Long-term cisplatin nephrotoxicity after childhood cancer: a systematic review and meta-analysis.

BACKGROUND: Cisplatin is a chemotherapeutic drug commonly used in the treatment of many childhood solid malignancies. It is known to cause long-term nephrotoxicity, most commonly manifesting as reduced glomerular filtration rate and hypomagnesaemia. Existing literature regarding the epidemiology of long-term nephrotoxicity in childhood cancer describes large variation in prevalence and risk factors. OBJECTIVES: This study is to evaluate the prevalence of, and risk factors for, long-term cisplatin nephrotoxicity after treatment for childhood cancer. STUDY ELIGIBILITY CRITERIA: Studies were eligible for inclusion if they: (i) evaluated participants treated with cisplatin who were diagnosed with cancer < 18 years of age; (ii) investigated any author-defined measure of nephrotoxicity; and (iii) performed this evaluation 3 or more months after cisplatin cessation. Studies whose scope was broader than this were included if appropriate subgroup analysis was performed. RESULTS: Prevalence of reduced glomerular filtration rate (GFR) ranged between 5.9 and 48.1%. Pooled prevalence of reduced GFR using studies with a modern consensus threshold of 90 ml/min/1.73 m2 was 29% (95% CI 0.0-58%). Prevalence of hypomagnesaemia ranged between 8.0 and 71.4%. Pooled prevalence of hypomagnesaemia was 37% (95% CI 22-51%). Substantial heterogeneity was present, with I2 statistics of 94% and 73% for reduced GFR and hypomagnesaemia respectively. All large, long-term follow-up studies described increased risk of reduced GFR with increasing cumulative cisplatin dose. Included studies varied as to whether cisplatin was a risk factor for proteinuria, and whether age was a risk factor for cisplatin nephrotoxicity. LIMITATIONS: A wide range of study methodologies were noted which impeded analysis. No studies yielded data from developing health-care settings. No non-English studies were included, further limiting generalisability. CONCLUSIONS: Both of the most common manifestations of long-term cisplatin nephrotoxicity have a prevalence of approximately a third, with increasing cumulative dose conferring increased risk of nephrotoxicity. Further work is needed to characterise the relationship between reduced GFR and hypomagnesaemia, investigate other risk factors and understand the interindividual variation in susceptibility to nephrotoxicity.

Hypomagnesaemia, an independent risk factor for the development of post-transplant diabetes mellitus in liver and renal transplant recipients? A systematic review.

BACKGROUND: Post-transplantation diabetes mellitus (PTDM) is common after solid organ transplantation. In the past decade, there has been increasing interest in the association between hypomagnesaemia and the development of PTDM. This systematic review aimed to investigate the current knowledge regarding the association between hypomagnesaemia and PTDM in adult liver and renal transplant recipients. METHODS: A literature search of five databases, Medline, Embase, ProQuest, Scopus and Google Scholar, as well as article reference lists, was performed. Eligible studies that focused on adult liver and renal transplant recipients without pretransplantation hyperglycaemia or diabetes were included. Other eligibility criteria included quantitative studies which reported magnesium concentrations, studies with at least 6 months of follow-up, and studies published in English. The Newcastle-Ottawa Assessment Tool was used for the quality assessment. RESULTS: In total, 12 studies were included in the final analysis. Eleven focused on renal transplantation and one on liver transplantation. All studies were medium to high quality with eight out of 12 achieving the highest rating of nine. Eight studies found a negative association between either pretransplant or early post-transplant serum magnesium concentration and the risk of PTDM, three studies found no association between these two variables, and one study found a positive association between the magnesium concentration at 8 weeks after transplantation and glycosylated haemoglobin A1C. CONCLUSIONS: Further large-scale prospective studies with at least 6 months of follow-up are needed to confirm these findings, particularly in liver transplantation, to further clarify and explore the relationship between hypomagnesaemia and PTDM.

