European Heart Journal: Acute Cardiovascular Care (2022) 11, 786–793 EDUCATIONAL PAPER

https://doi.org/10.1093/ehjacc/zuac104

Fluid management in acute kidney injury:

from evaluating fluid responsiveness
towards assessment of fluid tolerance
Eduardo R. Argaiz1, Philippe Rola2, Korbin H. Haycock3,

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and Frederik H. Verbrugge 4,5,*
1
Department of Nephrology and Mineral Metabolism, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City, Mexico; 2Intensive Care Unit, Santa Cabrini
Hospital, Montréal, QC, Canada; 3Department of Emergency Medicine, Loma Linda University Health, Loma Linda, CA, USA; 4Centre for Cardiovascular Diseases, University Hospital
Brussels, Laarbeeklaan 101, 1090 Jette, Belgium; and 5Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium

Received 21 August 2022; accepted 23 August 2022; online publish-ahead-of-print 7 September 2022

Despite the widespread use of intravenous fluids in acute kidney injury (AKI), solid evidence is lacking. Intravenous fluids mainly improve AKI due to
true hypovolaemia, which is difficult to discern at the bedside unless it is very pronounced. Empiric fluid resuscitation triggered only by elevated
serum creatinine levels or oliguria is frequently misguided, especially in the presence of fluid intolerance syndromes such as increased extravascular
lung water, capillary leak, intra-abdominal hypertension, and systemic venous congestion. While fluid responsiveness tests clearly identify patients
who will not benefit from fluid administration (i.e. those without an increase in cardiac output), the presence of fluid responsiveness does not guar­
antee that fluid therapy is indicated or even safe. This review calls for more attention to the concept of fluid tolerance, incorporating it into a practical
algorithm with systematic venous Doppler ultrasonography assessment to use at the bedside, thereby lowering the risk of detrimental kidney con­
gestion in AKI.
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* Corresponding author. Tel: +32 2 474 9657, Fax: +32 2 477 4159, Email: [email protected]
© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: [email protected].
Fluid management in acute kidney injury 787

Graphical Abstract

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Approach to fluid therapy in acute kidney injury. AKI, acute kidney injury; IAP, intra-abdominal pressure; LUS, lung ultrasound; LVOT VTI, left-ven­
tricular outflow tract velocity–time integral; VExUS, venous excess ultrasound score.
.............................................................................................................................................................................................
Keywords Acute kidney injury • Fluid therapy • Haemodynamics • Renal circulation • Ultrasonography

administration of fluids does not necessarily result in an increased cardiac

Introduction output (CO) with improved kidney perfusion. Moreover, even in distribu­
Acute kidney injury (AKI) is a common problem in both the general hos­ tive shock types, this is often not the case as the CO reserve has already
pital population and the critically ill population, affecting >20 and >50% of been exploited and alterations to intra-glomerular haemodynamics play a
patients, respectively.1 Acute kidney injury has many underlying causes, in­ dominant role.6,7 Finally, in patients with established tubular injury, GFR
cluding intrinsic and obstructive (i.e. the so-called post-renal), yet up to 75% will not improve with fluid administration, even if the initial precipitating
of cases are the consequence of haemodynamically mediated reductions in cause of AKI was true hypovolaemia.
the glomerular filtration rate (GFR).2,3 Haemodynamic AKI may be the Importantly, increasing evidence has shown that an overzealous ad­
consequence of reduced kidney perfusion because of hypovolaemia or im­ ministration of fluids, resulting in volume overload, is actually harmful
paired cardiac output (i.e. the classic ‘pre-renal’ AKI).4 Restoring kidney and associated with a higher risk of respiratory complications, infec­
perfusion rapidly reverses this condition as, by definition, the integrity of tions, an increased need and length of mechanical ventilation, and over­
the kidneys remains intact. Severe or prolonged hypoperfusion may ultim­ all mortality.8,9 In addition, volume overload and systemic venous
ately result in tubular epithelial cell injury and necrosis, which might be, to congestion decrease renal perfusion as well, leading to a similar pheno­
some extent, irreversible, leading to the progression of chronic kidney dis­ type of haemodynamic AKI that is probably much more common in the
ease.4 Hence, the traditional treatment strategy in AKI has usually im­ hospital than hypovolaemic AKI.7 Hence, fluid administration in AKI
plied the administration of intravenous fluids to correct hypovolaemia should be carefully tailored based on individual haemodynamic status,
and/or restore kidney perfusion.5 However, it should be recognized balancing the probability of a beneficial effect with potential harms.
that many patients with haemodynamic AKI do not respond to vol­ This review focuses on the underlying principles for a physiologically
ume administration. In patients with cardiogenic or obstructive shock, guided fluid management strategy in AKI, with an emphasis on fluid
788 E.R. Argaiz et al.

