768488 ACC European Heart Journal: Acute Cardiovascular CareVerbrugge

Education in Acute Cardiovascular Care

European Heart Journal: Acute Cardiovascular Care

Editor’s Choice-Diuretic resistance 2018, Vol. 7(4) 379­–389

© The European Society of Cardiology 2018
Reprints and permissions:
in acute heart failure sagepub.co.uk/journalsPermissions.nav
https://doi.org/10.1177/2048872618768488
DOI: 10.1177/2048872618768488
journals.sagepub.com/home/acc

Frederik H Verbrugge

Abstract
Diuretic resistance is a powerful predictor of adverse outcome in acute heart failure (AHF), irrespectively of underlying
glomerular filtration rate. Metrics of diuretic efficacy such as natriuresis, urine output, weight loss, net fluid balance, or
fractional sodium excretion, differ in their risk for measurement error, convenience, and biological plausibility, which
should be taken into account when interpreting their results. Loop diuretic resistance in AHF has multiple causes
including altered drug pharmacokinetics, impaired renal perfusion and effective circulatory volume, neurohumoral
activation, post-diuretic sodium retention, the braking phenomenon and functional as well as structural adaptations in
the nephron. Ideally, these mechanisms should guide specific treatment decisions with the goal of achieving complete
decongestion. Therefore, volume overload needs to be identified correctly to avoid poor diuretic response due to
electrolyte depletion or dehydration. Next, renal perfusion should be optimised if possible and loop diuretics should
be prescribed above their threshold dose. Addition of thiazide-type diuretics should be considered when a progressive
decrease in loop diuretic efficacy is observed with prolonged use (i.e., the braking phenomenon). Furthermore, thiazide-
type diuretics are a useful addition in patients with low glomerular filtration rate. However, they limit free water
excretion and are relatively contraindicated in cases of hypotonic hyponatremia, where acetazolamide is the better
option. Finally, ultrafiltration should be considered in patients with refractory diuretic resistance as persistent volume
overload after decongestive treatment is associated with worse outcomes. Whether more upfront use of any of these
individually tailored decongestion strategies is superior to monotherapy with loop diuretics remains to be shown by
adequately powered randomised clinical trials.

Learning objectives
•• To understand the concept of diuretic resistance in acute heart failure with its different definitions
•• To be aware of the prognostic significance of diuretic resistance in acute heart failure
•• To understand the mechanisms of diuretic resistance in acute heart failure
•• To develop a tailored approach to handle diuretic resistance in acute heart failure

Key points
•• Diuretic resistance in acute heart failure is defined either descriptively as the persistence of congestion despite
adequate decongestive treatment, or quantitatively as low natriuresis / urine output / net fluid loss / weight loss /
fractional sodium excretion per diuretic dose administered.
•• Irrespectively of its definition, diuretic resistance in acute heart failure is consistently associated with poor out-
comes and this remains true when adjusting for underlying glomerular filtration rate.
•• Diuretic resistance tracks poorly with changes in glomerular filtration rate during decongestive treatment, but is
more frequent in case of (more severe) underlying chronic kidney disease.

Department of Cardiology, Jessa Ziekenhuis, Belgium Corresponding author:

Frederik H Verbrugge, Department of Cardiology, Jessa Ziekenhuis,
Stadsomvaart 11, Hasselt, 3500, Belgium.
Email: frederik.verbrugge@zol.be
380 European Heart Journal: Acute Cardiovascular Care 7(4)

•• Diuretic resistance has multiple causes in acute heart failure including altered drug pharmacokinetics, impaired renal
perfusion and effective circulatory volume, neurohumoral activation, post-diuretic sodium retention, the braking
phenomenon and functional as well as structural adaptations in the nephron.
•• True diuretic resistance should be discerned from poor diuretic response due to electrolyte depletion or dehydration
•• The treatment approach to diuretic resistance in acute heart failure is focused ideally on the underlying mechanis-
tic cause implied.

Keywords
Cardio-renal syndrome, diuretics, heart failure, sodium

Date received: ; accepted:

Introduction congestion is associated with worse outcomes after AHF.

