nutrients

Review
Fluid Overload and Tissue Sodium Accumulation as Main
Drivers of Protein Energy Malnutrition in Dialysis Patients
Bernard Canaud 1,2, * , Marion Morena-Carrere 3 , Helene Leray-Moragues 4 and Jean-Paul Cristol 3,4

1 School of Medicine, Montpellier University, 34000 Montpellier, France

2 Global Medical Office, FMC-France, 94260 Fresnes, France
3 PhyMedExp, Department of Biochemistry and Hormonology, INSERM, CNRS, University Hospital Center of
Montpellier, University of Montpellier, 34000 Montpellier, France
4 Charles Mion Foundation, AIDER-Santé, 34000 Montpellier, France
* Correspondence: [email protected]

Abstract: Protein energy malnutrition is recognized as a leading cause of morbidity and mortality in
dialysis patients. Protein–energy-wasting process is observed in about 45% of the dialysis population
using common biomarkers worldwide. Although several factors are implicated in protein energy
wasting, inflammation and oxidative stress mechanisms play a central role in this pathogenic process.
In this in-depth review, we analyzed the implication of sodium and water accumulation, as well as
the role of fluid overload and fluid management, as major contributors to protein–energy-wasting
process. Fluid overload and fluid depletion mimic a tide up and down phenomenon that contributes
to inducing hypercatabolism and stimulates oxidation phosphorylation mechanisms at the cellular
level in particular muscles. This endogenous metabolic water production may contribute to hy-
ponatremia. In addition, salt tissue accumulation likely contributes to hypercatabolic state through
locally inflammatory and immune-mediated mechanisms but also contributes to the perturbation
Citation: Canaud, B.; of hormone receptors (i.e., insulin or growth hormone resistance). It is time to act more precisely
Morena-Carrere, M.; on sodium and fluid imbalance to mitigate both nutritional and cardiovascular risks. Personalized
Leray-Moragues, H.; Cristol, J.-P. management of sodium and fluid, using available tools including sodium management tool, has the
Fluid Overload and Tissue Sodium potential to more adequately restore sodium and water homeostasis and to improve nutritional status
Accumulation as Main Drivers of
and outcomes of dialysis patients.
Protein Energy Malnutrition in
Dialysis Patients. Nutrients 2022, 14,
Keywords: sodium; water; fluid overload; fluid depletion; dialysis adequacy; malnutrition
4489. https://doi.org/10.3390/
nu14214489

Academic Editor: Piergiorgio Bolasco

Received: 26 September 2022

1. Introduction
Accepted: 19 October 2022 Malnutrition is a common disorder in dialysis patients [1–3]. Protein–energy malnu-
Published: 25 October 2022 trition (PEM) or protein–energy-wasting (PEW) process is the most commonly observed
manifestation of this disorder [4]. As stated, in PEW process, malnutrition affects the two
Publisher’s Note: MDPI stays neutral
main components of body composition, namely protein stores (muscle mass, sarcopenia)
with regard to jurisdictional claims in
published maps and institutional affil-
and energy stores (fat mass) with different behaviors and/or severities [5]. According
iations.
to recent reviews, the prevalence of PEM in dialysis patients may range between 15 and
75% [6]. This imprecise estimate reflects several factors that are poorly considered, such
as criteria used to define PEM, variability of existing assessment tools, age-related factors,
geographical differences, stages of chronic kidney disease, and effects of renal replacement
Copyright: © 2022 by the authors. modalities [4,7–9]. Chronic kidney disease progression is associated with a worsening
Licensee MDPI, Basel, Switzerland. of protein energy malnutrition, culminating in end-stage kidney disease and in dialysis
This article is an open access article patients [10]. This deleterious phenomenon has been clearly highlighted within the MDRD
distributed under the terms and study and directly linked to the aggravation of uremic disorders marked by a spontaneous
conditions of the Creative Commons reduction of diet caloric and protein intakes [11,12]. In a recent international systematic
Attribution (CC BY) license (https:// review by Carrero et al., it was shown that prevalence of PEM in dialysis patients averaged
creativecommons.org/licenses/by/ 45% worldwide but with large variations according to country incomes [6]. As clearly
4.0/).

Nutrients 2022, 14, 4489. https://doi.org/10.3390/nu14214489 https://www.mdpi.com/journal/nutrients

Nutrients 2022, 14, 4489 2 of 14

clearly identified in this review, prevalence of PEM was 39%, 48%, and 63% in high-, mid-
Nutrients 2022, 14, 4489 dle-, and low-income countries, respectively [6]. 2 of 14

