Observational Study Finds Association of Dialysate Sodium with Mortality

How much dialysate sodium to give patients during hemodialysis treatments has been an area of interest for decades.

The amount of dialysate sodium prescribed has fluctuated over the years, from early days of dialysis, when 130 mmol/L or lower was common, to a peak of approximately 140 mmol/L in the mid-2000s, said Brendan Smyth, PhD, of the National Health and Medical Research Council Clinical Trials Centre at The University of Sydney in Australia. In the past 10 to 15 years, there has been a shift back down to 136 to 138 mmol/L, he said, although “without any large-scale data to prove that this was the right thing to do.” Dialysate sodium concentrations have fallen in each of the 12 countries included in the Dialysis Outcomes and Practice Patterns Study reports (1), a prospective cohort study of over 50,000 patients.

“The rationale for the change is straightforward: Sodium is bad,” Smyth said. “These [patients] are sodium overloaded, they’ve lost the ability to excrete sodium, [and] they’re water overloaded as well; the last thing we want is to give them more sodium in their dialysate. Indeed, small studies consistently show that lower dialysate sodium concentrations result in positive changes in fluid status with less weight gained in between [patient] dialysis sessions and better blood pressure.”

Now, new research published in JASN (2) has found, perhaps paradoxically, that lower dialysate sodium concentrations (≤138 mmol/L) were associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L), even after adjusting for multiple confounders.

The work, the largest observational study to our knowledge—in a multinational cohort of 68,196 patients receiving care from 875 Fresenius Medical Care NephroCare clinics in 25 countries—found that lower dialysate sodium was associated with a 57% increase in all-cause mortality (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.25–1.98).

The results were “very surprising,” said lead study author Jule Pinter, MD, of the University Hospital Würzburg in Germany. “I never thought there's a mortality association with the lower dialysis sodium. I would have thought that we’d see there is a cardioprotective effect or a null effect even.”

Pinter, Smyth, and colleagues (2) analyzed real-time electronic health records from a NephroCare clinical database between 2010 and 2019. The database contains patient characteristics, daily hemodialysis treatment data based on the values set for machines during each session, laboratory parameters, and medications. The authors included all patients starting maintenance hemodialysis treatment who had at least one bioimpedance spectroscopy measurement recorded within the first 90 days of their first treatment. Patients were followed until death, transplantation, change of modality, transfer to a non-Fresenius dialysis site, withdrawal from dialysis, or December 4, 2019.

Over 2.1 million patient-months of exposure, from more than 21.4 million hemodialysis sessions, were available for analysis. During the study period, 31.7% of patients (n = 21,644) died, 9.1% (n = 6217) received a kidney allograft, and 28.5% (n = 19,419) reached the end of the study date. The remaining 30.7% (n = 20,916) were withdrawn from the study before the end of follow-up.

Most patients (63.2%) received a dialysate sodium of 138 mmol/L; 15.8%, 139 mmol/L; or 20.7%, 140 mmol/L. The remainder received other prescriptions ranging from 132 to 137 mmol/L. The cohorts of patients receiving lower versus higher dialysate sodium prescriptions shared similar characteristics. Two-thirds were men, the mean age was 63, and the average relative fluid overload was not clinically significant. Most clinics (78.6%) used a default dialysate sodium policy under which all patients at the clinic received the same dialysate sodium prescription, unless altered by their physician.

The mortality risk associated with higher dialysate sodium was present regardless of patient serum sodium (HR, 2.56 [95% CI, 2.00–3.28] for those with hyponatremia; HR, 1.91 [95% CI, 1.49–2.46] for those with isonatremia; and HR, 1.68 [95% CI, 1.30–2.17] for those with hypernatremia).

“These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices,” the authors wrote. “It was clear to us that we saw a strong effect on mortality and it's worthwhile to keep on going to get better and randomized evidence to address” a critical question of how much dialysate sodium is appropriate, Pinter said. Smyth and colleagues also wrote an editorial (3) on the study.

Pinter and Smyth said that the findings highlight the importance of the ongoing Randomised Evaluation of Sodium Dialysate Levels on Vascular Events (RESOLVE) trial, a multinational effort, in which they are involved. RESOLVE, which aims to recruit 400 dialysis centers in multiple countries, is randomizing centers to use a default of either 137 mmol/L or 140 mmol/L dialysate sodium concentrations. Outcomes, including mortality and cardiovascular events, will be assessed on individual patients receiving care at those sites. So far, since 2016, investigators have enrolled over 200 centers in Australia, Germany, the United Kingdom, Malaysia, India, and Canada. Results are expected in 2026. Although there is not a substantial difference between the two concentrations being studied, “it's large enough that we expect that we should see a difference if one truly exists,” Smyth said.

How to remove water (and by default, salt) has been an ongoing critical question, Pinter noted, but not a lot of studies have been conducted to provide this needed evidence. In 2014, a consensus opinion (4) from the chief medical officers of 14 large dialysis companies in the United States recommended dialysate sodium be lowered as part of a “volume first” approach to lowering cardiovascular morbidity and death, Pinter said. “But [the authors] also acknowledged at the time that there were only 310 patients [who] had ever been included in randomized dialysate sodium trials worldwide.”

While the nephrology community awaits results of the RESOLVE trial, Pinter advises that nephrologists working with patients undergoing dialysis be conservative and careful but not to rely on observational data to change their prescription practices. “Do not change care until randomized evidence becomes available,” Pinter suggested.

Smyth agreed. “I would not suggest that a dialysis unit change [its] practice based on [this] paper,” he advised. “The data [are] observational, which means that dialysate sodium could be acting as a marker of some other difference in the way these patients are cared for,” he explained. While investigators tried to account for differences among sites, there is only so much that can be done statistically. “[The JASN article] should be seen as a call for a randomized study, and fortunately, we’ve got one on the way.”

For more information about the RESOLVE trial, see https://clinicaltrials.gov/study/NCT02823821. To join the RESOLVE study team, contact Brendan Smyth at brendan.smyth@sydney.edu.au.