Signs and symptoms of volume overload are the predomi-
nant reason for hospital admission in acute heart failure
(AHF).1 Loop diuretics are nearly ubiquitously prescribed
for this indication and are the only applied therapy in a
majority of cases.2 Response to loop diuretic therapy
may be assessed in many ways, either qualitatively (i.e. dis-
appearance of clinical congestion signs or normalisation of
cardiac filling pressures) or quantitatively (i.e. natriuresis,
urine output, net fluid loss or weight loss). Emerging evi-
dence indicates that response to decongestive treatment in
general and loop diuretics in particular may be an inde-
pendent prognostic factor in AHF.3 The frequently encoun-
tered clinical problem of diuretic resistance in AHF
therefore merits attention, especially because an evidence-
based approach is lacking and different treatment strategies
have failed to demonstrate meaningful benefits in ran-
domised clinical trials.4–6 This review aims to discuss the
concept of diuretic resistance in AHF, with its different
definitions and underlying mechanisms, to provide a better
pathophysiological insight and suggest an integrated treat-
ment approach.
The goal of decongestion in AHF
Over the past few decades, immense progress has been
made in the pharmacological and device treatment of
chronic heart failure with reduced ejection fraction. Indeed,
there has been a dramatic reduction in all-cause mortality,
from approximately 40% to 20% within 2 years after pres-
entation.7 Unfortunately, this progress stands in stark con-
trast to the lack of advancements made in AHF, in which
large randomised clinical trials have repeatedly failed to
show a reduction in either mortality or hospital readmis-
sions despite various different treatment strategies.4–6,8–10
Because there is little high-quality evidence to guide man-
agement decisions in AHF, treatment often remains empiri-
cal and according to local practice. One very consistent
finding however – both from real-world observational data
and post hoc analysis of clinical trials – is that persistent
Indeed, even when coming at the cost of worsening renal
function, better decongestion is associated with improved
hospital-free survival.11 A reasonable treatment goal in
AHF is thus to pursue complete decongestion while trying
to avoid iatrogenic harm, in particular with respect to the
kidneys. As intravenous loop diuretics are prescribed in the
overwhelming majority of patients to achieve this goal, it
makes sense to search for and validate metrics of their
efficacy.3
Loop diuretic efficacy: prognostic
marker or causal factor in AHF?
Working mechanism of loop diuretics
Loop diuretics inhibit the sodium–potassium–chloride
cotransporter (NKCC2) at the luminal side of the renal
tubules in the thick ascending limb of Henle’s loop, which
accounts for approximately 25% of the total renal sodium
reabsorption.12 The primary pharmacodynamic effect of
loop diuretics is therefore induction of natriuresis, chloru-
resis and kaliuresis. Yet, because they also impair the uri-
nary concentration capacity of the kidneys dependent on
the NKCC2, loop diuretics stimulate water loss as well as
producing hypo to isotonic urine.13
Loop diuretic efficacy
A very accurate metric for loop diuretic efficacy would be
the sodium content of tubular fluid that exits Henle’s loop.
To adjust for pharmacokinetics, one might subsequently
correct for loop diuretic plasma levels. Of course, tubular
fluid sampling is not achievable in patients with AHF and
systemic assessment of loop diuretic plasma levels would
be cumbersome. Therefore, alternative metrics have been
proposed to assess loop diuretic efficacy in a more practical
way. Although each has its strengths and limitations (Table
1), findings have been very consistent in demonstrating that
poor loop diuretic efficacy – hence diuretic resistance – is
associated with detrimental clinical outcomes (Table 2).
Verbrugge 381

Table 1.  Strengths and weaknesses of different loop diuretic efficacy metrics.

Metric Measurement error Convenience Plausibility

Natriuresis ++++/++a + +++
Urine output ++++/+a ++ ++
Net fluid loss – + ++
Weight loss ++ +++ +
Fractional sodium excretion ++++ + +++
Urinary sodium/furosemide concentration ++++ – ++++
aWith/without bladder catheter.

Table 2.  Loop diuretic efficacy metrics and outcome.

Metric References Outcome with diuretic resistance

Natriuresisa Verbrugge et al. (2015)24
Urine outputa Aronson et al. (2015)29
  Ter Maaten et al. (2015)28
Net fluid lossa Testani et al. (2014)14
  Aronson et al. (2015)29
Weight lossa Valente et al. (2014)26
  Voors et al. (2014)27
  Ter Maaten et al. (2015)28
  Ter Maaten et al (2016)68
  Aoki et al. (2017)69
Fractional sodium excretion Kumar et al. (2015)70
Urinary sodium/furosemide concentration Singh et al. (2014)23
  Doering et al. (2017)71
aPer 40 mg intravenous furosemide or equivalent dose.
Higher all-cause mortality
Higher all-cause mortality
Increased death or heart failure readmission
Higher all-cause mortality
Higher all-cause mortality
Higher all-cause mortality
Increased death or readmission due to
heart/kidney failure
Increased death or heart failure readmission
Increased early readmission
Increased death or heart failure readmission
Higher all-cause mortality
Increased death/heart transplantation or
heart failure readmission
Lower readmissions

Loop diuretic efficacy and prognosis in AHF
The exact mechanistic underpinning of the robust associa-
tion between loop diuretic efficacy and prognosis in AHF is
less obvious than at first sight. A logical explanation might
be that AHF patients who present with loop diuretic resist-
ance have a lower chance of achieving appropriate decon-
gestion. Yet, similar congestion signs were reported in
some cohorts at discharge in patients with versus without
diuretic resistance and still there was a difference in out-
comes.14 Alternatively, loop diuretic efficacy might be
interpreted as a renal stress test, indicating the reserve func-
tion of the kidneys to excrete sodium and water in analogy
to the maximal aerobic capacity being reflective of the car-
diac reserve during exercise. Finally, poor diuretic response
might also indicate that volume overload is not present and
sodium levels are possibly depleted.15,16 In the latter sce-
nario, diuretic therapy is unlikely to target the underlying
pathophysiological culprit of AHF and may be harmful
instead. Although diuretic resistance is clearly a risk marker
in AHF, it remains an open question whether interventions
that increase loop diuretic efficacy also lead to improved
outcomes in AHF. This would make it a causal factor and
hence an attractive end-point in future clinical trials. The
answer to this question may also depend on the metric
being used to define loop diuretic efficacy.
Strengths and weaknesses of loop
diuretic efficacy metrics
Measurement error
An important issue with all metrics of loop diuretic efficacy
is measurement error. Urine output is prone to substantial
collection error in the absence of a bladder catheter, and
even a simple measurement of weight can be hard to repro-
duce when patients are frail and unable to stand alone. Net
fluid balance is the most susceptible to measurement error
as both fluid intake and output must be assessed simultane-
ously. Indeed, even in rigorously collected data from large
randomised clinical trials, the correlation between metrics
such as weight loss and net fluid balance is very poor.17
Convenience/complexity
Some metrics of loop diuretic efficacy require more effort
to measure (i.e. net fluid balance) or need laboratory analy-
ses and/or calculations (i.e. natriuresis, fractional sodium
382 European Heart Journal: Acute Cardiovascular Care 7(4)

excretion, urinary sodium/furosemide ratio). In addition,

although urinary indices may contain interesting informa-
tion, their interpretation is not straightforward during diu-
retic therapy and requires more study, specifically in the
context of AHF.15