Urinary Acidification Does Not Explain the Absence of Nephrocalcinosis in a Mouse Model of Familial Hypomagnesaemia with Hypercalciuria and Nephrocalcinosis (FHHNC).

Patients with mutations in Cldn16 suffer from familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) which can lead to renal insufficiency. Mice lacking claudin-16 show hypomagnesemia and hypercalciuria, but no nephrocalcinosis. Calcium oxalate and calcium phosphate are the most common insoluble calcium salts that accumulate in the kidney in the case of nephrocalcinosis, however, the formation of these salts is less favored in acidic conditions. Therefore, urine acidification has been suggested to limit the formation of calcium deposits in the kidney. Assuming that urine acidification is causative for the absence of nephrocalcinosis in the claudin-16-deficient mouse model, we aimed to alkalinize the urine of these mice by the ablation of the subunit B1 of the vesicular ATPase in addition to claudin-16. In spite of an increased urinary pH in mice lacking claudin-16 and the B1 subunit, nephrocalcinosis did not develop. Thus, urinary acidification is not the only factor preventing nephrocalcinosis in claudin-16 deficient mice.

The kidney reabsorption-related magnesium depletion score is associated with increased likelihood of abdominal aortic calcification among US adults.

BACKGROUND: Kidney reabsorption plays a vital role in magnesium homeostasis. This study aimed to determine the relationship between the kidney reabsorption-related magnesium depletion score (MDS) and abdominal aortic calcification (AAC). METHODS: We obtained data for 2640 individuals from the National Health and Nutrition Examination Survey database and analysed the relationship between the MDS and AAC score. The MDS is a scoring system developed to predict the status of magnesium deficiency that fully considers the pathophysiological factors influencing the kidneys' reabsorption capability. AAC was quantified by the Kauppila score system based on dual-energy X-ray absorptiometry. We performed stratified analysis and multiple equation regression analysis. R and EmpowerStats were used for data analysis. RESULTS: A total of 2640 participants were included with the mean AAC score of 1.47 ± 0.07. Participants with higher MDSs tended to have higher AAC scores [MDS 0: 0.75 (0.56-0.93), MDS 1: 1.02 (0.84-1.21), MDS 2: 2.34 (1.80-2.87), MDS 3: 3.19 (2.46-3.92), MDS ≥4: 4.99 (3.49-6.49)]. Compared with those with an MDS of 0, the highest subgroup (MDS ≥4) was associated with a higher AAC score {ß = 4.24 [95% confidence interval (CI) 2.78-5.70], P < .001} and the association was not altered [ß = 1.81 (95% CI 0.54-3.09), P = .002] after adjusting for numerous covariates. Subgroup analyses showed that stronger associations between the MDS and AAC score were detected in adults with lower levels of magnesium intake and older age (all P for interaction <.05). CONCLUSIONS: The MDS is a promising tool for identifying individuals with magnesium deficiency status who may benefit from dietary magnesium supplementation to reduce the risks of AAC.

Association of magnesium sulfate use with mortality in critically ill patients with sepsis: a retrospective propensity score-matched cohort study.

