Curr Cardiol Rep (2013) 15:380

DOI 10.1007/s11886-013-0380-4

CONGESTIVE HEART FAILURE (J LINDENFELD, SECTION EDITOR)

Cardiorenal Syndrome: Pathophysiology and Treatment

Dmitry Shchekochikhin & Robert W. Schrier &
JoAnn Lindenfeld

# Springer Science+Business Media New York 2013

Abstract CRS is a common problem in patients with advanced heart failure. Arterial underfilling with consequent
neurohormonal activation, systemic and intrarenal vasoconstriction, and salt and water retention cause the main clinical
features of CRS which include a progressive decline in renal
function, worsening renal function during treatment of heart
failure (HF) decompensation and resistance to loop diuretics. Impaired renal function in HF patients often reflects
more advanced stages of cardiac failure, and thus is associated with a worse prognosis. However, a transient fall in
glomerular filtration rate may be a result of successful treatment of congestion, and thereby might not be associated with
decreased survival in HF patients. This review covers basic
pathophysiological mechanisms underlying the CRS and current trends in practical approaches to treat these patients.
Keywords Cardiorenal syndrome . CRS . Arterial
underfilling . Ultrafiltration . Heart failure . Worsening renal
function

Introduction
In 2004 a working group was appointed by the National
Heart, Lung, and Blood Institute to "evaluate the current

state of knowledge regarding interactions between the cardiovascular system and the kidney, to identify critical gaps
in our knowledge, understanding, and application of research tools, and to develop specific recommendations for
NHLBI in cardio-renal interactions related to HF and other
cardiovascular diseases" [1]. This group attributed
cardiorenal dysregulation in HF (HF) to interactions between the kidney and circulatory systems that result in
increased circulating volume and exacerbate the course of
HF [1]. The group defined CRS (CRS) as the extreme form
of cardiorenal dysfunction in which therapy to relieve the
congestive symptoms of HF is limited by a decline in renal
function manifested as a reduction in glomerular filtration
rate (GFR). Worsening renal function (WRF) during HF
management and the development of resistance to loop diuretics were included in the clinical features of CRS [2].
Although substantial attention has been focused on CRS in
the setting of acutely decompensated HF (ADHF), a widely
accepted definition of CRS had not been developed [36].
CRS has been defined as a complex pathophysiological
disorder of the heart and kidneys, in which acute or chronic
dysfunction of one organ may induce acute or chronic
dysfunction in the other. According to chronicity and the
primary organ affected, CRS was classified into 5 types [7].
&

This article is part of the Topical Collection on Congestive Heart

Failure
D. Shchekochikhin (*)
Department of Preventive and Emergency Cardiology,
I.M.Setchenovs First Moscow State Medical University, 119992,
6 (1), Bolshaya Pirogovskaya str., Moscow, Russia
e-mail: agishm@list.ru
R. W. Schrier
University of Colorado Denver, 12700 East 19th Ave C281,
Aurora, CO 80045, USA
e-mail: robert.schrier@ucdenver.edu
J. Lindenfeld
University of Colorado Denver, 1635 Aurora Ct F745, Room
7083, Aurora, CO 80045, USA
e-mail: Joann.Lindenfeld@ucdenver.edu

&
&

&
&

Type 1 (acute) Acute HF results in acute kidney

injury (AKI), previously called acute renal failure.
Type 2 Chronic cardiac dysfunction (e.g., chronic
HF) causes progressive chronic kidney disease (CKD),
previously called chronic renal failure.
Type 3 Abrupt and primary worsening of kidney
function due, for example, to renal ischemia or glomerulonephritis causes acute cardiac dysfunction, which
may be manifested by HF.
Type 4 Primary CKD contributes to cardiac dysfunction,
which may be manifested by coronary disease, HF, or
arrhythmias.
Type 5 (secondary) - Acute or chronic systemic disorders (e.g., sepsis or diabetes mellitus) that cause both
cardiac and renal dysfunction.

380, Page 2 of 9

Thus, Types 1 and 2 could be designated as CRS since

cardiac dysfunction is the initiating event. In contrast, Types
3 and 4 could be designated as renocardiac syndrome since
renal dysfunction is the initiating event. Lastly, in some
circumstances, mainly Type 5, involve both cardiac and
kidney dysfunction may be initiating events. Moreover, in
Types 1 and 2, the terms AKI and CKD respectively could
be misinterpreted, since the majority of the effects on the
kidney may be functional and thus reversible. In this review
we will focus on CRS during ADHF, i.e., Type 1.

Pathophysiology of CRS
In normal conditions, cross-talk between the heart and kidneys occurs through atrial-renal reflexes [8], which maintain
total body volume in normal range. For example, an increase in atrial pressure suppresses release of arginine vasopressin (AVP) through the Henry-Gauer Reflex and also
suppresses renal sympathetic tone [9]. The increase in filling
pressures also results in the release of natriuretic peptides
(ANP and BNP) [10]. The result of these atrial-renal reflexes is to increase renal sodium and water excretion.
However, in the setting of HF these normal responses are
attenuated by activation of neurohumoral systems caused by
arterial underfilling [11]. Underfilling of the arterial circulation occurs because of a decrease in cardiac output in lowoutput HF and arterial vasodilatation in high-output HF. In
both types of HF the inhibitory effect of the arterial stretch
baroreceptors on the neurohumoral systems are decreased,
leading to systemic and intrarenal vasoconstriction, as well
as enhanced renal water and sodium reabsorption [12]
(Fig. 1). The main mediators of these events are the reninangiotensin-aldosterone system, catecholamines and AVP.
An increase in renin secretion with secondary stimulation
of angiotensin II (Ang II) is observed during early stages of
Fig. 1 Volume regulatory
hypothesis. Sequence of events
in which reduced cardiac output
initiates renal sodium and water
retention. (With permission
from: Schrier RW. Body fluid
volume regulation in health and
disease: a unifying hypothesis.
Ann Intern Med.
1990;113(2):155-9) [12]

