The Cardiorenal Syndrome

Abstract

The term 'cardiorenal syndrome' (CRS) has increasingly been used in recent years without a constant meaning and a well-accepted definition. To include the vast array of interrelated derangements, and to stress the bidirectional nature of the heart-kidney interactions, the classification of the CRS today includes 5 subtypes whose etymology reflects the primary and secondary pathology, the time frame and simultaneous cardiac and renal codysfunction secondary to systemic disease. The CRS can generally be defined as a pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ. Type I CRS reflects an abrupt worsening of cardiac function (e.g. acute cardiogenic shock or decompensated congestive heart failure) leading to acute kidney injury. Type II CRS describes chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease. Type III CRS consists in an abrupt worsening of renal function (e.g. acute kidney ischemia or glomerulonephritis) causing acute cardiac disorder (e.g. heart failure, arrhythmia, ischemia). Type IV CRS describes a state of chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events. Type V CRS reflects a systemic condition (e.g. diabetes mellitus, sepsis) causing both cardiac and renal dysfunction. Biomarkers can help to characterize the subtypes of the CRS and to indicate treatment initiation and effectiveness. The identification of patients and the pathophysiological mechanisms underlying each syndrome subtype will help to understand clinical derangements, to make the rationale for management strategies and to design future clinical trials with accurate selection and stratification of the studied population.

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Blood Purif 2009;27:114 –126
DOI: 10.1159/000167018
The Cardiorenal Syndrome
Claudio Ronco a Chang-Yin Chionh a Mikko Haapio b Nagesh S. Anavekar c
Andrew House e Rinaldo Bellomo d
a Department of Nephrology, Ospedale San Bortolo, Vicenza , Italy;
b HUCH Meilahti Hospital, Division of
Nephrology, Helsinki , Finland;
c Department of Cardiology, The Northern Hospital, and
d Department of Intensive
Care, Austin Hospital, Melbourne , Vic., Australia;
e London Health Sciences Centre, Division of Nephrology,
London, Ont. , Canada
disease (e.g. chronic glomerular disease) contributing to de-
creased cardiac function, cardiac hypertrophy and/or in-
creased risk of adverse cardiovascular events. Type V CRS re-
flects a systemic condition (e.g. diabetes mellitus, sepsis)
causing both cardiac and renal dysfunction. Biomarkers can
help to characterize the subtypes of the CRS and to indicate
treatment initiation and effectiveness. The identification of
patients and the pathophysiological mechanisms underly-
ing each syndrome subtype will help to understand clinical
derangements, to make the rationale for management strat-
egies and to design future clinical trials with accurate selec-
tion and stratification of the studied population.
Copyr ight © 2009 S. Karger AG, B asel
Introduction
A large proportion of patients admitted to hospital,
especially in the critica l care setting, have various degrees
of heart and kidney dysfunction
[1] . Primary disorders of
one of these two organs often result in secondary dys-
function or injury to the other
[2] . Such pathophysiolog-
ical interactions represent the pathophysiological basis
for a clinical entity often referred to as the cardiorenal
syndrome (CRS)
[3] . A lthough generally defined as a con-
dition characterized by the initiation and/or progression
of renal insufficiency secondary to heart failure
[4] , the
term ‘c ard io re na l s ynd rom e’ is al so of ten use d to des cr ib e
Key Words
Acute kidney injury ⴢ Acute heart failure ⴢ Chronic kidney
disease ⴢ Cardiorenal syndrome ⴢ Renocardiac syndrome ⴢ
Heart-kidney interaction ⴢ Cardiovascular risk
Abstract
The term ‘cardiorenal syndrome’ (CRS) has increasingly been
used in recent years without a constant meaning and a well-
accepted definition. To include the vast array of interrelated
derangements, and to stress the bidirectional nature of the
heart-kidney interactions, the classification of the CRS today
includes 5 subtypes whose etymology reflects the primary
and secondary pathology, the time frame and simultaneous
cardiac and renal codysfunction secondary to systemic dis-
ease. The CRS can generally be defined as a pathophysiolog-
ical disorder of the heart and kidneys whereby acute or
chronic dysfunction in one organ may induce acute or chron-
