review www.kidney-international.

org

Sodium and water handling during hemodialysis:

new pathophysiologic insights and management
approaches for improving outcomes in end-stage OPEN

kidney disease
Bernard Canaud1,2, Jeroen Kooman3, Nicholas M. Selby4, Maarten Taal4, Susan Francis5,
Pascal Kopperschmidt6, Andreas Maierhofer6, Peter Kotanko7,8 and Jens Titze9,10,11
1
Centre for Medical Excellence, Fresenius Medical Care Deutschland, Bad Homburg, Germany; 2Montpellier University, Montpellier, France;
3
Maastricht Universitair Medisch Centrum – Maastricht, Netherlands; 4Centre for Kidney Research and Innovation, University of
Nottingham, Royal Derby Hospital Campus, Derby, UK; 5Sir Peter Mansfield Imaging Centre, University of Nottingham, UK; 6Fresenius
Medical Care Deutschland, GRD, Schweinfurt, Germany; 7Renal Research Institute, New York, New York, USA; 8Icahn School of Medicine at
Mount Sinai, New York, New York, USA; 9Division of Cardiovascular and Metabolic Disease, Duke-NUS, Singapore; 10Division of
Nephrology, Duke University Medical Center, Durham, North Carolina, USA; and 11Division of Nephrology and Hypertension, University
Clinic Erlangen, Germany

Space medicine and new technology such as magnetic Copyright ª 2019, International Society of Nephrology. Published by
resonance imaging of tissue sodium stores (23NaMRI) have Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
changed our understanding of human sodium homeostasis
and pathophysiology. It has become evident that body
sodium comprises 3 main components. Two compartments

have been traditionally recognized, namely one that is
circulating and systemically active via its osmotic action,
and one slowly exchangeable pool located in the bones.
The third, recently described pool represents sodium
stored in skin and muscle interstitium, and it is implicated
in cell and biologic activities via local hypertonicity and
sodium clearance mechanisms. This in-depth review
provides a comprehensive view on the pathophysiology
and existing knowledge gaps of systemic hemodynamic
and tissue sodium accumulation in dialysis patients.
Furthermore, we discuss how the combination of novel
technologies to quantitate tissue salt accumulation (e.g.,
23
NaMRI) with devices to facilitate the precise attainment of
a prescribed hemodialytic sodium mass balance (e.g.,
sodium and water balancing modules) will improve our
therapeutic approach to sodium management in dialysis
patients. While prospective studies are required, we think
that these new diagnostic and sodium balancing tools will
enhance our ability to pursue more personalized
therapeutic interventions on sodium and water
management, with the eventual goal of improving dialysis
patient outcomes.
Kidney International (2019) 95, 296–309; https://doi.org/10.1016/
j.kint.2018.09.024
KEYWORDS: cardiovascular outcomes; hemodialysis; patient outcomes; so-
dium mass balance; tissue sodium
Correspondence: Bernard Canaud, Centre for Medical Excellence – FMC
Deutschland GmbH, Else Kröner Strasse 1, Bad Homburg 61352, Germany.
E-mail: Bernard.Canaud@fmc-ag.com
Received 30 July 2018; revised 22 September 2018; accepted 24
September 2018
T
he hazard of excessive salt intake was elegantly dis-
cussed by McGregor and De Wardener more than 30
years ago in their essay “Salt, Diet and Health: Nep-
tune’s poisoned chalice; the origins of high blood pressure.”1
In this regard, chronic kidney disease (CKD) patients repre-
sent a particularly sensitive and vulnerable population,
because the ability to regulate sodium and water metabolism
progressively fails as kidney function declines. This situation
is extreme during intermittent renal replacement therapy in
patients with end-stage kidney disease (ESKD).2
Space medicine and novel magnetic resonance imaging of
tissue sodium stores (23NaMRI) have transformed our
traditional understanding of sodium homeostasis and path-
ophysiology.3,4 It has been established that total body sodium
includes 3 main components5: (i) the traditional model of
osmotically active sodium presenting in the total extracellular
space, and implicated in the control of extracellular fluid
volume, compartmental fluid composition, and hemody-
namic responses; (ii) a slowly exchangeable pool of sodium
located in the bones; (iii) a recently described component
stored in tissue (skin and muscle interstitium), representing
so-called “water-free tissue” storage (Figure 1). The latter
seems to not readily equilibrate with the extracellular fluid
compartment and may exert local hypertonicity, which in
turn triggers tissue-specific sodium clearance processes.6 So-
dium stored under the skin induces homeostatic-regulatory
activity in resident immune cells, which control lym-
phangiogenesis and blood pressure.7–9 Whereas systemic and
tissue sodium accumulation can have comparable patho-
physiological effects in part, tissue sodium accumulation may
also have different pathophysiologic and clinical conse-
quences that may be amenable to therapeutic strategies in

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B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients review

Diet Na intake

Extracellular Na
Osmotically active

Regulated

Nonregulated
Tissue Na Gut
Water-free storage Kidney
Glycosaminoglycan skin
(dialysate)
Interstitium
Skin- muscle
muscle – artery …

Figure 1 | Total body sodium (Na) homeostasis and location.

