Renal Dysfunction in Acute Decompensated Heart Failure

CLINICAL REVIEW
Cardiorenal Syndrome Type 1: Renal
Dysfunction in Acute Decompensated Heart
Failure
Kurt W. Prins, MD, PhD, Thenappan Thenappan, MD, Jeremy S. Markowitz, MD, and Marc R. Pritzker, MD
ABSTRACT
• Objective: To present a review of cardiorenal syndrome type 1 (CRS1).
• Methods: Review of the literature.
• Results: Acute kidney injury occurs in approximately
one-third of patients with acute decompensated heart
failure (ADHF) and the resultant condition was named
CRS1. A growing body of literature shows CRS1
patients are at high risk for poor outcomes, and thus
there is an urgent need to understand the pathophysiology and subsequently develop effective treatments. In this review we discuss prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for different treatment strategies, and ongoing clinical trials
and highlight questions and problems physicians will
face moving forward with this common and challenging condition.
• Conclusion: Further research is needed to understand the pathophysiology of this complex clinical
entity and to develop effective treatments.
A
cute decompensated heart failure (ADHF) is
an epidemic facing physicians throughout the
world. In the United States alone, ADHF
accounts for over 1 million hospitalizations annually,
with costs in 2012 reaching $30.7 billion [1]. Despite
the advances in chronic heart failure management,
ADHF continues to be associated with poor outcomes
as exemplified by 30-day readmission rates of over 20%
and in-hospital mortality rates of 5% to 6%, both of
which have not significantly improved over the past 20
years [2,3]. One of the strongest predictors of adverse
outcomes in ADHF is renal dysfunction. An analysis
from the Acute Decompensated Heart Failure National
Registry (ADHERE) revealed the combination of renal
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dysfunction (creatinine > 2.75 mg/dL and blood urea
nitrogen (BUN) > 43 mg/dL) and hypotension (systolic
blood pressure (SBP) < 115 mm Hg) upon admission was
associated with an in-hospital mortality of > 20% [4]. The
Organized Program to Initiate Lifesaving Treatment in
Hospitalized Patients with Heart Failure (OPTIMIZEHF) registry documented a 16.3% in-hospital mortality
when patients had a SBP < 100 mm Hg and creatinine
> 2.0 mg/dL at admission [5].
The presence of acute kidney injury in the setting of
ADHF is a very common occurrence and was termed
cardiorenal syndrome type 1 (CRS1) [6]. The prevalence
of CRS1 in single-centered studies ranged from 32%
to 40% of all ADHF admissions [7,8]. If this estimate
holds true throughout the United States, there would be
320,000 to 400,000 hospitalizations for CRS1 annually,
highlighting the magnitude of this problem. Moreover,
with the number of patients with heart failure expected to
continue to rise, CRS1 will only become more prevalent in
the future. In this review we discuss the prevalence, proposed pathophysiology including hemodynamic and nonhemodynamic factors, prognosticating variables, data for
different treatment strategies, ongoing clinical trials, and
highlight questions and problems physicians will face moving forward in this common and challenging condition.
Pathogenesis of CRS1
Hemodynamic Effects
The early hypothesis for renal dysfunction in ADHF centered on hemodynamics, as reduced cardiac output was
believed to decrease renal perfusion. However, analysis of
invasive hemodynamics from patients with ADHF suggested that central venous pressure (CVP) was actually a
From the Cardiovascular Division, Department of Internal
Medicine, University of Minnesota, Minneapolis, MN.
Vol. 22, No. 10 October 2015 JCOM 443
CARDIORENAL SYNDROME 1
better predictor of the development of CRS1 than cardiac
output. In a single-center study conducted at the Cleveland Clinic, hemodynamics from 145 patients with ADHF
were evaluated and surprisingly baseline cardiac index was
greater in the patients with CRS1 than patients without
renal dysfunction (2.0 ± 0.8 L/min/m2 vs 1.8 ± 0.4
L/min/m2; P = 0.008). However, baseline CVP was higher in the CRS1 group (18 ± 7 mm Hg vs 12 ± 6 mm Hg;
P = 0.001), and there was a heightened risk of developing
CRS1 as CVP increased. In fact, 75% of the patients with
a CVP of > 24 mm Hg developed renal impairment [9].
In a retrospective study of the Evaluation Study of Congestive Heart Failure and Pulmonary Arterial Catheter
Effectiveness (ESCAPE) trial, the only hemodynamic parameter that correlated with baseline creatinine was CVP.
However, no invasive measures predicted worsening renal
function during hospitalization [10]. Finally, an experiment that used isolated canine kidneys showed increased
venous pressure acutely reduced urine production. Interestingly, this relationship was dependent on arterial
pressure; as arterial flow decreased smaller increases in
CVP were needed to reduce urine output [11]. Together,
these data suggest increased CVP plays an important role
in CRS1, but imply hemodynamics alone may not fully
explain the pathophysiology of CRS1.
