CLINICAL EPIDEMIOLOGY www.jasn.

org
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Effect of Dialysate and Plasma Sodium on Mortality

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in a Global Historical Hemodialysis Cohort

Jule Pinter ,1 Brendan Smyth ,2,3 Stefano Stuard ,4 Meg Jardine ,2,5
Christoph Wanner ,1,6 Patrick Rossignol,7,8 David C. Wheeler ,9 Mark R. Marshall ,10
Bernard Canaud ,11 and Bernd Genser 12,13
Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT
7U9oaAfj on 07/03/2024

Background Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and
is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the
removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium
removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense
of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate
sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this
retrospective cohort, we aimed to assess whether prescribing a dialysate sodium #138 mmol/L has
an effect on survival outcomes compared with dialysate sodium .138 mmol/L after adjusting for plasma
sodium concentration.
Methods The study population included incident HD patients from 875 Fresenius Medical Care Neph-

CLINICAL EPIDEMIOLOGY
rocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (#138 or .138 mmol/L)
and plasma sodium (,135, 135–142, .142 mmol/L) concentrations defined exposure status. We used
multivariable Cox regression model stratified by country to model the association between time-varying
dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment
variables, including bioimpedance measures of fluid status.
Results In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions
per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in
20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized
concentration. During a median follow-up of 40 months, one third of patients (n521,644) died. Dialysate
sodium #138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total
population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations
and other confounding variables. Subgroup analysis did not show any evidence of effect modification by
plasma sodium concentrations or other patient-specific variables.
Conclusions These observational findings stress the need for randomized evidence to reliably define
optimal standard dialysate sodium prescribing practices.

JASN 35: 167–176, 2024. doi: https://doi.org/10.1681/ASN.0000000000000262

INTRODUCTION Received: August 10, 2023 Accepted: October 12, 2023.

Published Online Ahead of Print: November 15, 2023.

People receiving maintenance dialysis therapy for
kidney failure have a 5-year survival of 50%, worse
than people with many malignancies.1 The major
cause of morbidity and mortality in this population
is cardiovascular disease.2,3 Abnormal fluid status
See related article, “Are Observational Reports on the Association
of Dialysate Sodium with Mortality Enough to Change Practice?
Perspective from the RESOLVE Study Team,” on pages 229–231.
Correspondence: Dr. Jule Pinter, University Hospital Würzburg,
Oberdürrbacherstr 6, Würzburg 97080, Germany. Email: pinter_j@ukw.de

and plasma sodium concentrations, which are Copyright © 2023 by the American Society of Nephrology