Biological plausibility
An important limitation of urine output, weight loss and net
fluid balance is that these metrics do not distinguish
between dehydration and decongestion, the latter being the
removal of water and sodium. This distinction is relevant to
make as arginine vasopressin antagonists (i.e. vaptans) that Figure 1.  Loop diuretic pharmacokinetics.
induce pure water excretion without impact on natriuresis
relieve clinical congestion signs but have no impact on
long-term outcomes after AHF.18 It is important to recog-
nise that most AHF patients actually have normal to high
serum osmolality, reflecting total body water in proportion
to solute content.19,20 As extracellular volume is governed
by sodium and not water homeostasis, natriuresis and frac-
tional sodium excretion may better capture long-term
effects of loop diuretic therapy on volume status.12

Glomerular filtration rate versus loop

diuretic efficacy
Estimates of glomerular filtration rate (GFR) are widely
used to assess renal function. GFR reflects the clearance
function of the kidneys and therefore indicates well how
toxic waste products are removed from the blood. In con-
trast, sodium and volume homeostasis is predominantly
influenced by renal tubular function.12 During decongestive
treatment in AHF, only a modest correlation between wors-
ening GFR and biomarkers of tubular injury has been
found.21,22 This explains why loop diuretic efficacy tracks
poorly with incident worsening renal function during
decongestion and predicts outcomes in AHF irrespective of
underlying GFR.14,23–25 That said, the frequency of diuretic
resistance is clearly much higher with lower baseline GFR,
when more advanced underlying chronic kidney disease is
present.14,26–29 In conclusion, while GFR is an excellent
marker for chronic kidney disease and hence a good risk
marker for chronic heart failure when assessed in stable
conditions, loop diuretic resistance performs better for
prognostic stratification in AHF.14,30
Causes of loop diuretic resistance
Altered drug pharmacokinetics
Oral bioavailability.  To exert their effects on the NKCC2 at
the luminal side of the renal tubules, orally administered
loop diuretics must first be absorbed from the gastrointesti-
nal tract. Different pharmacological agents have shown sub-
stantial differences in oral bioavailability. While torasemide
and bumetanide are almost completely absorbed (80-100%),
Figure 2.  Loop diuretic dose–response curve.
furosemide demonstrates a highly variable oral bioavailabil-
ity (10-100%), especially when intake is combined with
food.31 Food intake reduces the maximal plasma concentra-
tion of all loop diuretics by approximately 50%, but pro-
longs the time of their presence in the blood (Figure 1). As
loop diuretic plasma levels need to exceed a critical thresh-
old to induce natriuresis, food intake increases the risk of
diuretic resistance, but in the case of diuretic efficacy effects
are prolonged. In addition, in AHF with marked volume
overload, especially when right heart failure is present, loop
diuretic absorption may be impaired because of gut oedema
and poor intestinal perfusion.32,33
Protein binding and tubular secretion of loop diuretics. Once
absorbed, loop diuretics are more than 90% bound to plasma
proteins. Therefore, the primary entrance of loop diuretics
into the renal tubules is not through glomerular filtration,
but rather through secretion by organic anion transporters
and the multidrug resistance-associated protein 4 in the
proximal tubules.34 Uraemic anions compete with loop
diuretic agents for proximal secretion, and the transport of
both is inhibited by metabolic acidosis.35,36 This explains the
shifted dose-response curve of loop diuretics in patients
with chronic kidney disease (Figure 2). In addition, low
Verbrugge 383
Figure 3.  Post-diuretic sodium retention and the braking phenomenon.
plasma protein levels may decrease the amount of protein-
bound loop diuretics offered to peritubular capillaries in the
proximal renal tubules. Hence lower effective tubular con-
centrations of loop diuretics are reached for any given
plasma level. Finally, significant proteinuria, as a result of
glomerular or tubular damage, increases protein binding of
loop diuretics in the renal tubular lumen, preventing their
pharmacological action.37
Impaired renal perfusion and effective
circulatory volume
In AHF, volume overload is often present outside the vascular
compartment (i.e. interstitial oedema, ascites and pleural effu-
sion) or pooled in systemic capacitance veins (mostly in the
splanchnic circulation).33 However, the kidneys are only able
to regulate the effective circulatory volume. In normal circum-
stances, the plasma refill rate is approximately 3–4 mL/kg per
hour, which explains how clinical congestion signs may disap-
pear over time with diuretic therapy. Yet situations may occur
in which renal perfusion is severely compromised and fluid
cannot be recruited. Obviously, in case of low-output heart
failure or cardiogenic shock, diuretic agents are ineffective
and renal perfusion must first be restored. Furthermore, exces-
sive abdominal congestion is associated with increased intra-
abdominal pressure and poor renal perfusion that can be
reversed by ultrafiltration or mechanical removal of ascites.38,39
Finally, evidence is accumulating that chronic sodium over-
load induces structural changes in the glycosaminoglycan con-
tent of the interstitial compartment that may promote oedema
formation and impair the plasma refill rate.40,41
Neurohumoral activation, post-diuretic
sodium retention and the braking
phenomenon
Post-diuretic sodium retention.  Loop diuretics directly stim-
ulate renin release in the afferent arteriole, which is
triggered by inhibited chloride transport via the NKCC2 in
macula densa cells lining the renal tubular lumen at the end
of Henle’s loop.12 Indeed, low chloride concentrations
inside macula densa cells depolarise their cell membrane,
