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Hypomagnesemia and Deficiency

Brenner & Rector's The Kidney, 6th ed., Copyright � 2000 W. B. Saunders Company


The terms "hypomagnesemia" and "Mg2+ deficiency" tend to be used interchangeably. However, a complex relationship exists between total body Mg2+ stores, serum Mg2+ concentration, and the Mg2+ level in different intracellular compartments. Since ECF Mg2+ accounts for only 1% of total body Mg2+ , it is hardly surprising that serum Mg2+ concentrations have been found to correlate poorly with overall Mg2+ status. Indeed, in patients with Mg2+ deficiency, serum Mg2+ concentrations may be normal or may be only slightly decreased and thus constitute a serious underestimation of the severity of the Mg2+ deficit. [33] However, no satisfactory clinical test for assaying body Mg2+ stores is available. Measurements of the Mg2+ content of erythrocytes, lymphocytes, skeletal muscle, and bone all have been used, but exhibit a poor correlation with each other and with clinical indicators of Mg2+ status. [34] [35]

The Mg2+ tolerance test is generally thought to be the best test of overall Mg2+ status (Table 24-1) (Table Not Available) . It is based on the observation that Mg2+ -deficient patients tend to retain a greater proportion of a parenterally administered Mg2+ load and excrete less in the urine than do normal individuals. [36] [37] Studies in Mg2+ -deficient rats indicate that the administered Mg2+ is rapidly diverted to non-ECF stores, so that the low urinary excretion is due to a small filtered load of Mg2+ delivered to the nephron. [38] By contrast, in normal rats given intravenous Mg2+ , the serum concentration and therefore filtered load rise dramatically, and Mg2+ spills into the urine because of the"threshold" effect (see Fig. 24-2) . Clinical studies indicate that the results of a Mg2+ tolerance test correlate well with Mg2+ status assessed from skeletal muscle Mg2+ content, and exchangeable [28] Mg pools. [36] Furthermore, studies in normomagnesemic alcoholic patients clinically suspected to be Mg2+ -deficient suggest that the test is more sensitive than the determination of serum Mg2+ alone. [37] However, the test is invalid in patients who have impaired renal function or a renal Mg2+ wasting syndrome, or in patients who are taking diuretics or other medications that induce renal Mg2+ wasting. For this reason, and also because of the time and effort required for performing the Mg2+ tolerance test, it is used infrequently in clinical practice.

The serum Mg2+ concentration, though an insensitive measure of Mg2+ deficit, remains the only practical test of Mg2+ status in widespread use. Surveys of serum Mg2+ levels in hospitalized patients indicate a high incidence of hypomagnesemia (presumably an underestimate of the true incidence of Mg2+ deficiency), ranging from 11% to 47% in general inpatients, [39] [40] [41] and 20% to 44% in patients admitted to intensive care units. [41] [42] [43] Furthermore, among intensive care unit patients, hypomagnesemia was associated with a twofold increased mortality compared to normomagnesemic patients. [41]
Etiology and Diagnosis

Mg2+ deficiency may be caused by decreased intake or intestinal absorption or by increased losses via the gastrointestinal tract, kidneys, or skin, or rarely may be due to sequestration in the bone compartment (Fig. 24-4) . The most common specific causes encountered in clinical practice are encapsulated in the"six Ds" mnemonic (cited with permission from Marshall A. Wolf, MD): diet, alcoholism ( drinking), diarrhea and malabsorption, diabetes mellitus, diuretics, and drugs such as aminoglycosides and amphotericin. The first step in determining the etiology is to distinguish between renal Mg2+ wasting and extrarenal causes of Mg2+ losses by performing a quantitative assessment of urinary Mg2+ excretion (Table 24-2) . If renal Mg2+ wasting has been excluded, the losses must be extrarenal in origin, and the underlying cause can usually be identified from the case history.

Figure 24-3 Model for TAL peritubular Mg2+ reabsorption. At the top are shown typical values for the Mg2+ concentration and electrical potential (psi). See text for explanation of the putative transport mechanisms. BSC bumetanide-sensitive Na-K-2Cl cotransporter; ROMK, inwardly rectifying apical K+ channel; NKA = Na+ ,K+ -ATPase; CaSR = Ca2+ -sensing receptor; CLC = basolateral Cl- channel.

Nutritional Deficiency

Human Mg2+ deprivation studies have demonstrated that induction of Mg2+ deficiency by dietary means in normal individuals is surprisingly difficult, [44] because nearly all foods contain significant amounts of Mg2+ , and renal adaptation to conserve Mg2+ is very efficient. After 3 weeks on a diet containing 13 mg of Mg2+ per day together with an orally administered ion exchange resin to deplete Mg2+ , study subjects sustained a cumulative deficit that was only 2% to 3% of total body Mg2+ stores. [44] Nevertheless, Mg2+ deficiency of nutritional origin is observed in three clinical settings: alcoholism, protein-calorie malnutrition, and parenteral feeding.