BACKGROUND: Trials have demonstrated lower rates of acute kidney injury in critically ill patients receiving magnesium supplementation, but they have yielded conflicting results regarding mortality. METHODS: This is a retrospective cohort study based on the MIMIC-IV (Medical Information Mart in Intensive Care-IV) database. Adult critically ill patients with sepsis were included in the analysis. The exposure was magnesium sulfate use during ICU stay. The primary outcome was 28-day all-cause mortality. Propensity score matching (PSM) was conducted at a 1:1 ratio. Multivariable analyses were used to adjust for confounders. RESULTS: The pre-matched and propensity score-matched cohorts included 10 999 and 6052 patients, respectively. In the PSM analysis, 28-day all-cause mortality rate was 20.2% (611/3026) in the magnesium sulfate use group and 25.0% (757/3026) in the no use group. Magnesium sulfate use was associated with lower 28-day all-cause mortality (hazard ratio [HR], 0.70; 95% CI, 0.61-0.79; P<0.001). Lower mortality was observed regardless of baseline serum magnesium status: for hypomagnesaemia, HR, 0.64; 95% confidence interval (CI), 0.45-0.93; P=0.020; for normomagnesaemia, HR, 0.70; 95% CI, 0.61-0.80; P<0.001. Magnesium sulfate use was also associated with lower ICU mortality (odds ratio [OR], 0.52; 95% CI, 0.42-0.64; P<0.001), lower in-hospital mortality (OR, 0.65; 95% CI, 0.55-0.77; P<0.001), and renal replacement therapy (OR, 0.67; 95% CI, 0.52-0.87; P=0.002). A sensitivity analysis using the entire cohort also demonstrated lower 28-day all-cause mortality (HR, 0.62; 95% CI, 0.56-0.69; P<0.001). CONCLUSIONS: Magnesium sulfate use was associated with lower mortality in critically ill patients with sepsis. Prospective studies are needed to verify this finding.

Evaluation of hypomagnesaemia in diabetic patients with nephropathy in a reference clinical laboratory: A comparative cross sectional study.

Serum Magnesium plays a significant role in different diabetic complications. This comparative cross sectional study was conducted to evaluate serum magnesium levels in patients with Type 2 Diabetes Mellitus (T2DM) with and without nephropathy. A total of 182 diabetic patients (91 with nephropathy and 91 without nephropathy) were included. Odds ratio were calculated and Mann Whitney U test was used to compare quantitative variables; p<0.05 was considered significant. The results showed that 64/91 (70.3%) patients with nephropathy had hypomagnesaemia as compared to 21/91 (23.07%) patients without nephropathy. The risk of hypomagnesaemia was higher in patients with nephropathy than without nephropathy (Odds ratio 2.7 vs 0.34). Median magnesium levels (1.73 mg/dl) were lower in patients with nephropathy as compared to patients without nephropathy (2.09 mg/dl), p<0.01. It is concluded that magnesium levels were significantly lower in patients with diabetic nephropathy as compared to without nephropathy.

Serum magnesium levels of term neonates with birth asphyxia and relationship to severity of asphyxia.

Background and Aims: Birth asphyxia is one of the three main causes of neonatal mortality in Nigeria. Hypomagnesaemia has been reported amongst severely asphyxiated babies. Despite this, the prevalence of hypomagnesaemia amongst newborns with birth asphyxia has not been well researched in Nigeria. This study set out to determine the prevalence of hypomagnesaemia in term neonates with birth asphyxia and the relationship (if any) between magnesium levels and the severity of birth asphyxia or encephalopathy. Methods: In this cross-sectional analytical study, the serum magnesium levels of consecutive cases of birth asphyxia were compared to that of gestational age-matched healthy term neonates. Babies with Apgar scores <7 in the 5th minute of life were recruited into the study. Blood samples were taken from each baby at birth and 48 h. Serum magnesium was measured using spectrophotometry. Results: Hypomagnesaemia was found in 36 (35.3%) babies with birth asphyxia and 14 (13.7%) healthy controls; this difference was statistically significant (χ2 = 18.098, P = 0.001), with an odds ratio of 3.4 (95% confidence interval = 1.7, 6.9). The median (interquartile range) levels of serum magnesium in babies with mild, moderate and severe asphyxia were 0.7 mmol/L (0.5-1.1), 0.7 mmol/L (0.4-0.9) and 0.7 mmol/L (0.5-1.0), respectively (P = 0.316), while those of babies with mild (stage 1), moderate (stage 2) and severe (stage 3) encephalopathy were 1.2 mmol/L (1.0-1.3), 0.7 mmol/L (0.5-0.8) and 0.8 mmol/L (0.6-1.0), respectively (P = 0.789). Conclusion: This study has shown that hypomagnesaemia was more common in babies with birth asphyxia and there was no relationship between magnesium levels and the severity of asphyxia or encephalopathy.