Protein–energy malnutrition in dialysis patients is most often characterized by in-

flammation and oxidative stress mechanisms [13–18]. Inflammation was identified early
byidentified
researchers in this review, prevalence
of Karolinska’s groupofasPEM was 39%,and
a prominent 48%,common
and 63% marker
in high-,ofmiddle-, and
malnutrition
low-income countries, respectively [6].
and atherosclerosis process in dialysis patients, the so-called malnutrition inflammation
Protein–energy
atherosclerosis (MIA)malnutrition in dialysis
syndrome [19,20]. patients
Later is most often
on, subclinical characterized
chronic by inflam-
inflammation was
mation and oxidative stress mechanisms [13–18]. Inflammation
confirmed by independent researchers as being associated in a broader pathophysiologic was identified early by
researchers of Karolinska’s group as a prominent and common marker of malnutrition
spectrum called malnutrition inflammation complex syndrome (MICS) [13,14].
and atherosclerosis process in dialysis patients, the so-called malnutrition inflammation
Protein energy malnutrition is now a well-recognized leading cause of morbidity and
atherosclerosis (MIA) syndrome [19,20]. Later on, subclinical chronic inflammation was
mortality
confirmed in by
dialysis patients
independent [14,21]. In
researchers that perspective,
as being associated innutritional consensus expert
a broader pathophysiologic
groups
spectrumhavecalled
drawn attention of
malnutrition the clinical community
inflammation complex syndrome to this (MICS)
matter in order to monitor
[13,14].
the nutritional status of dialysis patients more closely and to
Protein energy malnutrition is now a well-recognized leading cause of morbidityuse a panel of appropriate
and
tools, including
mortality inflammatory
in dialysis patients markers
[14,21]. In (CRP), in order to intervene
that perspective, nutritionalin consensus
a timely appropri-
expert
ategroups
fashion to prevent
have further deterioration
drawn attention of the clinicaland poor outcomes
community [4,22].in
to this matter Toorder
characterize
to monitorpro-
tein–energy
the nutritionalmalnutrition, a panel patients
status of dialysis of three more
to four biomarkers
closely and to isuseusually
a panel required. Without
of appropriate
going
tools,into detail, inflammatory
including biomarkers includemarkershypoalbuminemia, reducedin
(CRP), in order to intervene diet caloricappropriate
a timely and protein
fashion
intakes to prevent
(loss further
of appetite, deterioration
diet survey), changeand poor in outcomes [4,22]. To characterize
body composition (subjective protein–
global as-
energy malnutrition,
sessment, unintendedaweight panel ofloss,
three to four biomarkers
anthropometric, is usually
muscle required. Without
bioimpedance, loss of going
muscle
into detail, biomarkers include hypoalbuminemia, reduced diet caloric
mass), and CRP increase [4]. Protein energy malnutrition is associated with higher hospi- and protein intakes
(loss of appetite,
talization diet survey),
risk, including risk ofchange in body
infections, composition
falls, fractures,(subjective
vascular global
access assessment,
dysfunction,
unintended weight loss, anthropometric, muscle bioimpedance,
and poor healing after surgery [23,24]. Furthermore, mortality from all causes, loss of muscle mass), and
but partic-
CRP increase [4]. Protein energy malnutrition is associated with higher hospitalization
ularly from cardiovascular and infection origins, is significantly increased with the degree
risk, including risk of infections, falls, fractures, vascular access dysfunction, and poor
of protein–energy malnutrition [25].
healing after surgery [23,24]. Furthermore, mortality from all causes, but particularly
from cardiovascular and infection origins, is significantly increased with the degree of
2. protein–energy
Protein Energymalnutrition
Malnutrition Results from Several Causes
[25].
Protein–energy malnutrition has multiple causes in dialysis patients that may act in-
2. Proteinbut
dividually Energy
mostMalnutrition
likely tend toResults from Several
act in combination Causes
either simultaneously or sequentially
Protein–energy malnutrition has multiple causes
[26,27]. For practical reasons, causes of PEM are analyzed individually in dialysis patientsandthat
in amay
more actin-
individually
tegrated vision.but most likely tend
Schematically, theytobelong
act in combination
to four groups either
of simultaneously or sequen-
factors: patient-related fac-
tially
tors, [26,27]. For practical
uremic-related factors,reasons, causes of PEM
dialysis-related are analyzed
factors, individually and in a more
and intercurrent-illness-related-fac-
Figure 1 Causesintegrated
tors.ofThey are
protein vision. Schematically,
summarized
energy they
in Figure
malnutrition belong to
in 1.
dialysis four groups of factors: patient-related fac-
patients
tors, uremic-related factors, dialysis-related factors, and intercurrent-illness-related-factors.
They are summarized in Figure 1.

PATIENT-RELATED
1 FACTORS 2 UREMIC MILIEU-
RELATED FACTORS
Age – Gender – Life Style – Diet Habits –
Socioeconomic – Cultural Assets
Medical History
- Past 1 Uremic Waste Products Accumulation –
Associated Symptomatology (GI disorders)
Metabolic Acidosis - Oxidative Stress - Chlorine
Stress – Inflammation - Endocrine Disorders –
Hormone Imbalance – Hormone Resistance

PROTEIN
4 ENERGY
WASTING
2
4 INTERCURRENT
ILLNESS-RELATED 3 HEMODIALYSIS-
RELATED FACTORS
FACTORS Limited Efficiency of Renal Replacement Therapy –

