Effects of Increasing the Concentration of Dialysate Magnesium on Cardiovascular Health: A Narrative Review

Abstract

French

Purpose of review:

Cardiovascular disease (CVD) accounts for nearly half of deaths among people receiving maintenance hemodialysis. Observational and interventional data suggest that higher serum magnesium, achieved through higher dialysate magnesium concentrations or oral supplementation, may improve cardiovascular outcomes and survival. This review synthesizes current evidence and provides context for an ongoing cluster-randomized trial that is testing whether a center-wide dialysate magnesium concentration of 0.75 mmol/L, versus ≤0.50 mmol/L, delivered as a policy and sustained for up to four years, reduces the risk of major cardiovascular-related hospitalizations.

Sources of information:

Peer-reviewed articles.

Methods:

We searched MEDLINE and EMBASE for observational and interventional studies evaluating serum or dialysate magnesium concentrations and cardiovascular outcomes in patients with chronic kidney disease and/or kidney failure. We appraised the methodological quality of interventional trials. This review is divided into four sections: (1) epidemiological associations between serum magnesium concentrations and CVD outcomes, (2) the impact of a higher concentration of dialysate magnesium on CVD outcomes, (3) the impact of oral magnesium supplementation on CVD outcomes, and (4) ongoing trials.

Key findings:

Twenty studies, including 10 randomized controlled trials, were reviewed. Systematic reviews and meta-analyses show that hypomagnesemia is associated with higher risks of cardiovascular events and all-cause mortality in hemodialysis. Interventional studies indicate that higher dialysate magnesium concentrations or oral supplementation can improve surrogate markers of vascular health, including less vascular calcification and stiffness. Higher dialysate concentrations may also lower cardiovascular mortality. Given encouraging but predominantly surrogate-based evidence, adequately powered randomized trials are warranted.

Limitations:

Most trials were small, single-center, and of short duration. They relied on surrogate endpoints, and there was heterogeneity in interventions and outcome measures.

Keywords

chronic kidney disease hemodialysis dialysate magnesium cardiovascular disease cardiovascular mortality

Introduction

Over 3.5 million people around the world with kidney failure rely on regular hemodialysis sessions for their survival.¹ Unfortunately, cardiovascular disease (CVD) accounts for nearly half of their deaths, with cardiovascular mortality rates 10 to 20 times higher than the general population.^2,3 Effective interventions are urgently needed to reduce this risk.

One promising intervention is to raise serum magnesium concentrations to the upper end or slightly above the laboratory reference range. Serum magnesium is reported as either total magnesium (normal range 0.65-1.05 mmol/L, conversion: 1 mmol/L ~ 2.43 mg/dL) or ionized magnesium, the physiologically active fraction comprising approximately 55% to 70% of total magnesium (normal range 0.40-0.68 mmol/L).^4-6 Raising serum magnesium concentration can be achieved through oral supplementation or by raising the magnesium concentration in the dialysate.^7-10

Historically, low dialysate magnesium became standard to prevent hypermagnesemia in patients with reduced renal excretion, though this practice was driven by manufacturer specifications and clinical caution rather than explicit guideline recommendations.^11-14 Current knowledge reframes this approach by recognizing that hypomagnesemia is common in hemodialysis patients, with prevalence rates between 16 and 39%. This high prevalence of hypomagnesemia is attributable to factors such as dietary restrictions, poor protein and energy intake, the use of diuretics and proton pump inhibitors, and low dialysate magnesium concentrations.¹³,^15-17

Hypomagnesemia is associated with more muscle cramps, increased vascular calcification and stiffness, a greater propensity to arrhythmias, and a higher risk of CVD.^4,5,15,^18-21 In contrast, hypermagnesemia is typically mild and asymptomatic when serum magnesium remains below 2.0 mmol/L.¹⁴ In a recent observational study evaluating a dialysate magnesium concentration of 1.0 mmol/L, mean serum magnesium rose to 1.31 mmol/L and did not exceed 1.56 mmol/L in any patient.²² Clinical toxicity generally occurs at substantially higher concentrations than those targeted by supplementation strategies (e.g., diminished deep tendon reflexes at ~2.9-4.9 mmol/L; severe hypermagnesemia with cardiac arrest at >12.5 mmol/L), indicating a wide safety margin for the interventions discussed in this review.²³

