10: Regulation of Calcium, Magnesium, and Phosphate

• ▸ State the normal total plasma calcium concentration and the fraction that is free.

• ▸ Describe the distribution of calcium between bone and extracellular fluid and the role of bone in regulating extracellular calcium.

• ▸ Describe and compare the roles of the gastrointestinal tract and kidneys in calcium balance.

• ▸ Describe and compare bone remodeling and calcium buffering by bone.

• ▸ Describe the role of vitamin D in calcium balance.

• ▸ Describe how the synthesis of the active form of vitamin D (calcitriol) is regulated.

• ▸ Describe the regulation of parathyroid hormone secretion and state its major actions.

• ▸ Describe the source, major actions and regulation of FGF23.

• ▸ Describe the renal handling of phosphate and how it is regulated by parathyroid hormone and FGF23.

• ▸ Describe the renal handling of magnesium.

Calcium, magnesium, and phosphorus (in the form of phosphate) are major elemental constituents of the body, the majority of all of them being components of bone. Most of the nonbone fractions are compartmentalized in organelles within cells or complexed with cytosolic proteins, and only small fractions of any of these substances are free in the ECF. However plasma levels of these ions, even though representing small percentages of total-body amounts, are crucial for body function. Deviations lead to serious, even life-threatening pathologies. Calcium and phosphate are usually discussed together because both their physiological roles and mechanisms of regulation are intertwined. All 3 substances are regulated by cooperative interactions between the kidneys, the gastrointestinal (GI) tract, and the bone.

The Chemistry of Calcium, Magnesium, and Phosphate

The physiology and regulation of calcium, magnesium, and phosphate are critically dependent on their chemical properties. Calcium and magnesium are both divalent alkali metal cations that play similar roles in some contexts and different roles in others. Their free (noncomplexed) concentrations in the ECF are roughly the same (∼1 mM), low enough so that they are not significant components of plasma osmolality. However, being divalent, they are major contributors to the nonspecific layer of cations that are attracted to negative charges on plasma membranes and large plasma proteins. Alterations in plasma levels of either one of these species have major effects on the behavior of excitable cells because they alter the electric field sensed by voltage-gated channels. In contrast, their intracellular levels are vastly different from each other and these ions perform very different functions. The cytosolic concentration of magnesium (ie, the free dissolved component) is about 0.5 mM, only slightly lower than in the ECF, whereas the free intracellular calcium concentration is less than 1000th of magnesium. This difference and their different functional roles within cells are due to nuances of their chemistry.

As with all inorganic ions, calcium and magnesium are surrounded by hydration shells of water, and when interacting chemically with other ions or organic molecules, they must shed some or all of the water. Calcium is a larger ion and holds its water loosely, whereas the smaller ion magnesium holds water tightly. Thus magnesium, with its more strongly held water, is actually a larger volume object and is excluded from restricted sites in proteins accessible to calcium. A number of intracellular proteins possess binding sites for calcium and serve as calcium detectors. This allows very small changes in free intracellular calcium to be effective modulators of protein function in the face of a large background concentration of magnesium. Free calcium rises in brief bursts as components of intracellular signaling cascades, perhaps like a small flashlight intermittently illuminating parts of a dark room, whereas magnesium is like a floodlight of constant brightness.

Phosphate is the substance we previously encountered in Chapter 9 in association with titratable acidity. In the plasma it exists primarily as a mixture of monovalent (H₂PO₄⁻) and divalent phosphate (HPO₄²⁻), with a summed concentration of about 1 mM. A significant property of phosphate is its tendency to combine with calcium in various stoichiometric ratios and form insoluble complexes. In bone this tendency to precipitate is crucial for the formation and maintenance of bone structure, but when occurring elsewhere in the body it leads to soft tissue calcification. This chemical characteristic is a major reason why plasma phosphate levels must be controlled. Within the renal tubules calcium may combine with phosphate or oxalate and form renal calculi (kidney stones) that can grow large enough to block the ureter.

