For patients with ESRD undergoing hemodialysis, the importance of sodium removal by ultrafiltration to control extracellular volume expansion has been stressed since the earliest reports (1). Additional sodium can also be removed by diffusive transport if the dialysate sodium (DNa) level is set below the predialysis serum sodium (SNa) concentration (2,3). Vice versa, higher DNa levels translate into higher dialysate-to-SNa gradients, which are associated with thirst (3,4), interdialytic weight gain (IDWG) (5–7), and hypertension (8,9).
Using a patient’s predialysis SNa as a reference to prescribe individualized or tailored DNa has thus been considered rational (3,10,11), and various prospective interventional trials have found a significant decrease in IDWG by reducing DNa (10,12). As a result of previous guidelines and recommendations (8,9,13) and recent observational studies and commentaries (7,14,15), DNa tailoring may become routine clinical practice.
Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) and a simultaneous report from the Hemodialysis Study have demonstrated that predialysis SNa concentrations are inversely associated with mortality (16,17). Prior DOPPS analyses were restricted to patients with multiple SNa measurements and intriguingly suggested that, for patients with low mean SNa levels, higher DNa prescriptions are associated with lower mortality risk. In the current study, we have expanded the study population using “baseline” data obtained at entry of patients into the DOPPS and determined the following within various strata of SNa: (1) associations between IDWG and DNa, (2) associations between DNa and outcomes, and (3) the influence of IDWG on outcomes.
Materials and Methods
The DOPPS enrolls nationally representative samples of dialysis facilities from 12 different countries and random samples of hemodialysis patients from each participating facility. There have been four study phases (DOPPS 1–4) since the start of the DOPPS in the United States in 1996. Follow-up information is obtained every 4 months and includes laboratory measurements and dates of and diagnoses associated with patient hospitalization and death (18–20).
Both predialysis SNa measurement and the DNa prescription were available for 60% of eligible patients at their entry into DOPPS (baseline SNa). The percentages were 32% in DOPPS 1 (SNa was not recorded during the initial facility round in the United States and Japan), 65% in DOPPS 2, 78% in DOPPS 3, and 89% in DOPPS 4. All patients were included unless they were dialyzing against variable DNa concentrations (sodium modeling, n=6990; 13%), had an SNa value outside 126–150 mEq/L (n=224; <1%), or had a DNa prescription outside 125–155 mEq/L (n=583, 1%). Data from the DOPPS in the United States in phase 4 were not included because of incomplete data on hospitalizations and comorbid conditions. Compared with our previous study on mean SNa and mortality (16), 69% of patients in the present analysis were different. As a result, they represent a distinct study population that is less influenced by the frequency of laboratory measurements, possibly an indicator for patient care.
Directly measured data on IDWG—predialysis weight from one hemodialysis session minus postdialysis weight from the previous hemodialysis session—were not uniformly available. Because intradialytic weight loss correlates very strongly with the preceding IDWG (r=0.85–0.88 based on 6124 patients in DOPPS 4), we used the physiologically more meaningful term IDWG to refer to midweek measurements of baseline interdialytic weight loss, expressed as a percentage of “dry” weight or postdialysis weight. This approach is consistent with our previous analyses (21) and other previous reports (22,23).
Descriptive statistics were used to examine the prevalent cross-section of DOPPS 1–4 patients at baseline. Linear regression models were used to analyze (1) the association between the baseline DNa and patient characteristics and (2) IDWG as an outcome evaluated as a function of DNa and SNa. Models for baseline DNa as an outcome variable were adjusted for DOPPS phase and country in addition to all variables listed. (For example, when age is noted as a predictor of DNa, this variable has been adjusted for all other variables.) Adjustments for models with IDWG as an outcome variable are described in the figures. Adjustments for facility clustering were not appropriate for this analysis because many facilities prescribed a single DNa level to most of their patients. Assuming that baseline SNa in each facility would approximately follow a normal distribution (5), higher weight gain would be expected to cluster around facilities with a higher facility DNa, on the basis of evidence that DNa is associated with IDWG in studies at single facilities (5,6) and in prospective studies on DNa reduction (10,12).
Proportional hazards (time-to-event) models (Cox) were used to determine the association between mortality and combinations of DNa (four groups) and SNa (five groups) using a single reference category. Participants were followed until the earliest of death or up to 7 days after departure from the facility for kidney transplantation, change of treatment modality, withdrawal from dialysis, return of renal function, or transfer to another facility. Follow-up time was censored at the end of DOPPS phase for patients who did not depart from the facility. Cox models were adjusted as described in the figures. Similarly adjusted Cox models were used to examine the relationship between time to first hospitalization (excluding vascular access–related procedures) and combinations of DNa and SNa. Proportional hazards were confirmed by testing log(time) interactions and examining log-log survival plots. For calculations, we used MS Excel 2003 and SAS 9.2 for Windows (SAS Institute, Inc, Cary, NC).