Magnesium supplementation, either orally or by raising the concentration of dialysate magnesium, is considered safe in hemodialysis patients and has been associated with improved surrogate indicators of cardiovascular health. It may also reduce the risk of major adverse cardiovascular events, a hypothesis being tested in ongoing trials.^8,11 Oral magnesium is generally well-tolerated, but can be associated with gastrointestinal side effects such as diarrhea, and increased pill burden for patients on maintenance hemodialysis.^16,24 The efficacy of oral magnesium supplementation may also be reduced in patients taking medications that impair intestinal magnesium absorption, such as proton pump inhibitors.¹⁶

We are currently conducting a pragmatic, 137-center, cluster-randomized trial (Dial-Mag) to test whether a center-wide hemodialysate magnesium concentration of 0.75 mmol/L versus ≤0.50 mmol/L, delivered as a center-wide policy and sustained for up to four years, affects the rate of major cardiovascular-related hospitalizations.²⁵ We conducted this narrative review to summarize current evidence and provide context for the results of this trial. The review is divided into 4 sections and focuses on adults receiving maintenance hemodialysis:

Epidemiological associations between serum magnesium concentrations and CVD outcomes.

The impact of a higher concentration of dialysate magnesium on CVD outcomes.

The impact of oral magnesium supplementation on CVD outcomes.

Ongoing trials testing the effect of (a) magnesium supplementation or (b) a higher concentration of dialysate magnesium on CVD outcomes.

Methods

This is a narrative review that employed structured search methods to enhance comprehensiveness. We searched the MEDLINE and EMBASE databases using strategies described in Appendix 1 of the Supplemental Appendix. We also found additional articles by checking reference lists in Scopus and Google Scholar and by searching ClinicalTrials.gov for ongoing clinical trials. Eligibility criteria included adult chronic kidney disease (CKD) stage 3-5D populations, interventions involving dialysate magnesium concentration or oral magnesium supplementation, and outcomes assessing cardiovascular events or surrogate vascular markers

To enhance rigor and transparency, we critically appraised the methodological quality of randomized controlled trials (RCTs) and non-RCTs using a modified version of the Downs and Black criteria, consisting of 27 questions to evaluate validity, completeness, and power (Supplemental Appendix 2).²⁶ Each question is scored as 1 for “yes” and 0 for “no.” An additional question determines if the study indicates a clinically significant effect. Scores range from 0 to 28, with classifications for quality as follows: 0 to 14 (poor), 15 to 19 (fair), 20 to 25 (good), and 26 to 28 (excellent).

Review

Twenty published studies, including three meta-analyses, three retrospective cohort studies, one prospective observational cohort study, three matched cohort studies, and 10 RCTs, were reviewed and are summarized in Appendix 3 of the Supplemental Appendix.

Epidemiological Associations Between Serum Magnesium Concentrations and CVD Outcomes

One meta-analysis and three retrospective cohort studies described the relationship between serum magnesium concentrations and CVD outcomes. These studies suggest that lower pre-hemodialysis serum magnesium concentrations are associated with a higher risk of all-cause and cardiovascular mortality in CKD, especially in patients receiving maintenance hemodialysis.

The meta-analysis of 20 studies (N = 200 943) by Xiong et al⁵ indicated that hypomagnesemia is associated with a higher risk of mortality in individuals with CKD and kidney failure, while hypermagnesemia is associated with lower mortality risk. Two Japanese retrospective cohort studies (N = 142 555; N = 142 069) further support these findings, showing that hypomagnesemia is associated with higher cardiovascular and noncardiovascular mortality.^27,28 One study suggested the association between the concentration of serum magnesium and mortality is modified by the presence of hyperphosphatemia.²⁸ A recent cohort study from China (N = 267) showed that higher average serum magnesium concentrations are associated with better survival in individuals undergoing maintenance hemodialysis. The lowest magnesium quartile was associated with the worst prognosis for all-cause and cardiovascular mortality.²⁹

Recent data have nuanced the relationship between magnesium and mortality. In a 2025 cohort of 249 maintenance hemodialysis patients from Japan, higher ionized magnesium concentrations, particularly in the upper tertile (>0.64 mmol/L), were independently associated with all-cause mortality, whereas total serum magnesium was not.³⁰ These findings suggest that while low magnesium is harmful, very high ionized magnesium concentrations may also be undesirable, although this observation requires confirmation in larger studies.

