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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

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

296 Kidney International (2019) 95, 296–309


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 Another factor, which may play a role in the altered fluid
opens new perspectives, particularly in hemodialysis patients, dynamics in dialysis patients, is an increased capillary
that may eventually translate into improved patient outcomes. permeability.19
The aim of this review is to offer a comprehensive view on Cell and tissue active sodium and so-called osmotically inac-
the pathophysiologic role of sodium accumulation (systemic tive sodium. Chloride storage in the skin was first reported
hemodynamically active sodium and local tissue sodium) in more than 100 years ago,20 and found its way into the textbooks
CKD and dialysis patients, and to provide an outlook on new as a homeostatic-regulatory principle of body fluid homeosta-
technologies for monitoring salt accumulation in body sis.21 We do not know how, why, and when in the subsequent
compartments and also on the potential of novel therapeutic 100 years the medical community lost knowledge about the role
interventions. of sodium storage largely as sodium chloride in health and
disease. Cartilage sodium storage is well known; it is associated
SODIUM METABOLISM IN DIALYSIS PATIENTS: NEW INSIGHTS with the negative charge density of its glycosaminoglycan-rich
INTO ITS METABOLISM AND PATHOPHYSIOLOGIC ROLE interstitium.22,23 Similarly, increased elongation and sulfata-
Total body sodium distribution tion of the glycosaminoglycans occurs in the skin in experi-
Osmotically active sodium. Osmotically active sodium mentally induced sodium storage, suggesting that electrostatic
distributes in the extracellular fluid (ECF) compartment interaction between these negatively charged surfaces and so-
(Figure 3).10 Studies using tracer dilution or bioimpedance dium might lead to osmotically inactive sodium storage in the
technologies have evidenced ECF expansion in advanced skin.24–26 Recently, this concept of tissue sodium accumulation
CKD11 and dialysis patients.12,13 In various studies, 25% to was corroborated in tissue biopsies (skin, muscle, and arteries)
30% of dialysis patients were classified as severely fluid from dialysis patients and healthy subjects at the time of kidney
overloaded, defined as a “fluid overload” (FO) volume transplant.27 Analogous to the high osmolyte concentrations in
of $2.5 L assessed by bioimpedance spectroscopy (BIS).13–15 the renal medulla and their mode of action, sodium storage
We found in a recent study involving 8,883 prevalent he- seems to be part of a kidney-like counter-current system,
modialysis patients that only 34% of patients had a FO < 1.1 designed for cutaneous water conservation.28
23
L before dialysis.15 Also, interstitial pressure is correlated with NaMRI is crucial for transferring the evolving concept of
ECF volume in patients with CKD and edema.16 In general, sodium storage from basic research into the clinical arena.
ECF expansion results in increased plasma volume that may Ultra–high field 23NaMRI has shown that humans, similar to
directly affect blood pressure and cardiovascular status.17 rodents, store sodium below the keratinocyte layer.29 A 3T
The distribution of isotonic fluid across the extracellular 23
NaMRI reliably detects and quantifies sodium storage in
compartment is altered with hypoalbuminemia.18 Using skin and muscle.30–38 Classic “black-box balance studies,”
BIS we confirmed that serum albumin was lowest in pa- which have confirmed the relationship between water-free
tients with the highest FO.15 John et al. showed that ECF sodium storage and salt-sensitive hypertension,39 now can
was expanded in hypoalbuminemic as compared to nor- be transformed into 23NaMRI studies to quantify the rela-
moalbuminemic peritoneal dialysis patients, whereas tionship between tissue sodium storage and blood pressure in
plasma volume was comparable between both groups.18 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 increase in systemic blood pressure then increases salt
functionally coupled with systemic blood pressure level is no excretion at the cost of hypertension. Based on this concept,
longer restricted to animal studies.40–42 Clinical 23NaMRI sodium-driven FO in advanced CKD would thus necessarily
studies have revealed that in parallel to the development of lead to hypertension unless circulating volume is normalized
essential hypertension, humans store increasing amounts of (e.g., by diuretics or ultrafiltration).45
skin sodium as they age,40 large amounts of tissue sodium are Whereas extracellular volume is generally higher in hyper-
stored in patients with endocrine forms of hypertension,41 tensive compared with normotensive patients,12,46 there is also a
and hypernatremia may be a sodium-storage disorder.42 substantial overlap in blood pressure between normovolemic
Tissue sodium content is higher in patients with CKD, and fluid overload ESRD patients.14,47 Three factors might ac-
diabetes, or ESKD compared with healthy subjects.37 He- count for this phenomenon: (i) cardiac failure,48 which could
modialysis can mobilize sodium chloride tissue stores.43 contribute to the high mortality in normotensive patients with
FO49; (ii) hypoalbuminemia and/or increased capillary perme-
Sodium action: systemic circulating osmotically active versus ability leading to an altered distribution between plasma and
tissue local active sodium interstitial fluid18,19; and (iii) a difference in vascular response to
Isotonic fluid expansion can have varying hemodynamic fluid loading. According to Guyton’s concept, volume loading is
effects. Guyton’s hemodynamic concept posits that reduced followed by an increase in peripheral vascular resistance, but
renal sodium excretion leads to an increased cardiac output, this is not always the case.50 A recent study found that the
followed by an autoregulatory increase in systemic vascular difference in blood pressure between normotensive and hy-
resistance to prevent tissue hyperperfusion.44 The resulting 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 review

vascular resistance.51 Interestingly, the main hemodynamic studied in Tassin were dialyzed 3 times weekly for 8 hours,
parameter differentiating patients with nocturnal dialysis from but also with low dialysate sodium levels and strict sodium
conventional dialysis is a significantly different peripheral restricted diet.
