**2.2 Cardiorenal syndrome type 2 (chronic cardiorenal syndrome)**

Chronic HF leading to chronic kidney disease is the hallmark of CRS Type 2. The prevalence of CKD in HF cohorts has been variably reported depending on the patient population examined – e.g. hospitalized versus ambulatory patients. Further complicating our understanding of disease prevalence is the fact that early clinical trials of chronic HF excluded patients with established renal insufficiency and most did not determine glomerular filtration rate (GFR) which is of particular clinical importance given that HF is a disease of the elderly.

For example, the SOLVD (Studies of Left Ventricular Dysfunction) trials examined the impact of the angiotensin converting enzyme (ACE) inhibitor Enalapril on mortality and symptom development in patients with left ventricular dysfunction (The SOLVD Investigators, 1991; The SOLVD Investigators, 1992). While those with serum creatinine levels >2.0 mg/dL were excluded from the original trial, a retrospective analysis of study patients revealed at least moderate renal impairment (GFR < 60 ml/min) was present in 26% and 56% of participants in the prevention and treatment arms of the trial, respectively (Dries et al., 2000). Across the series of trials which composed the CHARM (The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Program, moderate renal impairment was detected in 36% of the 2680 study participants at baseline (Hillege et al., 2006).

Determining the prevalence of pre-existing CKD is particularly challenging among hospitalized HF patients. Some clinicians may attribute AKI at the time of HF

increasing body of literature suggesting that diuretics, in and of themselves, may be associated with worse outcomes in patients with ADHF independent of other relevant clinical variables. In a single centre retrospective analysis of 1354 patients admitted with ADHF, Eshaghian and colleagues (Eshaghian et al., 2006) demonstrated that patients requiring the highest doses of diuretics, stratified by quartiles, had higher rates of sudden death, death due to progressive pump failure and all cause mortality compared to patients in the lowest quartile of diuretic dose. This type of observation has fueled a growing interest in identifying alternate strategies for fluid management in the acute setting, independent of

Of particular concern among patients who present with the features of CRS Type 1 is the impact of diagnostic imaging and invasive cardiac procedures which may have an additional and direct toxic effect on the kidneys through a variety of mechanisms. Individuals who present with an acute deterioration in cardiac function will frequently require imaging or investigation to identify a precipitant or cause for their symptoms. Independently, percutaneous interventions and cardiac surgery impart a risk of AKI which is higher in patients who have pre-existing or concomitant acute renal insufficiency

Upwards of 70% of patients admitted to hospital with ADHF will experience a rise in serum creatinine over the course of their admission (Gottleib et al., 2002); this may be the result of therapies administered, either medical or invasive, or a consequence of the various pathophysiological processes which characterize CRS Type 1. Regardless of mechanism, worsening renal function portends a poor prognosis and is associated with higher mortality

Chronic HF leading to chronic kidney disease is the hallmark of CRS Type 2. The prevalence of CKD in HF cohorts has been variably reported depending on the patient population examined – e.g. hospitalized versus ambulatory patients. Further complicating our understanding of disease prevalence is the fact that early clinical trials of chronic HF excluded patients with established renal insufficiency and most did not determine glomerular filtration rate (GFR) which is of particular clinical importance given that HF is a

For example, the SOLVD (Studies of Left Ventricular Dysfunction) trials examined the impact of the angiotensin converting enzyme (ACE) inhibitor Enalapril on mortality and symptom development in patients with left ventricular dysfunction (The SOLVD Investigators, 1991; The SOLVD Investigators, 1992). While those with serum creatinine levels >2.0 mg/dL were excluded from the original trial, a retrospective analysis of study patients revealed at least moderate renal impairment (GFR < 60 ml/min) was present in 26% and 56% of participants in the prevention and treatment arms of the trial, respectively (Dries et al., 2000). Across the series of trials which composed the CHARM (The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) Program, moderate renal impairment was detected in

Determining the prevalence of pre-existing CKD is particularly challenging among hospitalized HF patients. Some clinicians may attribute AKI at the time of HF

diuretic administration (see section 3.8).

(Anderson et al., 1999; Best et al., 2002).

disease of the elderly.

rates. (Gottleib et al., 2002; Damman et al., 2007).

**2.2 Cardiorenal syndrome type 2 (chronic cardiorenal syndrome)** 

36% of the 2680 study participants at baseline (Hillege et al., 2006).

hospitalization solely to CRS Type 1 thereby underestimating the presence of concomitant CRS Type 2 in this cohort of patients. Novel biomarkers of AKI may help clinicians to decipher the relative contributions of CRS Type 1 versus CRS Type 2 in patients hospitalized for HF who have poor renal function upon presentation (Siew et al., 2011; Coca et al., 2008).

