Editorial

rieur Dialysate Sodium and the Milieu Inte

Finnian R. Mc Causland,* B. S. Tilley, and Sushrut S. Waikar*

Clin J Am Soc Nephrol 7: 57, 2012. doi: 10.2215/CJN.12101111

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 uids. Claude Bernards insight in the 1800s about the milieu intrieur (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 uid 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 125130 mEq/L (3), to facilitate sodium removal by diffusion. The advent of hydrostatic-driven ultraltration allowed dialysis times to be shortened while maintaining 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 symptoms was 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 uids ameliorated many of these unwanted side effects. Consequently, the standard DNa increased to the more recent range of 138140 mEq/L (3). The concept of improved hemodynamic stability with higher DNa also accounts for the development of sodium modeling 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 these measures (46), but they came with 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
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associate with reduced thirst and less IDWG compared with the use of xed 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 (1012). In this months CJASN, 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 ndings 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 and mortality 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 DNathe investigators performed subgroup analyses in those centers that did and did not individualize the DNa. Among those centers with nonindividualized DNa, higher DNa was associated with lower mortality (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% condence interval, 1.001.08 per 2 mEq/L higher DNa) and lower SBP. The authors argue that the nonindividualized analyses represent the ndings 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 ndings on SBP support this notion: SBP was lower with higher DNa in the individualized analyses, possibly because higher DNa may be used in those prone 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 sufciently large. In the nonindividualized analyses, there were several signicant imbalances: those with higher DNa were younger, less likely to be diabetic, and had lower serum albumin.

*Renal Division, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, Massachusetts; and Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, Massachusetts Correspondence: Dr. Sushrut S. Waikar, MRB-4, Brigham and Womens Hospital, Boston, MA 02446. Email: swaikar@ partners.org

Copyright 2012 by the American Society of Nephrology

Clinical Journal of the American Society of Nephrology

Multivariable modeling attempts to account for measured differences, but unmeasured confounding from differences in case-mix, physician practices, geographical imbalances, and other variables may have been missed or incompletely assessed and led to biased results. Indeed, analyses from DOPPS have previously demonstrated signicant geographic variability in hemodialysis practice patterns and outcomes (14,15), and one is left wondering if statistical adjustment for facility clustering and stratication by regionas done in the hospitalization and mortality analyses by Hecking et al.adequately captures such variability and their confounding effects on analyses examining outcomes among a select subcohort (i.e., those from facilities with nonindividualized dialysate sodium). Selection bias should also be considered in these analyses, because nearly 7000 individuals (13% of the eligible cohort) were excluded because of the use of sodium modeling. Because the time-average dialysate sodium concentration in sodium modeling algorithms is typically .140 mEq/L, these patients could have been included in the higher dialysate groups and shed additional light on this common and relatively untested prescription pattern. The implications of the study by Hecking et al. need to be considered in the context of recent studies conducted on dialysate and serum sodium. In a separate publication by Hecking et al. involving some of the same patients (31%), the association between dialysate sodium and mortality differed according to the SNa: dialysate sodium .140 mEq/L was associated with a trend toward higher mortality among those with serum sodium $140 mEq/L (HR, 1.26; P50.10), whereas higher DNa was associated with lower mortality among those with serum sodium ,137 mEq/L (HR, 0.77; P50.04) (16). We found similar results from analyses of a medium-sized dialysis organization in the United States (n52272): those treated with higher DNa ($140 mEq/L, including sodium modeling) had higher mortality only in the setting of higher SNa, with a trend toward lower mortality among those with lower SNa (17). In both our study and the CJASN study by Hecking et al., the effect of higher dialysate sodium on IDWG was clinically small, although statistically signicant: an increase of 0.17% of postdialysis body weight for every 2 mEq/L higher DNa (Hecking et al.) or 0.14% increase in DNa .140 mEq/L compared with DNa #140 mEq/L (Mc Causland et al.). We found no association between DNa and BP, a nding also noted by Munoz Mendoza et al., who examined the sodium gradient (i.e., dialysate serum sodium concentration) (18). Overall, taken in the context of other studies, it appears that higher DNa may be benecial in certain patients and detrimental in others. Higher DNa may be associated with a lower risk of hospitalization, despite a modest increase in IDWG and variable effect on SBP. The association between DNa and mortality is complex and may depend on SNa. Patients with lower SNa may experience better outcomes with higher, rather than lower, DNa; conversely, those with higher SNa may experience worse outcomes with higher DNa. Higher DNa may lead to improved intradialytic cardiovascular stability by promoting entry of uid from the intracellular to the extracellular compartment and possibly by facilitating vasopressin release (19). In certain patients, the potential benecial effect of improved cardiovascular stability with higher DNa may outweigh adverse effects from diffusive sodium gain.