CKD patients (Figure 2). This latter pathophysiologic aspect
opens new perspectives, particularly in hemodialysis patients,
that may eventually translate into improved patient outcomes.
The aim of this review is to offer a comprehensive view on
the pathophysiologic role of sodium accumulation (systemic
hemodynamically active sodium and local tissue sodium) in
CKD and dialysis patients, and to provide an outlook on new
technologies for monitoring salt accumulation in body
compartments and also on the potential of novel therapeutic
interventions.
SODIUM METABOLISM IN DIALYSIS PATIENTS: NEW INSIGHTS
INTO ITS METABOLISM AND PATHOPHYSIOLOGIC ROLE
Total body sodium distribution
Osmotically active sodium. Osmotically active sodium
distributes in the extracellular fluid (ECF) compartment
(Figure 3).10 Studies using tracer dilution or bioimpedance
technologies have evidenced ECF expansion in advanced
CKD11 and dialysis patients.12,13 In various studies, 25% to
30% of dialysis patients were classified as severely fluid
overloaded, defined as a “fluid overload” (FO) volume
of $2.5 L assessed by bioimpedance spectroscopy (BIS).13–15
We found in a recent study involving 8,883 prevalent he-
modialysis patients that only 34% of patients had a FO < 1.1
L before dialysis.15 Also, interstitial pressure is correlated with
ECF volume in patients with CKD and edema.16 In general,
ECF expansion results in increased plasma volume that may
directly affect blood pressure and cardiovascular status.17
The distribution of isotonic fluid across the extracellular
compartment is altered with hypoalbuminemia.18 Using
BIS we confirmed that serum albumin was lowest in pa-
tients with the highest FO.15 John et al. showed that ECF
was expanded in hypoalbuminemic as compared to nor-
moalbuminemic peritoneal dialysis patients, whereas
plasma volume was comparable between both groups.18
Another factor, which may play a role in the altered fluid
dynamics in dialysis patients, is an increased capillary
permeability.19
Cell and tissue active sodium and so-called osmotically inac-
tive sodium. Chloride storage in the skin was first reported
more than 100 years ago,20 and found its way into the textbooks
as a homeostatic-regulatory principle of body fluid homeosta-
sis.21 We do not know how, why, and when in the subsequent
100 years the medical community lost knowledge about the role
of sodium storage largely as sodium chloride in health and
disease. Cartilage sodium storage is well known; it is associated
with the negative charge density of its glycosaminoglycan-rich
interstitium.22,23 Similarly, increased elongation and sulfata-
tion of the glycosaminoglycans occurs in the skin in experi-
mentally induced sodium storage, suggesting that electrostatic
interaction between these negatively charged surfaces and so-
dium might lead to osmotically inactive sodium storage in the
skin.24–26 Recently, this concept of tissue sodium accumulation
was corroborated in tissue biopsies (skin, muscle, and arteries)
from dialysis patients and healthy subjects at the time of kidney
transplant.27 Analogous to the high osmolyte concentrations in
the renal medulla and their mode of action, sodium storage
seems to be part of a kidney-like counter-current system,
designed for cutaneous water conservation.28
23
NaMRI is crucial for transferring the evolving concept of
sodium storage from basic research into the clinical arena.
Ultra–high field 23NaMRI has shown that humans, similar to
rodents, store sodium below the keratinocyte layer.29 A 3T
23
NaMRI reliably detects and quantifies sodium storage in
skin and muscle.30–38 Classic “black-box balance studies,”
which have confirmed the relationship between water-free
sodium storage and salt-sensitive hypertension,39 now can
be transformed into 23NaMRI studies to quantify the rela-
tionship between tissue sodium storage and blood pressure in
clinical and epidemiological investigations. The idea that local

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review B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients

Hemodynamic Tonicity
Extracellular volume Extracellular tonicity
Cardiac output Extracellular Na
Osmotically active Body water distribution
Blood pressure Body fluid volume
Tissue perfusion

Tissue Na Metabolism
Storage buffer Water-free storage Local hypertonicity
Na accumulation Glycosaminoglycan & Na clearance disturbance
Aging Interstitium Cell & tissue action
Diet observance Skin- muscle
muscle – artery … Kidney water concentration
Pathologies Inflammation
Comorbidities Muscle wasting
Cardiac & vascular remodeling
Insulin resistance…

Figure 2 | Role of sodium (Na) according to the new understanding of physiology.

