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Advances in Peritoneal Dialysis, Vol. 27, 2011
Update on Cardiorenal
Syndrome: A Clinical
Conundrum
Our understanding of the cardiorenal syndrome con-
tinues to progress. Decades of research have led to a
better denition of the clinical cardiorenal syndrome
and have laid the groundwork for understanding its
pathophysiology. Although improvements have been
made, there are still knowledge gaps concerning the
interactions of these two organ systems. In the present
review, we examine those interactions in the setting
of acute and chronic cardiac decompensation and the
resulting impacts on renal dysfunction. Recognition
and prevention of this syndrome may help to better
serve a growing patient population.
Key words
Cardiorenal syndrome, chronic kidney disease, coro-
nary artery disease, heart failure
Introduction
The clinical entity known as the cardiorenal syndrome
is a growing conundrum. The term attempts to convey
the relationship between the cardiovascular and renal
organ systems, whose interconnection has actually
been appreciated for quite some time. Several decades
ago, Dr. Arthur Guyton described mechanisms of
feedback through cardiac hemodynamics that lead to
dysfunction of both organs.
This concept of worsening renal function second-
ary to poor left ventricular function has evolved to an
understanding of other pathophysiologic mechanisms.
Attempts to describe the interactions have led to aclinical classication system (Table I) based on the
initial organ and the chronicity of dysfunction (1).
Classication of a problem is helpful, but the contin-
ued morbidity and mortality reveal that understanding
the pathophysiology and potential treatment options
is paramount. In the present review, we focus on the
implications of acute and chronic cardiac decompen-
sation for renal dysfunction (cardiorenal syndrome
types 1 and 2).
Discussion
The acutely decompensated heart:
cardiorenal syndrome type 1
Renal dysfunction in the setting of an acutely de-
compensated heart has been shown to result in poor
outcomes. The Acute Decompensated Heart Failure
National Registry evaluated more than 100,000
patients admitted with a diagnosis of acute decom-
pensated heart failure. The registry showed that more
than 30% of patients hospitalized had a history of renal
insufciency and that 20% had serum creatinine levelsin excess of 2.0 mg/dL (2). In a subsequent analysis of
the registry, Fonarow et al. demonstrated that the best
predictors of in-hospital mortality were a high level of
blood urea nitrogen (>43 mg/dL) and serum creatinine
[sCr (>2.75 mg/dL)] at admission (3).
Acute cardiac decompensation is most commonly
caused by an ischemic event. The American Heart As-
sociation estimated that, in 2010, more than 1 million
people in the United States had either a new or recur-
rent ischemic coronary event (4). In this setting of an
acute coronary event, the potential complications of
Eric J. Chan,1 Kevin C. Dellsperger 1–3
From: 1Division of Cardiovascular Medicine, Department of
Internal Medicine; 2Department of Medical Pharmacology
and Physiology; and 3The Center for Health Care Quality,
University of Missouri, Columbia, Missouri, U.S.A.
TABLE I Cardiorenal syndrome (CRS) classicationa
CRS
type
Description
1 Acute cardiac decompensation leading to kidney
injury
2 Chronic heart fai lure leading to worsening renal
function
3 Acute kidney injury leading to cardiac dysfunction4 Chronic kidney disease leading to heart failure
5 Systemic conditions leading to both cardiac and renal
dysfunction
a Modied from Ronco et al. (1).
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Chan and Dellsperger 83
contrast-induced nephropathy (CIN) and cardiogenic
shock can lead to signicant renal dysfunction.
Contrast-induced nephropathy is a potential
complication of coronary angiograms performed in
the setting of ischemic heart disease. Various studies
have looked at whether changes in the available typesof radiocontrast media over the past several decades
have affected the incidence of CIN. One of those stud-
ies, performed by Rudnick et al., demonstrated that
the incidence of increased sCr (dened as an increase
greater than 1.0 mg/dL) was lower with a nonionic
than with an ionic contrast medium (3.2% vs 7.1%).
A subgroup analysis (Table II) showed that CIN was
higher in patients with both renal insufciency and
diabetes at baseline (5). The availability of various
contrast media has led to differences in reported
incidence rates, which range from 0% to as high as50% in high-risk individuals (6). Regardless of the
contrast medium used, the risk of CIN can potentially
be reduced by identifying high-risk patients and by
limiting the amount of contrast used.
