ACKD

Getting to the Heart of the Matter: Review of

Treatment of Cardiorenal Syndrome
Kausik Umanath and Sitaramesh Emani

Acute decompensated heart failure is a common cause of hospitalization with worsening kidney function or acute kidney injury
often complicating the admission, which can result in further dysfunction of both systems in the form of a cardiorenal syn-
drome. Therapy in this arena has been largely empiric as rigorous clinical trial data to inform therapeutic choices are lacking.
Here we review and discuss the available clinical evidence for common approaches to the management of this condition. A
multidisciplinary approach to the care of patients with cardiorenal syndrome that relies on the experience of nephrologists
and cardiologists to individualize treatment is critical given the paucity of rigorous clinical trial data.
Q 2017 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Acute Decompensated Heart Failure, Acute Kidney Injury, Cardiorenal, Hospitalization, Diuretics, Vasodilators,
Ultrafiltration

INTRODUCTION (plasma refill rate). Typically, a loop diuretic is used over

A large proportion of patients admitted to the hospital have
some degree of dysfunction of either the kidneys or the
heart.1 These 2 organ systems interact with one another
such that primary disease of one often results in secondary
dysfunction of the other.2 Recognition of this complex inter-
action along with the need to better codify these pathophys-
iological processes led to the formalization and
classification of the cardiorenal syndrome (CRS) and its 5
categories.3,4 Acute decompensated heart failure (ADHF)
is a common cause of hospitalization with worsening
kidney function or acute kidney injury (AKI) complicating
nearly 1 in 5 admissions.5 These patients were noted to
have an increased risk of mortality compared with ADHF
patients without AKI. AKI during an admission for heart
failure is also associated with repeat ADHF admissions.6
Thus, the evolution and management of CRS is a common
clinical problem, which significantly affects and individual
patient’s health and the health care system as a whole.
The classification and pathophysiological underpinnings
of CRS and its 5 categories have been reviewed in detail
elsewhere2-4 (Table 1). Therapeutic approaches to manage
congestion and fluid overload in patients with ADHF
while mitigating renal harm have centered on the use of di-
uretics, vasodilators, and extracorporeal approaches,
namely ultrafiltration (UF). Therapy in this arena has
been largely empiric as conclusive clinical trial data to
inform therapeutic choices are lacking. Our aim in this
article is to review and discuss the available clinical evi-
dence for common approaches to the management of
this condition.
DIURETICS
Diuretic therapy has been the mainstay of treatment for
ADHF as it assists with the relief of symptoms (shortness
of breath, lower extremity edema, etc.). Although these
agents reduce congestive symptoms, this improvement
may come at the cost of inciting a vicious cycle of neuro-
hormonal activation, AKI, and resultant diuretic resis-
tance. Diuretics can also cause adverse perturbations in
electrolyte balance and acid-base homeostasis. The goal
of diuretic therapy should reduce the extracellular fluid
volume at a rate commensurate with the rate of refilling
from the interstitium to the intravascular compartment
other agents like thiazides, which have limited efficacy in
states of reduced kidney function.8
Optimal diuretic strategies including dose, frequency,
and route of administration have not shown superiority
of any one approach over others. Salvador and colleagues
attempted to synthesize the available data via a Cochrane
meta-analysis in 2005 comparing bolus intravenous
administration of loop diuretics vs continuous infusion in
ADHF.9 The analysis covered 8 trials totaling 254 subjects
and found greater urine output, less ototoxicity (tinnitus
and hearing loss), and a similar frequency of electrolyte dis-
turbances in subjects given continuous infusion compared
with intermittent therapy. Unfortunately, the authors were
unable to compare effects on survival or kidney outcomes
because of heterogeneity and lack of sample size.
Subsequently, Allen and colleagues10 conducted a single-
center pilot study of 41 patients comparing bolus vs
continuous dosing of furosemide for ADHF. In this small
study, no difference was noted in serum creatinine change,
total urine output, or length of stay. This lead to the NIH-
sponsored Diuretic Optimization Strategies Evaluation
(DOSE) trial.11 This study was a prospective, placebo-
controlled trial in which 308 subjects were randomized
to receive intravenous furosemide either by continuous
infusion or bolus infusion every 12 hours. The trial used
a 2 3 2 factorial design in which subjects either received
a low or high dose of furosemide (the equivalent of 1 or
2.5 times the previous oral dose, respectively). The co-
primary end points were subjects’ global assessment of
symptoms, as quantified by area under the curve of the
score on a visual analogue scale over the course of 72 hours
From Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit,
MI; and Division of Cardiology, The Ohio State University Wexner Medical
Center, Columbus, OH.
Financial Disclosure: The authors declare that they have no relevant finan-
cial interests.
Address correspondence to Kausik Umanath, MD, MS, Division of
Nephrology and Hypertension, Clara Ford Pavilion 5, Henry Ford Hospital,
Detroit, MI 48202. E-mail: kumanat1@hfhs.org
Ó 2017 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2017.05.010

