Medical Physiology, 3rd Edition


Binding to plasma proteins and formation of Ca2+-anion complexes influence the filtration and reabsorption of Ca2+

We discuss whole-body calcium balance—as well as the hormonal control of free, ionized plasma calcium (Ca2+) levels—on page 1054. Here we consider the role of the kidney in calcium balance. The total calcium concentration in plasma is normally 2.2 to 2.6 mM (8.8 to 10.6 mg/dL). Table 36-6 summarizes the forms of calcium in the plasma. Some 40% binds to plasma proteins, mainly albumin, and constitutes the nonfilterable fraction. The filterable portion, ~60% of total plasma calcium, consists of two moieties. The first, ~15% of the total, complexes with small anions such as carbonate, citrate, phosphate, and sulfate. The second, ~45% of total calcium, is the ionized calcium (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 to 5.2 mg/dL).

TABLE 36-6

Components of Total Plasma Calcium





Ionized Ca2+




Diffusible calcium complexes




Nondiffusible (protein-bound) calcium




Total calcium




The distribution of 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+] and alkalosis acutely reduces it. Thus, acute alkalosis can cause signs and symptoms mimicking hypocalcemia. In addition, Ca2+ binding to proteins in the plasma depends on the concentrations of the proteins, particularly albumin. Thus, at a given [Ca2+], the total measured calcium will vary with serum albumin concentration. For example, in patients with low plasma albumin, total measured plasma calcium may be low despite a normal [Ca2+]. imageN36-13


Corrections for Plasma Calcium

Contributed by Gerhard Giebisch, Erich Windhager, Peter S. Aronson

Clinical laboratories routinely report total plasma calcium levels (8.8 to 10.6 mg/dL or 2.2. to 2.6 mM), not the ionized [Ca2+]plasma that the body tightly regulates. Because the fraction of total plasma calcium that is ionized varies greatly with the [albumin]plasma, the measured total plasma calcium is corrected for the patient's [albumin]plasma to obtain a corrected [Ca]plasma or adjusted [Ca]plasma.


(NE 36-5)

The equation assumes a normal [albumin]plasma of 4 g/dL.

Thus, the corrected [Ca]plasma in a patient with hypoalbuminemia (e.g., [albumin]plasma of 3 g/dL) is 0.8 mg/dL higher than the measured [Ca]plasma. The physician then applies the theoretical fractional distribution of the different calcium Ca2+ entities to the corrected [Ca]plasma.

A change in the level of the anions with which Ca2+ can form complexes also affects the distribution of different calcium Ca2+ entities. Tubule cells probably reabsorb Ca2+-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 two thirds of filtered Ca2+, with more distal segments reabsorbing nearly all of the remainder

The kidney reabsorbs ~99% of the filtered load of calcium, principally at the proximal tubule, the thick ascending limb (TAL), and the distal convoluted tubule (DCT) (Fig. 36-16A).


FIGURE 36-16 Calcium handling by the kidney. In A, the numbered yellow boxes indicate the approximate fraction of the filtered load that various nephron segments reabsorb. The green boxes indicate the fraction of the filtered load that remains in the lumen at various sites. The values in the boxes are approximations. AC, adenylyl cyclase; HETE, hydroxyeicosatetraenoic acid; PCT, proximal convoluted tubule; PST, proximal straight tubule.

Proximal Tubule

The proximal tubule reabsorbs ~65% of the filtered calcium, a process that is not subject to hormonal control. Virtually all proximal-tubule Ca2+ reabsorption occurs via the paracellular route (see Fig. 36-16B). 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. The passive paracellular reabsorption of calcium is very dependent on luminal [Ca2+]. Water reabsorption tends to increase luminal [Ca2+], generating a favorable transepithelial gradient that drives passive Ca2+ reabsorption by diffusion via the paracellular pathway. In addition, some calcium reabsorption may occur via solvent drag across the tight junctions. The greater the fluid reabsorption along the proximal tubule, the greater the reabsorption of Ca2+ via both diffusion and solvent drag. For this reason, a high-NaCl diet—which increases extracellular volume and thus lowers proximal-tubule Na+ and water reabsorption—reduces Ca2+ reabsorption and increases urinary Ca2+excretion. One consequence is an elevated risk of calcium kidney stones.

Thick Ascending Limb

The TAL reabsorbs ~25% of the filtered calcium (see Fig. 36-16C). Most of the Ca2+ reabsorption in the TAL occurs passively via a paracellular route, driven by the lumen-positive voltage. Thus, it is not surprising that loop diuretics (see p. 757), which block the generation of the lumen-positive transepithelial voltage, acutely inhibit Ca2+ reabsorption.

