Crs Clinicalh

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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).



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.



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).



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:

[email protected]

mailto:[email protected]

mailto:[email protected]

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