In chronic alcoholics, the intake of ethanol substitutes for the intake of important nutrients. Thus, approximately 20% to 25% of alcoholics are frankly hypomagnesemic, while most can be shown to be Mg2+ deficient using the

TABLE 24-2 -- Relative Merits of Different Indices of Urinary Mg2+ Excretion

Criteria for Renal Mg2 + Wasting Advantages Disadvantages
Mg2+ concentration (UMg ) >1.6 mg/dL Can be measured in a spot urine Varies with urine concentration
Fractional excretion of Mg2+ (Fe Mg) * >1% Can be measured in a spot urine
Adjusted for filtered load
Not well validated in literature
Mg2+ -to-creatinine ratio (UMg:Cr ) >0.02 (mg/mg) Can be measured in a spot urine
Expected to correlate with UMg V
Varies with gender and muscle mass
24-h Mg2+ excretion (UMg V) >24 mg Normal and abnormal values widely available in published studies of hypomagnesemia Requires 24-h urine collection

Figure 24-4 Major causes of hypomagnesemia and Mg2+ deficiency (see text for details).

where plasma ultrafilterable Mg2+ concentration, Pf Mg , can be estimated from 0.8 � total plasma Mg2+ concentration.



Mg2+ tolerance test. [37] [45] Ethanol can also acutely induce a brisk Mg2+ diuresis, but this is sustained only for several hours, and chronic renal Mg2+ wasting has not been convincingly shown to play a role in alcoholic Mg2+ deficiency. [46]


In one study of Nigerian children, protein-calorie malnutrition was found to be associated with universal, severe Mg2+ deficiency, as assessed by serum Mg2+ level, muscle Mg2+ content, and response to Mg2+ therapy. [47] However, the staple diet was cassava, which is particularly low in Mg2+ content, and most of the children studied also had prolonged diarrhea. Subsequent studies suggest that Mg2+ deficiency due to malnutrition alone is fairly uncommon. [48]

Patients receiving parenteral nutrition have a particularly high incidence of hypomagnesemia. [49] In general, these patients are sicker than the average inpatient and are more likely to have other conditions associated with a Mg2+ deficit, and ongoing Mg2+ losses. However, even in nutritionally replete subjects, the daily Mg2+ requirement for maintaining Mg2+ balance is increased during parenteral feeding, for unclear reasons. [50] Furthermore, hypomagnesemia may also be a consequence of refeeding syndrome. [51] In this condition, overzealous parenteral feeding of severely malnourished patients causes hyperinsulinemia, and rapid cellular uptake of glucose and water, together with phosphorus, potassium, and Mg2+ .
Intestinal Malabsorption

Generalized malabsorption syndrome due to conditions such as celiac disease, Whipple disease, and inflammatory bowel disease is frequently associated with intestinal Mg2+ wasting and Mg2+ deficiency. [15] [16] [52] Although the Mg2+ wasting has been attributed directly to intestinal mucosal damage, patients with mild-to-moderate malabsorption due to uncomplicated Crohn ileitis do not develop Mg2+ deficiency, [53] suggesting that other factors, such as luminal saponification, intestinal resection, and chronic diarrhea, may be responsible. In fat malabsorption with concomitant steatorrhea, free fatty acids in the intestinal lumen may combine with Mg2+ to form nonabsorbable soaps, a process known as saponification, thus contributing to impaired Mg2+ absorption. Indeed, the severity of hypomagnesemia in patients with malabsorption syndrome correlates with the fecal fat excretion rate, and in some patients reduction of dietary fat intake alone, which reduces steatorrhea, can correct hypomagnesemia. [52] Prior intestinal resection, particularly of the distal small intestine, is also an important cause of Mg2+ malabsorption, [15] and a confounding factor in many studies of patients with Crohn ileitis. Similarly, Mg2+ deficiency can be a late complication of jejunoileal bypass surgery performed for the treatment of obesity. [54]

In addition to Mg2+ deficiency as part of generalized malabsorption, there are approximately 40 cases reported in the literature of patients with primary hypomagnesemia due to an isolated, inherited defect in intestinal Mg2+ absorption. [55] [56] [57] [58] Most patients present in infancy, usually between 1 and 16 weeks of age, with tetany or seizures associated with severe hypomagnesemia and hypocalcemia. All the clinical and electrolyte abnormalities correct with high-dosage Mg2+ -supplementation alone, indicating that the hypocalcemia is a secondary consequence of the Mg2+ deficient state. Careful studies of metabolic balance demonstrate abnormally high fecal Mg2+ losses, and appropriate urinary Mg2+ conservation. [56] [57] Approximately 75% of reported cases are in males, and parental consanguinity has been documented in several instances, [55] [58] suggesting either an X-linked or autosomal recessive mode of inheritance. In one case, an affected individual was found to have a balanced translocation involving the X chromosome, suggesting that the disease locus may be located at the breakpoint, which was mapped to the Xp22.2 region. [59]
Diarrhea and Gastrointestinal Fistula.

The Mg2+ concentration of diarrheal fluid is high, ranging from 1 mg/dL to 16 mg/dL, [15] so Mg2+ deficiency may occur in patients with chronic diarrhea from any cause, even in the absence of concomitant malabsorption, [33] and in patients who abuse laxatives. By contrast, secretions from the upper gastrointestinal tract are low in Mg2+ content, and significant Mg2+ deficiency is therefore rarely observed with intestinal, biliary, or pancreatic fistula, ileostomy, or prolonged gastric drainage (except as a consequence of malnutrition). [15]
Cutaneous Losses.

Hypomagnesemia may be observed after prolonged intense exertion. For example, serum Mg2+ concentrations fall 20% on average after a marathon run. [60] About one quarter of the decrement in serum Mg2+ can be accounted for by losses in sweat, which can contain up to 0.5 mg/dL of Mg2+, [61] 61 with the remainder being most probably due to transient redistribution into the intracellular space. Hypomagnesemia occurs in 40% of patients with severe burn injuries during the early period of recovery. While hemodilution due to fluid resuscitation, hypoalbuminemia, poor nutritional intake, and aminoglycoside toxicity all are potential contributing factors, the major cause of hypomagnesemia is loss of Mg2+ in the cutaneous exudate, which can exceed 1 g/d. [62]

Redistribution to Bone Compartment.