Inflammation
As information about how hemodynamics incompletely
predict renal dysfunction in ADHF became available,
alternative hypotheses were investigated to gain a deeper
understanding of the pathophysiology underlying CRS1.
A pathological role of inflammation in CRS1 has gained
attention due to recent publications. First of all, serum
levels of the pro-inflammatory cytokines TNF-a and
IL-6 were elevated in patients with CRS1 when compared to health controls [12]. Interestingly, Virzi et al
showed that the median value of IL-6 was 5 times higher
in CRS1 patients when compared to ADHF patients
without renal dysfunction [13]. The negative consequences of elevated serum cytokines were demonstrated
when incubation of a human cell line of monocytes with
serum from CRS1 patients induced apoptosis in 81% of
cells compared to just 11% of cells with control serum
[12]. It is possible that cytokine-induced apoptosis could
occur in other cell types in different organs in patients
with CRS1, which may contribute to both cardiac and
renal dysfunction. Finally, analysis from a rat model of
CRS1 revealed macrophage infiltration into the kidneys
444 JCOM October 2015 Vol. 22, No. 10
and increased numbers of activated monocytes in the
peripheral blood. Interestingly, monocyte/macrophage
depletion using liposome clodronate prevented chronic
renal dysfunction in the rat model [14]. In summary,
these data suggest inflammation contributes to CRS1
pathophysiology, but more experimental data is needed
to determine if there is a causal relationship.
Oxidative Stress
Very recently, oxidative stress was proposed to play a role
in CRS1. Virzi et al analyzed serum levels of markers of
oxidative stress and compared ADHF patients without
renal impairment to CRS1 patients. The markers of
oxidative stress, which included myeloperoxidase, nitric
oxide, copper/zinc superoxide dismutase, and endogenous peroxidase, were all significantly higher in CRS1
patients [13]. While provocative, the tissues responsible
for the generation of these molecules and the subsequent
effects have not yet been fully elucidated.
The proposed pathophysiology is seen in the Figure.
Prognostication
Severity of Acute Kidney Injury
Initial publications did not document a strong link
between kidney injury and poor outcomes in ADHF.
Firstly, Ather et al performed a single-centered study
that investigated how change in renal function defined
by change in creatinine, estimated GFR, and BUN affected outcomes one year post admission for ADHF.
Kidney injury defined by a change in creatinine or in
estimated GFR was not associated with increased risk
of mortality, but a change in BUN was associated with
increased mortality in a univariate analysis [15]. Testani
et al retrospectively analyzed patients from the ESCAPE
trial and found worsening renal function defined by a
≥ 20% reduction in estimated GFR was not significantly associated with 180-day mortality, but there was
a trend towards higher mortality (hazard ration 1.4;
P = 0.11) [16]. Importantly, neither of 2 these studies assessed how severity of AKI impacted outcomes,
which may have contributed to the weak relationships
observed.
However, when AKI severity in CRS1 was quantified,
poor outcomes were more likely as AKI severity increased.
Firstly, Roy et al determined how AKI impacted adverse
events (mortality, rehospitalization, or need for dialysis)
rates in 637 patients with ADHF. Severity of AKI was
quantified using RIFLE, AKIN, and KDIGO guidelines
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CLINICAL REVIEW
Reduced Cardiac
Output
Increased Central
Venous Pressure
Systemic
Inflamation
Oxidative Stress
Renal Dysfunction
Figure. Proposed pathophysiology of CRS1. A combination of reduced cardiac output, increased central venous pressure,
systemic inflammation, and oxidative stress result in renal dysfunction in acute decompensated heart failure.
(Table 1), and the authors found that as the severity of
renal injury increased, the likelihood of an adverse event
was higher. In fact, the most severe AKI grade using all
3 AKI grading systems resulted in an odds ratio ranging
from 45.3 to 101.6 for an adverse event at 30 days when
compared to no kidney injury [7]. Hata et al documented
that AKI (defined using RIFLE criteria) in ADHF
resulted in a longer ICU stay, total hospital length of stay, and
higher in-hospital mortality rates, and patients with a failure-grade AKI had in-hospital mortality rate of 49.1% [17].
Finally, Li et al evaluated AKI in 1005 patients with
ADHF and showed that AKI defined by RIFLE, AKIN,
or KDIGO methods increased risk of in-hospital mortality, and that a KDIGO grade 3 AKI was associated
with a 35.5% in-hospital mortality rate [8]. These data
indicate CRS1 is associated with poor outcomes, and
there is a heightened risk of adverse events as AKI severity increases.
Diuretic Responsiveness
Using change in serum creatinine as a marker of renal impairment may not be the best choice for predicting outcomes in CRS1 because the lab values are not a real-time
measure of kidney function and serum creatinine can be
affected by both body mass and pharmaceutical agents.