In total, 29,593 patients from DOPPS phases 1–4 were eligible for and were included in the present analysis. Median follow-up time was 16.5 (interquartile range, 8.6–24.0) months. Mean (±SD) baseline SNa was 138.2±3.5 mEq/L in the study population and was unequally distributed throughout the DOPPS countries; levels were highest in Japan (139.0±3.2 mEq/L) and lowest in France (137.4±3.5 mEq/L), as previously observed for mean SNa (16).
Correlation of Variables of Interest at Baseline versus Follow-Up
SNa, DNa, and IDWG are recorded every 4 months in DOPPS phases 1, 3, and 4. For patients with at least three measurements of SNa, DNa, and IDWG (n=13,391), follow-up was defined as the mean of all subsequent measurements excluding baseline. Follow-up SNa and IDWG were highly correlated with baseline SNa and IDWG (r=0.59 and r=0.63, respectively). Mean follow-up DNa was within 1 mEq/L of baseline DNa in 86% of patients.
DNa Prescription Practices
As in our previous study of mean SNa (16), the DNa prescription in the present study population showed no correlation with baseline SNa (r=0.02). These data, analyzed at the patient level, suggested that DNa prescriptions were not tailored to the SNa. At the facility level, there was likewise no meaningful correlation between baseline facility mean SNa and mean DNa among 960 facilities (r=0.01).
Among facilities with reported SNa and DNa in at least five patients, 56% used the same level of DNa in 90%–100% of their patients, whereas the remaining 44% of facilities used various DNa concentrations. These two practice patterns were distributed unequally across the DOPPS countries (Figure 1) and suggest that many facilities individualize their DNa prescriptions, although not specifically according to SNa. Patient characteristics in facilities with individualized versus nonindividualized DNa are shown in Table 1. In facilities with individualized DNa, we identified several patient characteristics, including hypertension, residual renal function (i.e., urine output >200 mL/d), and male sex, as statistically significant predictors for lower DNa prescription according to linear regression models (Table 2).
IDWG and Predialysis Systolic BP
IDWG was slightly lower in facilities with individualized versus nonindividualized DNa (Table 1). When IDWG was treated as an outcome variable and DNa as a predictor in linear regression models, DNa prescriptions >142 mEq/L (mean, 144.2 mEq/L) were consistently associated with the highest IDWG, even when analyzed in different strata of SNa (Figure 2). Compared with patients with DNa <140 mEq/L, IDWG in patients with DNa >142 mEq/L was higher by 0.55% of total body weight (95% confidence interval [CI], 0.45%, 0.66%). Expressed continuously, IDWG increased by 0.17% of postdialysis body weight per 2 mEq/L higher DNa (95% CI, 0.15%, 0.20%), independent of SNa. Moreover, IDWG decreased by 0.10% of postdialysis body weight per 2 mEq/L higher SNa (95% CI, −0.11%, −0.09%), independent of DNa, suggesting that higher IDWG may lead to a slight dilution of the predialysis SNa.
Average predialysis systolic BP (SBP) was 4.8 mmHg lower in facilities with individualized DNa versus nonindividualized DNa (Table 1). With predialysis SBP as an outcome and DNa as a predictor in linear regression models, predialysis SBP decreased by 0.88 mmHg per 2 mEq/L higher DNa (95% CI, −1.21, −0.56 mmHg). In an analysis restricted to facilities with individualized DNa, predialysis SBP was 1.50 mmHg lower per 2 mEq/L higher DNa (95% CI, −1.90 to −1.10 mmHg). With analysis restricted to facilities with nonindividualized DNa, however, predialysis SBP was 0.66 mmHg higher per 2 mEq/L higher DNa (95% CI, 0.05, 1.28).
Mortality Associated with Predialysis SNa and DNa
We confirmed in the present study population that predialysis SNa was associated inversely with all-cause mortality (hazard ratio [HR], 0.94 per 2 mEq/L higher SNa [95% CI, 0.93, 0.96]; P<0.0001), as observed by Hecking et al. (16) and Waikar et al. (17). Because higher IDWG has been associated with a higher mortality risk (21,24), it might be hypothesized that higher DNa also would be associated with higher mortality. However, higher DNa concentrations were not associated with higher mortality across all subgroups of baseline SNa (Figure 3). Instead, the fully adjusted overall mortality HR (also adjusted for predialysis SNa) was lower with higher DNa (HR, 0.98 per 2 mEq/L higher DNa), without reaching statistical significance (95% CI, 0.95, 1.02; P=0.29). Of note, additional adjustments for IDWG and predialysis SBP did not systematically affect the overall mortality risk associated with various DNa prescriptions or the corresponding significance levels (Supplementary Figure 1: mortality HR, 0.98 per 2 mEq/L higher DNa [95% CI, 0.95, 1.01]). Moreover, the relation between DNa and mortality did not vary by level of IDWG (P for interaction = 0.79).
