Chapter 132
Cardiorenal Syndrome: An Overview
NP Singh, Anish Kumar, Taposh Sarkar
ABSTRACT
Cardiorenal syndrome (CRS) is a complex spiral of vascular disease
entity, in which affliction of one organ (kidney) may adversely impact
the functioning of the other (heart). Recent consensus conference has
clearly defined its various types and pathophysiology. Improved survival,
cardiovascular risk factors (diabetes, hypertension, dyslipidemia),
diagnostic and therapeutic intervention [contrast agent, improper
diuretic usage, nonsteroidal anti-inflammatory drugs (NSAIDs)] are
some contributors in its causation. A proper understanding of its
mechanism and subsequent individualized approach can stall its
progressive spiral. This chapter addresses preventive and established
therapeutic strategies such as diuretics and inotropes, in the CRS as
well as novel therapies that hold promise, such as arginine vasopressin
antagonists, adenosine A1 receptor antagonists and ultrafiltration.
INTRODUCTION
Cardiorenal syndrome is defined as disorders of the heart and
kidneys whereby acute or chronic dysfunction in one organ may
induce acute or chronic dysfunction of the other.1 The coexistence
of cardiac and renal disease significantly increases mortality,
morbidity, complexity and cost of care,2 and carries an extremely
bad prognosis. The exact cause of deterioration of kidney function
and the mechanism underlying this interaction are complex,
multifactorial in nature, and still not completely understood.
Renal dysfunction is one of the most important comorbidities in
heart failure. Reduced estimated glomerular filtration rate (eGFR)
seems to be a potent predictor of cardiovascular complications
and mortality. Patients with renal dysfunction have a significantly
increased risk of developing an adverse outcome after acute
myocardial infarction (AMI).3 The most common underlying risk
factors that account for renal dysfunction in the setting of heart
failure or cardiac dysfunction include hypertension, diabetes
mellitus, severe atherosclerotic disease, elderly age and a prior
history of renal insufficiency or heart failure.
CARDIORENAL CONNECTION
Both heart and the kidneys are richly vascular (the kidneys are
more vascular than the heart) and both organs are supplied by
sympathetic and parasympathetic innervations. These two organs
act in tandem to regulate blood pressure, vascular tone, diuresis,
natriuresis, intravascular volume homeostasis, peripheral tissue
perfusion and oxygenation. They have endocrine functions with
interdependent physiological hormonal actions regulated by arterial
natriuretic peptide, a vasodilator secreted from the heart and
renin-angiotensin-aldosterone system (RAAS). Also, vitamin D3,
erythropoietin and renalase are all secreted from the kidneys, and
are capable of cellular and humoral signaling. Dysfunction of either
of the two organs can cause dysfunction of the other (Figures 1 and
2). Changes in the RAAS, the imbalance between nitric oxide (NO)
and reactive oxygen species (ROS), the sympathetic nervous system
and inflammation are the cardiorenal connectors to develop CRS.
These connectors together decrease the sensitivity of erythropoietin,
and are responsible for renal anemia that also aggravates the clinical
conditions of cardiac failure (Figure 1).4,5
EPIDEMIOLOGY
Heart failure is a common chronic condition affecting 2% of
the adult population and resulting in over 1 million annual
admissions,6 making it the leading cause of hospitalization in both
developing and developed world adults over the age of 65 years.
Patients with chronic kidney disease (CKD) have a greater risk of
cardiovascular disease (CVD) mortality ranging from 15 to 30 times
that of healthy individuals, with an associated disproportionate
use of healthcare resources.7
PATHOPHYSIOLOGY
Three main factors have been implemented: (1) low-cardiac output;
(2) elevation of both intra-abdominal and central venous pressures
and (3) neurohormonal and inflammatory activation.
DIAGNOSIS
Early identification of worsening kidney function is essential for
early treatment of CRS. Use of biomarkers that become detectable
before the traditional tests for kidney function, including GFR
or serum creatinine have made to easier. Biomarkers such as
neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl--
D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1)
implicated in tubulointerstitial damage are being used to identify
acute kidney injury (AKI). Serum cystatin C is elevated earlier than
creatinine. Furthermore, while cystatin C in the serum is a marker
of reduced glomerular filtration, urinary cystatin C is a marker of
tubular dysfunction. Other biomarkers that have proven useful
include B-type natriuretic peptide (BNP), interleukin-18 (IL-18)
and fatty acid-binding protein (FABP). Tests for volume status
and end-organ perfusion are also useful in the diagnosis of CRS.