Therefore, the prognosticating ability of urine production relative to diuretic dose as a surrogate measure of
renal function in ADHF was investigated by several
groups (Table 2). Testani et al examined urine output
per 40 mg of furosemide and tracked outcomes in 2
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cohorts: patients admitted with ADHF at the University
of Pennsylvania (657 patients) and patients from the ESCAPE trial (390 patients). Patients were split into high
responders or low responders based on the median value.
In both of the patient cohorts, low diuretic efficiency was
associated with increased mortality using a multivariate
model (hazard ratio of 1.36 in the Penn patients and
2.86 in the ESCAPE patients). The combination of low
diuretic efficiency and high diuretic dose (> 280 mg in
the Penn cohort and > 240 mg in the ESCAPE cohort)
resulted in the worst prognosis, with mortality rates of
approximately 70% at 6 years in the Penn cohort and approximately 35% at 180 days in the ESCAPE cohort [18].
Voors et al performed a retrospective analysis of diuretic
responsiveness in 1161 patients from the Relaxin in Acute
Heart Failure (RELAX-AHF) trial. Diuretic responsiveness was defined as weight change (kg) per diuretic dose
(IV furosemide and PO furosemide) over 5 days and
then patients were separated into tertiles. The lowest
tertile group had an approximate 20% incidence of 60day combined end-point of death, heart failure or renal
failure readmission compared to less than 10% incidence
in the middle and upper tertiles. Interestingly, when the
effects of worsening renal function (WRF), defined as
creatinine change of ≥ 0.3 mg/dL, were examined in patients stratified by diuretic response, WRF did not offer
additional prognostic information [19].
Finally, Valenete et al analyzed diuretic response in
1745 patients from the PROTECT trial (Placebo-Controlled Randomized Study of the Selective A1-Adenosine
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CARDIORENAL SYNDROME 1
Table 1. Classification of Acute Kidney Injury Using RIFLE [68], AKIN [69], and KIDGO [70] Guidelines Based on
Creatinine or eGFR Changes
Classification
Stage
Definition Based on sCr
RIFLE
Risk
≥ 1.5-fold increase in baseline sCr or decrease in eGFR ≥ 25%
Injury
≥ 2.0-fold increase in baseline sCr or a decrease in eGFR ≥ 50%
Failure
≥ 3.0-fold increase in baseline sCr or decrease in eGFR ≥ 75%. If baseline sCr ≥ 4.0 mg/dL, then an
increase in sCr of 0.5 mg/dL
1
Increase in sCr ≥ 0.3 mg/dL or 1.5- to 1.9-fold increase in baseline sCr within 48 hours
2
2.0- to 2.9-fold increase in baseline sCr
3
≥ 3.0-fold increase in baseline sCr or if baseline sCr ≥ 4 mg/dL than an increase of ≥ 0.5 mg/dL
1
≥ 1.5-fold increase in baseline sCr within 7 days or ≥ 0.3 mg/dL increase within 48 hours
2
≥ 2.0-fold increase in baseline sCr
3
≥ 3.0-fold increase in baseline sCr or an increase to ≥ 4.0 mg/dL
AKIN
KDIGO
AKIN = acute kidney injury network; KDIGO = kidney disease improving global outcomes; RIFLE = risk, injury, failure, loss of kidney function
and end-stage kidney disease; sCr = serum creatinine.
Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion
and Renal Function). Diuretic response was calculated
using the weight change per 40 mg of furosemide, and
as diuretic response declined there was increasing risk of
60-day rehospitalization and 180-day mortality rates. In
fact, the lowest quintile responders had a 25% mortality
rate at 180 days [20].
Emerging Biomarkers
Urine Neutrophil Gelatinase-Associated Lipocalin
Because previous studies showed urinary levels of
NGAL was an earlier and more reliable marker of
renal dysfunction than creatinine in AKI [21], it was
studied as a possible biomarker for the development of
CRS1 in ADHF. A single-centered study quantified
levels of urine NGAL in 100 patients admitted with
heart failure and then tracked the rates of acute kidney injury. Urine NGAL was elevated in patients that
developed AKI and a cut-off value 12 ng/mL had a
sensitivity of 79% and specificity of 67% for predicting CRS1 [22]. While promising, further studies are
needed to better define the role of NGAL in CRS1.