Adv Chronic Kidney Dis. 2017;24(4):261-266 261

262 Umanath and Emani

Table 1. Classification of Cardiorenal Syndromes

Type Name
1 Acute cardiorenal syndrome
2 Chronic cardiorenal syndrome
3 Acute renocardiac syndrome
4 Chronic renocardiac syndrome
5 Secondary cardiorenal syndrome
Description
Acute worsening of cardiac function leading to decreased kidney function
Long-term abnormalities in cardiac function leading to decreased kidney function
Acute worsening of kidney function causing cardiac dysfunction
Long-term abnormalities in kidney function leading to cardiac disease
Systemic conditions causing simultaneous dysfunction of the heart and kidney

Adapted from House et al.7

and change in serum creatinine from baseline to 72 hours. taken in the context of no changes in serum creatinine by
Among several secondary end points were two kidney- 72 hours and over 60 days. Based on the available data, a
specific outcomes: worsening kidney function (defined reasonable approach for ADHF would be the use of
as an increase in serum creatinine .0.3 mg/dL at any high-dose diuretics via either bolus or continuous infu-
time from randomization to 72 hours) and changes in sion.
serum creatinine or cystatin C at baseline, 72 hours, and
60 days. VASODILATOR THERAPIES
In the comparison of bolus vs continuous infusion, no dif- When examining mechanisms of worsening CRS, a major
ference was noted in the primary efficacy end point of correlation between kidney function and central venous
patient-reported global assessment of symptoms. The dif- pressure (CVP) has been shown. In an analysis by Mullens
ference in serum creatinine at 72 hours compared with base- and colleagues,12 an increased CVP during ADHF was
line was also not statistically significant (0.05 6 0.3 mg/dL more predictive of worsening kidney function than other
bolus group and 0.07 6 indices of cardiac perfor-
0.3 mg/dL continuous infu- CLINICAL SUMMARY mance including cardiac in-
sion group, P ¼ 0.45).11 The dex or pulmonary capillary
authors also found no differ-  Disturbances in kidney and cardiac homeostasis result in wedge pressure. This associ-
ences across all the secondary challenges when managing patients with underlying ation is driven by the net
end points. Additionally, processes of either organ system. filtration pressure across the
they noted no interaction be-  Current treatments of cardiorenal syndromes focus on the
glomerulus, which is a func-
tween the factorial groups for use of diuretics, vasodilators, and ultrafiltration. tion of the pressure gradient
the co-primary end points. between afferent and
With regard to high-dose vs  The best clinical evidence exists for the use of diuretics, efferent vessels within the
low-dose strategies, a non- whereas evidence for the use of vasodilators and kidney. When CVP rises, the
ultrafiltration is inconclusive.
statistically significant trend net filtration pressure drops
toward greater improvement  Novel therapeutic agents that may play role in the as a result of a reduced pres-
in symptom score was noted treatment of cardiorenal syndromes are in development. sure gradient.13
in the high-dose group. The One strategy for treating
difference in serum creati- CRS in ADHF is to
nine at 72 hours compared with baseline was not statisti- improve kidney perfusion pressure by reducing CVP
cally significant (0.04 6 0.3 mg/dL low-dose group and through the use of vasodilating agents. The long-
0.08 6 0.3 mg/dL high-dose group, P ¼ 0.21). Among the standing standard of care for vasodilation in ADHF
secondary end points, the high-dose group was noted to has been nitroglycerin, which is recommended for relief
have statistically significant greater changes in weight of dyspnea when used with diuretic therapy.14 Accep-
loss, net fluid loss, and relief from dyspnea. These tance of nitroglycerin within this context has led to its
improved symptoms did not seem to come at the expense use as a comparator for other agents aimed at treating
of kidney function loss. Although there was a statistically ADHF and CRS.15-17 Despite the theoretical benefit of
significant increase in the event of worsening kidney func- nitroglycerin to decrease CVP through its venodilating
tion (23% in high-dose group, 14% in low-dose group, properties, thereby improving renal perfusion, minimal
P ¼ 0.04), there were no differences noted in the primary data exist looking at its efficacy in improving
end point (change in serum creatinine at 72 hours) as noted outcomes in CRS. The same lack of evidence exists for
earlier or changes in serum creatinine or cystatin C levels at nitroprusside, which is another commonly used agent
60 days. to treat ADHF.15
In summary, the available clinical evidence supports the
use of loop diuretics with equivalent safety and efficacy us- NESIRITIDE
ing either a bolus or continuous infusion dosing approach. Natriuretic peptides are naturally occurring amino acid
A high-dose strategy also appears to provide a trend to- rings that are involved in cardiorenal homeostasis through
ward improved symptom relief and some other favorable vasodilation and induction of natriuresis and diuresis.18-21
outcomes. Although there were increased worsening kid- A review of various natriuretic peptides, both analogues of
ney failure events with a high-dose strategy, this must be natural forms and synthetically designed forms, can be

