Nephrol Dial Transplant (2020) 35: ii23–ii30

doi: 10.1093/ndt/gfaa017

Sodium, volume and pressure control in haemodialysis patients

for improved cardiovascular outcomes

REVIEW
Jule Pinter1, Charles Chazot2, Stefano Stuard3, Ulrich Moissl3 and Bernard Canaud4

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

1
Renal Division, University Hospital of Würzburg, Würzburg, Germany, 2NephroCare France, Fresnes, France, 3Global Medical Office, FMC
Deutschland, Bad Homburg, Germany and 4Montpellier University, Montpellier, France

Correspondence to: Jule Pinter; E-mail: [email protected]

ABSTRACT cardiovascular disease [1–3]. The unique nature of cardiovascu-

Chronic volume overload is pervasive in patients on chronic hae- lar disease in chronic kidney disease Stage 5 dialysis (CKD5D)
modialysis and substantially increases the risk of cardiovascular patients is illustrated by the prevalence of left ventricular remod-
death. The rediscovery of the three-compartment model in so- elling leading to stiffening and failure [4]. A major aetiological
dium metabolism revolutionizes our understanding of sodium driver of this pathway appears to be sodium (Naþ) and fluid
(patho-)physiology and is an effect modifier that still needs to be retention [5, 6]. Yet, achieving adequate volume and blood pres-
understood in the context of hypertension and end-stage kidney sure (BP) control often remains an unmet need in this highly vul-
disease. Assessment of fluid overload in haemodialysis patients is nerable population [7–9]. Several reasons are commonly
central yet difficult to achieve, because traditional clinical signs of proposed to explain this fact that include short treatment time
volume overload lack sensitivity and specificity. The highest all- schedule [9, 10], poor reliability in clinical fluid assessment [11,
cause mortality risk may be found in haemodialysis patients pre- 12], difficulty in restoring extracellular fluid (ECF) volume by di-
senting with high fluid overload but low blood pressure before alysis [13], poor salt diet observance [14] and loss of residual kid-
haemodialysis treatment. The second highest risk may be found ney function [15].
in patients with both high blood pressure and fluid overload, while Optimal fluid volume and BP control in dialysis patients
high blood pressure but normal fluid overload may only relate to is an essential component of dialysis adequacy. Yet, the
moderate risk. Optimization of fluid overload in haemodialysis intermittency of treatment creates an ‘unphysiological profile’
patients should be guided by combining the traditional clinical and challenging clinical condition exposing patients to up
evaluation with objective measurements such as bioimpedance (interdialytic period) and down (intradialytic period) fluid
spectroscopy in assessing the risk of fluid overload. To overcome volume changes mirroring a large variability of BP changes
the tide of extracellular fluid, the concept of time-averaged fluid [16]. The exposure to cardiocirculatory stress may be double
overload during the interdialytic period has been established and edged, reflected by chronic fluid overload (FO) during the inter-
requires possible readjustment of a negative target post-dialysis dialytic period or by acute fluid depletion during the intradia-
weight. 23Na-magnetic resonance imaging studies will help to lytic period. The intensity of cardiac stress is directly related to
quantitate sodium accumulation and keep prescribed haemodia- fluid volume changes and time exposure within these different
lytic sodium mass balance on the radar. Cluster-randomization periods. Fluid removal rates >10–13 mL/h/kg are associated
trials (e.g. on sodium removal) are underway to improve our ther- with increased mortality [17–19] and fluid removal ‘toxicity’
apeutic approach to cardioprotective haemodialysis management. seems to even start much earlier, at >6–7 mL/h/kg [20, 21].
In this context, treatment time must be recognized as a
Keywords: bio-impedance spectroscopy, cardiovascular dis- significant disease modifier of cardiocirculatory stress leading
ease, haemodialysis, sodium metabolism, time-averaged fluid to end-organ damage via repetitive subclinical ischaemic
overload insults, e.g. cardiac stunning, cerebral white matter injury and
gut ischaemia [22].
The rediscovery of a kidney-independent reservoir and third
INTRODUCTION salt-storage glycose-aminoglycan-related skin compartment
Haemodialysis (HD) is a life-saving treatment, although patient demands readjustment of the concept that Naþ haemostasis
survival is poor. Rates of death are substantially higher than in depends solely on the kidney’s crucial function to regulate vol-
the general population and at least 50% of patients die due to ume and BP by renal pressure–natriuresis.
C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/
by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial
re-use, please contact [email protected] ii23
 Water-free stored Naþ, so-called osmotically inactive tissue physiological concept placing the kidney as key player of the
Naþ, must be differentiated from osmotically and haemody- regulation of extracellular volume and BP homoeostasis has
namically active Naþ, both of which may contribute to sys- been challenged by the group of Titze et al. after studying a
temic toxicity via local tissue and organ damage [23]. group of astronauts simulating a long-term flight to Mars [33].
Given the lack of Naþ homoeostasis and dependence on In this closed environment, Titze et al. were able to quantify
HD for Naþ removal, it seems likely that CKD5D patients are very precisely Naþ mass balance under stepwise fixed salt diet
more susceptible to this form of Naþ accumulation, leading to regimes. While salt intake was fixed, they noticed large varia-
Naþ toxicity, and their resultant adverse effects. tions in urinary Naþ excretion, and also changes in total body
Managing Naþ imbalance in CKD5D patients requires in- Naþ exhibited rhythmic fluctuations within a day, which were
novative approaches to assess Naþ excess in the body and HD not associated with parallel changes in body weight or extracel-
management that adequately restores salt and water homoeo- lular water. Interestingly, these Naþ variations correlated posi-
stasis [23]. In this article, we propose a comprehensive vision of tively with urinary aldosterone excretion and inversely to
Naþ, fluid and pressure management in CKD5D patients, urinary cortisol. The most striking finding finally was that total

