Appendix for Magnesium Deficiency in the Pathogenesis of Disease, by Dr. Mildred S. Seelig

Goldwater Memorial Hospital
New York University Medical Center
New York, New York
1980

(include the word "jacket" to search only in this book)

| Jacket | Preface | Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Appendix*

There are serious problems in assessing the magnesium status of patients, probably the most important reason that, despite the ubiquity of this element and its importance in so many enzyme systems and in function and structure of vital organs and bones, magnesium is usually one of the last clinical parameters to be explored (Whang et al., 1976/1980). When levels are sought, the results are often misleading. Each means of evaluation has its limitations, and in order to determine whether a patient is magnesium deficient (unless the deficiency is so profound as to cause unquestioned hypomagnesemia), a combination of approaches may be necessary. First of all, although magnesium is an intracellular cation, second in concentration only to potassium [the retention of which is dependent on magnesium-dependent enzymes (Reviews: Wacker and Vallee, 1958; Whang et al.1967; Whang, 1968, 1971; Seelig, 1972; Whang and Aikawa, 1977)], serum magnesium is generally the only parameter explored. Unfortunately, the reliability of serum magnesium values is dubious as an index of body levels, and even as an indication of abnormal blood levels, particularly when wide ranges of serum or plasma magnesium levels are accepted as "within normal limits" (infra vide).

With the limitations of serum magnesium values, the clinician must rely on indirect tests of magnesium metabolism, determinations of cellular magnesium levels (e.g., blood cells, skeletal muscle) generally being unattainable and not standardized (infra vide). Metabolic balance studies have provided important baseline data regarding magnesium requirements of normal subjects (Seelig, 1964). However, metabolic research units are necessary to obtain reliable results and the procedure is time consuming and cumbersome. Furthermore, when used with patients who have intrinsic (isolated, possibly familial) magnesium malabsorption, or who have renal magnesium wastage as a result of renal disease or a genetic trait, the results can be misleading. Prolonged studies, and periods of magnesium restriction (which might be of risk to patients with underlying magnesium deficiency) would be necessary to separate those who do not retain magnesium because their tissue stores are ample from those who have a metabolic abnormality resulting in magnesium malabsorption or renal wastage. Also, such studies are inapplicable to patients who require medication that can interfere with the intestinal absorption or renal tubular reabsorption of magnesium.

At this time, the most reliable method of evaluating a patient's magnesium status is determination of its 24-hour urinary output before and after a parenteral magnesium load, and evaluating the percentage retention in terms of renal function and serum magnesium levels (infra vide).

Serum magnesium levels are normally maintained within a very narrow range, with a coefficient of variation of only 10% to 20% (Alcock et al., 1960; Hanna, 1961b; Prasad et al., 1961; Stewart et al., 1963; Ginn, 1968; Hunt, 1969; Henrotte and Durlach, 1971; Rousselet and Durlach, 1971; Seelig and Berger, 1974), unless there is a profound deficiency, or magnesium load in the face of renal failure. Thus, the serum or plasma magnesium level is not a reliable index of magnesium deficiency (Walser, 1967; Gitelman and Welt, 1969; Henrotte and Durlach 1971; Rousselet and Durlach, 1971). To make matters worse, there are many sources of error even in the most reliable technic available, atomic absorption spectrophotometry (Table A-1). Thus, each laboratory should establish its own mean and narrow range of normal values (Hunt, 1969; Seelig and Berger, 1974). Not acceptable as "within normal limits" are values that fall between 1.5 and 2.5 mEq/liter, a wide range obtained from data reported from many laboratories, and that has been designated as the normal "reference" range (Unsigned, N Engl J M 1974) (Table A-2A) and (Table A-2B).

