Interdialytic weight gain and low dialysate sodium concentration in patients on chronic hemodialysis: a systematic review and meta-analysis

Purpose The present systematic review and meta-analysis aimed at evaluating the effect of low dialysate sodium concentration on interdialytic weight gain (IDWG) in chronic hemodialysis patients. Methods Studies were eligible for inclusion if they were English language papers published in a peer-reviewed journal and met the following inclusion criteria: (1) studies in adult patients (over 18 years of age), (2) included patients on chronic hemodialysis since at least 6 months; (3) compared standard (138–140 mmol/l) or high (> 140 mmol/l) dialysate sodium concentration with low (< 138 mmol/l) dialysate sodium concentration; (4) Included one outcome of interest: interdialytic weight gain. Medline, PubMed, Web of Science, and the Cochrane Library were searched for the quality of reporting for each study was performed using the Quality Assessment Tool of Controlled Intervention Studies of the National Institutes of Health. The quality of reporting of each cross-over study was performed using the Revised Cochrane Risk of Bias (RoB) tool for cross-over trials as proposed by Ding et al. Results Nineteen studies (710 patients) were included in the analysis: 15 were cross-over and 4 parallel randomized controlled studies. In cross-over studies, pooled analysis revealed that dialysate sodium concentration reduced IDWG with a pooled MD of − 0.40 kg (95% CI − 0.50 to − 0.30; p < 0.001). The systematic review of four parallel, randomized, studies revealed that the use of a low dialysate sodium concentration was associated with a significant reduction of the IDWG in two studies, sustained and almost significant (p = 0.05) reduction in one study, and not significant reduction in one study. Conclusion Low dialysate sodium concentration reduces the IDWG in prevalent patients on chronic hemodialysis.


Introduction
In many patients on chronic hemodialysis, interdialytic weight gain (IDWG) is greater than 4.0-4.5% of dry weight, the value recommended by the international guidelines [1].It is well known that a high IDWG may lead to an increased risk of cardiovascular diseases and cerebrovascular diseases, with ultimately a higher risk of mortality [2][3][4][5][6][7][8][9].Furthermore, IDWG is the cause of supplementary weekly dialysis sessions with consequent reduction of quality of life and a significant increase of economic costs.
An elevate intake of fluids and/or of foods contributes to high IDWG in patients on chronic hemodialysis.High intake of fluid is secondary to the disturbing and constant presence of thirst in such patients.Nevertheless, the adherence to fluid intake regimen is very difficult and frustrating, and rarely is successful [10][11][12][13][14][15][16][17][18].
The limitation of the IDWG is a challenge both for the patients and the physicians and is based on various types of interventions such the use of low dialysate sodium concentrations or patient level interventions [19].
The use of a low dialysate sodium concentration increases the removal of sodium during the dialytic session, and this leads to a reduced content of sodium in the body.As consequence, thirst is significantly reduced as well as the water intake in the interdialytic period.
Interestingly, it has been shown recently, that IDWG decreased significantly in Europe and in the USA and this was, at least in part, due to the use of a reduced sodium dialysate concentration during the dialytic session [2].
The present systematic review and meta-analysis aims to evaluate the efficacy of low dialysate sodium concentration in reducing IDWG in prevalent chronic hemodialysis patients.

Methods
This analysis was prospectively registered on the International Prospective Register of Systematic Reviews in Health and Social Care (PROSPERO) (CRD42022359763).

Eligibility criteria
Studies were eligible for inclusion if they were English language papers published in a peer-reviewed journal and met the following inclusion criteria: (1) primary research studies in adult patients (over 18 years of age), (2) included patients with end-stage renal disease on chronic hemodialysis since at least 6 months; (3) compared standard (138-140 mmol/l) or high (> 140 mmol/l) dialysate sodium concentration with low (< 138 mmol/l) dialysate sodium concentration; (4) Included one outcome of interest: interdialytic weight gain.We excluded studies on pediatric patients, pre-dialysis CKD patients, acute kidney injury patients, ESRD patients with other renal replacement therapy modalities, such as peritoneal dialysis and transplant.