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

which may have strong potential for reducing cardiac burden. body Naþ content exceeded weight gain, suggesting that Naþ
had accumulated in another compartment that is not osmoti-
HUMAN SODIUM HOMOEOSTASIS AND cally active. Skin and skeletal muscle represent the body’s major
IMPAIRED SODIUM METABOLISM Naþ ECF compartment without concomitant water accumula-
Total body Naþ is a critical determinant of extracellular tion (free-water Naþ), bound to negatively charged glycosami-
volume, plasma volume and BP [24, 25]. noglycan (GAG) [35–37]. Osmotically inactive skin Naþ can
Healthy persons in the steady state balance Naþ homoeostasis be mobilized by salt deprivation (e.g. salt diet restriction) and
through dietary intake and urinary output of Naþ [26]. depletion (e.g. dialysis), which induces a reduction of the nega-
In 1958, Strauss et al. first put forward the concept of a Naþ tively charged skin GAG content [33]. Conversely, dietary salt
set point to uphold this balance [27]. A person who was in bal- loading is associated with an increased synthesis of negatively
ance on a low salt diet, when given even a trace amount of so- charged GAG in the skin. These observations suggest that the
dium chloride (NaCl), promptly excreted that amount [27, 28]. storage of osmotically inactive Naþ in the skin is an active pro-
When, in contrast, the total amount of Naþ in his body was re- cess. Skin Naþ is stored directly under the keratinocyte layer in
duced further by a diuretic, and balance on a low Naþ intake a microenvironment that is hypertonic to plasma. The skin
was achieved, his response to an increment of Naþ was phagocytes sense the hypertonic accumulation of Naþ in the
dramatically different [27, 28]. He did not excrete the skin leading to activation of tonicity-responsive enhancer-bind-
additional NaCl until the amount lost following diuretic ing proteins, the secretion of vascular endothelial growth factors
administration was replaced [27, 28]. (VEGF-C) and a local modulation of the capillary lymphatic
In accordance with experimentally observed variations in system in the skin [38].
plasma Naþ, a variable set point regulatory system seems likely Hence, lymphatics may control how much Naþ is released
[29]. to the blood from the tissue store and thereby the amount the
In 1972, Guyton’s work illustrated the traditional nephrocen- kidney ‘sees’ [39].
tric two-compartment model of Naþ homoeostasis: the ECF Taken together, observations of salt storage in the skin to
volume within the intravascular space being in constant equilib- buffer free extracellular Naþ and macrophage modulation of
rium with the interstitial space volume while the kidneys regulate the extracellular matrix and lymphatics suggest that electrolyte
the balance between Naþ intake, extracellular and BP [30, 31]. homoeostasis in the body is not achieved by renal excretion
The central feature of the model is the linkage between BP alone, but also relies on extrarenal regulatory mechanisms in-
and Naþ balance, where any imbalance between salt intake and volving a kidney-like countercurrent system [40].
excretion leads to a progressive alteration in the filling of the Sodium-MRI has been introduced as a feasible diagnostic
vascular system and thus changes in BP [32]. tool to assess tissue Naþ content in patients with kidney disease.
This in turn alters Naþ excretion, a feature defined as the The skin Naþ content in 99 patients with mild to moderate
pressure–natriuresis relationship [32]. A key aspect of this con- CKD was measured by sodium-MRI and could be correlated
cept is that it puts the kidney at the very centre of long-term BP with the amount of left ventricular mass, proposing that skin
control. This means that any chronic change in BP must have Naþ content may play a yet to be defined pathophysiological
been accompanied by an alteration in the pressure–natriuresis role, unaffected by BP and total body overhydration [41].
relationship [32]. Recently, sodium-MRI was utilized to compare tissue Naþ
In recent years, the two-compartment model has been chal- and its removal in HD and age-matched healthy control
lenged by two major findings: firstly, clinical observation that patients [42]. Older (>60 years) HD patients showed increased
on a fixed Naþ diet intake total body Naþ content could ex- Naþ and water in skin and muscle and lower VEGF-C levels
ceed weight gain, suggesting that Naþ accumulated without be- compared with age-matched controls [42]. After HD, patients
ing osmotically active and that salt was stored in a third body with low VEGF-C levels had significantly higher skin Naþ con-
compartment [33]. Secondly, availability of measuring tissue tent compared with patients with high VEGF-C levels [42]. The
Naþ content in skin and muscles using 23Na-magnetic finding that tissue Naþ could be rapidly mobilized in response
resonance imaging (sodium-MRI) [34]. The traditional to intravascular volume reduction by HD therapy supports

ii24 J. Pinter et al.

the idea that an adequate dialysis dose can prevent excess patients with moderate or severe FO and that rapid changes or
Naþ storage in HD patients [42]. Although the mechanisms by the variability of fluid status could be of clinical importance.
which Naþ is rapidly removed from skin and muscle remain Zoccali et al. evaluated the relationship between baseline and
unclear, these data suggest that a pro-lymphangiogenic serum cumulative FO exposure and mortality over 1 year in 39 566 in-
profile does facilitate this process [42]. cident end-stage renal disease (ESRD) patients in a large dialysis
Quantifying Naþ tissue removal, e.g. with sodium-MRI network in 26 countries. The magnitude of death risk attribut-
studies, could improve strategies for managing HD patients. able to chronic FO was comparable with that of coronary artery
However, it remains unclear whether or not tissue Naþ excess disease or congestive heart failure per se or an increase in bio-
contributes to cardiovascular morbidity or mortality, and logical age of >12 years [6].
whether or not the accumulation of hidden and thus toxic Naþ The risk of FO was almost equally strong in hypertensive
in kidney failure may be reversible. Prospective trials on the (160 mmHg) and hypotensive (<130 mmHg) patients and
relationship between tissue Naþ content and hard clinical such risk also remained substantial in normotensive (130–
endpoints are required to clarify whether increased Naþ stor- 160 mmHg) patients as defined by pre-dialysis systolic blood

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

age is a cardiovascular risk factor and whether reducing skin pressure (pre-BP) [6].
R