Rarely are efforts made to differentiate among ionized, complexed, or protein-bound fractions of serum magnesium, since expensive equipment is required for measurement of the protein-bound and diffusible fractions (Silverman et al. 1954; Prasad et al. 1961; Walser, 1967; S. P. Nielsen, 1969; Cummings et al., 1968; Voskian et al., 1973). There are no readily available means of measuring ionized magnesium. Because many factors influence the degree of binding, complexing, or chelating of magnesium, the total content of magnesium in the serum is not simply related to the availability of magnesium, either extra- or intracellularly. For example, experimental dietary magnesium deficiency has caused an increase in the protein-bound fraction (Hoobler et al.., 1937; Morris and O'Dell, 1969) or decreased total and ultrafiltrable fraction (Woodward and Reed, 1969). Clinical magnesium deficiency of intestinal malabsorption (Silverman and Gardner, 1954) and of hepatic cirrhosis (Prasad et al., 1961) is associated with decreased protein-bound magnesium, and increased ultrafiltrable fraction. Possibly, the thyroid hormone affects the degree of protein-binding of magnesium (Soffer et al., 1941; Dine and Lavietes, 1942; Silverman et al., 1954; Prasad et al., 1961), but there is no accord as to the degree or the mechanism. The level of plasma citrate, which complexes part of the ultrafiltrable fraction of magnesium, is influenced by growth hormone (Hanna et al., 1961), adrenocorticosteroid hormone (Walser et al., 1963), estrogen (N. F. Goldsmith et al., 1970) and vitamin D (Carlsson and Hollunger, 1954). Not all of the magnesium-complexing or chelating anions in the body are known. Magnesium complexes comprise 14% of the total plasma magnesium: Mg citrate, 4%; magnesium HPO₄ 3%; unidentified complexes, 6% (Walser, 1961).

Furthermore, even the way the blood is drawn can affect the serum or plasma magnesium values. Levels are lower in serum from blood obtained quickly after applying the tourniquet than after prolonged venous stasis (Whang and Wagner, 1964, 1966; S. P. Nielsen, 1969). This may be referable to the egress of cellular magnesium in hypoxic states (Engel and Elin, 1970; Hochrein, 1966; Hochrein et al., 1967). In addition, dehydration or acidosis can yield spuriously high serum magnesium levels.

Until it is feasible to demonstrate cellular magnesium deficiency in a tissue that has metabolic characteristics and magnesium exchangeability, similar to that of the metabolically active tissues, conclusions as to the importance of magnesium in physiologic processes will remain open to dispute. Enzymatic studies of magnesium-dependent enzyme systems are important in providing clues as to the effects of suboptimal magnesium concentrations in the body, cells, and cell-fractions (Reviews: Wacker and Vallee, 1964; Walser, 1967; Wacker and Parisi, 1968; Heaton, 1978). Direct determinations of cellular magnesium levels, however, are necessary for clinical evaluation of the changing magnesium status of individuals under the influence of diseases and treatment regimens that alter magnesium retention.

Tissue magnesium levels have most frequently been estimated on the basis of analysis of erythrocytes for magnesium. Despite investigations for over 40 years, erythrocyte magnesium levels have not proven a reliable source of information as to the clinical magnesium status. Analyses of findings from over 20 studies indicate that the means of RBC-Mg are between 1.9-3.1 mmol/liter (1.8-6.2 mEq/liter) (Review: Henrotte and Durlach, 1971). The ranges, given as normal in individual studies, are often even wider (Table A-3). Such broad "normal" ranges make it difficult to detect significant changes in abnormal conditions.

Many procedures have been utilized in the effort to minimize sources of error, and to obtain uniformity of results. The first controlled study (Greenberg et al., 1933) showed that direct measurement of the magnesium content of saline-washed erythrocytes, and indirect measurement (subtracting plasma magnesium from whole blood magnesium, and correcting for differences in hematocrits) yielded comparable results. Washing erythrocytes with isotonic saline (Greenberg et al., 1933) or with buffer (Valberg et al., 1965) did not cause loss of cellular magnesium. Attempts to improve validity of magnesium analysis of packed erythrocytes have included: (1) correction for trapped plasma and for differences in hemoglobin (Valberg et al., 1965; S. Hellerstein et al., 1970); (2) use of cation-exchange resins to remove all Mg from cell fragments and hemolystates (Hunt and Manery, 1970; Frazer et al., 1972), (3) rapid separation cells and protein precipitates to prevent elution of magnesium into the hemolysate (Stephan and Speich, 1972; Welin and Speich, 1973); (4) saponification of unwashed erythrocytes without deproteinization (Rousselet and Durlach, 1971); (5) measurement of magnesium in washed and ashed cells, in terms of mg/g cells (Paschen et al., 1971), and (6) of weight per cell count (Valberg 1965; Rosner and Gorfein, 1968).