Sensitivity Analyses of Mortality Risk
Residual Renal Function.
In the preceding mortality analysis, the model was adjusted for residual renal function. To further determine whether patients without residual renal function might have a worse outcome because of higher IDWG, we restricted the analysis to patients with vintage >1 year and no urine volume >200 mL/d (n=13,331). In this analysis, the mortality HRs were 0.94 per 2 mEq/L higher SNa (95% CI, 0.92, 0.97) and 0.99 per 2 mEq/L higher DNa (95% CI, 0.94, 1.04), consistent with our overall model.
Individualized versus Nonindividualized DNa.
When the analysis was restricted to patients in facilities with nonindividualized DNa, DNa was significantly associated with lower all-cause mortality (HR, 0.88 per 2 mEq/L higher DNa [95% CI, 0.83, 0.94]). By contrast, in facilities with individualized DNa, the mortality HR was 1.04 per 2 mEq/L higher DNa (95% CI, 1.00, 1.08).
With analysis restricted to deaths from cardiovascular disease (CVD), the CVD mortality HR was 0.96 per 2 mEq/L higher DNa (95% CI, 0.90, 1.03). In facilities with nonindividualized DNa, the CVD mortality risk was significantly associated with lower CVD-mortality (HR, 0.81 per 2 mEq/L higher DNa [95% CI, 0.69, 0.94]). By contrast, in facilities with individualized DNa, the CVD mortality HR was 1.04 per 2 mEq/L higher DNa (95% CI, 0.97, 1.12).
Hospitalization Risk Associated with DNa and Predialysis SNa
DNa was inversely associated with the risk for first hospitalization from any cause, excluding vascular access procedures, in adjusted Cox models. This finding was consistent through all categories of baseline SNa (Figure 4). Overall, the hospitalization risk was 3% lower per 2 mEq/L higher DNa (HR, 0.97 [95% CI, 0.95, 1.00]; P=0.04), independent of SNa, and 3% lower per 2 mEq/L higher SNa (HR, 0.97 [95% CI, 0.96, 0.98]), independent of DNa. Adjusting the models for IDWG and predialysis SBP did not systematically affect the overall morbidity risk associated with various DNa prescriptions or the corresponding significance levels (Supplementary Figure 2: hospitalization HR, 0.97 per 2 mEq/L higher DNa [95% CI, 0.95, 1.00]; P=0.04).
Sensitivity Analyses of Hospitalization Risk
Restricting analyses to patients in facilities with nonindividualized DNa or individualized DNa prescriptions yielded consistent inverse correlations of DNa with hospitalization risk (HR, 0.97 per 2 mEq/L higher DNa in each analysis). The risk for hospitalization due to fluid overload (recorded only in DOPPS 2–4) was also lower with higher DNa (HR, 0.94 per 2 mEq/L higher [95% CI, 0.84, 1.05]).
Dialysate-to-SNa Gradient and Mortality
Our analyses of DNa within various strata of SNa did not identify an increased mortality risk associated with higher DNa. However, an additional technique was used to investigate whether the dialysate-to-SNa gradient (GNa) might be associated with mortality beyond SNa alone. First, we observed that the GNa was directly associated with mortality risk (HR, 1.05 per 2 mEq/L higher GNa [95% CI, 1.03, 1.06]). Then we created a random “faux DNa” for each patient, normally distributed about a mean of 140 mEq/L, with an SD of 1.85 mEq/L (as observed in this study). We created a “faux gradient” by subtracting the patient’s observed SNa from the faux DNa. The mortality results were essentially the same for faux GNa (HR, 1.05 per 2 mEq/L higher faux GNa [95% CI, 1.03, 1.06]) compared with the actual GNa and were consistent across five iterations, strongly suggesting that the association between the gradient and mortality is primarily attributable to the SNa component and not the DNa component of the gradient.
In the present study, we have shown that higher DNa prescriptions are associated with increased IDWG of the order of 0.17% of postdialysis weight (or 0.12 kg for a 70-kg patient) per 2 mEq/L higher DNa, but not with a higher risk for hospitalization or death. Instead, patients dialyzed with higher DNa concentrations had a significantly lower risk for hospitalization and, in facilities where all or almost all patients used the same DNa, a significantly lower risk for death.