Distal Convoluted Tubule

The DCT reabsorbs ~8% of the filtered Ca2+ load (see Fig. 36-16D). Despite the relatively small amount of Ca2+ delivered, the DCT is a major regulatory site for Ca2+ excretion. In contrast to the proximal tubule and TAL, the DCT reabsorbs Ca2+ predominantly via an active, transcellular route (see next section).

The quantitative contribution of the collecting ducts and tubules to Ca2+ reabsorption is quite small (~1% of the filtered load), and their role in regulating renal Ca2+ excretion is not well defined.

Transcellular Ca2+ movement is a two-step process, involving passive Ca2+ entry through apical channels and basolateral extrusion by electrogenic Na/Ca exchange and a Ca pump

Because [Ca2+]i is only ~100 nM (~10,000-fold less than in extracellular fluid), and because the membrane voltage across the apical membrane is approximately −70 mV, a steep electrochemical gradient favors Ca2+entry across the apical membrane. Work on the DCT shows that apical Ca2+ entry is passive, mediated by the epithelial Ca2+ channels TRPV5 and TRPV6 (ECaC1 and ECaC2).

As Ca2+ enters the tubule cell across the apical membrane, the Ca2+-binding proteins (i.e., calbindins) buffer the Ca2+, helping to keep [Ca2+]i low and maintaining a favorable gradient for Ca2+ influx. In addition, Ca2+ may temporarily enter certain organelles, particularly the endoplasmic reticulum and mitochondria. In the steady state, however, the cell must extrude across the basolateral membrane all the Ca2+ that enters across the apical membrane. Both primary and secondary active transporters participate in this Ca2+ extrusion against a steep electrochemical gradient. The primary active transporter is an ATP-driven plasma-membrane Ca2+ ATPase or pump (PMCA1b; see p. 118).

In addition to the Ca pump, an Na-Ca exchanger (NCX1; see pp. 123–124) also extrudes Ca2+ across the basolateral membrane of tubule cells. At physiologically low [Ca2+]i levels, when NCX1 is not very active, the major pathway for Ca2+ extrusion is the Ca pump. Only when [Ca2+]i increases does the NCX1 begin to make a significant contribution. Conversely, if the [Ca2+]i is normal and the inward Na+ electrochemical gradient falls (e.g., [Na+]i rises), the NCX1 can reverse direction and load the cell with Ca2+.

PTH and vitamin D stimulate—whereas high plasma Ca2+ inhibits—Ca2+ reabsorption

Table 36-7 summarizes factors that modulate Ca2+ handling by various segments of the nephron.

TABLE 36-7

Factors Affecting Ca2+ Reabsorption Along the Nephron imageN36-16




Proximal tubule

Volume contraction

Volume expansion



Furosemide and related diuretics




Vitamin D


Thiazide diuretics



Regulation of Ca2+ Reabsorption

Contributed by Gerhard Giebisch, Erich Windhager

In addition to the factors discussed beginning on page 789, several other factors modulate the handling of Ca2+.

Effective Circulating Volume

A reduction in effective circulating volume triggers four parallel effector pathways (see p. 836) that act to restore volume. One of these pathways—the sympathetic division of the autonomic nervous system—increases Na+ reabsorption by the proximal tubule (see pp. 766–768). Because proximal-tubule Ca2+ reabsorption depends largely on transepithelial voltage and solvent drag (see p. 787), which in turn depend on Na+ reabsorption, it is not surprising that volume contraction, which increases Na+ reabsorption, also increases Ca2+ reabsorption. Volume expansion has the opposite effects on both Na+ and Ca2+reabsorption.

Acid-Base Balance

Metabolic alkalosis increases renal Ca2+ reabsorption (i.e., decreases excretion) at the level of the DCT, probably by relieving the inhibition of apical TRPV5/TRPV6 Ca2+ channels by H+. This effect is independent of PTH status as well as of Na+ transport. The latter observation suggests that factors such as solvent drag and diffusion are not involved.

Phosphate Depletion

Chronic phosphate depletion impairs Ca2+ reabsorption at both proximal and distal sites. The effects are independent of the decrease in PTH secretion that follows phosphate depletion; the basis for the effect is otherwise unknown.