Adv Chronic Kidney Dis. 2017;24(4):261-266

 Therapies for Acute Cardiorenal Syndrome
found elsewhere.22 In the United States, nesiritide, an
analogue of brain natriuretic peptide (or B-type natriuretic
peptide), is the only commercially available agent for use
in the treatment of heart failure.
The Nesiritide Study Group initially evaluated the agent
in a combined efficacy and comparative improvements
trial. Hemodynamic parameters, including pulmonary
capillary wedge pressure, improved using nesiritide
compared with placebo, as did dyspnea scores although
this benefit was not seen in the comparative portion of
the trial vs standard heart failure therapies.23 Similar im-
provements in hemodynamics were reported in the Vaso-
dilitation in the Management of Acute CHF (VMAC) trial
but without improvement in dyspnea scores compared
with nitroglycerin.17 The effects of nesiritide on kidney
function were not reported in these trials, and no specific
mention was made regarding its use for CRS.
Following increased adoption of nesiritide in clinical
practice, concerns surfaced regarding the negative effects
on kidney function. In a meta-analysis of 1269 patients
pooled from 5 nesiritide trials, there appeared to be a
risk of worsening kidney function associated with the
use of nesiritide.24 In a follow-up meta-analysis of 3 trials
involving a total of 862 patients, nesiritide use had an asso-
ciation with increased mortality.25 These reports curbed
much of the initial enthusiasm around the use of nesiritide,
especially in the treatment of CRS.
To follow up on the reports of worsening outcomes, the
Acute Study of Clinical Effectiveness of Nesiritide in De-
compensated Heart Failure (ASCEND-HF) was designed
to rigorously evaluate the use of nesiritide in the treatment
of ADHF. Over 7100 patients were enrolled into this ran-
domized, double-blind, placebo-controlled study, which
was designed to evaluate improvement in dyspnea along
with rehospitalization and death within 30 days. Addi-
tionally, the trial included a prespecified safety end point
of worsening kidney function. Ultimately, no conclusive
benefit was seen using nesiritide; however, no worsening
kidney function was identified either, dispelling previous
safety concerns.16
In the Renal Optimization Strategies Evaluation (ROSE)
trial, 360 patients were randomized to the use of low-
dose dopamine, low-dose nesiritide, or placebo in an
attempt to evaluate the effect on combined urine output
and cystatin C levels. At the trial’s conclusion, no difference
in the combined end point was noted among groups.26
Interestingly, a very low dose of nesiritide was chosen
(0.005 mg/kg/min), which was lower than doses used in pre-
vious trials. In light of these results, it is difficult to differ-
entiate the role of nesiritide compared with other
vasodilators in the treatment of ADHF or especially in
CRS. For general use in ADHF, nesiritide carries the same
recommendation as nitroglycerin and nitroprusside.14
Interestingly, in highly specialized forms of CRS, such
as worsening kidney function that can occur after im-
plantation of a total artificial heart, nesiritide has been
shown to improve urine output and stabilize kidney
function.27 Such data imply a possible role for natriuretic
peptides in specific scenarios, but further work is needed
Adv Chronic Kidney Dis. 2017;24(4):261-266
263
to help define the role nesiritide could play in these
situations.
ULTRAFILTRATION
Extracorporeal removal of plasma water through the use
of an ultrafiltration (UF) circuit has potential benefits
compared with diuretic use including the removal of
isotonic plasma, increased sodium removal, decreased hy-
pokalemia, and decreased neurohormonal activation.28,29
UF has been evaluated for the treatment of ADHF and
CRS in several trials.
The Early Ultrafiltration in Patients with Decompensated
heart Failure and Observed Resistance to Intervention
with Diuretic Agents (EUPHORIA) trial was an early
investigation that showed the use of UF before the use of
IV diuretics decreased length of stay and readmission for
heart failure in a small group of patients.30 This study