leading to paracrine signalling towards the nearby afferent
arteriole where renin is ready to be released. With the
renin-angiotensin–aldosterone system already potently
activated in heart failure, this further contributes to sodium
avidity in between moments of diuretic administration.
This is especially relevant for furosemide and bumetanide
that have a relatively short half-life (1-3 hours) in compari-
son with torasemide (approximately 6 hours). Post-diuretic
sodium retention implies that when sodium intake is high,
it can match or even exceed the loss achieved with inter-
mittent loop diuretic administration (Figure 3).42 Interest-
ingly, although plasma renin activity increases acutely
with appropriate decongestion, such a rise does not seem
to translate into worse outcomes.43 In contrast, neurohu-
moral activation accompanied by poor diuretic efficacy or
persistent volume overload – hence diuretic resistance –
clearly does.24,43
The braking phenomenon.  It is well known that with repeated
administration of the same dose of loop diuretics, natriuresis
decreases over time (Figure 3). This may indicate decreasing
extracellular volume overload and removal of excess sodium
with appropriate decongestion.15 However, neurohumoral
activation of the sympathetic nerve and renin–angiotensin–
aldosterone system as well as structural and functional adap-
tations in the nephron may lead to an excessive braking
phenomenon despite persistent volume overload.
Structural and functional nephron
adaptations causing diuretic resistance
Distal nephron hypertrophy. Loop diuretics increase the
sodium and chloride load delivered to the distal nephron.
Over time, this exposure causes intrinsic renal adaptations
384 European Heart Journal: Acute Cardiovascular Care 7(4)
Figure 4.  Integrated management approach to treat volume overload and loop diuretic resistance in acute heart failure.
that impair natriuretic efficacy (i.e. distal tubular hypertro-
phy and increased local aldosterone secretion) and are
mediated by the thiazide-sensitive sodium-chloride sym-
porter and sodium-independent chloride/iodide transporter
or pendrin.44,45
Increased proximal tubular sodium reabsorption. For loop
diuretics to be effective, enough substrate must be available
to the NKCC2. In other words, enough sodium, potassium
and chloride should pass through the tubular lumen at the
level of the thick ascending limb of Henle’s loop. As
explained above, adequate renal perfusion is a prerequisite
to produce ultrafiltrate passing through the renal tubular
lumen and maintain a normal GFR. Importantly, renal auto-
regulation mechanisms aim to preserve GFR initially, even
when renal blood flow is already substantially depressed.12
This can be explained by a higher fraction of plasma being
filtered through the renal glomeruli when renal blood flow
is lower. The result is thicker blood with a higher oncotic
pressure entering the peritubular capillaries through the
efferent arteriole. In turn, this stimulates isotonic reabsorp-
tion in the proximal renal tubules and may lead to substan-
tially increased proximal tubular sodium reabsorption.12
The consequence is that less sodium (and chloride) is
offered to the more distal nephron and Henle’s loop, impair-
ing loop diuretic efficacy.12
Management approach to (loop) diuretic
resistance in AHF
As the mechanisms of loop diuretic resistance in AHF are
multifactorial, we propose an integrated management
approach (Figure 4). It should be emphasised though,
because of the lack of high-quality evidence from ran-
domised clinical trials, such recommendations rely heavily
on pathophysiological insights and observational data.
Verbrugge 385
Is volume overload the target culprit? When considering
(loop) diuretic therapy in AHF, one should never forget the
primary aim of this therapy, which is creating a net nega-
tive sodium balance to reduce extracellular volume and
hence relief signs and symptoms of congestion. Yet, in
some presentations of AHF, volume overload may not be
the target culprit. For example, cardiogenic shock due to
an acute coronary syndrome or fulminant myocarditis may
even require carefully administered fluids with the pur-
pose of haemodynamic stabilisation, despite the presence
of significant pulmonary oedema. Furthermore, flash pul-
monary oedema due to a hypertensive crisis or severe
mitral valve regurgitation is caused by volume misdistri-
bution rather than volume overload per se and might be
addressed better with vasodilator therapy or valve inter-
vention, respectively.46 In other phenotypes such as pri-
mary right heart failure or constrictive pericarditis, some
degree of volume overload may be necessary to maintain
adequate preload and is not the primary target of therapy.
Main indicators of volume overload are limb oedema, asci-
tes, pleural effusion, or significant weight gain over a
short-term period. In contrast, jugular venous distension,
orthopnoea, bendopnoea and pulmonary oedema are less
specific as they reflect increased cardiac filling pressures,
but not necessarily volume overload.
Are the kidneys adequately perfused?  If volume overload is
present and deemed to be the target culprit in AHF, there is
a clear indication for diuretic therapy. However, for diuretic
therapy to be successful, renal perfusion must be adequate.
Renal blood flow depends on mean arterial pressure, cen-
tral venous pressure and intrarenal vascular resistance.
Arterial hypotension during decongestive therapy is
strongly associated with worsening renal function and
should be avoided when possible.47 Furthermore, lowering
central venous pressure through administration of vasodila-
tor therapy may lower the need for diuretics in AHF.48 Spe-
cifically in the case of low cardiac output with normal or
elevated arterial blood pressure (i.e. high systemic vascular
resistance), intravenous sodium nitroprusside improves
organ perfusion and hence renal blood flow.49 Significant
ascites in the setting of AHF is usually associated with