Curr Cardiol Rep (2013) 15:380

HF [13]. Ang II has many effects, including increase in

thirst, stimulation of the sympathetic nervous system [8,
14], and systemic and renal vasoconstriction [13, 14]. Moreover, Ang II stimulates the synthesis of aldosterone, the
main salt-retaining hormone [15]. In normal settings
aldosterone-induced sodium retention is temporary and does
not cause edema because the increase in vascular volume
enhances sodium delivery to distal renal tubules which overrides the sodium retaining effect of aldosterone within 3 days
(aldosterone escape) [13, 14]. However, in patients with HF
this "aldosterone escape" is prevented by diminished renal
perfusion and impaired sodium delivery to the distal tubule.
The sodium that reaches the distal tubules is reabsorbed,
with resultant pulmonary congestion and edema [8, 13, 14].
Prolonged elevation in aldosterone also promotes fibrosis in
the failing myocardium which exacerbates cardiac dysfunction which in turn exacerbates the CRS [15].
Intrarenal vasoconstriction and decreased sodium delivery to the distal tubules also attenuates the salt losing effects
of natriuretic peptides [8, 16]. Another possible mechanism
of impaired natriuretic peptides action is the downregulation
of their receptors [14] (Fig. 2).
Although serum catecholamines are increased in patients
with HF, a decrease in myocardial catecholamines has been
observed [17]. The decrease in cardiac catecholamines is a
result of maximal myocardial secretion with limited uptake.
Thus the heart cannot respond to increased sympathetic
stimulation. Sympathetic stimulation also results in several
renal effects. Stimulation of alpha adrenergic receptors on
the proximal tubule enhances sodium reabsorption, while
beta-stimulation activates renin secretion in the juxtaglomerular
apparatus [8]. Moreover, in HF patients postglomerular capillary pressure falls and oncotic pressure rises, further enhancing
proximal tubular sodium reabsorption. Thus it is not surprising
that elevated plasma norepinephrine levels correlate with poor
prognosis in HF patients [16].

Curr Cardiol Rep (2013) 15:380

Fig. 2 Cardiorenal syndrome. Decreased baroreceptors sensitivity in

patients with chronic heart failure can worsen cardiac function by
increasing renin-angiotensin-aldosterone system (RAAS) and sympathetic activity, enhancing proximal fluid reabsorption, impairing aldosterone escape, and blunting the response to natriuretic peptides. Na,
sodium. (With permission from: Schrier RW. Role of diminished renal
function in cardiovascular mortality: marker or pathogenic factor? J
Am Coll Cardiol. 2006; 47:1-8) [8]

AVP, the antidiuretic hormone, is secreted from posterior

pituitary gland in response to increased plasma osmolality
and arterial underfilling. In HF there is nonosmotic release
of AVP, despite normal or even decreased serum osmolality
[18]. Activation of vasopressin V1 receptors results in an
increase in systemic vascular resistance and whereas V2 receptor activation results in an increase in water reabsorption in
the renal collecting ducts leading to hyponatremia. AVP also
enhances the activity of urea transporters in collecting ducts,
resulting in increased blood urea nitrogen [19].
In patients with advanced HF, arterial underfilling is
more pronounced resulting in even greater activation of
neurohormonal systems. This intense neurohumoral activation leads to volume retention, hyponatremia, and azotemia.
Systemic and intrarenal vasoconstriction and increased
proximal sodium and water reabsorption increase susceptibility of HF patients to secondary insults, such as
nephrotoxic agents (e.g., contrast media), sepsis and
hemodynamic alterations, including hypotension and increased renal venous pressure.

Increased Venous Pressure as a Cause of Diminished

Renal Function
In 1861 Ludwig observed in an experimental model that a
decrease in urine output as soon as central venous pressure
(CVP) increased above 10 mmHg [20]. In 1931 Winton also
showed the influence of elevated renal venous pressure on
isolated kidneys from dogs [21]. A rise in CVP with

Page 3 of 9, 380

transmission to the renal venous system increases renal

afterload and intrarenal pressure. The increase in intrarenal
pressure decreased renal perfusion and intratubular flow
resulting in a fall in GFR and an increase in sodium and
water reabsorption.
Volume overload therefore is a hallmark of ADHF. In a
prospective cohort study from Cleveland Clinic, increased
CVP and failure to decrease this elevated CVP with treatment were the most important hemodynamic factors causing
WRF [22]. Retrospective analysis of 2557 HF patients who
underwent cardiac catheterization revealed CVP as the most
important predictor of WRF and mortality [23]. Moreover,
increased intraabdominal pressure secondary to ascites and
visceral edema has been shown to correlate with WRF in HF
patients, and lowering intraabdominal pressure resulted in
increased GFR [24]. This fall in GFR is related to increase in
inferior vena caval and thus renal venous pressure secondary to the elevated intraabdominal pressure [25]. Thus, the
influence of increased venous pressure on WRF makes
decongestion a cornerstone of AHDF treatment in patients
with CRS.