Except for those who measure magnesium in ashed erythrocytes, and those using cation exchange resin on cell ghosts and hemolysates (Hunt and Manery, 1970; Paschen et al., 1971), the levels are determined in hemolysates, the cell ghosts being discarded with the rest of the precipitated protein. Most of the erythrocyte magnesium is in the hemoglobin, in association with the organic phosphates and enzymes, and is released when the cells are disrupted (Rose, 1968; Bunn et al., 1971). A portion of the erythrocyte magnesium, however, is bound to the membranes (Carvalho et al., 1963), and remains even after repeated washing (Fujii et al., 1973; Sato and Fujii, 1974). Although only 2-6% of the total erythrocyte magnesium is present in the membranes, which are separated from washed erythrocytes (Fujii et al., 1973), the hemolysis procedure may provide a source of error, particularly if the disrupted cell membranes remain in contact with the hemolysate for different lengths of time. Divalent cations (Mg²⁺, Ca²⁺ in the suspending medium are readily bound to the disrupted membranes, both internal and external surfaces of which are exposed to the medium (Sato and Fujii, 1974). Large and variable amounts of the cations are taken up by the stroma.

The significantly higher magnesium levels in reticulocytes and young erythrocytes than in old erythrocytes (Henriques and Orskov, 1939; Bang and Orskov, 1939; Dahl, 1950; Ginsberg et al., 1962; R. Bernstein, 1959) are probably responsible for the major discrepancies in reported normal erythrocyte levels. In experimentally induced reticulocytosis, the erythrocyte magnesium was 28.4 mEq/liter (in rabbits with 85% reticulocytes), in contrast to 7.8 mEq/liter in control rabbit erythrocyte (Ginsberg et al., 1962). Patients with high reticulocyte counts have higher erythrocyte magnesium levels than do those with low reticulocyte counts (Dahl, 1950; Ginsberg et al.1962: R. Bernstein, 1959). For example, a patient with 89.7% reticulocytes had RBC Mg of 4.0-4.7 mEq/liter (Ginsberg et al., 1962). Because reticulocytes and young erythrocytes remain at the top of the centrifuged column of red cells, and the older erythrocytes sediment to the bottom (Keitel, 1955; R. Bernstein, 1959; Ginsberg et al.1962), when erythrocytes are analyzed for magnesium, either the entire column should be studied (S. Hellerstein et al., 1960) to minimize the risk of obtaining aliquots from different levels, or only the lowest level, where the old erythrocytes are found, should be analyzed (Ross et al.1976/1980).

It is possible that marginal abnormalities in magnesium levels might be masked by procedures that measure only the hemolysate magnesium, even when the membranes are immediately separated from the hemolysate. In a study of RBC magnesium of anemic children (S. Hellerstein et al., 1970), their erythrocytes had significantly higher-than-control magnesium, in terms of Mg/cell solids, but not in terms of Mg of cells or of cell water. In a study of erythrocytes from convalescent cardiac patients (Borun, 1963) the older erythrocytes (from the botton of the centrifuged column of cells) had higher magnesium levels than did the young erythrocytes, in terms of Mg/L cell water, but not by dry weight. Whether use of agents that cause magnesium loss contribute to decreased magnesium levels in reticulocytes formed [e.g., during magnesium loss of active treatment of congestive heart failure (Wacker and Vallee, 1958; Seller et al., 1966; Wacker and Parisi, 1968; Seelig, 1972; Lim and Jacob, 1972b)] seems plausible. There is direct evidence that erythrocyte-magnesium levels are significantly below normal in patients with congestive heart failure (Seller et al., 1966; Lim and Jacob, 1972b).