ic dysfunction in the other organ. Type I CRS reflects an
abrupt worsening of cardiac function (e.g. acute cardiogen-
ic shock or decompensated congestive heart failure) leading
to acute kidney injury. Type II CRS describes chronic abnor-
malities in cardiac function (e.g. chronic congestive heart
failure) causing progressive and permanent chronic kidney
disease. Type III CRS consists in an abrupt worsening of renal
function (e.g. acute kidney ischemia or glomerulonephritis)
causing acute cardiac disorder (e.g. heart failure, arrhythmia,
ischemia). Type IV CRS describes a state of chronic kidney
Publis hed online: Januar y 23, 2009
Claudio Ronco, MD
Ospeda le San Bortolo
36100 Vicenza (Ita ly)
Tel. +39 0444 753 650, Fax +39 04 44 753 949
E-Mail cronco@goldnet.it
© 200 9 S. Karger AG, Basel
0253–5068/09/0271–0114$26.00/0
Accessible online at:
www.karger.com/bpu
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The Cardiorenal Syndrome Blood Purif 2009;27:114–126
115
the negative effects of reduced renal function on the hear t
and circulation (more appropriately named renocardiac
syndrome)
[5] . Unfortunately, despite the frequent use of
these terms in the literature, there is no consensus defini-
tion or classification for this condition or cluster of con-
ditions. The absence of a clear definition and the com-
plexity of heart and kidney interactions contribute to a
lack of clarity with regard to diagnosis and management
[6] . This is unfortunate as recent advances in basic and
clinical sciences have changed our understanding of or-
gan crosstalk and interactions and have demonstrated
that some therapies can have efficacy in attenuating both
cardiac and renal injury
[7] . All these considerations sug-
gest the need for a more clearly articulated definition of
the subtypes of the CRS in terms of clinical presentation,
pathophysiology, diagnosis and management
[5, 6] . In
this article, we examine the nature of this complex clini-
cal entity and discuss salient aspects of this condition and
potential interventions based on a logical approach to the
definition of its different clinical subtypes.
CRS: A Proposed Definition
The common understanding of the CRS is that a rela-
tively normal kidney is dysfunctional because of a dis-
eased heart
[8] with the assumption that in the presence
of a healthy heart, the same kidney would likely function
relatively normally
[9] . This concept, however, has re-
cently been challenged and a more articulated definition
for the CRS has been proposed
[5, 6] . Heart-kidney inter-
actions include a variety of conditions, either acute or
chronic, where the primary failing organ can be either
the heart or the kidney ( fig. 1, 2 )
[10] . For this reason, we
discuss the different heart-kidney interactions, which fall
under the umbrella of the CRS, using the def inition struc-
ture summarized in table 1
[5, 6] .
Cardiovascular mortality increased by end-stage renal dysfunction
Cardiovascular risk increased by kidney dysfunction
Chronic HF progression due to kidney dysfunction
• Uremia-related HF
• Volume-related HF
HF due to acute kidney dysfunction
• Volume/uremia-induced HF
• Renal ischemia-induced HF
• Sepsis/cytokin-induced HF
CKD secondary to HF
AKI secondary to contrast-induced nephropathy
AKI secondary to cardiopulmonary bypass
AKI secondary to heart valve replacement
AKI secondary to HF
Fig. 1. Heart and kidney interactions.
HF = Heart failure; CKD = chronic k idney
disease.
C-R
R-C
Chronic Acute
Fig. 2. The bidirec tional nature of the CR S and the acute or chron-
ic temporal characteristics of the syndrome.
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A major problem with previous terminology is that it
does not allow clinicians or investigators to identify and
fully characterize the relevant pathophysiological inter-
actions. This is important because such interactions dif-
fer according to the type of combined heart/kidney
disorder [11] . For example, while a diseased heart has
numerous negative effects on kidney function, renal in-
sufficiency can also signif icantly impair cardiac function
[10] . Thus, a large number of direct and indirect effects
of each organ dysfunction can initiate and perpetuate the
combined disorder of the two organs through a complex
combination of neurohumoral feedback mechanisms.
For this reason, a subdivision into different subtypes
seems to provide a more concise and logically correct ap-
proach to this condition. We will use such a subdivision
to discuss several issues of importance in relation to this
syndrome.