Cystatin C
Cystatin C is a ubiquitously expressed cysteine protease
that has a constant production rate and is freely filtered by
the glomerulus without being secreted into the tubules,
and has effectively prognosticated outcomes in ADHF
446 JCOM October 2015 Vol. 22, No. 10
[23]. Lassus et al showed an adjusted hazard ratio of 3.2
(2.0–5.3) for 12-month mortality when cystatin C levels
were elevated. Moreover, patients with the highest tertitle
of NT-proBNP and cystatin C had a 48.7% 1-year mortality. Interestingly, patients with an elevated cystatin C but
normal creatinine had a 40.6% 1-year mortality compared
to 12.6% for those with normal cystatin C and creatinine
[24]. Furthermore, Arimoto et al showed elevated cystatin
C predicted death or rehospitalization in a small cohort of
ADHF patients in Japan [25]. Also, Naruse et al showed
cystatin C was a better predictor of cardiac death than
estimated GFR by the Modification of Diet in Renal
Disease Study (MDRD) equation [26]. Finally, ManzanoFernandez et al showed the highest tertile of cystatin C
was a significant independent risk factor for 2-year death
or rehospitalization while creatinine and MDRD estimates
of GFR were not [27]. In agreement with Lassus et al,
elevations in either 2 or 3 of cystatin C, troponin, and
NT-proBNP predicted death or rehospitalization when
compared to those with normal levels of these 3 markers
[27]. In conclusion, cystatin C either alone or in combination with other biomarkers identifies high-risk patients.
Kidney Injury Molecule 1
Kidney injury molecule 1 (KIM-1) is a type-1 cell membrane glycoprotein expressed in regenerating proximal
tubular cells but not under normal conditions [28].
Although associated with increased risk of hospitalization
and mortality in chronic heart failure [29,30], elevated
levels of urinary KIM-1 did not predict mortality in
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CLINICAL REVIEW
Table 2. Definition of Diuretic Responsiveness (DR) by Study and Associated Patient Outcomes
Author
Definition of Diuretic Responsiveness
Outcomes
Testani et al
Urine output/40 mg of furosemide
Increased mortality in low DR
Voors et al
Weight change/diuretic dose over 5 days
Increased mortality and rehospitalization rates in low DR
Valente et al
Weight change/40 mg of furosemide
Increased mortality and rehospitalization rates in low DR
ADHF [31]. Further studies are needed to elucidate the
utility of KIM-1 in CRS1.
Treatment Approaches
Diuretics
Loop diuretics are the main treatment for decongestion of patients with CRS1. To date, no clinical trial
has compared the different loop diuretics (furosemide,
bumetanide, torsemide, or ethacrynic acid) to each other,
so there is no clear choice of which loop diuretic is the
best. However, dosing scheme was investigated in the
Dose Optimization Strategies Evaluation (DOSE) trial.
In this trial, 308 patients were randomized in a 1:1:1:1
design in which patients were placed in groups with lowdose (equivalent to oral dose) or high-dose (2.5 times
oral dose) intermittent parental therapy or alternatively
low-dose or high-dose continuous drip therapy. There
were no differences in dyspnea, fluid changes, change in
creatinine, hospital length stay, or rehospitalization and
death rates when the intermittent and drip approaches
were compared. However, the high-dose arm had decreased dyspnea, increased volume removal, but there
were more occurrences of AKIs when compared to the
low-dose arm [32].
In clinical practice, if loop diuretic treatment does not
result in the desired urine output, a second-site diuretic
may be added to potentiate diuresis. Unfortunately, there
is little data on this common clinical practice and thus
the optimal choice of second site agent (chlorthiazide or
metolazone) is unknown. Frequently, the deciding factor is based upon cost or concern that oral absorption of
metolazone will be ineffective. However, Moranville et al
recently performed a retrospective assessment comparing
chlorthiazide (22 patients) to metolazone (33 patients)
in ADHF patients with renal dysfunction defined by a
creatinine clearance of 15–50 mL/min. There was a nonsignificant trend towards increased urine output in the
metolazone group, no differences in the rates of adverse
events, and the chlorthiazide group actually had a longer
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hospital stay [33]. While potentially promising results,
the retrospective nature of the study made it difficult
to determine if the differences were due to treatment
approach or dissimilarities of patient illness. Nonetheless, physicians must remain vigilant when implementing
the second-site diuretic approach because it can lead to
marked diuretic response leading to metabolic derangements including hypokalemia, hyponatremia, hypomagnesaemia, and metabolic alkalosis.
Inotropes
The use of inotropic agents such as dobutamine or milrinone can be used to augment cardiac function when
there is a known low-output state for better renal perfusion in CRS1. Unfortunately, there is little objective data
available about the utility of this widely implemented
approach. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of a Chronic Heart
Failure (OPTIME-HF) trial did not show improved
renal function with milrinone treatment [34]. The use of
levosimendan, a cardiac calcium sensitizer that increases
contractility not currently approved in the United States,
was compared to dobutamine in the Survival of Patients
With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) trial, and there were no
differences in rates of renal failure when the 2 groups
were compared [35]. Nonetheless, if cardiac output is
severely compromised, inotropes can be used for CRS1
treatment, but they should be used cautiously due the
increased risks of lethal arrhythmias.