JASN 35: 167–176, 2024 ISSN : 1533-3450/1046-167 167

 CLINICAL EPIDEMIOLOGY www.jasn.org
common in chronic hemodialysis (HD) patients, are believed
to be major risk factors for poor cardiovascular outcomes.
Chronic fluid and sodium overload4,5 is reflected in
tissue sodium accumulation that has only recently been
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visualized by sodium magnetic resonance imaging, a 23Na
magnetic resonance imaging technique.6,7 Such sodium and
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fluid excess can be linked to vascular toxicity and further end-
organ damage.8 Optimizing fluid volume management and
restoring sodium mass balance in HD patients is a potential
strategy to reduce cardiovascular morbidity and mortality as
recently highlighted by the Kidney Disease Improving Global
Outcomes.9 However, excessive or rapid fluid depletion in-
duced by high ultrafiltration rate is recognized as a primary
contributor to dialysis-induced systemic stress.10
An alternative approach is to modulate sodium, fluid
volume balance, and tonicity in HD patients by acting on
diffusive sodium clearance.11 Unlike dietary sodium re-
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striction recommendations which can be difficult for pa-
tients to adhere to dialysate sodium is easily modifiable and
at negligible cost.11 Observational studies indicate a recent
shift toward using a lower dialysate sodium concentration,
presumably with the aim of decreasing interdialytic weight
gain, restoring sodium homeostasis, and preserving car-
diovascular function.12 However, considerable uncertainty
remains as to whether a lower dialysate sodium concen-
tration improves outcomes in HD patients.13 One obser-
vational study suggested that higher dialysate sodium
prescriptions may reduce the risk of mortality in patients
with low plasma sodium concentrations,14 whereas others
demonstrated a higher mortality risk in patients with
higher plasma sodium concentrations,15 leaving uncer-
tainty as to the true relationship between mortality and
both plasma and dialysate sodium.
Several randomized trials have shown that in a conven-
tional short dialysis treatment schedule (i.e., 3–4 hours), lower
dialysate sodium concentrations (,138 mmol/L) result in
modest reductions in intradialytic weight gain and BP but an
increase intradialytic hypotension events.13,16 No randomized
studies have been of sufficient size or duration to assess the
effect of lower dialysate sodium on cardiovascular or mortality
outcomes.13 In this retrospective multinational cohort study
of incident HD patients, our objective was to evaluate whether
prescribing a lower (#138 mmol/L) as compared with a
higher dialysate sodium (.138 mmol/L) adjusted for plasma
sodium concentrations has an effect on survival outcomes.
METHODS
As previously reported,17 we analyzed a clinical database of
an international dialysis network (NephroCare, Fresenius
Medical Care, FMC)4 that includes centers in 25 countries
in Europe, Africa, the Middle East, and Latin America
(Supplemental Table 2). Patients’ electronic medical re-
cords are centralized in the European Clinical Database 5
168 JASN
Significance Statement
This large observational cohort study aimed to investigate the
relationship between dialysate and plasma sodium concentrations
and mortality among maintenance hemodialysis patients. Using a
large multinational cohort of 68,196 patients, we found that lower
dialysate sodium concentrations (#138 mmol/L) were in-
dependently associated with higher mortality compared with
higher dialysate sodium concentrations (.138 mmol/L). The risk of
death was lower among patients exposed to higher dialysate so-
dium concentrations, regardless of plasma sodium levels. These
results challenge the prevailing assumption that lower dialysate
sodium concentrations improve outcomes in hemodialysis patients.
The study confirms that until robust evidence from randomized
trials that are underway is available, nephrologists should remain
cautious in reconsideration of dialysate sodium prescribing prac-
tices to optimize cardiovascular outcomes and reduce mortality in
this population.
(EuCliD 5) of FMC clinics.17 The EuCliD5 database is a
real-time electronic health record for routine clinical care
in dialysis centers.4,17 The database contains patient char-
acteristics, daily HD treatment data based on the values set
on the machine for each session, laboratory parameters,
and medications.17 The data quality of the analysis set (01-
2010 to 12-2019) is validated by the continuous quality
improvement program FMC initiated in 2007.18 Monthly
review of key performance indicators enables data driven,
objective, and continuous monitoring of clinical and op-
erational performances across all countries.18 These gov-
ernance processes ensure that clinical care is driven by
improvements in key performance indicators.18 This means
that the quality of therapy is not customized according to
insurance or reimbursement rate.18 Ethical approval was
granted by the Ethics Committee of Wuerzburg University
Hospital (Reference No. 255/22).
Patient Population
Incident patients commencing maintenance HD treatment,
irrespective of whether this was their first or subsequent
kidney replacement modality, were eligible if they had at
least one bioimpedance spectroscopy measurement recor-
ded within the first 90 days of their first treatment. Patients
who were prescribed a variable dialysate sodium and ultra-
filtration profile were excluded from this study. The pro-
vision of this fluid status assessment was included to adjust
for the mortality risk associated with baseline relative fluid
overload4 (Supplemental Figure 2) and to ensure compara-
bility of incident patients in the cohort. Follow-up started
the day after the first bioimpedance spectroscopy measure-
ment. Patients were followed until death, transplantation,
change of modality, transfer to a non-Fresenius dialysis site,
withdrawal from dialysis, or December 4, 2019, at which
time they were considered censored. We did not define a
minimum follow-up period. Follow-up was unavailable for
patients who left their NephroCare clinic after treat-
ment withdrawal.
JASN 35: 167–176, 2024

