Curr Treat Options Cardio Med (2016) 18:11

DOI 10.1007/s11936-015-0436-4

Heart Failure (W Tang, Section Editor)

Management of Cardio-Renal
Syndrome and Diuretic
Resistance
Frederik H. Verbrugge, MD, PhD1,*
Wilfried Mullens, MD, PhD1
W.H. Wilson Tang, MD2
Address
*,1
Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600,
Genk, Belgium
Email: frederik.verbrugge@zol.be
2
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland
Clinic, Cleveland Clinic Main Campus J3-4, 9500 Euclid Avenue, Cleveland, OH,
44195, USA

* Springer Science+Business Media New York 2016

This article is part of the Topical Collection on Heart Failure

Keywords Acetazolamide I Cardio-renal syndrome I Cardiotonic agents I Diuresis I Glomerular filtration rate I Heart
failure

Opinion statement
Diuretic resistance in acute heart failure has emerged as a powerful predictor of adverse
outcome, which is often independent of underlying glomerular filtration rate (GFR).
Metrics of diuretic efficacy differ in their accuracy, convenience, and biological plausibil-
ity, which should be taken into account when interpreting their results. Loop diuretic
efficacy depends on adequate delivery of both the pharmacological agent itself and its
substrate (i.e., sodium chloride) to the loop diuretic site of action at the luminal side of
the thick ascending limb of Henle’s loop. This requires an adequate dosing strategy, with
higher doses needed when GFR is low. Importantly, the kidneys are able only to regulate
the effective circulatory volume. Thus, specific problems of intravascular volume depletion
and poor cardiac output with impaired renal perfusion should be addressed. 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 GFR to maximally boost
fractional sodium excretion when nephron perfusion is poor. However, thiazide-type
diuretics limit free water excretion and should be withheld in cases of hypotonic
hyponatremia. Mineralocorticoid receptor antagonists (MRA) and acetazolamide are in-
teresting options to increase loop diuretic efficacy, but further study is needed to assess
whether improved diuretic efficacy also translates into clinical outcome benefits. Finally,
ultrafiltration should be considered in patients with refractory diuretic resistance as
persistent volume overload after decongestive treatment is associated with worse
11 Page 2 of 15 Curr Treat Options Cardio Med (2016) 18:11

outcomes. Whether more upfront use of individually tailored ultrafiltration is superior to

pharmacological therapy remains to be shown by adequately powered randomized clinical
trials.

Introduction
The interplay between the heart and the kidneys in heart
failure has puzzled many clinicians and researchers for
years. Historically, kidney dysfunction in heart failure
has been explained by insufficient cardiac output (i.e.,
forward failure) leading to poor renal perfusion and a
subsequent drop in glomerular filtration rate (GFR),
which is further exacerbated by neurohumoral upregu-
lation. However, contemporary evidence has demon-
strated that systemic venous congestion (i.e., backward
failure) contributes at least equally to impaired GFR in
heart failure [1]. In either way, cardio-renal syndrome is
generally defined as cardiac dysfunction preceding a
drop in GFR, which may occur in acute (type 1) as well
as chronic (type 2) heart failure [2]. On a population
level, both type 1 and type 2 cardio-renal syndrome are
associated with worse outcomes and increased mortality
[3]. Yet, when accompanied by successful treatment of
volume overload, short-time declines in GFR might even
track with better prognosis [4, 5]. A likely explanation is
that although the kidneys play a pivotal role in volume
homeostasis, GFR may represent a poor marker of
their diuretic capacity [6•]. Indeed, diuretic efficacy
in heart failure has recently emerged as a strong
predictor of event-free survival, with this relation-
ship virtually unaltered after correction for under-
lying GFR [7•, 8, 9•, 10, 11, 12•, 13]. These novel
insights have sparked interest in the phenomenon
of diuretic resistance. The aim of this review is to
summarize the underlying pathophysiological
mechanisms of diuretic resistance in heart failure
and cardio-renal syndrome, while offering a practi-
cal treatment approach for the interested clinician.

Diuretic resistance
Definition
Although intuitively clear, the question how to define diuretic resistance is
harder than at first look and no universally accepted definition is readily
available. In fact, the concept is somewhat subjective and does not account for
the underlying biological defect but rather a lack of treatment response. A
number of metrics have been proposed, each with different strengths and
fallacies (Table 1). For this purpose, a parameter reflecting diuretic efficacy is
chosen and assessed per standard dose of diuretics administered. As loop
diuretics continue to comprise the mainstay therapy to treat volume overload in
heart failure, diuretic efficacy has arbitrarily been expressed as weight, net fluid
balance, or urine output per 40 mg of intravenous furosemide-equivalent dose.
Hence, the more appropriate term would be loop diuretic efficacy, as the use of

Table 1. Metrics of diuretic efficacy/resistance

Metrica Convenience Accuracy Plausibility Volume status dependency

Weight loss +++ +++ + +++
Net fluid loss + + ++ +++
Urine output ++ ++ ++ +
Natriuresis + +++ +++ ++
a
Per 40 mg of intravenous furosemide-equivalent dose
Curr Treat Options Cardio Med (2016) 18:11 Page 3 of 15 11

other diuretics is usually not accounted for. Complicating the interpretation of

diuretic efficacy in heart failure is the fact that different metrics may correlate
poorly, indicating either substantial measurement error or differential biologi-
cal plausibility [14]. Moreover, there is no agreement for any metric on what
cut-off represents meaningful diuretic resistance. These lingering questions
hamper the implementation of diuretic efficacy metrics in clinical practice.
Thus, refining the definition of diuretic resistance should be the primary focus
of further research.