Epidemiology of Decreased Baseline Renal Function

Renal dysfunction is a prevalent comorbidity in HF, both in
stable outpatients and in hospitalized decompensated patients. As many as 40 % of the patients with coronary artery
disease and stable HF have been shown to have decreased
GFR (<60 ml/min/1.73 m2) [26]. ADHF represents a phase
of HF with dynamic changes in hemodynamics, neurohumoral activation and medication use, that could influence
renal function.
Baseline renal function during a HF admission has
been associated with prognosis in several studies. The
Acute Decompensated HF National Registry (ADHERE)
comprising 118,465 ADHF patients revealed that moderate (GFR 30-59 ml/min/1.73 m2) and severe renal
dysfunction (GFR 15-29 ml/min/1.73 m2) and kidney
failure (GFR < 15 ml/min/1.73 m2) occurs in 43.5 %,
13.1 % and 7.0 % of Acute HF patients respectively. Inhospital mortality increased from 1.9 % for patients
with normal renal function to 7.6 % for patients with
severe dysfunction [27]. Multivariate analysis showed
that although GFR was an independent predictor of
mortality, blood urea nitrogen (BUN) was the best predictor [27]. As renal function declines in ADHF, diuretic doses and use of vasoactive drugs and inotropic
agents increase while ACE use decreases. The importance of BUN in this patient population has been evaluated in several studies. Data from the Prospective
Randomized Evaluation of Cardiac Ectopy with
Dobutamine or Natrecor (PRECEDENT) trial included

380, Page 4 of 9

541 patients with systolic HF. BUN was found to be the

only significant mortality predictor during 1-year
follow-up. The BUN/creatinine ratio showed similar
prognostic significance [28]. Post-hoc analysis of the
Acute and Chronic Therapeutic Impact of a Vasopressin
Antagonists in Chronic HF (ACTIV in CHF) trial
showed an increase in 60-day mortality and rate of
death/rehospitalizations among the patients in the
highest quartile of baseline BUN. After adjustment for
covariates, BUN remained of prognostic significance;
however GFR and serum creatinine did not [29].
Decreased renal function at the time of an admission for
ADHF was associated with a negative prognostic impact
during long-term follow up. The Worcester HF Study
(WHFS) included 4350 ADHF patients followed for a total
of 50 years follow-up and found that late mortality from
increased from 39 to 51 % as renal dysfunction progressed
from mild to severe [30]. A recent prospective study of 355
ADHF patients with 6.5 years follow-up demonstrated that
the worsening discharge serum creatinine predicted a higher
long-term mortality. Increasing tertiles of discharge GFR
were independent predictors of better long-term survival.
Multivariate analysis revealed BUN as the only significant
predictor of long-term prognosis. BUN was more discriminative that GFR in predicting long-term survival [31].
Thus, baseline renal dysfunction in ADHF patients appears to be associated with increased mortality and
rehospitalization, independent of etiology and systolic function [32]. BUN is suggested to be a better prognostic factor
than serum creatinine or GFR. This may be because AVP
increases urea, but not creatinine, reabsorption [19].

Epidemiology of Worsening Renal Function

Worsening renal function in the setting of ADHF is a
complex phenomenon. In a retrospective analysis of
1002 ADHF patients an increase in serum creatinine
was observed in 70 % of the patients, including 20 %
with an increase of 0.5 mg/dl or more. WRF was
generally observed within the first 3 days of hospitalization, and was associated with increased in-hospital
mortality and prolonged length of stay even with an
increase as small as 0.1 mg/dl in serum creatinine.
However, the best specificity and sensitivity for WRF
has been shown to be an increase of 0.3 mg/dl or more
in serum creatinine [33].
Analysis of the Milrinone for Exacerbations of Chronic
HF (OPTIME-CHF) trial demonstrated a decrease in GFR
and an increase in BUN from admission to discharge in
most patients receiving milrinone. An increase in BUN of
10 mg/dl or more during hospitalization was associated with
a worse 60-day survival [34].

Curr Cardiol Rep (2013) 15:380

In a prospective study of 509 ADHF patients WRF,

defined as an increase in serum creatinine of 0.5 mg/dl or
more, was observed in 21 % of patients; 70 % of WRF
occurred during the first 6 days of hospitalization and was
associated with increased in-hospital mortality and increased length of stay. Risk factors for WRF in that study
included diabetes mellitus, baseline renal function and diastolic ventricular dysfunction. ACE inhibitors and diuretics
however were not associated with WRF [35].
WRF in the setting of ADHF has been associated with
specific complications such as sustained hypotension [34]
and the need for cardiopulmonary resuscitation and mechanical ventilation [27]. Moreover, patients with WRF were
twice as likely to have myocardial infarction, cardiogenic
shock, stroke, sepsis and atrial fibrillation [36].

WRF and Long-Term Prognosis

A retrospective study of 2465 ADHF patients with 2-years
follow-up reported an increase in post-discharge deaths and
re-hospitalizations in patients with WRF. The survival, however, was significantly decreased in patients who had not
recovered renal function on discharge, i.e. renal dysfunction
persisted [37]. Furthermore, Analysis of Vasodilatation in
the Management of Acute Congestive HF (VMAC) study
found an increase in 6-month mortality in patients with
persistent renal dysfunction for one month after admission
compared to patients with transient WRF. Moreover, in
multivariable model transient WRF did not increase mortality significantly [38].
In-hospital changes in renal function may be related
to different mechanisms and clinical pathways, and
they reflect different prognoses [32]. In the majority
of patients with ADHF, elevated central venous pressure may be the major contributor to WRF [22]. The
importance of decreasing congestion to improve survival in these patients has been shown in several
studies. Analysis of the Evaluation Study of Congestive HF and Pulmonary Artery Catheterization Effectiveness (ESCAPE) demonstrated the importance of
decreasing congestion on prognosis, as reflected by
hemoconcentration, even if WRF occurs. Moreover,
the patients with WRF had a greater decrease in systolic blood pressure due to greater doses of vasodilators and had greater decrease in body weight. In such
cases WRF was not associated with increased mortality; however it was associated with an increased rate of
post-discharge cardiovascular events [39, 40].
The Determining Optimal Dose and Duration of Diuretic
Treatment in People with Acute HF (DOSE-AHF) Trial
demonstrated the same 60-day outcome in high-dose and
low-dose diuretic groups, even though increased rates of