CRS Type I (Acute CRS)
Type I CRS or acute CRS is characterized by a rapid
worsening of cardiac function, which leads to acute kid-
ney injury (AKI) ( fig. 3 ). Acute heart failure (AHF) may
then be divided into 4 main subtypes
[12] : hypertensive
pulmonary edema with preserved left ventricular systol-
ic function, acute decompensated chronic heart failure
(ADCHF), cardiogenic shock, and predominant right
ventricular failure. Type I CRS is common. More than
one million patients in the USA alone are admitted to
hospital every year with either de novo AHF or with
ADCHF [12] . Among patients with ADCHF or de novo
AHF, premorbid chronic renal dysfunction is common
and predisposes to AKI
[13 , 14] . The mechanisms by
which the onset of AHF or ADCHF leads to AKI are mul-
tiple and complex
[4] . They are broadly described in a
previous publication
[6] . The clinical importance of each
of these mechanisms is likely to vary from patient to pa-
tient (e.g. acute cardiogenic shock vs. hypertensive pul-
monary edema) and situation to situation (AHF second-
ary to perforation of a mitral valve leaflet from acute bac-
terial endocarditis vs. worsening right heart failure
secondary to noncompliance with diuretic therapy). In
AHF, AKI seems to be more severe in patients with im-
paired left ventricular ejection fraction (LVEF) compared
to those with preserved LVEF
[15] and increasingly worse
when LVEF is further impaired. It achieves an incidence
of 1 70% in patients with cardiogenic shock
[16] . Further-
more, impaired renal function is consistently found as an
independent risk factor for 1-year mortality in AHF pa-
tients, including in patients with ST-elevation myocar-
dial infarction
[16 , 17] . A plausible reason for this inde-
pendent effect might be that an acute decline in renal
function does not simply act as a marker of illness sever-
ity, but also carries an associated acceleration in cardio-
vascular pathobiology leading to a higher rate of cardio-
vascular events both acutely and chronically, possibly
through the activation of inflammatory pathways
[9,
18] .
The salient clinical issues of type I CRS relate to how
the onset of AKI (de novo or in the setting of chronic re-
nal impairment) induced by primary cardiac dysfunct ion
impacts on diagnosis, therapy and prognosis and how its
presence can modify the general approach to the treat-
ment of AHF or ADCHF. The first important clinical
principle is that the onset of AKI in the setting of AHF or
ADCHF implies inadequate renal perfusion until proven
otherwise. This should prompt clinicians to consider the
diagnosis of a low cardiac output state and/or marked in-
crease in venous pressure leading to kidney congestion
and take the necessary diagnostic steps to either confirm
or exclude the diagnosis (careful physical examination
looking for ancillary signs and laboratory findings of a
low cardiac output state such as absolute or relative hypo-
tension, cold extremities, poor postcompressive capillary
Tab le 1. Proposed definitions of CRS
(1) CRS general definition: a pathophysiological disorder of the
heart and kidneys whereby acute or chronic dysfunction in one
organ may induce acute or chronic dysfunction in the other or-
gan
(2) CRS type I (acute CRS): abrupt worsening of cardiac function
(e.g. acute cardiogenic shock or decompensated congestive heart
failure) leading to AKI
(3) CRS type II (chronic CRS): chronic abnormalities in cardiac
function (e.g. chronic congestive heart failure) causing progres-
sive and permanent chronic kidney disease
(4) CRS type III (acute renocardiac syndrome): abrupt worsening
of renal function (e.g. acute kidney ischemia or glomerulone-
phritis) causing acute cardiac disorder (e.g. heart failure, arrhyth-
mia, ischemia)
(5) CRS Type IV (chronic renocardiac syndrome): chronic kidney
disease (e.g. chronic glomerular disease) contributing to de-
creased cardiac function, cardiac hypertrophy and/or increased
risk of adverse cardiovascular events
(6) CRS type V (secondary CRS): systemic condition (e.g. diabetes
mellitus, sepsis) causing both cardiac and renal dysfunction
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refill, confusion, persistent oliguria, distended jugular
veins, elevated or rising lactate). The second important
consequence of the development of type I CRS is that it
may decrease diuretic responsiveness. In a congestive
state (peripheral edema, increased body weight, pulmo-
nary edema, elevated central venous pressure), decreased
response to diuretics can lead to failure to achieve the de-
sired clinical goals. The physiological phenomena of di-
uretic breaking (diminished diuretic effectiveness sec-
ondary to postdiuretic sodium retention)
[19] and postdi-
uretic sodium retention [20] may also play an enhanced
part in this setting. In addition, concerns of aggravating
AKI by the administration of diuretics at higher doses or
in combination are common among clinicians. Such con-
cerns can also act as an additional, iatrogenic mechanism
equivalent in its effect to that of diuretic resistance (less
sodium removal). Accordingly, diuretics may best be giv-
en in AHF patients with evidence of systemic fluid over-
load with the goal of achieving a gradual diuresis. Furo-
semide can be titrated according to renal function, sys-
tolic blood pressure and history of chronic diuretic use.