Diuretic resistance and clinical outcome in heart failure

A number of recent studies did investigate the relationship between diuretic
efficacy and clinical outcome in patients with heart failure [7•, 8, 9•, 10, 11,
12•, 13, 15]. Despite differences in their study design and metrics used to define
diuretic efficacy, results are remarkably consistent and demonstrate that out-
comes are poor in case of diuretic resistance (Table 2). Most studies found that
patients with diuretic resistance had lower underlying GFR [7•, 8, 10, 11, 12•,
15]. However, the association between diuretic resistance and adverse clinical
outcome remains strong after correction for GFR [7•, 12•]. This implies that
diuretic efficacy and GFR each represent different aspects of kidney function.
Indeed, while GFR tracks well with the clearance function of the kidneys,
volume and electrolyte homeostasis is essentially a task performed by the renal
tubules [6•, 16]. After all, even when GFR is severely depressed at 20 mL/min,
28.8 L of fluid is still filtered through the glomeruli on a daily base, corre-
sponding to ∼4000 mEq of sodium [17]. Currently proposed metrics of diuretic

Table 2. Relationship between diuretic efficacy and clinical outcome in heart failure

Author (year) Metric Findings in patients with low diuretic efficacy

Testani et al. (2014) [7•]
Valente et al. (2014) [8]
Voors et al. (2014) [15]
Singh et al. (2014) [9•]
Aronson et al. (2015) [10]
Ter Maaten et al. (2015) [11]
Verbrugge et al. (2015) [12•]
Kumar et al. (2015) [13]
eGFR estimated glomerular filtration rate
a
Per 40 mg of intravenous furosemide-equivalent dose
Net fluid lossa Higher all-cause mortality (after correction for
diuretic dose, fluid output, and baseline
characteristics)
Weight lossa More heart failure readmissions after 60 days
Increased death, heart failure, or renal related
readmissions after 60 days
Higher all-cause mortality after 180 days
Weight lossa Increased death, heart failure, or renal related
readmissions after 60 days
Neutral effect on all-cause mortality after 180 days
Urinary sodium/furosemide Increased death, transplantation, or heart failure
concentration readmission (after correction for eGFR)
Net fluid lossa Higher all-cause mortality after 6 months
Urine outputa
Weight lossa Increased death or heart failure readmissions
Urine outputa after 30 days
Natriuresisa Increased death or heart failure readmission
(after correction for eGFR)
Fractional sodium excretion Higher all-cause mortality after 30 days
11 Page 4 of 15 Curr Treat Options Cardio Med (2016) 18:11

efficacy indirectly represent the ability of loop diuretics to increase the excreted
fraction of this filtered sodium load. Therefore, diuretic efficacy metrics com-
pared to GFR estimates may better predict the ability of the kidneys to suc-
cessfully achieve euvolemia [7•, 9•, 12•, 18]. As residual volume overload after
decongestive treatment remains the major driver of early readmissions and
adverse clinical outcome in heart failure, the consistent and strong correlation
with diuretic resistance can be explained [19].

Determinants of loop diuretic efficacy

Pharmacokinetics
Loop diuretics act in the thick ascending limb of Henle’s loop, where
they inhibit the sodium-potassium-chloride cotransporter (NKCC2) at
the luminal side of tubular cells lining this segment of the nephron
[6•]. In order to reach this site of action, orally administered loop
diuretics must first be absorbed from the gastro-intestinal tract. Different
pharmacological agents have shown substantial differences in oral bio-
availability. While torsemide and bumetanide are almost completely
absorbed (80-100 %), furosemide demonstrates a highly variable oral
bioavailability (10-100 %), especially when its intake is combined with
food [20–22]. Food intake reduces the maximal plasma concentration of
all loop diuretics with ∼50 % but prolongs the time of their presence in
the blood, which has important implications to efficacy [23]. Impor-
tantly, loop diuretic absorption may be impaired in decompensated
heart failure, which is explained by gut edema and poor intestinal
perfusion [24–26].
Once absorbed, loop diuretics are 990 % bound to plasma proteins.
Therefore, only a small fraction is filtered through the glomerulus.
Consequently, secretion by organic anion transporters in the proximal
tubules constitutes the main source of pharmacologically active mole-
cules reaching their site of action at the luminal side of the renal
tubules [27]. Urate and other organic anions compete with loop diuretic
agents for proximal secretion, and the transport of both is inhibited by
metabolic acidosis [28, 29]. This explains the shifted dose-response
curve of loop diuretics in patients with chronic kidney disease in whom
both organic anion waste products and acidosis are often present. In
addition, poor renal perfusion as well as low plasma protein levels may
further decrease the amount of protein-bound loop diuretics offered to
the peritubular capillaries of the proximal tubules for secretion, espe-
cially in heart failure. Hence, lower effective tubular concentrations of
loop diuretics are reached for any given plasma level. Finally, significant
proteinuria, because of glomerular or tubular damage, increases protein
binding of loop diuretics in the tubular lumen, preventing their phar-
macological action [30].

Substrate delivery
Apart from adequate delivery of loop diuretics to their site of action in the thick
ascending limb of Henle’s loop, another prerequisite for diuretic efficacy is that
enough substrate is available to the NKCC2. In other words, enough sodium,
Curr Treat Options Cardio Med (2016) 18:11 Page 5 of 15 11

potassium, and chloride should pass through the tubular lumen at this segment
of the nephron. As explained above, low GFR is not the only contributor to
impaired substrate delivery, as even patients with advanced chronic kidney
disease continue to filter substantial amounts of sodium and fluid. In normal
circumstances, ∼25 % of this filtered sodium load is reabsorbed by the thick
ascending limb of Henle’s loop. Yet, proximal tubular sodium reabsorption in
heart failure may be substantially increased because of poor renal perfusion and
increased neurohumoral activation. This may result in less sodium (and chlo-
ride) offered to the distal nephron, causing diuretic resistance [6•].