Previous studies have found that greater dialysate-to-SNa concentration gradients are associated with higher mortality, and our analyses by gradient confirm this observation (25). Because high gradients are typically observed in patients with low SNa who have an associated higher mortality risk, it was important to analyze the components of the gradient: SNa and DNa. Figure 3 supports the hypothesis that SNa explains the association of mortality with higher sodium concentration gradients by showing that mortality does not increase with DNa within each SNa group. Our additional analyses using a random variable DNa to create a faux gradient also indicate that the association between GNa and mortality depends on the mortality risk associated with lower SNa.
Encouragement to decrease the DNa concentration seem logical because thirst and IDWG can be reduced. However, the incremental IDWG, adjusted for SNa, was relatively small and our analyses did not identify an influence of IDWG on morbidity and mortality associated with DNa. Furthermore, viewing IDWG as a principal determinant of dialysis mortality may be questioned, for the following reasons:
- Only patients with very high levels of IDWG (>5.7% of body weight) have an elevated risk (21).
- The magnitude of the adjusted mortality risk previously identified with very large IDWG did not exceed 1.25 (24).
- IDWG is not synonymous with chronic fluid overload. When measured by bioimpedance (26) or inferred from slopes of intradialytic relative plasma volume (27), there are markedly higher mortality risks for overhydration (HR, 1.7) (26) or hypervolemia (HR, 2.1) (27) than for IDWG (21,24).
The mortality risk associated with higher DNa was significantly lower in facilities that did not individualize their DNa prescriptions but was higher in facilities that used individualized DNa. The former analysis represents a pseudo-randomized experiment in which a normally distributed range of patient SNa levels are subjected to the same DNa. The latter result is likely confounded by indication because sicker and older patients were treated with higher DNa (Table 2).
We obtained similarly divergent associations between predialysis SBP and DNa in facilities with individualized versus nonindividualized DNa. Predialysis SBP was higher with higher DNa prescriptions in nonindividualized DNa-facilities, suggesting that in the pseudo-randomized experiment of facilities with nonindividualized DNa, we could identify the physiologic effect of higher DNa on BP, demonstrated in small prospective clinical trials of reduced or individualized DNa (12,28,29). In contrast, the finding of relatively higher SBP associated with lower DNa prescriptions in individualized DNa facilities is likely confounded by indication because hypertension is associated with prescription of lower DNa (Table 2).
This study is observational; thus, we can only speculate as to why higher DNa does not appear to be harmful. A recent publication demonstrated that lower urinary sodium excretion is associated with higher CVD mortality (30), consistent with previous reports (31–34), and questioned the assumption that reductions in dietary salt intake could substantially reduce CVD events and medical costs (35). However, these observations may not be transferrable to patients undergoing hemodialysis. The observed benefits of higher DNa may be due to improved intradialytic cardiovascular stability, which may reduce the risks associated with intradialytic hypotension (36), myocardial stunning (37,38), and endotoxemia (39).
Other study limitations include the lack of quality control of the delivered dialysate concentration and our inability to identify which assay was used by various DOPPS facilities to determine predialysis SNa. However, our previous analysis at a single center showed that the difference between measured and prescribed DNa concentrations was on average very close to zero, and its distribution was not skewed (5). Regarding sodium assays, recommendations from the International Federation of Clinical Chemistry Expert Panel on the conversion of sodium levels obtained by direct potentiometry should ensure that these values correspond to indirect potentiometry, which is typically used in centralized laboratories (40), and thus most likely by most DOPPS facilities.
In conclusion, higher DNa prescriptions were associated with higher IDWG but also with a 3% lower risk for hospitalization for every 2 mEq/L higher DNa. In facilities that did not individualize DNa prescriptions, all-cause mortality risk was 12% lower with every 2 mEq/L higher DNa. These findings were independent of predialysis SNa. Thus, the benefit of reducing IDWG by decreasing DNa does not seem to translate into improved outcomes and, in the absence of randomized prospective studies, should be balanced carefully against a potentially increased risk for morbidity and death.
For the present analysis, M.H. received a research grant from the Else Kröner-Fresenius Foundation without restrictions on publications and has been a visiting scientist at Arbor Research Collaborative for Health.
Heather Van Doren provided editorial assistance for this manuscript, and Jinyao Zhang was consulted for additional statistical support (both employees of Arbor Research Collaborative for Health).
The DOPPS is administered by Arbor Research Collaborative for Health and is supported by scientific research grants from Amgen (since 1996), Kyowa Hakko Kirin (since 1999, in Japan), Genzyme (since 2009), and Abbott (since 2009), without restrictions on publications.
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.05440611/-/DCSupplemental.
See related editorial, “Dialysate Sodium and the Milieu Intérieur,” on pages 5–7.
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