High doses are not recommended and a continuous di-
uretic infusion might be helpful
[21] . In parallel, mea-
surement of cardiac output and venous pressure may also
help ensure continued and targeted diuretic therapy. Ac-
curate estimation of cardiac output can now be easily
achieved by means of arterial pressure monitoring com-
bined with pulse contour analysis or by Doppler ultra-
sound
[22–25] . Knowledge of cardiac output allows phy-
sicians to develop a physiologically safer and more logical
approach to the simultaneous treatment of AHF and AD-
CHF and AKI. If diuretic resistant fluid overload exists
despite an optimized cardiac output, removal of isotonic
fluid can be achieved by ultrafiltration ( fig. 4 ). This ap-
proach can be efficacious and clinically beneficial
[26] .
The presence of AKI with or without concomitant hyper-
kalemia may also affect patient outcome by inhibiting the
prescription of angiotensin-converting enzyme (ACE)
inhibitors and aldosterone inhibitors (drugs that have
been shown in large randomized controlled trials to in-
crease survival in the setting of heart failure and myocar-
dial infarction)
[27] . This is unfortunate because, provid-
ed there is close monitoring of renal function and potas-
sium levels, the potential benefits of these interventions
likely outweigh their risks even in these patients.
The acute administration of  -blockers in the setting
of type I CRS is generally not advised. Such therapy
should wait until the patient has stabilized physiologi-
cally and concerns about a low cardiac output syndrome
have been resolved. In some patients, stroke volume can-
not be increased and relative or absolute tachycardia sus-
tains the adequacy of cardiac output. Blockade of such
compensatory tachycardia and sympathetic system-de-
pendent inotropic compensation can precipitate cardio-
genic shock and can be lethal
[28] . Particular concern
applies to  -blockers excreted by the kidney such as aten-
olol or sotalol, especially if combined with calcium an-
tagonists
[29] . These considerations should not inhibit
the slow, careful and titrated introduction of appropriate
treatment with  -blockers later on, once patients are he-
modynamically stable.
This aspect of treatment is particularly relevant in pa-
tients with the CRS where evidence suggests that under-
treatment after myocardial infarction is common
[30] .
Attention should be paid to preserving renal function,
perhaps as much attention as is paid to preserving myo-
cardial muscle. Worsening renal function (WRF) during
admission for ST-elevation myocardial infarction is a
Acute
heart
dysfunction
Humorally mediated damage
Exogenous factors
Drugs
AKI
Hormonal factors
Immunomediated damage
Hemodynamically mediated damage
Fig. 3. Diagram illustrating and summa-
rizing the major pathophysiological inter-
actions between the heart and kidney in
type I CRS.
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Blood Purif 2009;27:114–126
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powerful and independent predictor of in-hospital and
1-year mortality
[16 , 17] . In a study involving 1,826 pa-
tients who received percutaneous coronary intervention,
even a transient rise in serum creatinine ( 1 25% com-
pared to baseline) was associated with increased hospital
stay and mortality
[31] . Similar findings have also been
shown among coronary artery bypass graft cohorts
[32] .
In this context, creatinine rise is not simply a marker of
illness severity but it rather represent a causative factor
for cardiovascular injury acceleration through the activa-
tion of hormonal, immunological and inflammatory
pathways
[9, 18] .
Given that the presence of type I CRS defines a popu-
lation with high mortality, a prompt, careful, systematic,
multidisciplinary approach involving invasive cardiolo-
gists, nephrologists, critical care physicians and cardiac
surgeons is both logical and desirable.
CRS Type II (Chronic CRS)
Type II CRS or chronic CRS is characterized by chron-
ic abnormalities in cardiac function (e.g. chronic conges-
tive heart failure) causing progressive chronic kidney in-
sufficiency ( fig. 5 ).
WRF in the context of heart failure is associated with
significantly increased adverse outcomes and prolonged
hospitalizations
[33] . The prevalence of renal dysfunction
in chronic heart failure has been reported to be approxi-
mately 25%
[33] . Even limited decreases in estimated glo-
merular filtration rate (GFR) of 1 9 ml/min appear to
confer a significantly increased mortality risk
[33] . Some
researchers have considered WRF a marker of severity of
generalized vascular disease
[33] . Independent predictors
of WRF include: old age, hypertension, diabetes mellitus
and acute coronary syndromes.
