Disorders of Magnesium Homeostasis—Hypo and Hypermagnesemia
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Magnesium is the fourth most abundant cation in the body and second most abundant within cells. It plays a key role in a variety of cellular processes. Magnesium is an important cofactor for adenosine triphosphatases (ATPases), and thereby in the maintenance of intracellular electrolyte composition. Ion channels involved in nerve conduction and cardiac contractility are regulated by magnesium. More than 300 enzymatic systems depend on magnesium for optimal function, including those involved in protein synthesis and deoxyribonucleic acid (DNA) replication. Magnesium deficiency is implicated in the pathogenesis of hypertension, type II diabetes mellitus, atherosclerosis, and asthma.
Normal serum magnesium concentration is between 1.7 and 2.5 mg/dL. Only 1% of the 21 to 28 g of magnesium in the body is contained within the ECF. Of the remainder, 67% is in bone and 20% in muscle. Figure 12.1 shows the distribution of magnesium within the body. In bone, the majority of magnesium is complexed in hydroxyapatite crystals. Approximately 30% of magnesium in bone is exchangeable with the ECF compartment. The rate of exchange is unclear. Magnesium within muscle and red cells is largely complexed to intracellular ligands and has limited ability to move from intracellular fluid (ICF) to ECF in conditions of total-body magnesium depletion.
FIGURE 12-1. Magnesium homeostasis. Daily magnesium fluxes between ECF, intestine, kidney, and bone are shown. In the steady state, net intestinal absorption and renal magnesium excretion are equal.
Magnesium is regulated by both GI tract and kidney, with kidney playing the more important role. The average North American diet contains approximately 200 to 350 mg of magnesium. The average daily requirement in men is 220 to 400 mg, and in women is 180 to 340 mg. The North American diet is only marginally adequate with respect to magnesium. The majority is complexed to chlorophyll in green leafy vegetables. Seafoods, nuts, meats, and grains are high in magnesium.
Magnesium absorption is inversely proportional to intake. Under normal circumstances 30% to 40% is absorbed. This can vary from a low of 25% with large magnesium intakes, to a high of 80% with dietary magnesium restriction. The majority of magnesium absorption occurs in small intestine via both a paracellular and transcellular pathway. Magnesium absorption is affected by water absorption and prolonged diarrheal states result in significant intestinal magnesium losses. Secretions from the upper GI tract are relatively low in magnesium (1 mg/dL), whereas those from colon are relatively high in magnesium (18 mg/dL).
The primary regulator of ECF magnesium concentration is the kidney. Only 30% of magnesium is bound to albumin. The remainder is freely filtered across the glomerulus. Renal magnesium reabsorption varies widely to maintain homeostasis. Reabsorption is reduced to near zero in the presence of hypermagnesemia or CKD. With magnesium depletion secondary to GI causes the fractional excretion of magnesium can be reduced to 0.5%. Twenty percent of magnesium is reabsorbed in the proximal tubule in adults. ECF volume status affects magnesium reabsorption in this segment. Volume contraction increases and volume expansion decreases magnesium reabsorption. The bulk of magnesium reabsorption occurs in the thick ascending limb (60% to 70%). Magnesium is reabsorbed paracellularly with the lumen-positive voltage acting as driving force (Figure 12.2). The voltage is generated by potassium exiting across the apical membrane through the ROMK channel. Potassium recycling is essential for Na+-K+-2Cl– function, given that the luminal potassium concentration is much lower than that of sodium or chloride. The lumen-positive potential difference is also augmented via the tight junction proteins claudin-16 and -19. Mutations in the genes encoding these proteins result in the autosomal recessive disease familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). As prourine moves through the thick ascending limb, which is permeable to sodium and chloride but not water, the sodium concentration falls from 140 mM to 30 mM. This results in a driving force for sodium and chloride to leak back into the lumen. Claudin-16 mediates sodium movement, while claudin-19 blocks chloride movement, augmenting the lumen-positive potential difference. This effect has been referred to as the dilution potential. Although a variety of peptide hormones increase magnesium reabsorption including parathyroid hormone (PTH), calcitonin, glucagon, and antidiuretic hormone (ADH), magnesium concentration at the basolateral surface of the thick ascending limb is the major determinant of magnesium reabsorption. In hypermagnesemic states, magnesium reabsorption approaches zero, and in hypomagnesemia, the loop reabsorbs virtually all of the filtered magnesium reaching it. This effect is presumably mediated via the calcium/magnesium-sensing receptor expressed along the thick ascending limb basolateral surface. The receptor senses elevated calcium and magnesium concentration and transduces this signal to the apical membrane resulting in an inhibition of potassium recycling via ROMK. This dissipates the lumen-positive voltage and decreases the driving force for magnesium reabsorption.
