Hypomagnesemia in Pediatric Heart Transplant Patients Treated with Tacrolimus.

OBJECTIVES: We aimed to investigate the frequency of hypomagnesemia and urinary magnesium excretion in pediatric heart transplant recipients. MATERIALS AND METHODS: In this study, 22 pediatric patients who underwent heart transplanted at a single center between March 2014 and April 2015 and who were treated with oral tacrolimus were analyzed prospectively. Serum magnesium, creatinine, and tacrolimus levels and total amount of urinary magnesium excretion were measured. Serum tacrolimus levels were measured 12 hours after the last dose of tacrolimus. RESULTS: Our patient group included 11 boys (50%) and 11 girls (50%) with a mean age of 16.72 ± 4.78 years. Serum tacrolimus levels were in the therapeutic range, with a mean of 1.48 ± 0.13 ng/mL (range, 1.2-1.69 ng /mL), mean fractional magnesium excretion was 8.59 ± 5.9% (range, 3%-22%), and 24-hour urinary magnesium excretion was 90.2 ± 62.95 mg/d. Hypermagnesuria was assessed in 80% of patients. We found 24-hour urinary magnesium excretion to be higher than normal in 27% of patients. There was no association between serum tacrolimus levels and serum magnesium levels or urinary magnesium excretion. CONCLUSIONS: Serum magnesium levels should be periodically measured in pediatric heart transplant patients treated with tacrolimus.

Data from Controlled Metabolic Ward Studies Provide Guidance for the Determination of Status Indicators and Dietary Requirements for Magnesium.

Determination of whether magnesium (Mg) is a nutrient of public health concern has been hindered by questionable Dietary Recommended Intakes (DRIs) and problematic status indicators that make Mg deficiency assessment formidable. Balance data obtained since 1997 indicate that the EAR and RDA for 70-kg healthy individuals are about 175 and 250 mg/day, respectively, and these DRIs decrease or increase based on body weight. These DRIs are less than those established for the USA and Canada. Urinary excretion data from tightly controlled metabolic unit balance studies indicate that urinary Mg excretion is 40 to 80 mg (1.65 to 3.29 mmol)/day when Mg intakes are <250 mg (10.28 mmol)/day, and 80 to 160 mg (3.29 to 6.58 mmol)/day when intakes are >250 mg (10.28 mmol)/day. However, changing from low to high urinary excretion with an increase in dietary intake occurs within a few days and vice versa. Thus, urinary Mg as a stand-alone status indicator would be most useful for population studies and not useful for individual status assessment. Tightly controlled metabolic unit depletion/repletion experiments indicate that serum Mg concentrations decrease only after a prolonged depletion if an individual has good Mg reserves. These experiments also found that, although individuals had serum Mg concentrations approaching 0.85 mmol/L (2.06 mg/dL), they had physiological changes that respond to Mg supplementation. Thus, metabolic unit findings suggest that individuals with serum Mg concentrations >0.75 mmol/L (1.82 mg/L), or as high as 0.85 mmol/L (2.06 mg/dL), could have a deficit in Mg such that they respond to Mg supplementation, especially if they have a dietary intake history showing <250 mg (10.28 mmol)/day and a urinary excretion of <80 mg (3.29 mmol)/day.

Proton pump inhibitor associated hypomagnasaemia - a cause for concern?

AIMS: In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. METHODS: To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. RESULTS: For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. CONCLUSION: We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually.

Hyperphosphatemia, hypocalcemia and increased serum potassium concentration as distinctive features of early hypomagnesemia in magnesium-deprived mice.

Magnesium-deficient patients show dysfunctional calcium (Ca(2+)) metabolism due to defective parathyroid hormone (PTH) secretion. In mice and rats, long-term magnesium (Mg(2+)) deprivation causes hyperphosphaturia and increases fibroblast growth factor 23 (FGF23) secretion, despite normal serum phosphate (Pi) and Ca(2+). Electrolyte disturbances during early hypomagnesemia may explain the response of mice to long-term Mg(2+) deprivation, but our knowledge of electrolyte homeostasis during this stage is limited. This study compares the effect of both short- and long-term Mg(2+) restriction on the electrolyte balance in mice. Mice were fed control or Mg(2+)-deficient diets for one to three days, one week, or three weeks. Prior to killing the mice, urine was collected over 24 h using metabolic cages. Within 24 h of Mg(2+) deprivation, hypomagnesemia, hypocalcemia and hyperphosphatemia developed, and after three days of Mg(2+) deprivation, serum potassium (K(+)) was increased. These changes were accompanied by a reduction in urinary volume, hyperphosphaturia, hypocalciuria and decreased Mg(2+), sodium (Na(+)) and K(+) excretion. Surprisingly, after one week of Mg(2+) deprivation, serum K(+), Pi and Ca(2+) had normalized, showing that mineral homeostasis is most affected during early hypomagnesemia. Serum Pi and K(+) are known to stimulate secretion of FGF23 and aldosterone, which are usually elevated during Mg(2+) deficiency. Thus, the hyperphosphatemia and increased serum K(+) concentration observed during short-term Mg(2+) deprivation may help our understanding of adaptation to chronic Mg(2+) deficiency.