tolerance, in addition to the more classic concept of fluid responsiveness, glomerular capillary pressure and filtration fraction, hence a lower
which might help clinicians to avoid unnecessary harm by excessive fluid GFR, might persist even in adequately resuscitated sepsis, due to effer­
administration. ent arteriolar vasodilation.17 In this particular setting, selective efferent
arteriolar vasoconstrictors (angiotensin II, vasopressin, and terlipressin)
Determinants of renal perfusion might represent an efficient strategy to restore urine output and
GFR.6,18,19 For example, norepinephrine is an afferent arteriolar con­
Mean arterial pressure (MAP) is not the only determinant of renal perfu­ strictor and therefore will tend to decrease glomerular pressure.
sion. Renal blood flow (RBF) is determined by the pressure gradient be­ However, norepinephrine infusion may increase kidney perfusion as
tween the inflow and the outflow pressures of the kidneys and by the
long as the increase in MAP maintains glomerular flow and pressure
vascular resistance to flow (RBF = ΔP/R).10 The inflow pressure of the kid­
more than it is decreased by the afferent constriction. When this is
ney is closely related to MAP, while the outflow pressure is determined by
not the case, using a decreased dose of norepinephrine along with a
the renal venous pressure or intra-abdominal pressure (IAP), depending vasopressin infusion to maintain MAP may have the added benefit of ef­
on which one is higher.11 Resistance is mainly determined by the radius
ferent arteriolar constriction along with the augmented MAP that is
of both the afferent and efferent arterioles.10 While vasoconstriction of
gained with vasopressin. Although these intra-glomerular haemo­
both arteriolar beds results in decreased RBF, efferent arteriolar vasocon­
dynamics cannot be readily assessed at the bedside, a good understand­
striction has less of an impact on the GFR because it increases the glom­

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ing of renal physiology may help the clinical interpretation.
erular capillary pressure and filtration fraction.7,12 Hypotension (i.e. For fluid administration to achieve an increase in kidney perfusion,
reduced MAP) markedly reduces RBF by decreasing inflow pressure.
fluid loading must result in an increased mean systemic filling pressure
On the other hand, increased outflow pressure may become the limiting
leading to increased preload and ultimately an increased CO
factor for kidney perfusion in the setting of abdominal compartment syn­
(Figure 1).20 Thus, evaluating the CO response to fluid loading is para­
drome13 or systemic venous congestion secondary to right-sided heart mount to determine whether fluid administration at least achieves this
failure or cirrhosis.14 In this setting, interstitial oedema within the encap­ goal.21 However, merely achieving a higher CO should not become a
sulated kidneys leads to compressive forces upon the intra-renal vessels
goal on itself, as the normal circulation is preload sensitive as well
and further increases impedance to RBF.14
and when fluids are administered up till the point of ‘no fluid respon­
siveness’, this will likely result in harmful volume overload.22 Rather,
Goals of fluid resuscitation in acute kidney CO should always be interpreted with respect to tissue oxygen de­
injury mands and optimized accordingly. This explains why indicators of tissue
perfusion such as the capillary refill time are more attractive resuscita­
The main goal of fluid resuscitation in AKI is to reverse kidney hypoper­
tion goals.23
fusion caused by true hypovolaemia or through a preload-sensitive de­
Independently from volume homeostasis, another goal of fluid ther­
crease in CO. In clinical practice, however, it is problematic that no
apy might be to correct electrolyte abnormalities and acid–base equi­
single or simple marker can be used to quantify oxygen delivery to
librium. Chloride-rich solutions such as 0.9% saline may be preferred
the tissues and/or renal perfusion. Indeed, the presence of oliguria
in patients with hypovolaemia, metabolic alkalosis, and hypochlorae­
not necessarily indicates impaired renal perfusion, as appropriate com­
mia.24 Isotonic bicarbonate solutions decrease the serum potassium
pensatory neurohumoral activation may lead to water and sodium re­
concentration in patients with metabolic acidosis and hyperkalaemia.25
tention and a diminished urine output.15,16 Furthermore, decreased
In a multicentre randomized controlled trial of critically ill patients with
sepsis and metabolic acidosis, the use of up to 1000 mL of 4.2% bicar­
bonate infusion significantly reduced the need for dialysis.26 Still, no
matter the reason for fluid administration, fluid tolerance (i.e. the ab­
sence of developing fluid overload) must be guarded continuously.