Acute or Subacute Illness Episodes – Infection –

Teeth and/or Periodontia
Surgical Intervention – Vascular Access Related
3 Unphysiological Profile HD – Tides up & Down
Phenomenon - Middle & Larger MW Compound
Retention - Residual Kidney Function
Bioincompatibility membrane & Circuit – Dialysis
Problems – Cardiovascular Disease - Lung Disease Microbial-Derived Dialysis Fluid Contamination –
Liver Disease - Cancer Electrolytes Prescription & HD Shift
Fluid Overload – Sodium Accumulation -
Hyponatremia

Figure
Figure 1. 1. Causesofofprotein–energy
Causes protein–energymalnutrition
malnutrition in
in dialysis
dialysispatients.
patients.
Nutrients 2022, 14, 4489 3 of 14
Nutrients 2022, 14, 4489 3 of 14

Patient-related factors depend mainly on age, gender, life and diet habits, socio-eco-
nomicPatient-related
conditions, cultural
factors assets,
dependpastmainly
medical onhistory (long standing
age, gender, life and history of disease
diet habits, socio-
and treatment),
economic and comorbid
conditions, cultural conditions
assets, past(diabetes, cardiac(long
medical history or liver disease).
standing Mostofofdisease
history them
are
andfixed factors out
treatment), andof medical conditions
comorbid reach [27,28].(diabetes, cardiac or liver disease). Most of them
are fixed factors outfactors
Uremic-related of medical reach
consist [27,28].
of all disorders associated with kidney failure that im-
Uremic-related
pact negatively factors
nutritional consist
status. of all is
Uremia disorders
a complex associated
disorderwith kidney
involving failure factors
multiple that im-
pact negatively nutritional status. Uremia is a complex disorder involving
that act synergistically to impede nutritional status [29]. To facilitate such analysis, multiple factors
we
that act categorizing
propose synergistically to impede
them nutritional
according to theirstatus [29]. To
two main facilitate such analysis,
pathophysiologic pathways: we
propose
firstly, categorizingfactors;
anti-anabolic them according
secondly, to their two main
pro-catabolic pathophysiologic
factors. pathways:
This is schematized firstly,
in Figure
2.anti-anabolic
As presented, factors;
on one secondly, pro-catabolic
hand, antianabolic factors.include
elements This is schematized
factors that tendin Figure 2. As
to reduce
presented,
nutrient on one
intake or hand, antianabolic(anorexia,
gut absorption elements include factors satiety,
gastroparesis, that tendtaste,
to reduce nutrient
medication)
intake contributing
[30,31], or gut absorption (anorexia,
to functional gastroparesis,
deficiencies satiety, taste,
and metabolic medication)
or endocrine [30,31],that
disorders con-
tributing to functional deficiencies and metabolic or endocrine disorders
impede cell or tissular processing of nutrients (vitamin deficiency, protein and amino acid that impede cell
or tissular processing of nutrients (vitamin deficiency, protein and
deficiency, hormonal deficiency, receptor impingement, anemia) [32–35]. On the other amino acid deficiency,
hormonal
hand, deficiency,
procatabolic receptor
factors impingement,
include anemia)fluid
metabolic acidosis, [32–35]. On the
overload, other hand,oxi-
inflammation, pro-
catabolic
dative factors
stress, include metabolic acidosis,
hyperparathyroidism, and uremic fluid overload,
toxin inflammation,
accumulation oxidative
that have cell andstress,
mi-
hyperparathyroidism,
Clustering factors andprotein
that[36,37].
favor uremic toxin
energy accumulation
wasting processthat have cell and mitochondrial
Figure 2 tochondrial toxicity
toxicity [36,37].

PRO-CATABOLIC
FACTORS
Uremic toxin accumulation
Mitochondrial Dysfonction
Metabolic Acidosis
Tides Phenomenon: Fluid overload/Depletion
Tissue Sodium and Water Accumulation
Oxidative & Chlorine Stress
Inflammation – HD Bioincompatibility

ANTI-ANABOLIC
FACTORS
Nutrient Intake Reduction and/or Gut
Absorption : anorexia, gastroparesis,
satiety, taste, medication
Deficiencies : vitamin, protein, amino-
PROTEIN ENERGY acid, hormonal deficiency, receptor
WASTING impingement, insulin resistance, GH
resistance, Testosterone deficiency

Figure
Figure2.2.Clustering
Clusteringfactors
factorsthat
thatfavor
favorthe
theprotein–energy-wasting
protein–energy-wastingprocess.
process.