Regardless of cause, renal insufficiency in hospitalized HF patients appears to be relatively common; among those enrolled in ADHERE, the prevalence of at least moderate renal impairment, as determined by GFR, was greater than 60% at baseline (Heywood et al., 2007). This is in sharp contrast to initial reports from the same registry which suggested a prevalence rate of only 20% when a serum creatinine of 2.0 mg/dL was employed as a cut off (Adams et al., 2005). Calculation of GFR, therefore, is paramount to accurately identifying the burden of renal disease in all forms of CRS.

The true burden of pre-existing renal dysfunction among patients with HF was best characterized in a meta-analysis performed by Smith and colleagues. In their systematic review of the literature, approximately 80,000 hospitalized and non-hospitalized patients with HF were identified across 16 clinical trials. While 29% of patients were found to have moderate to severe renal impairment (GFR <53 mL/min or cystatin C of >1.56 mg/dL), 63% were found to have at least some degree of impaired kidney function. Moreover, these findings are likely to underestimate the true prevalence of renal insufficiency in HF populations given that 8 of the clinical trials included in the meta-analysis excluded patients on the basis of age or an elevated serum creatinine at baseline (Smith et al., 2006).

In the meta-analysis performed by Smith and colleagues, renal impairment at baseline conferred an increased risk of mortality at one year follow-up compared to patients with normal kidney function (Smith et al., 2006). The adjusted hazard ratio for patients with any renal impairment or moderate to severe renal impairment was 1.56 and 2.31 respectively. Excess risk was conferred in an incremental fashion with each 10 mL/min reduction in GFR correlating to a 7% increase in the risk of death. This observation is strengthened by similar findings across a spectrum of clinical trials in both hospitalized and ambulatory HF populations (Adams et al., 2005; Dries et al., 2000; Fonarow et al., 2005; Heywood et al., 2007; Hillege et al., 2006).

Many of the pathophysiological mechanisms which characterize CRS Type 1 are also implicated in the development of CRS Type 2, although many of these processes may occur slowly and over longer periods of time. For example, elevated central venous pressure is strongly associated with a decline in eGFR among patients with chronic HF (Damman et al., 2009; Firth et al., 1988); as described above, the same is true for patients with ADHF and CRS Type 1. Elevated CVP and secondarily an elevation in renal venous pressure may trigger a number of downstream events, including interstitial ischemia, neurohormonal activation and decreased responsiveness to natriuretic peptides which all combine to reduce GFR directly or indirectly (Damman et al., 2007; Bock & Gottlieb, 2010) in the setting of chronic HF. Chronically low cardiac output, particularly in combination with micro and macrovascular renal disease, may also contribute to fibrosis and structural changes in the kidney which result in impaired renal function.

RAAS activation occurs in both HF and CKD with an associated increase in Angiotensin II levels (AII). AII mediates oxidative injury and endothelial dysfunction through both the formation of reactive oxygen species and a decrease in nitric oxide bioavailability. Each of

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 129

Volume overload due to impaired solute and fluid clearance may also result in hypertension and pulmonary edema. Moreover, the resultant elevations in intra-cardiac filling pressures reduce the transmyocardial perfusion gradient during diastole leading to sub-endocardial ischemia and overall worsening of ventricular function. Release of pro-inflammatory cytokines and reactive oxygen species in response to renal injury may result in endothelial dysfunction in addition to having direct toxic effects on the myocardium with resultant

Activation of the SNS and RAAS as a result of AKI may also lead to deleterious haemodynamic consequences including increased systemic vascular resistance and increased myocardial oxygen consumption, both of which lead to decreased cardiac output. While AII also causes left ventricular hypertrophy, ventricular remodeling and accelerates the development of atherosclerosis, these effects are likely of greater relevance in the setting

CRS Type 4 describes a clinical scenario where primary CKD leads to structural and/or functional cardiac abnormalities which may be associated with clinically significant adverse cardiac events. Indeed, the presence of CKD portends a poor cardiac prognosis with the attributable risk of adverse events correlating in a step-wise manner to reduction in GFR (Go et al., 2004). Moreover, individuals with CKD have an accelerated natural history of their cardiac disease and are more likely to die from cardiac causes rather than progress to renal

