Normal and Abnormal Magnesium Metabolism


Normal and Abnormal Magnesium Metabolism

Laurence Chan

Magnesium is the fourth most common cation in the human body, and it plays a critical role in many metabolic processes, including production and use of energy essential in the maintenance of normal intracellular electrolyte composition. Magnesium is necessary for a large number of enzymatic actions relating to the basic protein-synthesizing mechanisms. It maintains an important physiologic role particularly in cardiovascular and neuromuscular function. Approximately 60% of body magnesium is found in bone, and the remainder is found in cells. Only 1% is in extracellular fluid (ECF). As a result, the serum magnesium is a poor predictor of intracellular and total body stores and may grossly underestimate total magnesium deficit. Nevertheless, extracellular magnesium as measured in blood is broadly implicated in neuromuscular transmission and cardiovascular tone.

Overall, cellular and extracellular magnesium concentrations are carefully regulated by the gastrointestinal (GI) tract, kidney, and bone. GI losses and renal magnesium wasting constitute the major causes of magnesium deficiency. Several hereditary forms of hypomagnesemia have been discovered, including mutations in transient receptor potential melastatin type 6 (TRPM6), Claudin 16, Claudin 19, Cyclin M2 (CNNM2), and epidermal growth factor (EGF). Recently, mutations in magnesium transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of magnesium in cell viability (1). Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, EGF receptor inhibitors, calcineurin inhibitors, proton pump inhibitors, and antimicrobials. Magnesium supplementation, in addition to the use in hypomagnesemia, has been shown to be beneficial for preeclampsia, migraine, depression, coronary artery disease, and asthma. The therapeutic window of magnesium is wide, and in the absence of renal impairment, hypermagnesemia rarely occurs. Most cases of clinically significant hypermagnesemia are iatrogenic. Mild elevation in magnesium can occur in end-stage renal disease, tumor lysis syndrome, diabetic ketoacidosis, and in theophylline intoxication.

Normal Magnesium Metabolism

Magnesium is predominately an intracellular cation with less than 1% in the extracellular space. Owing to this distribution, total body magnesium concentrations are difficult to assess, and currently there is no simple accurate laboratory test to determine total body magnesium. The majority of our laboratory information comes from the determination of total magnesium in serum or plasma.


Magnesium in serum or plasma can be found in three fractions: an ultrafilterable fraction consisting of ionized magnesium (70%–80%), complex-bound magnesium (1%–2%), and a protein-bound non-ultrafilterable fraction (20%–30%). In current clinical laboratories, magnesium is measured predominantly as plasma or serum concentration by autoanalyzer photometry using a chromatogenic reagent such as xylidyl blue. The color produced, measured bichromatically at 520/800 nm, is proportional to the magnesium concentration (2).

Serum magnesium concentrations can be reported as mEq/L, mmol/L, or mg/dL. One mEq/L = 0.5 mmol/L and is approximately 1.2 mg/dL. Serum magnesium in healthy persons is closely maintained within a normal range that varies between laboratories but is roughly 1.50 to 2.2 mEq/L (0.75–1.10 mmol/L). Since the molecular weight of magnesium is 24.3 and the valence of +2, a normal range of plasma magnesium concentration of 1.4 to 1.7 mEq/L is equivalent to 0.70 to 0.85 mmol/L or 1.7 to 2.1 mg/dL. Serum levels <1.5 mEq/L usually indicate magnesium deficiency. When serum magnesium is between 1.5 and 1.7 mEq/L, a magnesium loading test can identify magnesium deficiency (1). A serum magnesium >2.2 mEq/L is diagnostic of hypermagnesemia.

Magnesium deficiency is commonly determined by measuring serum magnesium concentrations. However, serum magnesium values reflect only 1% of the body magnesium content, since most of the body’s magnesium is stored in bone, muscle, and soft tissues. Therefore, the serum magnesium may grossly underestimate total magnesium deficits. Although serum values are within the normal range, the body can be in a severely magnesium-depleted state. Consequently, the clinical impact of magnesium deficiency may be largely underestimated. Only 20% of the serum magnesium is protein bound, in contrast to calcium, which is 40% bound to serum proteins. The variations in plasma protein concentration have less effect on serum magnesium than on calcium concentration.