Pharmacodynamics
The direct pharmacodynamic effect of loop diuretics, when delivered to their
site of action with adequate substrate delivery, is natriuresis as well as
chloruresis and kaliuresis. As furosemide is excreted into urine unchanged, the
most accurate metric reflecting loop diuretic pharmacodynamics would be the
ratio of sodium over furosemide concentration in tubular fluid sampled from
the end of the thick ascending limb of Henle’s loop. Obviously, such sample is
not obtainable in clinical practice, yet the ratio can also be measured in urine
[9•]. As urinary furosemide excretion is taken into account, the urinary sodium/
furosemide ratio is independent of loop diuretic pharmacokinetics, yet still
influenced by substrate delivery and tubular sodium reabsorption more distal-
ly, namely, in the distal convoluted tubules and collecting ducts. The latter is
important as increased delivery of sodium to the distal nephron rapidly results
in hypertrophy of these segments, increasing reabsorption capacity and
preventing sodium loss [31].

Diuretic resistance versus volume depletion

From a cardiac standpoint, diuretics unload the heart by creating a net
negative sodium balance, which reduces extracellular volume. However,
this only applies when intravascular volume overload is effectively pres-
ent. It is important to realize that cardiac filling pressures, although
directly related to ventricular wall stress, are poor surrogates for volume
overload [32]. Confusingly, measurements reflecting pressure and vol-
ume overload in heart failure are often used interchangeably, yet they
may not be consistent. It has been shown that cardiac filling pressures
in heart failure often rise without meaningful increase in body weight,
arguing against volume overload as the cause [26, 33, 34]. When vol-
ume overload is not present, reducing extracellular volume with diuretics
is ineffective to unload the heart and may exacerbate neurohumoral
activation [6•, 16]. This has important implications for the interpreta-
tion of diuretic resistance, as the latter term should be reserved only for
the situation whereby intravascular volume is expanded. To complicate
matters, the concept of intravascular volume may also differ between
systemic and local (renal) perfusion, and currently there are limited
techniques to quantify or distinguish them. As clinical signs and symp-
toms lack sensitivity to detect subtle intravascular fluid overload, urinary
indices might help to evaluate the transition from volume overload to
depletion [9•, 35]. Indeed, when approaching euvolemia during
11 Page 6 of 15 Curr Treat Options Cardio Med (2016) 18:11

decongestive treatment with loop diuretics, urinary sodium and chloride

concentrations fall despite initially preserved urine output [35•]. Thus,
in this particular context, high urinary sodium and chloride concentra-
tions imply persistent volume overload with diuretic efficacy, while low
concentrations indicate volume depletion.
On the other hand, volume overload may be present in extravascular
compartments without strongly elevated cardiac filling pressures (i.e.,
peripheral edema, pleural effusion, or ascites). As the kidneys are able
only to regulate effective circulatory volume, such third-space volume
overload may persist despite diuretic treatment, especially when the
plasma refill rate is slow and intravascular volume depletion occurs,
mimicking diuretic resistance. In this situation, diuretic resistance be-
comes dependent on the inadequate perfusion to the kidneys, despite an
overall volume overloaded state (so-called intravascular depletion), and in
part a protective and survival mechanism for the body not to progress
further into dehydration. The exact mechanisms determining body fluid
distribution and the plasma refill rate remain poorly understood, but
interstitial proteoglycans and the endothelial glycocalyx probably play
some contributing role [36].
Management of cardio-renal syndrome
Assessment of volume overload
The first step in the management of a patient with cardio-renal syndrome, as
well as in any patient with acute heart failure, is to determine whether and
where volume overload is present as well as the potential contributors leading
to it. Clinical signs and symptoms such as orthopnea, rales, cardiomegaly, third
heart sound, jugular venous distension, hepatomegaly, and edema are certainly
helpful but may lack sensitivity to detect subtle fluid overload, even when
assessment is performed by experienced clinicians [37]. Body weight increase is
a very accurate parameter for volume overload but requires a good estimation
of dry body weight, which may not always be available and can vary over longer
follow-up time [38]. Biomarkers such as natriuretic peptides may be useful as
well to aid in the detection of subclinical volume overload, yet one should
realize that they track better with ventricular wall stress and hence cardiac filling
pressures when compared to volume overload per se [39]. Bioelectrical im-
pedance analysis is emerging as a tool to quantify total and extracellular body
water but relies on complex mathematical algorithms that are difficult to
interpret and have been insufficiently validated in patients with heart failure
[40–42]. Thus, in many perspectives, assessment of volume overload remains
an art of medicine and when in doubt the pragmatic option is often to try and
diurese the patient with a testing dose of diuretics.