Clinical evaluation of suspected

hypovolaemia in acute kidney injury
Initial evaluation of AKI should focus on a comprehensive history to as­
sess for obvious causes of fluid loss (i.e. gastrointestinal), careful chart
review, and evaluation of fluid in- and outputs.27 Physical examination
typically lacks the sensitivity to confirm a hypovolaemic state, but signs
like dry mucous membranes with diminished skin turgor may suggest
it.28 A routine work-up for AKI should rule out obstructive disease
and evaluate tubular integrity, proteinuria, and dysmorphic haematuria
to rule out intrinsic renal causes.29 It is often recommended to calculate
the fractional sodium excretion (FENa+) in patients not on diuretics to
discriminate ‘renal’ AKI (due to tubular necrosis) from ‘pre-renal’ AKI,
which is characterized by a low FENa+ <1%. However, it is important to
Figure 1 Relationship between the Frank–Starling curve for cardiac
realize that low FENa+ is not a reliable predictor of fluid responsiveness,
output (red) and venous return curve (blue). Increasing Pmsf through
as haemodynamic AKI with impaired renal perfusion due to vasodilation
venoconstriction or fluid loading results in an equilibrium at a higher
or congestion is associated with a low urine sodium concentration as
right atrial pressure. In the example of the drawing, this is associated well.30,31 Thus, haemodynamic AKI should be further investigated for
with an increase in cardiac output (i.e. fluid responsiveness). However, its culprit, which may or may not be true hypovolaemia.
further increasing Pmsf would lead to a further increase in right atrial The haemodynamic signature of hypovolaemia is characterized by low
pressure without meaningful gain in cardiac output, because the central venous pressure, low preload, low pulmonary pressures, low end-
Frank–Starling curve reaches its flat part (i.e. no fluid responsiveness). diastolic volume, a low CO and high systemic vascular resistance.32
Pmsf, mean systemic filling pressure. Discordant findings with this clinical picture should stimulate critical reflec­
tion on the use of fluids as a therapeutic strategy. Point-of-care ultrasound
Fluid management in acute kidney injury 789

allows examination of cardiac structure and function as well as objective permeability may manifest as pulmonary fluid intolerance.46
assessment of venous congestion at the bedside. Together with judicious Cardiogenic pulmonary oedema due to increased left atrial pressure is
use of invasive haemodynamic monitoring, ultrasound might be of great another obvious example.47,48 Under the diaphragm, increased IAP
help to better understand the clinical context.33,34 Findings of a significantly and the abdominal compartment syndrome are typical examples where
elevated central venous pressure or systemic venous congestion point to­ fluid administration may precipitate clinical deterioration and worsening
wards fluid intolerance and should dissuade from fluid administration in AKI, despite a persistently low preload.4,13 Finally, patients with condi­
most scenarios.22 Furthermore, an elevated CO is not compatible with tions causing impedance to venous return like severe pulmonary hyper­
hypovolaemia and any further potential gains in CO reserve with fluid tension, restrictive cardiomyopathy, or pericardial disease can present
therapy should be balanced against the risk of volume overload, consider­ with venous congestion and still be fluid responsive.49 However, in
ing tissue perfusion.35 such cases, fluid administration often exacerbates systemic venous con­
Haemodynamic assessment may be particularly challenging in patients gestion and increases right atrial pressure transmission to peripheral or­
with septic shock. In sepsis, venous dilation increases the unstressed blood gans through a non-compliant venous system, which may cause
volume and decreases mean systemic filling pressure to cause low preload congestive organ injury.50
(Figure 1).20 Capillary leak may further decrease the mean systemic filling
pressure.36 This explains why many signs, commonly associated with