Hypomagnesemia may occasionally accompany the profound hypocalcemia of hungry bone syndrome observed in some patients with hyperparathyroidism and severe bone disease immediately following parathyroidectomy. [63] In such cases, a state of high bone turnover exists, and sudden removal of excess PTH is believed to result in virtual cessation of bone resorption, with a continued high rate of bone formation and consequent sequestration of both Ca2+ and Mg2+ into bone mineral.

The diagnosis of renal Mg2+ wasting is made by demonstrating an inappropriately high rate of renal Mg2+ excretion in the setting of hypomagnesemia. Several indices of renal Mg2+ excretion are available (see Table 24-2) . While none has been systematically validated in large studies of patients with hypomagnesemia of various causes, the 24-hour urinary Mg2+ excretion test is the most widely used. Studies of human dietary Mg2+ deprivation indicate that the normal renal adaptive response is to conserve Mg2+ and allow less than 24 mg to be excreted daily. [6] [7] Thus, a 24-hour urine Mg2+ excretion rate greater than 24 mg in the setting of hypomagnesemia is considered diagnostic of renal Mg2+ wasting. [64] [65] If a 24-hour urine collection is not feasible, the spot urine Mg/Cr ratio may be used instead as a preliminary screening test. The fractional excretion of Mg2+ would seem to be the most rational indicator, as it is the only one that takes into account the filtered load. Unfortunately, it has yet to gain widespread acceptance and so few studies are available in the literature to support its use.

Excessive renal Mg2+ excretion may be caused a high urine flow rate (i.e., polyuria), or by a high urine Mg2+ concentration due to decreased tubular reabsorption of luminal Mg2+ , which may, in turn, be attributed to a defect in either proximal or distal tubule sites (Fig. 24-5) .

Renal Mg2+ wasting occurs with osmotic diuresis, as in the severe hyperglycemic state of diabetic ketoacidosis. [66] [67] Indeed, the estimated average Mg2+ deficit at presentation varies from 200 mg to 500 mg. [66] [67] Hypermagnesuria also occurs during the polyuric phase of recovery from acute renal failure in a native kidney, [68] recovery from ischemic injury in a transplanted kidney, [69] and in postobstructive diuresis. [69] In such cases, it is probable that residual tubule reabsorptive defects persisting from the primary renal injury play as important a role as polyuria itself in inducing renal Mg2+ wasting.
Extracellular Fluid Volume Expansion.

Chronic therapy with Mg2+ -free parenteral fluids, either crystalloid or hyperalimentation, [49] [50] can cause renal Mg2+ -wasting, in part because of ECF volume expansion. Renal Mg2+ wasting is also characteristic of hyperaldosteronism. [70] Infusion of mineralocorticoid into dogs does not affect renal Mg2+ handling acutely, [71] but Mg2+ wasting develops chronically over several days, concomitant with volume expansion. [72] Therefore, the Mg2+ wasting in this disorder is not directly due to the mineralocorticoid itself, but is a secondary consequence of volume expansion.
Defective Na+ Reabsorption in Distal Nephron.

Loop diuretics inhibit the apical membrane Na-K-2Cl cotransporter of the TAL and abolish the transepithelial potential difference, thereby inhibiting paracellular Mg2+ reabsorption


Figure 24-5 Differential diagnosis of renal Mg2+ wasting.
(see Fig. 24-3) . [73] Hypomagnesemia is therefore a frequent finding in patients receiving chronic loop diuretic therapy. [74] Thiazides, which block NaCl reabsorption via the electroneutral Na+ -Cl- cotransporter of the distal convoluted tubule (DCT), also inhibit Mg2+ reabsorption by an unknown mechanism. Indeed, it has been suggested that thiazide-induced hypomagnesemia increases the risk of arrhythmias in hypertensive patients. However, in a cohort of participants from the Multiple Risk Factor Intervention Trial treated chronically with chlorthalidone, the degree of hypomagnesemia was clinically and statistically insignificant. [75]


Classic Bartter syndrome is an autosomal recessive disorder characterized by Na+ wasting, hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism with normal or reduced blood pressure, urinary concentrating defect, and hypercalciuria, that usually presents in infancy or early childhood. [76] Most Bartter kindreds are due to inactivating mutations in one of the three transport proteins that mediate the TAL NaCl reabsorption/apical K+ recycling pathway (see Fig. 24-3) ; namely, the apical Na-K-2Cl cotransporter (BSC-1) [77] the apical inwardly rectifying K+ channel (ROMK-1), [78] or the basolateral Cl- channel (CLC-Kb). [79] All patients with Bartter syndrome are by definition hypercalciuric, and one third also have hypomagnesemia with inappropriate magnesuria, [76] consistent with loss of the TAL transepithelial potential difference that drives paracellular divalent cation reabsorption. Thus, the physiology of Bartter syndrome is essentially identical to that of chronic loop diuretic therapy.