Naþ content might improve cardiovascular outcomes in these EuCliDV (European Clinical Data System) is an interna-
patients. tional electronic health record repository that allows continu-
ous point-of-care data collection of routine clinical practice and
lab test information in HD patients from Fresenius Medical
THE BURDEN OF FLUID OVERLOAD AND
Care (FMC) clinics across 20 neighbouring countries across
CARDIAC DISEASE IN HAEMODIALYSIS
Europe, the Middle East and Asia. Among 31 349 incident
ECF overload is a major factor in morbidity of the HD popula- (2010–14) chronic HD patients in the EuClid database, Cox
tion. In a prospective study among 176 790 prevalent HD models were used to prospectively study the association be-
patients, Arneson et al. [43] have reported that, during a 2.5- tween FO, pre-BP and all-cause mortality risk, controlling for
year follow-up, 14% of the patients required hospital admission differences in demographics (age and gender), diabetes, conges-
for one or more episodes of FO, heart failure or pulmonary oe- tive heart failure and body mass index.
dema necessitating urgent fluid removal. Also, Plantinga et al. We report an inverse relationship between FO, pre-BP and
[44] have reported from a US cohort including 215 251 preva- all-cause mortality risk (FMC, unpublished data on file,
lent HD patients a 23% rate of readmission during a 30-day pe- Figure 1).
riod after discharge, 44% of them being related to pulmonary As Figure 1 indicates, the highest all-cause mortality risk was
oedema. When pulmonary oedema was the cause of the first ad- found in patients presenting with high FO but low pre-BP. The
mission, then pulmonary oedema represented 70% of the cause second highest risk was found with both high pre-BP and FO,
of readmission. This suggests that fluid excess may have been while high pre-BP but normal FO related to only moderate risk.
inadequately handled when transitioning from the hospital to This finding, supported by Zoccali et al. [6], described above,
the dialysis unit. In a report by the Dialysis Outcomes and points out that neither pre-BP nor FO should be treated as
Practice Patterns Study (DOPPS), Goodkin et al. [45] identified
the prevalence of congestive heart failure in, respectively, 46%
and 25% of the patients in the USA and in Europe. In the same
study, hypertension was present in 83 and 73% of the US and
European patients. It may be hypothesized that fluid excess was
the major underlying determining factor. Long-term exposure 12

to chronic FO triggers cardiac and vascular remodelling and the 10

development of diastolic dysfunction and chronic heart failure
Hazard ratio

8
in dialysis patients [46]. ECF excess is present early during the
6
CKD progression as shown by Essig et al. [47], and acts as a
continuum all along the CKD progression. These data partly ex- 4

plain the increased prevalence of cardiac events all along the 2

course of CKD [48] and the high prevalence of left ventricular 0 5
hypertrophy (LVH) and other cardiac abnormalities in incident 170
4
160
HD patients. In the Chronic Renal Insufficiency Cohort 150 3
L]
patients [49], 85% of the incident HD patients had LVH. LVH
BP 140 2 d[
sys oa
(pr 130 1 erl
is an adaptative mechanism to pressure and volume overloads. e-d 120 ov
ialy id
sis 110 0 Flu
Initially, LVH allows adequate stroke volume and adapted myo- ) 100 –1
cardium energy consumption. Later, the LVH becomes mal-
FIGURE 1: All-cause mortality hazard related to pre-dialysis systolic
adaptive, with diminished myocardial capillary density, blood pressure (BPsys) and fluid overload in 31 349 incident haemo-
cardiomyocyte death and fibrosis leading to heart failure [46]. dialysis patients observed over a period of four years from 2010 to
Recently Siriopol et al. [50] confirmed previous findings, 2014. The highest risk is seen for patients with high fluid overload
reporting an increased risk for cardiovascular mortality in and low blood pressure.

Volume control in haemodialysis for improved cardiovascular outcomes ii25

isolated factors, but the combination of both needs to be It is well-established that correcting FO improves BP con-
considered. trol. A pilot intervention trial probing dry weight with BCM
Recently, Bansal et al. reported a linear association between compared with conservative clinical assessment found that
higher systolic BP and risk of mortality in HD patients when every 1 L change in pre-dialysis FO was accompanied by a
systolic BP was measured outside of the dialysis unit despite 9.9 mmHg change in systolic pre-BP [56]. Machek et al. [57]
there being a U-shaped association between pre-BP and risk of demonstrated that correction of severe FO led to improvement
mortality [51]. This finding indicates that out-of-dialysis-unit in BP and reduced the use of antihypertensive medication by
systolic BP may be more important, feasible and of value for 35%. In addition, correction of previously unrecognized dehy-
cardiovascular risk assessment than previously thought [51]. dration led to 73% less intradialytic adverse events. In a ran-
domized controlled trial led by Onofriescu et al. [58], BIS-
VOLUME MONITORING, AND CLINICAL AND guided dry weight adjustment led to an improvement in both
DIAGNOSTIC MANAGEMENT TOOLS surrogate and hard endpoints in 131 patients. These findings
show that objective BIS-guided correction of fluid status can be
The attempt to achieve proper dry body weight appears to be of