Dialysis-related
Dialysis-relatedfactors
factors are
are superimposed conditionsto
superimposed conditions touremia
uremiawithwithdual
dualandandopposite
oppo-
site action.
action. OnOn oneone hand,
hand, hemodialysis
hemodialysis hashas a positive
a positive action
action by by controlling
controlling uremic
uremic disor-
disorders
ders
and and restoring
restoring internal
internal milieumilieu homeostasis
homeostasis through
through periodic
periodic reduction
reduction of nitrogenous
of nitrogenous waste
waste products
products and correction
and correction of electrolytic
of electrolytic and volume
and fluid fluid volume imbalance.
imbalance. On theOnother
the other
hand,
hand, hemodialysis
hemodialysis has ahas a negative
negative actionaction by creating
by creating unphysiological
unphysiological cyclic
cyclic shiftsshifts
andand by
by trig-
triggering directly protein muscle degradation to compensate for amino
gering directly protein muscle degradation to compensate for amino acid, peptides, and acid, peptides,
and nutrient
nutrient losses
losses [38].[38]. Dialysis-induced
Dialysis-induced nutritional
nutritional stressstress
tendstends
also toalso to reorientate
reorientate liver
liver protein
protein synthesis
synthesis towardtoward acuteproteins
acute phase phase proteins at the expense
at the expense of albuminof albumin
synthesis synthesis [39].
[39]. Further-
Furthermore,
more, dialysisdialysis
has beenhas been to
shown shown
induceto hypercatabolism
induce hypercatabolism
(increased (increased energy ex-
energy expenditure)
through the
penditure) releasethe
through of release
variousofstressors (hemodynamic
various stressors and metabolic
(hemodynamic factors) factors)
and metabolic [40] and
mediators
[40] resultingresulting
and mediators from bioincompatibility reactions (protein
from bioincompatibility reactionscascade
(proteinand cell activations)
cascade and cell
Nutrients 2022, 14, 4489 4 of 14

and blood–membrane interaction catalyzed by dialysis fluid impurity [41–43]. Factors that
contribute to protein–energy wasting in dialysis patients are summarized in Figure 2.
Intercurrent-illness-related factors occur more frequently in dialysis patients as mark-
ers of vulnerability and contributing to their morbidity. They should be considered ad-
ditional stressors and will not be discussed further. For example, they include various
episodes of infection, cardiac event, vascular access problem, and surgical or any interven-
tional acts.

3. Fluid Overload as a Cause of Protein Energy Malnutrition: Evidence-Based Facts

In this context, sodium and fluid imbalance, as well as their management, are emerging
factors that contribute to protein–energy malnutrition. This is the main focus of this review
to highlight this overlooked problem in dialysis patients. To facilitate description of the
link between fluid disorders and protein energy malnutrition, we split this pathway into
two parts, fitting with tides phenomena of intermittent hemodialysis. In brief, the tides
up phenomenon reflects fluid and sodium accumulation occurring during the interdialytic
period (as a result of diet and fluid intake and residual diuresis), while the tides down
phenomenon reflects fluid and sodium depletion resulting from dialytic treatment (as a
result of ultrafiltration and sodium depletion). Interestingly, both conditions are associated
with the protein–energy-wasting process.
Chronic fluid overload (FO), a surrogate marker of water bound sodium excess, is quite
common in hemodialysis patients. According to the method used to assess fluid status in
dialysis patients (clinical, instrumental, biomarkers), FO prevalence may differ substantially.
Using a non-invasive objective tool, such as multifrequency bioimpedance, to estimate fluid
status, it was determined that FO is present in 40 to 60% of dialysis patients. In this context,
it is interesting to note that FO prevalence is almost similar in hemodialysis and peritoneal
dialysis patients, as shown in recent prospective international studies using the same
MF-BIA tool [44–47]. Large retrospective cohort studies (MONDO Initiative) assessing
FO with MF-BIA have consistently reported a higher mortality risk associated with FO in
prevalent HD patients [48–51]. Furthermore, in these studies, it was also shown that the
relative risk of death was positively associated with fluid overload degree independently
from blood pressure levels and strongly linked to malnutrition inflammation complex
syndrome [13,49,50,52]. These findings have been confirmed in a large international cohort
study involving incident HD patients. As shown in this study, fluid overload at baseline is
associated with 30% higher mortality risk at 12 months, increasing to 60% when FO was
present one year later. Interestingly, mortality mainly from cardiovascular origins was
associated with the degree of FO independently from blood pressure levels and worsened
with higher time exposure [46]. These findings indicate that fluid overload is a common
feature in dialysis patients, frequently associated with hypoalbuminemia, protein energy
wasting process, and inflammatory markers, that highlights an unmet medical need [53].
Tissue sodium accumulation, as a surrogate marker of water free sodium stored in
skin and muscle, is another common feature of kidney disease and dialysis patients recently
identified as an additional vital risk factor [54]. Tissue sodium content, as measured
via 23 Na MRI, is substantially increased in kidney disease and dialysis patients, with
additional conditions that tend to worsen this condition (i.e., ageing, hypertension, cardiac,
diabetes, salt diet, dialysate sodium) [55–58]. It is also shown in experimental and clinical
studies that tissue sodium accumulation contributes via insulin resistance and inflammation
to protein–energy wasting [56,59,60].
Hyponatremia, a well-known marker of poor outcome in hemodialysis patients [61]
has been recently associated with severe fluid mixed disorders linked to intercurrent ill-
nesses [48,49,62,63]. Additionally, it has been shown in a large Japanese study that patients’
outcomes (all-cause mortality, stroke, lower limb amputation) were worsened with positive
plasma sodium changes and improved by negative plasma sodium changes [64]. These
findings suggest that increasing fluid volume depletion in isotonic (isonatric) or hypotonic
(hyponatric) dialysis conditions is preferable for improving outcome. As shown in a recent
Nutrients 2022, 14, 4489 5 of 14