The Physiology of Calcium

Calcium plays several roles in the body. First, it is a major constituent of bone, which contains 99% of total-body calcium. Second, it is used in cells as a second messenger, allowing for rapid transmission of signals from surface membrane channels or receptors to various cellular actions. Third, its presence in the ECF stabilizes the electrical sensitivity of voltage-gated membrane channels. Normal total plasma calcium is about 10 mg/dL (2.5 mM), of which about 1 mM is in the free ionized form. Another 1 mM of the total is reversibly bound to plasma proteins such as albumin, and the rest is complexed to anions with relatively low molecular weights, such as citrate and phosphate.

All body cells regulate free cytosolic calcium concentrations to very low levels in order to prevent formation of calcium complexes with the many forms of phosphate within cells, and to prevent inappropriate activation of signaling pathways. They do this with a variety of active transport systems (ATPases and antiporters) that remove calcium from the cytosol, either to the external medium or to intracellular organelles.

Calcium in the ECF is the source for calcium entering cells through calcium channels and is the calcium that triggers rapid exocytosis of neurotransmitters and signals contraction in smooth and cardiac muscle cells. As indicated earlier, the diffuse layer of extracellular cations associated with negatively charged membranes affects voltage-gated channels. Low levels of calcium fool sodium channels into sensing more depolarization than actually exists, leading to spontaneous firing of motor neurons. In turn, this firing triggers inappropriate muscle contraction, called low-calcium tetany. If severe enough, it leads to respiratory arrest because of spasms in the ventilatory muscles.¹

An important modulator of the effect of calcium on nerve membranes is the plasma pH. Serum albumin has many anionic sites that reversibly bind both protons and calcium. These ions compete for occupancy of the binding sites. As pH rises, protons dissociate and calcium ions take their place, thereby lowering the concentration of free calcium ions. In turn, this reduces the diffuse cationic layer associated with cell membranes. Thus, a patient with an acute alkalosis is more susceptible to tetany, whereas someone with acidosis will not manifest tetany at levels of total plasma calcium low enough to cause symptoms in normal people.

Elevated plasma calcium (hypercalcemia) is also a serious medical problem, particularly if the rise occurs rapidly. Hypercalcemia has multiple effects, again resulting from an effect on excitable cell function. Hypercalcemia leads to CNS depression, muscle weakness, and GI tract immotility.

Moment-to-moment regulation of plasma calcium is achieved, not by input and output from the body, but rather by moving calcium in and out of bone. The majority of bone substance consists of hydroxyapatite, a complex of calcium, phosphate, and hydroxyl groups.² Bone stores of calcium are an enormous buffer system that keeps plasma calcium nearly constant regardless of whole body balance. Thus, ordinary variations in ingestion and excretion of calcium have little effect on plasma levels because of this tight buffering. The long-term regulation of total calcium in bone is, of course, important for bone growth during childhood and bone integrity in adult life. Here the kidneys play an important but indirect role because (1) they excrete calcium in the urine and (2) are involved in forming the active form of vitamin D, which is a major controller of GI calcium absorption.

GI Tract

Most dietary calcium simply passes through the GI tract to the feces. The amount absorbed depends on many factors, particularly the quantity of calcium in the diet. Some of the calcium that is absorbed moves by a regulated active transcellular process in the duodenum. The majority is absorbed by paracellular diffusion in the lower small intestine, where intestinal content spends a far greater time than the few minutes in the much shorter duodenum, and thus has greater opportunity for passive absorption. The active transport system in the duodenum plays its most important role when dietary calcium is limited. Calcium enters duodenal cells passively through calcium-selective channels (members of the TRP family), binds reversibly to mobile cytosolic calcium binding proteins (called calbindins), and is then actively transported out the basolateral side via a Ca-ATPase and, to some extent, by a Na-Ca antiporter. Calbindins contain multiple binding sites for calcium and are free to diffuse throughout the cytosol. They act as delivery trucks for calcium, permitting large amounts of calcium to move from place to place within a cell, in this case from apical to basolateral membrane, all the while keeping the concentration of free calcium at a low level (Figure 10–1).