For example, in ALLHAT (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) the risk of myocardial infarction (MI)/stroke, revascularization, death due to coronary disease and all forms of atherosclerotic vascular disease was increased as GFR decreased (Wali & Henrich, 2005). Among patients with CKD who experience an acute coronary syndrome, prognosis may also be stratified according to GFR. Shlipak and colleagues reviewed approximately 130,000 elderly patients hospitalized with an acute coronary syndrome and found a 2.5 fold increased risk of death between patients in the highest (CrCl > 0.92 mL/sec) and lowest (CrCl 0.17-0.54 mL/sec) tertile of creatinine clearance (Shlipak et al., 2002). Moreover, an analysis of nearly 120,000 patients from the Cooperative Cardiovascular Project suggested that renal function was a more accurate predictor of long term mortality post-MI than left ventricular systolic function, the presence of heart failure or prior MI (Smith et al., 2008). This relationship has been demonstrated in a multitude of clinical trials across a variety of cardiac cohorts and the observation between

There are many postulates as to the mechanisms underlying poor cardiac outcomes in patients with chronic renal dysfunction. It would appear that the burden of coronary artery disease and myocardial ischemia is greater in patients with CKD than those without (Ix et al., 2003). This may be due to a higher preponderance of traditional risk factors for coronary artery disease in this patient population (Muntner et al., 2005; Parikh et al., 2006) or simply that CKD, in and of itself, imparts increased risk of adverse cardiac events (Levey et al., 2003). In the Framingham Offspring Cohort, two or more traditional cardiovascular risk factors were identified in 73% of patients with CKD (GFR <60 mL/min) compared to 51.4 %

apoptosis and myocardial fibrosis.

of Chronic Renocardiac Syndrome (CRS Type 4).

**2.4 Cardiorenal syndrome type 4 (chronic renocardiac syndrome)** 

replacement therapy (Collins et al., 2008; Foley et al., 2005; Keith et al., 2004).

CKD and poor cardiac outcomes remains robust (Ronco et al., 2008).

these processes, in turn, can result in haemodynamic abnormalities at the level of the heart and kidney contributing to a decline in GFR (Bock & Gottlieb, 2010).

While neurohormonal inhibition and diuretic therapy are the mainstay of pharmacological HF management, these agents are also implicated in the worsening of GFR associated with CRS Type 2. ACE inhibitors and angiotensin receptor blockers (ARBs) result in systemic hypotension as well as efferent arteriolar vasodilatation with an associated decline in intraglomerular pressure and GFR. These effects may be magnified in the presence of concomitant diuretic use and relative intra-vascular volume depletion. The treatment of CRS is discussed in detail below.

The presence of anemia is common in patients with HF, an observation which is consistent across a number of clinical trials in the HF arena. A review of the literature suggests a prevalence rate of between 9-25% depending on the HF patient population studied and the cut-off criteria used to diagnose anemia (Virani et al., 2008; Al-Ahmad et al., 2001; Sharma et al., 2004; Anand et al., 2005; Horwich et al., 2002). Regrettably, many of these studies excluded patients based on renal function and therefore the relative contribution of low GFR to the development of anemia in these patient cohorts is lacking. Anemia in the presence of HF portends a poor prognosis with absolute haemoglobin (Hgb) levels correlating with 1 year survival; a precipitous increase in mortality is observed when Hgb drops below 120 g/L (Horwich et al., 2002; Ezekowitz et al., 2003).

The development of anemia in CRS Type 2 is likely multifactorial and underpinned by a number of processes occurring simultaneously; malnutrition, the formation of reactive oxygen species, cytokine release and erythropoietin (EPO) deficiency/resistance have all been implicated. When present, anemia may lead to further cardiac and renal dysfunction through impaired oxygen delivery and tissue hypoxia, neurohormonal activation, decreased renal blood flow and expansion of plasma volume with resultant cardiac remodeling (McCullough & Lepor, 2005). These mechanisms establish and propagate a vicious cycle of maladaptive processes which lead to worsening anemia, HF and kidney function as a net result.

#### **2.3 Cardiorenal syndrome type 3 (acute renocardiac syndrome)**

The RIFLE Criteria define acute kidney injury as a twofold increase in serum creatinine or a GFR decrease by 50 percent or urine output of <0.5 mL/kg per hour for 12 hours (Bellomo et al., 2004). By this definition, AKI is prevalent in nearly 9% of hospitalized patients (Uchino et al., 2006) with an associated 4-fold increased risk of mortality compared to patients without evidence of renal injury (Ricci et al., 2008). Much of that excess risk may be attributable to cardiac sequelae of AKI. CRS Type 3 characterizes this interaction and may be defined broadly as primary acute kidney injury, due to any number of causes, which secondarily leads to acute cardiac dysfunction.