The Impact of a Higher Concentration of Dialysate Magnesium on CVD Outcomes

We reviewed eight interventional studies (five RCTs [N = 138], three non-RCTs [N = 137]) evaluating the effects of higher concentrations of dialysate magnesium on cardiovascular health in patients receiving hemodialysis. In one matched cohort study, the outcomes were all-cause and cardiovascular mortality. The other seven studies reported on surrogate outcomes of CVD, including coronary artery calcification (CAC) and arterial stiffness, as well as emerging biomarkers such as serum calcification propensity (T50) and calciprotein particle load.

All-Cause and Cardiovascular Mortality

To date, no randomized trials have assessed the effects of different concentrations of dialysate magnesium on mortality. Only one nonrandomized matched cohort study has directly evaluated this outcome.⁷ This study compared 25 patients dialyzed with 0.75 mmol/L magnesium with 50 patients dialyzed with 0.50 mmol/L (1:2 matching) and followed them for three years. During the three-year follow-up, deaths occurred in 20% of patients in the higher dialysate magnesium group and 36% of patients in the lower dialysate magnesium group. After adjustment for age and Charlson Comorbidity Index, higher dialysate magnesium was associated with a 65% lower risk of all-cause mortality (HR 0.35, 95% CI 0.13 to 0.97). Notably, there were no cardiovascular deaths in the higher dialysate magnesium group, compared with 14.5% at three years in the lower dialysate magnesium group.

Vascular Calcification and Stiffness

In patients receiving hemodialysis, a CAC score greater than 400 is associated with higher cardiovascular risk and mortality.³¹ Magnesium may slow CAC progression by inhibiting calciprotein particles (CPPs) maturation.³² In a nonrandomized matched cohort study of 40 patients receiving hemodialysis with CAC scores greater than 300, Srisuwarn et al³³ found that a higher concentration of dialysate magnesium (0.875 vs 0.35 mmol/L) did not slow overall CAC progression over 26 weeks; however, in a subgroup with lower baseline CAC (≤1600), the higher concentration significantly reduced CAC progression.

The T50 test measures the time for CPP maturation in serum, with lower values indicating higher calcification propensity and cardiovascular risk.¹⁹ In a randomized, parallel-group controlled trial of 57 patients receiving hemodialysis, increasing the concentration of dialysate magnesium from 0.5 to 1.0 mmol/L for 28 days prolonged T50 by an average of 73 minutes and significantly reduced inflammatory cytokines and CPP levels.³⁴ A subsequent post hoc analysis confirmed that a higher concentration of dialysate magnesium was associated with less CPP and systemic inflammation.³⁵

Additional vascular benefits have been observed in the outcomes pulse wave velocity and pulse pressure, both markers of arterial stiffness associated a higher risk of CVD in patients receiving hemodialysis.^36-39 In a randomized four-week crossover study of 39 patients receiving maintenance hemodialysis, Del Giorno et al⁴⁰ demonstrated that increasing the concentration of dialysate magnesium from 0.50 to 0.75 mmol/L led to reduced pulse wave velocity, pulse pressure, and systolic blood pressure. Additionally, patients receiving the higher concentration of dialysate magnesium had lower levels of parathyroid hormone, which may further reduce vascular calcification by limiting calcium and phosphate release from bone.

In summary, higher concentrations of dialysate magnesium were associated with improved vascular protection, including reduced arterial stiffness, better hemodynamic parameters, delayed CPP maturation, and lower systemic inflammation.^34,35,40 Evidence for slowing CAC progression is inconsistent, with benefits most apparent in patients with lower baseline calcification.³³ While these improvements in surrogate outcomes are encouraging, it remains uncertain whether they translate into fewer major clinical events.