Dopamine
Use of low-dose dopamine to stimulate D1 and D2 receptors as a way to increase renal blood flow and promote
increased glomerular filtration and urine production was
extensively studied in ADHF. A small trial showed use of
low dose dopamine had renal protective effects in a total
of 20 patients [36]. However, when larger trials were
conducted, such beneficial results were not consistently
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CARDIORENAL SYNDROME 1
observed. The Dopamine in Acute Decompensated
Heart Failure (DAD-HF I) trial compared low-dose
furosemide plus low-dose dopamine (5 µg/kg/min) to
high-dose furosemide alone in 60 patients. There were
no differences in total diuresis, hospital stay, and 60day mortality or rehospitalization rates, but there was a
reduction in the renal dysfunction at the 24-hour time
point in the dopamine-treated arm (6.7% versus 30%)
[37]. The Dopamine in Acute Decompensated Heart
Failure II trial randomized 161 ADHF patients to highdose furosemide, low-dose furosemide and lose dose
dopamine (5 µg/kg/min), or low-dose furosemide and
assessed dyspnea, worsening renal function, length of
stay, 60-day and one-year all-cause mortality and hospitalization for heart failure. Dopamine treatment did not
improve any of the outcomes measured [38]. Finally, the
most recent trial to examine the effects of dopamine was
the Renal Optimization Strategies Evaluation (ROSE)
trial. In this trial, there were 360 patients with ADHF
randomized to nesiritide or dopamine versus placebo in
a 2:1 design. When comparing dopamine (111 patients)
treatment to placebo (115 patients), there were no differences in urine output, renal function as determined by
cystatin C levels, or symptomatic improvements. However, there was more tachycardia in the dopamine group
[39]. Currently, there is not strong evidence supporting
routine use of dopamine in CRS1.
Nesiritide
Use of nesiritide, recombinant brain natriuretic peptide,
was also investigated as a way to enhance urine production through the natriuretic effects of the peptide. The
first attempt to explore this hypothesis was the B-Type
Natriuretic Peptide in Cardiorenal Decompensation
Syndrome (BNP-CARDS) trial. BNP-CARDS showed
a 48-hour infusion of nesiritide (39 patients) or placebo
(36 patients) in patients with ADHF and renal dysfunction (estimated GFR between 15–60 mL/min) did not
reduce the incidence of worsening renal function as defined by a rise in serum creatinine by 20% [40]. A similar
approach was implemented in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart
Failure (ASCEND-HF) trial which examined over 7000
patients with ADHF. 3496 patients were treated with
nesiritide and 3511 patients were treated with placebo for
24 hours and up to 7 days. Nesiritide treatment did not
alter dyspnea at 6 and 24 hours, improve renal function as
determined by creatinine change, or alter the combined
448 JCOM October 2015 Vol. 22, No. 10
end-point of rehospitalization or death 30 at days [41].
The ROSE trial examined the effects of nesiritide (117 patients) versus placebo (115 patients) for urine production,
change in renal function as defined by change in cystatin
C, and decongestion (urinary sodium excretion, weight
change, and change in NT-proBNP) at 72 hours. Nesiritide did not alter any of the outcomes investigated [39]. Finally, a single-centered study conducted at the Mayo Clinic
examined the effects of nesiritide (37 patients) or placebo
(35 patients) with ADHF and pre-existing renal dysfunction (estimated GFR between 20 and 60 mL/min). These
investigators found nesiritide treatment resulted in less
renal dysfunction as measured by creatinine and BUN,
but no changes in diuretic responsiveness, duration of
hospitalization, or rehospitalization rates. Nesiritide did
reduce serum endothelin levels, but had no effect on ANP,
NT-pro BNP, renin, angiotensin II, or aldosterone [42].
In summary, nesiritide does not appear to have significant
renal protective effects in ADHF.