regulation of electrolyte and water metabolism in the skin is
functionally coupled with systemic blood pressure level is no
longer restricted to animal studies.40–42 Clinical 23NaMRI
studies have revealed that in parallel to the development of
essential hypertension, humans store increasing amounts of
skin sodium as they age,40 large amounts of tissue sodium are
stored in patients with endocrine forms of hypertension,41
and hypernatremia may be a sodium-storage disorder.42
Tissue sodium content is higher in patients with CKD,
diabetes, or ESKD compared with healthy subjects.37 He-
modialysis can mobilize sodium chloride tissue stores.43
Sodium action: systemic circulating osmotically active versus
tissue local active sodium
Isotonic fluid expansion can have varying hemodynamic
effects. Guyton’s hemodynamic concept posits that reduced
renal sodium excretion leads to an increased cardiac output,
followed by an autoregulatory increase in systemic vascular
resistance to prevent tissue hyperperfusion.44 The resulting
increase in systemic blood pressure then increases salt
excretion at the cost of hypertension. Based on this concept,
sodium-driven FO in advanced CKD would thus necessarily
lead to hypertension unless circulating volume is normalized
(e.g., by diuretics or ultrafiltration).45
Whereas extracellular volume is generally higher in hyper-
tensive compared with normotensive patients,12,46 there is also a
substantial overlap in blood pressure between normovolemic
and fluid overload ESRD patients.14,47 Three factors might ac-
count for this phenomenon: (i) cardiac failure,48 which could
contribute to the high mortality in normotensive patients with
FO49; (ii) hypoalbuminemia and/or increased capillary perme-
ability leading to an altered distribution between plasma and
interstitial fluid18,19; and (iii) a difference in vascular response to
fluid loading. According to Guyton’s concept, volume loading is
followed by an increase in peripheral vascular resistance, but
this is not always the case.50 A recent study found that the
difference in blood pressure between normotensive and hy-
pertensive fluid overload patients was mainly related to systemic

Extracellular Na
Systemic
osmotically & Cell & tissue
hemodynamically Active sodium
active sodium
Interstitium
skin muscle-
Mechanical artery Na Metabolic Storage

Fluid overload Inflammation Aging

Hypertension Lymphangiogenesis Comorbid factors
Cardiac disease Muscle wasting Vascular stiffness
Vascular disease Insulin resistance
Lung disease Cardiac disease
Kidney disease Vascular disease
Brain disease Lung disease
Kidney disease
Brain disease
Organ damage

Poor outcome

Figure 3 | Pathophysiologic role of sodium (Na) accumulation and cross-talk.