Extracorporeal ultrafiltration
Art. line
Ven. line Blood pump
Prepump pressure
Prefilter pressure
Postfilter pressure
Filter
Ultrafiltrate
Heparin
Transmembrane pressure
TMP = Pi –  = (Pb – Pd) – 
Pb
Pd

Hydrostatic Oncotic
Fig. 4. Diagram presenting the technical features of ultrafiltration as applicable to patients with AHF and di-
uretic-resistant fluid overload.
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The mechanisms underlying WRF likely differ based
on acute versus chronic heart failure. Chronic heart fail-
ure is characterized by a relatively stable long-term situ-
ation of probably reduced renal perfusion, often predis-
posed by both micro- and macrovascular disease in the
context of the same vascular risk factors associated with
cardiovascular disease. However, although a greater pro-
portion of patients with a low estimated GFR have a worse
New York Heart Association class, no evidence of an as-
sociation between LVEF and estimated GFR can be con-
sistently demonstrated. Thus, patients with chronic heart
failure and preserved LVEF appear to have a similar esti-
mated GFR to patients with impaired LVEF ( ! 45%) [34] .
Neurohormonal abnormalities are present with excessive
production of vasoconstrictive mediators (epinephrine,
angiotensin, endothelin) and altered sensitivity and/or
release of endogenous vasodilatory factors (natriuretic
peptides, nitric oxide). Pharmacotherapies used in the
ma nagement of hea rt f ailu re have be en toute d as cont rib -
uting to WRF. Diuresis-associated hypovolemia, early
introduction of renin-angiotension-aldosterone system
blockade, and drug-induced hypotension have all been
suggested as contributing factors
[4] . However, their role
remains highly speculative. More recently, there has been
increasing interest in the pathogenetic role of relative or
absolute er ythrop oietin def iciency contributing to a more
pronounced anemia in these patients than might be ex-
pected for renal failure alone
[35] . Erythropoietin recep-
tor activation in the heart may protect from apoptosis,
fibrosis and inf lammation. In keeping with such experi-
mental data, prelimi nary clinical studies show that ery th-
ropoietin administration in patients with chronic heart
failure, chronic renal insufficiency and anemia leads to
improved cardiac function, reduction in left ventricular
size and lowering of B-type natriuretic peptide
[36] . Pa-
tients with type II CRS are more likely to receive loop
diuretics and vasodilators and also to receive higher dos-
es of such drugs compared to those with stable renal
function
[37] . Treatment with these drugs may partici-
pate in the development of renal injury. However, such
therapies may simply identify patients with severe hemo-
dynamic compromise and thus a predisposition to renal
dysfunction rather than being responsible for worsening
renal dysfunction. Regardless of the cause, reductions in
Chronic
heart
disease
Chronic hypoperfusion
Increased renal vasc. resist.
Increased venous pressure
Low cardiac output
Sclerosis-fibrosis
Chronic hypoperfusion
Necrosis-apoptosis
CKD
Low cardiac output
Subclinical inflammation
Endothelial dysfunction
Accelerated atherosclerosis
Fig. 5. Diagram illustrating and summarizing the major pathophysiological interactions between the heart and
kidney in type II CRS. CKD = Chronic kidney disease.
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renal function in the context of heart failure are associ-
ated with increased risk for adverse outcomes.
The Impact of the CRS on Medications
The proportion of individuals with chronic kidney dis-
ease (CKD) receiving appropriate risk factor modification
and/or interventional strategies is lower than the general
population, a concept termed ‘therapeutic nihilism’
[38] .
Many databases and registries have repeatedly shown that
these therapeutic choices seem to parallel WRF
[39–41] .
Among patients with end-stage kidney disease (ESKD;
CKD stage V), who are known to be at extreme risk, less
than 50% are on a combination of aspirin,  -blockers,
ACE inhibitors and statins
[42] . In a cohort involving over
140,000 patients, 1,025 with documented ESKD were less
likely to receive aspirin,  -blockers or ACE inhibitors af-
ter myocardial infarction. Yet those ESKD patients who
did receive the aspirin,  -blocker and ACE inhibitor com-
bination had similar risk reductions in 30-day mortality
when compared to non-ESKD patients who had received
conventional therapy
[41] . This failure to treat is not just
limited to ESKD patients. Patients with less severe forms
of CKD are a lso less likely to receive r isk-modifying med-
ications following myocardial infarction compared to
their normal renal function counterparts.