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hypovolaemia, may also be present in sepsis. A hyperdynamic heart Lung fluid intolerance: the acute
with decreased end-diastolic volume or ‘kissing ventricles’37 or low right respiratory distress syndrome
atrial pressure38 could easily be mistaken for hypovolaemia, while instead
excessive venodilation because of inflammatory cytokine release is the real and capillary leak
culprit. In fact, targeting higher right atrial pressures with fluid therapy in In ARDS, the alveolar-capillary membrane becomes damaged and leaky,
septic shock has not shown benefits in multiple randomized controlled allowing increased movement of water and proteins from the intravas­
trials.39,40 Alternatively, unstressed blood volume in sepsis may be re­ cular to the interstitial space, even with normal cardiac filling pres­
cruited through α-adrenergic-mediated venous constriction (i.e. vasopres­ sures.51 In this scenario, fluid administration carries the risk of further
sors),20 which might constitute a better physiologic strategy to address the worsening alveolar damage. In fact, randomized controlled trials involv­
underlying haemodynamic culprit and has potential benefits on clinical ing different fluid resuscitation strategies in patients with respiratory
outcomes.41 failure have suggested benefits of fluid restriction.52,53 Quantitative as­
sessment of extravascular lung water can be performed by invasive
thermal indicator dilution methods.54 The extravascular lung water in­
Fluid responsiveness vs. fluid tolerance dex (EVLWI) is associated with progression of acute lung injury55 and
There is a large amount of literature regarding the evaluation of sus­ has a close relationship with the severity of ARDS.56 Small studies
pected hypovolaemia by means of dynamic predictors of fluid respon­ have suggested clinical benefits when using increased EVLWI as a stop­
siveness.42 However, even in fluid responsive patients, intravenous ping point for fluid resuscitation in intensive care unit patients.57,58
fluids may not result in a sustained improvement in tissue perfusion.43 Besides the ARDS and respiratory failure setting, EVLWI is also asso­
Furthermore, patients with sepsis and distributive shock in particular ciated with increased mortality in diverse conditions of capillary leak
may continue to display responsiveness to fluid resuscitation, while at such as sepsis and burns.59
the same time, they already experience adverse effects.44 Risk assess­ Non-invasive evaluation of extravascular lung water may be per­
ment for this potential harm by fluid administration is known as fluid formed at the bedside using lung ultrasound. As the lungs mostly consist
tolerance evaluation.22 We would argue that evaluation of fluid toler­ of air, the ultrasound beam is usually not transmitted into the lung, but
ance should come before assessment of fluid responsiveness in most rather reflected by the pleural line back to the probe, leading to a rever­
if not all patients with AKI (Graphical Abstract). beration artefact known as (horizontal) A-lines. In the presence of lung
Several factors impact on the ability of each capillary bed to tolerate water, well-defined, vertical, and hyper-echogenic artefacts originate
or handle fluids. Age and pre-existing comorbidities like chronic renal, from the pleural line, extending >10 cm and obliterating A-lines; these
pulmonary, or cardiac diseases are important. The adult respiratory dis­ are called B-lines.60 Use of lung ultrasound to evaluate lung water out­
tress syndrome (ARDS) is a prime example of fluid intolerance due to performs chest radiography because of its higher specificity,61 and has
respiratory disease,45 yet any disease with increased vascular an excellent correlation with extravascular lung water measured by

Figure 2 Venous Doppler flow patterns according to the degree of systemic venous congestion.
790 E.R. Argaiz et al.

Table 1 Clinical examples of a risk/benefit analysis of fluid administration

Clinical scenario Fluid Fluid Sustained fluid Risk/benefit
tolerance? responsiveness? benefit? ratio
......................................................................................................................................................................................
AKI from true hypovolaemia (e.g. gastrointestinal fluid loss) Yes Yes Yes +/++++
AKI in young patient with sepsis and no comorbidities Yes Yes Possibly not +/++
AKI in a resuscitated young patient with pancreatitis and No Yes Probably not +++/+
B-lines on lung ultrasound
AKI in a patient with pulmonary hypertension presenting with No Possibly No ++++/+
nausea and vomiting with a high VExUS score
AKI in a patient with septic cardiomyopathy with no Yes No No ++++/No
congestion but negative passive leg rise test benefit

