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Clinical Nephrology, Vol. 7 No. 4 - 1977 (pp. 147-153)

Hypomagnesemia and hypermagnesemia

S. G. MASSRY and M. S. SEELIG

Division of Nephrology and Department of Medicine, the University of Southern California School of Medicine, Los Angeles, California, and the Department of Medicine, the Goldwater Memorial Hospital, New York University Medical Center, New York, New York, U. S. A.

Abstract. With the availability of reliable methods for measurement of magnesium in body fluids, a great deal of information has accumulated on magnesium homeostasis. We reviewed the pertinent data on various aspects of magnesium metabolism. The conditions associated with hypo- and hypermagnesemia and the clinical and laboratory findings as well as the management of these disorders are discussed. Finally, the effects of renal failure on magnesium homeostasis are presented.

Although magnesium (Mg) is predominantly an intracellular cation, participating in many membrane-enzymatic functions, technical difficulties in determining the cellular content of this cation in different tissues have mandated reliance on the blood levels of Mg as the index of deficiency. However, Mg deficiency may exist with normal or elevated levels of Mg in blood [Fitzgerald and Fourman, 1965, Lim et al. 1969].

The body of the adult human contains about 2000 mEq of Mg with half of this amount in the skeleton and the other half in soft tissues [Wacker and Parisi 1968]. The normal concentration of Mg in blood is maintained within narrow limits and ranges between 1.5-2.0 mEq/l. About 20-30% of Mg in blood is bound to proteins and the rest (75 ± 9%, (SD)) is present in a diffusible form. The major part of the diffusible fraction is made of free ionized Mg [Walser 1967]. The kidney plays an important role in maintaining blood Mg within the normal range. Oral or intravenous loads are rapidly excreted [Chesly and Tepper 1958, Heaton and Parson 1961], and in the magnesium deficient state or with rigid dietary restriction, Mg almost disappears from the urine [Barnes et al. 1958, Fitzgerald and Fourman 1965].

Renal handling of magnesium

The diffusible fraction of blood Mg is filtered at the glomerulus, and each day approximately 1800 mg of Mg is lost from plasma into glomeruli. Only 3-5% of filtered Mg is excreted in the urine. This conservation process is due to an effective tubular reabsorption of Mg.

Magnesium is actively reabsorbed throughout the nephron, although passive Mg reabsorption may occur in the proximal tubule. There is a maximum tubular reabsorptive capacity for Mg (Tm Mg). The tubular reabsorption of Mg may be reduced by various factors. These include: 1) extracellular fluid volume expansion, 2) renal vasodilatation, 3) osmotic diuresis, 4) diuretic agents, 5) cardiac glycosides, 6) hypercalcemia, 7) alcohol ingestion, 8) high sodium intake, 9) growth hormone, 10) thyroid hormone, 11) calcitonin, and 12) chronic mineralocorticoid excess. Parathyroid hormone enhances tubular reabsorption of Mg.

Available data regarding Mg secretion by the renal tubule are contradictory. However, the body of evidence indicates that if Mg secretion by the nephron exists, it plays a minor role in the renal handling of Mg. For more detailed information on the renal handling of Mg, the reader is referred to the extensive review of Walser [1967] and Massry and Coburn [1973].

Hypomagnesemia and magnesium deficiency

Severe hypomagnesemia is usually associated with Mg deficiency, and the latter indicates a decrease in the total content of body Mg. A state of Mg deficiency with hypomagnesemia may develop due to lack of intestinal absorption or excessive losses in feces [Balint and Hirschowitz 1961, Booth et al. 1963, Heaton et al. 1967, Savage and McAdam 1967], urine [Bar et al.1975, Davis et al. 1975, Eliel et al. 1960, Heaton et al. 1962, Horton and Biglieri 1962, Jones et al. 1966, King and Stanbury 1970, Massry et al. 1967a, Martin et al. 1958, 1959, Mendelson et al. 1959, Smith et al. 1962] or in other body fluids such as with biliary fistulas during nasogastric suction or prolonged lactation. Severe and prolonged dietary restriction (<1 mEq/day) in man can cause hypomagnesemia and symptomatic Mg deficiency [Shills 1969]. The various disease states associated with hypomagnesemia are listed in Table 1.