[The role of hypomagnesiuria in urolithiasis and renal colic: results from a prospective study of a metabolic evaluation protocola]. / Ruolo dell'ipomagnesuria nella colica renale da urolitiasi: risultati di uno studio prospettico sull'impiego di un protocollo di valutazione metabolica.

AIM: The stone disease of the urinary tract (urolithiasis) is a growing disease. The identification of metabolic disorders, treatable with prophylactic therapy, appears to be clinically important. The aim of this study was the analysis of metabolic disorders that promote and support the urolithiasis in a cohort of patients with renal colic at an Emergency Department. METHODS: In this prospective case series, we enrolled consecutive patients with renal colic treated at an Emergency Department within a Regional Teaching Hospital. We implemented a structured metabolic evaluation, which included blood chemistry studies, stone analysis and a 24-hour urine collection. We then evaluated the frequency of metabolic abnormalities alone or in combination. RESULTS: We enrolled 39 patients whit renal colic and a diagnosis of urolithiasis: 21 (54%) were males and the median age was 43.6 years (range 20-70). The most frequently observed type of stone was that of calcium oxalate (74%). Hypomagnesiuria was the most common metabolic abnormality found at the 24-hour urine collection (22/39, 56%), followed by hypocalciuria (31%), hypernatruria (20%), hyperuricuria (18%) and hyperoxaluria (15%). Among the associations of metabolic abnormalities, the hypocalciuria /hypomagnesuria was that observed with higher frequency (23%). CONCLUSION: We report an incidence of hypomagnesiuria (60%) in patients with renal colic higher than has ever been described in the literature. This result could be of importance in the knowledge of the pathogenesis of the urolithiasis and could have interesting implications in clinical practice.

[The functional tests in clinical diagnostic laboratory: the detection of magnesium deficiency in the loading test].

The article deals with the value and role of functional tests in practice of clinical diagnostic laboratories. The possibilities of evaluation of biological function of homeostasis according the changes of magnesium ions or calcium concentration in urine or blood hence reflecting the deficiency of these ions in vivo. The magnesium tolerant test is described It is demonstrated that it can be applied both in curative preventive institutions and ambulatories. In the examined group of patients, 78% had physiologic parameters of magnesium concentration, 17% suffered from hypermagnesiumuria and 5%--from hypermagnesiumuria. The magnesium deficiency of different degree was detected in 87% of patients. In the most part of patients with magnesium deficiency normomagnesiumuria was detected. Only in one case with normomagnesiumuria the magnesium deficiency was absent. In 30% of patients with magnesium deficiency the concentration of cation in day urine decreased up to 2.2 times after load dose. In absence of deficiency the monotony of cation's excretion was noted. Under the magnesium deficiency the character of process changed but velocity of excretion of magnesium after load probe slightly decreased relative to values before the load. The impact of alcohol under established magnesium deficiency results in increasing of velocity of excretion of this analyte. In patient with diabetes mellitus type II six months before the diagnosis of this disease the hidden deficiency of magnesium was detected. The magnesium deficiency was not detected after the antidiabetic treatment was applied The results permit to postulate the possibility of application oral load test with magnesium to assess the impact of various stress, physical, emotional and psychological factors. The detection of magnesium deficiency permit to broad the complex treatment, to accelerate and to enhance the results of treatment of diseases. Besides, the evaluation of patient's condition according the reaction of the organism to the probe with magnesium load is an essential element of personalized medicine.

[Unexplained chronic hypokalaemia in a young woman]. / Unklare chronische Hypokaliämie bei einer jungen Frau.