Patients presenting with cardiogenic shock al-
ready experience signicant mortality. When shock
is associated with kidney injury, mortality rates are
worse. Marenzi et al. published data on patients pre-
senting with an ST-elevation myocardial infarction
complicated by cardiogenic shock and showed that
acute kidney injury (AKI) occurred in more than 50%
of those patients. Patients whose course was compli-
cated by AKI had a mortality rate of 50%, which was
signicantly higher than the 2.2% in patients without
that complication (7). Koreny et al. showed similar
results in a population of post-infarction patients in
cardiogenic shock. The in-hospital mortality rates in
their analysis were increased by more than 30% in the
setting of acute renal failure compared with normal
renal function (8). These two studies demonstrate
that AKI is a serious complication that portends
poor outcomes.
Kidney injury in the heart disease setting islikely a result of hypoperfusion secondary to poor
cardiac output. In hypoperfused kidneys, the renin–
angiotensin–aldosterone system (RAAS) is activated.
The juxtaglomerular apparatus releases renin in this
setting, starting a cascade in which angiotensinogen is
eventually converted to angiotensin II (AngII), among
other byproducts (9). The AngII leads to vasoconstric-
tion, aldosterone secretion, and a high level of oxida-
tive stress. Vasoconstriction of the renal arterioles
is likely mediated by an increase of endothelin 1,
a byproduct of increased AngII levels (10). Otherend-products (such as aldosterone) result in water
retention by reabsorption of sodium from the distal
tubules. The net effect is an increase in pulmonary
vascular congestion and worsening renal ischemia
that perpetuates RAAS activation.
Early detection of AKI in this setting may poten-
tially protect the kidneys through early institution of
treatment. The commonly used biomarkers such as sCr
and blood urea nitrogen may not identify subtle injury
to the kidneys and may therefore delay diagnosis.
Recent research has focused on novel biomarkers
for the detection of AKI. One such marker, neutrophil
gelatinase–associated lipocalin (NGAL), is a protein
that has been shown in mouse models to be released
in early renal ischemia (11). In the setting of cardiac
surgery patients, Mishra et al. demonstrated that
NGAL concentrations were elevated several hours
after surgery—compared with days when sCr alone
is being measured (12). Recently, NGAL was also
noted to be overexpressed in hypertensive patients
and the walls of aortic aneurysms; it is also potentiallylinked to atherosclerosis (13). The pathophysiologic
mechanism is secondary to NGAL mediation through
the inammatory cascade and is released by activated
neutrophils. These other potential applications of
NGAL are being further investigated.
Chronic heart failure: cardiorenal syndrome type 2
In the setting of chronic heart failure, renal function
predicts outcomes. In one study, glomerular ltration
rate (GFR) was inversely proportional to the likelihood
of hospitalization and cardiovascular death (14). As
TABLE II Effect of nonionic contrast on the incidence of contrast-
induced nephropathy (CIN) in patients with or without concomitant
renal insufciency (RI) or diabetes (DM), or botha
Group Condition CIN incidence (%)
RI DM Nonionic contrast Ionic contrast
1 – – 0.0 0.0
2 – + 0.7 0.6
3 + – 4.1 7.4
4 + + 11.8 27.0
TOTAL 3.2 7.1
a From Rudnick et al. (5).
Renal insufciency = serum creatinine ≥ 1.5 mg/dL; CIN = increase
of serum creatinine by more than 1.0 mg/dL in 48 – 72 hours.
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84 Update on Cardiorenal Syndrome
alone in heart failure patients. The 433 patients en-
rolled into the study had a median baseline sCr of
1.5 mg/dL and a median GFR of 71.4 mL/min (16). In
a post-hoc analysis of the 193 patients in the PAC arm,
no correlations were observed for sCr or GFR with
pulmonary capillary wedge pressure, cardiac index, orsystemic vascular resistance. Patients in the PAC arm
had a signicantly improved cardiac index (to 2.4 L/
min/m2 from 1.9 L/min/m2), but that change did not
affect renal function (17). These results suggest that
mechanisms other than decreased perfusion secondary
to reduced cardiac output are at work (Figure 1).
Although improvement in cardiac output did not
improve renal function in the ESCAPE trial, a signi-
cant correlation was observed for right atrial pressure
with baseline sCr and GFR. That nding has been
validated in other studies. In 145 patients admittedwith decompensated heart failure, Mullens et al. dem-
onstrated that higher baseline central venous pressure
was associated with a higher risk of worsening renal
function. When a central venous pressure of less than
8 mmHg was achieved, the renal function worsened
less often (18). As in the ESCAPE trial, cardiac index
showed no correlation with worsening renal function,
showing that other cardiorenal hemodynamic interac-
tions such as systemic venous congestion can cause
renal dysfunction. Increases in venous pressure can
reduce the gradient across the glomerular capillary
bed, affecting renal perfusion. Studies have also sug-
gested that external compression of the renal veins
leads to worsened renal function (19). In this setting
of elevated right atrial pressure, it is interesting to
note that the release of atrial natriuretic peptides has
little effect in maintaining intravascular volume, a
result that may in part be secondary to the effects of
RAAS activation and resistance of the kidneys to atrial
natriuretic peptides.