Urine sediment examination should be performed in differentiating
CRS from other causes of AKI by excluding pathologic cells,
casts or crystals. Hyponatremia, when present, may indicate
excess antidiuretic hormone (ADH) and portend an overall poor
prognosis.
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Figure 1: Cardiorenal connection and its effect on erythropoietin. Imbalance between nitric oxide (NO) and reactive oxygen species (ROS), by increased
inflammation, increased activity of the rennin-angiotensin system, and increased activity of the sympathetic nervous system, causes cardiorenal syndrome
(CRS). These cardiorenal connectors decrease sensitivity to erythropoietin
Abbreviation: NO-ROS, Nitric oxide-reactive oxygen species
Source: van der Putten K, Braam B, Jie KE, et al. Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin
Pract Nephrol. 2008;4(1):47-57
Figure 2: Different types of cardiorenal syndrome (CRS) can be inter-
connected and patients may move from one type to another during the time
course of the combined disorders
Source: Ronco C, Costanzo MR, Bellomo R, Maisel AS (Eds). Fluid
Overload: Diagnosis and Management, illustrated edition. Basel,
Switzerland: Karger Publishers; 2010. pp. 33-8.
CARDIORENAL SYNDROME: CLASSIFICATION
AND MANAGEMENT
The CRS was classified into five categories, according to the
underlying etiologies and the nature of concomitant cardiac and
renal dysfunction (Table 1).
Acute Cardiorenal Syndrome: Type I
This appears to be a syndrome of worsening renal function
that frequently complicates hospitalized patients with acute
decompensated heart failure (ADHF) and acute coronary syndrome.
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One study proposed that patients with renal dysfunction had a
significantly increased risk (almost 4 times) of developing an adverse
outcome (recurrent acute coronary syndromes, revascularization,
left ventricular failure, death) after AMI.3 This entity has specific
treatment and prevention strategies.
Preventive Approaches
The basic principles include avoidance of volume depletion,
removal of superimposed renal toxic agents (NSAIDs agents,
aminoglycosides), minimization of the toxic exposure (iodinated
contrast, time on cardiopulmonary bypass) and possibly, the use
of antioxidant agents such as N-acetylcysteine and BNP in the
perioperative period after cardiac surgery. Use of continuous renal
replacement therapy (CRRT) provides three important protective
mechanisms that cannot be achieved pharmacologically as follows:
(1) it ensures euvolemia and avoids hypo- or hypervolemia; (2) it
provides sodium and solute (nitrogenous waste products) removal
and (3) by both mechanisms above, it may work to avoid both passive
renal congestion and a toxic environment for the kidneys.
Management
Type I CRS appears in the setting of ADHF or cardiogenic shock for
a number of reasons, with hemodynamic derangements ranging
from acute pulmonary edema with hypertension through severe
peripheral fluid overload to cardiogenic shock and hypotension.
Table 2 summarizes some practical recommendations for the
management of ADHF patients with Type I CRS. The goal of diuretic
use should be to deplete the extracellular fluid volume at a rate that
allows adequate time for intravascular refilling from the interstitium.
To achieve adequate diuresis, infusions of loop diuretics have been
demonstrated to have greater efficacy than intermittent dosing.8
If kidney function continues to worsen, blockade of the RAAS
may be a contributing factor, necessitating withholding or delaying
the introduction of angiotensin-converting-enzyme inhibitors
(ACEIs) or angiotensin receptor blockers (ARBs) in order to maintain
the GFR.