Free magnesium in blood can be measured with an ion-sensitive electrode. The fraction of total magnesium bound to protein and other substances depends upon the pH. pH-dependency of ionized free magnesium (iMg2+) in serum is expressed by the Siggaard-Andersen equation: iMg2+ (pH) = iMg2+ (7.4) × 10 × (7.4 − pH). During preparation of serum or plasma, considerable pH changes occur which have to be corrected on the basis of the above mentioned equation (2).

The total intracellular magnesium content approximates 8 to 10 mmol/L (10–20 mEq/L). However, most of the cell magnesium is bound to adenosine triphosphate (ATP) and other intracellular nucleotides, and in many enzyme complexes in which the Km is close to the free intracellular magnesium concentration. A number of techniques are available for the assay of cytosolic free magnesium. These include magnesium-selective electrodes, metallochromic indicators, P-31 nuclear magnetic resonance (NMR) spectroscopy, and fluorescent probes similar to those in the determination of cytosolic free calcium. Using magnesium-sensitive dyes based upon the FURA compound, the free cytosolic concentration is determined to be in the range of 0.6 to 0.8 mmol/L (1.2–1.6 mEq/L). However, there is some variation with cell type, and also some variation between regions of the cell. Intracellular magnesium concentrations can be determined non-invasively in vivo or in vitro by using NMR (3). The determination is based on the shift in the phosphorus (P-31) NMR spectrum of ATP, depending on the extent to which it is bound to magnesium. This technique is applicable to clinical studies in humans (4,5).


The average daily diet in North America contains approximately 20 to 30 mEq (240–360 mg) of elemental magnesium. The requirement for magnesium is considered to be about 18 to 33 mEq/day for young men and 15 to 28 mEq/day for women. This suggests that the average western diet is only marginally adequate for maintenance of magnesium levels in healthy adults. Moreover, the requirements are higher during the rapid growth of infancy and adolescence as well as pregnancy and lactation. Magnesium is ubiquitous in our diet and is especially abundant in green vegetables rich in chlorophyll (a chelator of magnesium), as well as in seafood, grains, nuts, and meats (2). The United States NHANES 2005-2006 survey reported that more than half of all adults have an inadequate intake of magnesium (6). It has been suggested that a chronic magnesium deficiency (serum magnesium <0.75 mmol/L) is associated with an increased risk of many clinical conditions, including atherosclerosis, hypertension, cardiac arrhythmia, metabolic syndrome, type 2 diabetes mellitus, and insulin resistance.


Under normal circumstances, the GI tract and kidney closely maintain magnesium balance (Fig. 7-1). It has been suggested that the minimum intake of magnesium required to maintain a positive balance in the body is approximately 0.3 mEq/kg/d.

Figure 7–1 Schematic display of normal overall body homeostasis of magnesium, including an approximate distribution in different tissues. GI, gastrointestinal; RBC, red blood cells.

Only about 1% to 2% of the 21 to 28 g (1,750–2,400 mEq) of magnesium present in the adult human body is in the ECF compartment. The principal cellular stores of magnesium in the body are bone (67%) and muscle (20%) (Fig. 7-1).

Normal muscle has 76 mEq of magnesium/kg of fat-free solids, and much of this is complexed to intracellular organic phosphate and proteins (6). The normal magnesium level in red blood cells is about 4.6 mEq/L, of which 84% is thought to be complexed to ATP. The magnesium content of erythrocytes appears to be inversely related to the age of the cell, with the reticulocytes containing about two times more magnesium than older red blood cells. As noted, bone is the principal body store of magnesium. The normal calcium to magnesium ratio in bone is 50:1, with the ratio in trabecular bone being consistently higher than that in cortical bone. The major portion of magnesium is complexed with apatite crystal rather than bone matrix. Approximately 30% of bone magnesium is present as a surface-limited ion on the bone crystal and is freely exchangeable (7,8). However, considerable uncertainty exists with regard to the ease of exchangeability of magnesium with its cellular source (7). Intracellular to extracellular distribution of magnesium is dissimilar to that of potassium. Minute changes in extracellular potassium rapidly result in changes in intracellular potassium concentration in muscle. Such shifts do not occur with magnesium because magnesium is bound to intracellular ligands and is not readily available for exchange in muscle. Less than 15% of muscle and erythrocyte magnesium is thought to be exchangeable (9).