Potential reasons for this therapeutic failure include
concerns about WRF, and/or therapy-related toxic effects
due to low clearance rates
[43, 44] . Bleeding concerns
with the use of platelet inhibitors and anticoagulants are
especially important with reduced renal function and ap-
pear to contribute to the decreased likelihood of patients
with severe CKD receiving aspirin and/or clopidrogrel
despite the fact that such bleeding is typically minor and
the benefits sustained in these patients
[45] . However,
several studies have shown that when appropriately ti-
trated and monitored, cardiovascular medications used
in the general population can be safely administered to
those with renal impairment and with similar benefits
[42, 44, 46] .
Newer approaches to the treatment of cardiac failure
such as cardiac resynchronization therapy have not yet
been studied in terms of their renal functional effects,
although preserved renal function after cardiac resyn-
chronization therapy may predict a more favorable out-
come
[47] . Vasopressin V2 receptor blockers have been
reported to decrease body weight and edema in patients
with chronic heart failure
[48] , but their effects in pa-
tients with the CRS have not been systematically studied
and a recent large randomized controlled trial showed no
evidence of a survival benefit with these agents
[49] .
CRS Type III (Acute Renocardiac Syndrome)
Type III CRS or acute renocardiac syndrome is char-
acterized by an abrupt and primary worsening of renal
function (e.g. AKI, ischemia or glomerulonephritis)
which then causes or contributes to acute cardiac dys-
function (e.g. heart failure, arrhythmia, ischemia). The
pathophysiological aspects are summarized in figure 6 .
The development of AKI as a primary event leading to
cardiac dysfunction (type III CRS) is considered less
common than type I CRS. This is partly because, unlike
type I CRS, it has not been systematically considered or
studied. However, AKI is a condition with a growing in-
cidence in hospital and intensive care unit patients. Using
the recent RIFLE consensus definitions and its Injury
and Failure categories, AKI has been identified in close
to 9% of hospital patients
[50] and, in a large intensive
care unit database, AKI was observed in more than 35%
of critically ill patients
[51] . AKI can affect the heart
through several pathways whose hierarchy is not yet es-
tablished. Fluid overload can contribute to the develop-
ment of pulmonary edema. Hyperkalemia can contribute
to arrhythmias and may cause cardiac arrest. Untreated
uremia affects myocardial contractility through the ac-
cumulation of myocardial depressant factors
[52] and can
cause pericarditis
[53] . Partially corrected or uncorrected
acidemia produces pulmonary vasoconstriction
[54] ,
which, in some patients, can significantly contribute to
right-sided heart failure. Acidemia appears to have a neg-
ative inotropic effect
[55] and may, together with electro-
lyte imbalances, contribute to an increased risk of ar-
rhythmias
[56] . Finally, as discussed above, renal isch-
emia itself may precipitate activation of inflammation
and apoptosis at cardiac level
[9] .
The development of AKI, especially in the setting of
chronic renal failure, can affect the use of medications
that normally would maintain clinical stability in pa-
tients with chronic heart failure. For example, an increase
in serum creatinine from 1.5 mg/dl (130  mol/l) to 2 mg/
dl (177  mol/l), with diuretic therapy and ACE inhibi-
tors, may provoke some clinicians to decrease or even
stop diuretic prescription; they may also decrease or even
temporarily stop ACE inhibitors. In some, maybe many
cases, this may not help the patient. An acute decompen-
sation of chronic heart failure may occur because of such
changes in medications. When this happens the patient
may be unnecessarily exposed to an increased risk of
acute pulmonary edema or other serious complications
of undertreatment.
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Finally, if AKI is severe and renal replacement therapy
is necessary, cardiovascular instability generated by rap-
id fluid and electrolyte shifts secondary to conventional
dialysis can induce hypotension, arrhythmias, and myo-
cardial ischemia
[57] . Continuous techniques of renal re-
placement, which minimize such cardiovascular insta-
bility appear physiologically safer and more logical in this
setting
[58] .
CRS Type IV (Chronic Renocardiac Syndrome)
Type IV CRS or chronic renocardiac syndrome is
characterized by primary CKD (e.g. diabetes or chronic
glomerular disease) contributing to decreased cardiac
function, ventricular hypertrophy, diastolic dysfunction
and/or increased risk of adverse cardiovascular events
( fig. 7 ).