Arrhythmogenicity, Myocardial Stunning, Hemodynamics, and Blood Pressure Stability

Magnesium stabilizes cardiac electrophysiology by modulating ion channels involved in depolarization and repolarization.^41-43 Corrected QT Interval (QTc) dispersion, the difference between the longest and shortest QT intervals measured across a standard 12-lead ECG, reflects heterogeneity of myocardial repolarization, which is associated with increased risk of ventricular arrhythmias and sudden cardiac death in patients receiving hemodialysis.^44-46 In a cross-over nonrandomized study of 22 patients, dialysate magnesium concentrations of 0.75 and 0.25 mmol/L were each administered for a single session two days apart.⁴⁷ Both sessions showed significant postdialysis reductions in mean blood pressure and QTc interval. Changes in QTc dispersion pre- versus postdialysis were not significant in either session, suggesting that higher dialysate magnesium does not adversely affect myocardial repolarization heterogeneity.

Myocardial stunning, transient ischemia-induced regional wall motion abnormality (RWMA) during dialysis, is associated with adverse cardiovascular outcomes and higher mortality.^48,49 Global longitudinal strain is a sensitive tool for detecting and quantifying stunning, with a segmental reduction of 20% or more indicating RWMA.⁵⁰ In a randomized crossover trial of 20 patients receiving two weeks of hemodialysis with 0.50 and 1.0 mmol/L dialysate magnesium, Jefferies et al⁵¹ found no between-group differences in peak-stress RWMA (15 minutes before the end of a dialysis session), intradialytic hemodynamics, or QTc interval. However, left ventricular ejection fraction declined significantly from pre-dialysis to peak stress during the 0.50 mmol/L period, while it remained stable during the 1.0 mmol/L period. Additionally, intradialytic serum magnesium declined during the 0.50 mmol/L period, and greater declines correlated with worsening global longitudinal strain, indicating subclinical myocardial dysfunction and heightened vulnerability to ischemia.

Kyriazis et al⁵² conducted two randomized crossover trials examining how dialysate magnesium concentration affects blood pressure and bioimpedance-derived measures of myocardial contractility (cardiac index and cardiac output) during hemodialysis. In study A, eight patients underwent four mid-week hemodialysis sessions with varying combinations of dialysate magnesium (0.25 or 0.75 mmol/L) and dialysate calcium (1.25 or 1.75 mmol/L). In study B, 14 patients received dialysate magnesium at 0.50 mmol/L for four weeks, followed by four weeks of dialysate magnesium at 0.25 and 0.75 mmol/L in random order with 1.25 mmol/L of dialysate calcium. The authors reported that a low concentration of dialysate magnesium (0.25 mmol/L), when paired with a low concentration of dialysate calcium (1.25 mmol/L), frequently caused intradialytic hypotension due to impaired myocardial contractility.⁵² In contrast, treatment with a higher concentration of dialysate magnesium (0.75 mmol/L) was associated with superior blood pressure stability.

In summary, higher dialysate magnesium concentrations did not affect QTc dispersion or myocardial stunning, while lower concentrations were associated with declining left ventricular ejection fraction, subclinical myocardial dysfunction, and intradialytic hypotension (Figure 1).

Figure 1.

Potential cardiovascular benefits of a higher concentration of dialysate magnesium (image generated using Gemini AI).⁵³

The Impact of Oral Magnesium Supplementation on CVD Outcomes

We reviewed seven studies (five randomized trials [N = 339] and two meta-analyses [N = 802]) examining the effects of oral magnesium supplementation and cardiovascular health in patients receiving hemodialysis. These studies assessed surrogate markers such as carotid intima-media thickness (cIMT), brachial artery flow-mediated dilation (FMD), C-reactive protein (CRP), and vascular calcification.

To assess whether magnesium supplementation affects cIMT, a surrogate marker of subclinical atherosclerosis, Turgut et al⁵⁴ randomized 47 patients receiving hemodialysis to oral magnesium citrate (610 mg every other day) or calcium acetate (control) for two months. Magnesium supplementation significantly improved bilateral cIMT and lowered PTH levels.

Mortazavi et al⁵⁵ reported similar results with a slightly different magnesium regimen. In this trial, 54 patients receiving hemodialysis were randomized to oral magnesium oxide (440 mg, three times per week) or placebo for six months. Magnesium supplementation significantly reduced cIMT, whereas cIMT increased in the placebo group. This effect remained significant after adjusting for several baseline characteristics. No between-group changes were observed in endothelial function, brachial artery flow-mediated dilation, or serum CRP levels.