Curr Cardiol Rep (2013) 15:380

WRF occurred in the high-dose group [41]. Thus, a decrease in GFR during decongestion treatment may not indicate a worse prognosis.
In a recently published post-hoc analysis of the Efficacy
of Vasopressin Antagonism in HF Study with Tolvaptan
(EVEREST) patients with persistent (up to 4 weeks) WRF
in ADHF were analyzed [42]. The patients with persistent
WRF had greater reduction in systolic blood pressure, body
weight and brain natriuretic peptide levels. In spite of these
improvements in markers of volume overload, the patients
with persistent WRF had decreased survival and increased
re-hospitalization rates [42]. One potential explanation for
these findings is that patients with WRF have higher neurohormonal activation with more secondary vasoconstriction
and volume retention [32, 43]. While the therapeutic reduction in congestion in these patients resolves pulmonary
symptoms, it may cause more hypoperfusion with more
cardiac impairment resulting in a worse prognosis.
These data suggest that relationship between congestion,
WRF and prognosis in ADHF is complex and requires
further investigation [32]. Transient WRF may reflect
short-term alterations in fluid status, associated with successful treatment of congestion, and may not be associated
with poor outcome. In contrast, persistent WRF may occur
in patients with more severe HF, neurohumoral activation,
and hemodynamic abnormalities, which are associated with
a worse prognosis [32].

Treatment
Treatment of patients with HF and decreased or decreasing renal function is a vexing clinical problem. To date
there is no specific treatment of CRS in ADHF that
unequivocally demonstrates benefit. We will discuss HF
treatments in patients with CRS, including treating congestion with diuretics and ultrafiltration, and use of vasoactive
medications.

Diuretics
Decreasing congestion is a cornerstone of ADHF treatment.
Congestion not only causes HF symptoms but likely contributes to myocardial remodeling and progressions of HF
[44, 45]. Diuretics therefore have become a first line treatment in ADHF patients with CRS. However, overdiuresis
can further decrease renal function, activate neuroactive
hormones, and thereby complicate further treatment. The
rate of fluid removal by diuretics should not exceed the
interstitial fluid mobilization rate. In patient with end-stage
renal disease such fluid mobilization has been estimated to
be 12-15 ml/min [46]. In patients with HF and arterial

Page 5 of 9, 380

underfilling there is little information about the optimal rate

of fluid mobilization.
The randomized double-blind controlled l trial Diuretic
Optimization Strategies Evaluation (DOSE) demonstrated
that there was no significant difference in global symptom
relief or change in renal function at 72 hours between
intermittent versus continuous infusion of furosemide or
between low dose (as patient outpatient dose) versus high
dose (x 2.5 times) furosemide [41]. The high-dose strategy
caused a mild renal dysfunction that was reversible at one
week. At 60-day follow-up there were no differences in
outcomes between strategies. However, the high-dose group
experienced more benefit at 72 hours in secondary outcomes, such as dyspnea, weight-loss and cardiac biomarkers. The mode and doses of diuretics in patients with
CRS, especially those who are unresponsive to initial doses,
needs investigation. The HF Society of America guideline
for AHDF recommends switching from bolus to continuous
infusion of diuretics in patients who appear to be
nonresponsive to diuretics [47]. However, this recommendation needs to be assessed in randomized studies. The
DOSE suggested that continuous infusion was not better
that bolus diuretics in all patients with ADHF but did not
specifically study patients initially unresponsive to diuretics.
Another approach to loop diuretic resistances is to add
agents that act in the distal nephron, such as thiazides or
metolazone. Alternatively, high, natriuretic doses of mineralocorticoid receptor antagonists (e.g., spironolactone 50100 mg) can be added. This approach was shown to be safe
in patients with advanced HF in a small, retrospective
single-center study [48], but should be tested in a large scale
randomized trial. With high dose mineralocorticoid receptor
antagonists, care must be taken to avoid patients with severe
renal dysfunction and to monitor potassium carefully. Ultrafiltration is another option.

Ultrafiltration
Ultrafiltration (UF) can theoretically avoid excess neurohormonal activation which occurs with loop diuretic blockade
of macula densa transport [49]. As early as 1974 UF was
used by Silverstein et al. to treat volume overload [50].
Since that time several small studies have demonstrated
benefit of UF in HF patients. In 2007 the first large study
on ultrafiltration in ADHF was published. The Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized
for Acute Decompensated HF (UNLOAD) included 200
patients in 28 centers with ADHF and volume overload.
Patients in UF arm had significantly greater weight loss at
48 hours and fewer requirements for vasoactive drugs. These patents demonstrated a trend to increase serum creatinine
during first week of the treatment. However, treatment with