FIGURE 12-2. Thick ascending limb magnesium transport model. Six transporters expressed in the thick ascending limb of Henle are associated with a Bartter-like syndrome: type I—the sodium-potassium-chloride cotransporter, NKCC2; type II—the ROMK potassium ion channel; type III—ClC-Kb, the basolateral chloride ion channel; type IV—barttin, a β subunit required for the trafficking of CLC-K (both ClC-Ka and ClC-Kb) channels to the basolateral membrane; type V—severe gain-of-function mutations in the calcium-sensing receptor; and type VI—mutations in both ClC-Ka and ClC-kb.
Approximately 5% to 10% of magnesium is reabsorbed in distal convoluted tubule (DCT) (Figure 12.3). Magnesium transport here is active and transcellular. Magnesium enters the cell passively through a channel (TRPM6) and exits actively via an unknown mechanism. The recent discovery that mutations in potassium channels (Kv1.1 and Kir4.1/5.1) and pro-epidermal growth factor (EGF) play a role in the pathogenesis of rare inherited disorders of renal magnesium wasting through their effects on magnesium entry into the distal convoluted tubule (DCT) via TRPM6 either directly or indirectly has shed further light on mechanisms of DCT magnesium transport. Potassium channels in the basolateral and luminal membranes affect the electrical driving force for magnesium entry across the luminal membrane. Recent studies also showed that EGF via binding to its receptor in the basolateral membrane regulates TRPM6.
FIGURE 12-3. Distal convoluted tubule magnesium transport model. Transporters expressed in distal convoluted tubule that are associated with renal magnesium wasting include the thiazide-sensitive Na+-Cl– cotransporter (Gitelman syndrome); the γ subunit of the Na+-K+-ATPase (isolated dominant hypomagnesemia); TRMP6 a magnesium channel (primary intestinal hypomagnesemia); Kv1.1; Kir4.1/5.1; and pro-EGF (pro-epidermal growth factor).
Despite differences in transport mechanisms compared to thick ascending limb, PTH, calcitonin, glucagon, ADH, and hypomagnesemia increase magnesium reabsorption in DCT. Amiloride increases magnesium reabsorption in distal nephron and is used therapeutically to reduce renal magnesium loss. Thiazide diuretics, on the other hand, cause mild magnesium wasting. Distal magnesium loss is partially offset by increased proximal reabsorption due to mild ECF volume contraction. The collecting duct plays a very limited role in magnesium reabsorption.
Hypomagnesemia is caused by decreased oral intake, increased GI losses, increased renal excretion, and magnesium shifts from ECF to ICF. GI and renal losses are the most common causes of hypomagnesemia.
Magnesium depletion was first appreciated in animals in 1932 with the report of locoism in cattle. Locoism or “grass staggers” closely resembles magnesium depletion in humans and occurs within 1 to 2 weeks after grazing on early spring grass that is high in ammonium. The ammonium complexes magnesium and phosphate, forming insoluble struvite in the intestinal lumen, preventing magnesium absorption. Cattle develop signs and symptoms of neuromuscular excitability, hypomagnesemia, hypocalcemia, and hypokalemia. In 1960, Vallee, Wacker, and Ulmer first reported magnesium deficiency in man. They described 5 patients with carpopedal spasm, Chvostek and Trousseau signs, and seizures.
GI causes of hypomagnesemia include decreased intake, malabsorption, diarrheal states, primary intestinal hypomagnesemia, and administration of proton pump inhibitors. Clinically significant magnesium depletion from decreased oral intake alone is rare because of the ubiquitous nature of magnesium in foods and the kidney’s ability to conserve magnesium. Hypomagnesemia was described in a number of patients with malabsorption. Serum magnesium concentration in these patients tends to correlate with the degree of steatorrhea. Presumably intestinal free fatty acids bind to magnesium forming insoluble soaps. Magnesium malabsorption is improved with a low-fat diet. Magnesium depletion can occur in any severe diarrheal state. Fecal magnesium increases as stool water increases and colonic secretions are high in magnesium. Proton pump inhibitor use has been associated with hypomagnesemia. Urinary magnesium excretion in these patients is low suggesting a possible GI pathogenesis.