The complex role of post-operative magnesium on the long term serum calcium and parathyroid hormone levels in patients undergoing total and near-total thyroidectomy.

Objective: To assess the role of hypomagnesaemia in the development of permanent hypocalcaemia following thyroidectomy. METHODS: The prospective cohort study was conducted from April 3, 2017, to January 2, 2020, at Surgical Unit 1, Benazir Bhutto Hospital, Rawalpindi, Pakistan, and comprised of patients of both genders undergoing total and near total thyroidectomy. Post-operative calcium and magnesium levels were noted, and the patients were followed up after 6 months and fasting serum calcium, magnesium and parathyroid hormone levels were checked. Signs and symptoms of hypocalcaemia were noted. Data was analysed using SPSS 22. RESULTS: Out of the 62 patients followed up, 57 (91.9%) were females and 5 (8.1%) males. The overall mean age was 38.5 ± 12.1 years Post-operative hypomagnesaemia was seen in 6(9.8%) patients and none developed follow-up hypocalcaemia. Post-operative magnesium levels were significantly negatively correlated with follow-up parathyroid hormone level (p=0.006). Fall in magnesium post-operatively and follow-up magnesium were positively correlated with follow-up parathyroid hormone (p<0.05). Permanent hypocalcaemia was seen in 7(11.4%) patients and it was significantly associated with pre-operative and post-operative calcium levels, post-operative symptoms of hypocalcaemia and readmission for hypocalcaemia after discharge (p<0.05). Follow-up hypomagnesaemia was significantly associated with follow-up hypocalcaemia (p=0.024) and follow-up symptoms of hypocalcaemia (p=0.031). Conclusion: Acute development of mild hypomagnesaemia post-operatively may be beneficial in early positive feedback for parathyroid hormone secretion. Hypomagnesemia 6 months after surgery may be involved in PTH organ resistance. The complex role of hypomagnesemia on PTH levels must be further explored.

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency.

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.

Serum magnesium, hepatocyte nuclear factor 1ß genotype and post-transplant diabetes mellitus: a prospective study.

BACKGROUND: Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. METHODS: This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1ß (HNF1ß) was also explored because HNF1ß regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. RESULTS: In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1ß SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05-6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90-5.57). No association between HNF1ß SNPs and PTDM was found in corresponding donors. CONCLUSIONS: A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1ß SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.

Phase separation as a therapeutic target in tight junction-associated human diseases.

Tight junctions (TJs) play an important role in the maintenance of epithelial and endothelial barriers. Zonula occludens (ZO) proteins are scaffolding molecules essential for the formation of TJ complexes, and abnormalities in ZO proteins have been implicated in various TJ-associated human diseases such as tumor invasion and metastasis, and barrier dysfunction. Recent studies reveal that liquid-liquid phase separation of ZO proteins drives the polymerization of TJ proteins into a continuous belt, which then recruits various proteins to form the TJ complex to regulate selective paracellular permeability and signal transduction. Herein, we describe recent advances on how ZO phase separation contributes to TJ formation and discuss the potential of phase separation as a target for the treatment of TJ-associated diseases.

Increased NEFA levels reduce blood Mg2+ in hypertriacylglycerolaemic states via direct binding of NEFA to Mg2.