Kidneys

The kidneys handle calcium by filtration and reabsorption. There is no secretion. Overall reabsorption of the filtered load is normally 98%, leaving only 2% to be excreted. The free component of plasma calcium (about 40%) is freely filterable. About 65% of the filtered load is reabsorbed in the proximal tubule. Another 20% is reabsorbed in the thick ascending limb of Henle's loop, and almost all the rest in the distal convoluted tubule and connecting tubule.

Calcium reabsorption in the proximal tubule and thick ascending limb of Henle's loop is passive and paracellular. Whereas the tight junctions in many regions of the tubule are impermeable to cations, the tight junctions in the proximal tubule and thick ascending limb permit passive cation flux. Water reabsorption in the proximal tubule concentrates calcium and drives paracellular flux, whereas the lumen-positive potential in the thick ascending limb is the major driving force. In both cases, the driving forces are dependent directly or indirectly on active sodium reabsorption as they are for so many other substances. In the distal tubule calcium reabsorption is active and transcellular. It uses the same general mechanism as in the GI tract, that is, entrance via calcium-specific TRP channels, diffusion bound to calbindins and active exit across the basolateral membrane by a combination of Ca-ATPase and Na-Ca antiport activity (Figure 10–2). Endocrine control of renal calcium handling is exerted in the distal tubule.

The amount of calcium excreted in the urine, when averaged over time, is equal to the net addition of new calcium to the body from the GI tract (recall that most dietary calcium is excreted directly and is not absorbed). Thus, the kidneys participate in maintaining a stable balance of total-body calcium. The change in renal excretion in response to changes in dietary input is much slower than the equivalent responses to dietary sodium, water, or potassium. For example, only about 5% of an increment in dietary calcium appears in the urine, whereas virtually all of an increased ingestion of water or sodium soon appears in the urine. The reason is that most of the dietary increment never gains entry to the blood because it fails to be absorbed from the GI tract. In contrast, when dietary intake of calcium is reduced to extremely low levels, there is a gradual reduction of urinary calcium.

What determines renal calcium excretion? Although the filtered load is somewhat variable, being the product of free plasma calcium and glomerular filtration rate (GFR), the GFR is regulated mainly to meet the needs of sodium and fluid balance, not calcium. In fact, an increase in urinary calcium excretion can be induced simply by administering salt. This feature is used clinically as an emergency procedure when calcium levels in the blood get alarmingly high, the treatment consisting of administering large amounts of saline, with the consequence that large amounts of calcium-containing fluid pass through the kidneys to the urine. Independent, calcium-specific regulation of calcium excretion is exerted in the distal tubule via control of active calcium reabsorption. We will describe this control shortly.

Bone

Bone is a complex tissue structurally and physiologically. It is the least understood, but in some ways the most important of the major effector systems for calcium management. Bone contains 99% of total-body calcium, primarily in the form of hydroxyapatite that is deposited on a tough collagen network. The equilibrium between crystalline hydroxyapatite and its dissolved components is highly labile, dependent on the local concentrations of calcium, phosphate, hydrogen ions and specific noncollagenous proteins in the immediate environment. Bone is penetrated by a labyrinth of tiny passageways containing fluid (bone fluid), cells (mostly osteocytes), and, in the larger passageways, blood vessels. Osteocytes, deep within bone, communicate with each other and surface cells via long cellular extensions containing gap junctions. Calcium moves back and forth between the bone surface and the inner recesses via this cellular network.

Bone fluid is separated from the ECF by a layer of surface-lining cells. These cells are flattened versions of the active osteoblasts involved in forming bone and bone remodeling (see below). The flux of calcium through or around the surface-lining cells is crucial in regulating the concentration of calcium in the ECF. Details of this how this occurs are lacking, but the result is clear: flux of calcium from a labile pool within bone is a powerful short-term buffering system that prevents large swings in plasma calcium concentration. It does not require hormonal signals. However, the set point for plasma calcium concentration maintained by the rapid movement of calcium in and out of bone is critically regulated by hormonal control, as discussed later.