380, Page 6 of 9

UF resulted in significantly fewer hospital readmissions

during 90-day follow-up [51]. Another study, Effects of
Ultrafiltration versus Diuretics on clinical, biohumoral and
hemodynamic variables in patients with Decompensated HF
(ULTRADISCO), showed greater clinical improvement and
larger decreases in aldosterone and N-terminal pro-B type
natriuretic peptide in the UF arm [52]. These studies predicted a specific benefit of UF treatment in ADHF patients with
CRS. The recent study Ultrafiltration in Decompensated HF
with CRS (CARRESS-HF) included 188 patients with acute
decompensated HF, WRF, and persistent congestion, however, failed to demonstrate benefit of UF compared to stepwise
pharmacological approach [53]. Patients in both groups had
the same weight loss, but patients in the UF group had a
greater increase in serum creatinine and more adverse events.
There were no differences in outcomes during 60-days followup. One potential explanation for these results is the heterogeneity of patients with ADHF and CRS. A small study
analyzed the impact of UF on ADHF in three different subgroups of patients with 1) volume overload and urine output
less then 1000 ml/24 h, 2) volume overload and urinary output
more then 1000 ml/24 h and 3) euvolemic patients. UF treatment resulted in increased diuresis with a fall in serum neurohormone levels in the first group but increased
neurohormone levels in the other two groups [54]. As noted
earlier, a transient increase in serum creatinine in HF patients
during treatment can represent short-term dehydration and be
a hall-mark of successful treatment. UF may be indicated in
some elderly populations with HF and preserved ejection
fraction. These patients often have CKD and are admitted
with severe volume overload. Due to hemodynamic instability
in this setting vasodilators or inotropes are not well tolerated
and diuretic resistance may be present. Thus, UF might be the
only option for treating congestion. It is clear, however, that
further studies are needed to test this hypothesis.

Vasodilators
The central focus in treatment of ADHF patients is to
decrease congestion with the expectation that as intravascular volume falls, cardiac filling pressures will decline and
symptoms will resolve. One approach is to decrease systemic vascular resistance, which would decrease mitral regurgitation, increase forward flow, and decrease filling pressures.
Sodium nitroprusside, nitroglycerine (higher doses for
arterial vasodilatation) and nesiritide are the main vasodilators used in ADHF patients. These medications may be of
value when there is a poor response to diuretics or the
necessity to resolve symptoms rapidly. Afterload reduction
by vasodilator agents can increase cardiac output reducing
arterial underfilling and thus resulting in improved renal
function in selected patients, such as those with dilated

Curr Cardiol Rep (2013) 15:380

cardiomyopathy and substantial mitral regurgitation [55,

56]. However, vasodilators may also cause hypotension
with resultant decreased renal perfusion pressure. Their
influence on renal function, therefore, is unpredictable. Concerns about WRF during natriuretic peptide, nesiritide, treatment have been reported [57]. Nevertheless, vasodilators
may be of value in highly selected patients with ADHF.

Inotropes
Inotropes may be indicated in hemodynamically unstable
patients with low CO (e.g., cardiac index < 2.0 l/min/m2),
and low systolic blood pressure (SBP), that restricts the use
of other vasoactive agents. Patents with high cardiac pressures (e.g., PCWP > 18 mmHg and/or right atrial pressure >
10 mmHg) and worsening of clinical symptoms may benefit
even though they are receiving optimal oral (ACE inhibitors, b-blockers, aldosterone antagonists) or intravenous (diuretics, vasodilators) therapy. Inotropes may also be of
benefit in critically ill patients with hemodynamic impairment and significant exercise limitation, and fluid overload
resistant to diuretics with renal and/or liver dysfunction [47,
58].
In more severe HF renal dysfunction may be a marker of
low CO. Thus, the need for inotrope use is crucial in order to
preserve blood pressure and peripheral perfusion both improving central and renal hemodynamics. The need for
inotropic therapy is associated with increased mortality;
both because it is a marker of advanced HF and also possibly due to the agents adverse events [58, 59]. Nevertheless, these agents may be used as first line treatment in HF
patients with hypotension (SBP < 100 mmHg) and peripheral hypoperfusion on a short-term basis and under close
monitoring [58, 60]. Inotropes may be used as a bridge to
more definitive treatment (e.g., cardiac transplantation) or,
most often, to facilitate a diuresis, decrease volume overload
and mitral regurgitation, thereby improving renal perfusion
and hemodynamics. The main inotropes in clinical practice
are dobutamine and the phosphoesterase inhibitor milrinone.
The calcium-channel sensitizer levosimendan is available in
Europe but not in the United States. A cross-over study of
dopamine and dobutamine in dilated cardiomyopathy revealed a sustained inotropic response at higher doses only
to the latter [61] which is why dobutamine is preferred over
dopamine as an inotrope. Several studies have assessed the
renal protective effect of low-dose (renal-dose) dopamine.
Meta-analysis in intensive care unit patients, however, revealed no benefit of low-dose dopamine for renal protection
[62]. Meanwhile, the recent Dopamine in Acute
Decompensated HF Study (DAD-HF) comparing highdose furosemide infusion with low-dose furosemide plus
low-dose dopamine demonstrated that both treatment

Curr Cardiol Rep (2013) 15:380

strategies had similar effects on urinary output, dyspnea

score and outcomes; however, the dopamine group had a
lower occurrence of WRF [63]. The inotrope, levosimendan,
showed an improvement in renal function in a small randomized study [64]; however, the main effect of any inotropic agent in ADHF is to improve cardiac function and
consequently renal function. There is no general consensus
about timing for starting inotropes. In a recent trial fluid
overloaded ADHF patients with WRF a stepwise approach
included inotropic treatment on day 3 in a case of poor
response to diuretics, low blood pressure and/or rightventricular failure. This approach was as effective as UF [53].