HISTORY AND CLINICAL FINDINGS: The 27 year old female patient presented with chronic hypokalaemia known for 6 years and current potassium values of 1.8 mmol/l. She reported having diarrhea for a few days, fever was denied. INVESTIGATIONS: Physical examination revealed dry skin and mucosa and a slim nutritional status, laboratory investigations showed a hypokalaemic, hypochloraemic alkalosis and hypomagnesaemia. Our first suspicion was an eating disorder or abuse of diuretics or laxatives. Urine analysis showed a high concentration of potassium and chloride, a screening for diuretics was negative. Due to the electrolyte constellation we assumed a Gitelman's Syndrome which was confirmed by genetic testing. TREATMENT AND COURSE: After intravenous substitution of potassium and cessation of diarrhea the potassium values stabilised at 2.5 - 3.0 mmol/l. After being discharged she continued oral substitution of potassium and no such period of severe hypokalaemia occurred again. CONCLUSION: Establishing a diagnosis for patients with chronic hypokalaemia may present difficulties. Urine analysis can help to find reasons for electrolyte disorders. Via measurement of urinary chloride concentration repetitious vomiting as stigmatising diagnosis could be excluded. Urine analysis also led to the diagnosis Gitelman syndrome, an inherited renal tubular disorder, which is suspected to count for 50 % of unexplained chronic hypokalemia.

Hipomagnesemias de origen genético / Hypomagnesemias of genetic origin

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Magnesium loss in magnesium deficient subjects with and without physical exercise during prolonged hypokinesia.

OBJECTIVE: To show the effect of hypokinesia (HK; diminished movement) on magnesium (Mg2+) loss in Mg2+ deficient subjects and the effect of physical exercise and on Mg2+ deficiency with and without physical exercise: Mg2+ balance, serum Mg2+ concentration and Mg2+ loss were measured. METHODS: Studies were conducted on 30 healthy male volunteers during a pre-experimental period of 30 days and an experimental period of 364 days. They were divided equally into three-groups: unrestricted active control subjects (UACS), continuous hypokinetic subjects (CHKS) and periodic hypokinetic subjects (PHKS). The UACS group ran average distances of 9.3 +/- 1.2 km.day-l; the CHKS group walked average distances of 0.9 +/- 0.2 km.day-l; and the PHKS group walked and ran average distances of 0.9 +/- 0.2 km and 9.3 +/- 1.2 km.day-l for 5-and 2-days per week, respectively. RESULTS: Mg2+ deficiency, serum Mg2+ level, fecal and urine Mg2+ loss increased (P < 0.05), in the PHKS and CHKS groups compared with their pre-experimental values and the values in the UACS group. However, serum Mg2+ concentration, urine and fecal Mg2+ loss and Mg2+ deficiency increased more (P < 0.05) in the PHKS group than in the CHKS group. CONCLUSIONS: Mg2+ deficiency is more evident with than without physical exercise and Mg2+ loss is exacerbated more with higher than lower Mg2+ deficiency. This indicates that Mg2+ deficiency with and without physical exercise and Mg2+ loss with higher and lower Mg2+ deficiency is due to inability of the body to use Mg2+ and more so when physically healthy subjects are submitted to prolonged periodic than continuous hypokinesia.

A case of magnesium deficiency associated with insufficient parathyroid hormone action and severe osteoporosis.

The relationship between osteoporosis and magnesium (Mg) deficiency is still controversial. Here we report a case of an 82-year-old woman with a giant adenomatous goiter and severe osteoporosis with multiple vertebral fractures, whose clinical course indicated that her osteoporosis was probably due to Mg deficiency. She visited our hospital for treatments of tetany. Laboratory data showed the existence of hypomagnesemia, hypocalcemia, hypokalemia, vitamin D deficiency, and slightly elevated intact PTH. Intravenous administration of Mg not only improved these electrolyte abnormalities but also increased serum levels of intact PTH, bone formation markers, 1,25-dihydroxyvitamin D, as well as bone resorption markers in the urine, and lowered urinary phosphate reabsorption. Hypomagnesemia on admission seemed to arise from long-lasting poor food intake and malnutrition, because it improved after the disappearance of dysphagia with a goiter resection. After the operation, BMD values at the lumbar spine and femoral neck obviously increased during 6 months of Mg supplementation without any specific therapies for osteoporosis. Mg deficiency in this case seemed to cause impaired secretion of PTH from the parathyroid and the refractoriness of bone and kidney to the hormone, which led to the suppression of both bone remodeling and renal vitamin D production. These processes were probably linked to her severe osteoporosis, which was reversed by Mg supplementation.

Acid-base status affects renal magnesium losses in healthy, elderly persons.

