Outcomes of Adopting a Higher Versus Lower Concentration of Hemodialysate Magnesium as a Center-Wide Policy (Dial-Mag): A Clinical Research Protocol of a Pragmatic, Registry-Based, Cluster Randomized Trial

Background The impact of simultaneous conversion of dialysate calcium (DCa) concentration from 3.0 to 2.6 mEq/L and dialysate magnesium (DMg) concentration from 1.0 to 1.2 mEq/L on mineral and bone metabolism in patients undergoing hemodialysis remains unknown. Methods We retrospectively recruited 52 patients undergoing hemodialysis who experienced a conversion of dialysates from dialysate A (DCa 3.0 mEq/L and DMg 1.0 mEq/L) to dialysate B (DCa 2.6 mEq/L and DMg 1.2 mEq/L) at a hemodialysis center. The effects of changing the DCa and DMg concentrations on serum bone and mineral parameters were examined over 7 months. Results A total of 48 patients were finally analyzed. After changing the dialysate, serum magnesium (Mg) levels increased significantly from 2.31 ± 0.38 at 0 months to 2.54 ± 0.43 mg/L at 7 months, and serum calcium (Ca) levels decreased significantly from 9.51 ± 0.80 at 0 months to 9.14 ± 0.57 mg/dL at 7 months, with no change in serum intact parathyroid hormone levels. Notably, the serum Ca-to-serum-Mg ratio and serum Ca × inorganic phosphate-to-serum-Mg ratio decreased significantly after dialysate conversion. Around 10% of patients started or increased the dose of vitamin D receptor activators, and 18% of patients started or increased the dose of Ca-based phosphate binders. Notably, the serum Mg levels in three patients exceeded 3.5 mg/dL during the observation period. Conclusions Conversion of DCa from 3.0 to 2.6 mEq/L and DMg from 1.0 to 1.2 mEq/L lowers serum Ca levels and increases serum Mg levels, possibly leading to decreased Ca loading and increased Mg storage among patients undergoing hemodialysis.

Background and Aims Cardiovascular calcification is highly prevalent among patients with end-stage renal disease (ESRD). Low normal serum magnesium has been linked to a more severe degree of vascular calcification and a decrease in patient survival. An inhibitory effect of extracellular magnesium on osteogenic transformation of vascular smooth muscle cells and the upregulation of anti-calcification protein have been confirmed in vitro. Increased dialysate magnesium concentration has also been shown to lower calcification propensity of the serum of maintenance hemodialysis (HD) patients. Method This study is an investigator initiated, single-blinded, parallel-group, matched case-control clinical trial that investigated the effect of high dialysate magnesium concentration for 24 weeks on the progression of coronary artery calcification (CAC) in maintenance HD patients. The changes in laboratory data and bone mineral density (BMD) were also examined. Seventy-six ESRD patients underwent CAC screening by multi-slice computed tomography and BMD measurement by dual-x-ray absorptiometry. Only patients with Agatston score>300 were included. They were matched according to the initial CAC score that fell within 20% of one another. Twenty patients were assigned to high dialysate magnesium concentration of 1.75 mEq/L and the matched controls were kept on standard dialysate magnesium concentration of 0.7 mEq/L. CAC and BMD measurements were repeated after 24 weeks. Laboratory data were obtained prior to dialysis at study entry, 8-week intervals during the study and 2 weeks after the study ended. Results There were no significant differences in age, sex, BMI, underlying diseases, dialysis vintage, medications, baseline CAC scores and BMD. The median baseline CAC Agatston score (Volume score) were 1923 (720) and 1672 (785) in the standard and high dialysate groups, respectively. At the end of the study, a significant increase in the CAC score was observed in both groups. Because majority of the included patients had severe calcification burden at baseline, patients were categorized into 2 subgroups using the median baseline CAC Agatston (1600) and Volume scores (700) as cut-offs. Among patients with CAC Agatston score <=1600, CAC score increased significantly in the standard dialysate magnesium group (P<0.01) but was stable in the high dialysate magnesium group (P=0.33). Among patients with CAC Agatston score >1600, the severity of CAC worsened in both groups. The progression of CAC was analyzed by the difference between the follow-up and the baseline square root transformed Agatston and Volume scores. In subgroup of patients with less severe calcification, more patients in the standard dialysate magnesium group progressed compared to the high dialysate magnesium group (P=0.03). In subgroup of patients with more severe calcification, the number of progressors were comparable among the 2 groups. Serum and ionized magnesium levels increased substantially during the study and returned to baseline after the return to standard dialysate magnesium concentration. The highest predialysis serum magnesium was 3.8 mg/dL. Most patients who received high dialysate magnesium reported the disappearance of symptoms of muscle cramps (P=0.01) and requested the high dialysate magnesium be continued after the end of the study. There were no significant changes in serum calcium, phosphate or PTH levels. The decline in BMD was observed in both groups but the difference did not reach statistical significance. Conclusion High dialysate magnesium was well tolerated and could ameliorate the progression of CAC in maintenance HD patients with mild to moderate vascular calcification.

