Renal Calcium Metabolism

Although bone harbors almost all of the body stores of calcium, the kidneys serve as the regulator of calcium homeostasis. Calcium filtered at the glomerulus is extensively reabsorbed by proximal tubules. This recovery proceeds without hormonal regulation and is governed by driving forces established by sodium absorption. Physiological adjustment of calcium transport occurs in distal tubules, where parathyroid hormone (PTH) regulates absorption. PTH also acts on proximal tubules to stimulate the formation of Vitamin D, which acts on intestine to promote calcium uptake. Hypercalcemia arises from primary or secondary excessive formation of PTH or the PTH-related peptide. Most diuretics augment calcium excretion, though thiazide diuretics dissociate sodium and calcium transport resulting in diminished calcium excretion. Other factors regulating renal calcium recovery include extracellular fluid volume, phosphate loading, and acid-base balance.

Keywords

Calcium transport, hypercalcemia, Milk Alkali syndrome, PTH, furosemide, thiazide diuretics, amiloride, acid-base balance, phosphate depletion, renal osteodystrophy

Introduction

Calcium supports diverse physiological roles as a structural element in bone and as a molecular trigger for second messenger signaling. To achieve this, homeostatic mechanisms regulate intracellular calcium at submicromolar levels, whereas extracellular calcium is in the millimolar range. The fact that intricate regulatory processes have evolved than enable ion concentrations to be maintained over several orders of magnitude underscores the importance of the varied biological functions of calcium in signal transduction, cell permeability, excitation-secretion and excitation-contraction coupling, and cell fertilization on the one hand, and maintenance of skeletal integrity on the other.

Calcium Chemistry

An adaptable coordination sphere, which facilitates binding to the irregular geometry of proteins, makes calcium particularly well suited for its biological roles. The ability to cross-link two proteins requires an ion with a high coordination number (which dictates the number of electron pairs that can be formed) and is generally six to eight for calcium. Such cross-linking of osseous structural proteins is enhanced at the relatively high calcium concentrations that are found in extracellular fluid. The variable bond length of the calcium ion permits formation of more extensive cross-linking involved in membrane stabilization by facilitating lipid polymorphism and formation of hexagonal arrays. Moreover, unlike disulfide or sugar-peptide cross-links, calcium linking is readily reversible. Despite these virtues, were intracellular free calcium (Ca ²⁺_i) of the same order as its extracellular concentration, the proper functioning of a variety of proteins and macromolecules would be impaired. Thus, from an evolutionary perspective, it is advantageous to maintain low concentrations of intracellular calcium.

The corollary of the benefits accruing from the physical characteristics of calcium at high extracellular concentrations defines a nearly ideal set of attributes that are desirable at submicromolar intracellular concentrations. By virtue of its low intracellular levels, changes of calcium activity can function as first or second messengers to activate effector targets. The fact that calcium can be rapidly bound and released, together with the high affinity and selectivity of many proteins for calcium, enhance its ability to regulate ion channels, calcium-dependent enzymes, and so on. Another advantage of low free intracellular calcium concentrations is that microcrystallization and precipitation of calcium phosphate is avoided. The evolution of high-energy phosphate compounds such as ATP may be selectively favored because they circumvent the microcrystallization and precipitation of calcium phosphate.

Serum Calcium

In adult humans, the calcium concentration of extracellular fluid averages 10 mg/dl (=5 mEq/l, 2.5 mM). Plasma calcium exists as three distinct chemical forms: protein-bound, complexed (but diffusible), and ionized. The relations between the various forms of calcium are shown schematically in Fig. 64.1 . Forty percent of the serum calcium is bound to plasma proteins, with albumin accounting for some 90% of this. Smaller percentages are bound, though with greater affinity, to ß-globulin, α ₂-globulin, α ₁-globulin, and γ-globulin. Ten percent of the serum calcium is complexed with small polyvalent anions. Calcium complexes are formed by ion pairing with phosphate and citrate and, to a lesser extent, with bicarbonate, and sulfate. The degree of complexation depends upon the concentrations of ionized calcium, the complexing anion, and the ambient pH. The different moieties of calcium are important because only diffusible calcium, i.e., the free plus complexed calcium, is filtered at the glomerulus and crosses cell membranes. A comprehensive discussion of the biologically relevant forms of calcium and their interrelations is available elsewhere.

The ultrafilterable, or ionized fractions, of calcium as summarized above are affected by changes in the total serum calcium concentration, blood pH, plasma protein concentration, and the concentration of complexing anions. Increases in total serum calcium concentrations are usually accompanied by concomitant elevations in the concentration of ultrafilterable calcium, at least up to a total concentration of about 4 mM. Above this concentration, the ultrafilterable fraction declines such that increases of ultrafilterable calcium no longer parallel elevations of total calcium concentration. Reduction in calcium ultrafiltration with hypercalcemia has been postulated to result from the formation of insoluble Ca ₃(PO ₄) ₂protein complexes. This idea is supported by the finding that ultrafilterable phosphate concentrations also decline. Conversely, hypocalcemia is generally associated with a fall in calcium ultrafiltration.