AIMS/HYPOTHESIS: The blood triacylglycerol level is one of the main determinants of blood Mg2+ concentration in individuals with type 2 diabetes. Hypomagnesaemia (blood Mg2+ concentration <0.7 mmol/l) has serious consequences as it increases the risk of developing type 2 diabetes and accelerates progression of the disease. This study aimed to determine the mechanism by which triacylglycerol levels affect blood Mg2+ concentrations. METHODS: Using samples from 285 overweight individuals (BMI >27 kg/m2) who participated in the 300-Obesity study (an observational cross-sectional cohort study, as part of the Human Functional Genetics Projects), we investigated the association between serum Mg2+ with laboratory variables, including an extensive lipid profile. In a separate set of studies, hyperlipidaemia was induced in mice and in healthy humans via an oral lipid load, and blood Mg2+, triacylglycerol and NEFA concentrations were measured using colourimetric assays. In vitro, NEFAs harvested from albumin were added in increasing concentrations to several Mg2+-containing solutions to study the direct interaction between Mg2+ and NEFAs. RESULTS: In the cohort of overweight individuals, serum Mg2+ levels were inversely correlated with triacylglycerols incorporated in large VLDL particles (r = -0.159, p ≤ 0.01). After lipid loading, we observed a postprandial increase in plasma triacylglycerol and NEFA levels and a reciprocal reduction in blood Mg2+ concentration both in mice (Δ plasma Mg2+ -0.31 mmol/l at 4 h post oral gavage) and in healthy humans (Δ plasma Mg2+ -0.07 mmol/l at 6 h post lipid intake). Further, in vitro experiments revealed that the decrease in plasma Mg2+ may be explained by direct binding of Mg2+ to NEFAs. Moreover, Mg2+ was found to bind to albumin in a NEFA-dependent manner, evidenced by the fact that Mg2+ did not bind to fatty-acid-free albumin. The NEFA-dependent reduction in the free Mg2+ concentration was not affected by the presence of physiological concentrations of other cations. CONCLUSIONS/INTERPRETATION: This study shows that elevated NEFA and triacylglycerol levels directly reduce blood Mg2+ levels, in part explaining the high prevalence of hypomagnesaemia in metabolic disorders. We show that blood NEFA level affects the free Mg2+ concentration, and therefore, our data challenge how the fractional excretion of Mg2+ is calculated and interpreted in the clinic.

Clinical characteristics of HNF1B-related disorders in a Japanese population.

BACKGROUND: Hepatocyte nuclear factor 1ß (HNF1B), located on chromosome 17q12, causes renal cysts and diabetes syndrome (RCAD). Moreover, various phenotypes related to congenital anomalies of the kidney and urinary tract (CAKUT) or Bartter-like electrolyte abnormalities can be caused by HNF1B variants. In addition, 17q12 deletion syndrome presents with multi-system disorders, as well as RCAD. As HNF1B mutations are associated with different phenotypes and genotype-phenotype relationships remain unclear, here, we extensively studied these mutations in Japan. METHODS: We performed genetic screening of RCAD, CAKUT, and Bartter-like syndrome cases. Heterozygous variants or whole-gene deletions in HNF1B were detected in 33 cases (19 and 14, respectively). All deletion cases were diagnosed as 17q12 deletion syndrome, confirmed by multiplex ligation probe amplification and/or array comparative genomic hybridization. A retrospective review of clinical data was also conducted. RESULTS: Most cases had morphological abnormalities in the renal-urinary tract system. Diabetes developed in 12 cases (38.7%). Hyperuricemia and hypomagnesemia were associated with six (19.3%) and 13 cases (41.9%), respectively. Pancreatic malformations were detected in seven cases (22.6%). Ten patients (32.3%) had liver abnormalities. Estimated glomerular filtration rates were significantly lower in the patients with heterozygous variants compared to those in patients harboring the deletion (median 37.6 vs 58.8 ml/min/1.73 m2; p = 0.0091). CONCLUSION: We present the clinical characteristics of HNF1B-related disorders. To predict renal prognosis and complications, accurate genetic diagnosis is important. Genetic testing for HNF1B mutations should be considered for patients with renal malformations, especially when associated with other organ involvement.

Hypomagnesaemia and other electrolytes imbalances in open and closed pediatrics cardiac surgery.