was followed by the Ultrafiltration versus IV Diuretics in
Patients Hospitalized for Acute Decompensated Conges-
tive Heart Failure (UNLOAD) trial, which showed early
UF produced greater weight and fluid loss compared
with IV diuretics with additional improvements in early
rehospitalization rates.31
Given these potential benefits, UF has been proposed as a
treatment option when confronted by CRS. To test this hy-
pothesis, the Cardiorenal Rescue Study in Acute Decom-
pensated Heart Failure (CARRESS-HF) was designed to
specifically evaluate the use of UF to treat ADHF in the
setting of worsening kidney function.32 UF was compared
with stepped pharmacologic therapy with diuretics based
on the results of the DOSE trial. The trial initially intended
to enroll 200 subjects but was stopped after 188 patients
were enrolled due to a lack of efficacy seen with UF in
the setting of higher adverse events with UF. Using the
bivariate primary end point of weight change and kidney
function change, UF fared worse than pharmacologic ther-
apy, driven primarily by changes in serum creatinine.33
From these results, there was no evidence supporting the
generalized use of UF to treat ADHF with CRS.
Some criticism does exist, however, with regard to the
design and implementation of CARRESS-HF. Among
these included, the insensitivity of short-term creatinine
changes at very small increments (0.23 mg/dL) in predict-
ing true worsening kidney failure34 and the use of fixed-
rate UF which was universally prescribed for all patients
randomized to the treatment arm.35 The latter point is
not ignorable because high rates of fluid removal may
overwhelm biological systems meant to protect against
hypotension or other adverse events. Clinical use of UF
often involves variable fluid removal rates that are
adjusted based on patient monitoring.
The role of adjustable rate UF in the treatment of ADHF
was shown to have sustained benefits through 1 year
without compromise in kidney function in the small
Continuous Ultrafiltration for Congestive Heart Failure
(CUORE) trial, which only enrolled 56 patients.36 UF’s
role in the treatment of ADHF was supposed to be clarified
by the Aquapheresis vs Intravenous Diuretics and Hospi-
talizations for Heart Failure (AVOID-HF) trial, in which
264 Umanath and Emani
Table 2. Summary of Evidence for Therapeutic Approaches in Cardiorenal Syndromes
Therapeutic Approach Mechanism
Loop diuretics Salt and water removal
Nesiritide Peptide which induces naturesis
Ultrafiltration Extracorporeal removal of fluid
Serelaxin Recombinant human relaxin-2 modulates arterial
compliance, cardiac output and renal blood flow
810 patients were to be enrolled and randomized to adjust-
able rate UF vs adjustable loop diuretics. Unfortunately,
the trial was terminated early after only 224 patients
were enrolled after the sponsor withdrew financial sup-
port as a strategic marketing decision but not due to safety
or efficacy concerns. As a result, the trial was underpow-
ered to demonstrate the utility of UF but instead only
showed a trend toward improvements with UF.37 To
date, the role of treating ADHF involving CRS with UF
is still unclear and in need of additional supporting data.
Further studies on UF in ADHF and CRS will need to
clarify present challenges in clinical use. First, at what
time point should UF be considered? Unclear from present
data is whether extracorporeal fluid removal be imple-
mented early in the course of AHDF or only after inefficacy
of diuretics therapies has occurred. The latter group may
better identify diuretic resistant patients for whom bypass-
ing renal mechanisms of fluid removal could be superior.
Second, the optimal rate of fluid removal remains un-
known, especially without an ability to estimate the
plasma refill rate. For patients undergoing UF, the concur-
rent use of diuretics remains unaddressed. Finally, studies
have yet to illuminate the time point at which UF therapy
can be discontinued and standard therapies resumed. As
can be seen, many questions remain and may explain the
ongoing difficulty in studying the therapy.
NOVEL AGENTS
Serelaxin, a recombinant human relaxin-2, has recently