Serum Magnesium and Mortality in Hemodialysis Patients in the United States: A Cohort Study

Purpose of review:Strategies to mitigate muscle cramps are a top research priority for patients receiving hemodialysis. As hypomagnesemia is a possible risk factor for cramping, we reviewed the literature to better understand the physiology of cramping as well as the epidemiology of hypomagnesemia and muscle cramps. We also sought to review the evidence from interventional studies on the effect of oral and dialysate magnesium-based therapies on muscle cramps.Sources of information:Peer-reviewed articles.Methods:We searched for relevant articles in major bibliographic databases including MEDLINE and EMBASE. The methodological quality of interventional studies was assessed using a modified version of the Downs and Blacks criteria checklist.Key findings:The etiology of muscle cramps in patients receiving hemodialysis is poorly understood and there are no clear evidence-based prevention or treatment strategies. Several factors may play a role including a low concentration of serum magnesium. The prevalence of hypomagnesemia (concentration of <0.7 mmol/L) in patients receiving hemodialysis ranges from 10% to 20%. Causes of hypomagnesemia include a low dietary intake of magnesium, use of medications that inhibit magnesium absorption (eg, proton pump inhibitors), increased magnesium excretion (eg, high-dose loop diuretics), and a low concentration of dialysate magnesium. Dialysate magnesium concentrations of ≤0.5 mmol/L may be associated with a decrease in serum magnesium concentration over time. Preliminary evidence from observational and interventional studies suggests a higher dialysate magnesium concentration will raise serum magnesium concentrations and may reduce the frequency and severity of muscle cramps. However, the quality of evidence supporting this benefit is limited, and larger, multicenter clinical trials are needed to further determine if magnesium-based therapy can reduce muscle cramps in patients receiving hemodialysis. In studies conducted to date, increasing the concentration of dialysate magnesium appears to be well-tolerated and is associated with a low risk of symptomatic hypermagnesemia.Limitations:Few interventional studies have examined the effect of magnesium-based therapy on muscle cramps in patients receiving hemodialysis and most were nonrandomized, pre-post study designs.

Dialysate Magnesium and Coronary Artery Calcification, Bone Mineral Density, and Cramping in Maintenance Hemodialysis: A Quasi-experimental Study

The effects on plasma and erythrocyte potassium and magnesium concentrations of low ( < 0.2 mEq/l) as compared with orthodox (1.50 mEq/l) dialysate magnesium concentrations have been studied in six patients on maintenance haemodialysis. On low magnesium dialysis, plasma magnesium concentrations were significantly decreased from hypermagnesaemic to normal levels but the high erythrocyte magnesium concentrations were unchanged. The plasma potassium decrease, usual during each dialysis, was unaffected. In contrast, erythrocyte potassium concentrations, which did not change during individual dialyses, were high when orthodox magnesium was present in the dialysate, and normal during low magnesium dialysis. Low magnesium dialysis has biochemical advantages in that it corrects hypermagnesaemia and maintains normal erythrocyte potassium concentrations which otherwise would be increased.

IntroductionPeople treated with haemodialysis are at increased risk for all-cause and cardiovascular mortality. Plasma magnesium concentration has been inversely associated with these risks. Therefore, plasma magnesium may be a new...