study monitoring natremia in hemodialysis patients using an automated sensor device,

hypotonic hyponatremia was detected in about 10% of patients and in all cases was associ-
ated with a protein–energy-wasting and inflammatory process due to severe intercurrent
illness [65]. Interestingly, correction of illness and readjustment of fluid status by significant
reduction of dry weight up to 20% with isonatric dialysis were able in the majority of cases
to mitigate risk, to correct hyponatremia, and to improve patients’ outcomes.
Clinical evidence linking fluid imbalance in dialysis patients with poor outcomes has
been briefly summarized in this paragraph. Interestingly, all pathophysiologic pathways
involved in these deleterious mechanisms are mediated by inflammation and associated
with the protein–energy-wasting process [48].

4. Pathophysiologic Mechanisms Linking Fluid Overload, Fluid Management, and

Protein Energy Malnutrition
While FO, inflammation, and malnutrition are independent risk factors for mortal-
ity [20,49,50,64], recent studies have shown that their combined presence may lead to
a cumulative risk profile [46,66]. From a pathophysiologic perspective, FO, inflamma-
tion, and protein energy malnutrition can also be mutually reinforcing and can act both
ways—from FO to inflammation and vice versa—suggesting that inflammation axis is
the main cause of malnutrition [48]. Clinical evidence linking FO and inflammation has
been recently summarized in a narrative review using objective tools to assess fluid status
(multifrequency bioimpedance, cardiac biomarkers) and inflammation biomarkers (CRP,
IL6) [53]. The pathophysiologic link is not clearly understood but likely involves several
mechanisms: endothelial dysfunction and increased vascular cell adhesion molecules
(VCAM-1); vascular leakage (increased capillary leak, angiopoietin 2); hypoalbuminemia
resulting from reorientation of liver protein synthesis to acute phase proteins in case of in-
flammation [67,68]; muscle proteolysis due to reprioritization of cellular energy metabolism
facing sodium accumulation or acute depletion [69,70]; gut endotoxin translocation (con-
gestion or ischemia) [71]; pulmonary alveolar edema (breakdown of alveolar epithelial
barrier) [72,73]; and finally tissue sodium storage activating immune and inflammatory
pathways (water-free sodium, lymphocytes Th-17) [74–76] (see Figure 3).
Rapid sodium removal and fluid depletion as summarized by high ultrafiltration
rate (>10 mL/h/kg) may lead to poor outcomes with increased cardiac risks [77,78]. This
has been consistently shown in several studies suggesting that intensive or aggressive
fluid management may lead to unwanted side effects. While these dialysis-induced risks
are mainly mediated using hypovolemia and repetitive ischemic cardiac insults [69,79],
some recent findings in animal experimental models suggest that fast sodium removal may
trigger catabolism, with reprioritization of cell metabolism being associated with muscle
proteolysis (release of free amino acids) to maintain tissue sodium content [70,80,81]. Fast
sodium removal achieved through hemodialysis via ultrafiltration and negative dialysate–
plasma sodium gradient is likely to contribute to muscle proteolysis and dialysis-induced
protein catabolism [34,41,82]. In addition, as recently shown in a phosphate kinetic study
relying on magnetic resonance spectroscopy, hemodialysis tends to preferentially deplete
phosphate from the intracellular compartment, reducing the availability of high-energy
phosphates and impairing ultimately mitochondrion and cellular metabolism [83].
Tissue sodium accumulation (skin, muscle) is associated with various pathophysi-
ologic findings involving on one side the cardiovascular system (i.e., hypertension, left
ventricular hypertrophy) independently from pressure level and mechanical consequences
but on the other side various metabolic pathways that have direct effects on nutritional
status (i.e., insulin resistance, muscle catabolism, cell energy metabolism) [54,56,84]. To
reconcile the mismatch, the authors advocated surplus endogenous free water generation
from exaggerated catabolic reactions and from enhanced renal accrual, which would make
any extra exogenous water intake unnecessary [80,81].
Nutrients 2022,
Nutrients 14, 4489
2022, 14, 4489 6 of 614of 14

Figure 3 Proposed pathophysiologic link between sodium, fluid, volume and PEM

Sodium, Water and Fluid Shifts in HD Patient

Fluid accumulation (interdialytic)/depletion (intradialytic)→ Tide up & down Phenomenon

Tissue
Endothelial Dysfunction
Sodium Storage
↓ NO (skin, muscle)
Vascular
↑ Angiopoietin 2 ↑ Insulin ↑ Growth Hormone
Leakage
Endothelin 1 Resistance Resistance
Dialysis-Induced
Catabolism
Congestive HF
Muscle Proteolysis ↓ Cardiac Output
& Tissue perfusion

Mitochondrial P Depletion
Dysfunction
Ubiquitin
Activation
Inflammation Lung Edema
Oxidative Peptide ↑ Hypoxemia
Phosphorylation catabolism
Uncoupling
Protein Energy AA Release
Metabolism Gut Translocation
Liver
Metabolic Water ↑ Acute Phase
↓ Albumin
Production Proteins

Hyponatremia
PROTEIN ENERGY WASTING PROCESS

Figure 3. Proposed
Figure pathophysiologic
3. Proposed linklink
pathophysiologic between sodium,
between fluid
sodium, volume,
fluid andand
volume, PEM.
PEM.

