Chapter 132

Cardiorenal Syndrome: An Overview

NP Singh, Anish Kumar, Taposh Sarkar

erythropoietin and renalase are all secreted from the kidneys, and
ABSTRACT are capable of cellular and humoral signaling. Dysfunction of either
of the two organs can cause dysfunction of the other (Figures 1 and
Cardiorenal syndrome (CRS) is a complex spiral of vascular disease
2). Changes in the RAAS, the imbalance between nitric oxide (NO)
entity, in which affliction of one organ (kidney) may adversely impact
the functioning of the other (heart). Recent consensus conference has and reactive oxygen species (ROS), the sympathetic nervous system
clearly defined its various types and pathophysiology. Improved survival, and inflammation are the cardiorenal connectors to develop CRS.
cardiovascular risk factors (diabetes, hypertension, dyslipidemia), These connectors together decrease the sensitivity of erythropoietin,
diagnostic and therapeutic intervention [contrast agent, improper and are responsible for renal anemia that also aggravates the clinical
diuretic usage, nonsteroidal anti-inflammatory drugs (NSAIDs)] are conditions of cardiac failure (Figure 1).4,5
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
EPIDEMIOLOGY
therapeutic strategies such as diuretics and inotropes, in the CRS as Heart failure is a common chronic condition affecting 2% of
well as novel therapies that hold promise, such as arginine vasopressin the adult population and resulting in over 1 million annual
antagonists, adenosine A1 receptor antagonists and ultrafiltration. 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
INTRODUCTION cardiovascular disease (CVD) mortality ranging from 15 to 30 times
Cardiorenal syndrome is defined as disorders of the heart and that of healthy individuals, with an associated disproportionate
kidneys whereby acute or chronic dysfunction in one organ may use of healthcare resources.7
induce acute or chronic dysfunction of the other.1 The coexistence
of cardiac and renal disease significantly increases mortality, PATHOPHYSIOLOGY
morbidity, complexity and cost of care,2 and carries an extremely
bad prognosis. The exact cause of deterioration of kidney function Three main factors have been implemented: (1) low-cardiac output;
and the mechanism underlying this interaction are complex, (2) elevation of both intra-abdominal and central venous pressures
multifactorial in nature, and still not completely understood. and (3) neurohormonal and inflammatory activation.
Renal dysfunction is one of the most important comorbidities in
heart failure. Reduced estimated glomerular filtration rate (eGFR) DIAGNOSIS
seems to be a potent predictor of cardiovascular complications Early identification of worsening kidney function is essential for
and mortality. Patients with renal dysfunction have a significantly early treatment of CRS. Use of biomarkers that become detectable
increased risk of developing an adverse outcome after acute before the traditional tests for kidney function, including GFR
myocardial infarction (AMI).3 The most common underlying risk or serum creatinine have made to easier. Biomarkers such as
factors that account for renal dysfunction in the setting of heart neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl--
failure or cardiac dysfunction include hypertension, diabetes D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1)
mellitus, severe atherosclerotic disease, elderly age and a prior implicated in tubulointerstitial damage are being used to identify
history of renal insufficiency or heart failure. acute kidney injury (AKI). Serum cystatin C is elevated earlier than
creatinine. Furthermore, while cystatin C in the serum is a marker
CARDIORENAL CONNECTION of reduced glomerular filtration, urinary cystatin C is a marker of
Both heart and the kidneys are richly vascular (the kidneys are tubular dysfunction. Other biomarkers that have proven useful
more vascular than the heart) and both organs are supplied by include B-type natriuretic peptide (BNP), interleukin-18 (IL-18)
sympathetic and parasympathetic innervations. These two organs and fatty acid-binding protein (FABP). Tests for volume status
act in tandem to regulate blood pressure, vascular tone, diuresis, and end-organ perfusion are also useful in the diagnosis of CRS.
natriuresis, intravascular volume homeostasis, peripheral tissue Urine sediment examination should be performed in differentiating
perfusion and oxygenation. They have endocrine functions with CRS from other causes of AKI by excluding pathologic cells,
interdependent physiological hormonal actions regulated by arterial casts or crystals. Hyponatremia, when present, may indicate
natriuretic peptide, a vasodilator secreted from the heart and excess antidiuretic hormone (ADH) and portend an overall poor
renin-angiotensin-aldosterone system (RAAS). Also, vitamin D3, prognosis.
 Nephrology Section 17

