Improving diagnosis and treatment of hypomagnesemia.

Magnesium is one of the most abundant cations in the body and acts as a cofactor in more than 600 biochemical reactions. Hypomagnesemia is a highly prevalent condition, especially in subjects with comorbid conditions, but has received less attention than other electrolyte disturbances. This review will discuss magnesium physiology, absorption, storage, distribution across the body, and kidney excretion. After reviewing the regulation of magnesium homeostasis, we will focus on the etiology and clinical presentation of hypomagnesemia. The role of laboratory medicine in hypomagnesemia will be the main purpose of this review, and we will discuss the laboratory tests and different samples and methods for its measurement. Although free magnesium is physiologically active, total serum magnesium is the most commonly used measurement in laboratory medicine and is apt for clinical purposes; however, it is not appropriately used, and many patients with hypomagnesemia remain undiagnosed and not treated. Using information technologies, laboratory medicine can largely improve the diagnosis and treatment of hypomagnesemia through the design and establishment of automatic demand management and result management interventions by acting in the first and last steps of the laboratory cycle, test requests, and actions taken after test results, to unmask patients with hypomagnesemia and improve the number of patients undergoing treatment.

Chronic magnesium deficiency causes reversible mitochondrial permeability transition pore opening and impairs hypoxia tolerance in the rat heart.

Chronic magnesium (Mg) deficiency induces and exacerbates various cardiovascular diseases. We previously investigated the mechanisms underlying decline in cardiac function caused by chronic Mg deficiency and the effectiveness of Mg supplementation on this decline using the Langendorff-perfused isolated mouse heart model. Herein, we used the Langendorff-perfused isolated rat heart model to demonstrate the chronic Mg-deficient rats (Mg-deficient group) had lower the heart rate (HR) and left ventricular pressure (LVDP) than rats with normal Mg levels (normal group). Furthermore, decline in cardiac function due to hypoxia/reoxygenation injury was significantly greater in the Mg-deficient group than in the normal group. Experiments on mitochondrial permeability transition pore (mPTP) using isolated mitochondria revealed that mitochondrial membrane was fragile in the Mg-deficient group, implying that cardiac function decline through hypoxia/reoxygenation injury is associated with mitochondrial function. Mg supplementation for chronic Mg-deficient rats not only improved hypomagnesemia but also almost completely restored cardiac and mitochondrial functions. Therefore, proactive Mg supplementation in pathological conditions induced by Mg deficiency or for those at risk of developing hypomagnesemia may suppress the development and exacerbation of certain disease states.

Dietary Magnesium Alleviates Experimental Murine Colitis through Modulation of Gut Microbiota.

Nutritional deficiencies are common in inflammatory bowel diseases (IBD). In patients, magnesium (Mg) deficiency is associated with disease severity, while in murine models, dietary Mg supplementation contributes to restoring mucosal function. Since Mg availability modulates key bacterial functions, including growth and virulence, we investigated whether the beneficial effects of Mg supplementation during colitis might be mediated by gut microbiota. The effects of dietary Mg modulation were assessed in a murine model of dextran sodium sulfate (DSS)-induced colitis by monitoring magnesemia, weight, and fecal consistency. Gut microbiota were analyzed by 16S-rRNA based profiling on fecal samples. Mg supplementation improved microbiota richness in colitic mice, increased abundance of Bifidobacterium and reduced Enterobacteriaceae. KEEG pathway analysis predicted an increase in biosynthetic metabolism, DNA repair and translation pathways during Mg supplementation and in the presence of colitis, while low Mg conditions favored catabolic processes. Thus, dietary Mg supplementation increases bacteria involved in intestinal health and metabolic homeostasis, and reduces bacteria involved in inflammation and associated with human diseases, such as IBD. These findings suggest that Mg supplementation may be a safe and cost-effective strategy to ameliorate disease symptoms and restore a beneficial intestinal flora in IBD patients.

Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome.

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.

Automatic laboratory interventions to unmask and treat hypomagnesemia in the Emergency Department.

INTRODUCTION: The significance of hypomagnesemia and the need for treatment are under-recognized in clinical practice. Our objective was to design, establish, and test two interventions to screen for patients with hypomagnesemia and increase the rate of treatment of hypomagnesemia in the Emergency Department (ED). MATERIAL AND METHODS: A prospective two-year study was conducted. The Laboratory Information System was set to automatically order plasma magnesium in ED patients with plasma calcium < 7.5 mg/dL (1.9 mmol/L) and/or plasma potassium < 2.5 mEq/L (2.5 mmol/L). We counted the number of identified cases of hypomagnesemia, and calculated the total economic cost per identified patient. The study had three periods "Central lab" "Stat lab" and "Stat lab with comment" according to the availability to measure plasma magnesium levels in the stat laboratory and the inclusion of an automatic comment in the laboratory report in cases of hypomagnesemia. We retrospectively reviewed the medical records of patients with magnesium < 1.5 mg/dL (0.6 mmol/L), to investigate whether they have been appropriately treated. RESULTS: A total of 410 plasma magnesium were measured due to our intervention; 179 due to hypokalemia and 231 due to hypocalcemia. Two hundred thirty (56.1%) of 410 showed hypomagnesemia. Each detected case resulted in reagent cost of 0.7$, when prompted by hypocalcemia, and 0.6$ when prompted by hypokalemia. The rate of patients with hypomagnesemia that were appropriately treated increased from 15% to 75% along the study period. CONCLUSIONS: Our strategies successfully identified patients with hypomagnesemia in the ED at a very affordable cost, and increased the percentage of patients with hypomagnesemia that received treatment.