The diagnosis of Mg deficiency is not easy since blood level of Mg does not always reflect the state of body Mg, and it may be a poor guide to the degree of Mg depletion [Fitzgerald and Fourman 1965, MacInryre et al. 1961]. Moreover, hypermagnesemia may occur in patients with renal failure, despite cellular Mg depletion [Lim et al. 1969]. The concentration of Mg in erythrocytes, Mg content of muscle, body exchangeable Mg and Mg balance have been used to assist in the diagnosis of Mg deficiency. These methods are either difficult to perform or do not provide a good index of the state of body magnesium. The fate of intravenous load of Mg may help in the diagnosis of Mg depletion [Fitzgerald and Fourman 1965]. Normal subjects excrete all the parenterally administered Mg within 24 to 48 hours, while subjects with Mg deficiency may retain more than 20% of an intravenous load of Mg. Therefore, the retention of an intravenously administered Mg is consistent with Mg deficiency, even in the presence of normal serum Mg [Fourman and Morgan 1962]. This test is valid only when renal function is normal and when Mg depletion is not due to the inability of the kidney to conserve Mg. .

Table 1 Causes of hypomagnesemia.


I. Decreased intake II. Decreased intestinal absorption
III. Excessive losses of body fluids IV. Excessive urinary losses
V. Miscellaneous

Table 2 Clinical manifestations and laboratory findings of magnesium depletion.

Clinical manifestations

Laboratory findings


The signs and symptoms of Mg depletion are. usually mixed with, and sometimes masked by, the clinical manifestations of the basic disorders which caused the Mg deficient state. The studies of Shills [1969], in which experimental Mg depletion was produced in humans, have helped delineate the clinical and laboratory .findings of pure Mg deficiency in man. The main clinical manifestations of Mg depletion include neuromuscular disturbances and behavioral abnormalities. These, as well as the laboratory findings, are listed in Table 2.

Magnesium deficiency is managed by replacement with Mg salts. Since the magnitude of the deficit is not easy to estimate, the planning of the replacement therapy is usually empirical. A deficit of 1 to 2 mEq per kilogram body weight may exist in the presence of significant hypomagnesemia. The. amount of Mg required will be twice the estimated deficit, since about 50% of the administered Mg will be lost in the urine even when marked deficiency of this ion exists. Magnesium sulphate (MgSO4,7H2O) is usually used for the parenteral therapy. The molecular weight of this hydrated compound is 246.5 and each gram of the salt contains 8.12 mEq of Mg. Repletion can be achieved either by intramuscular or intravenous administration of Mg. Usually about 40 to 50% of the deficit is given in the first day and the rest in divided doses during the following 2 to 4 days. In patients with normal renal function 50 mEq of Mg may be given intravenously over 4 to 6 hours and the intravenous dose should not exceed 100 mEq per 12 hours, or 16 mEq may be given intramuscularly every 2 to 4 hours during the first day of therapy. Frequent measurement of serum Mg during the administration of the ion is advised. The dosage of Mg should be substantially reduced in patients with renal failure and serial monitoring of serum Mg is mandatory in these patients.

Finally, attempts should be made to identify the underlying abnormality which has led to the deficient state, and if possible to treat the underlying cause. Also, efforts should be undertaken to prevent Mg depletion in any clinical setting which may predispose to its development. For example, in patients who require gastric suction, or in those who need prolonged intravenous fluid therapy, daily supplement of 10 to 15 mEq of magnesium could prevent magnesium depletion.