Achieve a euvolemic state

As residual volume overload after treatment for acute heart failure is a major
predictor of adverse outcomes, it is recommended to try and achieve strict
euvolemia in every patient, even when a decrease in GFR is observed [4, 5].
However, at the same time, intravascular volume depletion should be avoided
and may be a reason for de-escalating diuretic therapy and slow down the pace
Curr Treat Options Cardio Med (2016) 18:11 Page 7 of 15 11

of decongestive treatment rather than trying to overcome diuretic resis-

tance. When volume overload is mainly extravascular, external com-
pression (in case of peripheral edema) or direct fluid removal (in case
of ascites or pleural effusion) can be considered [43]. Hypotension
should be avoided, as arterial blood pressure represents the major driver
of renal perfusion and it is not only strongly related to GFR but also to
metrics of diuretic efficacy [8, 10, 11, 12•, 15, 44, 45]. Direct measure-
ments of plasma volume may offer a welcome solution for individual
patients in whom intravascular volume is hard to assess [46]. However,
such measurements are expensive and not yet readily available at most
centers, and more knowledge and experience are needed before their use
can be recommended in clinical practice.

Use of loop diuretics

In patients with signs or symptoms of intravascular volume overload, loop
diuretics remain the cornerstone of decongestive treatment [47]. As the use of
loop diuretics in acute heart failure is largely based on empirical evidence, the
optimal dose, administration schedule, and route remains unclear. The Diuretic
Optimization Strategies Evaluation (DOSE) trial showed no overall difference
in diuretic efficacy between bolus versus continuous administration, while the
use of higher doses was associated with a trend towards faster dyspnea relief,
significantly higher net fluid and weight loss, at the cost of an increased
incidence of rising serum creatinine in volume overloaded subjects with acute
heart failure [48]. To overcome impaired gastro-intestinal absorption, it is
common practice to administer loop diuretics intravenously in patients with
marked volume overload [24–26]. In addition, as loop diuretics have a rela-
tively short half-life (1.5-3, 1-2, and 3-6 h for furosemide, bumetanide, and
torsemide, respectively), the use of multiple doses per day may be needed for
obtaining a continuously net negative sodium balance, especially when adher-
ence to salt restriction is poor. Indeed, after their diuretic effects have weaned
off, loop diuretics induce a period of avid salt retention because they directly
stimulate renin release [6•, 49]. Continuous intravenous administration of is an
alternative method to overcome this form of diuretic resistance but may
lead to more pronounced neurohumoral activation [50, 51]. To enable
secretion by the proximal tubules and reach the NKCC2 on the luminal
side of the renal tubules, sufficient plasma concentrations are needed
when GFR is compromised [52]. Therefore, it is recommended to in-
crease the dose of loop diuretics in patients with chronic kidney dis-
eases. While a furosemide-equivalent dose of 40 mg is generally appro-
priate in patients with an estimated GFR 960 mL/min/1.73 m2, higher
doses should be used in patients with a lower GFR.

Approach to loop diuretic resistance

As the reasons for loop diuretic resistance are multifold, it is irrational to assume
that a one-size-fits-all approach would work well. As there is a paucity of data
from high-quality randomized clinical trials, our recommended approach
(Fig. 1) is largely based on insights into heart failure pathophysiology and
pharmacology.
11 Page 8 of 15 Curr Treat Options Cardio Med (2016) 18:11

Fig. 1. Individualized MAP treatment should be considered as autoregulation mechanisms are often disturbed in chronic heart
failure. BUN blood urea nitrogen, eGFR estimated glomerular filtration rate, LVAD left ventricular assist device, MAP mean arterial
blood pressure, MRA mineralocorticoid receptor antagonists, QD once daily.
Curr Treat Options Cardio Med (2016) 18:11 Page 9 of 15 11

Optimize renal perfusion

As the kidneys are able only to regulate the effective circulatory volume,
diuretic resistance may occur when the latter is impaired in case of poor
renal perfusion. As cardiac output in heart failure is rather insensitive to
changes in cardiac preload—because the Frank-Starling mechanism is
depleted—an improvement in organ perfusion may only be obtained
through direct stimulation of contractility with inotropes, reducing
afterload with vasodilators or mechanical support through a left ven-
tricular assist device (LVAD). Indeed, in most patients with advanced,
low-output heart failure and cardio-renal syndrome, renal dysfunction is
often reversible after LVAD implantation, indicating that impaired renal
perfusion is the underlying problem [53–56]. However, as LVAD therapy
remains to be associated with long-term complications such as driveline
infection, bleeding, and thrombosis, it still cannot be considered a
treatment solely for cardio-renal syndrome. Furthermore, because long-
term administration of inotropes is associated with worse survival in
heart failure, afterload reduction probably remains the best option to
increase the effective circulatory volume, yet its use may be limited by
low arterial blood pressure [57, 58].

Thiazide-type diuretics
Thiazide-type diuretics are probably the most frequently considered therapy in
case of loop diuretic resistance. They are effective mainly when the cause of
diuretic resistance is the so-called braking phenomenon. Indeed, with prolonged
exposure to proximally working diuretics, intrinsic renal adaptations that im-
pair diuretic efficacy occur (i.e., distal tubular hypertrophy and increased local
aldosterone secretion), which are largely mediated by the thiazide-sensitive
sodium-chloride symporter [31]. Alternatively, adding a thiazide-type diuretic
is useful in case of a severely impaired GFR because in this scenario the
fractional sodium excretion should be boosted maximally to ensure adequate
natriuresis [59]. However, a drawback of thiazide-type diuretics is that they
limit the capacity of the kidneys to produce diluted urine hence free water
excretion and therefore they should be avoided in hypotonic hyponatremia
[60]. Most clinical evidence to support the use of thiazide-type together with
loop diuretics in acute heart failure comes from small observational studies.
Those studies indicate a probable class effect and 75-90 % response rate in
patients considered loop diuretic resistant [61]. In addition, some intriguing
data from the stepwise pharmacological care arm in the Cardiorenal
Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF)
suggest that 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 ul-
trafiltration approach [62].