Net sodium balance during hemodialysis results from both diffusion and convection. Although one might assume that the difference between the dialysate and plasma sodium concentration is the simple factor governing diffusive clearance (or gain) of sodium and hence postdialysis SNa, the reality is likely more complicated, as evidenced by the fact that postdialysis SNa is variable and difcult to predict accurately; part of this results from unintended differences between prescribed and delivered (i.e., measured) DNa concentrations (20). The plasma water sodium concentration is determined by the total body exchangeable sodium, total body exchangeable potassium, and total body water (21,22)all three of which are in ux during hemodialysis. Physiochemical factors governing electrolyte ux across the dialysis membrane additionally include ionic activities of sodium, potassium, chloride, and bicarbonate; the GibbsDonnan effect near the membrane (which will vary among patients); and aggregation of proteins during dialysis that may lead to effective spatial variations of electric potential along the dominant ow direction. A fundamental approach by mathematically modeling these processes is needed to determine the physical mechanisms responsible for net sodium transport. Clinicians are faced with a number of options for dialysate sodium prescriptions: xed sodium concentrations at various levels; tailoring the dialysate to the serum sodium concentration; sodium modeling strategies; and, where available, online monitoring of plasma conductivity with automatic adjustment of dialysate conductivity. The manuscript by Hecking et al. provides important insights on the variability of clinical practice and hypothesis-generating results on associations between DNa and morbidity and mortality. Testing different dialysate prescriptions in randomized trials will be difcult, although important. Surrogate endpoints such as IDWG and BP may be misleading based on the intriguing results provided by Hecking et al. Differences in the response to DNa according to SNa (or other associated characteristics) further complicate any planned trial examining mortality as a primary endpoint. Lowering DNa or tailoring it to the SNa may be benecial for some, but harmful for those with lower SNa, suggesting that randomization should be stratied according to the baseline SNa or that separate interventional trials should be considered for those with lower SNa. Our dialysis patients have entrusted us with their milieu intrieurwe owe it to them to continuously strive to optimize the safe, effective, and evidence-based delivery of this life-sustaining therapy.
Disclosures None. References 1. Gross CG: Claude Bernard and the constancy of the internal environment. Neuroscientist 4: 380385, 1988 2. Flanigan MJ: Role of sodium in hemodialysis. Kidney Int Suppl 76: S72S78, 2000 3. Sam R, Vaseemuddin M, Leong WH, Rogers BE, Kjellstrand CM, Ing TS: Composition and clinical use of hemodialysates. Hemodial Int 10: 1528, 2006 4. Stiller S, Bonnie-Schorn E, Grassmann A, Uhlenbusch-Korwer I, Mann H: A critical review of sodium proling for hemodialysis. Semin Dial 14: 337347, 2001 5. Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M: Optimal composition of the dialysate, with emphasis on its

Clin J Am Soc Nephrol 7: 57, January, 2012

rieur, Mc Causland et al. Editorial: Dialysate Sodium and the Milieu Inte

6. 7.

8. 9.

10. 11. 12. 13.

14.