Magnesium homeostasis, parathyroid glands, and blood calcium

Hypermagnesemia suppresses the activity of the parathyroid glands [Buckle et al. 1968, Massry et al. 1970a]. The data on the effect of hypomagnesemia are variable. Levi et al. [1974] found that the blood levels of parathyroid hormone were not elevated during Mg depletion, despite the hypocalcemia, suggesting impaired function of the parathyroid glands. Anast and coworkers [1972] and Suh et al. [1973] each found a reduced or undetectable plasma level of immunoreactive parathyroid hormone in separate patients with Mg depletion. A similar finding was reported by Chase and Slatopolsky [1974]. In addition studies by Targovnik et al. [1971] showed that the release of parathyroid hormone from the parathyroid glands in vitro is markedly reduced when Mg concentration in the media was below 0.70 mg/dl. These findings are not necessarily inconsistent with data showing that acute reduction in the concentration of Mg in blood perfusing the parathyroid glands causes increased release of parathyroid hormone [Buckle et al. 1968]. Chronic hypomagnesemia may have a different effect on parathyroid gland metabolism and this effect may depend on the degree of the hypomagnesemia. There is also evidence that parathyroid gland activity may be normal or increased during chronic Mg deficiency. Sherwood [1970] and Connor et al. [1972] each reported elevated circulating levels of parathyroid hormone in an individual patient with Mg depletion, and parathyroid hyperplasia has been reported in calves with Mg deficiency. However, even when blood levels of parathyroid hormone are elevated during Mg depletion, they may not represent adequate or appropriate response of the parathyroid glands for the degree of the hypocalcemia.

Recent observations by Anast and co-workers [1976] and Rude and associates [1976] indicate that marked Mg deficiency may inhibit the release of parathyroid hormone from the parathyroid glands. They found that blood levels of the hormone increased markedly within one minute of the administration of Mg. These observations are consistent with in vitro studies showing that low Mg concentration in the incubation media diminishes the secretion of the parathyroid hormone [Targovnik et al. 1971], but not its synthesis [Hamilton et al. 1971] by bovine parathyroid glands.

The mechanisms underlying the hypocalcemia of Mg depletion are complicated and have been reviewed in detail by Massry [1977]. The available data indicate that multiple factors are responsible for such hypocalcemia. Relative or complete failure of the function of parathyroid glands, inhibition of release of parathyroid hormone from the glands, impaired skeletal response to parathyroid hormone, and abnormalities in the equilibrium between bone and extracellular fluid may each, or all, be operative in various species.

Hypermagnesemia

Elevated levels of plasma Mg are seen in patients with acute [Hamburger 1957, Massry et al. 1974] and chronic renal failure [Coburn et al. 1969, Randall et al. 1964], during the administration of pharmacologic doses of Mg, in some infants born to mothers who had been treated with Mg for eclampsia [Brady and Williams 1967], and during the use of oral purgatives or rectal enemas containing Mg [Fawcett and Gins 1943, Stevens and Wolf 1950]. Hypermagnesemia may also be present in patients with adrenal insufficiency [Hills et al..1955]. The signs and symptoms of hypermagnesemia are the result of the pharmacologic effects of this ion on the nervous and cardiovascular systems. Deep tendon reflexes are usually lost when blood Mg exceeds 6 mEq/l. Respiratory paralysis, narcosis, hypotension, and abnormal cardiac conduction may occur as blood levels of Mg approach 10 mEq/l.

Cessation of Mg administration and the intravenous injection of calcium salts are the initial mandatory steps in the management of symptomatic hypermagnesemia. The administration of 5-10 mEq (100-200 mg) of calcium ion may be adequate to reverse the manifestation of hypermagnesemia, although greater amounts may be needed. On occasion, peritoneal or even hemodialysis may be required to control severe hypermagnesemia. In patients who had respiratory paralysis, artificial respiration should be used until the level of blood Mg is lowered.

Magnesium metabolism in renal failure

Renal failure may be associated with disturbances in several aspects of Mg metabolism. These include the renal handling of Mg, its concentration in blood, tissue content of this ion, and its intestinal absorption and balance.

1. Renal handling of magnesium in renal failure

The daily urinary excretion of Mg is usually reduced in patients with advanced renal failure [Popovtzer et al. 1969, Randall et al. 1964]. In fifty patients with creatinine clearance of 1-30 ml/min studied in our laboratory, the urinary excretion of Mg per 24 hours ranged between 12-133 mg with a mean of 57 ± 31 (SD) mg [Popovtzer et al. 1969]. Only two-thirds of the patients had significant reduction in their excretory rates while the other third had either normal or increased excretion of Mg [Popovtzer et al. 1969]. In patients with uremia and salt wasting, such as those with chronic pyelonephritis, the 24 hour urinary excretion of Mg may be normal or high [Popovtzer et al. 1969], and renal Mg wasting has been reported in few such patients [Randall et al. 1964].