Magnesium and calcium deficiency in humans is related to a number of pathological phenomena such as arrhythmia, osteoporosis, migraine, and fatal myocardial infarction. Clinically established metabolic acidosis induces renal losses of calcium. In normal subjects, even moderate increases in net endogenous acid production (NEAP) impair renal calcium reabsorption but no information is available whether this also influences renal magnesium handling. The aim of the study was to examine the relation between NEAP and renal magnesium excretion in healthy, free-living, elderly subjects. The subjects (age 64 +/- 4.7 y, n = 85) were randomly selected from the population register in Gothenburg (Sweden). Magnesium, calcium, and potassium were measured in 24-h urine samples and NEAP was quantified as renal net acid excretion (NAE). NAE was positively correlated with excretions of magnesium (R(2) = 0.27, P < 0.0001) and calcium (R(2) = 0.30, P < 0.0001) but not potassium. When 24-h urinary magnesium excretion was adjusted for 24-h urinary potassium excretion, a biomarker for dietary potassium intake, the association between magnesium excretion and NAE remained significant (R(2) = 0.21, P < 0.0001). The significant association between potassium-adjusted magnesiuria and NAE suggests that the acid-base status affects renal magnesium losses, irrespectively of magnesium intake. Magnesium deficiency could thus, apart from an insufficient intake, partly be caused by the acid load in the body.

A mild magnesium deprivation affects calcium excretion but not bone strength and shape, including changes induced by nickel deprivation, in the rat.

An experiment was performed to determine the effect of a mild magnesium deprivation on calcium metabolism and bone composition, shape, and strength in rats, and whether nickel deprivation exacerbated or alleviated any changes caused by the magnesium deprivation. Weanling male rats were assigned to groups of 10 in a factorial arrangement, with variables being supplemental nickel at 0 and 1 mg/kg and magnesium at 250 and 500 mg/kg of diet. The basal diet contained about 30 ng Ni/g. Urine was collected for 24 h during wk 8 and 12, and rats were euthanized 13 wk after dietary treatments began. Mild magnesium deprivation decreased the urinary excretion of calcium and increased the tibia concentration of calcium but did not affect femur shape or strength (measured by a three-point bending test). Dietary nickel did not alter these effects of magnesium deficiency. Nickel deprivation increased the urinary excretion of phosphorus and the femur strength variables maximum force and moment of inertia. Strength differences might have been the result of changes in bone shape. Magnesium deprivation did not alter the effects of nickel deprivation on bone. The findings indicate that a mild magnesium deficiency affects calcium metabolism but that this does not markedly affect bone strength or shape, and these effects are not modified by dietary nickel. Also, nickel deprivation affects phosphorus metabolism and bone strength and shape; these effects apparently are not caused by changes in magnesium metabolism or utilization.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail.

Mutations in the gene for Claudin-16 (CLDN16) are linked to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a renal Mg2+ and Ca2+ wasting disorder that leads to progressive kidney failure. More than 20 mutations have been identified in CLDN16, which, with a single exception, affect one of two extracellular loops or one of four transmembrane domains of the encoded protein. Here, we describe a novel missense mutation, Cldn16 L203X, which deletes the entire C-terminal cytosolic domain of the protein. Surface expression of Cldn16 L203X is strongly reduced and the protein is instead found in the endoplasmic reticulum (ER) and lysosomes. ER-retained Cldn16 L203X is subject to proteasomal degradation. Cldn16 L203X present in lysosomes reaches this compartment following transport to the plasma membrane and endocytosis. Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X. Thus, endocytosis inhibitors may provide a novel therapeutic approach for FHHNC patients carrying particular Cldn16 mutations.

Urinary excretion of an intravenous 26Mg dose as an indicator of marginal magnesium deficiency in adults.

BACKGROUND: Measurement of magnesium (Mg) status is problematic because tissue Mg deficiency can be present without low serum Mg concentrations. OBJECTIVE: To evaluate a modified version of the Mg retention test using stable isotopes for the assessment of Mg status in general, and the detection of marginal Mg deficiency in particular. DESIGN: A modified version of the Mg retention test using a small dose of (26)Mg was evaluated for assessment of Mg status in 22 healthy subjects. Muscle Mg concentration was used as reference for Mg status. A muscle biopsy was taken from the lateral portion of the quadriceps muscle from each subject. After 2 to 4 weeks, 11 mg of (26)Mg (as MgCl(2) in 14 ml water) were injected i.v. over a period of 10 min and all urine was collected for the following 24 h. Excretion of the isotopic label was expressed as percentage of the administered dose excreted in urine within 24 h. RESULTS: Mean +/- s.d. Mg concentration in muscle was 3.85 +/- 0.17 mmol/100 g fat-free dried solids. Mean +/- s.d. excretion of the injected dose within 24 h was 7.9 +/- 2.1%. No correlation was found between muscle Mg concentration and excretion of the isotopic label (r (2 ) = 0.061, P = 0.27). CONCLUSIONS: In this study, urinary excretion of an intravenous Mg tracer was not influenced by muscle Mg concentration and its usefulness for the detection of marginal Mg deficiency could therefore not be demonstrated. SPONSORSHIP: Swiss Foundation for Nutrition Research and Swiss Federal Institute of Technology, Zurich, Switzerland.