ACE and ARB

The role of neurohumoral inhibitors in patients with advanced HF with CRS is not well defined in the literature.
ACE inhibitors or ARBs are often withheld or their doses
decreased when there is WRF. Short-term WRF during
initiation of ACEI/ARB however does not necessarily lead
to long-term renal dysfunction [65]. In chronic HF patients
with WRF treated with ACE inhibitors, serum creatinine
was stable over a 6-month period [66]. However, there are
no data on patients with advanced HF and CRS where
extreme activation of neurohumoral axis occurs. Neurohormonal activation results in vasoconstriction of afferent and
efferent renal arterioles potentially exacerbating renal dysfunction. This scenario may be worsened in cases of
diuretic-induced arteriolar hypovolemia and hypotension
[65]. WRF reflects maximal pre- and post-glomerular vasoconstriction and blocking angiotensin II may decrease
GFR. The initial decrease in GFR represents impaired renal
perfusion, but not intrinsic renal damage. In spite of WRF
these HF patients may benefit from ACE/ inhibitors or
angiotensin receptor blockers (ARB) stabilizing both cardiac and renal function [65]. Studies reveal that patients with
baseline renal dysfunction were less likely to receive
ACE/ARB, and the prescription rate of these medications
has been shown to be inversely related to the renal function
in HF patients [42]. Nevertheless, the clinical decision to
withhold ACE/ARB in cases of WRF may not be necessary,
and any evaluation of short-term risk versus long-term benefits needs to be addressed in future studies [65].
Risk factors for WRF with initiation of ACE/ARB
are hypotension (mean BP <60 mmHg), lower left
ventricular filling pressures (<15 mmHg), higher doses
of loop diuretics and hyponatremia (serum sodium
<137 mEq/L) [66, 67]. These risk factors reflect severe
HF with extreme neurohormonal activation.
Timing of initiation ACE/ARB in ADHF has not
been studied. As a general rule, neurohumoral inhibitors should be initiated after treatment of severe

Page 7 of 9, 380

congestion. Recommendations are to decrease the doses

of diuretics when initiating ACE/ARB in patients with
baseline decreased renal function or WRF and use
lower doses of medications [68]. Close monitoring of
renal function and avoiding falls in blood pressure are
important.

Conclusions
CRS, including progressive decline in renal function,
WRF during cardiac decompensation, and diuretic resistance, is frequently present in HF patients, especially
with advanced HF. The main symptom in this setting is
congestion due to salt and water retention. Thus,
treating congestion is a cornerstone of the treatment.
However, this therapy should not cause further perturbation of hemodynamic and neurohormonal systems. An
increase in serum creatinine during treatment of congestion does not necessarily require termination of medication. In some cases it reflects treatment success and
unmasks severe HF. While clinical judgment is pivotal
in treating patients with CRS, there is a need for better
evidence-based medicine.
Acknowledgments Dr. D. Shchekochikhins cardiorenal fellowship
was sponsored by the Russian Presidents Scholarship for Studying
Abroad and Gambro UF Solutions, Inc.

Compliance with Ethics Guidelines

Conflict of Interest Dmitry Shchekochikhin declares that he has no
conflict of interest.
Robert Schrier has been a consultant for Otsuka Pharmaceutical,
Janssen Pharmaceutical.
JoAnn Lindenfeld has been a consultant for St. Jude, Medtronic,
Boston Scientific. She has received grant support from Zensun and
Medtronic. She has received travel/accommodations expenses covered
or reimbursed from FDA, NIH, AHA, ACC, HFSA, and University of
Colorado.
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
Papers of particular interest, published recently, have been
highlighted as:
Of importance
Of major importance
1. National Heart Lung Blood Institute: NHLBI Working Group.
cardiorenal connections in HF and cardiovascular disease august

380, Page 8 of 9
20, 2004. Available at http://www.Nhlbi.Nih.Gov/meeting/workshops/cardiorenalhf-hd.Htm.
2. Liang KV, Williams AW, Greene EL, Redfield MM. Acute
decompensated HF and the CRS. Crit Care Med. 2008;36:S7588.
3. Bongartz LG, Cramer MJ, Doevedans PA, Joles JA, Braam B. The
severe CRS: Guyton revisited. Eur Heart J. 2005;26:117.
4. Heywood JT. The CRS: lessons from the adhere database and
treatment options. Heart Fail Rev. 2004;9:195201.
5. Boerrigter G, Burnett Jr JC. CRS in decompensated HF: prognostic
and therapeutic implications. Curr Heart Fail Rep. 2004;1:11320.
6. Bock JS, Gottlieb SS. CRS: new perspectives. Circulation.
2010;121:2592.
7. Ronco C, Haapio M, House AA, et al. CRS. J Am Coll Cardiol.
2008;52:1527.
8. Schrier RW. Role of diminished renal function in cardiovascular
mortality: marker or pathogenic factor? J Am Coll Cardiol.
2006;47:18.
9. Linden RJ, Kappagoda CT. Atrial receptors and renal blood flow.
In: Linden RJ, Kappagoda CT, editors. Atrial Receptors.
Cambridge: University Press; 1982. p. 2359.
10. Packer M. Neurohormone interaction and adaptations in congestive HF. Circulation. 1988;77:72130.
11. Sarraf M, Masoumi A, Schrier RW. CRS in Acute Decompensated
HF. Clin J Am Soc Nephrol. 2009;4:201326.
12. Schrier RW. Body fluid volume regulation in health and disease: a
unifying hypothesis. Ann Intern Med. 1990;113(2):1559.
13. Blankstein R, Bakris GL. Renal hemodynamic changes in HF.
Heart Fail Clin. 2008;4:41123.
14. Schrier RW, Abraham WT. Hormones and hemodynamics in HF.
N Engl J Med. 1999;341:5778.
15. Weber K. Mechanisms of disease: aldosterone in chronic HF. N
Engl J Med. 2001;345:168997.
16. Cohn JN, Levine TV, Olivari MT, et al. Plasma norepinephrine as a
guide to prognosis in patients with chronic congestive HF. N Engl
J Med. 1984;311:81923.
17. Kramer RS, Mason DT, Braunwald E. Augmented sympathetic
neurotransmitter activity in the peripheral vascular bed of patients
with congestive HF and cardiac norepinephrine depletion.
Circulation. 1966;33:62934.
18. Schrier RW, Berl T, Anderson RJ. Osmotic and nonosmotic control
of vasopressin release. Am J Physiol. 1979;236:F32132.
19. Schrier RW. Blood urea nitrogen and serum creatinine: not married
in HF. Circ Heart Fail. 2008;1(1):25.
20. Ludwig C. Lehrbuch d. Physiol, 2nd edition, 1861.
21. Winton FR. The influence of venous pressure on the isolated
mammalian kidney. J Physiol. 1931;72(1):4961.
22. Mullens W, Abrahams GS, Francis GS, et al. Importance of venous
congestion for worsening renal function in advanced decompensated
HF. J Am Coll Card. 2009;53(7):58996.
23. Damman K, van Deursen VM, Navis G, Voors AA, van
Veldhuisen DJ, Hillege HL. Increased central venous pressure is
associated with impaired renal function and mortality in a broad
spectrum of patients with cardiovascular disease. J Am Coll
Cardiol. 2009;53(7):5828.
24. Mullens W, Abrahams Z, Skouri HN, et al. Elevated intraabdominal
pressure in acute decompensated HF. A potential contributor to
worsening renal function? J Am Coll Cardiol. 2008;51(3):3006.
25. Kirsch AJ, Kayton M, Hensle TW, et al. Renal effects of CO2 insufflation: oliguria and acute renal dysfunction in a rat pneumoperitoneum
model. Urology. 1994;43:4539.
26. Ezekowitz J, McAlisher FA, Humphries KH, et al. The association
among renal insufficiency, pharmacotherapy, and outcomes in
6,427 patients with HF and coronary artery disease. J Am Coll
Cardiol. 2004;44(8):158792.
27. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS,
Wigneswaran JR, Wynne J. High prevalence of renal dysfunction