In summary, bone and muscle cells are the major intracellular magnesium pools in humans, of which only a small fraction is exchangeable with the ECF. Magnesium balance is a function of intake and excretion. The average daily magnesium intake is 360 mg (15 mmol). Approximately one-third of this magnesium is absorbed, principally in the small bowel through both a saturable transport system mediated by a channel encoded by the TRPM6 gene and passive diffusion. In the healthy adult, there is no net gain or loss of magnesium from bone so that balance is achieved by the urinary excretion of the approximately 100 mg (4.1 mmol) that is absorbed. Changes in intake are balanced by changes in urinary magnesium reabsorption, principally in the loop of Henle and the distal tubule

Gastrointestinal Absorption of Magnesium

About 30% to 40% of the normal dietary intake of magnesium is absorbed by the GI tract. The fraction of magnesium absorbed may increase to as high as 80% when the dietary magnesium intake is restricted to as low as 2 mEq/day and may decrease to 25% at high magnesium intakes of ≥45 mEq/day. Thus, magnesium absorption by the gut is nonlinear and varies inversely with intake. Magnesium absorption in humans and animals occurs primarily in the more distal portion of the small intestine, namely the jejunum and ileum (10). The small intestinal magnesium absorption appears to occur down an electrochemical gradient through a paracellular pathway.

In the colon transcellular absorption occurs. Magnesium crosses the brush border of the intestinal cell down an electrochemical gradient via the transient receptor potential melastatin channels TRPM6 and TRPM7 (1,11). The small intestinal paracellular pathway movement of magnesium occurs because of the positive magnesium chemical gradient across the paracellular channels. Magnesium absorption is also affected by paracellular water reabsorption. Bowel water absorption affects magnesium concentration and absorption, and severe prolonged diarrhea results in intestinal secretion of magnesium.

The control of intestinal magnesium absorption is not well understood. Most studies have suggested that vitamin D has little effect on magnesium absorption (12). A study carried out in vitamin D-deficient patients showed that magnesium absorption was only minimally reduced before vitamin D repletion, and even following repletion it increased only slightly in contrast to the large change in calcium absorption (13). Similarly, Schmulen et al. (14) found that physiologic doses of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) normalized the modest defect in jejunal magnesium absorption in uremic patients. This might imply that although vitamin D may have a small effect on proximal absorption of magnesium, it has little effect on the more distal sites for magnesium absorption in the small bowel. Unlike in the kidney, the basic absorptive systems of calcium and magnesium are independent of each other in the intestinal tract; calcium flux is normally twice that of the magnesium flux at similar luminal concentrations.

It is probable that only ionized magnesium is available for absorption, and the amount available is affected by progressive precipitation of magnesium as insoluble phosphates, carbonates, and soaps beginning in the ileum, colon, and (ultimately) stool. Alterations of luminal concentrations of calcium and phosphate also indirectly affect magnesium absorption. Conversely, the elevation of intraluminal magnesium concentration may precipitate phosphate and thereby allow for greater calcium absorption. Steatorrhea may potentiate magnesium malabsorption through the formation of nonabsorbable magnesium lipid salts (15).

The major portion of magnesium found in the stool is derived from the diet. The magnesium concentration in saliva, gastric secretions, bile, and pancreatic and intestinal secretions ranges from 0.3 to 0.7 mmol and amounts to only about 1% of the daily fecal output. Taken together, overall knowledge of the precise control and regulation of magnesium absorption in the intestinal tract is still lacking.

Genetic screenings and microarray-based expression studies have resulted in the identification of numerous magnesium-transporting proteins (Table 7-1). Our knowledge of renal magnesium transport has increased dramatically due to the discovery of the molecules involved in renal magnesium handling from the study of rare human genetic conditions (Table 7-2).

The understanding of these genetic conditions coupled with drug-induced disorder of magnesium homeostasis has enhanced our knowledge of normal and abnormal magnesium metabolism.

Renal Excretion of Magnesium

The status of body magnesium balance and particularly ECF magnesium concentration is largely determined by the renal excretion of magnesium. The main determinant of magnesium balance is the serum magnesium concentration itself, which directly influences renal excretion. Hypomagnesemia stimulates tubular reabsorption of magnesium, whereas hypermagnesemia inhibits it.