increased intra-abdominal pressure, which impairs renal
perfusion and may be alleviated by paracentesis.39 Finally,
when arterial blood pressure is low due to cardiogenic
shock, inotropes and/or mechanical assist devices should
be considered.
Consider loop diuretic pharmacokinetics. When a patient is
admitted to the hospital with marked volume overload, intra-
venous administration of loop diuretics may be preferred
over oral intake to overcome concerns about gastrointestinal
reabsorption and oral bioavailability. There is no difference
between bolus versus continuous administration with respect
to successful decongestion, but the latter is associated with
more pronounced neurohumoral activation.9,50,51 The benefit
of the continuous administration of loop diuretics is that
post-diuretic sodium retention does not occur, yet this can
also easily be overcome by repeating loop diuretic bolus
administration at 6-8 hour intervals if the patient is still vol-
ume overloaded. In addition, it is easy to adjust the pace of
decongestion with bolus therapy when the plasma refill rate
is impaired. Finally, it is crucially important to adjust the
dose of loop diuretics according to the GFR and plasma pro-
tein levels (Figure 2).
Assess loop diuretic efficacy to recognise loop diuretic resistance
early.  When administering loop diuretics, it is important to
assess the response to therapy and recognise diuretic resis-
tance early to intervene. In most patients, urine output and
weight loss suffice to evaluate loop diuretic efficacy. How-
ever, in patients with or at high risk of cardiorenal syn-
drome, following natriuresis may offer a better perspective
on decongestion success.15 The goal of diuretic treatment
should be to continue until clinical signs and symptoms of
volume overload have completely disappeared and cardiac
filling pressures have normalised.
Continuously assess the effective circulatory volume. When
clinical signs and symptoms of volume overload persist
despite rapidly decreasing loop diuretic efficacy, one should
consider that the effective circulatory volume is decreased.
This might be further supported by deteriorating GFR or
very low cardiac filling pressures. A simple treatment
response might be just to slow down the pace of diuretic
administration and allow more time for plasma refilling.
Sometimes there might be fluid entrapment in third space
compartments which can be tapped (e.g. ascites or pleural
effusion). Alternatively, the plasma refill rate may be
severely compromised because of low plasma oncotic pres-
sure, vascular leak, or alterations in the interstitial matrix.40,41
Compression stockings should be considered in such cases.
Intravenous albumin administration just before diuretic
therapy is effective to recruit peripheral oedema, especially
when plasma levels are low, but is expensive and has not
been shown to improve outcomes in AHF.
Optimise chronic heart failure therapy in the case of reduced
ejection fraction. Although pharmacological therapies in
AHF have not been demonstrated to reduce all-cause mor-
tality or heart failure readmissions in the long term, a hos-
pital admission should always be considered as an
opportunity to improve chronic heart failure therapy.52 The
neurohumoral system is both an important treatment target
in heart failure with reduced ejection fraction and mecha-
nistically implied in the occurrence of (loop) diuretic
resistance. Indeed, it has been well established that renin-
angiotensin-aldosterone system blockers decrease the
need for diuretics in congestive heart failure, especially in
the long term.53,54
386 European Heart Journal: Acute Cardiovascular Care 7(4)
Thiazide-type diuretics.  Thiazide-type diuretics are the most
frequently considered therapy in the case of loop diuretic
resistance in AHF. They are effective mainly when the
cause of diuretic resistance is distal tubular hypertrophy
because of prolonged exposure to loop diuretics.44 Alter-
natively, adding a thiazide-type diuretic up front is useful
in the case of a low GFR to boost the fractional sodium
excretion and ensure adequate natriuresis.55 A drawback of
thiazide-type diuretics is that they limit free water excre-
tion or the urinary dilution capacity of the kidneys and
therefore they should be avoided in hypotonic hyponatre-
mia.56 Most clinical evidence to support the use of thia-
zide-type together with loop diuretics in AHF comes from
small observational studies. Those indicate a probable
class effect and a 75-90% response rate in patients with
loop diuretic resistence.57 In addition, some intriguing data
from the stepwise pharmacological care arm in the Cardio-
renal Rescue Study in Acute Decompensated Heart Failure
(CARRESS-HF) suggest that the combination of a diuretic
efficacy-guided approach with step-up of thiazide-based
therapy provides effective diuresis without compromising
GFR, even when directly compared to an aggressive ultra-
filtration approach.58
Acetazolamide.  Acetazolamide is an old and largely forgot-
ten diuretic, which is still in use for the treatment of moun-
tain disease and obstructive sleep apnoea syndrome. As a
carbonic anhydrase inhibitor, it blocks sodium bicarbonate
reabsorption in the proximal tubules.12 Consequently, it
improves sodium delivery to the NKCC2 hence boosting
loop diuretic efficacy. One observational study in patients
with AHF and marked volume overload found that the
addition of acetazolamide improved loop diuretic efficacy
with approximately 100 mmol sodium excreted per 40 mg
of furosemide-equivalent dose.24 Furthermore, acetazol-
amide also improves thiazide-type diuretic efficacy, as it
potently downregulates pendrin expression in the distal
nephron.59 Pendrin, also known as the sodium-independent
chloride/iodide transporter, compensates for sodium and
chloride loss in the distal convoluted tubules and might be
an unrecognised source of diuretic resistance.45,60 While the