Gitelman syndrome is a variant of Bartter syndrome that is distinguished primarily by hypocalciuria (urinary Ca/Cr ratio 0.07, mg/mg). [76] Patients with Gitelman syndrome present later in life, usually after the age of 6 years, have milder symptoms, and usually have preserved urinary concentrating ability. [76] The genetic defect in these families is due to inactivating mutations in the DCT electroneutral thiazide-sensitive Na+ -Cl- cotransporter, TSC. [80] The difference in nephron segment site of the NaCl reabsorption defect can explain the difference between classic Bartter and Gitelman syndromes in urinary concentrating ability (NaCl reabsorption in the medullary TAL, but not the DCT, contributes to the medullary interstitium concentrating gradient) and Ca2+ excretion (NaCl reabsorption is required for generation of the driving force for Ca2+ reabsorption in the TAL but not the DCT), and these in turn mirror the differences observed with chronic loop and thiazide diuretic therapy. Interestingly, however, renal Mg2+ wasting and hypomagnesemia is universally found in patients with Gitelman syndrome, [76] in contrast to classic Bartter syndrome, in which only one third are hypomagnesemic, an anomaly that cannot readily be explained from the current knowledge of Mg2+ transport physiology, and that appears inconsistent with the negligible degree of magnesuria normally found in hypertensive patients receiving chronic thiazide diuretics. [75]
Hypercalcemia and Ca2+ -Sensing Disorders.

Elevated serum ionized Ca2+ levels directly induce renal Mg2+ wasting and hypomagnesemia, [28] a phenomenon that is most clearly observable in the setting of hypercalcemia due to malignant bone metastases. [81] In hyperparathyroidism, the situation is more complicated because the hypercalcemia-induced tendency to Mg2+ wasting is counteracted by the action of PTH, which stimulates Mg2+ reabsorption, so that renal Mg2+ handling is usually normal, [21] and Mg2+ deficiency is rare. [82]

In familial hypocalciuric hypercalcemia, the hypercalcemia is due to inactivating mutations in the Ca2+ sensing receptor that is normally expressed in the parathyroid gland, resulting in inappropriate PTH secretion, and in the TAL, causing hypocalciuria. [83] As a consequence of the inactivated Ca2+ -sensing receptor, the normal magnesuric response to hypercalcemia is impaired, [84] [85] and so these patients are paradoxically mildly hypermagnesemic. Activating mutations in the Ca2+ -sensing receptor cause the opposite syndrome, autosomal dominant hypoparathyroidism. [86] As might be expected, most such patients are mildly hypomagnesemic, [87] presumably owing to TAL Mg2+ wasting.
Tubule Nephrotoxins.

Cisplatin, which is widely used as a chemotherapeutic agent for solid tumors, frequently causes renal Mg2+ wasting. All patients receiving monthly cycles of cisplatin at a dose of 50 mg/m2 become hypomagnesemic during treatment. [88] The occurrence of Mg2+ wasting does not appear to correlate with the incidence of cisplatin-induced acute renal failure, and many patients with hypomagnesemia may have normal glomerular function. [89] Renal magnesuria continues after cessation of the drug for a mean of 4 to 5 months, but it can persist for years. [89] The pathogenesis of the magnesuria is unclear. Although the nephrotoxic effects of cisplatin are manifested histologically as acute tubular necrosis confined to the S3 segment of the proximal tubule, [90] the magnesuria does not correlate temporally with the clinical development of acute renal failure due to acute tubular necrosis. Furthermore, patients who become hypomagnesemic also develop hypocalciuria, suggesting, by analogy with Gitelman syndrome, that the reabsorption defect may actually be in the DCT. [91] Carboplatin, an analog of cisplatin, appears to be considerably less nephrotoxic and rarely causes either acute renal failure or hypomagnesemia.

Amphotericin B, the mainstay of therapy for systemic fungal infections, is a well-recognized tubule nephrotoxin that can cause renal K+ wasting, distal renal tubular acidosis, and acute renal failure, with tubule necrosis and Ca2+ deposition in the DCT and TAL on renal biopsy. Amphotericin B causes renal Mg2+ wasting and hypomagnesemia that is related to the cumulative dose administered, but it may be observed after a total dose of as little as 200 mg. [92] Interestingly, the amphotericin-induced magnesuria is accompanied by the reciprocal development of hypocalciuria, [93] so that as with cisplatin the serum Ca2+ concentration is usually preserved, again suggesting that the functional tubule defect resides in the DCT.

Aminoglycosides cause a syndrome of renal Mg2+ and K+ wasting with hypomagnesemia, hypokalemia, hypocalcemia, and tetany. [94] [95] [96] [97] [98] The incidence of hypomagnesemia does not appear to correlate with the serum concentrations of aminoglycoside achieved and may occur despite levels in the appropriate therapeutic range. [98] Most cases reported had a delayed onset of hypomagnesemia occurring after at least 2 weeks of therapy, and most of the patients received total doses in excess of 8 g, suggesting that it is the cumulative dose of aminoglycoside that is the key predictor

TABLE 24-3 -- Classification and Clinical Features of Inherited Renal Mg2+ Wasting Disorders

Isolated Familial Hypomagnesemia Familial Hypokalemia-Hypomagnesemia Familial Hypomagnesemia-Hypercalciuria
Fluid and electrolyte abnormalities -- Hypokalemia
Metabolic alkalosis
High renin and aldosterone
Distal renal tubular acidosis
Nephrogenic diabetes insipidus
Urinary Ca2+ excretion Normal
Structural renal abnormalities -- -- Nephrocalcinosis
Chronic renal failure No No Yes
Extrarenal manifestations -- -- Ocular abnormalities
Basal ganglia calcification
Putative site of tubule Mg2+ leak Unknown DCT TAL
Pattern of inheritance AD/AR AR? AR
References [110] [111] [112] [113] [114] [174] [115] [116] [117] [118] [127] [119] [120] [121] [122] [123] [124] [125] [126] [127]
AD = autosomal dominant; AR = autosomal recessive.