There is a second flux process between bone and plasma involving calcium called bone remodeling that affects calcium stores on a slower time scale. Remodeling, while it includes calcium, is directed toward maintaining the mechanical properties of bone rather than calcium levels in the blood. Remodeling consists of the simultaneous actions of giant, multinucleated cells called osteoclasts that erode little pits in the bone matrix, and their partners, nearby osteoblasts, which follow behind and fill in the pits with new bone matrix (like brick masons replacing bricks in a wall one brick at a time). The osteoclasts pump hydrogen ions and create an acidic micro space directly underneath them that solubilizes hydroxyapatite. The calcium and phosphate freed up by this process is then transported transcellularly by the osteoclasts to the ECF. The daily flux of calcium via remodeling is much less than that associated with rapid flux described above. Normally the fluxes associated with remodeling result in no net gain or loss of calcium, but imbalance in resorption of bone matrix relative to replacement causes gradual loss of bone density and pathology such as osteoporosis.

About 85% of total-body phosphate is located in bone as a partner with calcium in hydroxyapatite. Another 14% of body phosphate is located intracellularly in the form of a multitude of phosphorylated proteins and metabolic intermediates. The remaining 1% is in the ECF. Phosphate is plentiful in the diet, as it is contained in all proteins. The fraction absorbed from the GI tract varies somewhat with circumstances, typically being about 65% of the ingested amount, so that the total amount absorbed varies more or less directly with dietary input. Accordingly, regulation of body phosphate is exerted mainly via excretion by the kidneys. Phosphate absorption from the GI tract occurs throughout the small intestine by paracellular diffusion and by transcellular active transport. The active component uses several different Na-phosphate symporters in the apical membrane to bring phosphate into the intestinal enterocytes. The exit step is not characterized, but is presumed to be via a phosphate uniporter.

In the blood approximately 5% to 10% of the phosphate is protein bound, so that 90% to 95% is filterable at the renal corpuscle. Normally, approximately 75% of this filtered phosphate is actively reabsorbed in the proximal tubule. The mechanism uses the same sodium-phosphate symporters as in the GI tract.

As with other substances handled by filtration and tubular reabsorption, the rate of phosphate excretion can be changed by altering the filtered load or the rate of reabsorption. Even relatively small increases in plasma phosphate concentration (and, hence, filtered load) can produce relatively large increases in phosphate excretion. This occurs when plasma phosphate concentration increases as a result of increased dietary phosphate intake or release of phosphate from bone. The sodium-phosphate symporters are a tubular maximum-limited (T_m) system, and the normal filtered load is just a little higher than the T_m. This means that most of the filtered phosphate is reabsorbed, but some spills into the urine. It also means that the reabsorptive capacity is saturated in normal conditions, and any increase in filtered load simply adds to the amount excreted.

Calcium and phosphate are regulated by a web of interacting signals. For this reason we describe the regulation of both substances together. Control systems have 2 purposes: (1) on a short-term basis to keep the plasma level of calcium within a range that does not perturb excitable cell function and (2) on a longer-term basis to ensure that there is enough total calcium and phosphate in the body to maintain bone integrity. The key hormones that directly control calcium and phosphate are the active form of vitamin D (1,25-(OH)₂D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). These hormones regulate 3 crucial processes: (1) the input of calcium and phosphate into the body from the GI tract, (2) the excretion of calcium and phosphate by the kidneys, and (3) the movement of both substances between plasma and bone. These hormones also regulate the production of each other.

Vitamin D

The term vitamin D in common use denotes any member of a family of closely related molecules that are derived from cholesterol. One member, called vitamin D₃ (cholecalciferol), is synthesized in the skin by the action of ultraviolet radiation on precursors synthesized in the body. Another member, vitamin D₂ (ergocalciferol), is ingested in food derived from plants. Vitamin D supplements may contain either one. Although not identical structurally, vitamins D₂ and D₃ are equivalent in terms of their physiological roles in the body and can be considered to be the same vitamin. Until hydroxylated at the first and 25^th positions, vitamin D has no significant biological activity. It travels in the blood and becomes hydroxylated at the 25^th position by the liver and then hydroxylated again at the first position by proximal tubular cells within the kidneys to yield the active form, which is now, strictly speaking, a hormone. When the precursor is cholecalciferol (vitamin D₃), the active hormone is also called calcitriol. For the rest of this text, we will use calcitriol to denote the active hormone that is recognized by specific receptors in target tissues.