The erythrocyte membrane instability (and tendency toward hemolysis) that is found in magnesium deficiency (Larvor et al., 1965; Erlandson and Wehman, 1966; LaCelle and Weed, 1969; Cohlan et al., 1970; Oken et al., 1971; Battifora, 1971; Elin et al. l971b; Elin, 1973; Piomelli et al., 1973; Elin, 1976/1980) may provide another source of error when erythrocyte magnesium is obtained by analysis of the hemolysate. With progressive magnesium deficiency, associated with low intra- and extracellular magnesium levels, there is increased fragility of the erythrocytes and shortening of survival time (Elin, 1973). One may speculate that the defective erythrocyte membranes may have defective binding of magnesium, thereby releasing more during laboratory-hemolysis. Whether this might yield spuriously higher erythrocyte magnesium values in hemolysates, thereby masking cellular deficiency, remains to be investigated.

Still another limitation of erythrocyte magnesium is its unreliability, as an index of magnesium status at the time of the analysis. There is poor correlation between plasma and erythrocyte levels (Wallach et al., 1962; Valberg et al.1965; Hellerstein et al., 1970; Ross et al., 1976/1980), although in chronic conditions, such as long-term magnesium deficiency, malnutrition, chronic liver disease, and hypothyroidism, there may be low plasma and erythrocyte magnesium levels. Acute two- to fourfold increases in plasma magnesium (by intravenous infusions) are not accompanied by changes in erythrocyte levels (Wallach et al. 1962). Hemodialysis of hypermagnesemic patients, with magnesium-free or -low dialysates, has had little or no effect on erythrocyte magnesium (Paschen et al., 1971). Under usual circum stances, the red cell membrane permits only slow diffusion of magnesium (Wallach et al. 1962; Ginsberg et al. 1962). This is reflected by the very slow uptake of ²⁸Mg by erythrocytes (Zumoff et al. 1958; Care et al. 1959; Aikawa et al. 1960c; Rogers, 1961; Ginsberg et al. 1962; Aikawa, 1965; Hilmy and Somjen, 1968).

It has long been recognized that erythrocyte magnesium levels do not fall as quickly or as much as does plasma magnesium in acute magnesium deficiency (Tufts and Greenberg, 1937). However, lesser degrees of magnesium deficiency, if prolonged, can cause profound drops in erythrocyte magnesium, to half control values (Elin et al., 1971a,b). Most data indicate that erythrocyte magnesium levels reflect: (1) the magnesium status at the time of erythropoiesis (Tufts and Greenberg, 1937; MacIntyre et al. 1961; Dunn and Walser, 1966; Walser, 1967; Hellerstein et al., 1970; Elin et al. 1971a,b) and the age of the red cells (Henriques and Orskov, 1939; Bang and Orskov, 1939; Dahl, 1950; Bernstein, 1959; Ginsberg et al., 1962). Thus, the erythrocyte magnesium level is dependent, more on the age mix of the cells in the sample studied, than on the magnesium status at the time it is taken.

Analyses of skeletal muscle biopsies has been recommended as a more useful clinical index of intracellular magnesium than erythrocyte or plasma magnesium (MacIntyre et al, 1961; Dunn and Walser, 1966; Seller et al. 1966; Walser, 1967; Lim et al., 1969a,b; Drenick et al., 1969; Lim and Jacob, 1972a,b). The values for normal human skeletal muscle magnesium are similar to those for normal myocardium (Lim et al., 1969b; Bertrand, 1967; Tipton and Cook, 1963). (For tabulation of data from cattle, horses, pigs, dogs, and rodents, see Walser, 1967.) However, the muscle magnesium levels in experimental animal and human magnesium deficiencies and in clinical magnesium deficiency do not always indicate loss of magnesium. In many studies of acute magnesium deficiency, muscle levels remained essentially unchanged, or decreased only slightly (Cunningham, 1936a; Watchorn and McCance, 1937; Cotlove et al., 1951; Blaxter and Brook, 1954; Morris and O'Dell, 1961, Ko et al. 1962; Welt, 1964; Dunn and Walser, 1966; Bradbury et al. 1968; Woodward and Reed, 1969; Elin et al. 1971).