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

very beneficial in clinical routine [59, 60].
paramount importance in HD patients. Ideally, it has ‘Body volume rises between dialysis sessions and falls during
been defined as ‘the postdialysis body weight that allows treatments, like waves on the ocean. These dialysis tide waves
normal blood pressure before and at the end of the HD session are only part of the total volume status—underlying the waves
without antihypertensive medication, without clinical sign of is the postdialysis volume status, which ranges from volume de-
over- or underhydration and despite the interdialytic weight pletion to overload and can be compared to the level of tide’
gain (IDWG)’ [52, 53]. [53]. Nephrologist stakeholders stress the point that chronic FO
Yet, target weight determination is frequently based on trial- (defined as >15% above ‘normal’ ECF, equivalent to >2.5 L on
and-error methods and its correct evaluation is difficult to ob- average), unlike IDWG, exhibits a >2-fold increased mortality
tain [11]. Because traditional clinical signs of FO , such as pe- risk [53].
ripheral oedema and lung crackles, lack sensitivity and A cohort study from 3632 patients in 60 HD centres from
specificity, and intradialytic hypotension may be blurred by in- four countries demonstrated a significant inverse association
creased ultrafiltration (UF) rate, our clinical judgment in prob- between FO and IDWG [53]. HD patients who reached a state
ing for ‘dry weight’ needs to be complemented by objective of volume depletion after HD seemed to subsequently gain
measurements [14]. greater amounts of weight [53]. High IDWG is actually associ-
A number of technologies or biomarkers have been pro- ated with better outcomes in unadjusted mortality analyses [61]
posed, some of which, like the vena cava diameter to measure and thus may only partially reflect the risk of ECV expansion
intravascular volume, have not proven useful in daily routine [61].
for a variety of reasons. Other instrumental options, such as Nephrologists should, therefore, target the control of chronic
intradialytic blood volume monitoring from haematocrit or FO beyond the mere evaluation of IDGW [53].
protein concentration changes to determine plasma refilling In standard HD therapy, the target weight is prescribed to al-
from ECF accumulated in the interstitial spaces, are also know- low the patient to leave the HD unit proposedly ‘euvolemic’ (see
ingly limited by confounding factors such as hypoalbuminae- Figure 2). During the 44 or 68 h of the interdialytic interval, the
mia. More recently, lung echography assessing pulmonary cardiovascular system will be exposed to a ‘time-averaged fluid
hydration by B-lines (comets) count has been proposed. A re- overload’ (TAFO), comparable to the time-averaged concentra-
cent randomized trial with a lung ultrasound-guided strategy tion of a toxin. At normohydrated status, the TAFO is equiva-
showed no effect of dry-weight reduction on short-term BP var- lent to half of the IDWG.
iability despite BP decrease [54]. A trial testing the effect of a Hur et al. [62] have addressed the concept of TAFO in their
treatment policy guided by lung ultrasound in high-risk R
interventional controlled study with the BCMV. They have pre-
patients on HD, the Lung Water by Ultrasound-Guided scribed the UF volume to target normohydration not at the end
Treatment to Prevent Death and Cardiovascular Complications of the session but in the middle of the interdialytic period
in High-Risk ESKD Patients with Cardiomyopathy, is ongoing (Figure 2). Within 6 months of the study period, the BP, the
(ClinicalTrials.gov Identifier: NCT02310061). pulse wave velocity and the ventricular mass index decreased
Bioimpedance spectroscopy (BIS) provides measurement of significantly compared with the control group. Moreover, in a
total body and ECF compartments from the analysis of an alter- R
large cohort study with the BCMV, Dekker et al. [63] found a
native electric current pathway through tissues at different lev- better survival in patients with estimated post-dialysis overhy-
R
els of frequency [55]. The Body Composition MonitorV (BCM dration below 1.1 L. Thus, a negative fluid balance at the end
Monitor, Fresenius Medical Care, Bad Homburg, Germany) is a of the dialysis session may have a protective effect on the
multi-frequency bioimpedance device. It provides for each pa- patient’s cardiovascular system.
tient a normohydrated target weight from a database of healthy Related to this concept (TAFO), the risk of IDWG has to be
subjects according to age, gender, weight and height. Important placed in context with the objective volume status; relatively
datasets relating BCM monitoring to ECF and outcomes allow large interdialytic weight gains in patients who are dehydrated
us to disentangle the respective relationship between mortality at the end of dialysis are less of a risk signal than relatively small
and both ECF overload and BP. interdialytic weight gains in patients who are chronically fluid

ii26 J. Pinter et al.

 Pre OH

Pre OH
Normohydration (HS = 0 L)
TAFO

TAFO
Post OH

Post OH
Standard HD TAFO = 0 HD

FIGURE 2: During the standard dialysis session, the prescription of post-dialysis body weight targets normal extracellular fluid balance at the
end of the dialysis session. Yet, this exposes the patient to fluid accumulation all along the interdialytic interval, realizing a ‘time-averaged fluid
overload’ (TAFO ¼ half of the interdialytic weight gain). To avoid the exposure to TAFO during the interdialytic period (TAFO ¼ 0), the post-

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

dialysis fluid status should be negative. OH, overhydration.