Primary intestinal hypomagnesemia is an autosomal recessive disorder characterized by hypomagnesemia and hypocalcemia. Patients present in the first 6 months of life with symptoms of neuromuscular excitability including seizures secondary to hypomagnesemia and hypocalcemia. The hypocalcemia is resistant to therapy with calcium or vitamin D analogs. Passive intestinal magnesium transport is normal and large doses of oral magnesium reverse the hypomagnesemia and hypocalcemia. Mutations in the TRPM6 gene cause this disorder. TRPM6 is a member of the transient receptor potential (TRP) channel family and is expressed in intestine and DCT. TRPM6 is the pathway whereby magnesium crosses the apical membrane of epithelial cells in intestine and DCT. Renal magnesium wasting was described in these patients consistent with TRPM6 expression in kidney.
Renal magnesium losses are caused by primary defects in renal tubular reabsorption or secondary to a variety of systemic and local factors to which the kidney is responding normally. Primary renal defects are more likely to cause severe hypomagnesemia than secondary defects. Drug- or toxin-induced injury is the most common cause of primary renal magnesium wasting. Offending drugs include aminoglycosides, cis-platinum, amphotericin B, pentamidine, cyclosporine, tacrolimus, and EGF receptor inhibitors such as cetuximab and erlotinib. With cis-platinum, hypomagnesemia may persist for years after the drug is discontinued. Cyclosporine-induced hypomagnesemia is often associated with normal or elevated serum potassium and resolves rapidly after discontinuation of the drug. Molecular studies in cultured cells showed that cyclosporine administration downregulates TRPM6. This effect is mediated by inhibition of c-fos transcription. Hypomagnesemia may occur up to 2 weeks after a course of pentamidine. Hypomagnesemia was reported after tubular damage resulting from acute tubular necrosis, urinary tract obstruction, and delayed renal allograft function. This may result from increased flow in the loop of Henle that decreases magnesium reabsorption in this segment. Cetuximab and erlotinib are chemotherapeutic agents that bind to and inhibit activation of the EGF receptor. The role of the EGF receptor in magnesium transport in DCT is discussed further below. Leptospirosis has also been associated with hypomagnesemia and renal magnesium wasting, as well as acute kidney injury and phosphate wasting.
A variety of uncommon inherited renal magnesium wasting diseases have been described. They are subdivided based on whether the genetic defect is in a protein expressed in the loop of Henle or in the DCT.
Inherited diseases affecting magnesium reabsorption in the loop of Henle include FHHNC, autosomal dominant hypocalcemia (ADH), and Bartter syndrome. In all of these disorders, the driving force stimulating passive magnesium transport (lumen-positive voltage) is dissipated.
FHHNC is characterized by renal magnesium and calcium wasting. It presents in early childhood with recurrent urinary tract infections, nephrolithiasis, and a urinary concentrating defect. The associated hypercalciuria, incomplete distal renal tubular acidosis, and hypocitraturia result in nephrocalcinosis and a progressive decrease in glomerular filtration rate. One-third develop end-stage renal disease by early adolescence. Mutations in claudin-16 and -19 cause FHHNC. Claudin-16 and -19 are expressed in the tight junction of the thick ascending limb of Henle. Mutations in the genes encoding these proteins affect generation of the dilution potential, as discussed earlier.
Approximately 50% of patients with ADH have associated hypomagnesemia. ADH results from an activating mutation in the calcium/magnesium-sensing receptor. Activating mutations shift the receptor set-point and increase its affinity for calcium and magnesium. This signal is transduced to the apical membrane resulting in inhibition of potassium exit. The resulting reduction in lumen-positive transepithelial voltage reduces the driving force for magnesium and calcium reabsorption in the loop of Henle.
Bartter syndrome is caused by a variety of genetic defects in thick limb of the loop of Henle that present with renal salt wasting, hypokalemic metabolic alkalosis, and increased renin and aldosterone concentrations. Mutations in 6 ion transport proteins are described (Figure 12.2). All play a key role in transcellular sodium chloride transport and generation of the lumen-positive voltage that is the driving force for magnesium and calcium transport. These include Na+-K+-2Cl– cotransporter (NKCC2); apical membrane potassium channel (ROMK); basolateral membrane chloride channel (ClC-Kb); barttin, the β subunit of the basolateral membrane chloride channel; severe gain-of-function mutations of the calcium-sensing receptor; and mutations in both ClC-Ka and -Kb. The phenotype varies depending on the gene(s) mutated. Mutations in NKCC2 and ROMK are associated with severe salt wasting, neonatal presentation, and nephrocalcinosis. For unclear reasons hypomagnesemia is not common. Mutations in ClC-Kb present during adolescence and 50% have hypomagnesemia. Mutations in barttin are associated with sensorineural deafness and hypomagnesemia is not yet reported.