of toxicity. There is also no correlation between the occurrence of aminoglycoside-induced acute tubular necrosis and hypomagnesemia, and in fact most patients with this Mg2+ wasting syndrome have a normal serum creatinine. Mg2+ wasting persists after cessation of the aminoglycoside, often for several months. All aminoglycosides in clinical use have been implicated, including gentamicin, tobramycin, and amikacin, as well as neomycin when administered topically for extensive burn injuries. [99] This form of symptomatic aminoglycoside-induced renal Mg2+ wasting is relatively uncommon nowadays because of heightened general awareness of the toxicity of high doses and prolonged courses of therapy, and the availability of alternative antibiotics with broad gram-negative bactericidal activity. The condition is therefore confined to patients chronically predisposed to Pseudomonas spp. infections, mainly individuals with cystic fibrosis and bronchiectasis. However, asymptomatic hypomagnesemia can be observed in one third of individuals treated with a single course of an aminoglycoside at standard doses (3 to 5 mg/kg/d for a mean of 10 days). In these cases, the hypomagnesemia occurs, on average, 3 to 4 days after of the start of therapy and readily reverses after cessation of therapy. [100]


Intravenous pentamidine, at standard doses for treatment of Pneumocystis carinii pneumonia, causes hypomagnesemia owing to renal Mg2+ wasting in essentially all patients, [101] typically associated with hypocalcemia. The average onset of symptomatic hypomagnesemia occurs after 9 days of therapy, and the defect persists for at least 1 to 2 months after discontinuation of pentamidine. [101] [102] Hypomagnesemia is also observed in two thirds of acquired immunodeficiency syndrome (AIDS) patients with cytomegalovirus retinitis who are treated intravenously with the pyrophosphate analog foscarnet. [103] As with aminoglycosides and pentamidine, the hypomagnesemia of foscarnet is often associated with significant hypocalcemia. [103]

Cyclosporin A causes renal Mg2+ wasting and hypomagnesemia in patients after renal and bone marrow transplantation. [104] [105] [106] Mg2+ loss does not correlate either with the serum trough cyclosporine levels or with the development of cyclosporine-induced renal failure. [104] Interestingly, the development of hypomagnesemia correlates temporally with the onset and severity of neurologic symptoms, such as ataxia, tremor, depression, and transient dysphasia. [106] These symptoms had previously been attributed to direct cyclosporine neurotoxicity, but they may well be a secondary consequence of cyclosporine-induced Mg2+ deficiency.
Tubulointerstitial Nephropathies.

Renal Mg2+ wasting has occasionally been reported in patients with acute [107] or chronic [108] tubulointerstitial nephritis not caused by nephrotoxic drugs; for example, in chronic pyelonephritis and acute renal allograft rejection. Other manifestations of tubule dysfunction, such as salt wasting, hypokalemia, renal tubular acidosis, [108] and Fanconi syndrome, [107] may also be present and provide clues to the diagnosis.
Inherited Renal Mg2+ Wasting Disorders.

More than 50 cases of primary renal Mg2+ wasting have been reported in the literature. Although fairly heterogeneous, these patients can be broadly classified into three distinct clinical syndromes (Table 24-3) . [109]

Isolated familial hypomagnesemia [110] most commonly presents in childhood with tetany or seizures. [111] [112] [113] [114] Laboratory investigation reveals hypomagnesemia with inappropriate magnesuria, but usually no other electrolyte or renal disturbances, and renal biopsy is normal by light and electron microscopy as well as by standard immunofluorescence studies. [113] Both the autosomal dominant [113] and recessive [112] forms of transmission have been reported.

Familial hypokalemia-hypomagnesemia is defined as renal Mg2+ wasting associated with renal K+ wasting and hypokalemia. Most such cases also have hypocalciuria and metabolic alkalosis of varying severity, and would therefore now be classified as Gitelman syndrome. [115] However, some patients with familial hypokalemia-hypomagnesemia have features considered atypical for Gitelman syndrome, such as the absence of metabolic alkalosis, normal plasma renin activity, normal urinary aldosterone excretion, and histologically normal juxtaglomerular apparatus on renal biopsy. [116] [117] [118] This may simply reflect a less severe form of Gitelman's syndrome or may perhaps represent a different and distinct pathophysiologic entity. The application of genomic analysis in these families to detect mutations in the TSC gene implicated in Gitelman syndrome [80] should resolve this issue.

Familial hypomagnesemia-hypercalciuria is characterized by renal Mg2+ wasting in association with significant hypercalciuria. [119] [120] [121] [122] [123] [124] [125] [126] The major cause of morbidity in this disorder is probably the hypercalciuria, which causes hypocalcemia [122] and renal calculi [126] in some cases, and nephrocalcinosis in all. Nephrocalcinosis and renal stone disease, in turn, is thought to be the cause of recurrent urinary tract infections, [121] [123] distal renal tubular acidosis (usually incomplete), [119] [121] [124] nephrogenic diabetes insipidus, [119] [121] and progressive renal impairment that may lead to end-stage renal failure. [124] [126] The tendency to tissue calcium deposition may also be manifested as calcification of the basal ganglia, [122] [123] and chondrocalcinosis with crystal arthropathy. [120] There is also an association with several ocular abnormalities, including corneal calcification, chorioretinitis, keratoconus, macular colobomata, nystagmus, and myopia. [123] [125] [126] [127] The association of renal Mg2+ and Ca2+ leak suggests that the site of the tubule reabsorption defect in these patients may be the TAL. The mode of inheritance in at least two families is strongly suggestive of autosomal recessive transmission. [123] [126] Interestingly, several family members of affected individuals have been found to have medullary sponge kidney, not normally considered an inherited trait, but the significance of this is unclear. [123] [126]