vascular resistance.52 Patients from Tassin treated with long, What is the evidence for direct effects of tissue sodium on
slow dialysis also exhibited a markedly lower vascular resistance hemodynamics? Recent experimental and clinical studies
than did conventional HD patients, whereas markers of circu- support the notion that even in the absence of blood pressure
lating volume (e.g., vena cava diameter and atrial natriuretic increase, excess dietary sodium intake can harm target organs,
peptide) did not differ between the 2 groups.53 This paradoxical including blood vessels,27,62,66 heart,67 and brain.68,69 This has
response to fluid volume expansion raises the question of also been documented in observational studies relating di-
whether additional factors might explain such variation in he- etary sodium intake to blood pressure and cardiovascular
modynamic response. Recent evidence suggests that sodium outcomes.70
might have a direct role. High dietary salt intake is associated with hypertension,
What is the evidence for a direct effect of osmotically active and the prevalence of salt-sensitive hypertension increases
sodium on hemodynamics? Differences in vasoconstrictor with age. 23NaMRI demonstrated in 56 healthy controls and
functioning, which may be relevant in the different responses 57 patients with essential hypertension (age 22–90 years)32 an
to volume loading in ESKD patients, have traditionally age-dependent increase in muscle sodium content in men but
involved the sympathetic system and the renin-angiotensin- not in women; a corresponding lack of age-related change in
aldosterone system,54,55 although in the last decade a more muscle water content suggested water-free sodium storage. In
complex picture has emerged.56 Evidence mainly derived the skin, there was a remarkable age-related sodium deposi-
from experimental hypertension has shown that sodium may tion in men and, to a lesser extent, women. In contrast to
have an independent effect on vascular structure and func- muscle, increased skin sodium content was paralleled with
tion.57 Studies in normotensive salt-sensitive subjects have increasing skin water. In patients with refractory hyperten-
shown that dietary sodium loading increases the alpha-to- sion, tissue sodium was significantly increased compared with
beta adrenoceptor ratio, favoring a higher peripheral that in age-matched normotensive controls. This study sug-
vascular resistance.58,59 Moreover, in those studies the blood gests that tissue sodium storage may play a significant role in
pressure response to sodium intake was proportional to the cardiovascular morbidity independent from circulating
adrenoceptor density on lymphocytes, platelets, and skin fi- osmotically active sodium.32
broblasts.60 The vascular stiffening effect of sodium intake has The traditional model of ECF homeostasis involving the
been demonstrated in observational and interventional clin- renin-angiotensin-aldosterone system, pressure natriuresis,
ical studies.61,62 Recent research has shown that endothelial and modulated renal nerve activity via action on natriuretic
cells acting as vascular salt sensors modulated the mechanical and water diuresis has also been challenged in other studies.
