Are Observational Reports on the Association of Dialysate Sodium with Mortality Enough to Change Practice? Perspective from the RESOLVE Study Team
Authors: Brendan Smyth, Rathika Krishnasamy, Meg Jardine
Journal: Journal of the American Society of Nephrology (2023)

Sodium is an obligate component of dialysate fluid, essential for preventing cell lysis. In most settings, dialysate sodium (DNa) concentration is set as a facility-level default and not determined by individual clinical characteristics. Reports consistently find that most dialysis facilities practice a "default" approach to DNa. Initially, DNa levels may have been determined by technical factors. The DNa levels of the 1960s were around 130 mmol/L, creating a sodium diffusion gradient in the context of long slow dialysis sessions. As technologies advanced and population pressures mounted, dialysis sessions became shorter and DNa rose to support hemodynamic stability. Over the past decade, there has been increasing interest in the possibility that lower DNa concentrations may be a mechanism to reduce the excess cardiovascular disease seen in people with kidney failure. Disordered sodium and fluid homeostasis is a defining feature of kidney failure. Persistent sodium and fluid overload may mediate cardiovascular pathology through increased systolic blood pressure, greater thirst-driven interdialytic weight gain, and direct vascular toxicity, leading to left ventricular hypertrophy, myocardial fibrosis, and ultimately cardiac morbidity and mortality. There is a global momentum for a reduction in DNa concentrations. In fact, the average DNa concentration has fallen in every country included in the Dialysis Outcomes and Practice Patterns Study (DOPPS) reports.1 Interest in reducing DNa concentrations was most clearly stated in a proposal published in 2014 by a coalition of the major US dialysis providers.2 The statement acknowledged the need for randomized evidence but, in the meantime, called for a reduction of DNa concentrations to 134–138 mmol/L, along with lengthened dialysis session times and avoidance of sodium loading. These changes, however, are not supported by robust evidence. The observational evidence did not show improved survival with lower DNa, rather showed an association with harm for some subgroups. The DOPPS serial cross-sectional analyses of registry-level data from multiple countries conducted a series of analyses of DNa concentrations and mortality. DNa levels >140 mmol/L were associated with lower hospitalizations and, in units practising a default approach, with lower all-cause mortality.3 The association with better mortality was particularly apparent for people with lower serum sodium concentrations (<137 mmol/L).4 The DOPPS findings were consistent regardless of whether they restricted the analyses to units practising a default DNa approach or included units with individual DNa approaches. These reports were interpreted cautiously, given the inability to completely adjust for confounders, including the multiple differences in dialysis delivery. By contrast, a study of 2272 people in an American dialysis chain found that DNa concentrations >140 mmol/L were associated with an increased risk of mortality in individuals with higher predialysis serum sodium, compared with DNa concentrations of 140 or <140 mmol/L, although there was no significant association in those with lower predialysis sodium values.5 This study included relatively few patients (257 patients in total) who received a DNa concentration of <140 mmol/L underscoring one of the limitations of comparing different observational reports. What other evidence supports the enthusiasm for lower DNa concentrations? A relatively small randomized evidence base suggests improvements in some short-term cardiovascular surrogates. The randomized evidence base of <700 patients in 15 trials6–9 shows beneficial effects overall for some surrogates, including lower SBP and less interdialytic weight gain. An improvement in BP is persuasive, given the benefits for pharmaceutically induced blood pressure lowering in the dialysis10 as well as the general population. However the randomized DNa trials show more frequent intradialytic hypotension with lower DNa concentrations,6 a phenomenon associated with worse cardiovascular outcomes, as well as giving conflicting results for left ventricular hypertrophy.7,8 In this context, a new observational study sheds light on contemporary practice. Pinter et al.11 analyzed mortality in more than 68,000 incident hemodialysis patients under the care of a single dialysis chain in 25 countries comparing lower DNa concentrations (138 mmol/L or less, mostly 138 mmol/L) to higher DNa (>138 mmol/L, mostly 140 mmol/L). Lower DNa was associated with a 57% increase in all-cause mortality (hazard ratio, 1.57; 95% confidence interval, 1.25 to 1.98) compared with higher DNa after adjusting for multiple confounders. Unlike the earlier reports, the increased mortality associated with lower DNa was seen regardless of whether patients had low, normal, or high serum sodium levels but was particularly marked in those with low serum sodium (hazard ratio, 2.56; 95% confidence interval, 2.00 to 3.28). Strengths of this study include its inclusion of patients from a single chain, data extracted from a common electronic medical record, and the ability to adjust for multiple confounders. The Pinter report does not resolve the dilemma facing the dialysis community. The evidence for DNa concentrations remains confusing, whereas the observational evidence for mortality does not support the direction in which the world's dialysis units are moving. There is an urgency to generate high-quality evidence given DNa is an obligate part of hemodialysis delivery. The Randomized Evaluation of Sodium Dialysate Levels on Vascular Events (RESOLVE) study (NCT02823821) is an international cluster randomized quality assurance study led by a global coalition of clinicians, clinical researchers, and patient partners designed to provide definitive guidance for practice. Participating dialysis units already practising a default DNa approach are randomized to one of two default DNa concentrations in current practice, 137 and 140 mmol/L. Recruited units currently practice a default approach, which means they need not change their clinical approach and can continue to use nondefault DNa levels in individual circumstances. The study is embedded in clinical care in multiple countries, reflecting the diversity of clinical practice. It uses existing clinical information systems and clinical definitions to determine the components of its primary end point of all-cause death, myocardial infarction, and stroke. The study reflects clinical practice other than the replacement of arbitrary with randomized determination of default DNa concentration and the sharing of anonymized data to permit analysis. It operates with simplified consent (waiver or opt-out consent) with the approval of local Institutional Review Boards and in accordance with global and national statements criteria for simplified consent including that patients are not exposed to risks greater than those encountered in clinical practice.12 The choice of a cluster randomized design over an individually randomized one is important for a few reasons. First, most units currently practice a default approach, a finding confirmed by Pinter's analyses. Second, a cluster randomized design allows great generalizability of the study findings which is particularly important when the intervention cannot be avoided as with DNa for recipients of hemodialysis therapy. Third, inclusion of a broad population is particularly important when there are plausible suspicions of an interaction between frailty and the effect of treatments. Participants in conventional randomized trials often represent relatively healthier patients. This is also true of trials recruiting dialysis patients where participants often have better prognostic markers at study entry and experience roughly half the mortality rate of people in the general dialysis population.13 DNa may have different effects in healthier compared with frailer patients as suggested by the DOPPS analyses. People with low serum sodium may respond differently to DNa than those with higher sodium, and low serum sodium has a well-established association with frailty, including among dialysis patients. RESOLVE is well underway with six actively participating countries and others in preparation. Pinter's analysis has added materially to the urgency to complete the study by raising again uncertainties rather than providing definitive answers. The limitations of all the observational evidence are readily apparent. It is impossible to adjust for all known and unknown confounders, particularly for questions, such as sodium management, which may be affected by diet, culture, and ethnicity as well as multiple aspects of dialysis and general medical care. It even remains difficult to directly compare the large observational analyses, given the differences in populations, DNa distributions, and other dialysate practices. Meanwhile, variation in practice persists, perpetuating a situation in which some patients may have worse outcomes, if DNa concentration has an effect on cardiovascular outcomes and mortality. The issue of DNa concentration selection is one of many examples in health care where practice arises from arbitrary decisions. A RESOLVE-like approach could be considered for many aspects of health care delivery. Quality assurance approaches where randomization is embedded in continually evolving care delivery under appropriate ethical oversight could accelerate the advent of better outcomes for patients.