Plasma and Dialysate Sodium
The primary exposure was dialysate sodium concentration
prescribed in mmol/L increments, including fixed concentra-
tions. The term default was defined as the use of a standard-
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ized prescription for most of the patients within the clinic.
Analysis of the distribution of dialysate sodium revealed that a
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limited number of dialysate sodium prescriptions were pre-
scribed across all clinics and countries, suggesting that analysis
as a continuous variable or as a multi-level categorical variable
was not appropriate. Dichotomization resulted in minimal
information loss and increased model reliability. We therefore
dichotomized dialysate sodium levels at the cut-point of #138
and .138 mmol/L.
The secondary exposure variable was plasma sodium con-
centration. Plasma sodium was measured in accredited lab-
oratory results in accordance with ISO standards according to
Nephrocare standard operating procedures. We used the
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following previously described categories of hyponatremia
(,135 mmol/L), isonatremia (135–142 mmol/L), or hyper-
natremia (.142 mmol/L).19–21 We used the upper limit
of .142 mmol/L to define hypernatremia because the prev-
alence of serum sodium above 145 mmol/L is low in this
patient population.22
Fluid Status
We assessed fluid status using bioimpedance spectroscopy
measurements because the tests were routinely available at
NephroCare clinics and able to provide more objective as-
sessment than clinical assessment alone.4,23,24 The measure-
ments were obtained using the Body Composition Monitor
(BCM; FMC, Bad Homburg, Germany). BCM measurements
were taken with patients in the supine position before the start
of dialysis. BCM measures whole-body impedance at 50
frequencies between 5 kHz and 1 MHz. It determines extra-
cellular and intracellular resistance on the basis of the Cole
model, and a dedicated fluid volume model estimates extra-
cellular and intracellular water.25 These variables are used in a
three-compartment body composition model that divides
body weight into normally hydrated lean tissue mass, nor-
mally hydrated adipose tissue mass, and excess fluid.26 The
BCM algorithm and formula have been validated against gold
standard references (bromide and deuterium dilutions).23,25,27
BCM uses 21.1 to 1.1 L as normal values for fluid status.24
Relative fluid overload is derived as a weekly average mea-
surement by indexing the absolute excess fluid volume to the
volume of the extracellular water compartment.28,29 A thresh-
old equal to or .7% defines mild overload, whereas the
threshold of equal to or .13% in women or 15% in men
above normal fluid status is used in all NephroCare clinics to
define clinically significant relative fluid overload, which cor-
responds to an absolute increase of 12.5 L.24 Fluid depletion
means that a person is depleted of fluid by more than 7%
(i.e., ,21.1 L).24 Relative fluid overload is used as a perfor-
mance indicator in Nephrocare clinics to allow for compar-
isons among individuals.24
JASN 35: 167–176, 2024
www.jasn.org CLINICAL EPIDEMIOLOGY
Outcome
The primary end point of the study was all-cause mortality.
Vital status was recorded for each active HD patient in
the database.17
Subgroup Analysis
We prespecified important prognostic variables, such as age,
sex, time on HD, systolic BP predialysis, diabetes, cardiovas-
cular disease, and chronic heart failure for a conducting
subgroup analyses.
Statistical Analysis
The exposure status of plasma and dialysate sodium and fluid
status and other prespecified risk factors (Supplemental
Figure 1) were coded as time-varying variables on a monthly
panel. The monthly panel of patient-months allowed weekly
and individual measurements of HD sessions to be smoothed
and overcame the computational complexity of advanced
time-to-event models that allow for time-varying variables.
Clustering and potential heterogeneity of baseline hazard
among countries was addressed by fitting the models stratified
by country. In addition, we used a robust resampling esti-
mator to adjust for clustering by clinic. When two or more
measurements per month were available, we averaged the
monthly value. Missing values in repeated measurements over
the patient’s follow-up were replaced by the “last observation
carried forward” method. If the first value was missing, the
mean of the study population at baseline was imputed.
We previously observed a continuous exposure–risk asso-
ciation pattern when analyzing plasma sodium and all-cause
mortality in decile plots.17 For the bivariate joint exposure
classification of both markers (plasma and dialysate sodium),
we prespecified the categorical rationale on the basis of
pathophysiological natremia thresholds for plasma sodium
(three categories for hyponatremia, isonatremia, and hyper-
natremia) and data-dependent dichotomization of dialysate
sodium into #138 and .138 mmol/L (Methods section,
plasma and dialysate sodium). The reference category was
defined as the one with the lowest risk estimates.
Descriptive statistics of study variables were calculated,
stratified by exposure category, including means and SDs
for continuous variables and frequencies for categorical var-
iables. Where values were not normally distributed, medians
and interquartile ranges were calculated.
Multivariable Cox proportional hazards models, including
time-varying variables, were used to quantify the effect of
exposure on mortality risk adjusted for confounders.
Clustering by country and medical clinic was addressed by
stratifying models for country and using a robust sandwich
estimator for between-clinic variance. Covariates were se-
lected on the basis of a conceptual model that classified
risk factors that could potentially associate with mortality
(see Supplemental Figure 1 for dialysate sodium).
The aim was to obtain a consistent multivariable estimate
of the joint effect of the two exposure variables, adjusted for
Dialysate Sodium Cohort Study, Pinter et al. 169
 CLINICAL EPIDEMIOLOGY www.jasn.org
all confounding variables. Potential mediators, that is, var-
iables that might be on the pathway between exposure and
mortality, were not modeled as covariates (Supplemental
Figure 1) and not included in the model. First, we fitted a
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univariate model, including only exposure, and then a mul-
tivariable model adjusting for all potential confound-
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ing variables.
The pattern of association was visualized with bar charts
showing the multivariable adjusted hazard ratios (HRs) and
95% confidence intervals (CIs) of each of the five levels
compared with the reference level that showed the lowest
risk. Because we had no assumptions about the direction of
cause and effect, we chose to visualize the association between
plasma and dialysate sodium using density plots.
All statistical analyses were performed using STATA
(StataCorp. 2023. Stata Statistical Software: Release 18.
College Station, TX: StataCorp LLC).
7U9oaAfj on 07/03/2024
RESULTS
Patient Characteristics
Within the study period, 154,512 patients were identified as
incident HD patients in EuCliD5 from FMC clinics. Within
the first three months, on average, 31 (SD 10.5, median 35)
dialysate sodium, 3 (SD 3.0, median 3) plasma sodium, and
2.8 (SD 1.5, median 3) body composition measurements were
available per patient in 68,196 patients in 875 HD sites located in
25 countries (Supplemental Figure 2 and Supplemental Table 3).
Supplemental Table 5 presents the baseline characteristics of
the excluded patients. After aggregation of all available HD
sessions on a monthly time panel, 2,123,957 patient-months
of exposure from 21,416,647 HD sessions were available for
analysis. On average, individual patients contributed 307 (SD
281.5, median 221) dialysate sodium, 13 (SD 20.6, median 4)
plasma sodium, and 17.6 (SD 18.8, median 11) body com-
position measurements per patient to the analysis.
During the study period, 32% of patients (n521,644) died,
9.1% received a kidney transplant (n56217), and 28.4%
(n519,419) reached the end of the study date. The remainder
30.6% (n520,916) were withdrawn from the study before the
end of follow-up (Supplemental Table 4 list for full reasons).
Dialysate Sodium Prescription Pattern
Most patients received a dialysate sodium of 138 mmol/L
(63.2%), 139 mmol/L (15.8%), or 140 mmol/L (20.7%)
(Supplemental Table 1a), with the remainder (0.4%) receiving
other dialysate sodium prescriptions ranging from 132 to
137 mmol/L. During follow-up, the prescription was changed
in 1361 patients (2%).
Patients receiving lower versus higher dialysate sodium
prescriptions had largely similar characteristics (Table 1). Two
thirds of the cohort were men, the mean age was 63 years, and
the average relative fluid overload was not clinically signifi-
cant, that is, a value ,15% indicates mild overload, equivalent
170 JASN
to an absolute overload of .1.1 L but ,2.5 L above normal
fluid status (in a person weighing 70 kg). Patients prescribed
higher dialysate sodium had more patient-months of follow-
up with a history of heart failure or cardiovascular disease.
Dialysate sodium bath assignment was mostly nonover-
lapping across countries, with most clinics (78.6%) using a
default dialysate sodium policy (Supplemental Table 1b).
Plasma sodium was associated with dialysate sodium
prescription, but the difference is unlikely to be of clinical
significance (mean plasma sodium 137.9 (SD 2.8) versus
138.0 (SD 3.7) mmol/L, in the #138 and .138 mmol/L
dialysate sodium groups, respectively (Supplemental
Figure 3).
After adjustment for confounders, lower dialysate sodium
(#138 mmol/L) was independently associated with higher
mortality (multivariate HR for the total population 1.57,
95% CI, 1.25 to 1.98). The risk of mortality was greater for
patients with hyponatremia (HR 2.56, 95% CI, 2.00 to 3.28)
or isonatremia (HR 1.91, 95% CI, 1.49 to 2.46) as compared
with hypernatremia (HR 1.68, 95% CI, 1.30 to 2.17). There
was no evidence that high dialysate sodium modified the
association between lower plasma sodium and mortality
(P value for interaction 0.24) (Figure 1, Supplemental
Table 2).
The subgroup specific estimates were similar to the overall
estimate (pooled summary estimate (HR 1.55 95% CI, 1.44 to
1.66) (Figure 2 and Supplemental Table 6).
DISCUSSION
In this large cohort of 68,196 maintenance HD patients, we
examined dialysis prescription practices related to dialysate
sodium concentrations and the association of time-varying
dialysate and plasma sodium concentrations with relative risk
of death over a 10-year period. The risk of death seemed lower
in patients exposed to higher (.138 mmol/L) compared with
those prescribed lower (#138 mmol/L) dialysate sodium
concentrations when adjusted for plasma sodium concentra-
tions and other confounding variables, provided that fluid
status was adequately controlled. There was also no effect
modification between dialysate and plasma sodium.
We observed that a number of countries used a higher
dialysate sodium prescription, indicating that regional dif-
ferences may shape current practice. Our observation that
138 mmol/L was most commonly prescribed is consistent
with the Dialysis Outcomes and Practice Patterns Study.
Dialysis Outcomes and Practice Patterns Study reported in
2020 that dialysate sodium has been lowered by several
mmol/L worldwide over the past two decades.12 This change
in practice has not been driven by randomized evidence
obtained in high-quality outcome trials. Rather, it likely
reflects an eminence opinion, the “volume first” recom-
mendation of experts.30 It has been hypothesized that low-
ering dialysate sodium concentration may limit interdialytic
JASN 35: 167–176, 2024
 www.jasn.org CLINICAL EPIDEMIOLOGY