Talari et al⁵⁶ investigated the effects of magnesium supplementation on cIMT and glycemic control in patients with diabetes receiving hemodialysis, reporting similar benefits. In this study, 54 patients were randomized to oral magnesium oxide (250 mg daily) or placebo for 24 weeks. Magnesium supplementation significantly reduced left and right cIMT, lowered HbA1c, decreased total and low-density lipoprotein cholesterol, and reduced oxidative stress markers.

Bressendorff et al⁵⁷ conducted a three-arm randomized trial evaluating the safety and effects of oral magnesium on serum calcification propensity and intracellular magnesium in patients receiving hemodialysis. Thirty-six patients were randomized to placebo twice daily, 360 mg magnesium once daily plus placebo once daily, or 360 mg twice daily, administered as slow-release magnesium hydroxide for eight weeks. Magnesium supplementation produced a significant, dose-dependent increase in serum and urine magnesium but did not affect intracellular magnesium. The higher-dose group (720 mg/day) showed a significant improvement in serum calcification propensity, with T50 rising from 256 ± 60 to 296 ± 64 minutes (mean ± SD; P < .05).

Bressendorff et al⁵⁸ conducted a second randomized trial in 2023 (MAGiCAL-CKD) involving 148 adults with CKD (estimated glomerular filtration rate (eGFR) 15-45 ml/min per 1.73 m²), randomized to oral magnesium hydroxide (360 mg twice daily) or placebo for 12 months. While plasma magnesium concentrations increased significantly in the treatment group, there was no significant difference in baseline-adjusted CAC scores or T50 compared with placebo, contrasting with the improvements observed in their 2016 trial.

A 2018 systematic review and meta-analysis of seven RCTs (N = 306) was conducted, including healthy individuals and patients with chronic conditions, including 96 patients receiving hemodialysis. They found that magnesium supplementation significantly improved FMD, a marker of endothelial function, but in contrast to the studies above, had no overall effect on cIMT.⁵⁹ Subgroup analyses suggested greater cIMT reductions in patients receiving hemodialysis, with heterogeneity influenced by magnesium dose, treatment duration, and baseline cIMT.

A 2023 systematic review and meta-analysis of eight RCTs and one non-RCT (496 patients with CKD stage 3-4) found that magnesium supplementation increased serum magnesium concentration and modestly reduced left and right cIMT, serum calcium, and PTH levels, but did not significantly affect vascular calcification scores.⁶⁰

In summary, the current evidence suggests a beneficial role for oral magnesium supplementation in reducing surrogate markers of cardiovascular risk, particularly cIMT, and improving metabolic parameters in CKD and hemodialysis patients.

Ongoing Trials

We identified three ongoing randomized trials investigating the effects of oral magnesium supplementation or a higher dialysate magnesium concentration on CVD outcomes in patients receiving hemodialysis, including our Dial-Mag trial, which is currently being conducted across Canada.

Magnesium in chronic haemodialysis (MAGIC-HD) is a study protocol (Trial registration number: NTR6568/NL6393) assessing the safety and feasibility of stepwise increases in dialysate magnesium concentration, with hypermagnesemia (>1.25 mmol/L), bradycardia, and QTc prolongation as predefined safety endpoints.⁶¹ Patients are randomized 2:1 to either a stepwise, individualized increase in dialysate magnesium (0.50 → 0.75 → 1.00 mmol/L over eight weeks) or a fixed 0.50 mmol/L concentration. Participants will only proceed to 1.00 mmol/L magnesium dialysate if pre-dialysis plasma magnesium is below 1.15 mmol/L at week four. The trial is still in progress, with enrollment initiated in 2018. As of 2022, 43 of the planned total of 53 participants had been randomized. Its individualized titration approach will provide safety and feasibility data for progressively higher concentrations of dialysate magnesium.

A randomized clinical trial in Texas (ClinicalTrials.gov Identifier: NCT03565913) is evaluating effervescent calcium magnesium citrate (EffCaMgCit) in patients with CKD stage 5.⁶² The trial tests whether EffCaMgCit, compared with calcium acetate, can delay CPP formation, potentially reducing vascular calcification and cardiac hypertrophy-fibrosis. To date, 269 patients have been enrolled in a two-year treatment period, with trial completion expected by the end of 2025.