The hydroxylation step occurring in the kidneys that produces calcitriol is the key control point in its production. That step is regulated by PTH and FGF23. Specifically, PTH stimulates this step (produces more calcitriol), whereas FGF23 inhibits it.

The major action of calcitriol on effector systems is to stimulate transcellular absorption of calcium, and to a lesser extent, phosphate, by the duodenum. (It may also increase passive calcium absorption in the lower small intestine by effects on tight junctions.) As well, it stimulates the renal-tubular reabsorption of both calcium and phosphate. Its primary mode of action is to increase the genetic expression of the protein components in the transport pathways. These actions serve functionally to increase or preserve the supply of the main building blocks for the synthesis of hydroxyapatite in bone, that is, calcitriol is effectively a bone-promoting hormone. Calcitriol also has some complicated actions on bone cells, best characterized as permissive for normal bone turnover. The influences of calcitriol on bone and the kidney are far less important than its actions on the GI tract to stimulate absorption of calcium (and phosphate).

In terms of the other hormones, calcitriol inhibits the synthesis of PTH in the parathyroid glands. Since PTH stimulates calcitriol production, this action completes a classic negative feedback loop that maintains normal levels of both hormones. Calcitriol also stimulates production of FGF23.

The major event in calcitriol deficiency is decreased calcium absorption from the GI tract, resulting in decreased availability of calcium for bone formation or reformation. In children, the newly formed bone protein matrix fails to be calcified normally because of the low availability of calcium, leading to the disease rickets.³

PTH

The parathyroid glands are small (pea sized or less) nodules of tissue embedded within the thyroid gland in the neck. Normally a person has 4 parathyroid glands. They secrete PTH (parathyroid hormone), an 84-amino-peptide hormone. The GI tract, kidneys, and bone are all subject to direct or indirect control by PTH. All of its normal activity is contained in the first 34 amino acids, and synthetic PTH can be made containing only this component. The PTH half-life in the plasma is very short (< 10 min), mostly due to rapid degradation in the liver,⁴ with renal filtration and uptake playing a secondary role. PTH secretion is controlled on a moment-to-moment basis by the calcium concentration of the ECF bathing the cells of the parathyroid glands. Decreased plasma calcium concentration stimulates PTH secretion, and increased plasma concentration inhibits secretion. Extracellular calcium acts directly on the parathyroid glands by binding to a novel class of calcium receptors coupled to G-protein-linked signaling cascades that inhibit the secretion of PTH. Low extracellular calcium stimulates PTH secretion by removing a tonic inhibition. This is a sensitive control system designed to keep free plasma calcium at about 1 mM.

Another regulator is plasma phosphate. Elevated phosphate stimulates PTH secretion by stimulating the capacity of the parathyroid gland to synthesize PTH, so that chronically high levels of phosphate lead to elevated PTH. A third regulator, as mentioned previously, is calcitriol, which inhibits PTH synthesis. On a moment-to-moment basis, calcium is the primary acute regulator.

PTH exerts at least 5 distinct effects on calcium and phosphate homeostasis (summarized in Figure 10–2 showing the response to hypocalcemia.

1. PTH actions on bone acutely increase the movement of calcium and phosphate from the labile pool in bone into the ECF. The mechanism of action is not clear, but the effect is to raise the set point for plasma calcium between plasma and bone fluid, that is, net efflux continues until plasma calcium rises to a new level.

2. PTH stimulates the bone remodeling process. Normally remodeling results in no net change in total bone calcium, but when PTH remains elevated, the result is erosion of bone hydroxyapatite.

3. PTH stimulates the hydroxylation step in the kidneys that generates calcitriol. The increased calcitriol stimulates calcium uptake from the GI tract and ensures that enough new calcium enters the body to replace losses in the urine.

