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
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
found elsewhere.22 In the United States, nesiritide, an to help define the role nesiritide could play in these
analogue of brain natriuretic peptide (or B-type natriuretic situations.
peptide), is the only commercially available agent for use
in the treatment of heart failure. ULTRAFILTRATION
The Nesiritide Study Group initially evaluated the agent Extracorporeal removal of plasma water through the use
in a combined efficacy and comparative improvements of an ultrafiltration (UF) circuit has potential benefits
trial. Hemodynamic parameters, including pulmonary compared with diuretic use including the removal of
capillary wedge pressure, improved using nesiritide isotonic plasma, increased sodium removal, decreased hy-
compared with placebo, as did dyspnea scores although pokalemia, and decreased neurohormonal activation.28,29
this benefit was not seen in the comparative portion of UF has been evaluated for the treatment of ADHF and
the trial vs standard heart failure therapies.23 Similar im- CRS in several trials.
provements in hemodynamics were reported in the Vaso- The Early Ultrafiltration in Patients with Decompensated
dilitation in the Management of Acute CHF (VMAC) trial heart Failure and Observed Resistance to Intervention
but without improvement in dyspnea scores compared with Diuretic Agents (EUPHORIA) trial was an early
with nitroglycerin.17 The effects of nesiritide on kidney investigation that showed the use of UF before the use of
function were not reported in these trials, and no specific IV diuretics decreased length of stay and readmission for
mention was made regarding its use for CRS. heart failure in a small group of patients.30 This study
Following increased adoption of nesiritide in clinical was followed by the Ultrafiltration versus IV Diuretics in
practice, concerns surfaced regarding the negative effects Patients Hospitalized for Acute Decompensated Conges-
on kidney function. In a meta-analysis of 1269 patients tive Heart Failure (UNLOAD) trial, which showed early
pooled from 5 nesiritide trials, there appeared to be a UF produced greater weight and fluid loss compared
risk of worsening kidney function associated with the with IV diuretics with additional improvements in early
use of nesiritide.24 In a follow-up meta-analysis of 3 trials rehospitalization rates.31
involving a total of 862 patients, nesiritide use had an asso- Given these potential benefits, UF has been proposed as a
ciation with increased mortality.25 These reports curbed treatment option when confronted by CRS. To test this hy-
much of the initial enthusiasm around the use of nesiritide, pothesis, the Cardiorenal Rescue Study in Acute Decom-
especially in the treatment of CRS. pensated Heart Failure (CARRESS-HF) was designed to
To follow up on the reports of worsening outcomes, the specifically evaluate the use of UF to treat ADHF in the
Acute Study of Clinical Effectiveness of Nesiritide in De- setting of worsening kidney function.32 UF was compared
compensated Heart Failure (ASCEND-HF) was designed with stepped pharmacologic therapy with diuretics based
to rigorously evaluate the use of nesiritide in the treatment on the results of the DOSE trial. The trial initially intended
of ADHF. Over 7100 patients were enrolled into this ran- to enroll 200 subjects but was stopped after 188 patients
domized, double-blind, placebo-controlled study, which were enrolled due to a lack of efficacy seen with UF in
was designed to evaluate improvement in dyspnea along the setting of higher adverse events with UF. Using the
with rehospitalization and death within 30 days. Addi- bivariate primary end point of weight change and kidney
tionally, the trial included a prespecified safety end point function change, UF fared worse than pharmacologic ther-
of worsening kidney function. Ultimately, no conclusive apy, driven primarily by changes in serum creatinine.33
benefit was seen using nesiritide; however, no worsening From these results, there was no evidence supporting the
kidney function was identified either, dispelling previous generalized use of UF to treat ADHF with CRS.
safety concerns.16 Some criticism does exist, however, with regard to the
In the Renal Optimization Strategies Evaluation (ROSE) design and implementation of CARRESS-HF. Among
trial, 360 patients were randomized to the use of low- these included, the insensitivity of short-term creatinine
dose dopamine, low-dose nesiritide, or placebo in an changes at very small increments (0.23 mg/dL) in predict-
attempt to evaluate the effect on combined urine output ing true worsening kidney failure34 and the use of fixed-
and cystatin C levels. At the trial’s conclusion, no difference rate UF which was universally prescribed for all patients
in the combined end point was noted among groups.26 randomized to the treatment arm.35 The latter point is
Interestingly, a very low dose of nesiritide was chosen not ignorable because high rates of fluid removal may
(0.005 mg/kg/min), which was lower than doses used in pre- overwhelm biological systems meant to protect against
vious trials. In light of these results, it is difficult to differ- hypotension or other adverse events. Clinical use of UF
entiate the role of nesiritide compared with other often involves variable fluid removal rates that are
vasodilators in the treatment of ADHF or especially in adjusted based on patient monitoring.