overloaded. A moderately negative target weight would be de- A clear modifiable source of Naþ exposure in HD patients
sirable in both of these groups of patients. and a promising intervention to improve cardiovascular mortal-
We are aware that this concept may appear highly provoca- ity is to reduce DNaþ during HD treatment [13].
tive bearing in mind how deleterious the effects of overesti- The recent Cochrane review evaluated 12 randomized trials
mated fluid removal rate can be. Yet we believe that the concept of low (<138 mmol/L) versus neutral (138–140 mmol/L) or
expands our understanding of how to reduce the large cardio- high (>140 mmol/L) DNaþ for HD patients, including 310
vascular morbidity and mortality in HD patients. patients, did not examine hard clinical endpoints such as car-
diovascular or all-cause mortality [66]. The authors rated the
quality of evidence as low and concluded that the effect of the
DIALYSATE SODIUM PRESCRIPTION, intervention on overall patient health and well-being is cur-
SODIUM BALANCE AND SODIUM REMOVAL rently unknown [66].
A recent cross-sectional snapshot of all EuCliD patients (data The questions at heart remain whether lowering DNaþ pre-
from 52 000 HD patients, as of July 2019, FMC unpublished vents cardiac remodelling and sudden cardiac death by improv-
data on file) demonstrated that dialysate Naþ (DNaþ) pre- ing Naþ regulation and FO or whether the benefit of lowering
scriptions range from 134 to 143 mmol/L. A DNaþ concentra- DNaþ in reducing left ventricular mass is offset by increased
tion of 138 mmol/L is utilized in roughly 50% of all patients and myocardial stunning and micro-injury [10, 13]. The ongoing
140 mmol/L is the second most common, with 15%. global Randomised Evaluation of SOdium dialysate Levels on
Whereas Eastern European countries tend to utilize lower Vascular Events (RESOLVE) Trial investigates whether lower
DNaþ concentrations, and Russia seems to prescribe the lowest DNaþ may improve cardiovascular outcomes and will deter-
concentrations between 135 and 137 mmol/L in two-thirds of mine comparative effectiveness of two default DNaþ concen-
patients, Italy prefers higher DNaþ concentrations, trations (ClinicalTrials.gov Identifier: NCT02823821).
140 mmol/L. On the contrary, a proof of principle study of the ‘0 Na diffu-
Future studies are necessary to understand cultural behav- sion’ concept—an option developed for newer HD machines —
iour, ethnic factors, common beliefs or eminence to explain the was recently undertaken and proved that automated DNaþ in-
unit-, region- and provider-specific DNaþ prescription pattern dividualization by ‘Naþ control’ approaches isonatraemic dial-
practices in Europe and bordering the Mediterranean Sea. ysis in the clinical setting without the need to determine
In HD patients, Naþ balance depends on dietary intake and the plasma Naþ concentration [67]. Automated Naþ control
Naþ removal during HD [64]. An excessive Naþ load is associ- holds the promise to avoid diffusive Naþ load or removal
ated with high mortality [25]. A post hoc analysis from The during HD and future studies are needed to determine whether
Hemodialysis Study considering 1800 chronic HD patients isonatraemic dialysis could have any effect on hard clinical end-
showed a significantly increased risk of death with a dietary points [67].
Naþ load >2.5 g/die [25]. Patient education for low salt diet
may reduce IDWG by 30% [65]. However, recent data suggest HOW TO BEST APPROACH EUVOLAEMIA—
that educating patients with kidney disease to reduce dietary STATE OF THE ART 2020
Naþ does not lead to the desired outcome [14]. The heterogeneity in the ESRD population challenges the ne-
The dialyser must serve as the salt-excretory function and phrologist in HD practice to combine disease management with
should precisely remove the amount of Naþ that has accumu- the patient’s attainable treatment goal and prognosis [68].
lated during the interdialytic period. Naþ removal during HD The context is complex and a multidimensional approach to
occurs via convective (78%) and diffusive losses (22%) be- Naþ, fluid and pressure management in HD patients may be
tween dialysate and plasma Naþ concentration [64]. The dif- required to improve cardiovascular outcomes in HD patients
fuse Naþ gradient during HD ‘fine tunes’ Naþ balance. (Figure 3). The pillars of clinical, instrumental and patient

Volume control in haemodialysis for improved cardiovascular outcomes ii27

 1 Clinical management
• Probing dry weight
• Treatment time
• Ultrafiltration rate
• HD prescription

2 Instrumental and imaging management

4 Advanced analytics management • Bioimpedance spectroscopy
• Artificial intelligence • Echocardiography
• Machine learning • Lung US
• Predictive medicine • Sodium balance module
• 23Na MRI

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

3 Patient management
• Patient symptoms
• Residual kidney function
• Hemodynamic tolerance
• Blood pressure and volume control

FIGURE 3: Multidimensional approach to sodium, fluid and pressure management in haemodialysis patients. US, ultrasound; 23Na MRI,
magnetic resonance imaging of tissue sodium stores.

management need to complement each other to correctly assess Yet, before we know for certain, we need rigorous cardiovas-
the patient’s dry weight, and achieve BP control and haemody- cular outcome studies and thorough study interventions such
namic tolerance of HD therapy, while reassuring patient accep- as the above-mentioned (e.g. effect of UF rate thresholds) on
tance of HD duration and sequence. volume status, fluid-related hospitalizations and cardiovascular
Some dialysis facilities have implemented incremental dialy- outcomes while ensuring the patient’s acceptance to therapy.
sis as a preventive measure at the start of renal replacement
therapy. Other dialysis facilities permit a degree of initial over- ADVANCED ANALYTICS MANAGEMENT
hydration to preserve residual renal function, which may im-
Artificial intelligence (AI) is already successfully applied to sup-
prove outcomes [69]. A recent DOPPS analysis [70] confirmed
port physicians in the decision-making process of patients’ care
the previous finding [71] for incident HD patients that urine presenting either with chronic (e.g. anaemia management) or
output of at least 1 cup daily was associated with better survival acute kidney failure (e.g. fluid resuscitation in the intensive care
and it may be of value to routinely ask patients a simple unit) [76–79]. AI relies today on two main paths, known as
question about urine output. Diuretics may lessen chronic FO symbolic reasoning (expert systems, symbolic AI) and machine
in patients with preserved residual kidney function, but this learning (deep learning, neural networks, connectionist AI),
approach has not been evaluated [72]. each with their own advantages and limitations. Expert systems
Some experts have suggested imposing UF rate thresholds require perfect knowledge of physiological processes and inter-
(such as 13 mL/h/kg) to reduce UF-related risk [73]. UF profil- actions to provide reliable prediction based on rational algo-
ing (decelerating UF rate to match declining plasma refill rate) rithms. Machine learning (connectionist AI) requires a large
and sequential dialysis (isolated UF followed by combined HD amount of data (big data) to learn and define its own rules
and UF) are other potential HD prescription changes to reduce (open and not guided), in order to provide reliable prediction
the harm of rapid UF rate [72]. but lack of model interpretability. A third pathway is emerging,
Finally, as once demonstrated by the Tassin group, increased which combines the two approaches of symbolic reasoning
frequency or duration of HD sessions may bring high volume (symbolic AI) and machine learning (connectionist AI) (such
status, left ventricular mass and BP under control by more ef- as deep symbolic learning and/or enabling neural networks).
fectively reducing ECF load than conventional HD [9]. Yet, it is too early today to define what will be the best approach
Unfortunately, classic randomized controlled trials in HD for future predictive and supportive medicine [80].
thus far have failed to yield any meaningful information in the Expert systems based on AI outperform experienced neph-
area of dose and frequency of HD, mainly due to methodologi- rologists in assessing dry weight in HD patients [81].
cal issues, such as statistical errors, unfeasible trial efficiency, re- Preliminary and proof-of-concept studies based on machine
cruitment challenges and applicability of results to the research learning AI have been performed in the field of fluid and haemo-
question [74]. Cluster randomization may be a novel and dynamic management of HD patients to train and validate mod-
advantageous trial method and a potential mean to overcome els on a large patient dataset [82]. As shown, AI is able to predict
these barriers [75]. reliably individual session-specific patient haemodynamic

ii28 J. Pinter et al.