Hyponatremia
Rapid sodium removalis difficult to explain
and fluid in anas
depletion anuric dialysis patient
summarized by highinultrafiltration
which dialysis is the
rate
main source of exchange (sodium and water) with external milieu
(>10 mL/h/kg) may lead to poor outcomes with increased cardiac risks [77,78]. This has [61]. Several hypotheses
beenhave been advocated:
consistently shown Firstly, the studies
in several release suggesting
of mediatorsthat (vasopressin,
intensive or angiotensin
aggressive2)fluid[85] or
factors (tonicity,
management thirst)
may lead tothat affect sodium-free
unwanted side effects.water
While intake
theseordialysis-induced
retention; secondly, vascular
risks are
leakage
mainly and sick-cell
mediated syndrome linked
using hypovolemia to inflammation
and repetitive ischemic that facilitate
cardiac water
insults intercompart-
[69,79], some
mental
recent imbalance
findings [86,87];
in animal thirdly, reorientation
experimental models suggest of liver protein
that fast synthesis
sodium removal to may
acutetrig-
phase
ger catabolism, with reprioritization of cell metabolism being associated with muscle pro- be
proteins, reducing albumin circulating levels. A new and interesting hypothesis may
formulated
teolysis (releaseaccording to the findings
of free amino acids) toinmaintain
rodent models
tissue of tissue content
sodium sodium content
[70,80,81].on Fast
muscle
metabolism. As suggested by this model, muscle catabolism and
sodium removal achieved through hemodialysis via ultrafiltration and negative dialy- renal recycling of urea in
presence of tissue salt excess was found to be a key osmotic force
sate–plasma sodium gradient is likely to contribute to muscle proteolysis and dialysis- in minimizing free water
loss [70].
induced In thecatabolism
protein context of [34,41,82].
dialysis patients, tissue salt
In addition, accumulation
as recently shownand in adepletion
phosphate might
ki- be
perceived as the main driving forces of tissue catabolism (proteins,
netic study relying on magnetic resonance spectroscopy, hemodialysis tends to preferen- carbohydrates, lipids)
anddeplete
tially oxidation mechanisms
phosphate from leading to increased
the intracellular endogenousreducing
compartment, production theofavailability
metabolic waterof
(sodium-free) [88]. In this case, hyponatremia will result
high-energy phosphates and impairing ultimately mitochondrion and cellular from a salt-driven catabolic
metabo- state,
with
lism [83]. muscle mass loss, enhanced proteins, carbohydrate and lipid breakdown, as well
as from reprioritization of global energy muscle metabolism at the cellular level (mito-
Tissue sodium accumulation (skin, muscle) is associated with various pathophysio-
chondrion) associated with an intense oxidation phosphorylation process leading to an
logic findings involving on one side the cardiovascular system (i.e., hypertension, left ven-
excessive production and accumulation of endogenous metabolic water (sodium-free) [88].
tricular hypertrophy) independently from pressure level and mechanical consequences
In brief, these tides up and down phenomena, reflecting interdialytic fluid and sodium
but on the other side various metabolic pathways that have direct effects on nutritional
accumulation and intradialytic fluid and sodium depletion, respectively, are likely in-
status (i.e., insulin resistance, muscle catabolism, cell energy metabolism) [54,56,84]. To
volved in the protein–energy malnutrition of hemodialysis patients [84]. During a tide
reconcile the mismatch, the authors advocated surplus endogenous free water generation
up phenomenon, sodium and fluid accumulation tends to trigger inflammation and its
from exaggerated catabolic reactions and from enhanced renal accrual, which would
related consequences (inflammation axis). During a tide down phenomenon, sodium and
make any extra exogenous water intake unnecessary [80,81].
fluid depletion associated with stressors of dialysis-induced systemic stress tend to trigger
Hyponatremia is difficult to explain in an anuric dialysis patient in which dialysis is
catabolism and muscle proteolysis. As suggested in Figure 4, fluid management exposes
the main source of exchange (sodium and water) with external milieu [61]. Several hy-
hemodialysis patients to continuous protein–energy-wasting processes, a risk that can
potheses have been advocated: Firstly, the release of mediators (vasopressin, angiotensin
 dium accumulation and intradialytic fluid and sodium depletion, respectively, are likely
involved in the protein–energy malnutrition of hemodialysis patients [84]. During a tide
up phenomenon, sodium and fluid accumulation tends to trigger inflammation and its
related consequences (inflammation axis). During a tide down phenomenon, sodium and
fluid depletion associated with stressors of dialysis-induced systemic stress tend to trigger
Nutrients 2022, 14, 4489 catabolism and muscle proteolysis. As suggested in Figure 4, fluid management exposes 7 of 14
hemodialysis patients to continuous protein–energy-wasting processes, a risk that can be
mitigated by optimizing treatment schedule, increasing dietary intake, or promoting
physical exercise.
Figure 4 Four clinicalbe mitigated by optimizing treatment schedule, increasing dietary intake, or promoting
steps involved in sodium, water and fluid volume management in HD patient
physical exercise.