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

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
Figure 2: Different types of cardiorenal syndrome (CRS) can be inter- a number of reasons, with hemodynamic derangements ranging
connected and patients may move from one type to another during the time from acute pulmonary edema with hypertension through severe
course of the combined disorders peripheral fluid overload to cardiogenic shock and hypotension.
Source: Ronco C, Costanzo MR, Bellomo R, Maisel AS (Eds). Fluid Table 2 summarizes some practical recommendations for the
Overload: Diagnosis and Management, illustrated edition. Basel, management of ADHF patients with Type I CRS. The goal of diuretic
Switzerland: Karger Publishers; 2010. pp. 33-8. 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
CARDIORENAL SYNDROME: CLASSIFICATION demonstrated to have greater efficacy than intermittent dosing.8
AND MANAGEMENT If kidney function continues to worsen, blockade of the RAAS
may be a contributing factor, necessitating withholding or delaying
The CRS was classified into five categories, according to the
the introduction of angiotensin-converting-enzyme inhibitors
underlying etiologies and the nature of concomitant cardiac and
(ACEIs) or angiotensin receptor blockers (ARBs) in order to maintain
renal dysfunction (Table 1).
the GFR.
For Type I CRS patients with preserved or elevated blood pressure,
Acute Cardiorenal Syndrome: Type I vasodilators such as nitroglycerin and nitroprusside are often used to
This appears to be a syndrome of worsening renal function relieve symptoms and improve hemodynamics. When patients have
that frequently complicates hospitalized patients with acute low blood pressure and poor renal perfusion, positive inotropes such
decompensated heart failure (ADHF) and acute coronary syndrome. as dobutamine or phosphodiesterase inhibitors may be required.9
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 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 heart may reduce apoptosis, fibrosis and inflammation. Hence, there
acute decompensated heart failure (ADHF) patients with has been intense interest in using erythropoiesis-stimulating agents
cardiorenal syndrome (CRS) (Katerina Koniari et al.)9 in heart failure patients.12
Restrict fluid and sodium intake
Acute Renocardiac Syndrome: Type III
Increase furosemide dose
Although AKI is documented as an important cause of acute heart
Use continuous intravenous furosemide
disorder, the pathophysiological mechanisms likely go beyond
Add thiazides or metolazone simple volume overload and hypertension, and the recent consensus
Add renoprotective dopamine at 23 mcg/kg/min definition for AKI will aid in the investigation and analysis of
epidemiologic data. The development of new biomarkers, and the
Add inotrope or vasodilator (according to systolic blood pressure)
study of prevention and management strategies in AKI following
Start ultrafiltration radiocontrast or cardiac surgery, will increase our knowledge of this
Insert intra-aortic balloon pump syndrome.
Insert another device
Preventive Approaches
The major management principle concerning this syndrome is
Chronic Cardiorenal Syndrome: Type II intra- and extravascular volume control with either use of diuretics
This subtype is a separate entity from acute CRS as it indicates a more and forms of extracorporeal volume and solute removal (CRRT,
chronic state of kidney disease complicating chronic heart disease. ultrafiltration, hemodialysis).
This is an exceptionally common problem. For instance, in patients
hospitalized with congestive heart failure (CHF), approximately Management
63% meet the kidney disease outcomes quality initiative (K/DOQI) In Type III CRS, AKI occurs as a primary event (e.g. acute
definition of stages 35 CKD (eGFR < 60 mL/min/1.73 m2).10 glomerulonephritis) or secondary event (e.g. radiocontrast,
exogenous or endogenous nephrotoxins, postsurgical, etc.) and
Preventive Approaches cardiac dysfunction is a common and often times fatal sequela. A
Pharmacologic therapies that have been beneficial for chronic CVD common example of Type III CRS occurring in the hospital setting is
have been either neutral or favorable to the kidneys including use contrast nephropathy, particularly in patients undergoing coronary
of RAAS antagonists, beta-adrenergic blocking agents and statins. and other angiographic procedures who have risk factors such
Furthermore, other strategies including glycemic control in diabetes as pre-existing CKD, diabetes, older age or volume contraction.
and blood pressure control in those with hypertension.11 In these susceptible populations, prevention may provide the
best opportunity to treat or avoid Type III CRS. Many potential
Management preventive strategies have been studied, including parenteral
Interruption of the RAAS is the primary aim in the management of hydration (hypotonic or isotonic saline or bicarbonate), diuretics,
Type II CRS. However, RAAS blockade can lead to significant decrease mannitol, natriuretic peptides, dopamine, fenoldopam, theophylline
in kidney function and/or elevated potassium. However, creatinine and N-acetylcysteine.13
tended to stabilize, and in many instances, improved over the Treatment of primary kidney diseases such as acute
course of the study. In terms of aldosterone blockade, drugs such as glomerulonephritis or kidney allograft rejection may potentially
spironolactone and eplerenone are important adjuncts to therapy in lessen the risk of Type III CRS, but this has not been systematically
patients with severe heart failure. Both CHF and CKD are associated studied. Furthermore, many immunosuppressive drugs used for such
with anemia, which is commonly treated with erythropoiesis- treatment have adverse effects on the cardiovascular system through
stimulating agents. Furthermore, the action of erythropoietin in the their effects on blood pressure, lipids and glucose metabolism.
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 Nephrology Section 17

Chronic Renocardiac Syndrome: Type IV CONCLUSION

A large body of evidence has accumulated demonstrating the graded Cardiorenal syndrome is an interdependent involvement of both
and independent association between level of CKD and adverse the heart and the kidney in a spiral fashion. Decrease in GFR or
cardiac outcomes. creatinine clearance in patients with decompensated heart failure
involves longer hospital stays, higher hospital costs, higher in-
Preventive Approaches hospital mortality rates and more readmissions but still the prognosis
Optimal treatment of CKD with blood pressure and glycemic control, is grave. Earlier use of slow high-dose intravenous diuretics, dialysis
RAAS blockers and disease-specific therapies, when indicated, with ultrafiltration for treatment of congestion, inotropes and left
are the best means of preventing this syndrome. Morbidities of ventricular assistant device to stabilize the hemodynamics and
CKD, including bone and mineral disorder and anemia, should be maintenance of the renal perfusion is the vital component for a short
managed according to CKD guidelines. period of time, which is a clinical challenge of initial management.
There is no selective pharmacological therapy available to directly
Management influence the four cardiorenal connection (balance between NO and
The management of Type IV CRS is a multifaceted approach focusing ROS, RAAS, inflammation and the sympathetic nervous system),
on the decline of cardiovascular risk factors and complications other than ACEI and aldosterone inhibitors to block the RAAS and
common to CKD patients. These include, but are not limited to, anemia, inhibit oxidative stress and inflammation. Postulation to intervene
hypertension, altered bone and mineral metabolism, dyslipidemia, all these connectors may stop the cascade of cardiorenal connection
smoking, albuminuria and malnutrition.14 Several therapies target to prevent severe CRS.
ing such uremic complications as anemia, homocysteine, calcium-
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