE REABSORPTION Volume expansion Furosemide and related diuretics Phosphate depletion Collecting duct - AVP. adenosine triphosphate. The other half of Ca2+ reabsorption by the TAL occurs via the transcellular pathway (see next section). In A. transcellular route (see next section). 35-16D). the DCT reabsorbs Ca2+ predominantly via an active. This segment reabsorbs approximately 8% of the filtered Ca2+ load (Fig. 810)-it i s easy to dissociate Ca 2+ transport in the DCT from Na+and water reabsorption. page 808 page 809 Table 35-6. adenylyl cyclase. which make the transepithelial voltage more positive. The green boxes indicate the fraction of the filtered load that remains in the lumen after these segments. HETE. Despite the relatively small amount of Ca2+ delivered. Evidence against a substantial component of paracellular Ca2+ reabsorption is that-under a variety of experimental maneuvers (p. indirectly increase Ca2+ reabsorption. AC. ATP. arginine vasopressin. . In contrast to the proximal tubule and TAL.

Activation of Gαs raises [cAMP]i and stimulates PKA (p. 35-16C. a component of the cytoskeleton. Parathyroid Hormone and Vitamin D Stimulate-Whereas High Plasma Ca2+ Inhibits-Ca2+ Reabsorption Table 35-6 summarizes factors that modulate Ca2+ handling by various segments of the nephron. if the [Ca2+ ]i is normal and the inward Na+electrochemical gradient falls (e. and because the membrane voltage across the apical membrane is about -70 mV. As we saw in our discussion of phosphate handling. Involving Passive Ca 2+ Entry Through Apical Channels and Basolateral Extrusion by Electrogenic Na/Ca Exchange and an ATP-Driven Ca2+ Pump We have seen that the contribution of the transcellular route to Ca 2+ reabsorption increases steadily from the proximal tubule to the TAL and to the DCT. PMCA is present in several nephron segments. PARATHYROID HORMONE.. PTH acts by binding to the PTH 1R receptor. and their role in regulating renal Ca2+ excretion is not well defined. as well as interaction sites for ankyrin (p.5% of the filtered load). 100)-activate calmodulin (p. which stimulates Ca2+ reabsorption in the thick ascending limb. 64). The primary active transporter is an ATP-driven plasma-membrane Ca2+ ATPase or pump (PMCA. which in turn would stimulate basolateral Ca2+ extrusion mechanisms. 97). p. 68) also extrudes Ca2+ across the basolateral membrane of tubule cells. Because [Ca2+]i is only approximately 100 nM (∼10.i levels. an Na-Ca exchanger (NCX. Increases in [Ca2+ ]i -such as those triggered by PTH via PLC and inositol triphosphate (IP3). Ca2+ -binding proteins buffer the Ca2+. Whether similar Ca 2+ channels play a role in transcellular Ca2+ reabsorption in the proximal tubule and TAL is unknown. This Ca2+ channel. and raise plasma [Ca2+ ]. and cGMP-stimulated protein kinase (PKG). calcitonin at low concentrations also increases Ca2+ reabsorption via cAMP in both . with its highest density in the basolateral membrane of the DCT. Such an increase in Ca2+ permeability would increase [Ca2+]i.g. The most important regulator of renal Ca2+ reabsorption is PTH. (p. and maintaining a favorable gradient for Ca2+ influx. Like PTH. PTH appears to increase the open probability of apical Ca2+ channels (see Fig. the Na-Ca exchanger can reverse direction and load the cell with Ca2+. helping to keep [Ca2+ ]i low. PKC. however. and extracellular H+blocks channel activity. [Na+]i rises). when the Na-Ca exchanger is not very active. 1093). Only when [Ca2+]i increases does the Na-Ca exchanger begin to make a significant contribution. As Ca2+ enters the tubule cell across the apical membrane. In the steady state. Both pathways are essential for the action of PTH on apical Ca2+ entry. the cell must extrude across the basolateral membrane all the Ca2+ that enters across the apical membrane. and the connecting tubule. 35-16B -D). In addition. has consensus phosphorylation sites for PKA. In addition to the Ca2+ pump. Regardless of the nephron segment. but by an epithelial Ca2+ channel (ECaC). On the other hand. which apparently couples to two heterotrimeric G proteins and activates two kinases (p. At physiologically low [Ca2+ rsqb. Activation of Gαq ultimately stimulates a PKC (p. Mg2+ competes with Ca2+ for entry into the cytoplasm. particularly the endoplasmic reticulum and mitochondria. the major pathway for Ca2+ extrusion is the Ca2+ pump. p. 102) and thus stimulate PMCA. Ca2+ may temporarily enter certain organelles.000-fold less than in extracellular fluid). increase Ca2+ reabsorption. 21). Transcellular Ca2+ Movement Is a Two-Step Process. 102) that is unusual in being insensitive to phorbol esters. the distal convoluted tubule. a steep electrochemical gradient favors Ca2+ entry across the apical membrane.The quantitative contribution of the collecting ducts and tubules to Ca2+ reabsorption is quite small (∼1. Work on the DCT shows that apical Ca 2+ entry is passive and is mediated not by a voltage-gated Ca2+ channel. Both primary and secondary active transporters participate in this Ca2+ extrusion against a steep electrochemical gradient. tubule cells apparently use the same general mechanism to move Ca2+ through the cell from lumen to blood (Fig. D).