15.

inuence on blood pressure. Nephrol Dial Transplant 19: 785 796, 2004 Sang GL, Kovithavongs C, Ulan R, Kjellstrand CM: Sodium ramping in hemodialysis: A study of benecial and adverse effects. Am J Kidney Dis 29: 669677, 1997 Song JH, Park GH, Lee SY, Lee SW, Lee SW, Kim MJ: Effect of sodium balance and the combination of ultraltration prole during sodium proling hemodialysis on the maintenance of the quality of dialysis and sodium and uid balances. J Am Soc Nephrol 16: 237246, 2005 Levin NW, Zhu F, Keen M: Interdialytic weight gain and dry weight. Blood Purif 19: 217221, 2001 de Paula FM, Peixoto AJ, Pinto LV, Dorigo D, Patricio PJ, Santos SF: Clinical consequences of an individualized dialysate sodium prescription in hemodialysis patients. Kidney Int 66: 12321238, 2004 Raimann JG, Thijssen S, Usvyat LA, Levin NW, Kotanko P: Sodium alignment in clinical practiceimplementation and implications. Semin Dial 24: 587592, 2011 Penne EL, Levin NW, Kotanko P: Improving volume status by comprehensive dietary and dialytic sodium management in chronic hemodialysis patients. Blood Purif 30: 7178, 2010 Santos SF, Peixoto AJ: Sodium balance in maintenance hemodialysis. Semin Dial 23: 549555, 2010 Hecking M, Karaboyas A, Saran R, Sen A, Inaba M, Rayner H, Horl WH, Pisoni RL, Robinson BM, Sunder-Plassmann G, Port FK: Dialysate sodium concentration and the association with interdialytic weight gain, hospitalization, and mortality. Clin J Am Soc Nephrol 7: 92100, 2012 Goodkin DA, Bragg-Gresham JL, Koenig KG, Wolfe RA, Akiba T, Andreucci VE, Saito A, Rayner HC, Kurokawa K, Port FK, Held PJ, Young EW: Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: The Dialysis Outcomes and Practice Patterns Study (DOPPS). J Am Soc Nephrol 14: 32703277, 2003 Goodkin DA, Young EW, Kurokawa K, Prutz KG, Levin NW: Mortality among hemodialysis patients in Europe, Japan, and the

16.

17.

18.

19. 20. 21.

22.

United States: Case-mix effects. Am J Kidney Dis 44[Suppl 2]: 1621, 2004 Hecking M, Karaboyas A, Saran R, Sen A, Horl WH, Pisoni RL, Robinson BM, Sunder-Plassmann G, Port FK: Predialysis serum sodium level, dialysate sodium, and mortality in maintenance hemodialysis patients: The Dialysis Outcomes and Practice Patterns Study (DOPPS) [published online ahead of print September 22, 2011]. Am J Kidney Dis doi:10.1053/j.ajkd.2011.07.013 Mc Causland FR, Brunelli SM, Waikar SS: Dialysate sodium, serum sodium and mortality in maintenance hemodialysis [published online ahead of print September 2, 2011]. Nephrol Dial Transplant doi:10.1093/ndt/gfr497 Munoz Mendoza J, Sun S, Chertow GM, Moran J, Doss S, Schiller B: Dialysate sodium and sodium gradient in maintenance hemodialysis: A neglected sodium restriction approach? Nephrol Dial Transplant 26: 12811287, 2011 Shimizu K, Kurosawa T, Sanjo T: Effect of hyperosmolality on vasopressin secretion in intradialytic hypotension: A mechanistic study. Am J Kidney Dis 52: 294304, 2008 Hecking M, Kainz A, Horl WH, Herkner H, Sunder-Plassmann G: Sodium setpoint and sodium gradient: Inuence on plasma sodium change and weight gain. Am J Nephrol 33: 3948, 2011 Edelman IS, Leibman J, OMeara MP, Birkenfeld LW: Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 37: 12361256, 1958 Nguyen MK, Kurtz I: New insights into the pathophysiology of the dysnatremias: A quantitative analysis. Am J Physiol Renal Physiol 287: F172F180, 2004

Published online ahead of print. Publication date available at www. cjasn.org. See related article, Dialysate Sodium Concentration and the Association with Interdialytic Weight Gain, Hospitalization, and Mortality, on pages 92100.