OBJECTIVE AND BACKGROUND: During the past decade, many researchers have indicated that open cardiac surgery, using cardiopulmonary bypass, could be an essential factor to induce post-operative electrolyte imbalances which may be followed by life threatening complications such as arrhythmia. Nevertheless, by this time there may be a few researches about comparing of hypomagnesaemia and other electrolyte imbalances between open, on pump, and closed, off pump, heart operation. METHODS: In this cohort study conducted at Rajaie Heart Center in Tehran from December 2014 to August 2015, we evaluated hypomagnesaemia, hypocalcemia, hypokalemia and hyponatremia in 205 children aged under 15 years who underwent open (101 children) and closed (104 children) cardiac surgery. Repeated measures ANOVA, paired t test and Chi-square/Fisher exact test were used for analysis the data in SPSS version 21. RESULTS: According to our study the frequency of electrolyte imbalances including hypomagnesaemia after pediatric heart surgery is relatively high (28.7% hypomagnesaemia at the second day) with more occurrence in closed cardiac operations. There was no significant relationship between hypomagnesaemia and pump time duration (P>0.05). On the other hand, this research indicated that there is significant relationship between post-operative hypomagnesaemia and some other variables including cyanotic heart disease (P=0.01) and concurrent electrolyte imbalance such as hypocalcaemia and hypokalemia (P<0.05). CONCLUSION: Early evaluation and correction of hypomagnesaemia should be considered after both closed and open heart operation.

Magnesium deficiency prevents high-fat-diet-induced obesity in mice.

AIMS/HYPOTHESIS: Hypomagnesaemia (blood Mg2+ <0.7 mmol/l) is a common phenomenon in individuals with type 2 diabetes. However, it remains unknown how a low blood Mg2+ concentration affects lipid and energy metabolism. Therefore, the importance of Mg2+ in obesity and type 2 diabetes has been largely neglected to date. This study aims to determine the effects of hypomagnesaemia on energy homeostasis and lipid metabolism. METHODS: Mice (n = 12/group) were fed either a low-fat diet (LFD) or a high-fat diet (HFD) (10% or 60% of total energy) in combination with a normal- or low-Mg2+ content (0.21% or 0.03% wt/wt) for 17 weeks. Metabolic cages were used to investigate food intake, energy expenditure and respiration. Blood and tissues were taken to study metabolic parameters and mRNA expression profiles, respectively. RESULTS: We show that low dietary Mg2+ intake ameliorates HFD-induced obesity in mice (47.00 ± 1.53 g vs 38.62 ± 1.51 g in mice given a normal Mg2+-HFD and low Mg2+-HFD, respectively, p < 0.05). Consequently, fasting serum glucose levels decreased and insulin sensitivity improved in low Mg2+-HFD-fed mice. Moreover, HFD-induced liver steatosis was absent in the low Mg2+ group. In hypomagnesaemic HFD-fed mice, mRNA expression of key lipolysis genes was increased in epididymal white adipose tissue (eWAT), corresponding to reduced lipid storage and high blood lipid levels. Low Mg2+-HFD-fed mice had increased brown adipose tissue (BAT) Ucp1 mRNA expression and a higher body temperature. No difference was observed in energy expenditure between the two HFD groups. CONCLUSIONS/INTERPRETATION: Mg2+-deficiency abrogates HFD-induced obesity in mice through enhanced eWAT lipolysis and BAT activity.

Thiazide but not loop diuretics is associated with hypomagnesaemia in the general population.