a form of nephrogenic diabetes insipidus (see box on p. 35-16C).. probably 20-hydroxyeicosatetraenoic acid (HETE). which is on Ca2+ absorption in the gastrointestinal tract (p. reducing stimulation of Na/K/Cl cotransport by cAMP (p. The latter observation suggests that factors such as solvent drag and diffusion are not involved. Metabolic alkalosis increases renal Ca2+ reabsorption (i. Second. resulting in a decrease in the lumen-positive transepithelial potential. 971). which couples to at least two G proteins. Third. elevating [Ca2+ ]i and stimulating PKC (p. which increases Na+reabsorption. EFFECTIVE CIRCULATING VOLUME. In the cortical TAL. The kidney. and thus a reduction in paracellular Ca2+ reabsorption. The mechanism appears to be the following: Extracellular Ca2+ binds to a basolateral Ca2+ -sensing receptor (CaSR). 1095) increases Ca2+ reabsorption in the distal nephron. One of these pathways-the sympathetic division of the ANS-increases Na+reabsorption by the proximal tubule (p. also increases Ca2+ reabsorption. By keeping urine [Ca2+] relatively low.e. Chronic phosphate depletion impairs Ca2+ reabsorption at both proximal and distal sites. ACID-BASE BALANCE. . an increase in plasma [Ca2+] directly inhibits Na+and K+ reabsorption. increasing levels of arachidonic acid and one of its P450 metabolites. an increase in basolateral [Ca2+] inhibits both the Na/K/Cl cotransporter and K+channels on the apical membrane (Fig. 787). and the collecting ducts. the distal convoluted tubule. 807). page 809 page 810 VITAMIN D. An interesting consequence of reduced Na+reabsorption induced by high plasma [Ca2+] is an inhibition of the kidney's ability to generate a concentrated urine (p. responds directly to changes in extracellular [Ca2+]. it is not surprising that volume contraction. 833). 864) that act to restore volume. probably by relieving the inhibition of apical ECaC Ca2+ channels by H+. Acting on gene transcription. The latter inhibits apical Na/K/Cl cotransporters and K+channels. Thus. This effect is independent of the PTH status. the basis for the effect is otherwise unknown. vitamin D (p. 787). 843).the TAL and the DCT. decreases excretion) at the level of the distal convoluted tubule. and indirectly-by reducing the lumen-positive voltage generated by apical K+ recycling-inhibits the paracellular reabsorption of Ca2+ and Mg2+ (see later). Because proximal tubule Ca2+ reabsorption depends largely on transepithelial voltage and solvent drag (p. PHOSPHATE DEPLETION. 103). CaSR activates Gαq. activation of a member of the Gi/Go family stimulates PLA2 (p. which also inhibits Na/K/Cl cotransport. vitamin D upregulates the Ca2+ -binding protein. DIURETICS. chronic hypercalcemia results in a dilute urine. A reduction in effective circulating volume triggers four parallel effector pathways (p. the medullary thick ascending limb. 102). complementing the major Ca2+ -retaining action of vitamin D. First. which contributes to enhanced Ca2+ reabsorption by keeping [Ca2+]i low during increased Ca2+ traffic through the cell. The effects are independent of the decrease in PTH secretion that follows phosphate depletion. Indeed. 1092). activation of Gαi decreases [cAMP]i. The Ca2+ -sensing receptor is also present in the proximal tubule. Volume expansion has the opposite effects on both Na+and Ca2+ reabsorption. this effect may help avoid Ca2+ stones under conditions of high Ca2+ excretion. In renal tubule cells. as well as of Na+transport. PLASMA Ca2+ LEVELS. which in turn depend on Na+reabsorption. similar to the parathyroid gland (p.

Thiazide diuretics (p. such as furosemide. Amiloride (p. the effects of thiazides and amiloride are exceptions to the general rule that Ca2+ and Na+excretion parallel each other. 779) inhibit Na/Cl cotransport and stimulate Ca2+ reabsorption in the distal convoluted tubule. Accordingly. Printed from STUDENT CONSULT: Medical Physiology (on 24 August 2006) © 2006 Elsevier . secondarily stimulating basolateral Ca2+ extrusion. The steeper electrical gradient increases apical Ca2+ entry. thus hyperpolarizing the cell. furosemide (p. whereas those acting on the distal nephron. amiloride augments Ca2+ reabsorption by enhancing the gradient for apical Ca2+ entry. 779) inhibits apical Na+channels in the initial and cortical collecting tubules and hyperpolarizes the apical membrane. Thus. Thus. In the TAL. paracellular Ca 2+ reabsorption.Among diuretics. such as thiazides and amiloride. only the powerful loop diuretic furosemide is appropriate for treating hypercalcemic states. In contrast. and thus the driving force for passive. of these drugs. The stimulatory effects of thiazides and of amiloride on apical Ca2+ uptake require physiologic PTH levels to keep the apical Ca2+ channels open. decrease Ca2+ reabsorption. increase Ca2+ reabsorption. 778) reduces the lumen-positive voltage. Inhibiting apical Na/Cl cotransport lowers [Cl-]i in the DCT cell. urinary Ca2+ excretion increases in parallel with Na+excretion. like the thiazides. those acting on the thick ascending limb.