A reconnaissance survey of farmers' awareness of hypomagnesaemic tetany in UK cattle and sheep farms.

Hypomagnesaemic tetany (HypoMgT) in ruminants is a physiological disorder caused by inadequate intake or impaired absorption of magnesium (Mg) in the gut. If it is not detected and treated in time, HypoMgT can cause the death of the affected animal. A semi-structured questionnaire survey was conducted from July 2016-2017 to assess farmers' awareness of HypoMgT in cattle and sheep in the UK. The questionnaire was distributed to farmers at farm business events and agricultural shows, and through a collaborative group of independent veterinary practices to their clients. Farmers were asked about (i) the incidence of presumed HypoMgT (PHT); (ii) their strategies to treat or prevent HypoMgT; (iii) mineral tests on animals, forage and soil, and (iv) farm enterprise type. A total of 285 responses were received from 82 cattle, 157 mixed cattle and sheep, and 46 sheep farmers, of whom 39% reported HypoMgT in their livestock, affecting 1-30 animals. Treatment and/or prevention against HypoMgT was reported by 96% respondents with PHT and 79% of those without. Mineral tests on animal, forage, and soil was conducted by 24%, 53%, and 66% of the respondents, respectively, regardless of PHT. There was a highly significant association between the use of interventions to tackle HypoMgT and the incidence of PHT (p < 0.01). The top three treatment/prevention strategies used were reported as being free access supplementation (149), in feed supplementation (59) and direct to animal treatments (drenches, boluses and injections) (45) although these did vary by farm type. Although some (9) reported using Mg-lime, no other pasture management interventions were reported (e.g., Mg-fertilisation or sward composition). Generally, the results indicate that UK farmers are aware of the risks of HypoMgT. A more integrated soil-forage-animal assessment may improve the effectiveness of tackling HypoMgT and help highlight the root causes of the problem.

Hypomagnesemia and hypermagnesemia.

Introduction:Magnesium is an essential element which also has pleiotropic effects in humans. Recent studies have altered our interpretation of a disturbed magnesium balance both leading to hypomagnesemia and hypermagnesemia. Methods: a narrative review of their clinical relevance is presented. Results: Although magnesium balance is strictly controlled by the kidneys, hypomagnesemia is fairly common, especially in people with comorbid conditions. Increased renal magnesium wasting, often aggravated by drugs, is commonly found in conditions associated with unfavorable outcomes such as diabetes mellitus and sepsis. Depending on its severity hypomagnesemia may reveal itself by potentially hazardous neurological and cardiovascular symptoms. Intravenous magnesium is an evidence-based treatment of torsades de pointes and preeclampsia irrespective of the presence of preexisting hypomagnesemia. Magnesium deficiency and/or hypomagnesemia has been linked to cardiovascular disease, vascular calcification and endothelial function both in vitro and in vivo. (Severe) hypermagnesemia can be life-threatening but is almost exclusively observed in patients with substantially decreased kidney function associated with high magnesium intake through supplements or magnesium containing cathartics or antacids. Conclusion:It remains unclear whether mild hypermagnesemia confers survival benefit especially in subjects with decreased kidney function. The role of oral magnesium supplementation of chronic mild asymptomatic hypomagnesemia also merits further exploration through interventional studies in various study populations.

[Michaelis-Manz syndrome. A case report]. / Síndrome de Michaelis-Manz. A propósito de un caso clínico.

Michaelis-Manz syndrome is an autosomal recessive hereditary tubulopathy associated with mutations in the tight-junction proteins claudin-16 and claudin-19, which are present in the distal convoluted tubule and the loop of Henle in the kidney. Claudin-19 is also expressed in the retinal pigmentary epithelium. The clinical picture causes hypomagnesemia, hyper-calciuria and nephrocalcinosis that can lead to renal failure, which is the condition that marks the prognosis of the disease. Ophthalmologically patients can present macular coloboma, myopic staphyloma and nystagmus. We present the case report of an 18-year-old man suffering from hereditary hypomagnesemia, hypercalciuria and nephrocalcinosis, or Mich-aelis-Manz syndrome, with macular coloboma and stable visual acuities. Keywords. Hypomagnesemia. Hypercalciuria. Nephrocalcinosis. Macular coloboma.

Role of Magnesium Deficiency in Promoting Atherosclerosis, Endothelial Dysfunction, and Arterial Stiffening as Risk Factors for Hypertension.