PURPOSE: Hypomagnesaemia has been associated with various adverse outcomes. Loop and thiazide diuretics promote urinary magnesium excretion. However, it is unknown if this links to hypomagnesaemia. We study if loop or thiazide diuretic use affects serum magnesium levels and if it associates with hypomagnesaemia. In addition, we study the effect of combining a potassium-sparing diuretic with a thiazide diuretic on the presence of hypomagnesaemia. METHODS: The study performed a cross-sectional analysis within 9820 participants from the prospective Rotterdam Study. Hypomagnesaemia was defined as a serum magnesium level ≤0.72 mmol/L. Participants were categorized by defined daily dose (DDD), and all analyses were adjusted for age, sex, BMI, eGFR, serum potassium levels, proton pump inhibitor use, and comorbidities. RESULTS: Loop diuretic use was associated with higher serum magnesium levels (<1 DDD: 0.004 mmol/L 95% CI: -0.008; 0.017; 1 DDD: 0.023 mmol/L 95% CI: 0.013; 0.032; >1 DDD: 0.043 mmol/L 95% CI: 0.028; 0.057). Thiazide diuretic use was associated with lower serum magnesium levels (<1 DDD: -0.013 mmol/L 95% CI: -0.023; -0.002; ≥1 DDD: -0.018 mmol/L 95% CI: -0.028; -0.010), resulting in an increased odds ratio of hypomagnesaemia of 3.14 (95% CI: 1.67; 5.92) and 2.74 (95% CI: 1.57; 4.77), respectively. These effects were predominantly seen in participants using diuretics for more than 390 days. Combining thiazide diuretics with a potassium-sparing agent was not associated with lower serum magnesium levels or hypomagnesaemia. CONCLUSIONS: Thiazide diuretic use is associated with lower serum magnesium levels and an increased risk of hypomagnesaemia. This increased risk is not seen in participants using a combination of thiazide diuretics with a potassium-sparing agent. The use of loop diuretics is not associated with an increased risk of hypomagnesaemia.

Familial hypomagnesaemia, Hypercalciuria and Nephrocalcinosis associated with a novel mutation of the highly conserved leucine residue 116 of Claudin 16 in a Chinese patient with a delayed diagnosis: a case report.

BACKGROUND: Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. CASE PRESENTATION: A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C > G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. CONCLUSIONS: We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient.

Reversible cerebellar oedema secondary to profound hypomagnesaemia.

Magnesium is the second most abundant intracellular cation. Deficiency can cause several neurological complications, including cerebellar syndromes, with various MRI findings. These include cerebellar oedema, presumably through a similar mechanism to that in posterior reversible encephalopathy syndrome (PRES). People particularly vulnerable to deficiency include those with high alcohol consumption, excessive loss due to gastrointestinal pathology and those taking certain medications, including proton pump inhibitors. We report three patients with cerebellar syndromes associated with hypomagnesaemia. These cases support the previously reported association between hypomagnesaemia and reversible cerebellar dysfunction and illustrate the range of potential presentations. They highlight an uncommon but treatable cause of cerebellar ataxia that may present to acute neurological liaison services.

Magnesium lactate in the treatment of Gitelman syndrome: patient-reported outcomes.

Background: Gitelman syndrome (GS) is a rare recessively inherited renal tubulopathy associated with renal potassium (K) and magnesium (Mg) loss. It requires lifelong K and Mg supplementation at high doses that are at best unpalatable and at worst, intolerable. In particular, gastrointestinal side effects often limit full therapeutic usage. Methods: We report here the analysis of a cohort of 28 adult patients with genetically proven GS who attend our specialist tubular disorders clinic, in whom we initiated the use of a modified-release Mg preparation (slow-release Mg lactate) and who were surveyed by questionnaire. Results: Twenty-five patients (89%) preferred the new treatment regimen. Of these 25, 17 (68%) regarded their symptom burden as improved and seven reported no worsening. Of the 25 who were not Mg-treatment naïve, 13 (59%) patients reported fewer side effects, 7 (32%) described them as the same and only 2 (9%) considered side effects to be worse. Five were able to increase their dose without ill-effect. Overall, biochemistry improved in 91% of the 23 patients switched from therapy with other preparations who chose to continue the modified-release Mg preparation. Eleven (48%) improved both their Mg and K mean levels, 3 (13%) improved Mg levels only and in 7 cases (30%), K levels alone rose. Conclusions: Patient-reported and biochemical outcomes using modified-release Mg supplements were very favourable, and patient choice should play a large part in choosing Mg supplements with GS patients.