Parathyroid Hormone

The most important regulator of renal Ca2+ reabsorption is PTH, which stimulates Ca2+ reabsorption in the DCT and the connecting tubule. Regarding TRPV5, PTH increases transcription and open probability, and inhibits endocytosis, thereby stimulating Ca2+ reabsorption. In addition to its effects to stimulate apical Ca2+ entry, PTH also upregulates expression of calbindin and NCX1.

As we saw in our discussion of phosphate handling (see pp. 786–787), PTH acts by binding to the PTH1R receptor, which apparently couples to two heterotrimeric G proteins and activates two kinases (see p. 1061), PKA (see p. 57) and PKC (see pp. 60–61) Both pathways are essential for the action of PTH on apical Ca2+ entry.

Vitamin D

Acting on gene transcription, vitamin D (see pp. 1063–1067) increases Ca2+ reabsorption in the distal nephron; this renal reabsorption complements the major Ca2+-retaining action of vitamin D, Ca2+ absorption in the gastrointestinal tract (see p. 938). In renal tubule cells, vitamin D upregulates TRPV5 Ca2+-binding proteins, which contribute to enhanced Ca2+ reabsorption by keeping [Ca2+]i low during increased Ca2+ traffic through the cell.

Plasma Ca2+ Levels

As discussed on page 768, extracellular Ca2+ binds to a basolateral Ca2+-sensing receptor (CaSR) in the TAL, which leads to a reduction in the lumen-positive transepithelial potential. CaSR activation also leads to a reduction in paracellular Ca2+ permeability in this nephron segment. Because Ca2+ reabsorption in the TAL is predominantly passive and paracellular (see p. 787), these CaSR-mediated decreases in driving force and permeability lead to reduced Ca2+ reabsorption and thus increased Ca2+ excretion, tending to compensate for hypercalcemia. imageN36-14


Effect of Hypercalcemia on Ability to Create a Concentrated Urine

Contributed by Gerhard Giebisch, Erich Windhager

As noted on page 791hypercalcemia (i.e., high plasma [Ca2+]), acting via the CaSR, reduces Na+ reabsorption by the TAL. One result is of this action is reduced osmolality in the renal medulla, which in turn impairs the kidney's ability to generate concentrated urine (see p. 811). Indeed, chronic hypercalcemia results in a dilute urine, a form of nephrogenic diabetes insipidus (see Box 38-1). By keeping urine [Ca2+] relatively low, this effect may help avoid Ca2+ stones under conditions of high Ca2+ excretion.

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 (see p. 811). Indeed, chronic hypercalcemia results in a dilute urine, a form of nephrogenic diabetes insipidus (see p. 819). By keeping urine [Ca2+] relatively low, this effect may help avoid Ca2+ stones under conditions of high Ca2+ excretion.


Among diuretics, those acting on the TAL, such as furosemide, acutely decrease Ca2+ reabsorption, whereas those acting on the distal nephron, such as thiazides and amiloride, increase Ca2+ reabsorption. Thus, of these drugs, only the powerful loop diuretic furosemide is appropriate for treating hypercalcemic states. In the TAL, furosemide (see p. 757) reduces the lumen-positive voltage, and thus the driving force for passive, paracellular Ca2+ reabsorption. Accordingly, with furosemide, urinary Ca2+ excretion increases in parallel with Na+ excretion.

In contrast to furosemide, thiazides and amiloride increase Ca2+ reabsorption. Thiazide diuretics (see p. 758) inhibit Na/Cl cotransport and stimulate Ca2+ reabsorption in the DCT. Inhibiting apical Na/Cl cotransport lowers [Cl]i in the DCT cell, thus hyperpolarizing the cell. The steeper electrical gradient increases apical Ca2+ entry, secondarily stimulating basolateral Ca2+ extrusion. Amiloride (see pp. 758–759) inhibits apical Na+ channels in the initial and cortical collecting tubules and hyperpolarizes the apical membrane. Thus, like the thiazides, amiloride augments Ca2+ reabsorption by enhancing the gradient for apical Ca2+ entry.

Volume depletion induced by any of these diuretics will increase Na+ reabsorption by the proximal tubule and thus secondarily increase passive proximal Ca2+ reabsorption (see p. 787). In the case of thiazides and amiloride, volume depletion further decreases Ca2+ excretion. Physicians exploit the ability of thiazides to reduce Ca2+ excretion, particularly in a state of mild volume contraction, to lower urinary [Ca2+] in patients with calcium-containing kidney stones. In the case of furosemide, if the patient is allowed to become volume depleted, the proximal effect will blunt the primary calciuric effect.