On a normal dietary intake of magnesium, urinary magnesium excretion averages 100 to 150 mg/day or 8 to 12 mEq/day. In patients receiving supplementary oral magnesium-containing antacids, urinary magnesium excretion can increase to 500 to 600 mg/day or more with little change in serum magnesium levels. Similarly, when dietary magnesium restrictions are imposed, 24-hour urinary magnesium excretion decreases in 4 to 6 days to as low as 10 to 12 mg (1 mEq) (16). Thus, the ability of the kidney to conserve magnesium is excellent when it is needed.

In chronic kidney disease (CKD) the fractional excretion of magnesium rises sharply as glomerular filtration rate progressively falls, thus protecting against the development of significant hypermagnesemia. Urinary magnesium excretion can approximate the filtered load of magnesium with marked hypermagnesemia secondary to high dietary intake or intravenous magnesium infusion. Studies in several species have shown that there is a threshold value for magnesium excretion, close to the normal magnesium concentration (17). Thus, when serum magnesium concentration falls slightly, urinary magnesium excretion rapidly decreases to very low values. Conversely, when serum magnesium rises slightly above normal, magnesium excretion rapidly increases.


Approximately 70% of plasma magnesium is in the ionic form with the remaining 30% bound to plasma protein. As a result, about 70% to 80% of plasma magnesium is freely filtered at the glomerulus.


Magnesium transport differs from that of most other ions in that the proximal tubule is not the major site of reabsorption. Fractional magnesium absorption is substantially less than that of sodium or calcium. Only 15% to 25% of the ultrafilterable magnesium is reabsorbed passively in the proximal tubule. Luminal magnesium concentrations rise along the length of the proximal convoluted tubule to a value as high as 1.5 times greater than that of the ultrafilterable magnesium in glomerular filtrate (Fig. 7-2) (18). The major influence on proximal magnesium reabsorption is the status of the ECF volume. Absorption is enhanced in states of volume depletion, whereas absorption is decreased in volume-expanded states.


The early micropuncture studies of Morel et al. (18) indicated that, unlike most cations, the loop of Henle is the major site of magnesium reabsorption. Magnesium concentration in the early distal tubule fluid is only 60% to 70% of the ultrafilterable magnesium concentration, suggesting that some 50% to 60% of the filtered magnesium is reabsorbed in the loop of Henle, primarily in the thick ascending limb (Fig. 7-2).

Magnesium absorption in the loop of Henle is passive via a paracellular pathway and dependent on the transepithelial voltage gradient partly generated by a sodium back-leak into the lumen via the paracellular protein Claudin 16 (19) (Fig. 7-3).

In hypermagnesemic states, magnesium reabsorption in the loop of Henle approaches zero (20). Conversely, in hypomagnesemic states, the loop of Henle more avidly reabsorbs magnesium, allowing only minimal amounts, <3%, of the filtered load to reach the distal tubules and be excreted in the urine (21).

An important interaction between calcium and magnesium has been observed in the thick ascending limb. It is well known that hypercalcemia (20) or hypermagnesemia inhibits both magnesium and calcium reabsorption (21,22). Studies show that this effect is mediated by the calcium-sensing receptor present on the basolateral membrane of the thick ascending limb and distal collecting tubule, which modulates absorption by changes in plasma divalent cation concentrations (23,24).

Figure 7–2 Normal distribution of magnesium reabsorption as a percentage of the ultrafilterable magnesium at the glomerulus.

Figure 7–3 A model of magnesium transport mechanisms in the hick ascending limb of Henle’s loop (TAL). Magnesium absorption is paracellular, driven by the electrochemical gradient partly generated by a complex of Claudin-16 and Claudin-19. Sodium is reabsorbed via the apical Na/K/2Cl cotransporter (NKCC2), and pumped out basolaterally by the Na/K ATPase. Chloride exits via the chloride channel composed of chloride channel Kb (ClC-Kb) and Barttin. Potassium is recycled apically via the inwardly rectifying K channel (ROMK), thereby generating a lumen-positive transtubular voltage. The Ca/Mg sensing receptor also plays a role in magnesium absorption.