The National Kidney Foundation divides CKD into 5
stages based on a combination of severity of kidney dam-
age and GFR
[59] . Individuals with CKD, particularly
those receiving renal replacement therapies, are at ex-
tremely high cardiovascular risk
[60] . About 50% of
deaths in CKD stage V cohorts are attributed to cardio-
vascular disease; namely coronary artery disease and its
associated complications
[54] . The 2-year mortality rate
following myocardial infarction in patients with CKD
stage V is high and estimated to be 50%
[61] . In compar-
ison, the 10-year mortality rate after myocardial infarc-
tion for the general population is 25%.
Type IV CRS is becoming a major public health prob-
lem. A large population of individuals entering the tran-
sition phase towards ESKD is emerging. National Kidney
Foundation guidelines define these individuals as having
CKD
[62] . CKD, which also encompasses ESKD, is de-
fined as persistent kidney damage (confirmed by renal
biopsy or markers of kidney damage) and/or a GFR
! 60 ml/min/1.73 m 2 for more than 3 months [59] . This
translates into a serum creatinine level of 6 1.3 mg/dl
which would ordinarily be dismissed as not being repre-
sentative of significant renal dysfunction. Using these
criteria, current estimates of CKD account for at least 11
million individuals and rising
[63] .
The association between increased cardiovascu lar risk
and renal dysfunction originally stemmed from data
arising from ESKD or stage V CKD cohorts. The leading
cause of death in such patients is cardiovascular with
1 40% of mortality being cardiovascular event related.
This observation is supported by the Australian and New
Zealand Dialysis and Transplant Registry, the United
States Renal Data System and the Wave 2 Dialysis Mor-
bidity and Mortality Study. Based on these findings, it is
now well established that CKD is a significant risk factor
for cardiovascular disease, such that individuals with ev-
idence of CKD have between a 10- to 20-fold increased
risk for cardiac death compared to age-matched and sex-
matched controls without CKD
[63] . As discussed, part
of this problem may be related to the fact that such indi-
viduals are also less likely to receive risk-modifying inter-
ventions compared to their non-CKD counterparts
[61,
64, 65] .
A
KI
Acute
heart
dysfunction
Humoral
signalling
Drop of GFR
Electrolyte, acid-base
and coagulation imbalances
Volume
expansion
Sympathetic activation
RAA activation,
vasoconstriction
Fig. 6. Diagram illustrating and summa-
rizing major pathophysiological interac-
tions between the hear t and kidney in type
III CRS. RAA = Renin-angiotensin-aldo-
sterone.
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122
Less severe forms of CKD also appear to be associated
with significant cardiovascular risk. Evidence for in-
creasing CVD morbidity and mortality tracking with
mild to moderate renal dysfunction has mainly stemmed
from community-based studies
[66 –70] . All these studies
documented an inverse relationship between renal func-
tion and adverse cardiovascular outcomes. In particular,
the association between reduced renal function and car-
diovascular risk appears to consistently occur at estimat-
ed GFR levels below 60 ml/min/1.73 m
2 , the principal
GFR criterion used to define CKD.
Amo ng h ig h card iov as cular risk coh orts, ba seline c re-
atinine clearance is a signif icant and independent predic-
tor of short-term outcomes (180 days of fol low-up), name-
ly death and myocardial infarction
[63] . Similar findings
were also noted among patients presenting with ST-ele-
vation myocardial infarction
[71] , an effect independent
of thrombolysis
[41, 72] .
Other large-scale studies that have examined the rela-
tionship between renal function and cardiovascular out-
comes among high cardiovascular risk cohorts with left
ventricular dysfunction have included the Studies of Left
Ventricular Dysfunction, Trandolapril Cardiac Evalua-
tion, Survival and Ventricular Enlargement and Valsar-
tan in Acute Myocardial Infarction trials. These studies
excluded individuals with baseline serum creatinine lev-
els of 6 2.5 mg/dl. In all these studies, reduced renal
function was associated with significantly higher mortal-
ity and adverse cardiovascular event rates
[73–76] .
Renal insufficiency is highly prevalent among patients
with heart failure and is an independent prognostic fac-
tor in both diastolic and systolic ventricular dysfunction
[77] . It is an established negative prognostic indicator in
patients with severe heart failure [77] . The logical practi-
cal implications of the plethora of data linking CKD with
cardiovascular disease is that more attention needs to be
paid to reducing risk factors and optimizing medications
in these patients and that undertreatment due to con-
cerns about pharmacodynamics in this setting may have
lethal consequences at the individual level and huge po-
tential adverse consequences at the public health level.