Clinical Manifestations

Hypomagnesemia may cause symptoms and signs of disordered function of the cardiac, neuromuscular and central nervous system (Table 24-4) . It is also associated with imbalance of other electrolytes, such as K+ and Ca2+ . However, many patients with hypomagnesemia are completely asymptomatic. [128] Thus, the clinical importance of hypomagnesemia remains controversial. Furthermore, many of the cardiac and neurologic manifestations attributed
ore, many of the cardiac and neurologic manifestations attributed

TABLE 24-4 -- Clinical Manifestations of Mg2+ Deficiency
  Electrocardiographic abnormalities
    Nonspecific T wave changes
    U waves
    Prolonged QT and QU interval
    Repolarization alternans
    Ventricular ectopy
    Monomorphic ventricular tachycardia
    Torsades de pointes
    Ventricular fibrillation
    Enhanced digitalis toxicity
  Muscle weakness
  Muscle tremor and twitching
  Positive Trousseau and Chvostek signs
  Vertical and horizontal nystagmus
  Generalized seizures
  Multifocal motor seizures

to Mg2+ deficiency may also be explained by hypokalemia and hypocalcemia, which often coexist in the same patient.

Cardiovascular System.

Mg2+ has protean and complex effects on myocardial ion fluxes, among which its effect on the sodium pump (Na+ , K+ -ATPase) is probably the most important. Since Mg2+ is an obligate cofactor in all reactions that require adenosine triphosphate (ATP), it is essential for activity of the Na+ ,K+ -ATPase, [129] which is responsible for actively pumping K+ into the cell, thereby maintaining an outwardly directed K+ gradient and a hyperpolarized resting membrane potential. During Mg2+ deficiency, Na+ ,K+ -ATPase function is impaired. The intracellular K+ concentration falls, [130] which may potentially result in a relatively depolarized resting membrane potential, so that the excitation threshold for activation of an action potential is more easily attainable, thus predisposing to ectopic excitation and tachyarrhythmias. Furthermore, the magnitude of the outward K+ gradient is decreased, reducing the driving force for the K+ efflux needed to terminate the cardiac action potential, so that repolarization is delayed.

Electrocardiographic changes may be observed with isolated hypomagnesemia and usually reflect abnormal cardiac repolarization, including bifid T waves and other nonspecific abnormalities of T wave morphology, [131] U waves, [132] prolongation of the QT or QU interval [133] [134] [135] and, rarely, electrical alternation of the T or U wave (Fig. 24-6) (Figure Not Available) . [132] [136]

Numerous anecdotal reports indicate that hypomagnesemia alone can predispose to cardiac tachyarrhythmias, particularly of ventricular origin, including torsades de pointes, [135] monomorphic ventricular tachycardia, [134] and ventricular fibrillation, [133] which may be resistant to standard therapy and may respond only to Mg2+ repletion. Many of the reported patients also had a prolonged QT interval, [133] [134] [135] which is known to predispose to torsades de pointes, but may also increase the period of vulnerability to R-on-T phenomena, which, in the setting of exaggerated cardiac excitability, may be the trigger for other types of ventricular tachyarrhythmias. In addition, hypomagnesemia facilitates the development of digoxin cardiotoxicity. [137] Since both cardiac glycosides and Mg2+ depletion inhibit the Na+ ,K+ -ATPase, their additive effects on intracellular K+ depletion may account for their enhanced toxicity in combination.

The existence of occasional patients with clear hypomagnesemia-induced arrhythmias is undisputed. However, the magnitude of the risk of arrhythmias among patients with hypomagnesemia in general, the issue of whether mild hypomagnesemia carries the same risk as severe hypomagnesemia, and the relative importance of Mg2+ deficiency versus coexistent hypokalemia or intrinsic cardiac disease in the pathogenesis of the arrhythmia remain highly controversial. No well-controlled studies have been performed to answer these questions. In the most frequently cited study by Dyckner of 342 patients with acute myocardial infarction admitted to a coronary care unit, complex ventricular ectopy, ventricular tachycardia, and ventricular fibrillation were three times more frequent during the first 24 hours in hypomagnesemic patients than in normomagnesemic ones. [138] In a control group of patients without myocardial infarction, ventricular ectopy and arrhythmias were not associated with hypomagnesemia. The major flaw in this study was the failure to control for hypokalemia, a well-established risk factor for ventricular arrhythmias. Indeed, the prevalence of hypokalemia was high (30%) in the hypomagnesemic patients with ventricular arrhythmias, and exceeded its prevalence in patients without arrhythmias (10%), so that the serum K+ concentration was almost certainly an important confounder. In addition, there was no attempt to monitor or control for the use of antiarrhythmic agents between the different subgroups. Since such drugs may have both antiarrhythmic and proarrhythmic activity, differences in their use between the subgroups of patients may also have confounded the interpretation of this study.

Neuromuscular System.