Curr Cardiol Rep (2013) 15:380

and its impact on outcome in 118,465 patients hospitalized with
acute decompensated HF: a report from the ADHERE database. J
Card Fail. 2007;13(6):42230.
28. Aronson D, Mittlemann MA, Burger AJ. Elevated blood urea
nitrogen level as a predictor of mortality in patients admitted for
decompensated HF. Am J Med. 2004;116(7):46673.
29. Filippatos G, Rossi J, Lloyd-Jones DM, et al. Prognostic value of
blood urea nitrogen in patients hospitalized with worsening HF:
insights from the Acute and chronic therapeutic impact of a vasopressin antagonists in chronic HF (ACTIV in CHF) study. J Card
Fail. 2007;13(5):3604.
30. Ismailov RM, Goldberg RJ, Lessard D, Spencer FA. Decompensated
HF in the setting of kidney dysfunction: a community-wide perspective. Nephron Clin Pract. 2007;107(4):c14755.
31. Gotsman I, Zwas D, Planer D, Admon D, Lotan C, Keren A. The
significance of serum urea and renal function in patients with HF.
Medicine (Baltimore). 2010;89(4):197203.
32. Brandimarte F, Vaduganathan M, Mureddu GF, et al. Prognostic
implications of renal dysfunction in patients hospitalized with HF:
data from the last decade of clinical investigations. Heart Fail Rev.
2012. doi:10.1007/s10741-012-9317-z. Excellent review on epidemiology and prognosis in CRS.
33. Gottlieb SS, Abraham W, Butler J, et al. The prognostic importance of different definitions of worsening renal function in congestive HF. J Card Fail. 2002;8(3):13641.
34. Klein L, Massie BM, Leimberger JD, et al. Admission or changes
in renal function during hospitalization for worsening HF predict
postdischarge survival: results from the Outcomes of a Prospective
Trial of Intravenous Milrinone for Exacerbations of Chronic HF
(OPTIME-CHF). Circ Heart Fail. 2008;1(1):2533.
35. Cowie MR, Komaja M, Murray-Thomas T, Underwood J, Tiko
B. Prevalence and impact of worsening renal function in patients hospitalized with decompensated HF: results of the prospective outcomes study in HF (POSH). Eur Heart J. 2006;
27(10):121622.
36. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at
admission, and impact of worsening renal function among patients
hospitalized with HF. J Am Coll Cardiol. 2004;43:617.
37. Lanfear DE, Peterson EL, Campbell J, et al. Relation of worsening
renal function during hospitalization for HF to long-term outcomes
and rehospitalization. Am J Cardiol. 2011;107(1):748.
38. Aronson D, Burger AJ. The relationship between transient and
persistent worsening renal function and mortality in patients with
acute decompensated HF. J Card Fail. 2010;16(7):5417. The
difference between transient and persistent WRF for prognosis.
39. Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: insight from the ESCAPE trial. J Am Coll Cardiol.
2008;51(13):126874.
40. Testani JM, Coca SG, McCauley BD, Shannon RP, Kimmel SE.
Impact of changes in blood pressure during the treatment of acute
decompensated HF on renal and clinical outcomes. Eur J Heart
Fail. 2011;13(8):87784.
41. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients
with acute decompensated HF. N Engl J Med. 2011;364(9):797805.
First randomized study on diuretics in ADHF.
42. Blair JE, Pang PS, Schrier RW, et al. Changes in renal function
during hospitalization and soon after discharge in patients admitted
for worsening HF in the placebo group of the EVEREST trial. Eur
Heart J. 2011;32(20):256372.
43. Ruggenenti P, Remuzzi G. Worsening kidney function in
decompensated HF: treat the heart, dont mind the kidney. Eur
Heart J. 2011;32(20):24768.
44. Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic
compensated to acute decompensated HF:pathophysiological insights
obtained from continuous monitoring of intracardiac pressures.
Circulation. 2008;118:143341.