Table 1. Descriptive statistics of study variables stratified by the dialysate sodium level
Variable Dialysate Sodium £138 mmol/L Dialysate Sodium >138 mmol
Patient-months of exposure 1,360,919 (64.1%) 763,038 (35.9%)
Age, at begin of follow-up (yr) 62.578 (14.902) 63.513 (14.694)
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Male (%) 62 59
Ethnicity, White (%) 63 50
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BMI (kg/m2) 27.5 (6.0) 27.1 (6.1)

Weight 73.7 (17.0) 71.3 (16.4)
Time since the begin of renal replacement therapy, i.e., dialysis 30.5 (24) 25.2 (21.1)
vintage (d)
Systolic BP (mm Hg) 141.5 (20.8) 139.4 (19.9)
Creatinine (mg/dl) 7.3 (2.6) 7.3 (2.6)
Hemoglobin (g/L) 110.3 (14.7) 108.684 (16.159)
CRP (mg/L), median (IQR) 10.0 (7.7) 9.5 8.3
Leukocytes (3109 cells/L) 6.9 (1.4) 7.0 (1.7)
Albumin (g/L) 39.1 (5.0) 38.6 (4.7)
Ferritin (ng/ml) 557.9 (418.1) 558.9 (439.9)
Phosphate (mg/dl) 4.5 (1.3) 4.6 (1.4)
FO pre rel avw. (%) 9.7 (9.6) 9.5 (10.0)
Hemodialysis treatment time (min) 246.6 (21.2) 244.7 (11.9)
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Interdialytic weight gain (kg, mean) 1.8 (1.2) 1.9 (1.4)