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B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients
vascular resistance.51 Interestingly, the main hemodynamic
parameter differentiating patients with nocturnal dialysis from
conventional dialysis is a significantly different peripheral
vascular resistance.52 Patients from Tassin treated with long,
slow dialysis also exhibited a markedly lower vascular resistance
than did conventional HD patients, whereas markers of circu-
lating volume (e.g., vena cava diameter and atrial natriuretic
peptide) did not differ between the 2 groups.53 This paradoxical
response to fluid volume expansion raises the question of
whether additional factors might explain such variation in he-
modynamic response. Recent evidence suggests that sodium
might have a direct role.
What is the evidence for a direct effect of osmotically active
sodium on hemodynamics? Differences in vasoconstrictor
functioning, which may be relevant in the different responses
to volume loading in ESKD patients, have traditionally
involved the sympathetic system and the renin-angiotensin-
aldosterone system,54,55 although in the last decade a more
complex picture has emerged.56 Evidence mainly derived
from experimental hypertension has shown that sodium may
have an independent effect on vascular structure and func-
tion.57 Studies in normotensive salt-sensitive subjects have
shown that dietary sodium loading increases the alpha-to-
beta adrenoceptor ratio, favoring a higher peripheral
vascular resistance.58,59 Moreover, in those studies the blood
pressure response to sodium intake was proportional to the
adrenoceptor density on lymphocytes, platelets, and skin fi-
broblasts.60 The vascular stiffening effect of sodium intake has
been demonstrated in observational and interventional clin-
ical studies.61,62 Recent research has shown that endothelial
cells acting as vascular salt sensors modulated the mechanical
stiffness of cells’ plasma membrane via the activation of
epithelial sodium channels and the release of NO in response
to plasma sodium and potassium concentrations changes.63
Direct sodium effect on vascular structure and function
appears also to be mediated by endogenous ouabain-like sub-
stances, which are secreted in the hypothalamus in response to
an increase in cerebrospinal fluid sodium concentration. Release
of ouabains may subsequently activate the adrenals and sym-
pathetic nervous system, but may also directly affect vascular
tone and remodeling. A ouabain-related mediator likely
involved in this mechanism is the endogenous a1 Naþ Kþ-
ATPase inhibitor marinobufagenin (MBF), which is synthesized
by the adrenal cortex.57 MBF induces vasoconstriction through
inhibition of vascular smooth muscle Naþ-Kþ-ATPase and
activates the NAD(P)H oxidase, leading to an increase in
oxidative stress.57,64 Recently Jablonski et al. showed increased
urinary MBF after salt loading in middle-aged and/or older
subjects. Moreover, MBF was related to systolic blood pressure,
aortic pulse wave velocity, and endothelial cell expression of
NAD(P)H oxidase-p47phox.65
The question is whether an increased removal of sodium,
and the associated mediation in vasoactive mechanisms, may
be responsible for the decrease in systemic vascular resistance
observed in patients with long dialysis sessions. Evidence for
this is circumstantial only and based on the fact that patients
Kidney International (2019) 95, 296–309
review
studied in Tassin were dialyzed 3 times weekly for 8 hours,
but also with low dialysate sodium levels and strict sodium
restricted diet.
What is the evidence for direct effects of tissue sodium on
hemodynamics? Recent experimental and clinical studies
support the notion that even in the absence of blood pressure
increase, excess dietary sodium intake can harm target organs,
including blood vessels,27,62,66 heart,67 and brain.68,69 This has
also been documented in observational studies relating di-
etary sodium intake to blood pressure and cardiovascular
outcomes.70
High dietary salt intake is associated with hypertension,
and the prevalence of salt-sensitive hypertension increases
with age. 23NaMRI demonstrated in 56 healthy controls and
57 patients with essential hypertension (age 22–90 years)32 an
age-dependent increase in muscle sodium content in men but
not in women; a corresponding lack of age-related change in
muscle water content suggested water-free sodium storage. In
the skin, there was a remarkable age-related sodium deposi-
tion in men and, to a lesser extent, women. In contrast to
muscle, increased skin sodium content was paralleled with
increasing skin water. In patients with refractory hyperten-
sion, tissue sodium was significantly increased compared with
that in age-matched normotensive controls. This study sug-
gests that tissue sodium storage may play a significant role in
cardiovascular morbidity independent from circulating
osmotically active sodium.32
The traditional model of ECF homeostasis involving the
renin-angiotensin-aldosterone system, pressure natriuresis,
and modulated renal nerve activity via action on natriuretic
and water diuresis has also been challenged in other studies.
By exposing either animal or healthy humans to various levels
of salt intake it has been shown that extracellular volume
conservation and natriuresis result from a renal mechanism
favoring conservation of water rather than sodium. The renal
counter-current concentration mechanism relies on enhanced
urea transporter recycling of urea in the kidney and on urea
production by liver and skeletal muscle, a mechanism with
substantial energy requirements.71 Hemodynamic change
produced by salt loading and depletion has also been explored
in salt-sensitive, salt-resistant, normotensive, and hypertensive
volunteers.39 The main factor differentiating both groups was
the modulation of peripheral vascular resistance following salt
loading and unloading. Sodium balance remained similar in
both phenotypes during salt loading or depletion. The authors
concluded that salt-sensitive subjects are unable to modulate
total peripheral resistance in response to salt depletion, mir-
roring their inability to vasodilate in response to salt loading. It
then follows that differences in water balance observed between
these groups reflect differences in interstitial compartment salt
storage that may relate to vascular dysfunction in salt-sensitive
subjects.39
High dietary sodium intake increases blood pressure in
animal models and humans. In animal studies, it has been
shown that blood pressure might be affected by dermal so-