Arterial hypertension is a disease with a complex pathogenesis. Despite considerable knowledge about this socially significant disease, the role of magnesium deficiency (MgD) as a risk factor is not fully understood. Magnesium is a natural calcium antagonist. It potentiates the production of local vasodilator mediators (prostacyclin and nitric oxide) and alters vascular responses to a variety of vasoactive substances (endothelin-1, angiotensin II, and catecholamines). MgD stimulates the production of aldosterone and potentiates vascular inflammatory response, while expression/activity of various antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) and the levels of important antioxidants (vitamin C, vitamin E, and selenium) are decreased. Magnesium balances the effects of catecholamines in acute and chronic stress. MgD may be associated with the development of insulin resistance, hyperglycemia, and changes in lipid metabolism, which enhance atherosclerotic changes and arterial stiffness. Magnesium regulates collagen and elastin turnover in the vascular wall and matrix metalloproteinase activity. Magnesium helps to protect the elastic fibers from calcium deposition and maintains the elasticity of the vessels. Considering the numerous positive effects on a number of mechanisms related to arterial hypertension, consuming a healthy diet that provides the recommended amount of magnesium can be an appropriate strategy for helping control blood pressure.

Efficacy and tolerability of magnesium plus protein for managing hypomagnesemia in pediatric kidney transplant patients.

We sought to investigate whether magnesium oxide bound to soy protein (MGP) increases serum magnesium concentrations with less diarrhea compared to commonly prescribed magnesium salts. Subjects were switched to MGP at a near-equivalent daily elemental magnesium dose. Mean serum magnesium levels were compared. If magnesium levels remained <1.7 mg/dL after switching to MGP, subjects were enrolled into Part 2 and received a one-time MGP dose adjustment. The MGP daily dose was increased by 266 mg. For both parts 1 and 2, subjects recorded the number and quality of their stools to assess gastrointestinal (GI) tolerability of MGP. Twelve pediatric kidney transplant recipients completed Part 1. Mean serum magnesium levels increased from 1.61 (SD 0.1) on standard MG to 1.69 (SD 0.1); t(11) = 2.6, P = .02 on MGP. Five subjects completed Part 2, and all achieved serum magnesium ≥1.7 mg/dL (mean 1.75 mg/dL, SD 0.06; t(4) = 2.7, P = .06). Subjects reported the same number of, but looser bowel movements with MGP; however, individuals did not perceive intolerable GI symptoms with MGP therapy and all chose to remain on MGP at the end of the study. At an equivalent mg/kg/d dose of elemental magnesium, serum magnesium levels on MGP were significantly higher.

Persistent severe hypomagnesemia caused by proton pump inhibitor resolved after laparoscopic fundoplication.

Magnesium deficiency can cause a variety of symptoms, including potentially life-threatening complications such as seizures, cardiac arrhythmias and secondary electrolyte disturbances. Hypomagnesemia can be a serious adverse effect to proton pump inhibitor (PPI) therapy, which is worrying due to the widespread use of PPIs. Current evidence suggest that the mechanism of PPI induced hypomagnesemia is impaired intestinal magnesium absorption. In this report, we present the case of a long-term PPI user with persistent hypomagnesemia with severe symptoms at presentation. He was unable to stop PPI treatment because of severe reflux symptoms, and was dependent on weekly intravenous magnesium infusions, until his magnesium levels finally normalized without the need for supplementation after a successful laparoscopic fundoplication.

Identification of the first large deletion in the CLDN16 gene in a patient with FHHNC and late-onset of chronic kidney disease: case report.

BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal disease characterized by tubular disorders at the thick ascending limb of Henle's loop. It is caused by mutations in the tight junction structural proteins claudin-16 or claudin-19, which are encoded by the CLDN16 and CLDN19 genes, respectively. Patients exhibit excessive wasting of calcium and magnesium, nephrocalcinosis, chronic kidney disease, and early progression to end-stage renal failure during infancy. CASE PRESENTATION: We here report the phenotype and molecular analysis of a female Brazilian patient with a novel large homozygous deletion in the CLDN16 gene. The proband, born from consanguineous parents, presented the first symptoms at age 20. Clinical examination revealed hypocalcemia, hypomagnesemia, nephrocalcinosis, mild myopia, high serum levels of uric acid and intact parathyroid hormone, and moderate chronic kidney disease (stage 3). She and her mother were subjected to CLDN16 and CLDN19 mutational analysis. In addition, the multiplex ligation-dependent probe amplification method was used to confirm a CLDN16 multi-exon deletion. Direct sequencing revealed a normal CLDN19 sequence and suggested a large deletion in the CLDN16 gene. Multiplex ligation-dependent probe amplification showed a homozygous CLDN16 multi-exon deletion (E2_E5del). The patient initiated conventional treatment for familial hypomagnesemia with hypercalciuria and nephrocalcinosis and progressed to end-stage kidney disease after five years. CONCLUSIONS: This study provides the first report of a large homozygous deletion in the CLDN16 gene causing familial hypomagnesemia with hypercalciuria and nephrocalcinosis with late onset of the first symptoms. This description expands the phenotypic and genotypic characterization of the disease. The late-onset chronic kidney disease in the presence of a homozygous deletion in the CLDN16 gene reinforces the great variability of genotype-phenotype manifestation in patients with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.