Ultrafiltration volume (ml) 1966 (1337) 1943 (1389)
Ultrafiltration rate (ml, max prescribed) 872 (254) 901 (279)
Kt/V 1.4 (0.3) 1.4 (0.3)
Vascular access
Fistula (%) 59 64
Catheter (%) 36 27
Graft (%) 3 1
Other (%) 5 5
Diabetes mellitus (%) 24.1 27.8
Liver disease (%) 6 7
Cardiovascular diseases (%) 33 36
Peripheral vascular disease (%) 3 2
Chronic heart failure (%) 9 13
Malignancy (%) 32 30
Dementia (%) 1 1
Connective tissue disease (%) 6 6
Chronic lung disease (%) 5 4
Descriptive statistics of monthly measurements shown are percentages (for categorical data) or mean (SD) unless otherwise stated. Any value .15%
fluid overload/extracellular water above the reference category of normal fluid status is defined as severe fluid overload or in absolute terms $ excess of
2.5 L above normal fluid status; Kt/V, solvent clearance per body fluid volume (dialysis efficiency). BMI, body mass index; CRP, C-reactive protein; FO pre rel
avw, relative average weekly fluid overload before dialysis is a % value derived from recorded body composition measurements; IQR, interquartile range.

weight gain, facilitate BP control, and thereby reduce the
incidence of left ventricular hypertrophy and associated
cardiovascular events.11,31 However, this assumption was
not confirmed in a recent randomized controlled trial, a
multicenter surrogate parameter study from New Zealand
enrolling 99 patients. This study investigated whether low-
ering the dialysate sodium concentration to 135 mmol/L
compared with the conservative standard of 140 mmol/L
reduced left ventricular mass.16 Serial cardiac magnetic
resonance imaging showed no such reduction.16
Our study showed that higher dialysate sodium concen-
trations (.138 mmol/L) were associated with lower mortality.
A recent Cochrane meta-analysis of randomized data from
310 patients showed that lower dialysate sodium was strongly
associated with intradialytic hypotension, which could poten-
tially lead to more adverse ischemic events and therefore
higher mortality.13
In our study, we did not observe any interaction between
dialysate and plasma sodium concentrations. This observa-
tion contrasts with the results of a previous observational
study, which showed a lower mortality among hyponatremic
HD patients when they were dialyzed against a higher di-
alysate sodium.14 Large observational analyses have shown
that plasma sodium in HD patients has strong associations
with mortality.17,32 However, there is conflicting evidence as
to whether changing the dialysate sodium prescription in
hyponatremic patients improves outcomes.14,20 Given that
many patients are frail, have comorbidities, and are prone to
protein energy wasting,33 increasing dialysate sodium to
maintain isotonicity could represent a clinically signifi-
cant intervention. This measure may help preserve volemia
during dialysis sessions and provide protection against ad-
verse ischemic events. However, we do not know whether a
higher dialysate sodium is protective.13–16 This observational

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 CLINICAL EPIDEMIOLOGY www.jasn.org

3.0
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2.5
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HR, 95% CI

2.0

1.5

1.2

1.0
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0.8

Hyponatremia Isonatremia Hypernatremia

Figure 1. Mortality risk association of dialysate sodium concentration (£138> mmol/l) in hyponatremia, isonatremia, and hy-
pernatremia. Hazard ratios (HR) along y-axis are shown with 95% confidence intervals (95% CI, Whisker) in relation to the ref-
erence category with the lowest risk estimates. Hazard ratios in red: dialysate sodium #138 mmol/L; Hazard ratios in blue: di-
alysate sodium .138 mmol/L. X-axis categorized in hyponatremia (plasma sodium ,135 mmol/L), isonatremia (plasma
sodium5135–142 mmol/L), and hypernatremia (plasma sodium .142 mmol/L).19–21 Estimates are adjusted for age, sex, body
mass index, ethnicity, and concomitant diseases (diabetes mellitus, liver disease, chronic heart failure, cardiovascular disease,
cancer, dementia, connective tissue disease, chronic lung disease, serum creatinine, leukocytes, ferritin, hemoglobin, vascular
access, and Kt/V [dialysis efficacy]).