dium accumulation and lymphangiogenesis mediated by
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review B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients
vascular endothelial growth factor C (VEGF-C).71 Such a
buffering mechanism of sodium dietary intake was unknown
in humans. In a recent study, skin electrolytes, blood pressure,
and plasma VEGF-C were assessed in 48 healthy participants
randomized to a low-sodium diet (70 mmol sodium/d) and
high-sodium diet (200 mmol/d) for 7 days. A significant in-
crease in 24-hour mean blood pressure was noted with salt
loading in women but not in men. Skin sodium increased
significantly between low- and high-sodium diets. Interest-
ingly, a sex-specific effect was also observed, marked by a
significant skin sodium increase in men but not in women,
suggesting a sex-specific difference in sodium-buffering ca-
pacity. Skin sodium correlated with blood pressure, stroke
volume, and peripheral vascular resistance in men but not in
women. No change was noted in plasma VEGF-C. These
findings suggest that the skin may buffer dietary sodium
intake by reducing the hemodynamic consequences of
increased salt, and this may be influenced by sex.72 Such a
study has not yet been performed in ESRD patients, but the
clinical relevance of this question is high, acknowledging the
sex difference in mortality in this population.73
Extracellular fluid overload, tissue sodium accumulation, and
outcome parameters: is tissue sodium accumulation the
missing piece in this pathophysiologic circle?
Most evidence regarding the relation between outcomes and
FO has been obtained using bioimpedance spectroscopy13 or
vector graph bioimpedance.74 Whereas research on the rela-
tionship between FO and outcome has traditionally focused
on ESRD patients,15,75,76 recent evidence has shown that FO
was already prevalent in stage 4 CKD patients and associated
with increased mortality.77 Interestingly, although the rela-
tionship between tissue sodium storage and outcome has not
been studied in detail, an association between tissue sodium,
assessed by 23NaMRI, and left ventricular hypertrophy has
been observed in advanced CKD patients.36
Conventionally, the relationship between FO and outcomes
has been explained in terms of increased cardiovascular risk in
advanced CKD.45 Indeed, a near linear relation between FO and
left ventricular hypertrophy has been described.78 Moreover, a
relationship between FO and endothelial dysfunction, as
measured by VCAM-1 and interleukin-6 levels, has recently
been observed.79 However, the fact that even small levels of FO,
which are unlikely to have major hemodynamic effects, are
associated with outcomes suggests that the relationship between
FO and outcomes may not be directly causative. Indeed, there is
mounting evidence that FO and tissue sodium accumulation
may be part of multidimensional clusters of risk factors that
impact outcomes, including inflammation and malnutrition.
Noncardiovascular consequences of fluid overload. Various
studies have confirmed a link between FO and systemic
inflammation in dialysis patients, using various markers of fluid
status and systemic inflammation, respectively, including C-
reactive protein, tumor necrosis factor-a, and interleukin-6.80–82
FO may lead to inflammation by bowel congestion and subse-
quent endotoxemia, as has been described in patients with heart
300
failure.83 In renal failure, evidence for a possible effect of gut
edema on systemic inflammation is more circumstantial, sug-
gested by the relationship between systemic endotoxemia and
fluid status, assessed by vena cava echography.82 Systemic
inflammation may also induce FO through hypoalbuminemia
or cardiac stunning,18,81 impairing the tolerance to fluid removal
during dialysis. Interestingly, McIntyre et al. observed in 120
hemodialysis patients that circulating endotoxin was signifi-
cantly increased with dialysis-induced hemodynamic stress (e.g.,
hypotension, high ultrafiltration rate) leading to subclinical gut
ischemia and endotoxin translocation from the gut.84 More-
over, inflammation may directly lead to increased capillary
leakage, reducing the tolerance to fluid removal because of
translocation of fluid from the intravascular to the interstitial
compartment. However, in a study directly assessing systemic
albumin leakage by the transcapillary escape rate of 125I-albu-
min, Yu et al. observed primarily a relationship with markers of
thrombocyte activation and hypoalbuminemia, but not with
markers of systemic inflammation,19 suggesting a more com-
plex picture. At present, despite substantial evidence on the
relationship between FO and inflammation in ESRD, there is no
solid evidence that correction of FO improves systemic
inflammation.85
Observational data have also shown a relationship between
FO and malnutrition. This holds true for biochemical
markers, such as serum albumin.81 However, the patho-
physiology of hypoalbuminemia in dialysis patients is multi-
factorial and includes nutritional factors, inflammation and
possibly increased capillary leak.19 There is also evidence for a
more direct relationship between FO and body composition
change; Hung et al. observed a negative relation between FO,
expressed as the FO index >7% of ideal dry weight by BIS,
and lean tissue mass.81 The reason for this relationship is
unclear. Proposed factors involved may be a failure to adjust
dry weight with an unnoticed decline in tissue or fat mass, or
the concomitant presence of inflammation. We recently
showed in 8883 prevalent dialysis patients that FO of >1.1 L
was observed in isolation (19% of patients), but was present
(18% of patients) in tandem with malnutrition and/or
inflammation.86 The presence of 1 or more risk factors was
associated with an incremental risk of mortality, translating to
an additive or amplifier effect. Of note, only 12% of patients
did not have a single risk factor. However, further studies
assessing the relation between FO and malnutrition should
preferably also include methods other than bioimpedance,
because changes in fluid status and osmotic pressure during
dialysis were recently shown to affect the estimation of lean
and adipose tissue mass using this technique.87
Previous studies using tracer dilution techniques have
suggested that malnutrition might have a direct effect on the
distribution of body fluid compartments.10 In a study in
nonrenal patients, the ratio between ECF and body weight
was higher in malnourished patients, although the ratio be-
tween ECF and height was not different.88