1
Monitoring fluid and sodium Clinical: dry weight probing
Instrumental: RBV, BCM, LUS
Treatment Schedule status in dialysis patients Biomarker: BNP, Copeptin…
Adjustment:
Time, frequency,
modality, Dialysate
sodium
4 2
Fine tuning fluid and Restoring fluid and
sodium imbalance to sodium homeostasis
outcomes Diet counseling
Dialysis: time, frequency,
ultrafiltration, sodium
management
3 Residual kidney function
Dialysis tolerance Probing and
Hemodynamic status
Echocardiography
monitoring

Figure4.4.Four
Figure Fourclinical
clinicalsteps
stepsinvolved
involved
inin sodium,
sodium, water,
water, andand fluid
fluid volume
volume management
management in patient.
in HD HD pa-
tient.
5. Fluid Management and Correction of Fluid Imbalance
Optimal fluid and sodium management constitute a cornerstone component of dialysis
adequacy in reducing cardiovascular burden in this fragile population. This is summarized
in the dry weight probing approach [89,90]. Unfortunately, this basic component tends to be
overlooked in favor of more attractive uremic toxins for improving cardiovascular burden.
Dry weight policy in dialysis patients is a clinical priority that relies on the continuous
and fine monitoring of patient conditions as well as anticipation when intercurrent event
occurs (i.e., intervention, illness, infection) to preemptively readjust dry weight [91]. Fluid
and sodium management represents a key component in dialysis patients working both
ways—on one side to prevent fluid overload when secondary catabolism occurs and on the
other side to prevent protein–energy wasting associated with chronic fluid overload [51].
Several recent reviews have been dedicated to this topic, to which we refer interested
readers for more detailed information [54,92,93]. In this paragraph, we summarized the
main points to address this problem in two sections: Firstly, how to monitor adequately
fluid status of dialysis patients; secondly, how to restore fluid and sodium homeostasis.
This is briefly schematized in Figure 4.

5.1. Monitoring Fluid and Sodium Status in Dialysis Patients

Clinical management is a global process that permits the attainment and maintenance
of “dry weight” in dialysis patients [90]. However, it is a very subjective approach that
takes advantage of using support tools for supporting clinical decision-making. In brief,
dry weight must be reassessed and adjusted on a regular basis, taking into account the
nutritional status of the patient as well as intercurrent events that may occur. In practice,
frequent reassessment of dry weight (session-by-session to monthly) is recommended to
follow patient clinical condition changes. Various non-invasive methods (offline or online
HD machine) are currently proposed to assess fluid volume status and hemodynamic
equilibrium. Chest X-ray may be used to assess lung overload and calculate cardiothoracic
index (CTI). Inferior vena cava diameter (IVCD) assessed with a US probe is proposed
Nutrients 2022, 14, 4489 8 of 14

to monitor intravascular volume and right atrial pressure at bedside in dialysis patients.
However, its implementation is not easy, and its predictive value on hemodynamic stability
is limited. Relative blood volume changes (RBVC), reflecting the vascular refilling rate
(VRR), measured by an optical sensor are also proposed to estimate volume status. This
tool may help to identify individual critical volume (risk of intradialytic hypotension) and
to reduce the incidence of intradialytic hypotension. Long-term benefits still remain to be
proved. Multifrequency bioimpedance (MF-BIS) is commonly used to assess fluid status
and repartition in hemodialysis patients [94,95]. Several studies have confirmed that the
MF-BIS is an easy-to-use, reliable, and reproducible tool for assessing volume status and
relative fluid overload as well as body composition in dialysis patients. The lung ultrasound
(LUS) method has also been proposed for assessing lung overload (extravascular edema)
by measuring the thickness of interlobular septa. The thickening of interlobular septa
via edema generates beams visualized as B lines (i.e., COMET tails) [73,96]. The simple
numbering of these B lines provides an estimate of lung overload and cardiac dysfunction
with highly predictive values of morbidity or mortality. Vascular stiffness estimated from
pulse wave velocity (PWV) measurement provides an indirect way of assessing sodium
content with highly predictive value on morbidity. Sodium MRI (23Na MRI) is proposed
for assessing tissue sodium content (skin, muscles). This method remains a clinical research
tool for evaluating the specific effects of new therapies or treatment regimens on tissue
content [97,98]. Cardiac biomarkers are proposed for assessing myocardium structural or
functional consequences associated with volume overload. Echocardiography is currently
used to assess sodium overload and its cardiac consequences. Different echocardiographic
criteria (volume of the atria, ventricular volume, left ventricular mass, thickness of the
ventricular septum, ejection fraction, pulmonary arterial pressure) are recommended for
the monitoring of dialysis patients. Atrial natriuretic peptides (ANP, BNP, and NT-proBNP)
were the most widely used to assess volume overload [99]. Copeptin (a precursor of
vasopressin) has recently been introduced to estimate volume depletion. Markers from the
troponin family (troponins I and T) can be used to detect myocardial ischemic insults.

