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

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

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

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 %

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 131

Management of the CRS presents a challenge to the clinician. Treatment of HF with standard therapies often results in worsening of renal function. Moreover, most randomized clinical trials of HF therapies, including β-blockers, ACE inhibitors, ARBs and aldosterone antagonists, have excluded patients with significant renal dysfunction. Therefore, the results of these trials, most showing significant reductions in morbidity and mortality in the general HF population, may not be applicable to the CRS population. Observational studies and small randomized studies, however, have suggested that many of these drug classes may have similar benefit in patients with renal dysfunction (Berger et al., 2007; Cice et al., 2003). A number of novel strategies have been described that may offer specific benefit in the CRS

Management of chronic CRS is overall similar to the management of HF in general, employing a combination of diuretics, inhibitors of the RAAS, and β-blockers. In the hospitalized patient with CRS and ADHF, diuretics remain a mainstay of therapy, but may be supplemented by additional therapies including novel pharmacologic agents, inotropic

While fluid removal with diuretics is a cornerstone of HF management, diuretic resistance is highly prevalent in patients with decreased renal function, making this aspect of care for the patient with CRS particularly challenging. Furthermore, effective diuresis can result in further deterioration in renal function, particularly when the rate of fluid removal exceeds the rate of fluid movement from the extravascular space to the intravascular space, resulting in low effective circulating volume. Thus, two of the greatest obstacles in treating patients with CRS are overcoming diuretic resistance and effectively removing fluid without

Loop diuretics (LD) such as furosemide act at the thick ascending limb of the loop of Henle, inhibiting the Na+/K+/2Cl- cotransporter. LD are protein bound, preventing filtration at the glomerulus, but are actively secreted in the proximal tubule. Effective delivery to the loop of Henle requires effective delivery to the bloodstream (through intestinal absorption or direct intravenous administration), adequate renal blood flow, intact proximal tubule secretion, and delivery of tubular contents to the more distal nephron. There are therefore a number of

Delayed intestinal absorption is common in patients with HF, owing to intestinal wall edema. This can be most effectively overcome by using intravenous LD in patients who are markedly volume overloaded, and transitioning to oral administration once signs of congestion elsewhere (i.e. peripheral edema, venous congestion on chest X-ray) have resolved. Reduced renal blood flow (RBF) and GFR are also prevalent in patients with HF and CRS as a result of intrinsic renal dysfunction, decreased cardiac output, and alteration in glomerular haemodynamics by agents such as non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors, and ARBs. Avoiding agents such as NSAIDs, optimizing systemic hemodynamics, and increasing LD dose can help to overcome this aspect of resistance to LD. Similarly, proximal tubular secretion of LD is reduced in patients with CRS

mechanisms by which diuretic resistance may occur (Jentzer et al., 2010).

population, although data from clinical trials have not always been encouraging.

**3. Management of the cardiorenal syndrome** 

support, and ultrafiltration.

compromising renal function.

**3.1 Diuretics** 

of participants without CKD. A statistically significant increase in hypertension and diabetes along with a trend towards increased dyslipidemia were more prevalent in the CKD cohort (Parikh et al., 2006). Existing data would suggest that CKD is independently associated with a higher risk for cardiovascular endpoints in affected patients; the magnitude of this excess risk, however, does not support elevating CKD to the level of a cardiovascular disease equivalent as is the case with diabetes or prior MI (Wattanakit et al., 2006).

Other potential pathophysiological processes involved in the development and acceleration of coronary atherosclerosis in patients with CKD include abnormalities of mineral metabolism leading to vascular calcification and endothelial dysfunction secondary to both chronic inflammation and EPO deficiency. Uremia, hypertension and increased vascular stiffness contribute to progressive left ventricular hypertrophy and diastolic dysfunction, which in time may progress to systolic dysfunction. Neurohormonal activation results in myocardial fibrosis and maladaptive ventricular remodelling which may hasten this process. In the presence of volume expansion, patients with either systolic or diastolic dysfunction remain at high risk for developing decompensated heart failure.

Observational trials very clearly demonstrate that those with CKD, as a result of actual or perceived contraindications, are less likely to receive efficacious and evidence based therapies compared to cohorts of patients with normal renal function (Al-Suwaidi et al., 2002; Parikh et al., 2006). An even more important observation is that those patients with CKD who do receive appropriate guideline based interventions have better outcomes (Shlipak et al., 2002); therapeutic prejudice of healthcare teams and providers in relation to patients with renal dysfunction is most certainly misplaced, particularly since this group of patients have a high burden of disease and therefore may receive the greatest degree of benefit from aggressive intervention.

#### **2.5 Cardiorenal syndrome type 5 (secondary cardiorenal syndrome)**

Secondary cardiorenal syndrome is the result of a systemic disorder leading to simultaneous cardiac and renal injury; each of these processes may be acute or chronic in nature and CRS Type 5 does not preclude involvement of other organs and tissue beds. Moreover, other subtypes of the CRS may exist concomitantly due to pre-existing co-morbidities.

The prevalence of CRS Type 5 overall has not been well described, primarily due to a paucity of data in this arena, however the frequency of cardiac and renal involvement for specific systemic disease states may be described in the literature. For example, myocardial injury in the absence of an acute coronary syndrome, as manifested by a positive troponin assay, is present in up to one-half of patients with sepsis admitted to a critical care unit (Amman et al., 2003). Similarly, AKI may occur in 70% of this patient population (Kim et al., 2011). Dysfunction of either or both organ systems portends a poor prognosis.

Connective tissue disease, sarcoidosis, amyloidosis, diabetes and sepsis are the most commonly referred to systemic process that may predispose to secondary CRS (Ronco et al., 2008). While a discussion of cardiac and renal involvement in each of these disease states is beyond the scope of this chapter, it is clear that definitive treatment must be focused at correcting the underlying pathophysiological process while providing supportive care for the heart and kidneys in the interim.