Adenosine A1 Receptor Antagonists
The use of adenosine receptor antagonists to prevent adenosine-mediated vasoconstriction of renal vasculature in
ADHF has also been examined. The first study conducted was a small double-blind randomized-controlled trial
that investigated the effects of rolofylline, an adenosine
A-1 antagonist, in patients with ADHF and an estimated
creatinine clearance of 20-80 mL/min. The study had 27
patients in the placebo arm, 29 patients that received 2.5
mg of rolofylline, 31 patients received 15 mg of rolofylline, 30 patients received 30 mg of rolofylline, and 29
patients received 60 mg of rolofylline, all of which was
daily for up to 3 days. Rolofylline treatment increased
urine output on day 1 and improved renal function on
day 2 [43]. These positive results led to the Placebo-Controlled Randomized Study of Selective Adenosine A1
Receptor Antagonist Rolofylline for Patients with Acute
Decompensated Heart Failure and Volume Overload to
Assess Treatment Effect on Congestion and Renal Function (PROTECT) Trial. PROTECT assessed the effects
of rolofylline (1356) or placebo (677) in patients with
ADHF and an estimated creatinine clearance between
20 and 80 mL/min. There were no significant differences in renal function out to 14 days, but rolofylline led
to more weight loss than placebo [44,45]. In a subgroup
analysis of patients with severe baseline renal dysfunction (creatinine clearance of less than 30 mL/min),
rolofylline reduced the combined 60-day end-point of
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CLINICAL REVIEW
hospitalization due to cardiovascular or renal cause and
death [45]. Finally, the Effects of KW-3902 Injectable
Emulsion on Heart Failure Signs and Symptoms, Diuresis, Renal Function, and Clinical Outcomes in Subjects
Hospitalized with Worsening Renal Function and Heart
Failure Requiring Intravenous Therapy (REACH-UP)
trial probed the effects of rolofylline (36 patients) or
placebo (40 patients) in patients with ADHF and renal
impairment (creatinine clearance of 20-60 mL/min).
Rolofylline treatment did not alter renal function, but
there was a nonsignificant trend towards reduction in
60-day combined end-point of hospitalization due to
renal or cardiovascular causes or death [46]. In summary,
the use of rolofylline has not been conclusively associated
with improved outcomes in CRS1.
Vasopressin Antagonists
The use of vasopressin antagonists to induce aquaphoresis and combat hyponatremia was studied in ADHF.
Vasopressin antagonists were first investigated in the
Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist (ACTIV) trial. ACTIV involved 3 doses
of tolvaptan (78 patients received 30 mg, 84 patients
received 60 mg, and 77 patients received 90 mg) versus
placebo (80 patients), and tolvaptan increased urine production and decreased body weight compared to placebo
without compromising renal function. A post-hoc analysis of patients with renal dysfunction (BUN > 29 mg/dL)
and severe volume overload revealed a survival benefit
at 60 days [47]. The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan
(EVERST) trial compared placebo (2061 patients) versus
30 mg/day of tolvaptan (2072 patients) within 48 hours
after admission in an identical 2-trial design. Tolvaptan
increased weight loss and reduced dyspnea acutely but
did not alter all-cause mortality or cardiovascular or heart
failure hospitalization rates out to 24 months post index
hospitalization [48,49]. These data suggest vasopressin
antagonists may potentiate diuresis acutely but likely do
not improve long-term outcomes.
Corticosteroids
The use of corticosteroids in ADHF has been controversial as there were initial concerns that corticosteroids
would increase fluid retention. However, corticosteroids
augmented diuretic response and improved renal function in 13 ADHF patients who had inadequate response
to sequential nephron blockage [50]. Furthermore,
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Zhang et al showed that prednisone treatment in 35
patients admitted with ADHF increased urinary volume,
reduced dyspnea, reduced uric acid, and improved renal
function [51]. These promising results led to the Cardiac
Outcome Prevention Effectiveness of Glucocorticoids in
Acute Decompensated Heart Failure (COPE-ADHF)
trial. In this single-centered study, 102 patients with
ADHF were randomized to either placebo [51] or corticosteroids [51] and the outcomes recorded included
urinary volume, change in creatinine, and cardiovascular death at 30 days. Use of corticosteroids improved
renal function, increased urine output, and reduced
mortality (3/51 in corticosteroid group versus 10/51 in
the placebo group) [52]. The mechanisms underlying
the improvements with corticosteroids were not determined, but were hypothesized to be facilitation of natriuretic peptides or dilation of renal vasculature through
activation of nitric oxide pathway or dopaminergic
system.
Serelaxin
Serelaxin is a recombinantly expressed human relaxin-2,
a peptide hormone present during pregnancy which
facilitates physiological cardiovascular and renal adaptations [53–55], which showed potential benefits in CRS1.
Analysis of the RELAX-AHF trial revealed serelaxin
reduced incidence of worsening renal function at day 2
of treatment as defined by changes in serum creatinine,
cystatin C, and BUN. Importantly, worsening renal function defined by cystatin C changes was associated with
increased 180-day mortality in this analysis [56]. The
mechanisms by which serelaxin prevented renal dysfunction are currently unknown as serelaxin treatment did not
improve diuretic efficiency [19].
Ultrafiltration
Another treatment choice in CRS1 is mechanical removal
of salt and water via ultrafiltration. Ultrafiltration
showed early promise in Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute
Decompensated Heart Failure trial (UNLOAD) trial. In
this study, 200 patients with ADHF were randomized to
either ultrafiltration or medical management with loop
diuretics. Use of ultrafiltration increased volume removal
without any differences in renal function and reduced
rehospitalization rates at 90 days [57].