Information sources and search strategy
A comprehensive search to identify crossover and/or parallel randomized trials studies on effects of lower dialysate concentration on IDWG in patients on chronic hemodialysis was performed.Searches were run on January 22, 2023.The following databases were searched for relevant studies: Medline, PubMed, Web of Science, and the Cochrane Library.The search terms and mesh headings included "hemodialysis/haemodialysis" AND ("weight" OR "gain" OR "weight gain" OR "interdialytic weight gain") AND ("salt" OR "NaCl" OR "fluid" OR "water" OR "sodium") AND "dialysate" as the search terms.This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Selection process and data collection process
Two authors independently reviewed the manuscripts against the eligibility criteria and quality assessment tools.Two authors independently reviewed the titles and abstracts, and full texts of potential studies were retrieved for further appraisal.In case of disagreement between the two authors, a third author was referred.We also performed a manual search for eligible studies by checking the reference lists of relevant original and review articles.Conference abstracts and literature reviews were excluded.Similarly, studies not comparing standard and low sodium dialysate concentration were excluded.Any discrepancies were resolved by consensus upon discussion with another co-author.Data extraction tables (Tables 1 and 2) were compiled to record study characteristics and participant characteristics.

Data items
The outcome for which data was sought was IDWG.

Study risk of bias assessment
The quality of reporting for each study was performed by two researchers (GP, MA) using the Quality Assessment Tool of Controlled Intervention Studies of the National Institutes of Health [42].
The quality of reporting of each cross-over study was performed by two researchers (GP, MA) using the Revised Cochrane Risk of Bias (RoB) tool for cross-over trials as proposed by Ding et al. [43].

Statistical analysis / synthesis methods
The primary outcome was the mean IDWG and compared in terms of the mean difference (MD).

Certainty assessment
Overall evidence was qualified using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidelines for both cross-over and parallel-group observational studies.Results of the quality of evidence criteria are reported in Tables 3 and 4.

Search results (study selection)
A total of 1240 publications were identified via electronic databases.After screening the titles, abstracts, and full texts, 19 studies that met the inclusion criteria were included for analysis.The PRISMA flowchart is shown in Fig. 1.Of the 19 included studies, 15 were cross-over studies and 4 were parallel groups studies.We divided the analysis into two sections: (1) comparison of standard and low dialysate sodium concentration through crossover prospective studies comprising 15 studies; (2) comparison of standard and low dialysate sodium concentration through prospective randomized parallel studies, comprising 4 studies.

Comparison of standard and low sodium dialysate concentration through crossover prospective studies
Overall, 483 patients were included.The number of patients in each individual study ranged from 7 to 92.The used dialysate sodium concentrations (mEq/l) varied largely: 138 vs 141 in one study, 135 vs 140 in two studies, 137 vs 140 in one study, 130 vs 140 in one study, 136 vs 140 in two studies, 135 vs

Comparison of standard and low sodium dialysate concentration through prospective randomized parallel studies
Overall, 247 patients were included.The number of patients in each individual study ranged from 38 to 99.The used Legend: 1. Was the study described as randomized, a randomized trial, a randomized clinical trial, or an RCT? 2. Was the method of randomization adequate (i.e., use of randomly generated assignment)?3. Was the treatment allocation concealed (so that assignments could not be predicted)?4. Were study participants and providers blinded to treatment group assignment? 5. Were the people assessing the outcomes blinded to the participants' group assignments?6. Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, co-morbid conditions)?7. Was the overall drop-out rate from the study at endpoint 20% or lower of the number allocated to treatment?8. Was the differential drop-out rate (between treatment groups) at endpoint 15 percentage points or lower?9. Was there high adherence to the intervention protocols for each treatment group?10.Were other interventions avoided or similar in the groups (e.g., similar background treatments)?11.Were outcomes assessed using valid and reliable measures, implemented consistently across all study participants?12. Did the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power?13.Were outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)?14.Were all randomized participants analyzed in the group to which they were originally assigned, i.e., did they use an intention-to-treat analysis?