In the distal convoluted tubule, fine-tuning of magnesium reabsorption occurs. Genetic diseases that produce hypomagnesemia have helped elucidate important components of distal magnesium transport. Magnesium transport in the distal tubule is active and transcellular, with reabsorption occurring via an apical transient receptor potential channel, melastatin subtype 6 (TRPM6) (19,25) (Fig. 7-4).

The mechanisms for cytoplasmic diffusion and basolateral transport are not yet known (26). Sex hormones, acid–base status, and peptide hormones such as calcitonin, glucagon, arginine, vasopressin, and parathyroid hormone (PTH) enhance magnesium uptake in distal convoluted tubule cells (23,26,27) possibly via modulation of TRPM6. Mutations in TRPM6 cause autosomal recessive hypomagnesemia with secondary hypocalcemia (HSH), which is due both to impaired intestinal absorption of magnesium and a renal magnesium leak.

Recently, EGF has been demonstrated to be a magnesiotropic hormone directly stimulating TRPM6 activity (28). This explains the finding that magnesium wasting occurs in patients with colorectal cancer who are treated with cetuximab, an EGF receptor (EGFR)-targeted monoclonal antibody that prevents receptor stimulation (29).

Furthermore, both tacrolimus and cyclosporine A decrease TRPM6 expression, possibly explaining the hypomagnesemia seen in patients treated with these medications (25).

Physiologic and Pharmacologic Effects

The importance of magnesium in the body can be traced back in history. The first documented use of magnesium in medicine was in 1697 when Dr. Grew identified magnesium sulfate as the major ingredient of Epsom salt which was extracted from a well in Epsom, England, and was used over the years to treat abdominal pain, constipation, muscle strains, and cerebral edema (30). The chemistry of magnesium and other alkali metals was characterized by Humphrey Davy in 1808 (31) and the first determination of the element was in plasma in 1920 (32). Magnesium plays a critical and necessary role in intracellular metabolism. Magnesium is necessary for a wide spectrum of enzymatic reactions, including various phosphokinases and phosphatases (33), which are involved in energy storage and use. Phosphatases are particularly important because magnesium functions primarily to form magnesium ATP, which is a substrate for these enzymes. These ion-sensitive ATPases are situated in the intracellular compartments and membranes to regulate the flow of potential energy from the mitochondria and cytoplasm. Recognized magnesium ATPases include ouabain-sensitive Mg2+/Na+/K+ATPase, ouabain-insensitive Mg2+, HHCO3ATPase, and Mg2+/Ca2+ATPase, which are associated with the sodium, proton, and calcium pumps, respectively. They are all essential for ionic control of the cell composition (34). Magnesium also is involved in protein synthesis through its action on nucleic acid polymerization, its role in ribosomal binding to ribonucleic acid (RNA), and in the synthesis and degradation of deoxyribonucleic acid (DNA). In addition to its role in phosphorylation of glucose, magnesium may also control mitochondrial oxidative metabolism (35). Adenylate cyclase, critical in the generation of the intracellular secondary messenger 3′,5′-cyclic adenosine monophosphate (cAMP), also has been shown to be dependent on magnesium (36). Intracellular magnesium has also been shown to have an important regulatory function on both K+ and Ca2+ channels (37).

Figure 7–4 A model of magnesium transport mechanisms in the DCT. Magnesium is transcellular via the recently identified magnesium channel TRPM6 in the apical membrane. It is driven by the hyperpolarized membrane potential generated by the apical potassium channel, Kv1.1. Basolateral magnesium exit may occur through Cyclin M2 (CNNM2), which acts as a magnesium channel or transporter. The link between the defect in the apical thiazide-sensitive NCC seen in Gitelman syndrome or the basolateral chloride channel (ClC-Kb) defect seen in Bartter syndrome with sensorineural deafness has not been clearly identified. The basolateral EGF receptor that modulates the apical TRPM6 magnesium channel is also depicted. NCC, NaCl cotransporter; DCT, distal convoluted tubule; Kv1.1, voltage-gated potassium channel 1.1; NCC, sodium chloride cotransporter; TRPM6, transient receptor potential melastatin type 6.

Intracellular magnesium is found in the free-ion form or complexed to proteins or organophosphates. The free magnesium concentration determines the effect of concentrations of the high-energy nucleotide complex magnesium ATP. Knowledge of the true ionic concentration of magnesium in the cell is important but difficult to measure. It is thought that only about 5% to 15% of cellular magnesium is truly ionized (38).