The kidney has a vital role in magnesium homeostasis and, although the renal handling of magnesium is highly adaptable, this ability deteriorates when renal function declines significantly. In moderate chronic kidney disease (CKD), increases in the fractional excretion of magnesium largely compensate for the loss of glomerular filtration rate to maintain normal serum magnesium levels. However, in more advanced CKD (as creatinine clearance falls <30 mL/min), this compensatory mechanism becomes inadequate such that overt hypermagnesaemia develops frequently in patients with creatinine clearances <10 mL/min. Dietary calcium and magnesium may affect the intestinal uptake of each other, though results are conflicting, and likewise the role of vitamin D on intestinal magnesium absorption is somewhat uncertain. In patients undergoing dialysis, the effect of various magnesium and calcium dialysate concentrations has been investigated in haemodialysis (HD) and peritoneal dialysis (PD). Results generally show that dialysate magnesium, at 0.75 mmol/L, is likely to cause mild hypermagnesaemia, results for a magnesium dialysate concentration of 0.5 mmol/L were less consistent, whereas serum magnesium levels were mostly normal to hypomagnesaemic when 0.2 and 0.25 mmol/L were used. While dialysate magnesium concentration is a major determinant of HD or PD patients’ magnesium balance, other factors such as nutrition and medications (e.g. laxatives or antacids) also play an important role. Also examined in this review is the role of magnesium on parathyroid hormone (PTH) levels in dialysis patients. Although various studies have shown that patients with higher serum magnesium tend to have lower PTH levels, many of these suffer from methodological limitations. Finally, we examine the complex and often conflicting results concerning the interplay between magnesium and bone in uraemic patients. Although the exact role of magnesium in bone metabolism is unclear, it may have both positive and negative effects, and it is uncertain what the optimal magnesium levels are in uraemic patients.

Impact of Serum Magnesium Levels on Kidney and Cardiovascular Prognosis and Mortality in CKD Patients

Thiamine diphosphate (TDP) and magnesium are co-factors for key enzymes in human intermediary metabolism. However, their role in the systemic inflammatory response (SIR) is not clear. Therefore, the aim of the present study was to examine the relation between acute changes in the SIR and thiamine and magnesium dependent enzyme activity in patients undergoing elective knee arthroplasty (a standard reproducible surgical injury in apparently healthy individuals). Patients (n = 35) who underwent elective total knee arthroplasty had venous blood samples collected pre- and post-operatively for 3 days, for measurement of whole blood TDP, serum and erythrocyte magnesium, erythrocyte transketolase activity (ETKA), lactate dehydrogenase (LDH), glucose and lactate concentrations. Pre-operatively, TDP concentrations, erythrocyte magnesium concentrations, ETKA and plasma glucose were within normal limits for all patients. In contrast, 5 patients (14%) had low serum magnesium concentrations (< 0.75 mmol/L). On post-operative day1, both TDP concentrations (p < 0.001) and basal ETKA (p < 0.05) increased and serum magnesium concentrations decreased (p < 0.001). Erythrocyte magnesium concentrations correlated with serum magnesium concentrations (rs = 0.338, p < 0.05) and remained constant during SIR. Post-operatively 14 patients (40%) had low serum magnesium concentrations. On day1 serum magnesium concentrations were directly associated with LDH (p < 0.05), WCC (p < 0.05) and neutrophils (p < 0.01). Whole blood TDP and basal ETKA increased while serum magnesium concentrations decreased, indicating increased requirement for thiamine and magnesium dependent enzyme activity during SIR. Therefore, thiamine and magnesium represent potentially modifiable therapeutic targets that may modulate the host inflammatory response. Erythrocyte magnesium concentrations are likely to be reliable measures of status, whereas serum magnesium concentrations and whole blood TDP may not.ClinicalTrials.gov: NCT03554668.