Mineralocorticoid receptor antagonists

Despite the fact that mineralocorticoid receptor antagonists (MRA) con-
stitute an integral part of the guideline-recommended pharmacologic
therapy for chronic heart failure, there is a paucity of data regarding
their specific use in acute heart failure. Nevertheless, MRA exhibit mild
11 Page 10 of 15 Curr Treat Options Cardio Med (2016) 18:11

but effective natriuretic effects [63]. Moreover, they minimize potassium

wasting by loop diuretics. Therefore, there might be a strong rationale to
continue oral maintenance dosages of MRA and even increase dosing
when GFR is stable and serum potassium levels are G5.5 mEq/L. There
have been extensive experience in patients with decompensated cirrhosis
for MRA, with starting doses of 100 mg of spironolactone up to four
times daily [64]. The Study of High-Dose Spironolactone versus Placebo
Therapy in Acute Heart Failure (ATHENA-HF, NCT02235077) is cur-
rently testing the hypothesis that high-dose spironolactone will lead to a
greater proportional reduction in natriuretic peptide levels during the
first 96 h of decongestive treatment in patients with acute heart failure
and clear signs of volume overload as suggested by smaller single-center
studies [65].

Acetazolamide
Acetazolamide is an old and largely forgotten diuretic, which is still in
use for the treatment of mountain disease and obstructive sleep apnea
syndrome. As a carbonic anhydrase inhibitor, it blocks sodium bicar-
bonate reabsorption in the proximal tubules [6•]. Consequently, it
improves substrate delivery to the NKCC2 (i.e., sodium as well as
chloride and potassium through solvent drag), hence boosting loop
diuretic efficacy. Moreover, increasing the chloride load offered to the
NKCC2 at the level of macula densa reduces renin release, with poten-
tially favorable effects on neurohumoral activation [51, 66]. One obser-
vational study in patients with acute heart failure and marked volume
overload found that the addition of acetazolamide improved loop di-
uretic efficacy with ∼100 mEq sodium excreted per 40 mg of
furosemide-equivalent dose [12•]. Furthermore, acetazolamide also im-
proves thiazide-type diuretic efficacy, as it potently downregulates
pendrin expression in the distal nephron [67]. Pendrin, also known as
the sodium-independent chloride/iodide transporter, can compensate for
sodium and chloride loss in the distal convoluted tubules and might be
an unrecognized source of diuretic resistance [68, 69]. 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 [67, 70]. This concept is further supported by one small
randomized trial including 24 patients with volume overload refractory
to loop diuretic therapy [71]. All these patients demonstrated a greatly
reduced fractional sodium excretion, which was easily overcome by the
addition of acetazolamide. However, there are currently no data on
benefits of add-on acetazolamide, either with short-term or long-term
use. One small prospective study (NCT01973335) may hopefully pro-
vide further justification.

Ultrafiltration
As loop diuretic therapy results in the production of hypotonic urine,
while ultrafiltration removes isotonic plasma and hence more sodium
for the same amount of water, it has been hypothesized that the latter
might be a superior decongestion strategy [72]. Indeed, in the
Curr Treat Options Cardio Med (2016) 18:11 Page 11 of 15 11

Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for

Acute Decompensated Heart Failure (UNLOAD) study, which included
200 patients with acute heart failure and clear signs of volume overload,
ultrafiltration outperformed loop diuretics, producing greater weight and
fluid loss [73]. Moreover, the 90 days readmission rate was also signif-
icantly lower in the ultrafiltration compared to loop diuretic group,
presumably due to more effective decongestion [73]. These findings are
somewhat in contradiction with the results of the much larger CARRESS-
HF (n = 2033), which found no better decongestion—and hence not
better clinical outcome—with ultrafiltration compared to pharmacologi-
cal care with strong emphasis on combinational treatment [74]. More-
over, catheter-related adverse events and bleeding complications were
more frequent in the ultrafiltration group [74]. In addition, GFR im-
proved significantly more with pharmacological care after 60 days [74].
In the light of these results, we would recommend optimizing pharma-
cological 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 [75]. One important point of critic
to CARRESS-HF might be, however, that the pharmacological care arm
allowed decongestive treatment to be titrated very carefully on an indi-
vidual base, according to diuretic efficacy. In contrast, the ultrafiltration
rate was preset at a constant rate of 200 mL/h, which was only changed
for technical reasons or clinical requirements as assessed by the treating
physician. This potentially has put patients in the ultrafiltration arm at
greater risk for intravascular volume depletion and hypotensive episodes,
which might have been associated with more harmful neurohumoral
activation. The Aquapheresis Versus Intravenous Diuretics and Hospital-
ization for Heart Failure (AVOID-HF) trial could have filled this im-
portant gap of evidence [76•]. Regrettably, the sponsor of this trial
unilaterally decided to terminate 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 underpowered.
Because of this reason, results should be interpreted very cautiously, but
the estimated days to a first heart failure event were in favor of the
adjustable ultrafiltration group versus the adjustable loop diuretics group
(62 versus 34 days; P value = 0.106). Therefore, individually titrated ul-
trafiltration therapy may still have a role in the treatment of cardio-renal
syndrome, yet more evidence is needed.

