Dialysate sodium and the milieu intérieur.

The life-sustaining technology of maintenance hemodialysis attempts to accomplish in a dozen or so hours a week what the kidneys labor to do 24 hours per day: maintain the optimal composition and volume of body fluids. Claude Bernard’s insight in the 1800s about the milieu intérieur (“all of the vital mechanisms, however varied they may be, have always one goal, to maintain the uniformity of the conditions of life in the internal environment”) (1) are not easily achieved by an intermittent therapy, particularly for sodium and fluid balance, which normal kidneys regulate constantly. As reviewed by Flanigan, in the early days of hemodialysis, patients were mostly dialyzed twice per week for .8 hours per session with very high glucose dialysate solutions to remove excess water via the creation of an osmotic gradient (2). A lower dialysate sodium (DNa) concentration was used, typically in the range of 125–130 mEq/L (3), to facilitate sodium removal by diffusion. The advent of hydrostatic-driven ultrafiltration alloweddialysis times to be shortenedwhilemaintaining satisfactory clearance, as measured by urea kinetic modeling. However, these shorter dialysis sessions came at the price of increased dialysis-related complaints, including nausea, headaches, abdominal pain, muscle cramps, dizziness, fainting, seizures, and hypotension (2). This constellation of symptomswas referred to as the disequilibrium syndrome and was felt to be related to rapid changes in the chemical composition of the extracellular and intracellular compartments.Many early theories centered on the role of osmolality shifts, and anecdotal evidence suggested that the administration of hypertonic fluids ameliorated many of these unwanted side effects. Consequently, the “standard” DNa increased to the more recent range of 138–140 mEq/L (3). The concept of improved hemodynamic stability with higher DNa also accounts for the development of sodiummodeling as a treatment option, where the DNa concentration at the start of dialysis is high and subsequently declines during the course of the procedure. Previous studies have reported improved hemodynamic stability with thesemeasures (4–6), but they camewith downsides— an association with increased thirst (6), interdialytic weight gain (IDWG) (7), and BP (8). Individualization of the DNa has been investigated as one of many attempts to offset these presumed detrimental effects. Indeed, alignment of the DNa with the predialysis serum sodium concentration (SNa) has been shown to associatewith reduced thirst and less IDWG compared with the use of fixed DNa concentrations greater than SNa (9). Based on these important observations, several thoughtful commentators have argued that the DNa should be lowered or tailored to the SNa (isonatric) to lessen diffusive sodium gain and thereby lower BP, minimize IDWG, and improve clinical outcomes (10–12). In thismonth’sCJASN, Hecking et al. (13) present the results of an observational study of SNa and DNa in Dialysis Outcomes and Practice Patterns Study (DOPPS), a large international database of dialysis patients that has provided important insights into worldwide treatment patterns in hemodialysis. Their findings run counter to what many may have predicted: higher DNa appeared to be associated with lower risk of hospitalization despite being associated with higher IDWG. The associations with mortality and systolic BP (SBP) were not as straightforward. In the overall dataset, there appeared to be no association between DNa andmortality and 0.88 mmHg lower SBP for every 2 mEq/L higher DNa. Because of the variability in treatment patterns— 55% of patients were from facilities using largely a single DNa, whereas 44%were from facilities that had variable DNa—the investigators performed subgroup analyses in those centers that did and did not individualize theDNa. Among those centers with “nonindividualized” DNa, higherDNawas associatedwith lowermortality (hazard ratio [HR] of 0.88 per 2 mEq/L higher DNa) and higher SBP. Among those centers with “individualized” DNa, higher DNa was associated with higher mortality (HR, 1.04; 95% confidence interval, 1.00–1.08 per 2 mEq/L higher DNa) and lower SBP. The authors argue that the “nonindividualized” analyses represent the findings of a pseudo-randomized experiment, suggesting that because DNa was not adjusted according to patient characteristics, there is little possibility for confounding by indication. Indeed, their findings on SBP support this notion: SBP was lower with higher DNa in the individualized analyses, possibly because higher DNa may be used in thoseprone to intradialytic hypotension,whereas SBP was higher in the nonindividualized analyses, possibly from increased salt loading. However, the nonindividualized analyses are not comparable to a balanced randomized trial, in which differences across groups are expected to be minimal if sufficiently large. In the nonindividualized analyses, there were several significant imbalances: those with higher DNa were younger, less likely to be diabetic, and had lower serum albumin. *Renal Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, Massachusetts