Another pathophysiologic mechanism that mayexplain worsening renal function in the setting of
chronic heart failure is an increase in sympathetic
activation. Catecholamine levels increase in an attempt
to improve inotropic and chronotropic responses of the
left ventricle, improving cardiac output. Although ini-
tially helpful, chronic sympathetic activation leads to
downregulation of beta receptors and serves to dimin-
ish cardiac output. Other negative effects such as left
ventricular hypertrophy can also worsen ventricular
function. Vasoconstriction caused by catecholamines
can lead to RAAS activation, perpetuating positive
mentioned earlier, the background pathophysiology is
thought to be poor cardiac output that leads to activa-
tion of RAAS and negative myocardial remodeling.
Although this concept is the prevailing one, it may
not be the only pathophysiologic mechanism lead-
ing to worsening renal function. The feed-forwardmechanisms of AngII and increased inammatory
markers and reactive oxygen species (Figure 1) further
exacerbate these abnormalities (15).
The Evaluation Study of Congestive Heart Failure
and Pulmonary Artery Catheterization Effectiveness
(ESCAPE) trial assessed the effectiveness of therapy
guided by a pulmonary artery catheterization (PAC)
compared with that guided by clinical assessment
FIGURE 1 Schematic diagram of the potential mechanisms by
which congestive heart failure may exacerbate renal dysfunction
and feed forward to worsening heart failure. The vicious cycle
of worsening heart failure that begets worsening renal function
begetting worsening heart failure is perpetuated by inammatory
mediators and reactive oxygen species (ROS). RAAS = renin–
angiotensin–aldosterone system; IL = interleukin; TNFα = tumor
necrosis factor α; TGFβ = transforming growth factor β; AngII =
angiotensin II; SNS = sympathetic nervous system. Adapted from
Shah and Greaves (15).
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Chan and Dellsperger 85
feedback mechanisms. Increased venous congestion
and activation of the sympathetic nervous system may
both serve to explain the results of the ESCAPE trial,
demonstrating that renal dysfunction in chronic heart
failure goes beyond just poor cardiac output.
Gaps in our understanding of cardiorenal syndrome
types 1 and 2
Most of the knowledge about the pathophysiology of
cardiorenal syndrome type 2 suggests that hemody-
namically guided therapy should improve outcomes.
However, the ESCAPE trial, a well-conducted trial
that set out to test that hypothesis, showed no differ-
ence. Given those ndings, a key remaining question
is “Why does optimizing hemodynamics to increase
cardiac index not improve renal function?”
Current understanding suggests that there must be a trigger for renal dysfunction at the initiation
of these massive neurohormonal adjustments so
common in chronic heart failure. Work conducted
to understand this early trigger may prevent car-
diorenal syndrome type 2. In addition, the current
understanding of cardiorenal syndrome type 1 may
be enhanced by the knowledge gained. In either
scenario, substantial work at the basic pathophysi-
ologic level must be undertaken to further knowledge
so that these signicant conditions can be treated
and prevented.
Summary
The management of cardiorenal syndrome is an
evolving challenge. Loop diuretics remain the
standard therapy in exacerbated acute heart failure,
although their overuse can cause hypovolemia and
RAAS activation. Initial studies on other options,
such as nesiritide and ultraltration, seem promis-
ing, and more denitive trials are still underway.
Adenosine receptor antagonists are another area ofcurrent investigation, because blockade of adenosine
receptors has been shown to affect the vascular tone
of renal arterioles. The availability of these treatment
options is expanding, but effective treatment begins
with an understanding of the pathophysiology of the
cardiorenal axis. Future studies of novel markers for
prevention and potential treatments for reversal of
renal dysfunction caused by heart failure will perhaps
alleviate the impact of cardiorenal syndrome. Until
then, this clinical entity will continue to be a complex
challenge for all clinicians.
Disclosures
The authors have no nancial conicts of interest to
declare.
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Corresponding author:
Kevin C. Dellsperger, MD PhD, CE 549, DC 375.00,
University of Missouri Health Care, One HospitalDrive, Columbia, Missouri 65212 USA.
E-mail:
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