Because skeletal and cardiac muscle are structurally more comparable than the myocardium is to other tissues, and the magnesium levels in the two tissues are similar (Tipton and Cook, 1963; Wallach et al., 1966a,b, 1967; Lazzara et al., 1963; Walser, 1967), muscle biopsies would seem to provide a useful index of myocardial magnesium levels. However, the exchangeability of skeletal muscle magnesium is much slower than is that of more metabolically active tissues, such as the heart, kidneys, and liver (Aikawa, 1963; Gilbert, 1960; Review: Walser, 1967) (Table A-4). Furthermore, young animals show lower levels of muscle magnesium more rapidly when magnesium deficient than do older animals (Tufts and Greenberg 1937b; Cotlove et al. 1951; MacIntyre and Davidsson, 1958; Morris and O'Dell, 1961; Smith et al., 1962) and greater losses are seen in chronic than in acute deficiencies (MacIntyre et al. 1961; Montgomery 1960, 1961a; Booth et al. 1963; Whang and Welt, 1963). It is possible that the failure of skeletal muscle magnesium to show a significant response to acute deficiency might reflect a high percentage of tightly bound magnesium in skeletal magnesium (Elin et al., 1971)

Since cardiovascular and renal tissues are vulnerable to damage caused by acute and chronic magnesium deficiencies, it is important to select a tissue for analysis that is more likely than are plasma, red cells, or muscle to reflect the magnesium status of those organs.

It seems likely that leukocytes, which are the most readily available nucleated, metabolically active cells, should provide a more reliable index of magnesium levels of such tissues as the heart and kidneys than the serum, erythrocytes, or skeletal muscle. Lymph nodes and spleen, for example, have magnesium exchangeability, in terms of speed of uptake of the isotope and the concentration attained by 24hours, closest to that of heart, kidneys, and liver. We are attempting to develop a procedure for isolating white blood cells, by a means that does not traumatize the membranes, and that will be adaptable to laboratories lacking sophisticated equipment (Ross et al. 1976/1980). In our first venture, we analyzed the total white cell isolate, using a modification of the Boyum (1968) procedure (dextran/hypaque sedimentation), without attempting to separate the small and large mononuclear cells from the polymorphonuclear cells. We have now simplified, somewhat, a time-consuming, cumbersome procedure that has the intrinsic defect of analyzing mixed cells, and are studying lymphocyte magnesium levels (Ross, Seelig, and Berger, in preparation). A similar method has been used by M. P. Ryan and his colleagues in monitoring lymphocyte magnesium levels in patients with congestive heart failure (Counihan et al. 1978a,b). Since there is no standard procedure, nor standard values for white blood cell magnesium, listing our values would be premature until considerably more data have been accrued.

The most practical means of evaluating the magnesium status relatively quickly, and with facilities that are readily available, is the determination of 24-hour urinary magnesium output before and after a magnesium load. (We have already discussed possible risk of magnesium loading in the presence of hypercalcemia. Renal failure also militates against a test that might result in marked hypermagnesemia.)

Fitzgerald and Fourman (1956) found that two volunteers, who retained almost none of injected magnesium, as the sulfate, during a control period of adequate magnesium intake, retained 25% and 42% of parenterally administered magnesium (49 and 82 mEq over 2 and 3 days, respectively). Patients whose chronic magnesium deficiency secondary to steatorrhea might have been missed on the basis of their serum magnesium levels (which were 1.39, 1.67, 1.69, and 1.75 mEq/liter), retained 37% to 79% the first 24 hours after receiving 84 mEq of magnesium, given as magnesium sulfate or chloride infusions (Fourman and Morgan, 1962). Thoren (1963) then confirmed earlier observations that normal subjects excrete at least 80-85% of parenterally (i.v. or i.m.) administered magnesium within 24 hours, and found that many of his surgical patients retained considerably more. He concluded that patients who retain more than 20-25% of magnesium (e.g., 20 mEq in two divided doses) are probably repleting a deficit. He commented, however, that patients with magnesium deficiency due to renal magnesium loss, might not be detected by this test. Jones and Fourman (1966) extended the studies of percentage retention of parenteral magnesium infusions (84 mEq) to patients with hypoparathyroidism and found that all seven retained more than 50%, three retaining about 80%.