stiffness of cells’ plasma membrane via the activation of By exposing either animal or healthy humans to various levels
epithelial sodium channels and the release of NO in response of salt intake it has been shown that extracellular volume
to plasma sodium and potassium concentrations changes.63 conservation and natriuresis result from a renal mechanism
Direct sodium effect on vascular structure and function favoring conservation of water rather than sodium. The renal
appears also to be mediated by endogenous ouabain-like sub- counter-current concentration mechanism relies on enhanced
stances, which are secreted in the hypothalamus in response to urea transporter recycling of urea in the kidney and on urea
an increase in cerebrospinal fluid sodium concentration. Release production by liver and skeletal muscle, a mechanism with
of ouabains may subsequently activate the adrenals and sym- substantial energy requirements.71 Hemodynamic change
pathetic nervous system, but may also directly affect vascular produced by salt loading and depletion has also been explored
tone and remodeling. A ouabain-related mediator likely in salt-sensitive, salt-resistant, normotensive, and hypertensive
involved in this mechanism is the endogenous a1 Naþ Kþ- volunteers.39 The main factor differentiating both groups was
ATPase inhibitor marinobufagenin (MBF), which is synthesized the modulation of peripheral vascular resistance following salt
by the adrenal cortex.57 MBF induces vasoconstriction through loading and unloading. Sodium balance remained similar in
inhibition of vascular smooth muscle Naþ-Kþ-ATPase and both phenotypes during salt loading or depletion. The authors
activates the NAD(P)H oxidase, leading to an increase in concluded that salt-sensitive subjects are unable to modulate
oxidative stress.57,64 Recently Jablonski et al. showed increased total peripheral resistance in response to salt depletion, mir-
urinary MBF after salt loading in middle-aged and/or older roring their inability to vasodilate in response to salt loading. It
subjects. Moreover, MBF was related to systolic blood pressure, then follows that differences in water balance observed between
aortic pulse wave velocity, and endothelial cell expression of these groups reflect differences in interstitial compartment salt
NAD(P)H oxidase-p47phox.65 storage that may relate to vascular dysfunction in salt-sensitive
The question is whether an increased removal of sodium, subjects.39
and the associated mediation in vasoactive mechanisms, may High dietary sodium intake increases blood pressure in
be responsible for the decrease in systemic vascular resistance animal models and humans. In animal studies, it has been
observed in patients with long dialysis sessions. Evidence for shown that blood pressure might be affected by dermal so-
this is circumstantial only and based on the fact that patients 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 failure.83 In renal failure, evidence for a possible effect of gut
buffering mechanism of sodium dietary intake was unknown edema on systemic inflammation is more circumstantial, sug-
in humans. In a recent study, skin electrolytes, blood pressure, gested by the relationship between systemic endotoxemia and
and plasma VEGF-C were assessed in 48 healthy participants fluid status, assessed by vena cava echography.82 Systemic
randomized to a low-sodium diet (70 mmol sodium/d) and inflammation may also induce FO through hypoalbuminemia
high-sodium diet (200 mmol/d) for 7 days. A significant in- or cardiac stunning,18,81 impairing the tolerance to fluid removal
crease in 24-hour mean blood pressure was noted with salt during dialysis. Interestingly, McIntyre et al. observed in 120
loading in women but not in men. Skin sodium increased hemodialysis patients that circulating endotoxin was signifi-
significantly between low- and high-sodium diets. Interest- cantly increased with dialysis-induced hemodynamic stress (e.g.,
ingly, a sex-specific effect was also observed, marked by a hypotension, high ultrafiltration rate) leading to subclinical gut
significant skin sodium increase in men but not in women, ischemia and endotoxin translocation from the gut.84 More-
suggesting a sex-specific difference in sodium-buffering ca- over, inflammation may directly lead to increased capillary
pacity. Skin sodium correlated with blood pressure, stroke leakage, reducing the tolerance to fluid removal because of
volume, and peripheral vascular resistance in men but not in translocation of fluid from the intravascular to the interstitial
women. No change was noted in plasma VEGF-C. These compartment. However, in a study directly assessing systemic
findings suggest that the skin may buffer dietary sodium albumin leakage by the transcapillary escape rate of 125I-albu-
intake by reducing the hemodynamic consequences of min, Yu et al. observed primarily a relationship with markers of
increased salt, and this may be influenced by sex.72 Such a thrombocyte activation and hypoalbuminemia, but not with
study has not yet been performed in ESRD patients, but the markers of systemic inflammation,19 suggesting a more com-
clinical relevance of this question is high, acknowledging the plex picture. At present, despite substantial evidence on the
sex difference in mortality in this population.73 relationship between FO and inflammation in ESRD, there is no
solid evidence that correction of FO improves systemic
Extracellular fluid overload, tissue sodium accumulation, and inflammation.85
outcome parameters: is tissue sodium accumulation the Observational data have also shown a relationship between
missing piece in this pathophysiologic circle? FO and malnutrition. This holds true for biochemical
Most evidence regarding the relation between outcomes and markers, such as serum albumin.81 However, the patho-
FO has been obtained using bioimpedance spectroscopy13 or physiology of hypoalbuminemia in dialysis patients is multi-
vector graph bioimpedance.74 Whereas research on the rela- factorial and includes nutritional factors, inflammation and