analysis reaffirms that, until robust evidence from large
clinical trials with definitive end points becomes available,
currently available evidence is insufficient to advocate for a
change in current clinical practice.
The Randomized Evaluation of dialysate SOdium Levels
on Vascular Events study (ClinicalTrials.gov Identifier,
NCT02823821) randomizes decisions that are currently
arbitrary. This study, which is underway, evaluates the
comparative effectiveness of a dialysate sodium of 137
versus 140 mmol/L on major adverse cardiovascular events
and death. In doing so, RESOLVE is expected to determine
which dialysate sodium is clinically superior, filling a crit-
ical knowledge gap in practice recommendations in the
Kidney Disease Outcomes Quality Initiative guidelines34
and standardizing global HD practice. Until the optimal
dialysate sodium is known, data from large-scale observa-
tional studies could help us to understand whether the
observed higher mortality association with lower dialysate
sodium concentrations may be explained by the effect of
dialysate sodium on the longitudinal course of intradia-
lytic BP.13
Strengths of our study are that it is the largest observational
study of the topic to date, with over two million dialysate
sodium measurements and that our model findings were
robust after multiple adjustments for prognostically impor-
tant variables, including adjustment for differences between
countries, clinics, and baseline fluid status. We recognize that
dialysate sodium is only one factor in sodium and water
homeostasis. Other factors, such as a strict dry weight probing
approach relying on ultrafiltration management (net ultrafil-
tration volume and optimal ultrafiltration rate) as well as salt
diet restriction and preservation of residual kidney function,
are of paramount importance in this context. Given the
uncertainty surrounding the complex interplay of chronic
fluid overload, water imbalance, and sodium toxicity, future
studies should investigate the combined effects of fluid over-
load and plasma and dialysate sodium concentrations on all-
cause and cardiovascular mortality at the patient level, rather
than focusing on individual measurements.
Our study design did not allow us to examine the role of
intradialytic hypotension as a mediator of clinical outcomes,
and future causal models using structural equation modeling
or other approaches35 might be useful in determining the
importance of low BP and other factors on the causal pathway.
To account for different mortality effects, which may be
driven by patient selection for dialysis eligibility or other
practice differences, we stratified our model by country.
However, we cannot rule out the possibility of confounding
by indication. In our analysis, the policy of one standard
prescription seemed to be region specific rather than driven

172 JASN JASN 35: 167–176, 2024

 www.jasn.org CLINICAL EPIDEMIOLOGY

HR
Subgroup with 95% CI
Legend:
Males 1.45 [1.10,1.91]
= Point estimate
CnMxXT34aGx5kdebfnh0m+gozkJVznepmoepZFOeg2cSwxxTy2wmA0tKkrw7/+31lI6cbZYmdSu60XxILw2FWIPkYGuntm1DU10a

Females 1.80 [1.36,2.39]

presented as hazard
Age t 65 years 1.47 [1.17,1.85] ratio (HR)
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Age < 65 years 1.71 [1.20,2.43] = 95%

confidence interval (CI)
Albumin t 3,5 g/dl 1.55 [1.14,2.11]
= Pooled summary
Albumin < 3,5 g/dl 1.56 [1.21,2.01]
estimate
Time on HD d 12 months 1.32 [1.05,1.65] Abbreviations: BP
syst.= predialytic
Time on HD > 12 months 1.67 [1.17,2.38]
systolic blood pressure.
BP syst. < 90 mmHG 1.31 [0.38,4.54]
BP syst. 90 –130 mmHG 1.72 [1.35,2.20]
BP syst. > 130 mmHG 1.45 [1.01,2.09]
Diabetes 1.84 [1.23,2.75]
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No Diabetes 1.49 [1.17,1.90]

Cardiovascular disease 1.87 [1.21,2.89]
No cardiovascular disease 1.48 [1.16,1.89]
Chronic heart failure 1.52 [0.74,3.12]
No chronic heart failure 1.54 [1.20,1.97]

Pooled summary estimate 1.55 [1.44,1.66]

Higher risk >138 mmol/l Higher risk d 138 mmol/l

1/2 1 2 4

Figure 2. Forest plot showing the effect of low dialysate sodium (£138 mmol/L) in different strata of the study population. HD,
hemodialysis. HD, hemodialysis. Figure 2 can be viewed in color online at www.jasn.org.

by patient comorbidities or other important patient-specific
variables. A limitation of our study is the lack of variance in
low dialysate sodium exposure within countries. There were
countries where all clinics in our study population used the
same dialysate sodium prescription. Therefore, propensity
score matching was unfeasible, and we could not completely
separate the effects of country from the effect of low dialysate
sodium and had to assume no effect modification.
Future studies could compare mortality outcomes between
clinics that follow an individualized dialysate sodium ap-
proach and those using a default dialysate sodium or a
self-automated electrolyte balance module approach. In ad-
dition, studies should assess the effects of dialysate sodium
adjustment during patients’ follow-up, prompted by changes
in BP or ultrafiltration goals/interdialytic weight gain, which
our time-varying Cox model could not account for. At the
current time, it must be acknowledged that the most common
practice seems to be the use of a fixed dialysate, and in this
cohort, the dialysate sodium concentration was rarely changed
across countries and dialysis clinics during the 10-year fol-
low-up.
The dataset’s magnitude posed its challenges, resulting in
computational limitations, such as the inability to handle
missing data with multiple imputation.
Another limitation of this study is that the dialysate
sodium measurements available for analysis were those
prescribed and set in the machine and not necessarily those
delivered to the patient. However, a recent meta-analysis of
seven small and mostly single-center studies suggests that,
on average, prescribed and measured dialysate sodium
is similar.36
Using this large contemporary cohort, we showed that a
higher dialysate sodium of .138 mmol/L was independently
associated with a lower risk of mortality, irrespective of
plasma sodium concentration provided fluid volume is ade-
quately controlled. On the basis of these data, it is advisable
for nephrologists to exercise caution when reducing dialysate
sodium concentration without robust randomized evidence
supporting optimal standard dialysate sodium prescribing
practices. Instead, nephrologists should prioritize attention
to fluid volume control.
DISCLOSURES
B. Canaud reports Employer: Scientific consultant for Fresenius Med-
ical Care, Germany up to December 2022—Retired from December 2022;
and Consultancy: Senior scientist consultant for Fresenius Medical Care