Summarizing, FO appears to be part of a cluster of car-
diovascular and noncardiovascular risk factors, including
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B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients
endothelial dysfunction, systemic inflammation and malnu-
trition, as shown in observational studies. Also, although part
of the relationship between mild FO and outcomes may be
explained by its noncardiovascular correlates, in large studies
it remains an independent risk factor after adjusting for
multiple confounders.19,89 The exact nature of these re-
lationships is not well elucidated, thus highlighting the need
to study novel causative links—for example, the role of tissue
sodium content.
Relationship between tissue sodium and nutritional
status. New findings challenge the dogma that high salt
intake leads only to increased thirst, water intake, diuresis,
and blood pressure. Titze and colleagues have shown recently
that salt intake and tissue sodium content may have various
nutritional and metabolic effects. Salt loading activates an
adaptive regulatory network in the kidney, muscle, and liver,
which enables the reprioritization of energy metabolism to
conserve plasma water in the setting of high salt intake.71 This
phenomenon requires high energy consumption and may
contribute to muscle wasting observed in CKD patients.90,91
Interestingly, this deleterious process may be reduced by
protein and energy intake.71,92 Furthermore, tissue sodium
accumulation was shown recently to be associated with
muscle structural and functional disturbances contributing to
peripheral insulin resistance.93
Tissue sodium accumulation has been observed in a
number of degenerative or inflammatory pathologies that are
associated with poor outcomes.94–96 For example, tissue so-
dium and water content has been explored in a model of
acute muscle atrophy obtained by unloading the calf muscles
of 1 leg.97 In 12 healthy males 1 calf muscle was submitted to
60 days of unloading with an orthosis device while the other
calf served as a control. 23NaMRI and turbo spin-echo se-
quences in magnetic resonance imaging were obtained from
the control and orthosis leg. In the orthosis leg, muscle vol-
ume decreased significantly. In parallel, tissue sodium content
increased in calf muscles (10% to 17%), while it did not
change significantly in the active leg.97
Recent data suggest that excessive sodium stored in the
muscle and skin in dialysis patients may contribute to
metabolic disorders. An association between tissue sodium
and peripheral insulin resistance has been shown recently.
Eleven hemodialysis patients and 8 controls underwent
hyperinsulinemic-euglycemic-euaminoacidemic clamp
studies to measure disposal rates of glucose and leucine.93
Calf 23NaMRI was used to quantitate muscle and skin tis-
sue sodium. Compared with controls, hemodialysis pa-
tients had lower disposal rates of glucose and leucine and
higher muscle sodium concentration; skin sodium did not
differ.
Tissue sodium and accelerated aging. Sodium accumula-
tion may also be associated with premature aging. There is
circumstantial evidence for a premature aging process in ure-
mia, leading to phenotypic alterations such as early cardiovas-
cular disease and muscle wasting. Telomere length in patients
with ESRD is decreased compared with controls.98 Biomarkers
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review
of aging, such as CDKN2A/p16INK4a and SA-b-Gal in arterial
samples, are increased in transplanted ESRD patients.99 Inter-
estingly, an inverse relationship between sodium intake and
telomere length was observed in overweight teens in a popu-
lation study.100 Although there is as yet no direct evidence for a
relation between fluid and/or sodium overload and an accel-
erated aging process, we speculate that potential causative
mechanisms exist, such as oxidative stress and inflammation,
which are established drivers of aging.101 Sodium promotes
cellular senescence in cultured HeLa cells and primary mouse
embryonic fibroblasts.102 Tissue sodium measured by 23Na-
MRI imaging associates with aging, salt-sensitive hyperten-
sion,32 and various degenerative pathologies.103
TRADITIONAL AND NEW TOOLS FOR MONITORING SALT
ACCUMULATION ACROSS DIFFERENT BODY COMPARTMENTS
Clinical tools
Restoring salt and water homeostasis in hemodialysis patients
has been the nephrologist’s quest for the Holy Grail since the
1960s.104 Salt and water management in dialysis patient relies
on 3 components: (i) the accurate assessment of fluid and
sodium status; (ii) the adequate removal of excess salt and
water; and (iii) a salt dietary restriction while preserving re-
sidual kidney function.
While clinical assessment of fluid status, hemodynamic
stability, and patient perception is difficult, it remains the
cornerstone of hemodialysis patient management, including
the regular setting of “dry weight.”105,106 Dry weight indicates
the post-dialysis weight at which, in theory, no signs of fluid
imbalance (neither excess nor depletion) are present, blood
pressure is in the normal range, and the patient feels
comfortable without functional limitations.107 Dry weight is
probed over time by clinicians and reassessed periodically.108
Further work has led investigators to refine assessment of the
dry weight concept.109 Several studies, including the ran-
domized dry-weight reduction in hypertensive hemodialysis
patients (DRIP) study, have shown that a clinical approach
focused on tight control of dry weight was associated with
positive mid- and long-term outcomes.110–114 However,
recent findings using intradialytic cardiac magnetic resonance
imaging have documented that the hemodynamic stress
induced by hemodialysis was associated with damage of the
heart and other organs.115,116 These findings challenge an
overly strict dry weight policy, considering the risk of repet-
itive ischemic insults particularly in fragile patients (e.g.,
diabetes, elderly, peripheral vascular disease).117,118
Given the shortcomings of clinical assessment, biomarkers
or instrument-based tools have been proposed to more
objectively define dry weight (Figure 4).119
Biomarkers
Cardiac biomarkers have been used extensively to disentangle
fluid status and cardiac dysfunction in dialysis patients.
Natriuretic peptides (atrial natriuretic peptide, brain natri-
uretic peptide, and N-terminal pro b-type natriuretic peptide)
are the most popular ones for assessing FO.120,121 Copeptin,
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review B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients

Na monitoring
Clinical parameters
Clinical assessment
Dry weight, vital
parameters (BP, HR)
Patient perception
Instrument parameters
BIA, RBVC,
Lung US, IVCD, echocardiog
Biomarker parameters
BNP, NT-ProBNP, troponin
copeptin, MBG
Calf skin and muscle 23Na MRI
Na handling
Extracellular Na
Osmotically active Dietary counseling
Residual kidney function
Diuretics
Renal replacement
Tissue Na treatment schedule
Water-free storage Time – frequency - modality
Glycosaminoglycan
Automated & controlled
sodium balancing module
Embedded on HD machine

Figure 4 | Precise management of sodium (Na) in hemodialysis (HD) patients. BIA, bioimpedance analysis; BP, blood pressure; BNP, brain
natriuretic peptide; HR, heart rate; IVCD, intraventricular conduction delay; MBG, marinobufagenin; NT-proBNP, N-terminal prohormone of BNP;
RBVC, relative blood volume change; US, ultrasound.

used as a surrogate marker of arginine vasopressin, is more
sensitive to fluid depletion.122 Although these biomarkers
have been shown to be quite useful for patient risk stratifi-
cation, their specificity, sensitivity, and/or clinical value to
manage fluid status have remained limited or contested.123,124
Multi-marker approaches and time-trend analysis have been
proposed to better support physician decision-making in
stratifying cardiovascular risk, but this raises financial is-
sues.125,126 Whatever the predictive clinical value of these
biomarkers in fluid management, health economics and
practical usability must be determined before their adoption
in daily clinical practice.127,128
Instrument-based tools
Inferior vena cava diameter change determined by ultrasound
has been proposed to monitor extracellular volume in dialysis
patients.129,130 However, the practical difficulty in imple-
menting ultrasound in a dialysis facility and the poor pre-
dictive value on blood pressure response in probing dry
weight has precluded its widespread use.131
Relative blood volume change and plasma refill rate
during dialysis can be assessed by online blood volume
sensors.132 In expert hands relative blood volume mea-
surement provides useful insights into a patient’s volume
status,133 but randomized controlled trials have produced
conflicting results.134,135
Multifrequency bioimpedance spectroscopy analysis is an
easy-to-use, reliable, and affordable tool to guide fluid man-
agement, with even subtle variations in fluid status being
related to outcomes.136–138 In addition, extensive use of bio-
impedance spectroscopy in clinical studies (retrospective and
prospective) has generated substantial clinical evidence sup-
porting the notion that precise fluid management might
improve intermediate patient outcomes, although trials so far
have included only selected hemodialysis populations.139,140
Further outcome-based studies are required to definitively
establish whether multifrequency spectroscopy has a place as
a noninvasive point of care measurement to guide fluid
management in dialysis patients.141
More recently, lung ultrasound has been used in chronic
hemodialysis patients to track asymptomatic pulmonary fluid
accumulation (extravascular edema). Thickening of inter-
lobular septa due to water accumulation generates comet tail-
like signs, visible by ultrasound. Counting the B lines of these
“comets” provides an estimate of lung water and predicts
patient outcomes.142–145
23
NaMRI has recently been introduced to quantitate tissue
sodium in CKD patients.146–148 It has been shown that he-
modialysis can mobilize sodium tissue stores, contributing
significantly to the net sodium mass balance (Figure 5).43
Complex logistics, costs, and limited availability of 23NaMRI
render it currently an experimental tool. Of note, a recent
pilot study explored the use of portable 23NaMRI.149
TRADITIONAL AND INNOVATIVE FLUID AND SODIUM
MANAGEMENT: ALGORITHMS, MODELING, AND SUPPORTIVE
DECISION TOOLS
Optimal management of fluid and sodium in dialysis patients
requires restricting interdialytic salt intake and adjusting
dialytic salt and fluid removal.150–152 This conventional
method calls for adjusting dry weight based on clinical
judgment and ancillary tools described above.153 However,
this approach may be hampered by the discontinuous nature
of the hemodialysis, dietary preferences, and intolerance of
patients to fluid and sodium removal.154
Aggressive management of sodium and fluid excess to
restore fluid homeostasis either by high ultrafiltration rate or
high dialysate-to-plasma sodium concentration gradient has

302 Kidney International (2019) 95, 296–309

B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients review

a Man, 75 years, b Man, 77 years,

Figure 5 | Representative lower-limb 23Na magnetic resonance imaging (Na-MRI) features from 2 end-stage renal disease patients
before and after hemodialysis (HD). (a) Patient with high sodium ion (Naþ) removal after HD; ultrafiltration (UF) rate: 2.7 l. (b) Patient with low
Naþ removal; UF rate: 3.5 l. Standards as represented by lower circles contain 10, 20, 30, and 40 mmol/l Naþ. Reprinted from Dahlmann A,
Dörfelt K, Eicher F, et al. Magnetic resonance-determined sodium removal from tissue stores in hemodialysis patients. Kidney Int. 2015;87:434–
441,43 with permission from Elsevier. Copyright ª 2015 International Society of Nephrology.

been associated with increased risk of mortality.115,155 A
combination of these practice features increases significantly
the negative impact of each one on patient outcomes.89,156
Currently, the optimal way to improve excess isotonic fluid
and sodium is to increase either dialysis frequency and/or
dialysis time, reduce dietary salt intake, and preserve residual
kidney function. However, these approaches may not always
be acceptable to patients or applicable by dialysis providers.157
In recent years algorithms to quantify dialytic sodium and
water mass transfer have been developed, based either on
mass balance equations,158,159 or by modeling sodium mass
transfer using ionic dialysance with dialysate and plasma so-
dium concentrations.160,161
DIRECT SALT AND WATER MONITORING AND HANDLING IN
HEMODIALYSIS PATIENTS: NEW OPPORTUNITY FOR
PERSONALIZING CARE AND IMPROVING OUTCOMES
As determined by 23NaMRI, it is possible to clear a substantial
amount of water-free sodium from skin and muscle
interstitium by hemodialysis.43 However, because the total
amount of salt stored in the tissues cannot be determined in
clinical practice, the dialysis prescription (time duration,
frequency, and dialysate electrolyte concentration) is based
only on plasma sodium. Preliminary studies have shown that
following acute hypertonic saline infusion in healthy in-
dividuals, only one-half of the sodium can be recovered in the
urine, suggesting that the difference is stored in skin and
muscle interstitium.162
Additionally, in order to correct sodium excess more
effectively, several researchers have recently developed algo-
rithms to quantify dialytic sodium and water mass transfer
either by using mass balance equations based on conservation
laws158 or by modeling sodium mass transfer using ionic
dialysance with dialysate and plasma sodium concentra-
tions.161 These studies have confirmed the validity of such an
approach by direct dialysis quantification. They have also
shown clearly that sodium and water mass transfer and ki-
netics might be considered a patient characteristic, because