tionship between FO and outcome has traditionally focused possibly increased capillary leak.19 There is also evidence for a
on ESRD patients,15,75,76 recent evidence has shown that FO more direct relationship between FO and body composition
was already prevalent in stage 4 CKD patients and associated change; Hung et al. observed a negative relation between FO,
with increased mortality.77 Interestingly, although the rela- expressed as the FO index >7% of ideal dry weight by BIS,
tionship between tissue sodium storage and outcome has not and lean tissue mass.81 The reason for this relationship is
been studied in detail, an association between tissue sodium, unclear. Proposed factors involved may be a failure to adjust
assessed by 23NaMRI, and left ventricular hypertrophy has dry weight with an unnoticed decline in tissue or fat mass, or
been observed in advanced CKD patients.36 the concomitant presence of inflammation. We recently
Conventionally, the relationship between FO and outcomes showed in 8883 prevalent dialysis patients that FO of >1.1 L
has been explained in terms of increased cardiovascular risk in was observed in isolation (19% of patients), but was present
advanced CKD.45 Indeed, a near linear relation between FO and (18% of patients) in tandem with malnutrition and/or
left ventricular hypertrophy has been described.78 Moreover, a inflammation.86 The presence of 1 or more risk factors was
relationship between FO and endothelial dysfunction, as associated with an incremental risk of mortality, translating to
measured by VCAM-1 and interleukin-6 levels, has recently an additive or amplifier effect. Of note, only 12% of patients
been observed.79 However, the fact that even small levels of FO, did not have a single risk factor. However, further studies
which are unlikely to have major hemodynamic effects, are assessing the relation between FO and malnutrition should
associated with outcomes suggests that the relationship between preferably also include methods other than bioimpedance,
FO and outcomes may not be directly causative. Indeed, there is because changes in fluid status and osmotic pressure during
mounting evidence that FO and tissue sodium accumulation dialysis were recently shown to affect the estimation of lean
may be part of multidimensional clusters of risk factors that and adipose tissue mass using this technique.87
impact outcomes, including inflammation and malnutrition. Previous studies using tracer dilution techniques have
Noncardiovascular consequences of fluid overload. Various suggested that malnutrition might have a direct effect on the
studies have confirmed a link between FO and systemic distribution of body fluid compartments.10 In a study in
inflammation in dialysis patients, using various markers of fluid nonrenal patients, the ratio between ECF and body weight
status and systemic inflammation, respectively, including C- was higher in malnourished patients, although the ratio be-
reactive protein, tumor necrosis factor-a, and interleukin-6.80–82 tween ECF and height was not different.88
FO may lead to inflammation by bowel congestion and subse- Summarizing, FO appears to be part of a cluster of car-
quent endotoxemia, as has been described in patients with heart diovascular and noncardiovascular risk factors, including

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

endothelial dysfunction, systemic inflammation and malnu- of aging, such as CDKN2A/p16INK4a and SA-b-Gal in arterial
trition, as shown in observational studies. Also, although part samples, are increased in transplanted ESRD patients.99 Inter-
of the relationship between mild FO and outcomes may be estingly, an inverse relationship between sodium intake and
explained by its noncardiovascular correlates, in large studies telomere length was observed in overweight teens in a popu-
it remains an independent risk factor after adjusting for lation study.100 Although there is as yet no direct evidence for a
multiple confounders.19,89 The exact nature of these re- relation between fluid and/or sodium overload and an accel-
lationships is not well elucidated, thus highlighting the need erated aging process, we speculate that potential causative
to study novel causative links—for example, the role of tissue mechanisms exist, such as oxidative stress and inflammation,
sodium content. which are established drivers of aging.101 Sodium promotes
Relationship between tissue sodium and nutritional cellular senescence in cultured HeLa cells and primary mouse
status. New findings challenge the dogma that high salt embryonic fibroblasts.102 Tissue sodium measured by 23Na-
intake leads only to increased thirst, water intake, diuresis, MRI imaging associates with aging, salt-sensitive hyperten-
and blood pressure. Titze and colleagues have shown recently sion,32 and various degenerative pathologies.103
that salt intake and tissue sodium content may have various
nutritional and metabolic effects. Salt loading activates an TRADITIONAL AND NEW TOOLS FOR MONITORING SALT
adaptive regulatory network in the kidney, muscle, and liver, ACCUMULATION ACROSS DIFFERENT BODY COMPARTMENTS
which enables the reprioritization of energy metabolism to Clinical tools
conserve plasma water in the setting of high salt intake.71 This Restoring salt and water homeostasis in hemodialysis patients
phenomenon requires high energy consumption and may has been the nephrologist’s quest for the Holy Grail since the
contribute to muscle wasting observed in CKD patients.90,91 1960s.104 Salt and water management in dialysis patient relies
Interestingly, this deleterious process may be reduced by on 3 components: (i) the accurate assessment of fluid and
protein and energy intake.71,92 Furthermore, tissue sodium sodium status; (ii) the adequate removal of excess salt and
accumulation was shown recently to be associated with water; and (iii) a salt dietary restriction while preserving re-
muscle structural and functional disturbances contributing to sidual kidney function.