5.2. Restoration of Fluid and Sodium Homeostasis

Restoration of fluid and sodium imbalance relies on three main components: The
first component is dietary counseling and educating patients to reduce sodium and fluid
intakes with the support of specialized dieticians; the second component is based on the
preservation of residual renal function. This aspect is fundamental but unfortunately will
concern a limited number of patients over a short period of time; the third component
relates to the treatment schedule program and dialysis prescription. For space reasons, only
dialysis-related aspects will be discussed in this paragraph. Three items may be initiated to
achieve this target: Firstly, weekly treatment time; secondly, ultrafiltration volume and rate;
thirdly, dialysate sodium prescription.
Weekly dialysis treatment time is the main factor that conditions total ultrafiltered
volume and ultrafiltration rate per session. Several studies have documented that an
hourly ultrafiltration rate greater than 13 mL/kg was associated with an increased risk of
mortality of almost 50% [78,100]. Preserving volemia should be a focused priority when
establishing a dialysis treatment schedule [99]. Duration of dialysis sessions should be
tailored to patients’ needs and tolerances to prevent reaching critical ultrafiltration rates
and intradialytic hypotension [101]. This common sense approach is unfortunately not
often applied for practical, logistical, or simply individual refusal reasons [100].
The prescription of dialysate sodium concentration is another important compo-
nent in the prescription of dialysis that has been neglected [102,103]. The prescription of
sodium dialysate responds in the majority of cases to a fixed prescription (sodium dialysate
138 or 140 mmol/l), to which the patient will adjust. Dialysate sodium prescription should
be better individualized best based on a dialysate–plasma sodium gradient [82,93,104]. In
fact, dialysate–plasma sodium gradient (d-pNa) conditions the diffusive sodium fluxes.
Three clinical situations can be then observed: Firstly, the gradient is positive, in this case
Nutrients 2022, 14, 4489 9 of 14

a diffusive sodium load is achieved resulting in sodium gain, reducing the net mass of
sodium removed and increasing plasma tonicity during the dialysis session; secondly,
the gradient is negative. In this case, a diffusive sodium removal is achieved, leading to
sodium depletion while increasing the net mass of sodium removed and reducing plasma
tonicity; thirdly, the gradient is neutral, in this case, there is no diffusive sodium transfer
(isonatremic dialysis or zero diffusive condition), and the net sodium depletion relies only
on convective transfers by ultrafiltration without plasma tonicity changes. It is important to
highlight that the sodium mass removed in dialysis is mainly achieved via convection (80 to
100%) or ultrafiltration (intradialytic weight loss), while the diffusive part represents only a
variable component ranging between 0 to 30% depending on the dialysate–plasma gradient.
In brief, fine-tuning of a dialysate sodium prescription may be beneficial on sodium mass
balance, tonicity changes, and dialysis tolerance. Automated dialysate sodium alignment
is facilitated by means of a sodium management module embedded on a certain dialysis
machine that permits an automated adjustment of dialysate sodium to plasma sodium
concentration according to the prescription. In addition, this sodium management module
gives sodium mass removed and plasma sodium concentration in real time [105–107].
As a brief summary, it is time to take fluid balance and nutrition seriously, particularly
in dialysis patients, with appropriate measures to reduce protein–energy wasting burden
in this fragile population [108].

6. Conclusions
As highlighted in this in-depth narrative review, sodium and water imbalance and
fluid management in dialysis patients tend to be strongly associated with the protein–
energy-wasting process. Fluid and sodium imbalance in dialysis patients are superimposed
factors that tend to precipitate highly malnutritional exposed patients. Inflammation, and
its related pathways, is the main source of protein energy wasting. Tissue sodium accumu-
lation and depletion, as well as their metabolic consequences, tend to worsen nutritional
conditions. Hyponatremia, a condition associated with poor outcomes, is strongly associ-
ated with mixed water and sodium disorders. We hypothesize that hyponatremia reflects
intense hypercatabolism, resulting in metabolic water production from cellular oxidation
phosphorylation processes. It is time to act more precisely on sodium and fluid imbalance
to mitigate both cardiovascular and nutritional risks and to improve patient-reported out-
comes. Personalized management of sodium and fluid using available tools, including
sodium management tools, has the potential to more adequately restore sodium and water
homeostasis and to improve the nutritional status of dialysis patients. In brief, fluid and
sodium imbalance must be considered to be strong determinants of the protein–energy-
wasting process requiring more precise approaches. This new hypothesis deserves further
interventional clinical and nutritional studies to be validated.

Author Contributions: Conceptualization and writing-original draft preparation was equally dis-
tributed by B.C., M.M.-C., H.L.-M. and J.-P.C. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: No ethical approval was needed.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: B.C. is scientific consultant for F.M.C., M.M.-C., H.L.-M., J.-P.C. have no conflict
of interest.

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