Nonetheless, it is also equally important to acknowledge
that clinicians looking after these patients are often faced
with competing therapeutic choices and that, with the
exception of MERIT-HF
[78] , large randomized con-
trolled trials that have shaped the treatment of chronic
heart failure in the last two decades have consistently ex-
cluded patients with significant renal disease. Such a lack
CKD
Acquired risk factors
Primary nephropathy
Anemia
Uremic toxins
Ca/P abnormalities
Nutritional status, BMI
Na-H2O overload
Chronic inflammation
Anemia and malnutrition
Ca/P abnormalities
Na-H2O overload
Unfriendly milieu
Inflammation
Sclerosis-fibrosis
Glomerular/interstitial
damage
Dialysis
Chronic
heart
disease
Fig. 7. Diagram illustrating and summarizing the major pathophysiological interactions between the heart and
kidney in type IV CRS.
Color versi on available onlin e
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The Cardiorenal Syndrome Blood Purif 2009;27:114–126
123
of CKD population-specific treatment effect data makes
therapeutic choices particularly challenging. In particu-
lar, in patients with advanced CKD, the initiation or in-
creased dosage of ACE inhibitors can precipitate clini-
cally significant worsening of renal function or marked
hyperkalemia. The latter may be dangerously exacerbat-
ed by the use of aldosterone antagonists. Such patients, if
aggressively treated, become exposed to a significant risk
of developing dialysis dependence or life-threatening hy-
perkalemic arrhythmias. If too cautiously treated, they
may develop equally life-threatening cardiovascular
complications. In these patients, the judicious use of all
options while taking into account patient preferences, so-
cial circumstances, other comorbidities and applying a
multidisciplinary approach to care seems the best ap-
proach.
CRS Type V (Secondary CRS)
Type V CRS or secondary CRS is characterized by the
presence of combined cardiac and renal dysfunction due
to systemic disorders ( fig. 8 ). There is limited systematic
information on type V CRS, where both the kidneys and
the heart are affected by other systemic processes. Al-
though there is an appreciation that, as more organs fail,
mortality increases in critical illness, there is limited in-
sight into how combined renal and cardiovascular fail-
ure may differently affect such outcome compared to, for
example, combined pulmonary and renal failure. None-
theless, it is clear that several acute and chronic diseases
can affect both organs simultaneously and that the dis-
ease induced in one can affect the other and vice versa.
Several chronic conditions such as diabetes and hyper-
tension are discussed as part of type II and type IV
CRS.
In the acute setting, severe sepsis represents the most
common and serious condition, which can affect both
organs. It can induce AKI while leading to profound
myocardial depression. The mechanisms responsible for
such changes are poorly understood but may involve the
effect of tumor necrosis factor on both organs
[79, 80] .
The onset of myocardial functional depression and a
state of inadequate cardiac output can further decrease
renal function as discussed in type I CRS and the devel-
opment of AKI can affect cardiac function as described
in type III CRS. Rena l ischemia may then induce fu rther
myocardial injury
[9] in a vicious cycle, which is injuri-
ous to both organs. Treatment is directed at the prompt
identification, eradication and treatment of the source of
infection while supporting organ function with inva-
sively guided fluid resuscitation, and inotropic and vaso-
pressor drug support. In this setting, all the principles
discussed for type I and type III CRS apply. In these sep-
tic patients, preliminary data using more intensive renal
replacement technology suggest that blood purification
may have a role in improving myocardial performance
while providing optimal small solute clearance
[81] . De-
spite the emergence of consensus definitions
[82] and
many studies
[83, 84] , no therapies have yet emerged to
prevent or attenuate AKI in critically ill patients. On the
other hand, clear evidence of the injurious effects of pen-
tastarch fluid resuscitation in septic AKI has recently
emerged
[85] . Such therapy should, therefore, be avoided
in septic patients.
Systemic
diseases
Altered
metabolism
Hemodynamic changes
Exogenous toxins
Drugs
Immunological
response
Neurohumoral activation
Combined
heart-kidney
dysfunction
Fig. 8. Diagram illustrating and summa-
rizing the major pathophysiological inter-
actions between the heart and kidney in
type V CRS.
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124
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In both chronic and acute situations, an appreciation
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National Univ. of Singapore
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