For Type I CRS patients with preserved or elevated blood pressure,
vasodilators such as nitroglycerin and nitroprusside are often used to
relieve symptoms and improve hemodynamics. When patients have
low blood pressure and poor renal perfusion, positive inotropes such
as dobutamine or phosphodiesterase inhibitors may be required.9
 Section 17 Chapter 132 Cardiorenal Syndrome: An Overview

TABLE 1Classification of cardiorenal syndrome proposed by Ronco et al2

Type Name Mechanism Clinical conditions Markers
Type I Acute cardiorenal Abrupt worsening of cardiac Acute cardiogenic shock and acutely ET-1,troponin, CPK-MB
syndrome function leading to acute decompensated congestive heart failure
kidney injury
Type II Chronic cardiorenal Chronic abnormalities in Chronic congestive heart failure ET-1, BNP
syndrome cardiac function causing
progressive and potentially
permanent kidney disease
Type III Acute renocardiac Abrupt worsening of kidney Acute kidney ischemia and glomerulonephritis TNF-alfa, IL-1, IL-6, IL-8
syndrome function causing acute
cardiac disorder
Type IV Chronic renocardiac Chronic kidney disease Chronic glomerular and interstitial disease PTH, CPP product,
syndrome contributing to decline in cystatin C
cardiac function
Type V Secondary cardiorenal Systemic condition causing Diabetes mellitus, sepsis
syndrome both cardiac and kidney
dysfunction
Abbreviations: ET-1, Endothelin-1; CPK-MB, Creatine phosphokinase-MB; BNP, B-type natriuretic peptide; TNF, Tumor-necrosis factor; IL, Interleukin; PTH,
Parathyroid hormone; CPP, Calcium-phosphate product; Ellipses indicate not applicable.

TABLE 2Practical recommendations for the management of
acute decompensated heart failure (ADHF) patients with
cardiorenal syndrome (CRS) (Katerina Koniari et al.)9
Restrict fluid and sodium intake
Increase furosemide dose
Use continuous intravenous furosemide
Add thiazides or metolazone
Add renoprotective dopamine at 23 mcg/kg/min
Add inotrope or vasodilator (according to systolic blood pressure)
Start ultrafiltration
Insert intra-aortic balloon pump
Insert another device
Chronic Cardiorenal Syndrome: Type II
This subtype is a separate entity from acute CRS as it indicates a more
chronic state of kidney disease complicating chronic heart disease.
This is an exceptionally common problem. For instance, in patients
hospitalized with congestive heart failure (CHF), approximately
63% meet the kidney disease outcomes quality initiative (K/DOQI)
definition of stages 35 CKD (eGFR < 60 mL/min/1.73 m2).10
Preventive Approaches
Pharmacologic therapies that have been beneficial for chronic CVD
have been either neutral or favorable to the kidneys including use
of RAAS antagonists, beta-adrenergic blocking agents and statins.
Furthermore, other strategies including glycemic control in diabetes
and blood pressure control in those with hypertension.11
Management
Interruption of the RAAS is the primary aim in the management of
Type II CRS. However, RAAS blockade can lead to significant decrease
in kidney function and/or elevated potassium. However, creatinine
tended to stabilize, and in many instances, improved over the
course of the study. In terms of aldosterone blockade, drugs such as
spironolactone and eplerenone are important adjuncts to therapy in
patients with severe heart failure. Both CHF and CKD are associated
with anemia, which is commonly treated with erythropoiesis-
stimulating agents. Furthermore, the action of erythropoietin in the
heart may reduce apoptosis, fibrosis and inflammation. Hence, there
has been intense interest in using erythropoiesis-stimulating agents
in heart failure patients.12
Acute Renocardiac Syndrome: Type III
Although AKI is documented as an important cause of acute heart
disorder, the pathophysiological mechanisms likely go beyond
simple volume overload and hypertension, and the recent consensus
definition for AKI will aid in the investigation and analysis of
epidemiologic data. The development of new biomarkers, and the
study of prevention and management strategies in AKI following
radiocontrast or cardiac surgery, will increase our knowledge of this
syndrome.
Preventive Approaches
The major management principle concerning this syndrome is
intra- and extravascular volume control with either use of diuretics
and forms of extracorporeal volume and solute removal (CRRT,
ultrafiltration, hemodialysis).
Management
In Type III CRS, AKI occurs as a primary event (e.g. acute
glomerulonephritis) or secondary event (e.g. radiocontrast,
exogenous or endogenous nephrotoxins, postsurgical, etc.) and
cardiac dysfunction is a common and often times fatal sequela. A
common example of Type III CRS occurring in the hospital setting is
contrast nephropathy, particularly in patients undergoing coronary
and other angiographic procedures who have risk factors such
as pre-existing CKD, diabetes, older age or volume contraction.