The Dial-Mag trial (ClinicalTrials.gov Identifier: NCT04079582) is a large, cluster-randomized study currently underway across 137 hemodialysis centers in four Canadian provinces, with an estimated enrollment of 25,000 patients and planned reporting in 2027.²⁵ Centers are randomized 1:1 to a dialysate magnesium concentration of 0.75 mmol/L or ≤0.5 mmol/L as a center-wide policy for up to four years. The two primary outcomes are (1) a composite of all-cause mortality or major cardiovascular-related hospitalization (myocardial infarction, congestive heart failure, or ischemic stroke) obtained from healthcare databases, and (2) self-reported muscle cramps via patient questionnaires. This will be the first adequately powered trial to directly test whether a center-wide higher versus lower dialysate magnesium concentration affects mortality and major cardiovascular hospitalizations.

Conclusion

Cardiovascular disease remains the leading cause of mortality in patients with kidney failure on hemodialysis. Evidence suggests that a higher concentration of dialysate magnesium may be a promising, low-cost strategy to reduce cardiovascular risk, and this is currently being evaluated in ongoing trials. Magnesium administration, via dialysate or oral supplementation, is generally safe in patients with CKD and those receiving dialysis.^8,61 Observational studies show that hypomagnesemia is associated with a higher risk of CVD and all-cause mortality.^4-6,²⁶ Interventional studies and meta-analyses indicate that increasing dialysate or oral magnesium may improve surrogate markers of cardiovascular risk, such as vascular calcification and stiffness.^8,9,40 However, the effect of magnesium interventions on mortality and major CVD events remains uncertain, warranting larger interventional trials that are adequately powered for these outcomes. High-quality evidence is lacking to inform clinical practice in this area, and definitive trials are needed.

Supplemental Material

sj-docx-1-cjk-10.1177_20543581261454463 – Supplemental material for Effects of Increasing the Concentration of Dialysate Magnesium on Cardiovascular Health: A Narrative Review

Supplemental material, sj-docx-1-cjk-10.1177_20543581261454463 for Effects of Increasing the Concentration of Dialysate Magnesium on Cardiovascular Health: A Narrative Review by Bryn Tannar, Hareth Al-Hellawi, Jessica M. Sontrop, Rey R. Acedillo, Ahmed A. Al-Jaishi, Sierra Anderson, Amit Bagga, David Berry, Eliot Beaubien, Peter G. Blake, Clara Bohm, Pierre Antoine Brown, Joe Bueti, Christopher T. Chan, Brenden Cote, Andrea C. Cowan, Nicole E. Day, Varun Dev, Miten Dhruve, Laura Gregor, Claire Harris, Swapnil Hiremath, Geena Joseph, Srinu Kammila, Mercedeh Kiaii, Lauren Killin, Eswar Kumar Kolusu, Eduardo Lacson, Bin Luo, Jennifer M. MacRae, Amber O. Molnar, Bharat Nathoo, Matthew J. Oliver, Sanjay Pandeya, Malvinder S. Parmar, David Perkins, Kathleen Quinn, Joanna Sasal, Nikhil Shah, Tanya Shulman, Samuel A. Silver, Anurag Singh, Andrew Steele, Irina St.Louis, Navdeep Tangri, Robert H. Ting, Stephanie Thompson, Marcello Tonelli, Hans Vorster, Davinder Wadehra, Ron Wald, Justin Walters, Shaoyee Yao, James Zacharias and Amit X. Garg in Canadian Journal of Kidney Health and Disease

Footnotes

ORCID iDs

Bryn Tannar

Clara Bohm

Pierre Antoine Brown

Andrea C. Cowan

Swapnil Hiremath

Bin Luo

Amber O. Molnar

Malvinder S. Parmar

Samuel A. Silver

Anurag Singh

Navdeep Tangri

Stephanie Thompson

Amit X. Garg

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding support was provided by the Canadian Institutes of Health Research, Strategy for Patient-Oriented Research for Innovative Clinical Trials (grant no. MYG 433752). Dr AG was supported by the Kay Family Chair in Transformational Kidney Care.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental Material

Supplemental material for this article is available online.

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