Comparison of standard and low dialysate sodium concentration through prospective crossover studies
As shown in Fig. 2, compared to neutral or high dialysate sodium concentration, low dialysate sodium concentration reduced IDWG with a pooled MD of − 0.40 kg (95% CI − 0.50 to − 0.30; p < 0.001).As no significant heterogeneity was observed (p = 0.91 and I 2 = 0%), the pooled analysis was performed using a fixed-effect model.Funnel plots were generated to assess publication bias in the included studies.
As shown in Fig. 3, no obvious asymmetry, indicating no clear evidence of publication bias, was observed.

Comparison of standard and low dialysate sodium concentration through prospective randomized parallel studies
A two-group, parallel-design study randomized 99 patients  to − 0.54]), and 12 months (− 0.57 [− 0.86 to − 0.27]) [36].In the study of Liu et al. [37], after 1-month period of dialysis with standard dialysate sodium concentration at 138 mmol/l (baseline), the dialysate sodium was switched to 136 mmol/l in the intervention group (28 patients), whereas remained at 138 mmol/l in the control group (29 patients).
Each patient was followed up over a 12-month period.IDWG at baseline and 12 months was in the intervention group 3.3 ± 0.7 kg and 2.8 ± 0.6 kg (p < 0.05) and, in the control group, 3.1 ± 0.8 kg and 3.0 ± 1 kg (p > 0.05).Akdag et al. [38] randomized 46 patients, dialyzed with 140 dialysate sodium concentration, into a control group (24 patients) that maintained the dialysate 140 mmol sodium concentration and a treatment group in which the dialysate sodium concentration was reduced to 137 mmol/l.IDWG at baseline and 6 months was, in the intervention group, 2.2 ± 0.9 kg and 1.6 ± 0.

Risk of bias in studies
As shown in Table 3, cross-over design was appropriate in all studies.Five out of 15 crossover studies randomly allocated participants.Carry-over effects were not reported in any of the studies.Allocation of concealment was not reported in any crossover studies.Blinding of participants or study personnel was present in 9 studies, absent in 3, and indeterminate in 3. Data for every period were provided in every study.Relevant information about the completeness of outcome data was provided in every study.All the outcomes were fully reported in every study.All studies were apparently free of other problems.The overall rating was "low risk of bias" in 10 studies and "some concerns of bias" in 5 studies.Table 4 shows that the overall score of randomized, controlled studies comparing standard and low sodium dialysate concentration ranged from 7 to 12, being 12 in three studies and 7 in one study.
Using GRADE, the certainty of the meta-analytic evidence (the extent of confidence the estimate of effect is correct) was considered high certainty.We did not strongly suspect publication bias in the studies eligible for the Fig. 2 Forest plot of comparison between low dialysate sodium concentration and high dialysate sodium concentration about interdialytic weight gain (kg) in crossover studies Fig. 3 Funnel plot for interdialytic weight gain in crossover studies meta-analysis.We judged the evidence to have no serious indirectness, because despite variability, studies compared interventions to hemodialysis populations, and all studies used a direct measure of IDWG as the primary outcome.Considering that the sample size in the meta-analysis (n = 483) meets the optimal information size criterion, we did not downgrade due to imprecision.