Conclusions
The clinical challenge of diuretic resistance in acute heart failure requires
a meticulous understanding of causes with consequently a differentiation
of possible strategies, acknowledging the transition from acute manage-
ment to long-term prevention and stabilization. Although it has been
shown consistently that diuretic resistance is associated with worse out-
come in acute heart failure, it remains to be demonstrated that im-
proving diuretic efficacy with dedicated therapies in cardio-renal syn-
drome translates into better clinical outcome and this should be
11 Page 12 of 15 Curr Treat Options Cardio Med (2016) 18:11

explored further in randomized clinical trials. If confirmed, it would

make a strong case for diuretic resistance being an important and
modifiable risk factor rather than an innocent risk marker in patients
with acute heart failure and volume overload.

Compliance with Ethical Standards

Conflict of Interest
Frederik H. Verbrugge and Wilfried Mullens each declare no potential conflicts of interest. W.H. Wilson Tang is a
section editor for Current Treatment Options in Cardiovascular Medicine.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:
• Of importance

1. Dupont M, Mullens W, Tang WH. Impact of systemic
venous congestion in heart failure. Curr Heart Fail Rep.
2011;8:233–41.
2. Ronco C, Haapio M, House AA, et al.
Cardiorenal syndrome. J Am Coll Cardiol.
2008;52:1527–39.
3. Damman K, Valente MA, Voors AA, et al. Renal im-
pairment, worsening renal function, and outcome in
patients with heart failure: an updated meta-analysis.
Eur Heart J. 2014;35:455–69.
4. Testani JM, Chen J, McCauley BD, et al. Potential effects
of aggressive decongestion during the treatment of
decompensated heart failure on renal function and
survival. Circulation. 2010;122:265–72.
5. 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 inter-
action with renal function. Circ Heart Fail. 2012;5:54–62.
6.• Verbrugge FH, Dupont M, Steels P, et al. The kidney in
congestive heart failure: ‘Are natriuresis, sodium, and
diuretics really the good, the bad and the ugly?’. Eur J
Heart Fail. 2014;16:133–42.
This review gives a comprehensive overview of the mechanisms
of renal sodium handling in heart failure, providing the back-
ground that is needed to mechanistically understand the mul-
tiple causes of diuretic resistance.
7.• Testani JM, Brisco MA, Turner JM, et al. Loop diuretic
efficiency: a metric of diuretic responsiveness with
prognostic importance in acute decompensated heart
failure. Circ Heart Fail. 2014;7:261–70.
Important paper showing the relationship between loop di-
uretic efficacy and good clinical outcome, independently from
underlying glomerular filtration rate.
8. Valente MA, Voors AA, Damman K, et al. Diuretic re-
sponse in acute heart failure: clinical characteristics and
prognostic significance. Eur Heart J. 2014;35:1284–93.
9.• Singh D, Shrestha K, Testani JM, et al. Insufficient
natriuretic response to continuous intravenous furose-
mide is associated with poor long-term outcomes in
acute decompensated heart failure. J Card Fail.
2014;20:392–9.
Observational study suggesting that substrate delivery and
loop diuretic pharmacokinetics are the predominant reason for
diuretic resistance in advanced heart failure.
10. Aronson D, Burger AJ. Diuretic response: clinical and he-
modynamic predictors and relation to clinical outcome. J
Card Fail. 2015. doi:10.1016/j.cardfail.2015.07.006.
11. Ter Maaten JM, Dunning AM, Valente MA, et al. Di-
uretic response in acute heart failure-an analysis from
ASCEND-HF. Am Heart J. 2015;170:313–21. e4.
12.• Verbrugge FH, Dupont M, Bertrand PB, et al. Determi-
nants and impact of the natriuretic response to diuretic
therapy in heart failure with reduced ejection fraction
and volume overload. Acta Cardiol. 2015;70:265–73.
Small observational study showing the potential of acetazol-
amide to increase loop diuretic efficacy.
13. Kumar D, Bagarhatta R. Fractional excretion of sodium
and its association with prognosis of decompensated
heart failure patients. J Clin Diagn Res. 2015;9:OC01–3.
14. Testani JM, Brisco MA, Kociol RD, et al. Substantial
discrepancy between fluid and weight loss during acute
Curr Treat Options Cardio Med (2016) 18:11
decompensated heart failure treatment. Am J Med.
2015;128:776–83. e4.
15. Voors AA, Davison BA, Teerlink JR, et al. Diuretic re-
sponse in patients with acute decompensated heart
failure: characteristics and clinical outcome–an analysis
from RELAX-AHF. Eur J Heart Fail. 2014;16:1230–40.
16. Verbrugge FH, Grieten L, Mullens W. Management of
the cardiorenal syndrome in decompensated heart
failure. Cardiorenal Med. 2014;4:176–88.
17. Palmer LG, Schnermann J. Integrated control of Na
transport along the nephron. Clin J Am Soc Nephrol.
2015;10:676–87.
18. Verbrugge FH, Nijst P, Dupont M, et al. Prognostic
value of glomerular filtration changes versus natriuretic
response in decompensated heart failure with reduced
ejection. J Card Fail. 2014;20:817–24.
19. Gheorghiade M, Shin DD, Thomas TO, et al. Conges-
tion is an important diagnostic and therapeutic target
in heart failure. Rev Cardiovasc Med. 2006;7 Suppl