Magnesium and infection risk after kidney transplantation: An observational cohort study

Vascular calcification, which significantly increases cardiovascular and other causes of mortality, is highly prevalent in hemodialysis patients. The aim of the present study was to examine the association between serum magnesium levels and vascular calcification in hemodialysis patients. 390 nondiabetic patients on maintenance hemodialysis (226 males and 164 females, 59 +/- 13 years) were examined. Hand roentgenography was performed in each patient, and visible vascular calcification of the hand arteries was evaluated. Blood was drawn to measure serum calcium, phosphate, magnesium and intact parathyroid hormone levels. There were 52 patients (38 males and 14 females) with vascular calcification, and 338 (188 males and 150 females) without. Serum phosphate was significantly higher in the former compared with the latter group (p < 0.005); serum intact parathyroid hormone was significantly higher (p < 0.05), whereas serum calcium was not statistically different between the two groups. Serum magnesium was significantly lower in patients with vascular calcification than in those without (2.69 +/- 0.28 vs. 2.78 +/- 0.33 mg/dl, p < 0.05). Multivariate logistic regression analysis revealed that serum magnesium concentration was a significant independent factor associated with the presence of vascular calcification in hemodialysis patients (odds ratio 0.28, 95% CI 0.09 - 0.92/1 mg/dl increase in serum magnesium, p = 0.036) after adjustment for age, gender, duration of hemodialysis, calcium, phosphate and intact parathyroid hormone concentrations. Hypomagnesemia is significantly associated with the presence of vascular calcification of the hand arteries, independent of serum calcium and phosphate levels. These results suggest that higher serum magnesium concentrations may play an important protective role in the development of vascular calcification in hemodialysis patients, and that magnesium concentration of dialysis fluid may be reconsidered in view of preventing vascular calcification in hemodialysis patients.

ABSTRACTIntroduction: The use of antidiabetic drugs is expected to substantially increase since diabetes mellitus incidence rises. Currently used antidiabetic drugs have a positive safety profile, but they are associated with certain acid-base and electrolyte abnormalities. The aim of the review is to present the current data regarding the antidiabetic drugs-associated acid-base and electrolyte abnormalities.Areas covered: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been linked with the scarce, but serious, complication of euglycemic diabetic ketoacidosis, as well as with an increase in serum potassium, magnesium and phosphorus levels. Metformin use has been associated with the development of lactic acidosis, although many studies have doubt the direct link with this serious complication. Additionally, metformin in some studies has been linked with a decrease in serum magnesium levels. Insulin administration is associated with a reduction in serum potassium, magnesium and phosphorus concentration, along with reduced renal magnesium excretion. Pioglitazone is associated with an increase in serum magnesium levels. Current data regarding the pathophysiological mechanisms, precipitants, risk factors and presentation of the above abnormalities are discussed in the present review.Expert opinion: Clinicians should choose appropriately between antidiabetic drugs based not only on their hypoglycemic efficacy and effects on cardiovascular risk but also based on the patient’s specific risk to develop acid-base or electrolyte derangements.

ObjectiveOur purpose is to evaluate whether serum magnesium when entering the ICU is related to 28-day in-hospital all-cause mortality in the pediatric ICU.MethodsWe used the PIC database to conduct a retrospective analysis to investigate the first-time serum magnesium levels of 10,033 critically ill children admitted to the pediatric ICU, and analyzed association between serum magnesium and all-cause mortality. Smoothing spline plots, subgroup analysis and segmented multivariate logistic regression analysis were conducted to estimate the relative risk between serum magnesium and all-cause mortality. The shape of the curve was used to describe the relationship between magnesium and 28-day in-hospital mortality.ResultsThere is a non-linear relationship between serum magnesium and 28-day in-hospital all-cause mortality. The U-type relationship between serum magnesium and all-cause mortality was observed. The optimal range of serum magnesium with the lowest risk of mortality was 0.74–0.93 mmol/L. As the serum magnesium level reaches the turning point (0.74 mmol/L), the risk of death decreases by 60% for every 0.1 mmol/L increase in serum magnesium; when the serum magnesium level exceeds 0.93, an increase of 0.1 mmol/L increases the risk of death by 38 %.ConclusionSerum magnesium has a U-shaped relationship with 28-day in-hospital all-cause mortality. Both low and high serum magnesium can increase the risk of death. The best serum magnesium range when the risk of death is the lowest is 0.74–0.93 mmol/L.

Serum Calcification Propensity in Children on Chronic Hemodialysis