reaction to dialysis-related prescriptions on multiple relevant 11. Wizemann V, Schilling M. Dilemma of assessing volume state–the use and
haemodynamic parameters (e.g. intradialytic heart rate and BP the limitations of a clinical score. Nephrol Dial Transplant 1995; 10:
2114–2117
changes and trends), dialysis efficiency parameters (e.g. UF rate, 12. Agarwal R, Andersen MJ, Pratt JH. On the importance of pedal edema in
electrolyte composition), but also large sets of data including an- hemodialysis patients. Clin J Am Soc Nephrol 2008; 3: 153–158
thropometric, lab tests, medication and fluid volume status. 13. Marshall MR, Dunlop JL. Are dialysate sodium levels too high? Semin Dial
Availability of accurate, longitudinal, real-life data is a key factor 2012; 25: 277–283
for the development of reproducible predictive models, meaning 14. Zoccali C, Mallamaci F. Mapping progress in reducing cardiovascular risk
with kidney disease: managing volume overload. Clin J Am Soc Nephrol
that such an approach relies on a fully digitalized and connected 2018; 13: 1432–1434
IT system that feeds cloud computing systems with big data 15. Shemin D, Bostom AG, Laliberty P et al. Residual renal function and mor-
flow. Predictive and supportive medicine including fluid, pres- tality risk in hemodialysis patients. Am J Kidney Dis 2001; 38: 85–90
sure and haemodynamic management of HD patients are in the 16. Canaud B, Chazot C, Koomans J et al. Fluid and hemodynamic manage-
pipeline, but more granular information and studies are required ment in hemodialysis patients: challenges and opportunities. J Bras Nefrol
2019; 41: 550–559
for generalizability. 17. Flythe JE, Kimmel SE, Brunelli SM. Rapid fluid removal during dialysis is

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

associated with cardiovascular morbidity and mortality. Kidney Int 2011;
CONCLUSION 79: 250–257
18. Movilli E, Gaggia P, Zubani R et al. Association between high ultrafiltration
Naþ, fluid and pressure control are of critical importance in HD rates and mortality in uraemic patients on regular haemodialysis. A 5-year
patients to reduce cardiac disease burden and improve outcome. prospective observational multicentre study. Nephrol Dial Transplant 2007;
As highlighted in this review, it is of utmost importance to restore 22: 3547–3552
19. Saran R, Bragg-Gresham JL, Levin NW et al. Longer treatment time and
Naþ and fluid homoeostasis by correcting chronic FO but at the
slower ultrafiltration in hemodialysis: Associations with reduced mortality
same time prevent acute fluid depletion during HD sessions. This in the DOPPS. Kidney Int 2006; 69: 1222–1228
situation is challenging and complex and requires a multidimen- 20. Assimon MM, Wenger JB, Wang L et al. Ultrafiltration rate and mortality
sional approach. New technology may facilitate monitoring (clin- in maintenance hemodialysis patients. Am J Kidney Dis 2016; 68: 911–922
ical, instrumental, imaging and analytics) and action (Naþ 21. Chazot C, Vo-Van C, Lorriaux C et al. Even a moderate fluid removal rate
balancing algorithm, dialysis options), but should remain under during individualised haemodialysis session times is associated with de-
creased patient survival. Blood Purif 2017; 44: 89–97
scrutiny of pertinent clinical judgement, facilitated by measures 22. Jefferies HJ, Virk B, Schiller B et al. Frequent hemodialysis schedules are as-
such as increasing treatment time and diet modifications. sociated with reduced levels of dialysis-induced cardiac injury (myocardial
stunning). Clin J Am Soc Nephrol 2011; 6: 1326–1332
23. Canaud B, Kooman J, Selby NM et al. Sodium and water handling during
FUNDING
hemodialysis: new pathophysiologic insights and management approaches
J.P. is supported by the German Research Foundation for improving outcomes in end-stage kidney disease. Kidney Int 2019; 95:
(Deutsche Forschungsgemeinschaft, DFG), Project No. 296–309
24. Reinhardt HW, Seeliger E. Toward an integrative concept of control of total
413657723 (Clinician Scientist-Programme UNION CVD).
body sodium. News Physiol Sci 2000; 15: 319–325
25. Mc Causland FR, Waikar SS, Brunelli SM. Increased dietary sodium is inde-
CONFLICT OF INTEREST STATEMENT pendently associated with greater mortality among prevalent hemodialysis
patients. Kidney Int 2012; 82: 204–211
J.P. declares no conflict of interest. C.C., S.S., U.M. and B.C. are 26. Simpson FO. Sodium intake, body sodium, and sodium excretion. Lancet
employed by Fresenius Medical Care. 1988; 2: 25–29
27. Strauss MB, Lamdin E, Smith WP et al. Surfeit and deficit of sodium; a ki-
netic concept of sodium excretion. AMA Arch Intern Med 1958; 102:
REFERENCES 527–536
1. Liyanage T, Ninomiya T, Jha V et al. Worldwide access to treatment for 28. Hollenberg NK. Set point for sodium homeostasis: surfeit, deficit, and their
end-stage kidney disease: a systematic review. Lancet 2015; 385: 1975–1982 implications. Kidney Int 1980; 17: 423–429
2. DeJager DJ, Grootendorst DC, Jager KJ et al. Cardiovascular and noncardio- 29. Risvoll GB, Thorsen K, Ruoff P et al. Variable setpoint as a relaxing compo-
vascular mortality among patients starting dialysis. JAMA 2009; 302: nent in physiological control. Physiol Rep 2017; 5: e13408
1782–1789 30. Guyton AC, Coleman TG, Cowley AV Jr et al. Arterial pressure regulation.
3. USRDS: United States Renal Data System. 2018 Annual Data Report Overriding dominance of the kidneys in long-term regulation and in hyper-
Volume 2: End-Stage Renal Disease. Chapter 5: Mortality. https://www. tension. Am J Med 1972; 52: 584–594
usrds.org/ (20 December 2019, date last accessed) 31. Guyton AC. Blood pressure control–special role of the kidneys and body
4. Wanner C, Amann K, Shoji T. The heart and vascular system in dialysis. fluids. Science 1991; 252: 1813–1816
Lancet 2016; 388: 276–284 32. Malpas S. Editorial comment: Montani versus Osborn exchange of views.
5. Charra B, Chazot C, Jean G et al. Role of sodium in dialysis. Minerva Urol Exp Physiol 2009; 94: 381–382
Nefrol 2004; 56: 205–213 33. Rakova N, Juttner K, Dahlmann A et al. Long-term space flight simulation
6. Zoccali C, Moissl U, Chazot C et al. Chronic fluid overload and mortality in reveals infradian rhythmicity in human Na(þ) balance. Cell Metab 2013;
ESRD. J Am Soc Nephrol 2017; 28: 2491–2497 17: 125–131
7. Kundhal K, Lok CE. Clinical epidemiology of cardiovascular disease in 34. Kopp C, Linz P, Wachsmuth L et al. (23)Na magnetic resonance imaging of
chronic kidney disease. Nephron Clin Pract 2005; 101: c47–c52 tissue sodium. Hypertension 2012; 59: 167–172
8. Cozzolino M, Mangano M, Stucchi A et al. Cardiovascular disease in dialysis 35. Titze J, Shakibaei M, Schafflhuber M et al. Glycosaminoglycan polymeriza-
patients. Nephrol Dial Transplant 2018; 33 (Suppl 3): iii28–iii34 tion may enable osmotically inactive Naþ storage in the skin. Am J Physiol
9. Ok E, Asci G, Chazot C et al. Controversies and problems of volume control Heart Circ Physiol 2004; 287: H203–H208
and hypertension in haemodialysis. Lancet 2016; 388: 285–293 36. Schafflhuber M, Volpi N, Dahlmann A et al. Mobilization of osmotically in-
10. Flythe JE, Mc Causland FR. Dialysate sodium: rationale for evolution over active Naþ by growth and by dietary salt restriction in rats. Am J Physiol
time. Semin Dial 2017; 30: 99–111 Renal Physiol 2007; 292: F1490–F1500