A number of pathophysiological processes may be initiated as a consequence of AKI which have significant downstream cardiac effects. Biochemical abnormalities including hyperkalemia may pre-dispose to malignant cardiac arrhythmias and an increased risk of sudden cardiac death. Acidemia and uremia have direct myocardial depressant effects and may precipitate acute biventricular cardiomyopathy; these effects are exacerbated in the face of volume expansion.

these processes, in turn, can result in haemodynamic abnormalities at the level of the heart

While neurohormonal inhibition and diuretic therapy are the mainstay of pharmacological HF management, these agents are also implicated in the worsening of GFR associated with CRS Type 2. ACE inhibitors and angiotensin receptor blockers (ARBs) result in systemic hypotension as well as efferent arteriolar vasodilatation with an associated decline in intraglomerular pressure and GFR. These effects may be magnified in the presence of concomitant diuretic use and relative intra-vascular volume depletion. The treatment of CRS

The presence of anemia is common in patients with HF, an observation which is consistent across a number of clinical trials in the HF arena. A review of the literature suggests a prevalence rate of between 9-25% depending on the HF patient population studied and the cut-off criteria used to diagnose anemia (Virani et al., 2008; Al-Ahmad et al., 2001; Sharma et al., 2004; Anand et al., 2005; Horwich et al., 2002). Regrettably, many of these studies excluded patients based on renal function and therefore the relative contribution of low GFR to the development of anemia in these patient cohorts is lacking. Anemia in the presence of HF portends a poor prognosis with absolute haemoglobin (Hgb) levels correlating with 1 year survival; a precipitous increase in mortality is observed when Hgb drops below 120

The development of anemia in CRS Type 2 is likely multifactorial and underpinned by a number of processes occurring simultaneously; malnutrition, the formation of reactive oxygen species, cytokine release and erythropoietin (EPO) deficiency/resistance have all been implicated. When present, anemia may lead to further cardiac and renal dysfunction through impaired oxygen delivery and tissue hypoxia, neurohormonal activation, decreased renal blood flow and expansion of plasma volume with resultant cardiac remodeling (McCullough & Lepor, 2005). These mechanisms establish and propagate a vicious cycle of maladaptive processes which lead to worsening anemia, HF and kidney function as a net

The RIFLE Criteria define acute kidney injury as a twofold increase in serum creatinine or a GFR decrease by 50 percent or urine output of <0.5 mL/kg per hour for 12 hours (Bellomo et al., 2004). By this definition, AKI is prevalent in nearly 9% of hospitalized patients (Uchino et al., 2006) with an associated 4-fold increased risk of mortality compared to patients without evidence of renal injury (Ricci et al., 2008). Much of that excess risk may be attributable to cardiac sequelae of AKI. CRS Type 3 characterizes this interaction and may be defined broadly as primary acute kidney injury, due to any number of causes, which

A number of pathophysiological processes may be initiated as a consequence of AKI which have significant downstream cardiac effects. Biochemical abnormalities including hyperkalemia may pre-dispose to malignant cardiac arrhythmias and an increased risk of sudden cardiac death. Acidemia and uremia have direct myocardial depressant effects and may precipitate acute biventricular cardiomyopathy; these effects are exacerbated in the face

and kidney contributing to a decline in GFR (Bock & Gottlieb, 2010).

is discussed in detail below.

result.

g/L (Horwich et al., 2002; Ezekowitz et al., 2003).

secondarily leads to acute cardiac dysfunction.

of volume expansion.

**2.3 Cardiorenal syndrome type 3 (acute renocardiac syndrome)** 

Volume overload due to impaired solute and fluid clearance may also result in hypertension and pulmonary edema. Moreover, the resultant elevations in intra-cardiac filling pressures reduce the transmyocardial perfusion gradient during diastole leading to sub-endocardial ischemia and overall worsening of ventricular function. Release of pro-inflammatory cytokines and reactive oxygen species in response to renal injury may result in endothelial dysfunction in addition to having direct toxic effects on the myocardium with resultant apoptosis and myocardial fibrosis.

Activation of the SNS and RAAS as a result of AKI may also lead to deleterious haemodynamic consequences including increased systemic vascular resistance and increased myocardial oxygen consumption, both of which lead to decreased cardiac output. While AII also causes left ventricular hypertrophy, ventricular remodeling and accelerates the development of atherosclerosis, these effects are likely of greater relevance in the setting of Chronic Renocardiac Syndrome (CRS Type 4).