4. PTH increases renal tubular calcium reabsorption, mainly by an action on the distal convoluted tubule. At this location, it acts rapidly through activation of kinases that phosphorylate regulatory proteins on a short-term basis. It also acts, on a slower time scale to increase synthesis of all the components of the transport pathway. The increased uptake of calcium from the tubular lumen increases basolateral extrusion (by a combination of Ca-ATPase activity and Na-Ca antiporter activity). The overall effect is to decrease urinary calcium excretion and retain body calcium.

5. PTH reduces the proximal tubular reabsorption of phosphate, thereby increasing urinary phosphate excretion and decreasing extracellular phosphate concentration.

The adaptive value of the first 4 effects results in a higher extracellular calcium concentration and thus compensates for the lower calcium concentration that originally stimulated PTH secretion. When PTH acts on bone, both calcium and phosphate are released into the blood. Similarly, calcitriol enhances the intestinal absorption of both calcium and phosphate, so that the processes that restore calcium to its normal level are simultaneously acting to increase the plasma phosphate above normal. But this is an unwanted action because of the tendency to form insoluble precipitates of calcium phosphate. Under the influence of PTH, plasma phosphate does not actually increase, because of PTH's inhibition of tubular phosphate reabsorption. Indeed, this effect is so potent that plasma phosphate may actually decrease when PTH levels are elevated.

There are nuances to the actions of PTH on bone that have important clinical implications. The response of bone to PTH depends on the pattern of its plasma concentration over time. PTH can either promote resorption of hydroxyapatite (its usual action), or if administered intermittently, promote deposition. Primary hyperparathyroidism, resulting from a primary defect in the parathyroid glands (eg, a hormone-secreting tumor), generates a continuous excess hormone level and causes enhanced bone resorption. This leads to bone thinning and the formation of completely calcium-free areas or cysts. In this condition plasma calcium often increases and plasma phosphate decreases; the latter caused by increased urinary phosphate excretion. A seeming paradox is that urinary calcium excretion is increased despite the fact that tubular calcium reabsorption is enhanced by PTH. The reason is that the elevated plasma calcium concentration induced by the effects of PTH causes the filtered load of calcium to increase even more than it increases the reabsorptive rate. Because the filtered load is so great, there is also an increased amount not reabsorbed, (ie, excreted). This result nicely illustrates the necessity of taking both filtration and reabsorption (and secretion, if relevant) into account when analyzing excretory changes of any substance. And as mentioned earlier, the high urinary calcium content promotes the formation of stones.

In contrast to what happens with the continuous presence of elevated PTH that accelerates bone resorption and release of calcium, intermittent rises (produced by infusions once per day) actually increase deposition of calcium in bone. Intermittent infusion of PTH is used therapeutically to increase bone density in osteoporosis patients.

FGF23

Fibroblast growth factor 23 (FGF23) is a peptide hormone synthesized by osteoblasts and osteocytes in bone. It is primarily a negative regulator of phosphate, but has indirect actions on calcium. FGF23 secretion is increased in response to elevated levels of phosphate. It is also stimulated by calcitriol. In the kidney there are FGF23 receptors that are located in the distal tubule. Distal tubule cells contain the membrane protein Klotho, which is a co-receptor required in order for target cells to bind FGF23. FGF23 has 2 actions in the kidney: (1) it decreases reabsorption of phosphate (an action similar to that of PTH) and (2) it decreases production of calcitriol (an action opposite to that of PTH). Since these actions occur in the proximal, not distal tubule, it is suggested that distal tubule cells, upon binding FGF23, signal nearby proximal tubule cells by a paracrine messenger.

The interplay between calcitriol, PTH, and FGF23 acts to maintain adequate amounts of calcium and phosphate in bone and a normal level of free plasma calcium. Calcitriol stimulates uptake and retention of calcium and phosphate. PTH responds to changes in plasma calcium acutely to normalize plasma calcium via retrieval from a labile bone pool and by raising phosphate excretion, thereby preventing a rise in the product of calcium and phosphate concentrations that would otherwise promote soft tissue calcification. PTH also ensures an ongoing level of calcitriol and normal bone turnover via remodeling. FGF23 acts as brake on calcitriol production, preventing too much calcium and phosphate uptake, and stimulates phosphate excretion, thereby decreasing the tendency of phosphate to stimulate PTH production. Figure 10–3 shows the hormonal response to a rise in plasma phosphate, while Table 10–1 summarizes the effects of the various hormones.