However, when ultrafiltration was employed specifically in CRS1 patients in the Cardiorenal Rescue Study
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CARDIORENAL SYNDROME 1
in Acute Decompensated Heart Failure trial (CARESSHF), UF was not superior to medical treatment. There
were 188 patients studied in CARESS-HF, and in the
ultrafiltration arm there was increased risk of renal
dysfunction, no differences in volume removal, and no
change in rehospitalization rates at 90 days [58]. When
trying to reconcile UNLOAD and CARESS-HF, the
medical treatment arm in CARESS-HF was much more
standardized and aggressive and UNLOAD was earlier
implementation of ultrafiltration, which may have explained the differences. Interestingly, ultrafiltration was
hypothesized to be advantageous over diuretic therapy
through reduced activation of the renin-angiotensinaldosterone system, but analysis of the patients from
CARESS-HF showed higher levels of plasma renin activity and no difference in aldosterone levels in ultrafiltration patients [59].
Two meta-analyses have examined the use of ultrafiltration versus medical management in ADHF and both
showed ultrafiltration was more effective in volume removal than medical therapy but did not improve rehospitalization or mortality rates [60,61]. This fact combined
with the risks of vascular access placement and bleeding
from anticoagulation limits to routine use of ultrafiltration in CRS1.
Continuous Renal Replacement Therapy
Once renal function deteriorates to the point that renal
replacement therapy is needed for both volume removal
and solute clearance in CRS1, continuous renal replacement therapy (CRRT) may be implemented. Unfortunately, there are few available data for this group of
advanced CRS1 patients to guide physicians. There was
a single-centered study conducted in Egypt that randomized 40 ADHF patients to either IV furosemide
or CRRT. The patients treated with CRRT had greater
weight loss and decreased length of stay in the ICU, but
there were no differences in dialysis dependence rates
or 30-day mortality [62]. Two single-centered studies
reported outcomes associated with advanced CRS1 requiring CRRT. In a study conducted at the Cleveland
Clinic, 63 patients with CRS1 were treated with ultrafiltration, of which 37 were converted to CRRT due to
worsening renal function. Of the 37 patients treated with
CRRT, 16 died in the hospital and 4 were discharged
with hospice care [63]. In another retrospective study
performed at the University of Alabama-Birmingham,
use of rescue CRRT in advanced CRS1 was examined
450 JCOM October 2015 Vol. 22, No. 10
in 37 patients. 23 patients died during hospitalization
and 2 were discharged to hospice care [64]. Combination of the Cleveland Clinic and University of AlabamaBirmingham studies revealed patients requiring CRRT
in the setting of advanced CRS1 had an in-hospital
mortality or palliative discharge rate of 60.8% (45/74).
Clearly, this population needs further investigation to
prevent such poor outcomes.
A summary of treatment approaches for CRS1 is presented in Table 3.
Future Treatment Options
Ongoing and Unreported Clinical Trials
Unfortunately, none of the current treatments for CRS1
have definitive improvements in outcomes, but there are
several ongoing clinical trials which will hopefully identify
novel treatment strategies. First of all, the Acetazolamide
and Spironolactone to Increase Natriuresis in Congestive
Heart Failure (Diuresis-CHF) trial is being conducted in
Belgium. This study will examine the effects of acetazolamide with low dose diuretic versus high dose diuretics
in one aim and the effects of upfront spironolactone in
another. The outcomes analyzed will include total natriuresis, potassium homeostasis, NT-proBNP changes,
change in renal function, peak serum levels of renin and
aldosterone, weight change, urine volume, and change
in edema (NCT01973335). The Protocolized Diuretic
Strategy in Cardiorenal Failure (ProDius) trial is being
performed at the University of Pittsburgh, and will determine the effects of a protocolized diuretic approach to
target 3-5 liters of urine production a day versus standard
therapy and will track the change in body weight, length
of hospitalization, reshospitalization rates, mortality rates,
venous compliance of internal jugular vein, clinical decongestion, change in renal function, and urine output
(NCT01921829). The Levosimendan versus Dobutamine
for Renal Function in Heart Failure (ELDOR) study
is ongoing in Sweden and will probe the acute effects
of levosimendan and dobutamine on renal perfusion.
The endpoints will include changes in renal blood flow,
GFR, renal vascular resistance, central hemodynamics,
renal oxygen extraction and consumptions, and filtration
fraction (NCT02133105). Finally, the Safety and Efficacy of Low Dose Hypertonic Saline and High Dose
Furosemide for Congestive Heart Failure (REaCH) trial
probed the effects of combination of hypertonic saline
and furosemide versus furosemide in patients with ADHF
and renal impairment defined by a GFR<60 mL/min.