Changes in the concentration of serum proteins are usually accompanied by parallel changes in the total serum calcium concentration so that the ultrafilterable fraction remains constant. In severe hypoproteinemia, however, the ultrafilterable fraction increases.

The concentration of ionized Ca ²⁺varies inversely with blood pH. Acidemia increases ionized Ca ²⁺concentrations, whereas alkalemia causes decreases. Increases in the serum concentration of complexing anions, such as phosphate, citrate, sulfate, or bicarbonate, reduce the ionized Ca ²⁺concentration by sequestering Ca ²⁺.

The amount of calcium in the extracellular fluid represents a dynamic balance between intestinal absorption, renal reabsorption, and osseous resorption. Symptoms of hypocalcemia vary in relation to the ionized serum calcium concentration. Mild reductions of calcium are associated with paresthesias and muscle cramps; more severe decreases of calcium may induce seizures. Increases of plasma calcium, on the other hand, have been implicated in attenuation of the renal effects of parathyroid hormone (PTH), the antidiuretic action of vasopressin, and reduced renal concentrating capacity. A schematic representation of calcium balance, for an adult human, is shown in Fig. 64.2 . Assuming a daily dietary calcium intake of 1,000 mg, net intestinal absorption amounts to about 200 mg, with the remaining 800 mg excreted in the feces. In balance, net intestinal absorption is matched by urinary excretion, while calcium accretion and loss from bone are equal. Thus, approximately 200 mg of calcium are excreted daily. In adults, net calcium balance is effectively zero, suggesting that in the absence of a calcium challenge such as lactation, the kidneys represent the dominant regulatory site of calcium metabolism.

The renal responses to alterations of extracellular calcium are transduced by the calcium-sensing receptor (CaSR), which is expressed prominently at the sites of PTH and vasopressin action in the kidney.

Calcium Transport Along the Nephron

General Considerations, Calcium Clearance

Maintenance of extracellular calcium balance requires the daily urinary excretion of 200 mg of calcium. The amount of calcium excreted equals the difference between that filtered and reabsorbed:

calcium excreted=filtered load – calcium reabsorbed

or,

?Ca2+?=(GFR×?????2+)−TCa2+UCa2+V=(GFR×PCa2+uf)−TCa2+
U Ca 2 + V = ( GFR × P C a 2 + u f ) − TCa 2 +

where U _{Ca ²⁺}is the concentration of calcium in the urine, V is the rate of urine flow, GFR is the glomerular filtration rate, ?????2+
P C a 2 + u f
is the concentration of ultrafilterable calcium in plasma (filtered load being the production of GFR and plasma ultrafiltrable calcium), and T _{Ca ²⁺}is the rate of net Ca ²⁺reabsorption.

Unlike phosphate or magnesium, which exhibit saturable reabsorptive kinetics (i.e., a tubule reabsorption maximum, T ^m), most studies suggest that calcium does not display such behavior. However, some evidence for a calcium ??(????2+)
T m ( T C a 2 + m )
has been advanced. The ????2+
T C a 2 + m
is conventionally determined by measuring calcium excretion as a function of the plasma calcium, or ultrafilterable calcium, concentration. Two explanations have been proposed for the apparent failure of calcium excretion to saturate at elevated serum calcium concentrations. It has been argued that, in vivo , only a limited excursion of ultrafilterable plasma calcium concentrations can be tolerated and that within this range the filtered load of calcium may be less than the ????2+
T C a 2 + m
. It has also been postulated that since the bulk of calcium absorption is passive and may be accomplished by a combination of diffusion and solvent drag, no ????2+
T C a 2 + m
exists.

Calcium is reabsorbed throughout its passage along the nephron. As detailed below and shown schematically in Fig. 64.3 , 60–70% of the filtered calcium is reabsorbed by proximal tubules, an additional 20% by thick ascending limbs, and 5–10% by distal tubules. Final adjustments of calcium excretion are achieved in collecting ducts, where transport may be absorptive or secretory. The net result of these processes is that only 0.5–1.5% of the filtered calcium is normally excreted in the voided urine.

The interested reader is referred to several excellent monographs for more comprehensive treatments of calcium homeostasis and clearance micropuncture and isolated tubule studies of renal calcium transport.

Glomerular Filtration

The renal disposition of calcium begins with its ultrafiltration across the capillaries of the glomerulus. The ultrafilterable forms of calcium include ionized Ca ²⁺and calcium complexed to small anions. Calcium bound to plasma proteins is not filtered. The calcium concentration in the ultrafiltrate, measured by directly sampling tubular fluid from Bowman’s space is 1.31 mM, or 63% of that in plasma. This value compares favorably to that of ultrafiltrate prepared with artificial membranes.

Glomerular ultrafiltration is a passive process, driven by the net hydraulic and osmotic pressure gradient across the capillary membranes. The glomerulus is generally not considered a site of regulation of calcium absorption or homeostasis. However, it should be borne in mind that PTH depresses the glomerular ultrafiltration coefficient K _f, which may thereby diminish single nephron filtration rates and contribute to the hormone’s calcium-sparing action (cf. Hypercalcemia ). mRNA transcripts for the type 1 PTH receptor (PTH1R) and type 2 PTH receptor (PTH2R) are expressed in glomeruli.