Kidney International (2019) 95, 296–309 303

review B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients

Figure 6 | Schematic representation of the electrolyte balancing control (EBC) module embedded in the hemodialysis (HD) monitoring
device. The EBC integrates sodium and water handling capacity based on microsensoring ionic fluxes (inflow, outflow) and integrating sodium
mass balance equivalent (overall: diffusive þ convective [UF]) based on central processor unit (CPU) analytics. UF, ultrafiltration.

the intra-individual variability was relatively narrow while
inter-individual variability was substantial.163 Several putative
causal factors were associated with these individual sodium
and water profiles, including sodium or osmotic set point,
including lifestyle, diet,164,165 and possibly malnutrition and
inflammation.89,166 In addition, it has been shown clearly that
acting on sodium and water mass transfer by individualizing
dialysis sodium prescription makes it possible to alter patient
perception (reduce thirst and salt and water intake), reduce
interdialytic weight gain, and modify short-term outcomes
(reduce dry weight and blood pressure).167,168 However, this
Combining machine-embedded online electrolyte
balancing, instrument-based assessment of fluid status, and
point-of-care 23NaMRI will lay the path for precise and
personalized sodium and fluid management, and eventually
improve hemodialysis patient outcomes (Figure 8).
Exploring the clinical validity of this integrated approach
warrants collaborative academy-industry research, and the
Normalized frequency of treatments [%]

approach is hampered by the need for frequent laboratory

sampling, which is impractical for routine use.
Modern biosensors and analytics allow for a direct, precise,
and personalized control of dialytic sodium and water
removal.169 Calibrated conductivity meters or microsensors
placed in dialysate inlet and outlet streams have been used to
develop specific algorithms to determine precisely the fraction
of sodium among the bulk of electrolytes.170 Furthermore, due
to a closed circuit these sensors ensure a precise mass balance.
Combined with advanced analytics embedded in the dialysis
machine, this provides a way to measure and adjust intra-
dialytic sodium and water balance per individualized pre-
scription. In a recent pilot study, intradialytic salt mass transfer
and zero diffusive sodium balance were automatically and
–7 –6 –5 –4 –3 –2 –1 0 1 2 3 4 5 6 7
successfully achieved using ionic conductivity measurements
combined with a mathematical algorithm executed by the he-
modialysis machine (electrolyte balancing module,
Figure 7 | Frequency distribution of intradialytic plasma sodium
Figure 6).171 This automated sodium control system targeting (iPNa) changes when dialyzing 30 patients either with a standard
zero diffusive transfer narrowed the distribution of plasma fixed dialysate sodium (Na) of 138 mmol/l (bars with horizontal
sodium changes (Figure 7). The SD was reduced by w36% lines) or with automated sodium control and a target of
0 diffusive transfer (bars with vertical lines). Each treatment phase
when switching from standard to sodium-controlled treat-
consists of 100 hemodialysis (HD) sessions. The SD of the distribution
ments, suggesting that the intra-individual variation in sodium was reduced by approximately 36% when switching from standard to
removal was reduced. sodium-controlled treatments.

304 Kidney International (2019) 95, 296–309

B Canaud et al.: Optimizing sodium management in CKD and hemodialysis patients
(e.g., skin and
Figure 8 | Potential benefits of a new technical solution, direct sodium (Na), and water control in hemodialysis patients for improving
hemodialysis patient outcomes. MRI, magnetic resonance imaging.
added value of this concept to patient care needs to be
challenged by clinical outcome studies.
CONCLUSION
The dialysis adequacy concept has evolved over time and has
been informed by clinical experience. We have long since
moved away from simply focusing on Kt/V, and dialysis ad-
equacy is now a multitargeted approach that includes several
domains aiming to restore internal milieu homeostasis and
optimize patient experience. After more than 50 years of renal
replacement therapy, restoring extracellular volume,
achieving adequate blood pressure control, and preserving
hemodynamic stability are still elusive and of highest prior-
ity.172 Restoring sodium mass balance in dialysis patients has
evolved from a clinical dry-weight approach to fluid man-
agement utilizing diagnostic instruments to a new era of
direct dialysis sodium and water control utilizing advanced
technology and analytics.
It has become evident that total-body sodium comprises
3 main components. Two have been traditionally recog-
nized: 1 that is circulating and systemically active via its
osmotic action, and 1 slowly exchangeable pool of sodium
located in the bones. The third is sodium stored in skin and
muscle interstitium. This pool is implicated in cell and
biologic activities via local hypertonicity and sodium
clearance mechanisms.
New tools for monitoring and managing sodium and
water in dialysis patients are required for a targeted and
personalized approach. Emerging innovations have the
potential to improve patient outcomes by improving he-
modynamic stability and dialysis tolerance. Furthermore,
this is also an illustration of translational medicine in
which new findings (e.g., tissue sodium accumulation) lead
to innovative tools (e.g., 23NaMRI and dialytic sodium
Kidney International (2019) 95, 296–309
review
(e.g., automated
controlled Na balancing
system)
balancing) to improve patient outcomes and perception.
This proposed integrated approach to sodium and fluid
management warrants rigorous prospective outcome
studies.
DISCLOSURE
BC, PKot, and AM are employees of Fresenius Medical Care. All the
other authors declared no competing interests.
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