generated a lot of enthusiasm for the treatment of ADHF
and CRS. Human relaxin-2 is a peptide that regulates
maternal adaptations to pregnancy,38 including increased
arterial compliance, cardiac output, and renal blood flow
each of which is potentially relevant to the treatment of
ADHF and CRS.39,40 The RELAX in Acute Heart Failure
(RELAX-AHF) trial randomly assigned 1161 subjects
with acute heart failure to standard care plus 48-hour infu-
sions of placebo or serelaxin (30 mg/kg/day) within
16 hours of presentation.41 The trial demonstrated statisti-
cally significant improvement in dyspnea symptom scores
and fewer deaths at 180 days (hazard ratio 0.63, P ¼ 0.019),
although the latter was a secondary end point. More pa-
tients assigned to the placebo group (9%) relative to the
Comments
No evidence of renal harm
Utility in symptom improvement
Best evidence based guidance is to use high dose
either via bolus or continuous infusion
Small signal of renal harm in early studies, larger study
showed no harm
Not used uniformly as data are mixed and inconclusive
Controversial due quality of studies and mixed
populations; in diuretic responsive subjects UF as
initial therapy may signal renal harm
Promising data, ongoing second phase III trial
serelaxin group (6%) had adverse events related to kidney
impairment, P ¼ 0.03. A subsequent analysis illustrated
more favorable changes in serum creatinine and plasma
cystatin C over the first 14 days of the study.42 Although
these changes are noteworthy, the drug has yet to gain reg-
ulatory approval. Two large phase IIIb studies
(NCT01870778 and NCT02065868) are presently ongoing
with results expected sometime this year.43,44
CHALLENGES IN STUDYING CRS
Identifying the best method to treat ADHF and CRS re-
mains an enigma for today’s clinician. A rigorous review
of clinical trial data illustrates that while effective therapies
exist, the heterogeneous and complex pathophysiology of
CRS often stand in the way of discerning clear answers to
define optimal therapeutic approaches (Table 2). Among
these challenges is the poor differentiation of CRS sub-
types when patients clinically present. Perhaps the an-
swers for better treatment strategies will lie in better
understanding of the CRS subgroups; types 1 to 5 may
not respond the similarly to each therapy. Future investi-
gations may benefit from enrolling patients from a clinical
phenotype to evaluate response to therapy. Of course,
while conceptually favorable, this approach will be chal-
lenged by our own limitations in making such distinctions,
especially in patients who present acutely. Nonetheless,
such considerations may be required in future studies.
SUMMARY
Acute kidney injury as a result of ADHF occurs commonly
and approaches to management involve volume removal
and symptom improvement. Loop diuretic therapy to
reduce renovascular congestion remains the mainstay of
therapy. Dosing and administration methods do not
appear to impact outcomes, although time to improve-
ment in symptoms may occur with more aggressive
dosing strategies. Symptoms can also be improved with
concurrent administration of vasodilator therapies. Vaso-
dilitation can drop CVP and may improve renal perfusion,
which are important determinants to kidney function in
the setting of ADH. Nitroglycerin is the accepted standard
for vasodilator therapies, but the use of nitroprusside
and nesiritide can also be considered. UF offers an
Adv Chronic Kidney Dis. 2017;24(4):261-266
 Therapies for Acute Cardiorenal Syndrome
extracorporeal fluid removal option, which allows bypass-
ing potentially altered kidney function in CRS. Efficacy
studies have shown variable results, in part due to current
unknowns in the management of UF, such as volume
removal rate. Novel agents affecting vascular physiology
are undergoing testing, which preliminary results suggest-
ing a potential role in the treatment of CRS. However,
additional studies will need to confirm benefit before reg-
ulatory approval of these agents. The treatment of ADHF
and CRS remains a challenge and will continue to be the
focus of future investigation.
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