peripheral insulin resistance.93 While clinical assessment of fluid status, hemodynamic
Tissue sodium accumulation has been observed in a stability, and patient perception is difficult, it remains the
number of degenerative or inflammatory pathologies that are cornerstone of hemodialysis patient management, including
associated with poor outcomes.94–96 For example, tissue so- the regular setting of “dry weight.”105,106 Dry weight indicates
dium and water content has been explored in a model of the post-dialysis weight at which, in theory, no signs of fluid
acute muscle atrophy obtained by unloading the calf muscles imbalance (neither excess nor depletion) are present, blood
of 1 leg.97 In 12 healthy males 1 calf muscle was submitted to pressure is in the normal range, and the patient feels
60 days of unloading with an orthosis device while the other comfortable without functional limitations.107 Dry weight is
calf served as a control. 23NaMRI and turbo spin-echo se- probed over time by clinicians and reassessed periodically.108
quences in magnetic resonance imaging were obtained from Further work has led investigators to refine assessment of the
the control and orthosis leg. In the orthosis leg, muscle vol- dry weight concept.109 Several studies, including the ran-
ume decreased significantly. In parallel, tissue sodium content domized dry-weight reduction in hypertensive hemodialysis
increased in calf muscles (10% to 17%), while it did not patients (DRIP) study, have shown that a clinical approach
change significantly in the active leg.97 focused on tight control of dry weight was associated with
Recent data suggest that excessive sodium stored in the positive mid- and long-term outcomes.110–114 However,
muscle and skin in dialysis patients may contribute to recent findings using intradialytic cardiac magnetic resonance
metabolic disorders. An association between tissue sodium imaging have documented that the hemodynamic stress
and peripheral insulin resistance has been shown recently. induced by hemodialysis was associated with damage of the
Eleven hemodialysis patients and 8 controls underwent heart and other organs.115,116 These findings challenge an
hyperinsulinemic-euglycemic-euaminoacidemic clamp overly strict dry weight policy, considering the risk of repet-
studies to measure disposal rates of glucose and leucine.93 itive ischemic insults particularly in fragile patients (e.g.,
Calf 23NaMRI was used to quantitate muscle and skin tis- diabetes, elderly, peripheral vascular disease).117,118
sue sodium. Compared with controls, hemodialysis pa- Given the shortcomings of clinical assessment, biomarkers
tients had lower disposal rates of glucose and leucine and or instrument-based tools have been proposed to more
higher muscle sodium concentration; skin sodium did not objectively define dry weight (Figure 4).119
differ.
Tissue sodium and accelerated aging. Sodium accumula- Biomarkers
tion may also be associated with premature aging. There is Cardiac biomarkers have been used extensively to disentangle
circumstantial evidence for a premature aging process in ure- fluid status and cardiac dysfunction in dialysis patients.