diuretic and natriuretic capacity of acetazolamide is poor
on its own, it might well be a very efficient booster of
diuretic efficacy in combination diuretic therapy.59,61 This
concept is further supported by one small randomised trial
including 24 patients with volume overload refractory to
loop diuretic therapy.62 All these patients demonstrated a
greatly reduced fractional sodium excretion, which was
easily overcome by the addition of acetazolamide. At the
moment, there are insufficient data to recommend add-on
or even up-front therapy with acetazolamide in addition to
loop diuretics. Intriguingly, however, sodium-glucose
transporter 2 inhibitors that also block sodium transport in
the proximal renal tubules greatly increase loop diuretic
efficacy and are among the most promising drugs under
investigation in chronic heart failure.63
Ultrafiltration.  As loop diuretic therapy results in the pro-
duction of hypotonic urine, while ultrafiltration removes
isotonic plasma and hence more sodium for the same
amount of water, it has been hypothesised that the latter
might be a superior decongestion strategy.64 Indeed, in the
Ultrafiltration versus Intravenous Diuretics for Patients
Hospitalized for Acute Decompensated Heart Failure
(UNLOAD) study, which included 200 patients with AHF
and clear signs of volume overload, ultrafiltration outper-
formed loop diuretics, producing greater weight and fluid
loss.65 Moreover, the 90-day readmission rate was also sig-
nificantly lower in the ultrafiltration compared to loop
diuretic group, presumably due to more effective deconges-
tion.65 These findings are somewhat in contradiction to the
results of the much larger CARRESS-HF study(n=2033),
which found no better decongestion – and hence no better
clinical outcome – with ultrafiltration compared to pharma-
cological care with strong emphasis on combinational treat-
ment.4 Moreover, catheter-related adverse events and
bleeding complications were more frequent in the ultrafil-
tration group. In addition, GFR improved significantly
more with pharmacological care after 60 days.4 In light of
these results, we would recommend optimising pharmaco-
logical therapy first, with ultrafiltration reserved as bail-
out in cases of refractory congestion. Nevertheless, it
should be noted that such patients generally have a very
poor prognosis.66 One important point of criticism to CAR-
RESS-HF might be, however, that the pharmacological
care arm allowed decongestive treatment to be titrated very
carefully on an individual base, according to diuretic effi-
cacy. In contrast, the ultrafiltration rate was pre-set at a
constant rate of 200 mL per hour, which was only changed
for technical reasons or clinical requirements, as assessed
by the treating physician. This has potentially put patients
in the ultrafiltration arm at greater risk of intravascular vol-
ume depletion and hypotensive episodes, which might have
been associated with more harmful neurohumoral activa-
tion. The Aquapheresis Versus Intravenous Diuretics and
Hospitalization for Heart Failure (AVOID–HF) trial could
have filled this important gap in the evidence.67 Regretta-
bly, the sponsor of this trial unilaterally decided to termi-
nate the study after only 27% of the intended study
population was recruited, despite the absence of any futility
or safety concerns, rendering the trial severely underpow-
ered. For this reason, results should be interpreted very cau-
tiously, but the estimated days to a first heart failure event
were in favour of the adjustable ultrafiltration group versus
the adjustable loop diuretics group (62 versus 34 days; P
value 0.106). Therefore, individually titrated ultrafiltration
therapy may still have a role to play in the treatment of
cardiorenal syndrome, yet more evidence is needed.
Verbrugge 387
Conclusions
Loop diuretic resistance is a frequently encountered problem
in AHF and portends poor prognosis. It is therefore impor-
tant for the clinician to assess loop diuretic efficacy in AHF
patients, when providing decongestive treatment. Different
metrics for loop diuretic resistance have all been consistently
associated with adverse clinical outcomes. Yet it remains an
open question whether therapies that boost diuretic efficacy
or prevent diuretic resistance improve prognosis in AHF. The
mechanisms of loop diuretic resistance in AHF are multifac-
torial and require an integrated approach.
Conflict of interest
The author declares that there is no conflict of interest.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
References
1. Adams KF Jr, Fonarow GC, Emerman CL, et al.
Characteristics and outcomes of patients hospitalized for
heart failure in the United States: rationale, design, and
preliminary observations from the first 100,000 cases in
the Acute Decompensated Heart Failure National Registry
(ADHERE). Am Heart J 2005; 149: 209–216.
2. Fonarow GC and Corday E. Overview of acutely decom-
pensated congestive heart failure (ADHF): a report from the
ADHERE registry. Heart Fail Rev 2004; 9: 179–185.
3. Verbrugge FH, Mullens W and Tang WH. Management of
cardio-renal syndrome and diuretic resistance. Curr Treat
Options Cardiovasc Med 2016; 18: 11.
4. art BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in
decompensated heart failure with cardiorenal syndrome. N
Engl J Med 2012; 367: 2296–2304.
5. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopa-
mine or low-dose nesiritide in acute heart failure with renal
dysfunction: the ROSE acute heart failure randomized trial.
JAMA 2013; 310: 2533–2543.
6. Packer M, O’Connor C, McMurray JJV, et al. Effect of ula-
ritide on cardiovascular mortality in acute heart failure. N
Engl J Med 2017; 376: 1956–1964.
7. Sacks CA, Jarcho JA and Curfman GD. Paradigm shifts in
heart-failure therapy – a timeline. N Engl J Med 2014; 371:
989–991.
8. Massie BM, O’Connor CM, Metra M, et al.; for the
PROTECT Investigators and Committees. Rolofylline, an
adenosine A1-receptor antagonist, in acute heart failure. N