The fraction of filtered Mg excreted increases as renal failure progresses [Coburn et al. 1969, Popovtzer et al. 1969, 1970] and the increment is more marked when the glomerular filtration rate is less than 10 ml/min. It is important to consider the changes in the fraction of filtered Mg in view of the renal handling of sodium, since the tubular reabsorption of these two ions are interrelated [Brunette et al. 1969, Massry et al. 1967b]. Indeed, there is a positive and significant correlation between the fraction of filtered Mg excreted and that of sodium in patients with glomerular filtration rate below 40 ml/min [Popovtzer 1970]. A similar relationship was observed in dogs with experimental renal failure [Gutman et al. 1969].

The mechanisms responsible for the alterations in the renal handling of Mg in renal failure are not completely understood. As indicated earlier, tubular reabsorption of Mg exhibits a Tm. In renal failure filtered Mg per nephron is augmented secondary to the increased filtration rate in the residual nephron [Bricker et al. 1964]. Under these circumstances, filtered Mg may exceed Tm Mg and the fraction of filtered Mg excreted is increased. Other factors may also be operative in advanced renal failure. Recent studies have shown that uremic serum contains a humoral factor which decreases renal tubular reabsorption of sodium and causes natriuresis [Bourgoignie et al. 1972], and such a factor is probably similar to that present in the blood of animals undergoing extracellular fluid volume expansion [Bricker et al. 1968]. Such a factor may be partly responsible for the augmented fractional excretion of sodium and Mg in the late stages of renal insufficiency.

We have evaluated renal handling of Mg during the diuretic phase of acute renal failure in 10 patients. The fraction of filtered Mg excreted is increased, and there is a positive and significant correlation between it and that of sodium.

2. Serum magnesium in renal failure

a) Acute renal failure: The effect of acute renal failure on the blood concentration of Mg was studied by Massry et al. [1974] in 10 patients. Hypermagnesemia was present in all but one patient during the oliguric phase. The highest values noted in the various patients ranged between 2.2 and 4.6 mg/100 ml. During the diuretic phase the levels fell to normal or slightly below normal. The magnesium concentration in serum was normal after recovery. The diffusible levels of serum Mg were also increased during the oliguric phase of the acute renal failure but the percent diffusible fraction (75 ± 5%) was not different from that observed in normal subjects.

b) Chronic renal failure: The concentration of Mg in blood is usually normal in patients with early renal failure, but distinct hypermagnesemia is common in patients with advanced renal failure [Coburn et al. 1969]. The percent of serum Mg which is not bound to protein is 76 ± 8%, a value which is not different from 75 ± 9% observed in normals [Coburn et al. 1969]. Abrupt increases in serum Mg can occur when the patients consume Mg containing antacids or laxatives [Randall et al.1964]. It should be mentioned that hypomagnesemia has been reported in some patients with renal failure [Hanna 1961, Walser 1969].

c) Effect of hemodialysis: The levels of serum Mg in patients undergoing hemodialysis are clearly related to the concentration of Mg in dialyzate, as well as the dietary intake of this ion. It is known that Mg readily crosses the dialysis membrane, and its movement depends upon the gradient between the concentration of diffusible Mg in blood and the concentration of Mg in dialyzate [Ogden and Holmes 1966]. Schmidt et al. [1971] reported total Mg losses as high as 700 mg per dialysis when dialyzate Mg was 0.27 mg/100 ml. The importance of dialyzate Mg levels in determining the predialysis blood Mg concentrations is demonstrated by our observations in patients treated in two separate dialysis centers, one utilizing dialyzate with 0.6 mg/100 ml of Mg and the other 1.8 mg/100 ml; predialysis blood Mg level ranged from 1.7 to 2.5 mg/100 ml and from 3.0 to 5.0 mg/l00 ml in the two centers, respectively [Coburn et al. 1969]. Similar observations were found by others [Blomfield et al. 1970].