mia, leading to phenotypic alterations such as early cardiovas- Natriuretic peptides (atrial natriuretic peptide, brain natri-
cular disease and muscle wasting. Telomere length in patients uretic peptide, and N-terminal pro b-type natriuretic peptide)
with ESRD is decreased compared with controls.98 Biomarkers 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 Na handling
Clinical parameters Extracellular Na
Clinical assessment Osmotically active Dietary counseling
Dry weight, vital Residual kidney function
parameters (BP, HR) Diuretics
Patient perception
Instrument parameters Renal replacement
BIA, RBVC, Tissue Na treatment schedule
Lung US, IVCD, echocardiog Water-free storage Time – frequency - modality
Biomarker parameters Glycosaminoglycan
BNP, NT-ProBNP, troponin
copeptin, MBG Automated & controlled
sodium balancing module
Calf skin and muscle 23Na MRI 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 have included only selected hemodialysis populations.139,140
sensitive to fluid depletion.122 Although these biomarkers Further outcome-based studies are required to definitively
have been shown to be quite useful for patient risk stratifi- establish whether multifrequency spectroscopy has a place as
cation, their specificity, sensitivity, and/or clinical value to a noninvasive point of care measurement to guide fluid
manage fluid status have remained limited or contested.123,124 management in dialysis patients.141
Multi-marker approaches and time-trend analysis have been More recently, lung ultrasound has been used in chronic
proposed to better support physician decision-making in hemodialysis patients to track asymptomatic pulmonary fluid
stratifying cardiovascular risk, but this raises financial is- accumulation (extravascular edema). Thickening of inter-
sues.125,126 Whatever the predictive clinical value of these lobular septa due to water accumulation generates comet tail-
biomarkers in fluid management, health economics and like signs, visible by ultrasound. Counting the B lines of these
practical usability must be determined before their adoption “comets” provides an estimate of lung water and predicts
in daily clinical practice.127,128 patient outcomes.142–145
23
NaMRI has recently been introduced to quantitate tissue
Instrument-based tools sodium in CKD patients.146–148 It has been shown that he-
Inferior vena cava diameter change determined by ultrasound modialysis can mobilize sodium tissue stores, contributing
has been proposed to monitor extracellular volume in dialysis significantly to the net sodium mass balance (Figure 5).43
patients.129,130 However, the practical difficulty in imple- Complex logistics, costs, and limited availability of 23NaMRI
menting ultrasound in a dialysis facility and the poor pre- render it currently an experimental tool. Of note, a recent
dictive value on blood pressure response in probing dry pilot study explored the use of portable 23NaMRI.149
weight has precluded its widespread use.131
Relative blood volume change and plasma refill rate TRADITIONAL AND INNOVATIVE FLUID AND SODIUM
during dialysis can be assessed by online blood volume MANAGEMENT: ALGORITHMS, MODELING, AND SUPPORTIVE
sensors.132 In expert hands relative blood volume mea- DECISION TOOLS
surement provides useful insights into a patient’s volume Optimal management of fluid and sodium in dialysis patients
status,133 but randomized controlled trials have produced requires restricting interdialytic salt intake and adjusting
conflicting results.134,135 dialytic salt and fluid removal.150–152 This conventional
Multifrequency bioimpedance spectroscopy analysis is an method calls for adjusting dry weight based on clinical
easy-to-use, reliable, and affordable tool to guide fluid man- judgment and ancillary tools described above.153 However,
agement, with even subtle variations in fluid status being this approach may be hampered by the discontinuous nature
related to outcomes.136–138 In addition, extensive use of bio- of the hemodialysis, dietary preferences, and intolerance of
impedance spectroscopy in clinical studies (retrospective and patients to fluid and sodium removal.154
prospective) has generated substantial clinical evidence sup- Aggressive management of sodium and fluid excess to
porting the notion that precise fluid management might restore fluid homeostasis either by high ultrafiltration rate or
improve intermediate patient outcomes, although trials so far high dialysate-to-plasma sodium concentration gradient has

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

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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 Combining machine-embedded online electrolyte
inter-individual variability was substantial.163 Several putative balancing, instrument-based assessment of fluid status, and
causal factors were associated with these individual sodium point-of-care 23NaMRI will lay the path for precise and
and water profiles, including sodium or osmotic set point, personalized sodium and fluid management, and eventually
including lifestyle, diet,164,165 and possibly malnutrition and improve hemodialysis patient outcomes (Figure 8).
inflammation.89,166 In addition, it has been shown clearly that Exploring the clinical validity of this integrated approach
acting on sodium and water mass transfer by individualizing warrants collaborative academy-industry research, and the
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
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.

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(e.g., automated
(e.g., skin and
controlled Na balancing
system)

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 balancing) to improve patient outcomes and perception.
challenged by clinical outcome studies. This proposed integrated approach to sodium and fluid
management warrants rigorous prospective outcome
CONCLUSION
studies.
The dialysis adequacy concept has evolved over time and has
DISCLOSURE
been informed by clinical experience. We have long since BC, PKot, and AM are employees of Fresenius Medical Care. All the
moved away from simply focusing on Kt/V, and dialysis ad- other authors declared no competing interests.
equacy is now a multitargeted approach that includes several
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