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CLINICAL REVIEW
Table 3. Summary of Treatment Approaches for CRS1 Including Pathophysiology Targeted, Benefits, and Drawbacks
Treatment
Strategy
Pathophysiology
Targeted
Diuretics
Level of
Evidence*
Benefits
Drawbacks
Volume overload and elevated CVP
Effective for volume removal
Metabolic derangements
1b
Inotropes
Reduced cardiac output
May improve renal perfusion in low output state
Increased risk of arrhythmias
5
Dopamine
Altered renal perfusion
No clear benefits
Increased risk of arrhythmias
(tachycardia)
1b
Nesiritide
Volume overload
No clear benefits
Cost and hypotension
1b
Adenosine antagonists
Adenosine-mediated renal
vasoconstriction
May potentiate diuresis
Not FDA-approved, seizures
1b
ADH antagonists
Volume overload and hyponatremia
May potentiate diuresis and improve hyponatremia
Costs, no improvements in hard outcomes
1b
Corticosteroids
Unknown: Possibly renal
perfusion and anti-
inflammatory effects
Increased urine output, improved renal function and survival
Hyperglycemia, hypertension, and delirium
1b
Serelaxin
Unknown: Possibly renal
perfusion
Reduced incidence of renal
impairment
Not FDA-approved
2b
Ultrafiltration
Volume overload and elevated CVP
Increased fluid removal as compared to diuretic management
Costs and risks of complications associated with
access placement and
anticoagulation
1a
Continuous renal replacement therapy
Volume overload and elevated CVP
No clear benefits
Costs and risks of complications associated with
access placement and
anticoagulation
2b
*1a: systematic reviews (with homogeneity) of randomized controlled trials; 1b: individual randomized controlled trials (with narrow confidence interval); 2b: individual cohort study or low-quality randomized controlled trials (eg, < 80% follow-up); 5: expert opinion without explicit
critical appraisal, or based on physiology, bench research, or "first principles."
The outcomes were change in renal function, diuretic
response, length of hospital stay, readmission rates, weight
loss, BNP levels, and included a cost analysis. The study
was completed but results are not currently available
(NCT01028170)
Should Inflammation Be Targeted in CRS1?
Although proposed to play a role in the pathophysiology
of CRS1, inflammation has not been explicitly targeted
as a treatment for CRS1. One possible way to combat
inflammation could be inhibition of the IL-6 pathway,
which is support by preclinical work as previous studies
showed IL-6 knockout mice were resistant to HgCl2-induced renal injury and death [65] and IL-6 has negative
inotropic effects in both isolated cardiomyocytes [66]
and intact animals [67]. Thus, IL-6 antagonism may improve both cardiac and renal function, an ideal scenario
for CRS1 patients. The availability of tocilizumab, an
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FDA-approved humanized antibody to the IL-6 receptor, may allow for investigation of this hypothesis in the
future. Although not examined in the COPE-ADHF
trial, an alternative explanation for the improvements
associated with corticosteroids treatment were the antiinflammatory effects. If this were true, corticosteroids
would represent a relatively cheap treatment option for
CRS1 patients, but more studies need to be conducted
before this approach is widely implemented. Finally, use
of cytokine profiling may be used to enrich a population
of CRS1 patients that could be investigated in future
clinical trials using anti-inflammatory medications.
Unanswered Questions Moving Forward
Severity of AKI and Treatment Effects
An important unknown that warrants further investigation is if the severity of AKI should dictate treatment
choice in CRS1. As discussed above, increasing severity
Vol. 22, No. 10 October 2015 JCOM 451
CARDIORENAL SYNDROME 1
of AKI resulted in elevated risk of adverse events, but
it remains unknown whether different treatments offer
benefits for more or less severe renal impairment. Perhaps, future studies aimed at defining outcomes from
different treatment strategies stratified by severity of
renal dysfunction may reveal which patients benefit from
the various treatment options for CRS1.
How Do We Best Define Renal Dysfunction in CRS1?
Currently, there is no accepted definition of renal dysfunction in CRS1. As discussed above, using the AKIN,
KDIGO, or RIFLE scoring systems or diuretic responsiveness effectively differentiated outcomes in patients
with CRS1. However, an agreed-upon definition would
likely benefit the field going forward so this population
could be systematically investigated in future studies.
Conclusion
In summary, CRS1 is a common clinical entity associated
with poor patient outcomes. A complex pathophysiology marked by reduced cardiac output, increased central
venous pressure, inflammation, and oxidative stress
underlies the disease process. Unfortunately, no current
treatment approach shows consistent improvements in
outcomes, highlighting the urgent need for further research to reduce the burden that CRS1 imposes.
Corresponding author: Kurt W. Prins, MD, PhD, MMC
580 Mayo, 420 Delaware St SE, Minneapolis, MN 55455,
[email protected].
Funding/support: Dr. Prins is funded by NIH F32 grant
HL129554 and Dr. Thenappen is funded by AHA Scientist
Development Grant 15SDG25560048.
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