JASN 35: 167–176, 2024 Dialysate Sodium Cohort Study, Pinter et al. 173
 CLINICAL EPIDEMIOLOGY www.jasn.org
up to December 2022. B. Genser received a consulting fee from FMC for
conducting the statistical analysis. M. Jardine reports Research Funding:
Baxter, CSL, Dimerix with all payments to my institution; Honoraria:
AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, MSD, Occuryx and
Vifor, and directs honoraria to clinical research programs; Advisory or
CnMxXT34aGx5kdebfnh0m+gozkJVznepmoepZFOeg2cSwxxTy2wmA0tKkrw7/+31lI6cbZYmdSu60XxILw2FWIPkYGuntm1DU10a
Leadership Role: Chinook, CSL, Janssen. All honoraria directed to clinical
research programs; and Speakers Bureau: AstraZeneca, Boehringer
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Ingelheim, Janssen, and directs speaker fees to clinical research
programs. M.R. Marshall reports Ownership Interest: Microsoft Corpo-
ration. J. Pinter received a grant from Fresenius Medical Care for author-
ship related expenses regarding journal publication, abstract submission,
organization, management and travel costs for conference presentations.
P. Rossignol reports Consultancy: AstraZeneca, Bayer, Boehringer Ingel-
heim, CinCor, Idorsia, KBP, NovoNordisk, Sanofi, Servier, Sequana med-
ical, Vifor; Ownership Interest: Cardiorenal cofounder (stocks); G3P
(stock options); Research Funding: Relypsa Inc. and Vifor Fresenius
Medical Care Renal Pharma, and a Vifor Pharma Group Company;
Honoraria: Dr. Rossignol reports personal fees from AstraZeneca, Bayer,
Boehringer Ingelheim, CinCor, Idorsia, KBP, NovoNordisk, Sanofi, Se-
quana medical, Servier, Vifor; Patents or Royalties: CardioRenal co-
7U9oaAfj on 07/03/2024
founder (a company developing a home potassium self-monitoring
device); Advisory or Leadership Role: ESH: “hypertension and the kidney”
working group board member since 2016; WG board member HFA,
Cardio renal (2016–) and translational 2016–2020; WG board member
Eurecam ERA-EDTA 2021–2023; WG on biomarkers board member HFA,
2020–2022; KDIDO executive committee member since 2023; and Speak-
ers Bureau. B. Smyth reports Research Funding: In-kind support provided
by iX Biopharma (Singapore) for investigator-initiated research; Hono-
raria: Research Review Australia; CSL-Vifor (funds to institution); and
Advisory or Leadership Role: Unpaid committee positions for not-for-
profit organisations/clinical trials (ANZSN Research Advisory Commit-
tee, INCH-HD study SC, RESOLVE trial SC); Paid position with CSL-Vifor
(funds to institution). S. Stuard is an employee of Fresenius Medical Care;
Ownership Interest: Fresenius Medical Care; and Patents or Royalties: Fre-
senius Medical Care. C. Wanner has received honoraria for advisory or
educational activities from Amgen, Astellas, AstraZeneca, Bayer, Boehringer
Ingelheim, CSL-Vifor, Fresenius Medical Care, Gilead, GSK, MSD, Novo-
Nordisk and grants from Boehringer Ingelheim and Sanofi to the institution.
C. Wanner also reports Consultancy: AstraZeneca, Bayer, Boehringer Ingel-
heim, CSL-Vifor, GSK, MSD, NovoNordisk; Honoraria: Amicus, Chiesi, Eli-
Lilly, FMC, Novartis, Sanofi, Stadapharm, Takeda; and Other Interests or
Relationships: European Renal Association (ERA). D.C. Wheeler has an
ongoing consultancy contract with AstraZeneca. In the last 2 years he has
received honoraria/consultancy fees from Astellas, Bayer, Boehringer Ingel-
heim, Eledon, Galderma, Gilead, GlaxoSmithKline, Janssen, Prokidney, Tri-
cida, Vifor and Zydus for clinical trial related, Advisory or Educational
activities. D.C. Wheeler also reports Consultancy: George Clinical, Merck
Sharp and Dohme, Pfizer, ProKidney; Advisory Boards, Trial Committees and
Consultancy; Honoraria: Amgen, Astellas, AstraZeneca, Bayer, Boehringer
Ingelhiem, GalaxoSmithKline, Janssen, Napp, Merck Sharp and Dohme,
Napp, Pharmacosmos, Reata, Vifor Fresenius; Advisory or Leadership
Role: AstraZeneca; and Speakers Bureau: Amgen, Astellas, AstraZeneca,
Janssen, Merck Sharp and Dohme, Mundipharma, Napp, Vifor Fresenius.
FUNDING
Jule Pinter is funded and supported by the German Research Foun-
dation (DFG, Projektnr. 413657723 [Clinician Scientist-Program
UNION-CVD]). The statistical analysis was funded by FMC. BS is
supported by an Early Career Fellowship Award from the Royal Austral-
asian College of Physicians.
174 JASN
ACKNOWLEDGMENTS
The National Medical Directors of NephroCare-Fresenius Medical Care
supervised the data collection and were responsible for checking the data
quality at the country level. These tasks were performed by the following
individuals: Goran Imamovic (Bosnia and Herzegovina), Zarko Belavic
(Croatia), Daniela Voiculescu (Romania), Konstantin Gurevich (Russia),
Reina Dovc-Dimec (Slovenia), Zoran Paunic (Serbia), Charles Swanepoel
(South Africa), Fatih Kircelli (Turkey), Nick Richards (United Arab Emirates),
Tomas Jirka, Michaela Sagova (Czech Republic), Martin Lepiksoo (Estonia),
Erzsebet Ladanyi (Hungary), Miroslaw Kroczak (Poland), Jaroslav Rose-
nberger (Slovakia), Dariusz Zarczynski (Sweden), Charles Chazot (France),
Alex Heaton (Ireland), Attilio Di Benedetto (Italy), Pedro Ponce (Portugal),
Jose Ignacio Merello and Rosa Ramos (Spain), Alex Heaton (United King-
dom), Cristina Marelli (Argentina), Eufronio Dalmeida (Brazil), Eduardo
Machuca (Chile), Victor Delgado (Colombia), and Leonor Briones (Ecuador).
AUTHOR CONTRIBUTIONS
Conceptualization: Bernard Canaud, Bernd Genser, Mark R. Marshall,
Jule Pinter.
Data curation: Bernd Genser, Jule Pinter.
Formal analysis: Bernd Genser.
Funding acquisition: Jule Pinter, Stefano Stuard.
Investigation: Jule Pinter.
Methodology: Bernard Canaud, Bernd Genser, Meg Jardine, Mark R. Mar-
shall, Jule Pinter, Brendan Smyth.
Project administration: Jule Pinter.
Resources: Jule Pinter, Stefano Stuard.
Supervision: Bernard Canaud, Bernd Genser, Christoph Wanner.
Visualization: Bernard Canaud, Bernd Genser, Jule Pinter.
Writing – original draft: Bernard Canaud, Bernd Genser, Jule Pinter.
Writing – review & editing: Bernard Canaud, Bernd Genser, Meg Jardine,
Mark R. Marshall, Jule Pinter, Patrick Rossignol, Brendan Smyth, David
C. Wheeler.
DATA SHARING STATEMENT
Partial restrictions to the data and/or materials apply. Data can be shared
upon specific request.
SUPPLEMENTAL MATERIAL
This article contains the following supplemental material online at http://
links.lww.com/JSN/E551.
Supplemental Figure 1. Conceptual framework for the epidemiologic effect
of dialysate sodium exposure.
Supplemental Figure 2. Patient selection and analysis procedures.
Supplemental Figure 3. Distribution of plasma sodium in subgroups de-
fined by dialysate sodium prescription.
Supplemental Table 1. Distribution of dialysate sodium prescription.
Supplemental Table 2. Joint bivariate mortality risk association of plasma
and dialysate sodium.
Supplemental Table 3. Distribution of patients among countries.
Supplemental Table 4. Reasons for censoring.
Supplemental Table 5. Descriptive statistics of study variables in ex-
cluded patients.
JASN 35: 167–176, 2024