In these susceptible populations, prevention may provide the
best opportunity to treat or avoid Type III CRS. Many potential
preventive strategies have been studied, including parenteral
hydration (hypotonic or isotonic saline or bicarbonate), diuretics,
mannitol, natriuretic peptides, dopamine, fenoldopam, theophylline
and N-acetylcysteine.13
Treatment of primary kidney diseases such as acute
glomerulonephritis or kidney allograft rejection may potentially
lessen the risk of Type III CRS, but this has not been systematically
studied. Furthermore, many immunosuppressive drugs used for such
treatment have adverse effects on the cardiovascular system through
their effects on blood pressure, lipids and glucose metabolism.
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Chronic Renocardiac Syndrome: Type IV
A large body of evidence has accumulated demonstrating the graded
and independent association between level of CKD and adverse
cardiac outcomes.
Preventive Approaches
Optimal treatment of CKD with blood pressure and glycemic control,
RAAS blockers and disease-specific therapies, when indicated,
are the best means of preventing this syndrome. Morbidities of
CKD, including bone and mineral disorder and anemia, should be
managed according to CKD guidelines.
Management
The management of Type IV CRS is a multifaceted approach focusing
on the decline of cardiovascular risk factors and complications
common to CKD patients. These include, but are not limited to, anemia,
hypertension, altered bone and mineral metabolism, dyslipidemia,
smoking, albuminuria and malnutrition.14 Several therapies target
ing such uremic complications as anemia, homocysteine, calcium-
phosphate product and hyperparathyroidism are supported by
observational studies demonstrating the association between
adverse cardiovascular events and these conditions.
Secondary Cardiorenal Syndromes: Type V
This subtype does not have a primary and secondary organ
dysfunctions, situations do arise where both organs simultaneously
are targeted by systemic illnesses, either acute or chronic. Examples
include sepsis, systemic lupus erythematosus (SLE), amyloidosis
and diabetes mellitus.
Preventive Approaches
There are no proven methods to prevent or ameliorate this form
of CRSs at this time. Supportive care with a judicious intravenous
fluid approach and the use of pressor agents as needed to avoid
hypotension are reasonable but cannot be expected to avoid AKI or
cardiac damage.15
Management
Examples of Type V CRS include a heterogeneous group of disorders
such as sepsis, SLE, amyloidosis and diabetes mellitus. It is difficult
to formulate a treatment strategy to encompass all of these disorders,
but more important is the recognition that injury to one organ is
likely to influence or injure the other organ and vice versa. Therapies
directed to the improvement in function of one organ need to
consider the interaction with, and role of the other. As sepsis is one
of the more common acute disorders that involves multiple organs,
and often causes co-dysfunction of kidneys and heart. Recognition
of Type V CRS as an entity in sepsis and other systemic disorders will
allow further research into the signaling and mechanisms of injury,
and allow for the development of rational and efficient therapies.
FUTURE DIRECTIONS IN TREATMENT OF
CARDIORENAL SYNDROME
Potentially promising pharmacological approaches include selective
adenosine A1 receptor blockers, which have a variety of effects on
intrarenal hemodynamics and tubular function,16 and vasopressin
antagonists (V2 receptor antagonists vaptans, e.g. conivaptan and
tolvaptan).17 Adenosine can lower cortical blood flow, resulting
in antinatriuretic responses. A1 receptor antagonists have been
shown to cause diuresis and natriuresis while minimally affecting
potassium excretion or glomerular filtration. Other interventions
include the earlier use of dialysis and ultrafiltration, and ultimately,
left ventricular assist devices to manage these patients effectively, at
least in the short-term.
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Section 17
CONCLUSION
Cardiorenal syndrome is an interdependent involvement of both
the heart and the kidney in a spiral fashion. Decrease in GFR or
creatinine clearance in patients with decompensated heart failure
involves longer hospital stays, higher hospital costs, higher in-
hospital mortality rates and more readmissions but still the prognosis
is grave. Earlier use of slow high-dose intravenous diuretics, dialysis
with ultrafiltration for treatment of congestion, inotropes and left
ventricular assistant device to stabilize the hemodynamics and
maintenance of the renal perfusion is the vital component for a short
period of time, which is a clinical challenge of initial management.
There is no selective pharmacological therapy available to directly
influence the four cardiorenal connection (balance between NO and
ROS, RAAS, inflammation and the sympathetic nervous system),
other than ACEI and aldosterone inhibitors to block the RAAS and
inhibit oxidative stress and inflammation. Postulation to intervene
all these connectors may stop the cascade of cardiorenal connection
to prevent severe CRS.
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