Magnesium Deficiency

Because magnesium is an essential element for both plants and animals, it exists almost everywhere in our environment. Thus, it is rare to see spontaneous magnesium depletion from dietary indiscretion unless it is severe. Still, it has been suggested that the normal dietary intake of magnesium is marginal. The first description of symptoms related to hypomagnesemia was in 1960 when Vallee et al. (39) described five patients with hypomagnesemia and symptoms and signs that are now felt to be classic for magnesium depletion. These patients had carpopedal spasms with positive Chvostek and Trousseau signs, and three of the five subjects also had convulsions. All patients’ symptoms and signs abated following magnesium administration. Several investigators have attempted to produce magnesium depletion in humans by placing subjects on a low magnesium intake. In most studies, only minimal magnesium depletion has been induced. Shils (40), however, was able to cause severe magnesium depletion in seven patients who were placed on diets extremely low in magnesium for an extended period of time. Symptoms that appeared to be related to magnesium depletion developed in six of the seven patients; five had a positive Trousseau sign, and two of these patients also had a positive Chvostek sign. All patients became lethargic and showed generalized weakness, anorexia, nausea, and apathy. Biochemical abnormalities included hypomagnesemia, hypocalcemia, hypokalemia, and decreased total body exchangeable potassium. All abnormalities reverted to normal with replacement of magnesium alone.

Clinical Conditions Associated with Magnesium Depletion


Gastrointestinal causes of magnesium depletion can be divided into four categories: decreased intake, steatorrheic states, severe diarrheal states, and selective magnesium malabsorption (Table 7-3). Caddell and Goddard (41) found serum magnesium to be subnormal in 19 of 28 children with protein calorie malnutrition (kwashiorkor). This was felt to have resulted from the combination of poor intake of magnesium, vomiting, and diarrhea. Similarly, magnesium depletion has been described in hospitalized patients who have been maintained on parenteral nutrition for prolonged periods of time (42,43).

Steatorrheic State

Hypomagnesemia has been described in a number of patients with small bowel disease. Booth et al. (15) found that 15 of 42 patients with malabsorption syndromes had subnormal serum magnesium levels. They were able to show a rough correlation between serum magnesium levels and the degree of steatorrhea, suggesting that the magnesium malabsorption might be a consequence of the formation of insoluble magnesium soaps. Supporting this possibility is the finding that magnesium absorption was improved when the patients were placed on a low-fat diet. The small bowel diseases with the highest incidence of hypomagnesemia are idiopathic steatorrhea and disease of the distal ileum.

Diarrheal States

Besides the steatorrheic states, magnesium depletion can occur in any severe diarrheal state (44,45). As with potassium, fecal magnesium excretion is related to the total water content where the stool magnesium concentration is approximately 6 mEq/L (45). Magnesium depletion also has been described in patients following jejunoileal bypass surgery for the treatment of morbid obesity, probably from a combination of factors, including malabsorption, shortened transit time, and diarrhea (46).

Hereditary Magnesium Absorptive Defect

Several patients have been described who have a defect in the GI absorption of magnesium (4749). In this disorder of HSH, profound hypomagnesemia develops in the first few months of life. The absorptive defect can be overcome, however, by an oral intake of high-dose magnesium. Most of these patients have severe hypomagnesemia, hypocalcemia, tetany, and seizures. The defect is an autosomal recessive disorder and results in the failure of active transcellular magnesium absorption. It is due to a mutation in the TRPM6 gene, which encodes for the apical membrane TRPM6 channel in the intestine and the distal convoluted tubule (50,51) (Table 7-1).


Renal magnesium wasting can be of two distinct types. One represents a primary kidney defect, whereas the second represents the kidney’s normal response to a variety of systemic and local factors that increase magnesium losses (Table 7-3). Symptomatic hypomagnesemia is much more likely to be seen in the state of primary renal magnesium wasting. The hallmark of both of these states is a disproportionately elevated urinary magnesium excretion in association with hypomagnesemia. Normally, when serum magnesium falls only slightly owing to extrarenal causes, urinary magnesium falls to <1 mEq/day (12 mg/day), whereas if the kidney is responsible for the magnesium losses, urinary magnesium is increased relative to the hypomagnesemic state (>4 mEq/day). Thus, urinary magnesium should be measured before magnesium replacement to determine whether the hypomagnesemic state resulted from renal or extrarenal causes.