Application of the magnesium-loading test for proof of suspected magnesium deficiency in infancy was first reported in England (Wilkinson and Harris, 1969; Harris and Wilkinson, 1971). These investigators, who had found magnesium therapy useful over a ten-year period, in the treatment of infants in poor condition because of persistent diarrhea, other causes of loss of gastrointestinal fluids, or who were unresponsive to calcium or other therapy, reported that they were able to prove magnesium depletion in 20 of 29 cases in which the magnesium-loading dose (0.5 mEq/kg) was used, 40% or more of the dose being retained. They administered between 0.24 to 5.71 mEq Mg by mouth in 4, by gastrostomy or nasogastric tube in 2, intramuscularly in 1, and intravenously in 22. Among 9 whose serum magnesium had been measured, it was above the normal range of 1.4 to 1.9 mEq/liter in 2, one of whom retained over half of the test done. The serum magnesium was normal in 4 patients, 3 of whom were magnesium deficient. All 3 with hypomagnesemia retained over 70% of the test dose. Caddell et al. (1973b) and Caddell and Olson (1973) similarly found that the lowest magnesium plasma levels (in 40 babies with kwashiorkor or marasmus or both) were correlated with the highest magnesium retentions, and that some with normal plasma magnesium levels had high retentions. These investigators did not find low preload magnesium urinary excretion to be a helpful guide; 7 of 25 who excreted less than 1 mEq of magnesium per 24 hours retained a mean of on 23.3% of the magnesium load and clinical magnesium deficiency was not diagnosed. Caddell (1975) and her colleagues (Caddell and Olson, 1973; Caddell et al. 1973b, 1975a; Byrne and Caddell, 1975) have evaluated magnesium-load test in neonatal, normal, and low-birth-weight infants and infants during the first few months of life, and designed a shorter test (infra vide), as well as using this test to evaluate the magnesium status postpartum (Caddell et al. 1973a, 1975b). In the magnesium-loading studies of postpartum women, Caddell et al, (1973, 1976) found that among Thai women with ample magnesium intakes, the postpartum women retained more magnesium than did nulliparous young women, but not nearly as much as did many of the American women (particularly young multiparous women) However, except for women with plasma magnesium levels below 1.2 mEq/liter, the amount of magnesium retained was not reflected by the plasma levels.

Although, ideally, it is desirable to obtain a 24-hour urine sample for base-line magnesium levels (and for creatinine output to permit evaluation of renal function before and after the magnesium load), the clinical status may be too precarious to permit so long a delay before instituting magnesium therapy when there are signs suggesting its depletion. In that event, a single pretreatment urine and blood sample for magnesium and creatinine levels must suffice, and the 24-hour posttreatment urine collected for analysis. Those, whose test is part of a diagnostic procedure, should have magnesium laxatives and antacid withheld for 48 hours before the pretreatment collection and during the test. If medically acceptable, withhold strong magnesium-wasting diuretics, such as furosemide or ethacrynic acid, or substitute a thiazide diuretic for the duration of the test.

After collecting urine for 24 hours and taking a blood sample for magnesium and creatinine levels, 2 ml of 50% MgSO₄ (100 mg of magnesium) should be injected deep into each buttock. Collect the next 24-hour urine, and draw blood at the end of the collection period for magnesium and creatinine analysis. It is often of value to have the specimens analyzed for additional electrolytes, such as calcium, sodium, potassium, and phosphorus. Subtract the amount of magnesium in the preload 24-hour urine from that in the postload 24-hour urine and calculate the percentage of the load that was retained.