Genetic disorders resulting in magnesium wasting in the distal convoluted tubule include isolated dominant hypomagnesemia (IDH), Gitelman syndrome, autosomal recessive isolated renal hypomagnesemia (IRH), and autosomal dominant hypomagnesemia and EAST (epilepsy, ataxia, sensorineural deafness, and tubulopathy)/SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte disorders) syndromes. IDH is an autosomal dominant disorder associated with hypocalciuria and chrondrocalcinosis. It is caused by a defect in the FXYD2 gene that encodes the γ subunit of the basolateral Na+-K+-ATPase in the DCT. Mutations result in subunit retention in the Golgi complex. How a mutation in this subunit results in isolated renal magnesium wasting and increased calcium reabsorption is unclear. Hepatocyte nuclear factor (HNF) 1B is a transcription factor that regulates FXYD2. This gene is mutated in maturity onset diabetes of the young type 5 and explains the hypomagnesemia secondary to renal magnesium wasting that occurs in up to half of affected individuals. Gitelman syndrome results from loss of function mutations in the thiazide-sensitive sodium chloride cotransporter (NCC). Mutant NCC is trapped in the Golgi and not trafficked to the apical membrane. Patients present in adolescence with symptoms of hypomagnesemia and almost always have associated hypocalciuria. Gitelman syndrome results in more profound hypomagnesemia than is seen with chronic thiazide therapy. TRPM6 is downregulated with both Gitelman syndrome and thiazide administration. Autosomal recessive IRH is the result of mutations in pro-EGF. As a result pro-EGF is either mistargeted or processed by proteases and does not make its way to the basolateral membrane. EGF stimulates magnesium reabsorption in DCT in a paracrine fashion. Pro-EGF, a type 1 membrane protein, is cleaved to EGF that binds to its receptor in the basolateral membrane. EGF receptor binding stimulates magnesium transport by causing TRPM6 insertion into the luminal membrane. Patients with IRH have severe hypomagnesemia secondary to renal magnesium wasting, seizures, and mental retardation. Autosomal dominant hypomagnesemia presents with severe renal magnesium wasting, muscle weakness and cramping, tetany, tremor, and cerebellar atrophy. Mutations in the KCNA1 gene that encodes the voltage gated potassium channel Kv1.1 were described. The channel is expressed in the luminal membrane. Mutated channels exert a dominant-negative effect on wild type channels, hence the autosomal dominant mode of inheritance. The channel is responsible for maintaining the electrical driving force for magnesium entry across the luminal membrane. This is important because magnesium concentrations are similar in the tubular lumen (1.1 mM) and within the DCT cell (0.8 mM). Magnesium entry depolarizes the cell and Kv1.1 by extruding potassium from the cell maintains the negative membrane potential. EAST/SeSAME syndrome is caused by mutations in the KCNJ10 gene that encodes the inward rectifying potassium channel Kir4.1. Kir4.1 is expressed in kidney, inner ear, and brain. The associated tubulopathy is similar to Gitelman syndrome with hypomagnesemia, hypocalciuria, hypokalemia, and metabolic alkalosis. Kir4.1 is expressed in the basolateral membrane and helps maintain Na+-K+-ATPase activity by allowing potassium recycling across the basolateral membrane.
A variety of systemic and local factors affect magnesium reabsorption in the proximal tubule, thick ascending limb of Henle, and DCT, resulting in secondary renal magnesium wasting. In proximal tubule, magnesium reabsorption is decreased by volume expansion, as might occur after saline infusion and osmotic diuresis. In the loop of Henle, magnesium reabsorption is inhibited by furosemide. This effect is mild because of an associated increase in proximal reabsorption. Hypercalcemia also results in magnesium wasting. Calcium binds to the calcium/magnesium receptor in the basolateral membrane of the loop of Henle decreasing the lumen-positive voltage that drives paracellular magnesium transport. Thiazide diuretics act in DCT to inhibit magnesium transport.
Magnesium shifts from ECF to ICF can occur as with calcium. These are uncommon causes of hypomagnesemia and can result after parathyroidectomy, refeeding, and in patients with hyperthyroidism. Hypomagnesemia develops in patients with burns because of magnesium losses through skin. Magnesium loss is proportional to the skin area burned.