Outcomes of a Higher vs. Lower Hemodialysate Magnesium Concentration (Dial-Mag)

1. Statement of the health problem or issue In end-stage kidney disease, dialysis is needed to remove toxins and electrolytes that would otherwise accumulate in a patient's blood. The fluid used in dialysis, the dialysate, contains magnesium, and the lower the concentration of dialysate magnesium, the more magnesium is removed from a patient's body during dialysis. Understanding the optimal amount of magnesium to include in the dialysate is crucial as magnesium regulates more than 300 enzymes in the body and is vital to heart, muscle, and bone health. In Canada, the dialysate is prepared by central suppliers and contains magnesium in concentrations of 0.38, 0.5, or 0.75 mmol/L. In the absence of clinical trial evidence, there is no consensus on what magnesium concentration is best, and all 3 concentrations are used today in Canadian hemodialysis centres.
2. Objective of the project In outpatients receiving conventional hemodialysis, to determine if providing a higher versus lower dialysate magnesium concentration (0.75 vs. ≤0.5 mmol/L) as a centre policy alters outcomes important to patients and their providers.
3. Outline This is a pragmatic, two-arm, parallel-group, cluster-randomized, open-label, multicentre, comparative-effectiveness trial embedded into routine care in hemodialysis centres in Canada. Centres have been randomized to, and are receiving a dialysate magnesium concentration of 0.75 mmol/L or ≤0.5 mmol/L in the intervention and control groups, respectively. Patients receiving maintenance hemodialysis at these centres will be followed for study outcomes during the trial follow-up period. The trial is highly pragmatic to facilitate high intervention adherence and extensive uptake of the findings; pragmatic features include (i) broad eligibility criteria, (ii) all eligible dialysis centres offering facility-based maitenance hemodialysis were recruited into the trial, (iii) participating centres are well representative of the variety of setting patients recieve care in, (iv) intervention implementation within routine clinical care delivered by dialysis unit personnel rather than researchers, (v) flexible intervention delivery and use of co-interventions, (vi) follow-up of patient outcomes using routinely collected data sources, (vii) an intention-to-treat analysis using all available data, and (viii) outcomes highly relevant to patients.
4. What is unique/innovative about the project? The investigator usually needs to study a large number of patients in a clinical trial to reliably understand the effects of a treatment. Normally, a study with 15,000 patients would cost more than $15 million dollars to conduct; however, this study will provide a reliable answer to the question being asked and cost less than $4 million. This is because the majority of data is already being collected by the healthcare system. For example, when a patient is hospitalized for a heart attack or stroke, this information is recorded in a secure healthcare database. The investigator will be able to analyze these healthcare data at the end of the study (and link patient outcomes to the type of dialysis treatment received (i.e. treatment or control). This innovative study design means that the study will be much larger (but cost much less) than a traditional clinical trial. This pragmatic trial includes all patients who receive facility-based maintenance hemodialysis in participating centres. High-risk patients with multiple comorbidities, including cognitive impairments or disabilities, who are often excluded from trials because of their high-risk status are eligible for participation in the Dialysate Magnesium trial. By including patients from a variety of medical, ethnic, geographic, and socioeconomic backgrounds, the results of the trial should be broadly generalizable.
5. What is the impact of the proposed research?

For patients with severe kidney failure (10,000 in Ontario and >2 million worldwide), hemodialysis provides a life-saving treatment option; however a tragic 20-40% of patients die within one year of starting hemodialysis. The dialysate is a critical component of hemodialysis, yet little evidence is available to guide its optimal formulation. Dialysate magnesium in particular has received little scientific attention until recently, with new research suggesting that a higher dialysate magnesium concentration may benefit patients. Outcomes that may be improved include mortality, cardiovascular outcomes, and muscle cramps.

While it is possible to raise the concentration of serum magnesium through oral supplements, using dialysis to do this is simpler and safer. It has little to no additional cost, does not add to a patient's pill burden, is not dependent on an adherent patient taking their pills, and avoids the gastrointestinal side effects of oral magnesium supplements.

If the investigator is able to demonstrate that a higher dialysate magnesium concentration improves patient outcomes, this formulation can be readily adopted to improve the care of ∼2 million patients receiving hemodialysis worldwide.