The process of skeletal muscle contraction begins with the opening of voltage-dependent L-type Ca2+ channels in the plasma membrane when depolarized by an action potential. This stimulates the release of Ca2+ from intracellular stores in the sarcoplasmic reticulum via the Ca2+ release channel. The increase in cytosolic Ca2+ causes contraction of the myofibrils. Contraction is terminated when Ca2+ is returned to its stores in the sarcoplasmic reticulum by a Ca2+ -ATPase pump. Mg2+ is known to block both plasma membrane L-type Ca2+ channels [139] and intracellular Ca2+ release channels, [140] and is also a necessary cofactor for the activity of the sarcoplasmic reticulum Ca2+ -ATPase. Thus, hypomagnesemia would be expected to augment skeletal muscle contractile activity and to delay muscle relaxation.

Patients with isolated hypomagnesemia do develop symptoms and signs of neuromuscular irritability, including tremor, muscle twitching, Trousseau and Chvostek signs, and frank tetany. [141] These may be exacerbated by a coexistent electrolyte abnormality, such as hypocalcemia, [128] a frequent concomitant of hypomagnesemia, or hypokalemic metabolic alkalosis that may occasionally be present as a manifestation of the same underlying disorder; for example, in Gitelman syndrome. [76]

Hypomagnesemia also frequently presents with seizures that may be generalized and tonic-clonic in nature, [141] or multifocal motor seizures, [142] and are sometimes triggered by loud noises. [141] Interestingly, noise-induced seizures and sudden death are also characteristic of mice made hypomagnesemic by dietary Mg2+ deprivation. The effects of Mg2+ deficiency on brain neuron excitability are thought to be mediated by N-methyl-D-aspartate (NMDA)-type glutamate receptors. Glutamate is the principal excitatory neurotransmitter in the brain and acts as an agonist at NMDA receptors, opening a cation conductance that depolarizes the postsynaptic membrane. Extracellular Mg2+ normally blocks NMDA receptors, so hypomagnesemia may release inhibition of glutamate-activated depolarization of the postsynaptic membrane, thereby triggering epileptiform electrical activity. [143]

Vertical nystagmus is a rare but diagnostically useful neurologic sign of severe hypomagnesemia. [144] In the absence of a structural lesion of the cerebellar or vestibular pathways, the only recognized metabolic causes are Wernicke encephalopathy and severe Mg2+ deficiency. [144] The specific pathogenesis is unknown.
Electrolyte Homeostasis.

Patients with hypomagnesemia are frequently also hypokalemic. Many of the conditions associated with hypomagnesemia that have been outlined earlier can cause simultaneous Mg2+ and K+ losses, such as severe malnutrition, diarrhea, burn injury, polyuria, hyperaldosteronism, Bartter and Gitelman syndromes, and the administration of diuretics, aminoglycosides, or amphotericin B. However, hypomagnesemia, by itself, can induce hypokalemia in both humans and experimental animals, and such patients are often refractory to K+ repletion until their Mg2+ deficit is corrected. [145] The cause of hypokalemia appears to be depletion of intracellular K+ due to impaired Na+ -K+ -ATPase function, [130] together with renal K+ wasting, so that the K+ leaked from cells is lost in the urine. The physiologic mechanism of renal K+ wasting in hypomagnesemia is unknown. In hypomagnesemic rats, the site of impaired K+ reabsorption lies between the late proximal and superficial distal tubule, suggesting a defect in the TAL. [146] However, these rats respond well to parenteral K+ repletion and retain even more of the administered K+ than do normomagnesemic controls, suggesting that they are a poor model for the human disease.

Hypocalcemia is present in approximately half of the patients with hypomagnesemia. [128] The major cause is impairment of PTH secretion resulting from Mg2+ deficiency, which is reversed within 24 hours by Mg2+ repletion. [147] In addition, hypomagnesemic patients also have low circulating 1,25-dihydroxyvitamin D levels, [148] and end-organ resistance to both PTH [147] and vitamin D. [149]

Figure 24-6 (Figure Not Available) Electrocardiographic manifestations of hypomagnesemia. A. Bifid T waves. B. U wave alternans. C. Sinus rhythm with prolonged QT interval, followed by ventricular fibrillation. ( A from Chen W, Fu X, Pan Z, et al: ECG changes in early stage of magnesium deficiency. Am Heart J 104:1115-1116, 1982. B from Bashour T, Rios JC, Gorman PA: U wave alternans and increased ventricular irritability. Chest 64:377-379, 1973. C from Loeb HS, Pietras RJ, Gunnar RM, et al: Paroxysmal ventricular fibrillation in two patients with hypomagnesemia. Circulation 37:210-215, 1968, with permission.)

TABLE 24-5 -- Magnesium Salts Commonly Used for Replacement and Supplementation
Salt Formula Typical Dose Unit Elemental Mg Content
mg mEq
Sulfate MgSO4 7H2 O 2 mL 50% soln/amp = 1 g
10 mL 50% soln/amp = 5 g
Oxide MgO 140 mg tab (Uro-Mag)
400 mg tab (Mag-Ox 400)
Chloride MgCl2 6H2 O 833 mg tab (Mag-L) 100 8
Gluconate C12 H22 MgO14 2H2 O 500 mg tab (Magonate) 27 2.2
Lactate C6 H10 MgO6 2H2 O 835 mg tab (Mag-Tab SR) 84 7



Mg2+ deficiency may sometimes be prevented. Individuals in whom dietary intake has been reduced, or who are receiving parenteral nutrition, should receive Mg2+ supplementation. The recommended daily allowance of Mg2+ in adults is 350 mg (29 mEq) * for men and 280 mg (23 mEq) for women. [150] Thus, in the absence of dietary Mg2+ intake, an appropriate supplement would therefore be one 140-mg tablet of Mg oxide, three to four times daily, or the equivalent dose of an alternative oral Mg2+ -containing salt (Table 24-5) . Since the oral bioavailability of Mg2+ is approximately one third in patients with normal intestinal function, the equivalent parenteral maintenance requirement of Mg2+ would be 8 mEq daily.