Primary Renal Magnesium Wasting

Primary renal magnesium wasting can occur from either inherited or acquired causes. A number of inherited forms of renal magnesium wasting have been described recently (Table 7-2).

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

The most severe form of renal magnesium wasting results from an impairment of tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle’s loop (52,53). This autosomal recessive disorder known as familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) (1,11) results from mutations in the CLDN16 gene, which encodes the renal tight junction protein Claudin-16 (formally paracellin-1) (Fig. 7-3). This protein is thought to allow selective back-leak of sodium over chloride into the tubule lumen, enhancing the driving force for paracellular magnesium reabsorption (11). Clinical and laboratory features of FHHNC include presentation at a young age with nephrocalcinosis, polyuria, CKD, hypomagnesemia, and increased urinary magnesium and calcium excretion. Hypomagnesemia is unresponsive to magnesium replacement, and progression to end-stage renal disease is common. FHHNC may occasionally be due to mutation in Claudin-19. In addition to hypomagnesemia, and nephrolithiasis, such patients have ocular involvement with macular colobomata, nystagmus, and myopia.

Na/K ATPase Mutation

An autosomal dominate disorder of hypomagnesemia with hypocalcemia has been linked to a heterozygous mutation of FXYD2 on chromosome 11q23 (54). This encodes for a γ subunit of the basolateral Na+/K+ ATPase. The mutation results in misrouting of this subunit and defective magnesium reabsorption in the distal convoluted tubule where this subunit is normally expressed in the basolateral membrane (55) (Fig. 7-4).

Epidermal Growth Factor Gene Mutation

Isolated recessive hypomagnesemia (IRH) is a rare disorder due to a mutation of the EGF precursor protein. EGF is a magnesiotropic hormone that stimulates TRPM6, an apical magnesium channel in the distal convoluted tubule. The defect in this gene results in decreased TRPM6-mediated apical magnesium uptake in the distal convoluted tubule and magnesium wasting (19,28) (Fig. 7-4).

Voltage-Gated Potassium Channel

A mutation in the gene KCNA1 that encodes the voltage-gated potassium channel Kv1.1 is the cause of isolated autosomal dominant hypomagnesemia discovered in a large Brazilian family. This channel colocalizes with the magnesium channel TRPM6 in the distal collecting tubules. Wild-type Kv1.1 appears to control TRPM6 magnesium reabsorption via the creation of an appropriate potential across the luminal membrane (1).

Hepatocyte Nuclear Factor-1-β Gene Mutations

Hypomagnesemia and renal magnesium wasting have been reported in 8 of 18 patients (44%) with known mutations in the hepatocyte nuclear factor-1-β (HNF-1-β) gene. HNF-1-β is a transcription factor that regulates the expression of the gamma subunit of Na/K ATPase. These findings suggest that some mutations of HNF-1-β can activate this subunit, thereby causing hypomagnesemia, in association with early-onset diabetes and renal malformations (1,56).

Cyclin M2 Mutations

Mutations in the Cyclin M2 (CNNM2) gene have been implicated in families with dominant isolated renal magnesium wasting. CNNM2 encodes a transmembrane protein that is localized to the basolateral membrane of the thick ascending limb and distal convoluted tubule (1).

Autosomal Dominant Hypocalcemia

Activating mutations in the calcium-sensing receptor located in the parathyroid chief cell and basolateral membrane of the thick ascending limb of the loop of Henle and distal convoluted tubule results in autosomal dominant hypocalcemia (ADH). The defect results in decreased kidney calcium and magnesium reabsorption and often hypomagnesemia (57).