CRS. For general use in ADHF, nesiritide carries the same The role of adjustable rate UF in the treatment of ADHF
recommendation as nitroglycerin and nitroprusside.14 was shown to have sustained benefits through 1 year
Interestingly, in highly specialized forms of CRS, such without compromise in kidney function in the small
as worsening kidney function that can occur after im- Continuous Ultrafiltration for Congestive Heart Failure
plantation of a total artificial heart, nesiritide has been (CUORE) trial, which only enrolled 56 patients.36 UF’s
shown to improve urine output and stabilize kidney role in the treatment of ADHF was supposed to be clarified
function.27 Such data imply a possible role for natriuretic by the Aquapheresis vs Intravenous Diuretics and Hospi-
peptides in specific scenarios, but further work is needed talizations for Heart Failure (AVOID-HF) trial, in which
810 patients were to be enrolled and randomized to adjust- serelaxin group (6%) had adverse events related to kidney
able rate UF vs adjustable loop diuretics. Unfortunately, impairment, P ¼ 0.03. A subsequent analysis illustrated
the trial was terminated early after only 224 patients more favorable changes in serum creatinine and plasma
were enrolled after the sponsor withdrew financial sup- cystatin C over the first 14 days of the study.42 Although
port as a strategic marketing decision but not due to safety these changes are noteworthy, the drug has yet to gain reg-
or efficacy concerns. As a result, the trial was underpow- ulatory approval. Two large phase IIIb studies
ered to demonstrate the utility of UF but instead only (NCT01870778 and NCT02065868) are presently ongoing
showed a trend toward improvements with UF.37 To with results expected sometime this year.43,44
date, the role of treating ADHF involving CRS with UF
is still unclear and in need of additional supporting data. CHALLENGES IN STUDYING CRS
Further studies on UF in ADHF and CRS will need to Identifying the best method to treat ADHF and CRS re-
clarify present challenges in clinical use. First, at what mains an enigma for today’s clinician. A rigorous review
time point should UF be considered? Unclear from present of clinical trial data illustrates that while effective therapies
data is whether extracorporeal fluid removal be imple- exist, the heterogeneous and complex pathophysiology of
mented early in the course of AHDF or only after inefficacy CRS often stand in the way of discerning clear answers to
of diuretics therapies has occurred. The latter group may define optimal therapeutic approaches (Table 2). Among
better identify diuretic resistant patients for whom bypass- these challenges is the poor differentiation of CRS sub-
ing renal mechanisms of fluid removal could be superior. types when patients clinically present. Perhaps the an-
Second, the optimal rate of fluid removal remains un- swers for better treatment strategies will lie in better
known, especially without an ability to estimate the understanding of the CRS subgroups; types 1 to 5 may
plasma refill rate. For patients undergoing UF, the concur- not respond the similarly to each therapy. Future investi-
rent use of diuretics remains unaddressed. Finally, studies gations may benefit from enrolling patients from a clinical
have yet to illuminate the time point at which UF therapy phenotype to evaluate response to therapy. Of course,
can be discontinued and standard therapies resumed. As while conceptually favorable, this approach will be chal-
can be seen, many questions remain and may explain the lenged by our own limitations in making such distinctions,
ongoing difficulty in studying the therapy. especially in patients who present acutely. Nonetheless,
such considerations may be required in future studies.
NOVEL AGENTS
Serelaxin, a recombinant human relaxin-2, has recently SUMMARY
generated a lot of enthusiasm for the treatment of ADHF Acute kidney injury as a result of ADHF occurs commonly
and CRS. Human relaxin-2 is a peptide that regulates and approaches to management involve volume removal
maternal adaptations to pregnancy,38 including increased and symptom improvement. Loop diuretic therapy to
arterial compliance, cardiac output, and renal blood flow reduce renovascular congestion remains the mainstay of
each of which is potentially relevant to the treatment of therapy. Dosing and administration methods do not
ADHF and CRS.39,40 The RELAX in Acute Heart Failure appear to impact outcomes, although time to improve-
(RELAX-AHF) trial randomly assigned 1161 subjects ment in symptoms may occur with more aggressive
with acute heart failure to standard care plus 48-hour infu- dosing strategies. Symptoms can also be improved with
sions of placebo or serelaxin (30 mg/kg/day) within concurrent administration of vasodilator therapies. Vaso-
16 hours of presentation.41 The trial demonstrated statisti- dilitation can drop CVP and may improve renal perfusion,
cally significant improvement in dyspnea symptom scores which are important determinants to kidney function in
and fewer deaths at 180 days (hazard ratio 0.63, P ¼ 0.019), the setting of ADH. Nitroglycerin is the accepted standard
although the latter was a secondary end point. More pa- for vasodilator therapies, but the use of nitroprusside
tients assigned to the placebo group (9%) relative to the and nesiritide can also be considered. UF offers an
extracorporeal fluid removal option, which allows bypass- erin for treatment of decompensated congestive heart failure: a ran-
ing potentially altered kidney function in CRS. Efficacy domized controlled trial. JAMA. 2002;287:1531-1540.
studies have shown variable results, in part due to current 18. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML. Diverse bio-
logical actions of atrial natriuretic peptide. Physiol Rev.
unknowns in the management of UF, such as volume
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are undergoing testing, which preliminary results suggest- (patho)physiological significance in humans. Kidney Int.
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additional studies will need to confirm benefit before reg- 20. Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide
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receptors, and cyclic guanosine monophosphate-dependent
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