1:S12–24.
20. Beermann B, Midskov C. Reduced bioavailability and
effect of furosemide given with food. Eur J Clin
Pharmacol. 1986;29:725–7.
21. McCrindle JL, Li Kam Wa TC, Barron W, et al. Effect of
food on the absorption of frusemide and bumetanide
in man. Br J Clin Pharmacol. 1996;42:743–6.
22. Brater DC. Diuretic therapy. N Engl J Med.
1998;339:387–95.
23. Bard RL, Bleske BE, Nicklas JM. Food: an unrecognized
source of loop diuretic resistance. Pharmacotherapy.
2004;24:630–7.
24. Vasko MR, Cartwright DB, Knochel JP, et al. Furose-
mide absorption altered in decompensated congestive
heart failure. Ann Intern Med. 1985;102:314–8.
25. Gottlieb SS, Khatta M, Wentworth D, et al. The effects
of diuresis on the pharmacokinetics of the loop di-
uretics furosemide and torsemide in patients with heart
failure. Am J Med. 1998;104:533–8.
26. Verbrugge FH, Dupont M, Steels P, et al. Abdominal
contributions to cardiorenal dysfunction in congestive
heart failure. J Am Coll Cardiol. 2013;62:485–95.
27. Wilcox CS. New insights into diuretic use in patients
with chronic renal disease. J Am Soc Nephrol.
2002;13:798–805.
28. Loon NR, Wilcox CS. Mild metabolic alkalosis impairs
the natriuretic response to bumetanide in normal hu-
man subjects. Clin Sci (Lond). 1998;94:287–92.
29. Uwai Y, Saito H, Hashimoto Y, et al. Interaction and
transport of thiazide diuretics, loop diuretics, and ac-
etazolamide via rat renal organic anion transporter
rOAT1. J Pharmacol Exp Ther. 2000;295:261–5.
30. Kirchner KA, Voelker JR, Brater DC. Intratubular albu-
min blunts the response to furosemide-A mechanism
for diuretic resistance in the nephrotic syndrome. J
Pharmacol Exp Ther. 1990;252:1097–101.
31. Kim GH. Long-term adaptation of renal ion trans-
porters to chronic diuretic treatment. Am J Nephrol.
2004;24:595–605.
Page 13 of 15 11
32. Marik PE, Baram M, Vahid B. Does central venous
pressure predict fluid responsiveness? A systematic re-
view of the literature and the tale of seven mares. Chest.
2008;134:172–8.
33. Adamson PB, Magalski A, Braunschweig F, et al. On-
going right ventricular hemodynamics in heart failure:
clinical value of measurements derived from an im-
plantable monitoring system. J Am Coll Cardiol.
2003;41:565–71.
34. Fallick C, Sobotka PA, Dunlap ME. Sympathetically
mediated changes in capacitance: redistribution of the
venous reservoir as a cause of decompensation. Circ
Heart Fail. 2011;4:669–75.
35.• Verbrugge FH, Nijst P, Dupont M, et al. Urinary com-
position during decongestive treatment in heart failure
with reduced ejection fraction. Circ Heart Fail.
2014;7:766–72.
Observational study suggesting that the measurement of uri-
nary sodium and chloride concentrations might help to assess
intravascular volume status.
36. Nijst P, Verbrugge FH, Grieten L, et al. The pathophys-
iological role of interstitial sodium in heart failure. J
Am Coll Cardiol. 2015;65:378–88.
37. Stevenson LW, Perloff JK. The limited reliability of
physical signs for estimating hemodynamics in chronic
heart failure. JAMA. 1989;261:884–8.
38. Chaudhry SI, Wang Y, Concato J, et al. Patterns of
weight change preceding hospitalization for heart fail-
ure. Circulation. 2007;116:1549–54.
39. Shah MR, Hasselblad V, Tasissa G, et al. Rapid assay
brain natriuretic peptide and troponin I in patients
hospitalized with decompensated heart failure (from
the Evaluation Study of Congestive Heart Failure and
Pulmonary Artery Catheterization Effectiveness Trial).
Am J Cardiol. 2007;100:1427–33.
40. Coodley EL, Segal JL, Smith DH, et al. Bioelectrical
impedance analysis as an assessment of diuresis in
congestive heart failure. Ann Pharmacother.
1995;29:1091–5.
41. Gastelurrutia P, Nescolarde L, Rosell-Ferrer J, et al.
Bioelectrical impedance vector analysis (BIVA) in sta-
ble and non-stable heart failure patients: a pilot study.
Int J Cardiol. 2011;146:262–4.
42. Alves FD, Souza GC, Aliti GB, et al. Dynamic changes in
bioelectrical impedance vector analysis and phase an-
gle in acute decompensated heart failure. Nutrition.
2015;31:84–9.
43. Mullens W, Abrahams Z, Francis GS, et al. Prompt
reduction in intra-abdominal pressure following large-
volume mechanical fluid removal improves renal in-
sufficiency in refractory decompensated heart failure. J
Card Fail. 2008;14:508–14.
44. Testani JM, Coca SG, McCauley BD, et al. Impact of
changes in blood pressure during the treatment of
acute decompensated heart failure on renal and clinical
outcomes. Eur J Heart Fail. 2011;13:877–84.
45. Dupont M, Mullens W, Finucan M, et al. Determinants
of dynamic changes in serum creatinine in acute de-
compensated heart failure: the importance of blood
11 Page 14 of 15
pressure reduction during treatment. Eur J Heart Fail.
2013;15:433–40.
46. Miller WL, Mullan BP. Understanding the het-
erogeneity in volume overload and fluid distri-
bution in decompensated heart failure is key to
optimal volume management: role for blood
volume quantitation. JACC Heart Fail.
2014;2:298–305.
47. Fonarow GC, Corday E. Overview of acutely de-
compensated congestive heart failure (ADHF): a
report from the ADHERE registry. Heart Fail Rev.
2004;9:179–85.