Curr Cardiol Rep (2013) 15:380

45. Jain P, Massie BM, Gattis WA, Klein L, Gheorghiade M. Current
medical treatment for the exacerbation of chronic HF resulting in
hospitalization. Am Heart J. 2003;145(2 Suppl):S3S17.
46. Fauchauld P. Effects of ultrafiltration of body fluid and transcapillary
colloid osmotic gradient in hemodialysis patients, improvements in
dialysis therapy. Contrib Nephrol. 1989;74:1705.
47. Lindenfeld J, Albert NM, Boehmer JP, et al. Executive summary:
HFSA 2010 comprehensive HF practice guidelines. J Card Fail.
2010;16(6):475539.
48. Shchekochikhin D, Lindenfeld J, Schrier RW. Increased
Spironolactone in Advanced HF: Effect of Doses Greater Than
25 mg/day on Plasma Potassium Concentration. Cardiorenal Med.
2013;3:16.
49. Francis GS, Siegel RM, Goldsmith SR. Acute vasoconstrictior
response to intravenous furosemide in patients with chronic congestive HF. Activation of the nuerohumoral axis. Ann Intern Med.
1985;103(1):16.
50. Silverstein ME, Ford CA, Lysaght MJ, Henderson LW.
Treatment of severe fluid overload by ultrafiltration. N Engl
J Med. 1974;291(15):74751.
51. Constanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration
versus intravenous diuretics for patients hospitalized for acute
decompensated HF. J Am Coll Cardiol. 2007;49(6):67583.
52. Giglioi C, Landi D, Cecchi E, et al. Effect of ultrafiltration vs
diuretics on clinical, biohumoral and haemodynamic variables in
patients with decompensated HF : the ULTRADISCO study. Eur J
Heart Fail. 2011;13(3):33746.
53. Bart BA, Goldsmith SR, Lee KL, et al. Ultrafiltration in
decompensated HF with CRS. N Engl J Med. 2012;367(24):2296
304. Randomized study on UF versus pharmacological approach in
CRS.
54. Marenzi G, Grazi S, Giraldi F, et al. Interrelation of humoral factors,
hemodynamics, and fluid and salt metabolism in congestive HF:
effects of extracorporeal ultrafiltration. Am J Med. 1993;94(1):4956.
55. Rosario LB, Stevenson LW, Solomon SD, et al. The mechanism of
decrease in dynamic mitral regurgitation during HF treatment:
importance of reduction in the regurgitant orifice size. J Am Coll
Cardiol. 1998;32:181924.
56. Stevenson LW, Brunken RC, Belil D, et al. Afterload reduction with vasodilators and diuretics decreases mitral regurgitation during upright exercise in advanced HF. J Am Coll
Cardiol. 1990;15(1):17480.

Page 9 of 9, 380
57. Publication Committee for the VMAC Investigators (Vasodilatation
in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive HF: a randomized control trial. J Am Coll Cardiol. 2002;288(5):5772002.
58. Parissis JT, Rafouli-Stergiou P, Stasinos V, et al. Inotropes in
cardiac patients: update 2011. Curr Opin Crit Care. 2010;16:432
41. Good review on inotropes in ADHF and CRS.
59. Follath F, Yilmaz MB, Delgado JF, et al. Clinical presentation,
management and outcomes in the Acute HF Global Survey of
Standard Treatment (ALARM-HF). Intensive Care Med.
2011;37:61926.
60. Elkayam U, Tasissa G, Binanay C, et al. Use and impact of
inotropes and vasodilator therapy in hospitalized patients with
severe HF. Am Heart J. 2007;153:98104.
61. Leier CV, Heban PT, Huss P, Bush CA, Lewis RP. Comparative
Systemic and Regional Hemodynamic Effects of D opamine and
Dobutamine in Patients with Cardiomyopathic HF. Circulation.
1978;58:46675.
62. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis:
low-dose dopamine increases urine output but does not prevent
renal dysfunction or death. Ann Intern Med. 2005;142(7):51024.
63. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamine
infusion on renal function in hospitalized HF patients: results of
the Dopamine in Acute Decompensated HF (DAD-HF) Trial. J
Card Fail. 2010;16:92230.
64. Zemljic G, Bunc M, Yazdanbakhsh AP, Vrtovec B. Levosimendan
improves renal function in patients with advanced chronic HF
awaiting cardiac transplantation. J Card Fail. 2007;13(6):41721.
65. Valika AA, Gheorghiade M. Ace inhibitor therapy for HF in
patients with impaired renal function: a review of the literature.
Heart Fail Rev. 2012. doi:10.1007/s10741-011-9295-6. Review on
ACE inhibitors treatment in patients with CRS.
66. Ljungman S, Kjekshus J, Swedberg K. Renal function in severe
congestive HF during treatment with enalapril (the Cooperative
North Scandinavian Enalapril Survival Study [CONSENSUS]
Trial). Am J Cardiol. 1992;70(4):47987.
67. Oster JR, Meterson BJ. Renal and electrolyte complications of
congestive HF and effects of therapy with angiotensin-converting
enzyme inhibitors. Arch Intern Med. 1992;152(4):70410.
68. Packer M. Functional renal insufficiency during long-term therapy
with captopril and enalapril in severe chronic HF. Ann Intern Med.
1987;106(3):34654.