The procedure is as above, except that the magnesium load (0.4 to 0.5 mEq/kg, as magnesium sulfate or magnesium chloride, diluted in 100 cc 6% dextrose in water or 0.9% saline) is given over a 45-minute period.

The procedure is as for adults, with the time for delivery extended to 1-1 1/2 hours. Harris and Wilkinson (1971) caution that no talcum powder should be used during collection periods, and that the collecting vessel (i.e., plastic bag) should be rinsed at least six times with de-ionized water.

Caddell et al, (1975) and her co-workers (Byrne and Caddell, 1975; Caddell et al., 1975a) have modified the test to allow for shorter collection periods for infants up to 6 months of age. Preload plasma cations and 8-hour urinary levels of magnesium, calcium, potassium, sodium, and creatinine are determined. An intramuscular injection of 50% sulfate (0.12 ml/kg, equivalent to 0.49 mEq/kg of body weight) is given to infants whose plasma magnesium levels do not exceed 2.0 mEq/liter, who are well hydrated, and who have good renal function. Caddell cautions that although even premature neonates can excrete an excessive magnesium load (as has been shown by the rapid drops of serum magnesium levels in symptomatic hypermagnesemic infants born to eclamptic mothers given high doses of magnesium within 24 hours of delivery) (Brady and Williams, 1967; Soka et al., 1972), neonatal infants have immature renal function (Rubin et al. 1949; Wilkinson, 1973). Thus, the risk of producing hypermagnesemia and of reciprocally increasing urinary calcium excretion must be kept in mind. Caddell (1975) has observed that most of the magnesium load was usually excreted during the first 8 hours postload, although in a few instances neonatals excreted more magnesium in the second 8-hour period. The 24-hour reading usually provided a reliable reading of the amount retained. Infants who retained more magnesium had lower plasma levels of magnesium than did those who retained less. For example, full-term infants who retained 80% of the load had preload plasma magnesium levels of 1.50 mEq/liter; the prematures with plasma magnesium levels averaging 1.59 mEq/liter retained 85.67 ± 2.2 of the load. Those with preload plasma levels of 1.77 and 1.90 mEq/liter (full term and premature) retained 28.2 ± 3.04 and 21.5 ± 0.89, respectively (Byrne and Caddell, 1975). However, despite the grouped evidence correlating low plasma magnesium levels with high retentions, the authors pointed out that in their series individual instances of magnesium deficiency of infancy would have been infrequently diagnosed on the basis of the plasma values alone. The infants had higher plasma magnesium levels at the end of the load test than at the beginning, an effect attributed to normalization of low initial values and incomplete renal clearance of the load (Caddell, 1975).

Freeman and Pearson (1966) reported a patient with renal magnesium wastage, detected because the amount of (preload) magnesium excreted was inappropriately high in view of her hypomagnesemia, and who exhibited only partial renal conservation of magnesium on moderate reduction of her magnesium intake. They pointed out that a prerequisite for the magnesium-loading test is normal renal mechanisms for conserving magnesium.

Parfitt (1976/1980) has developed a model for assessing the tubular reabsorption of magnesium that plots data for U_MgV/GFR against the plasma magnesium level. He points out that short-term renal conservation of magnesium passively reflects the fall of plasma magnesium levels. Long-term depletion results in active renal magnesium conservation, which might result from an increase in its maximum tubular (Tm) reabsorption. However, in a prolonged magnesium depletion study (Shils, 1969a), no increase in tubular magnesium reabsorption was observed, and a maximum Tm has, in fact, been demonstrated for magnesium (Barker et al., 1959; Averill and Heaton, 1966; Massry et al., 1969). Thus, agents that cause renal magnesium wastage do so by lowering Tm_Mg/GFR transiently or permanently. In the case of the metabolic abnormality that interferes with renal tubular magnesium reabsorption, the Tm_Mg/GFR is abnormally low.

(include the word "jacket" to search only in this book)

| Jacket | Preface | Contents | Introduction (Chapter 1) |
Chapter: | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 |
| Appendix | Bibliography (A-D), (E-K), (L-R), (S-Z) |

*All figures and tables for Appendix*