48. 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.
49. Ellison DH. Diuretic therapy and resistance in conges-
tive heart failure. Cardiology. 2001;96:132–43.
50. Mentz RJ, Stevens SR, DeVore AD, et al. Decongestion
strategies and renin-angiotensin-aldosterone system
activation in acute heart failure. JACC Heart Fail.
2015;3:97–107.
51. Verbrugge FH, Tang WH, Mullens W. Renin-
Angiotensin-aldosterone system activation during de-
congestion in acute heart failure: friend or foe? JACC
Heart Fail. 2015;3:108–11.
52. Kramer BK, Schweda F, Riegger GA. Diuretic treatment
and diuretic resistance in heart failure. Am J Med.
1999;106:90–6.
53. Khot UN, Mishra M, Yamani MH, et al. Severe renal
dysfunction complicating cardiogenic shock is not a
contraindication to mechanical support as a bridge to
cardiac transplantation. J Am Coll Cardiol.
2003;41:381–5.
54. Sandner SE, Zimpfer D, Zrunek P, et al. Renal function
and outcome after continuous flow left ventricular
assist device implantation. Ann Thorac Surg.
2009;87:1072–8.
55. Hasin T, Topilsky Y, Schirger JA, et al. Changes in renal
function after implantation of continuous-flow left
ventricular assist devices. J Am Coll Cardiol.
2012;59:26–36.
56. Brisco MA, Kimmel SE, Coca SG, et al. Prevalence and
prognostic importance of changes in renal function
after mechanical circulatory support. Circ Heart Fail.
2014;7:68–75.
57. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral
milrinone on mortality in severe chronic heart failure.
The PROMISE Study Research Group. N Engl J Med.
1991;325:1468–75.
58. O’Connor CM, Gattis WA, Uretsky BF, et al. Continu-
ous intravenous dobutamine is associated with an in-
creased risk of death in patients with advanced heart
failure: insights from the Flolan International Ran-
domized Survival Trial (FIRST). Am Heart J.
1999;138:78–86.
59. Knauf H, Mutschler E. Functional state of the nephron
and diuretic dose-response–rationale for low-dose
combination therapy. Cardiology. 1994;84 Suppl
2:18–26.
Curr Treat Options Cardio Med (2016) 18:11
60. Verbrugge FH, Steels P, Grieten L, et al.
Hyponatremia in acute decompensated heart fail-
ure: depletion versus dilution. J Am Coll Cardiol.
2015;65:480–92.
61. Jentzer JC, DeWald TA, Hernandez AF. Combina-
tion of loop diuretics with thiazide-type diuretics
in heart failure. J Am Coll Cardiol.
2010;56:1527–34.
62. Grodin JL, Stevens SR, de Las Fuentes L, et al.
Intensification of medication therapy for
cardiorenal syndrome in acute decompensated
heart failure. J Card Fail. 2016;22:26–32.
63. van Vliet AA, Donker AJ, Nauta JJ, et al.
Spironolactone in congestive heart failure refrac-
tory to high-dose loop diuretic and low-dose an-
giotensin-converting enzyme inhibitor. Am J
Cardiol. 1993;71:21A–8.
64. Santos J, Planas R, Pardo A, et al. Spironolactone alone
or in combination with furosemide in the treatment of
moderate ascites in nonazotemic cirrhosis. A random-
ized comparative study of efficacy and safety. J Hepatol.
2003;39:187–92.
65. Ferreira JP, Santos M, Almeida S, et al. Mineralo-
corticoid receptor antagonism in acutely decom-
pensated chronic heart failure. Eur J Intern Med.
2014;25:67–72.
66. Schnermann J. Juxtaglomerular cell complex in the
regulation of renal salt excretion. Am J Physiol.
1998;274:R263–79.
67. 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.
68. Amlal H, Soleimani M. Pendrin as a novel target
for diuretic therapy. Cell Physiol Biochem.
2011;28:521–6.
69. Soleimani M, Barone S, Xu J, et al. Double knockout of
pendrin and Na-Cl cotransporter (NCC) causes severe
salt wasting, volume depletion, and renal failure. Proc
Natl Acad Sci U S A. 2012;109:13368–73.
70. Hanley T, Platts MM. Acetazolamide (diamox) in the
treatment of congestive heart-failure. Lancet.
1956;270:357–9.
71. Knauf H, Mutschler E. Sequential nephron blockade
breaks resistance to diuretics in edematous states. J
Cardiovasc Pharmacol. 1997;29:367–72.
72. 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.
73. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafil-
tration versus intravenous diuretics for patients hospi-
talized for acute decompensated heart failure. J Am
Coll Cardiol. 2007;49:675–83.
74. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in
decompensated heart failure with cardiorenal syn-
drome. N Engl J Med. 2012;367:2296–304.
75. Patarroyo M, Wehbe E, Hanna M, et al. Cardiorenal
outcomes after slow continuous ultrafiltration therapy
Curr Treat Options Cardio Med (2016) 18:11
in refractory patients with advanced decompensated
heart failure. J Am Coll Cardiol. 2012;60:1906–12.
76.• Costanzo MR, Negoianu D, Fonarow GC, et al.
Rationale and design of the Aquapheresis Versus
Intravenous Diuretics and Hospitalization for
Heart Failure DAVOID-HF] trial. Am Heart J.
2015;170:471–82.
Page 15 of 15 11
Methods paper of the AVOID-HF trial which compared indi-
vidually tailored ultrafiltration with adjustable loop diuretics
in patients with acute heart failure and clear signs of volume
overload. Although a trend towards a benefit with ultrafiltra-
tion was observed, the study was regrettably terminated by the
sponsor, rendering its results severely underpowered and
inconclusive.