Volume control in haemodialysis for improved cardiovascular outcomes ii29

37. Fischereder M, Michalke B, Schmockel E et al. Sodium storage in human 61. Hecking M, Moissl U, Genser B et al. Greater fluid overload and lower inter-
tissues is mediated by glycosaminoglycan expression. Am J Physiol Renal dialytic weight gain are independently associated with mortality in a large
Physiol 2017; 313: F319–F325 international hemodialysis population. Nephrol Dial Transplant 2018; 33:
38. Machnik A, Neuhofer W, Jantsch J et al. Macrophages regulate salt- 1832–1842
dependent volume and blood pressure by a vascular endothelial growth 62. Hur E, Usta M, Toz H et al. Effect of fluid management guided by bioimpe-
factor-C-dependent buffering mechanism. Nat Med 2009; 15: 545–552 dance spectroscopy on cardiovascular parameters in hemodialysis patients:
39. Wiig H, Luft FC, Titze JM. The interstitium conducts extrarenal storage of a randomized controlled trial. Am J Kidney Dis 2013; 61: 957–965
sodium and represents a third compartment essential for extracellular vol- 63. Dekker MJ, Marcelli D, Canaud BJ et al. Impact of fluid status and inflam-
ume and blood pressure homeostasis. Acta Physiol 2018; 222: e13006 mation and their interaction on survival: a study in an international hemo-
40. Titze J, Luft FC. Speculations on salt and the genesis of arterial hyperten- dialysis patient cohort. Kidney Int 2017; 91: 1214–1223
sion. Kidney Int 2017; 91: 1324–1335 64. Lee SW. Sodium balance in maintenance hemodialysis. Electrolyte Blood
41. Schneider MP, Raff U, Kopp C et al. Skin sodium concentration correlates Press 2012; 10: 1–6
with left ventricular hypertrophy in CKD. J Am Soc Nephrol 2017; 28: 65. Kayikcioglu M, Tumuklu M, Ozkahya M et al. The benefit of salt restriction
1867–1876 in the treatment of end-stage renal disease by haemodialysis. Nephrol Dial
42. Dahlmann A, Dorfelt K, Eicher F et al. Magnetic resonance-determined so- Transplant 2009; 24: 956–962
dium removal from tissue stores in hemodialysis patients. Kidney Int 2015; 66. Dunlop JL, Vandal AC, Marshall MR. Low dialysate sodium levels for

Downloaded from https://academic.oup.com/ndt/article/35/Supplement_2/ii23/5803067 by guest on 25 June 2024