Evidence exists indicating that abrupt increments in the concentration of serum Mg may acutely inhibit the release of parathyroid hormone [Buckle et al. 1968, Massry et al. 1970a]. Indeed, the acute elevation of serum Mg, produced by either Mg infusion or by increasing the Mg concentration of dialyzate, was associated with a fall in the blood levels of parathyroid hormone in patients undergoing regular hemodialysis [Freeman and Deftos 1973, Pletka et al. 1971]. Whether chronic hypermagnesemia, such as that observed in advanced uremia, may alter the function of parathyroid glands is unknown.

3. Tissue content of magnesium in renal failure

a) Red blood cells (RBC): The content of Mg in the RBC of uremic patients undergoing treatment with hemodialysis is usually higher than that of normals [Schmidt et al. 1971]; and the content of Mg in RBC in these patients correlate well with the concentration of Mg in their blood [Blomfield et al. 1970].

b) Skin: The Mg content of the skin in patients undergoing maintenance hemodialysis is affected by the concentration of magnesium in dialyzate. We have evaluated the Mg content of skin in two populations of patients treated with hemodialysis for periods of two months to five years with dialyzate containing Mg in concentrations of either 1.8 or 0.6 mg/100 ml. Although there was an overlap between the individual values, the skin content of Mg was significantly higher (P <.01) in the group treated with dialyzate containing 1.8 mg/l00 ml [Massry et al. 1970b].

c) Muscle: The magnesium content of muscle in patients with renal failure has been found to be low, normal or elevated [Contiguglia et al. 1972, Lim et al. 1969]. Thus, Lim et al. [1969] found that the mean magnesium content in the muscles of nine uremic patients (55.03 ± 7.4 (SE) mEq/kg of dry fat free solids) is significantly lower (P <.05) than that of normal subjects (71.80 ± 2.5 mEq/kg dry fat free solids). The magnesium content in the muscle of patients treated with dialysis was not different from that observed in the non-dialyzed patients. On the other hand, Contiguglia et al. [1972] reported that the magnesium contents of muscle from normal and uremic patients were not different, 75 ± 8.6 and 80.9 ± 14.3 mEq/kg fat free dry solids, respectively.

d) Bone: Magnesium content of bone is increased in uremia. Contiguglia et al. [1972] found that magnesium content of both cortical and trabecular bone was increased by 66%. These observations were confirmed later by Berlyne et al. [1972]. Alfrey and Miller [1973] found that bone contains at least two distinct magnesium pools. One is rapidly exchangeable and constitutes 30% of total bone magnesium. The other is a non-exchangeable pool. In patients with uremia, the excess magnesium in bone is distributed in both pools. The most probable cause for the increase in bone magnesium in patients with chronic renal failure is the hypermagnesemia, usually present in these patients.

Intestinal absorption of magnesium in renal failure

There are not adequate data on intestinal absorption of Mg in patients with renal failure. The information available is on calculation of net absorption of Mg obtained from balance studies. Clarkson et al. [1965] studied six patients with creatinine clearance rates below 30 ml/min and noted that the fraction of magnesium absorbed varied between .16 and .47. Kopple and Coburn [1973] found this fraction to range between .24 and .63. Evaluation of the available data indicate that net magnesium absorption in relation to dietary intake in normal subjects and uremic patients is not different. Thus, it appears that chronic renal failure does not reduce intestinal magnesium absorption and this ion is readily absorbed by these patients independent of the presence of hypermagnesemia and the body's need for magnesium. In contrast, Brannan et al. [1976], utilizing in vivo intestinal perfusion techniques, found that patients with end state renal disease have a severe depression of Mg absorption. The reason for the difference between the results of these acute studies and those obtained from balance studies is not evident.

Reprint requests to Dr. Shaul G. Massry
Chief, Division of Nephrology, USC School of Medicine
2025 Zonal Avenue, Los Angeles, CA. 90033, U.S.A.

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