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trans-pulmonary thermodilution, even in cases of early or subclinical of ascites, nasogastric tube placement, or surgical decompression
pulmonary congestion.62–64 Lung ultrasound has been shown useful should be prioritized.76
to monitor lung congestion in patients with AKI,65,66 and several studies
have found rapid B-line resolution with haemodialysis or ultrafiltra­
tion.67 Whether or not from cardiogenic origin, the presence of Fluid intolerance in the setting of systemic
B-lines on lung ultrasound constitutes a strong risk indicator of fluid ad­ venous congestion
ministration, even when classic markers of fluid responsiveness are
Systemic venous congestion is the condition whereby increased right at­
present.22
rial pressure is back-transmitted to peripheral organs.77,78 Evaluation of
increased right atrial pressure can be performed at the bedside via direct
invasive measurements34 or non-invasive echo evaluation of the internal
Abdominal fluid intolerance: jugular vein79 and the IVC diameter with its collapsibility index.80 A
short-axis view of the IVC, allowing assessment of both long and short
intra-abdominal hypertension diameters, is better correlated with right atrial pressure as the trans­
and compartment syndrome ected IVC is rarely round but rather oval.81,82 In most patients, a pleth­
Tense ascites, abdominal surgery, and accumulation of fluids in third oric, non-collapsing IVC strongly suggests fluid intolerance and the risk
spaces with inflammatory conditions may increase IAP with significant of further worsening of systemic venous congestion. In severe venous
haemodynamic repercussions. Normal IAP in critically ill patients is congestion, backwards transmission of increased right atrial pressure
5–7 mmHg, with elevations >12 mmHg defined as intra-abdominal to peripheral organs may result in congestive organ injury such as con­
hypertension. A sustained IAP elevation (usually >20 mmHg) leading gestive hepatopathy or cardio-renal syndrome.83 The severity of right
to organ dysfunction is termed abdominal compartment syndrome.13 atrial pressure transmission to abdominal organs can be readily assessed
Organ dysfunction in this setting is caused by hypoperfusion because at the bedside using venous Doppler on ultrasonography to evaluate
of reduced abdominal perfusion pressure (MAP-IAP). An abdominal flow patterns in the liver and intra-renal veins (Figure 2).50,84
perfusion pressure target of ≥60 mmHg is associated with improved Normal blood flow in the central veins, including the hepatic veins, is
survival in abdominal compartment syndrome.68 Abdominal compart­ pulsatile in nature. This pulsatility reflects the normal changes in right
ment syndrome is directly reflected by kidney function as AKI is primar­ atrial pressure that occur during the normal cardiac cycle. In the ab­
ily mediated by a reduction in RBF.4 Systemic haemodynamic sence of congestion, the distensible lumen of the peripheral veins
consequences of abdominal compartment syndrome involve reduced causes the attenuation of this pulsatile pattern in more distally located
venous return from functional obstruction of the inferior vena cava veins and venules. As such, normal flow patterns in the portal and
(IVC) resulting in lower extremity oedema and reduced preload.69 intra-renal veins is continuous or only minimally pulsatile.50 As conges­
Importantly, aggressive fluid resuscitation in patients with or at risk of tion worsens, peripheral venous walls stretch and backwards transmis­
abdominal hypertension typically leads to fluid accumulation and tissue sion of pressure is enhanced. This results in quantifiable alterations in
oedema in the abdominal compartment, further increasing IAP and po­ venous flow pattern characterized by pulsatile portal flow and intermit­
tentially precipitating an abdominal compartment syndrome. Significant tent interruptions of intra-renal venous flow.84 Importantly, volume ex­
elevations in IAP have been consistently shown to correlate with the pansion in fluid intolerant patients results in worsening patterns of
volume of administered fluids.70,71 venous flow,85 while fluid removal can reverse these alterations.86,87
Evaluation of suspected intra-abdominal hypertension can be easily Alterations in intra-renal flow have been strongly associated with ad­
confirmed by indirect IAP measurement using a fluid-filled bladder cath­ verse clinical outcomes in patients with congestive heart failure88 and
eter.72 Focused ultrasonography may add suspicion for the diagnosis pulmonary hypertension.89 In both conditions, altered intra-renal
when observing a collapsed IVC in the presence of increased flow patterns were the strongest independent predictor of morbidity
intra-abdominal fluid or dilated bowel loops.73,74 It is important to real­ and mortality. It is likely that renal congestion results in a viscous cycle
ize that (with the exception of a passive leg rise manoeuvre), classic in­ of sodium retention and worsening venous congestion, as the presence
dicators of fluid responsiveness are present in case of intra-abdominal of flow alterations has been linked with diuretic resistance.85 In a pro­
hypertension.75 Nevertheless, fluid administration carries a high risk of spective study of patients undergoing cardiac surgery, increased pulsa­
clinical deterioration as it is not effective to increase preload in a sus­ tility in portal venous flow was shown to be the most important
tained way and contributes to worsening abdominal congestion. predictor of congestive AKI.90 Other studies have also linked pulsatile
Other treatment strategies such as early vasopressors, paracentesis portal flow with the development of congestive encephalopathy91
Fluid management in acute kidney injury 791

and congestive hepatopathy,92 supporting the role of systematic ven­ 9. Douglas IS, Alapat PM, Corl KA, Exline MC, Forni LG, Holder AL, Kaufman DA, Khan A,
ous Doppler assessment with ultrasonography for evaluating congest­ Levy MM, Martin GS, Sahatjian JA, Seeley E, Self WH, Weingarten JA, Williams M,
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Kolkman K, Wilmer A. Results from the International Conference of Experts on
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HM, Prowle JR, Bihorac A, Finkel KW, Zarbock A, Forni LG, Lynch SJ, Jensen J, Kroll S,
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mortality among patients with septic shock: the ANDROMEDA-SHOCK randomized
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