Engl J Med 2010; 363: 1419–1428.
9. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in
patients with acute decompensated heart failure. N Engl J
Med 2011; 364: 797–805.
10. O’Connor CM, Starling RC, Hernandez AF, et al. Effect of
nesiritide in patients with acute decompensated heart failure.
N Engl J Med 2011; 365: 32–43.
11. Metra M, Davison B, Bettari L, et al. Is worsening renal
function an ominous prognostic sign in patients with acute
heart failure? The role of congestion and its interaction with
renal function. Circ Heart Fail 2012; 5: 54–62.
12. Verbrugge FH, Dupont M, Steels P, et al. The kidney in con-
gestive heart failure: ‘are natriuresis, sodium, and diuretics
really the good, the bad and the ugly?’. Eur J Heart Fail
2014; 16: 133–142.
13. Mullens W, Verbrugge FH, Nijst P, et al. Renal sodium avid-
ity in heart failure: from pathophysiology to treatment strate-
gies. Eur Heart J 2017; 38: 1872–1882.
14. Testani JM, Brisco MA, Turner JM, et al. Loop diuretic effi-
ciency: a metric of diuretic responsiveness with prognostic
importance in acute decompensated heart failure. Circ Heart
Fail 2014; 7: 261–270.
15. Verbrugge FH, Nijst P, Dupont M, et al. Urinary composition
during decongestive treatment in heart failure with reduced
ejection fraction. Circ Heart Fail 2014; 7: 766–772.
16. Verbrugge FH, Grodin JL, Mullens W, et al. Transient
hyponatremia during hospitalization for acute heart failure.
Am J Med 2016; 129: 620–627.
17. Testani JM, Brisco MA, Kociol RD, et al. Substantial dis-
crepancy between fluid and weight loss during acute decom-
pensated heart failure treatment. Am J Med 2015; 128:
776–783 e4.
18. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects
of oral tolvaptan in patients hospitalized for worsening heart
failure: the EVEREST Outcome Trial. JAMA 2007; 297:
1319–1331.
19. Vaduganathan M, Goldsmith SR, Senni M, et al. Contrasting
acute and chronic effects of tolvaptan on serum osmolality in
the EVEREST trial. Eur J Heart Fail 2016; 18: 185–191.
20. Verbrugge FH. Decongestion: more than meets the eye! Eur
J Heart Fail 2016; 18: 192–194.
21. Dupont M, Shrestha K, Singh D, et al. Lack of significant renal
tubular injury despite acute kidney injury in acute decompen-
sated heart failure. Eur J Heart Fail 2012; 14: 597–604.
22. Verbrugge FH, Dupont M, Shao Z, et al. Novel urinary bio-
markers in detecting acute kidney injury, persistent renal
impairment, and all-cause mortality following decongestive
therapy in acute decompensated heart failure. J Card Fail
2013; 19: 621–628.
23. Singh D, Shrestha K, Testani JM, et al. Insufficient natriuretic
response to continuous intravenous furosemide is associated
with poor long-term outcomes in acute decompensated heart
failure. J Card Fail 2014; 20: 392–399.
24. Verbrugge FH, Dupont M, Bertrand PB, et al. Determinants
and impact of the natriuretic response to diuretic therapy in
heart failure with reduced ejection fraction and volume over-
load. Acta Cardiol 2015; 70: 265–273.
25. Ter Maaten JM, Rao VS, Hanberg JS, et al. Renal tubular
resistance is the primary driver for loop diuretic resistance in
acute heart failure. Eur J Heart Fail 2017; 19: 1014–1022.
26. Valente MA, Voors AA, Damman K, et al. Diuretic response
in acute heart failure: clinical characteristics and prognostic
significance. Eur Heart J 2014; 35: 1284–1293.
27. Voors AA, Davison BA, Teerlink JR, et al.; for the RELAX–
AHF Investigators. Diuretic response in patients with acute
decompensated heart failure: characteristics and clinical
388 European Heart Journal: Acute Cardiovascular Care 7(4)
outcome – an analysis from RELAX–AHF. Eur J Heart Fail
2014; 16: 1230–1240.
28. er Maaten JM, Dunning AM, Valente MA, et al. Diuretic
response in acute heart failure – an analysis from ASCEND–
HF. Am Heart J 2015; 170: 313–321.
29. Aronson D and Burger AJ. Diuretic response: clinical and
hemodynamic predictors and relation to clinical outcome. J
Card Fail 2016; 22: 193–200.
30. Damman K, Valente MA, Voors AA, et al. Renal impairment,
worsening renal function, and outcome in patients with heart
failure: an updated meta-analysis. Eur Heart J 2014; 35:
455–469.
31. McCrindle JL, Li Kam Wa TC, et al. Effect of food on the
absorption of frusemide and bumetanide in man. Br J Clin
Pharmacol 1996; 42: 743–746.
32. Vasko MR, Cartwright DB, Knochel JP, et al. Furosemide
absorption altered in decompensated congestive heart fail-
ure. Ann Intern Med 1985; 102: 314–318.
33. Verbrugge FH, Dupont M, Steels P, et al. Abdominal contri-
butions to cardiorenal dysfunction in congestive heart fail-
ure. J Am Coll Cardiol 2013; 62: 485–495.
34. Hasegawa M, Kusuhara H, Adachi M, et al. Multidrug resist-
ance-associated protein 4 is involved in the urinary excretion
of hydrochlorothiazide and furosemide. J Am Soc Nephrol
2007; 18: 37–45.
35. Loon NR and Wilcox CS. Mild metabolic alkalosis impairs
the natriuretic response to bumetanide in normal human sub-
jects. Clin Sci (Lond) 1998; 94: 287–292.
36. Uwai Y, Saito H, Hashimoto Y, et al. Interaction and trans-
port of thiazide diuretics, loop diuretics, and acetazolamide
via rat renal organic anion transporter rOAT1. J Pharmacol
Exp Ther 2000; 295: 261–265.
37. Kirchner KA, Voelker JR and Brater DC. Intratubular albu-
min blunts the response to furosemide – a mechanism for
diuretic resistance in the nephrotic syndrome. J Pharmacol
Exp Ther 1990; 252: 1097–1101.
38. Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-
abdominal pressure in acute decompensated heart failure: a
potential contributor to worsening renal function? J Am Coll
Cardiol 2008; 51: 300–306.
39. Mullens W, Abrahams Z, Francis GS, et al. Prompt reduction
in intra-abdominal pressure following large-volume mechan-
ical fluid removal improves renal insufficiency in refractory
decompensated heart failure. J Card Fail 2008; 14: 508–514.
40. Nijst P, Cops J, Martens P, et al. Endovascular shedding mark-
ers in patients with heart failure with reduced ejection frac-
tion. Microcirculation 2018; 25: doi: 10.1111/micc.12432