Proximal Convoluted Tubule

Following its ultrafiltration across the glomerular capillaries, calcium is reabsorbed throughout the nephron. As shown in Fig. 64.3 , the majority of the filtered calcium is recovered by the proximal tubules. The proximal nephron of both superficial and juxtamedullary tubules consists of three ultrastructurally distinct segments: S ₁, S ₂, and S ₃. Operationally, however, calcium transport has been characterized in the microscopically recognized proximal convoluted tubules, corresponding primarily to the S ₁segment, and to a lesser extent in superficial proximal straight tubules ( pars recta ), S ₂segments.

Sixty to Seventy percent of the filtered calcium is absorbed by the end of the proximal convoluted tubule. Using in vivo micropuncture techniques, Lassiter and colleagues, and subsequently others, demonstrated that two-thirds of the filtered calcium is reabsorbed by the end of the accessible proximal convolution in the rat. Somewhat less complete absorption, 37–45%, obtains in the rabbit. Remarkably, in the hamster, which exhibits the most robust calcium-sparing effect of PTH, calcium absorption by proximal tubules is negligible. This observation underscores the primacy of distal segments in regulating final calcium excretion.

In general, random collections of proximal tubule fluid samples under control conditions result in tubular fluid to glomerular filtrate calcium ratios, (TF/GF) _{Ca ²⁺}between 1.0 and 1.2. Based on these findings it is commonly held that the concentration of calcium within the proximal tubular fluid remains essentially identical to that of glomerular filtrate or ultrafilterable plasma (UF) calcium, i.e., that calcium transport along the length of the proximal convoluted tubule proceeds essentially as an isoosmotic process. These observations, in turn, have been interpreted as indicating that the bulk of calcium absorption is energetically passive. However, a detailed examination of calcium absorption along the length of the accessible superficial proximal tubule revealed that (TF/GF) _{Ca ²⁺}increases from a value close to unity at the earliest micropuncture locations to a value of about 1.2, still relatively early in the nephron, and stayed constant for the remaining accessible portions of the proximal nephron. The cause of the elevated (TF/GF) _{Ca ²⁺}ratios is unclear but may have its origin in molecular sieving of calcium at the luminal pole of the tight junctions as calcium absorption lags behind that of water. Alternatively, the presence of nontransported, anionically complexed calcium within the lumen might contribute to or account for the elevated values of (TF/GF) _{Ca ²⁺}. Inasmuch as the proximal tubule transepithelial voltage is about −2.5 mV, these findings are consistent with the idea that a component of proximal calcium transport may be energetically active since it proceeds against an electrochemical gradient.

Proximal Straight Tubule

Because proximal straight tubules ( pars rectae ) do not extend to the surface of the kidney and are not amenable to conventional micropuncture techniques, calcium transport by this segment has been less thoroughly studied than in proximal convoluted tubules. Indirect estimates of calcium reabsorption derived from the difference between the calcium concentration of fluid samples obtained from late proximal convoluted tubules and those from the tip of the loop of Henle suggested that 10% of the filtered calcium is recovered by proximal straight tubules. This approach necessitates obtaining proximal samples from a superficial nephron, while the samples from the loop of Henle are taken from the tip of a juxtamedullary nephron. Nonetheless, direct in vitro microperfusion studies of proximal straight tubules substantiated the conclusion that proximal straight tubules absorb 10% of the filtered calcium.

Mechanisms of Proximal Tubule Calcium Transport

Calcium absorption by proximal tubules may be mediated by a combination of passive and active transport mechanisms. The transepithelial absorption of calcium can be conceptually described by the following relation:

calcium absorption=passive transport+active transport

where passive absorption is the sum of diffusion and solvent drag. These relations can be expressed formally as:

<SPAN role=presentation tabIndex=0 id=MathJax-Element-7-Frame class=MathJax style="POSITION: relative" data-mathml='JCa2+=PCa2+(ΔCCa2++ZiRTC¯Ca2+Δψ)diffusion+(1−σCa2+)C¯Ca2+Jvsolventdrag+JCa2+activeactivetransport’>?Ca2+=?Ca2+(??Ca2++ZiRT?⎯⎯⎯Ca2+??)diffusion+(1−?Ca2+)?⎯⎯⎯Ca2+??solventdrag+?activeCa2+activetransportJCa2+=PCa2+(ΔCCa2++ZiRTC¯Ca2+Δψ)diffusion+(1−σCa2+)C¯Ca2+Jvsolventdrag+JCa2+activeactivetransport
J Ca 2 + = P Ca 2 + ( Δ C Ca 2 + + Zi RT C ¯ Ca 2 + Δ ψ ) diffusion + ( 1 − σ Ca 2 + ) C ¯ Ca 2 + J v solvent drag + J Ca 2 + active active transport

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