Effect of low dialysate sodium concentration on intradialytic hypotensive events
In eleven studies, the number of intradialytic hypotensive events per total number of dialytic sessions has been reported.In most of these studies (9 out of 11), the frequency of intradialytic hypotensive events did not differ significantly between treatments performed with low and high sodium dialysate concentrations (Table 5).In the study of Marshall et al.,

Discussion
The meta-analysis of 13 crossover randomized studies shows that the use of a low dialysate sodium concentration reduces the IDWG in prevalent patients on chronic hemodialysis, with a pooled MD of − 0.42 kg.In addition, the present systematic review of four parallel, randomized, controlled studies reveals that the use of a low dialysate sodium concentration is associated with a significant reduction of the IDWG in two studies, sustained and almost significant (p = 0.05) in one study, and not significant in the fourth one.
It could be questioned that the − 0.40 kg reduction observed in the pooled analysis may represent an effect that can be considered as being clinically small.Indeed, it seems that, when compared with other studies [2,36], such reduction in considerable and deserve attention.In the Dialysis Outcomes and Practice Patterns Study (DOPPS), the IDWG reduction, during a 10-year period of observation, was − 0.29 kg and − 0.25 kg, in the USA/Canada and in Europe, respectively [2].Surprisingly, two recent systematic reviews have led to conflicting results [49,50].Basile et al. reported that, in most studies included in their review, patients on higher sodium dialysate had a significantly higher IDWG and that three interventional studies found no substantial differences in such parameter while in one study a reduction in total body weight in both patients undergoing low (135 mmol/l) or high (140 mmol/l) dialysate sodium concentration, but the difference between these two groups did not attain statistical significance [49].The results of the study of Dunlop et al. demonstrated that low dialysate reduced IDWG compared to neutral or high dialysate (10 studies, 352 participants: MD − 0.35 kg, 95% CI − 0.51 to − 0.18), but the results were considered by the authors themselves as being clinically small [50].
However, it has been argued that the use of a low dialysate sodium concentration may be, in some cases, associated with adverse events such as intra-dialytic hypotension, as consequence of an intradialytic hemodynamic instability [36,49].
Interestingly, the present systematic review shows that in most studies, the frequency of intradialytic hypotensive events did not differ significantly between patients receiving hemodialysis with low or high sodium dialysate concentration [22,26,27,30,32,34,35,39]. The study of Marshall et al.only reported that hypotensive events were more frequent with lower sodium dialysate concentration [36].The present review has some limitations.First, the length of the studies was extremely variously ranging from one week to twelve months.In this regard, it remains essentially unknown the mid-term and long-term effect of the use of low sodium dialysate concentration.Second, the "low" dialysate sodium concentrations used in the 20 studies were also extremely various.Consequently, it is impossible to define an "ideal" dialysate sodium concentration to be used in the clinical practice to reduce the IDWG.Third, studies were characterized by high complexity and heterogeneity.
In conclusion, the present systematic review and metaanalysis suggests that the use of a low sodium concentration in the dialysate is associated with a statistically significant reduction of the IDWG in patients on chronic hemodialysis without a significant increase of intradialytic hypotensive events.Given the high complexity and diversity of the studies, it is amenable that, a prospective, randomized study with an adequate sample size and sex distribution, definition of residual renal function and use of diuretics, use of dietary counseling during the study, definition of the difference between prescribed and serum sodium concentration will be performed in the next future.

Fig. 1 Full
Fig.1Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of our analysis

Table 1
Studies on the effect of low dialysate sodium concentration on interdialytic weight gain (IDWG): cross-over and cohort studies

Table 2
Studies on the effect of low dialysate sodium concentration on interdialytic weight gain (IDWG): randomized studies Data are expressed as * mean ± SD and ** median [95% CI] ; sex distribution [male%]: ranged 48.1-93.7;sample size: ranged from 10 to 92 patients) but not for others (use of HDF absent in all studies; use of diuretics absent in all studies but one; wash out absent in all studies but one; report of renal

Table 3
Quality analysis of cross-over studies on the effect of low dialysate sodium concentration on interdialytic weight gain Legend: 1. appropriate cross-over design; 2. the randomized order of receiving treatment; 3. carry-over effects; 4. unbiased data; 5. allocation concealment; 6. blinding; 7. incomplete outcome data; 8. selective outcome reporting; 9. other biases

Table 5
Frequency of intradialytic hypotensive events: comparison of low and high sodium dialysate concentrations