41. Nijst P, Verbrugge FH, Grieten L, et al. The pathophysio-
logical role of interstitial sodium in heart failure. J Am Coll
Cardiol 2015; 65: 378–388.
42. Aliti GB, Rabelo ER, Clausell N, et al. Aggressive fluid and
sodium restriction in acute decompensated heart failure:
a randomized clinical trial. JAMA Intern Med 2013; 173:
1058–1064.
43. Nijst P, Verbrugge FH, Martens P, et al. Plasma renin activity
in patients with heart failure and reduced ejection fraction
on optimal medical therapy. J Renin Angiotensin Aldosterone
Syst 2017; 18: 1470320317729919.
44. Kim GH. Long-term adaptation of renal ion transporters to
chronic diuretic treatment. Am J Nephrol 2004; 24: 595–605.
45. Amlal H and Soleimani M. Pendrin as a novel target for diu-
retic therapy. Cell Physiol Biochem 2011; 28: 521–526.
46. Verbrugge FH, Grieten L and Mullens W. New insights into
combinational drug therapy to manage congestion in heart
failure. Curr Heart Fail Rep 2014; 11: 1–9.
47. Dupont M, Mullens W, Finucan M, et al. Determinants of
dynamic changes in serum creatinine in acute decompen-
sated heart failure: the importance of blood pressure reduc-
tion during treatment. Eur J Heart Fail 2013; 15: 433–440.
48. Cotter G, Metzkor E, Kaluski E, et al. Randomised trial of
high-dose isosorbide dinitrate plus low-dose furosemide ver-
sus high-dose furosemide plus low-dose isosorbide dinitrate
in severe pulmonary oedema. Lancet 1998; 351: 389–393.
49. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitro-
prusside for advanced low-output heart failure. J Am Coll
Cardiol 2008; 52: 200–207.
50. Mentz RJ, Stevens SR, DeVore AD, et al. Decongestion strat-
egies and renin-angiotensin-aldosterone system activation in
acute heart failure. JACC Heart Fail 2015; 3: 97–107.
51. Verbrugge FH, Tang WH and Mullens W. Renin–angiotensin–
aldosterone system activation during decongestion in acute
heart failure: friend or foe? JACC Heart Fail 2015; 3: 108–111.
52. Verbrugge FH, Duchenne J, Bertrand PB, et al. Uptitration of
renin–angiotensin system blocker and beta-blocker therapy
in patients hospitalized for heart failure with reduced versus
preserved left ventricular ejection fractions. Am J Cardiol
2013; 112: 1913–1920.
53. van Vliet AA, Donker AJ, Nauta JJ, et al. Spironolactone in
congestive heart failure refractory to high-dose loop diuretic
and low-dose angiotensin-converting enzyme inhibitor. Am J
Cardiol 1993; 71: 21A–28A.
54. Ponikowski P, Voors AA, Anker SD, et al.; and Authors/
Task Force Members. 2016 ESC Guidelines for the diag-
nosis and treatment of acute and chronic heart failure: the
Task Force for the diagnosis and treatment of acute and
chronic heart failure of the European Society of Cardiology
(ESC) developed with the special contribution of the Heart
Failure Association (HFA) of the ESC. Eur Heart J 2016;
37: 2129–2200.
55. Knauf H and Mutschler E. Functional state of the nephron
and diuretic dose-response – rationale for low-dose combina-
tion therapy. Cardiology 1994; 84 (Suppl. 2): 18–26.
56. Verbrugge FH, Steels P, Grieten L, et al. Hyponatremia in
acute decompensated heart failure: depletion versus dilution.
J Am Coll Cardiol 2015; 65: 480–492.
57. Jentzer JC, DeWald TA and Hernandez AF. Combination of
loop diuretics with thiazide-type diuretics in heart failure. J
Am Coll Cardiol 2010; 56: 1527–1534.
58. Grodin JL, Stevens SR, de Las Fuentes L, et al.
Intensification of medication therapy for cardiorenal syn-
drome in acute decompensated heart failure. J Card Fail
2016; 22: 26–32.
59. Zahedi K, Barone S, Xu J, et al. Potentiation of the effect
of thiazide derivatives by carbonic anhydrase inhibitors:
molecular mechanisms and potential clinical implications.
PLoS One 2013; 8: e79327.
60. Soleimani M, Barone S, Xu J, et al. Double knockout of pen-
drin and Na-Cl cotransporter (NCC) causes severe salt wast-
ing, volume depletion, and renal failure. Proc Natl Acad Sci
USA 2012; 109: 13368–13373.
Verbrugge 389
61. Hanley T and Platts MM. Acetazolamide (diamox) in the
treatment of congestive heart failure. Lancet 1956; 270:
357–359.
62. Knauf H and Mutschler E. Sequential nephron block-
ade breaks resistance to diuretics in edematous states. J
Cardiovasc Pharmacol 1997; 29: 367–372.
63. Verbrugge FH, Martens P and Mullens W. SGLT-2 inhibitors
in heart failure: implications for the kidneys. Curr Heart Fail
Rep 2017; 14: 331–337.
64. Ali SS, Olinger CC, Sobotka PA, et al. Loop diuretics can
cause clinical natriuretic failure: a prescription for volume
expansion. Congest Heart Fail 2009; 15: 1–4.
65. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration
versus intravenous diuretics for patients hospitalized for
acute decompensated heart failure. J Am Coll Cardiol 2007;
49: 675–683.
66. Patarroyo M, Wehbe E, Hanna M, et al. Cardiorenal out-
comes after slow continuous ultrafiltration therapy in refrac-
tory patients with advanced decompensated heart failure. J
Am Coll Cardiol 2012; 60: 1906–1912.
67. Costanzo MR, Negoianu D, Fonarow GC, et al. Rationale
and design of the Aquapheresis Versus Intravenous Diuretics
and Hospitalization for Heart Failure (AVOID–HF) trial. Am
Heart J 2015; 170: 471–482.
68. Ter Maaten JM, Valente MA, Damman K, et al. Combining
diuretic response and hemoconcentration to predict rehospi-
talization after admission for acute heart failure. Circ Heart
Fail 2016; 9: pii: e002845.
69. Aoki S, Okumura T, Sawamura A, et al. Usefulness of the
combination of in-hospital poor diuretic response and sys-
temic congestion to predict future cardiac events in patients
with acute decompensated heart failure. Am J Cardiol 2017;
119: 2010–2016.
70. Kumar D and Bagarhatta R. Fractional excretion of
sodium and its association with prognosis of decompen-
sated heart failure patients. J Clin Diagn Res 2015; 9:
OC01–OC03.
71. Doering A, Jenkins CA, Storrow AB, et al. Markers of diu-
retic resistance in emergency department patients with acute
heart failure. Int J Emerg Med 2017; 10: 17.