Gitelman Syndrome

Gitelman syndrome is caused by a heterogeneous group of loss-of-function mutations usually in the solute carrier family 12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC) (52) (Fig. 7-3). In a minority of patients the mutation is in the CLCNKB gene encoding the chloride channel CID-Kb, the same gene mutation defect found in Bartter syndrome with sensorineural deafness suggesting a highly variable phenotype in patients with CLCNKB mutations (58). Gitelman syndrome is an autosomal recessive heritable kidney disease characterized by hypomagnesemia, hypocalciuria, and hypokalemia metabolic alkalosis. This syndrome occurs in an older age group and usually has mild clinical symptoms, although patients may complain of musculoskeletal cramps, muscle weakness, muscle stiffness, arthralgias, nocturia, polydipsia, and thirst (57,58). The mechanism for the moderate renal magnesium wasting in Gitelman syndrome has not been definitively characterized (58) but may relate to reduced abundance of the TRPM6 epithelial magnesium channels in the distal convoluted tubule (59).

Bartter Syndrome

Bartter syndrome, a defect in the chloride channel of the thick ascending limb cells, also may be associated with mild hypomagnesemia. Several different basolateral chloride channels play a role in chloride reabsorption; hence different clinical subtypes of Bartter syndrome were described (Table 7-4). In contrast to Gitelman syndrome, Bartter syndrome occurs at a younger age. It often presents in childhood and may be associated with growth and mental retardation, hypokalemia, and metabolic alkalosis. Polyuria and polydipsia are present due to decreased urinary concentrating ability (59) (Table 7-4).

Drug-Induced Renal Magnesium Wasting

The acquired forms of renal magnesium wasting are largely drug induced. Osmotic diuretics such as mannitol increase urinary magnesium excretion. Both loop diuretics and thiazide can inhibit net magnesium reabsorption, while potassium-sparing diuretics may enhance magnesium transport and lower magnesium excretion. Renal magnesium wasting has been well documented in a number of patients receiving aminoglycosides (60,61). Renal magnesium wasting also has been described in patients receiving cis-diaminedichloro platinum (cis-DDP) (62). In one series, 23 of 44 patients treated with cis-DDP developed hypomagnesemia. Two of these patients required hospitalization because of severe symptomatic magnesium depletion. In an additional report of 50 patients treated with multiple courses of combined chemotherapy with cis-DDP, 76% developed hypomagnesemia (63). This defect in renal magnesium handling can persist for months after the cis-DDP has been discontinued (63,64).

Table 7–4 Gitelman and Bartter Syndrome


Gene Affected

Gene Product

Clinical Presentation

Functional Studies

Gitelman syndrome



Gitelman syndrome

Concentrating capacity normal/near normal and diluting capacity reduced

Bartter syndrome type I



Antenatal Bartter syndrome (hyperprostaglandin E syndrome)

Concentrating capacity reduced and diluting capacity reduced

Bartter syndrome type II



Antenatal Bartter syndrome

Concentrating capacity reduced and diluting capacity reduced

Bartter syndrome type III



Classical Bartter syndrome

Concentrating capacity reduced and diluting capacity reduced

Bartter syndrome type IV


Barttin (B-subunit of CLC-Ka and CLC-Kb)

Antenatal Bartter syndrome (hyperprostaglandin E syndrome) and sensorineural deafnessa

Concentrating capacity reduced and diluting capacity reduced

Bartter syndrome type IVB


CLC-Ka and CLC-Kb

Antenatal Bartter syndrome (hyperprostaglandin E syndrome) and sensorineural deafnessa

Concentrating capacity reduced and diluting capacity reduced

Bartter syndrome type V



Bartter syndrome with hypocalcemia

Concentrating capacity reduced and diluting capacity reduced

Genetics and presentation of Bartter and Gitelman syndromes. There are six Bartter syndrome subtypes (I, II, III, IV, IVB, and V) corresponding to six genetic defects.
NKCC2, furosemide-sensitive sodium-potassium-2 chloride cotransporter; ROMK, renal outer medullary potassium channel; CLC-Kb, chloride channel Kb; CLC-Ka, chloride channel Ka; CaSR, calcium-sensing receptor; NCCT, thiazide-sensitive sodium chloride cotransporter.
aSensorineural deafness occurs because ClC-Ka and CLC-Kb are highly expressed in the inner ear and interact with other transport proteins (e.g., NKCC1) to maintain the high potassium concentration in the endolymph that is required for normal hearing. Some experts classify the mild salt-losing effect of gain-of-function mutations in the calcium-sensing receptor as Bartter syndrome type V.

Dec 22, 2019 | Posted by in NEPHROLOGY | Comments Off on Normal and Abnormal Magnesium Metabolism
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