Once patients develop symptomatic Mg2+ deficiency, they should clearly be repleted with Mg2+ . However, the importance of treatment of asymptomatic Mg2+ deficiency remains controversial. Given the clinical manifestations outlined earlier, it would seem prudent to replete all Mg2+ -deficient patients with a significant underlying cardiac or seizure disorder, patients with concurrent severe hypocalcemia or hypokalemia, and patients with isolated asymptomatic hypomagnesemia if it is severe (< 1.4 mg/dL).
Intravenous Replacement.

In the inpatient setting, the intravenous route of administration of Mg2+ is favored because it is highly effective, inexpensive, and usually well tolerated. The standard preparation is MgSO4 7H2 O (see Table 24-5) . The initial rate of repletion depends on the urgency of the clinical situation. In a patient who is actively seizing or who has a cardiac arrhythmia, 8 to 16 mEq (1 to 2 g) may be administered intravenously over 2 to 4 minutes; otherwise, a slower rate of repletion is safer. Because the added extracellular Mg2+ equilibrates slowly with the intracellular compartment, and because renal excretion of extracellular Mg2+ exhibits a threshold effect, approximately 50% of parenterally administered Mg2+ spills into the urine. [151] A slower rate and prolonged course of repletion would be expected to decrease these urinary losses, and therefore would be much more efficient and effective at repleting body Mg2+ stores. The magnitude of the Mg2+ deficit is difficult to gauge clinically and cannot be readily deduced from the serum Mg2+ concentration. In general, however, the average deficit can be assumed to be 1 to 2 mEq/kg body weight. [151] A simple regimen for nonemergent Mg2+ repletion is to administer 64 mEq (8 g) of MgSO4 over the first 24 hours, then 32 mEq (4 g) daily for the next 2 to 6 days. It is important to remember that serum Mg2+ levels rise early, while intracellular stores take longer to replete, so Mg2+ repletion should continue for at least 1 to 2 days after the serum Mg2+ level normalizes. In patients with renal Mg2+ wasting, additional Mg2+ may be needed to replace ongoing losses. In patients with a reduced glomerular filtration rate, the rate of repletion should be reduced by 25% to 50%, [151] the patient should be carefully monitored for signs of hypermagnesemia, and the serum Mg2+ level should be checked frequently.

The main adverse effects of Mg2+ repletion are due to hypermagnesemia as a consequence of an excessive rate or amount of Mg2+ administered. These effects include facial flushing, loss of deep tendon reflexes, hypotension, and atrioventricular block. Monitoring of tendon reflexes is a useful bedside test for detecting Mg2+ overdose. In addition, intravenous administration of large amounts of MgSO4 results in an acute decrease in the serum ionized Ca2+ level, [152] [153] related to increased urinary Ca2+ excretion, and complexing of Ca2+ by sulfate. Thus, in an asymptomatic patient who is already hypocalcemic, administration of MgSO4 may further lower the ionized Ca2+ level and thereby precipitate tetany. [153] The administration of Mg2+ with sulfate as the anion may have an additional theoretical disadvantage. Since sulfate cannot be reabsorbed in the distal tubule, it favors the development of a negative luminal electrical potential, thereby increasing K+ secretion. In Mg2+ -depleted rats with hypokalemia, repletion with Mg2+ in the form of a non-sulfate salt was associated with correction of the hypokalemia, while repletion with MgSO4 resulted in persistent hypokalemia and kaliuresis. [154]
Oral Replacement.

Oral Mg2+ administration is used either initially for repletion of mild cases of hypomagnesemia or for continued replacement of ongoing losses in the outpatient setting, after an initial course of intravenous repletion. A number of oral Mg2+ salts are available (see Table 24-5) , but little is known about their relative oral bioavailability or efficacy, and all of them cause diarrhea in high doses. Mg hydroxide and Mg oxide are alkalinizing salts with the potential to cause systemic alkalosis, while the sulfate and gluconate salts may potentially exacerbate K+ wasting, as discussed earlier. The appropriate dose of each salt can be estimated, if ongoing losses are known, by determining its content of elemental Mg2+ from Table 24-5

* The Mg2+ content of Mg2+ salts is generally referred to in terms of milliequivalents. To convert to the equivalent grams of salt, or grams of elemental Mg, refer to Table 24-5 .

, and assuming a bioavailability of approximately one third for normal intestinal function. In patients with intestinal Mg2+ malabsorption, this dose may need to be increased two to four fold.

Potassium-Sparing Diuretics.

In patients who have inappropriate renal Mg2+ wasting, potassium-sparing diuretics that block the distal tubule epithelial Na+ channel, such as amiloride and triamterene, may reduce renal Mg2+ losses. [155] This may be particularly useful in patients who are refractory to oral repletion or who require such high doses of oral Mg2+ that they develop diarrhea. In rats, amiloride and triamterene can be demonstrated to reduce renal Mg2+ clearance at baseline and after induction of a Mg2+ diuresis by furosemide, but the mechanism is unknown. [156] One possibility is that these drugs may favor passive reabsorption of Mg2+ in the late distal tubule, or collecting duct, by reducing luminal Na+ uptake and inhibiting the development of a lumen-negative transepithelial potential difference.




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