Supplemental Table 6. Distribution of dialysate sodium prescription in
different subgroups.
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Dialysate Sodium Cohort Study, Pinter et al. 175
 CLINICAL EPIDEMIOLOGY www.jasn.org

AFFILIATIONS

1
Department of Medicine, Division of Nephrology, University Hospital Würzburg, Würzburg, Germany
2
NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
CnMxXT34aGx5kdebfnh0m+gozkJVznepmoepZFOeg2cSwxxTy2wmA0tKkrw7/+31lI6cbZYmdSu60XxILw2FWIPkYGuntm1DU10a

3
Department of Renal Medicine, St George Hospital, Sydney, Australia
4
Global Medical Office, FMC Germany, Bad Homburg, Germany
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5
Concord Repatriation General Hospital, Sydney, Australia
6
Department of Clinical Research and Epidemiology, Renal Research Unit, Comprehensive Heart Failure Center, Wuerzburg, Germany
7
Université de Lorraine, Centre d’Investigations Cliniques-Plurithématique 1433 CHRU de Nancy, U1116 Inserm and F-CRIN INI-CRCT
(Cardiovascular and Renal Clinical Trialists), Nancy, France
8
Princess Grace Hospital, and Monaco Private Hemodialysis Centre, Monaco
9
Department of Renal Medicine, University College London, London, United Kingdom
10
Middlemore Hospital, Otahuhu, Auckland, New Zealand
11
University of Montpellier, Montpellier, France
12
High5Data GmbH, Heidelberg, Germany
13
Department of General Medicine, Center for Preventive Medicine & Digital Health, Mannheim Medical Faculty, Ruprecht Karls University
Heidelberg, Heidelberg, Germany
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176 JASN JASN 35: 167–176, 2024