87: 434–441 chronic haemodialysis. Cochrane Database Syst Rev 2019; 1: Cd011204
43. Arneson TJ, Liu J, Qiu Y et al. Hospital treatment for fluid overload in the 67. Sagova M, Wojke R, Maierhofer A et al. Automated individualization of di-
medicare hemodialysis population. Clin J Am Soc Nephrol 2010; 5: alysate sodium concentration reduces intradialytic plasma sodium changes
1054–1063 in hemodialysis. Artif Organs 2019; 43: 1002–1013
44. Plantinga LC, King LM, Masud T et al. Burden and correlates of readmis- 68. Vandecasteele SJ, Kurella Tamura M. A patient-centered vision of care for
sions related to pulmonary edema in US hemodialysis patients: a cohort ESRD: dialysis as a bridging treatment or as a final destination? J Am Soc
study. Nephrol Dial Transplant 2018; 33: 1215–1223 Nephrol 2014; 25: 1647–1651
45. Goodkin DA, Young EW, Kurokawa K et al. Mortality among hemodialysis 69. Obi Y, Streja E, Rhee CM et al. Incremental hemodialysis, residual kidney
patients in Europe, Japan, and the United States: case-mix effects. Am J function, and mortality risk in incident dialysis patients: a cohort study. Am
Kidney Dis 2004; 44 (Suppl 2): 16–21 J Kidney Dis 2016; 68: 256–265
46. Weiner DE, Brunelli SM, Hunt A et al. Improving clinical outcomes among 70. Hecking M, McCullough KP, Port FK et al. Self-reported urine volume in
hemodialysis patients: a proposal for a “volume first” approach from the hemodialysis patients: predictors and mortality outcomes in the
chief medical officers of US dialysis providers. Am J Kidney Dis 2014; 64: International Dialysis Outcomes and Practice Patterns Study (DOPPS). Am
685–695 J Kidney Dis 2019; 74: 425–428
47. Essig M, Escoubet B, de Zuttere D et al. Cardiovascular remodelling and ex- 71. Shafi T, Jaar BG, Plantinga LC et al. Association of residual urine output
tracellular fluid excess in early stages of chronic kidney disease. Nephrol with mortality, quality of life, and inflammation in incident hemodialysis
Dial Transplant 2008; 23: 239–248 patients: the choices for healthy outcomes in caring for end-stage renal dis-
48. Go AS, Chertow GM, Fan D et al. Chronic kidney disease and the risks of ease (CHOICE) study. Am J Kidney Dis 2010; 56: 348–358
death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: 72. Assimon MM, Flythe JE. Rapid ultrafiltration rates and outcomes among
1296–1305 hemodialysis patients: re-examining the evidence base. Curr Opin Nephrol
49. Bansal N, Keane M, Delafontaine P et al. A longitudinal study of left ven- Hypertens 2015; 24: 525–530
tricular function and structure from CKD to ESRD: the CRIC study. Clin J 73. Agar JW. Personal viewpoint: limiting maximum ultrafiltration rate as a po-
Am Soc Nephrol 2013; 8: 355–362 tential new measure of dialysis adequacy. Hemodial Int 2016; 20: 15–21
50. Siriopol D, Siriopol M, Stuard S et al. An analysis of the impact of fluid over- 74. Twardowski ZJ, Misra M. A need for a paradigm shift in focus: from Kt/
load and fluid depletion for all-cause and cardiovascular mortality. Nephrol Vurea to appropriate removal of sodium (the ignored uremic toxin).
Dial Transplant 2019; 34: 1385–1393 Hemodial Int 2018; 22: S29–S64
51. Bansal N, McCulloch CE, Lin F et al. Blood pressure and risk of cardiovas- 75. Ford I, Norrie J. Pragmatic trials. N Engl J Med 2016; 375: 454–463
cular events in patients on chronic hemodialysis. Hypertension 2017; 70: 76. Barbieri C, Mari F, Stopper A et al. A new machine learning approach for
435–443 predicting the response to anemia treatment in a large cohort of end stage
52. Charra B, Laurent G, Chazot C et al. Clinical assessment of dry weight. renal disease patients undergoing dialysis. Comput Biol Med 2015; 61:
Nephrol Dial Transplant 1996; 11 (Suppl 2): 16–19 56–61
53. Hecking M, Karaboyas A, Antlanger M et al. Significance of interdialytic 77. Barbieri C, Molina M, Ponce P et al. An international observational study
weight gain versus chronic volume overload: consensus opinion. Am J suggests that artificial intelligence for clinical decision support optimizes
Nephrol 2013; 38: 78–90 anemia management in hemodialysis patients. Kidney Int 2016; 90:
54. Loutradis C, Sarafidis PA, Theodorakopoulou M et al. Lung ultrasound- 422–429
guided dry-weight reduction in hemodialysis patients does not affect short- 78. Celi LA, Hinske LC, Alterovitz G et al. An artificial intelligence tool to pre-
term blood pressure variability. Am J Hypertens 2019; 32: 786–795 dict fluid requirement in the intensive care unit: a proof-of-concept study.
55. Kotanko P, Levin NW, Zhu F. Current state of bioimpedance technologies Crit Care 2008; 12: R151
in dialysis. Nephrol Dial Transplant 2008; 23: 808–812 79. Davoudi A, Malhotra KR, Shickel B et al. Intelligent ICU for autonomous
56. Moissl U, Arias-Guillen M, Wabel P et al. Bioimpedance-guided fluid man- patient monitoring using pervasive sensing and deep learning. Sci Rep 2019;
agement in hemodialysis patients. Clin J Am Soc Nephrol 2013; 8: 1575–1582 9: 8020
57. Machek P, Jirka T, Moissl U et al. Guided optimization of fluid status in 80. Stuart Russell PN. Artificial Intelligence: A Modern Approach, Global edn.
haemodialysis patients. Nephrol Dial Transplant 2010; 25: 538–544 Harlow, UK: Pearson Education Limited, 2016.
58. Onofriescu M, Hogas S, Voroneanu L et al. Bioimpedance-guided fluid 81. Niel O, Bastard P, Boussard C et al. Artificial intelligence outperforms expe-
management in maintenance hemodialysis: a pilot randomized controlled rienced nephrologists to assess dry weight in pediatric patients on chronic
trial. Am J Kidney Dis 2014; 64: 111–118 hemodialysis. Pediatr Nephrol 2018; 33: 1799–1803
59. Covic A, Ciumanghel AI, Siriopol D et al. Value of bioimpedance analysis 82. Barbieri C, Cattinelli I, Neri L et al. Development of an artificial intelligence
estimated “dry weight” in maintenance dialysis patients: a systematic review model to guide the management of blood pressure, fluid volume, and
and meta-analysis. Int Urol Nephrol 2017; 49: 2231–2245 dialysis dose in end-stage kidney disease patients: proof of concept and first
60. Tabinor M, Davies SJ. The use of bioimpedance spectroscopy to guide fluid clinical assessment. Kidney Dis 2019; 5: 28–33
management in patients receiving dialysis. Curr Opin Nephrol Hypertens
2018; 27: 406–412 Received: 20.12.2019; Editorial decision: 13.1.2020

ii30 J. Pinter et al.