Chronic Renal Failure

Much of the physiology we have described is illustrated by the case of chronic renal failure, in which loss of functioning nephrons decreases many renal functions, including GFR, production of calcitriol, and excretion of phosphate. The pathophysiology is complicated, but demonstrates the workings of the feedback system involved in calcium and phosphate homeostasis. Decreased excretion of phosphate due to low GFR causes increased plasma phosphate (hyperphosphatemia) that in turn causes elevated levels of PTH and FGF23. High FGF23 and the decrease in functioning nephrons both serve to reduce the renal production of calcitriol. The low calcitriol leads to additional problems, namely reduced calcium uptake from the GI tract and removal of the inhibitory action of calcitriol on PTH synthesis. The high PTH (secondary hyperparathyroidism) stimulates excessive bone resorption, leading to osteoporosis. Another serious complication is calcification of vascular smooth muscle, in part due to the high levels of phosphate. One goal in the treatment of hyperphosphatemia associated with chronic renal failure is reduction of phosphate absorption from the GI tract. This is accomplished by feeding the patient high doses of phosphate binders, of which calcium is one. The calcium forms complexes with phosphate in the GI tract, reducing the availability of absorbable phosphate. Another clinical intervention is to provide exogenous calcitriol. This hormone suppresses expression of the PTH gene in the parathyroid gland. It also increases GI absorption of phosphate, the very thing we are trying to inhibit, but its ability to lower the synthesis of PTH is the more important action because this reduces the excessive resorption of bone stimulated by PTH.

The majority of total-body magnesium exists in bone. Magnesium is not chemically linked with other components of hydroxyapatite, but is adsorbed to its surface. Most of the remaining body magnesium is located within cells where it forms complexes with ATP and serves as a cofactor for several enzymes. Although the intracellular levels and functions of magnesium and calcium are quite different, their extracellular concentrations, functions, and transport are remarkably similar. As with calcium, the normal fraction of dietary magnesium absorbed from the GI tract is less than 50%. Details are lacking, but it is believed that the major absorptive mechanism is paracellular diffusion throughout the small intestine. About 60% of plasma magnesium is free, 30% is adsorbed to albumin, and the rest is complexed with small anions. The free component is freely filtered, and then handled by the nephron almost identically to calcium. About 20% of the filtered load is reabsorbed in the proximal tubule and 70% in the thick ascending limb of the loop of Henle, in both cases by the paracellular route. These are somewhat different proportions than for calcium (65% is reabsorbed in the proximal tubule) and may reflect differences in the selectivity of the tight junctions. The distal tubule actively reabsorbs magnesium. The apical influx is via a magnesium-specific class of TRP channels. This flux is driven primarily by the negative membrane potential because the free cytosolic magnesium concentration is similar to that in the lumen. The basolateral exit step is active, but its mechanism is not established. In the healthy body, renal excretion of magnesium is regulated to maintain balance with input and to keep plasma levels steady. It is believed that regulation is exerted on the activity of apical membrane TRP channels, but the hormonal or other signaling pathways remain unknown.

• Calcium has a strong tendency to associate with small anions and restricted sites on proteins that are not accessible to magnesium.

• Moment-to-moment maintenance of plasma calcium primarily involves calcium flux between bone and plasma.

• The kidneys reabsorb almost all filtered calcium, the key site of regulation being in the distal tubule.

• The key action of vitamin D is to ensure adequate absorption of calcium from the GI tract.

• Regulation of calcium and phosphate are interdependent and involve interactions between calcitriol, PTH, and FGF23.

• Keeping phosphate levels in the normal range is required to permit normal calcium deposition and retrieval from bone.

• Magnesium is transported by the GI tract and kidney in a manner very similar to calcium.