**3.1 Diuretics**

130 Chronic Kidney Disease

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

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

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

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 sub-

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.,

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

equivalent as is the case with diabetes or prior MI (Wattanakit et al., 2006).

dysfunction remain at high risk for developing decompensated heart failure.

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

types of the CRS may exist concomitantly due to pre-existing co-morbidities.

2011). Dysfunction of either or both organ systems portends a poor prognosis.

benefit from aggressive intervention.

the heart and kidneys in the interim.

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 compromising renal function.

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

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

CRS.

renal dysfunction.

with normal renal function.

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 133

of intermittent boluses of HSS with loop diuretics and moderate dietary sodium restriction resulted in more rapid diuresis, normalization of neurohormonal activity, shorter hospitalizations, and less renal dysfunction (Licata et al., 2003; Paterna et al., 2000). After discharge, these results were maintained by continuing moderate sodium restriction (<2.8 g/day) with strict fluid restriction (<1 L/day), resulting in fewer readmissions and improved survival compared to continued strict sodium (<2 g/day) and similar fluid restriction. The mechanism by which HSS provides these benefits is unclear, but may be related to the osmotic load drawing interstitial fluid into the intravascular space, leading to neurohormonal blockade, reduced vascular resistance, improved cardiac output, and reduced interstitial edema. In addition, the sodium load in the kidney may induce a sort of transient diabetes insipidus, resulting in rapid diuresis (Di Pasquale et al., 2007). Further research and larger scale studies are required to confirm the benefits of HSS in patients with

Inhibitors of the renin-angiotensin system, including ACE inhibitors and ARBs have proven survival benefit in patients with left ventricular dysfunction (The SOLVD Investigators, 1991; The SOLVD Investigators, 1992), and have also been shown to slow the rate of decline of renal function in patients with diabetic chronic kidney disease (Lewis et al., 1993). It stands to reason, therefore, that these agents would be beneficial in the CRS, although largescale clinical trials in the HF population have typically excluded patients with significant

The CHARM studies investigated the effects of candesartan compared with placebo in a broad population of patients with HF. Patients with serum creatinine >3.0 mg/dL were excluded, but among the study population, there was no statistically significant interaction between eGFR and treatment effect, suggesting a mortality benefit of ARBs in patients with HF and mild-to-moderate renal dysfunction that is equivalent to that seen in patients with HF and preserved renal function (Hillege et al., 2006). An analysis of CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) which demonstrated a mortality benefit of enalapril compared to placebo in patients with HF, found a greater benefit in patients with baseline serum creatinine above the median (123 umol/L) than in those with serum creatinine below the median (Swedberg et al., 1990). A retrospective analysis of the Minnesota Heart Survey stratified 4573 patients hospitalized with HF by GFR, and revealed that patients at all stages of CKD had reduced in-hospital mortality when an ACE inhibitor or ARB was used in hospital, and reduced one-year mortality when discharged on an ACE inhibitor or ARB (Berger et al., 2007). This same analysis, however, demonstrated that patients with severe renal dysfunction were far less likely to receive either agent than those

In HF, elevated angiotensin II levels cause efferent arteriolar vasoconstriction, elevating glomerular filtration pressure and preserving GFR. Inhibition of this process with ACE inhibitors or ARBs may result in an initial decline in GFR, but in the long term protects the glomerulus from high filtration pressures and may help to preserve long-term renal function (Heywood, 2004). Although there appear to be benefits of using these agents in the CRS population, caution must be taken when initiating ACE inhibitors and ARBs in patients with renal dysfunction, particularly with regard to volume status and avoidance of NSAIDs.

**3.2 Renin-angiotensin-aldosterone system antagonists** 

because organic acids that accumulate in the uremic state compete for the same transporters; increased doses of LD may be required to overcome this problem.

Through intravascular volume depletion, LD may result in activation of the RAAS. This leads to increased sodium absorption by the proximal and distal tubule. This issue is compounded by the fact that post-diuretic rebound sodium avidity occurs between bolus doses of LD, negating much of the natriuretic benefit achieved. Strict dietary sodium restriction and administration of RAAS antagonists (i.e. ACE inhibitors and ARBs) may help to prevent this. Historically, it has been believed that continuous infusions of diuretics may also be effective in minimizing rebound sodium absorption; the recent DOSE (Diuretic Strategies in Patients with Acute Decompensated Heart Failure) trial suggests that there may be no difference in diuretic efficacy between intermittent intravenous bolus dosing and continuous infusions (Felker et al., 2011).

The "braking phenomenon" is a short-term effect, whereby the nephron becomes less sensitive to LD after an initial dose. This is thought to result from upregulation of the Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle. Higher doses of LD may be necessary to overcome this. With chronic LD administration, distal tubule hypertrophy occurs. This allows increased distal sodium reabsorption, tending to negate the inhibition of sodium reabsorption that has occurred in the loop of Henle.

A strategy of combination diuretic administration, with the addition of a thiazide diuretic such as metolazone 5-10 mg 30 minutes prior to LD administration can help to prevent sodium retention by this mechanism. Thiazides inhibit the NaCl cotransporter in the distal convoluted tubule. Caution is needed, however, as combination diuretic therapy can result in profound electrolyte abnormalities. Serum levels of potassium and magnesium must be closely monitored and infrequent metolazone dosing (i.e. three times per week) or coadministration of a potassium-sparing diuretic may be necessary to prevent life-threatening hypokalemia.

Finally, sodium and water retention may be upregulated in the distal nephron in patients with CRS, mediated by elevated levels of aldosterone and vasopressin, respectively. Administration of aldosterone antagonists or other potassium-sparing diuretics will minimize sodium retention in this situation; the new vasopressin antagonists have a role in preventing excessive absorption of free water (see section 3.6). Free water restriction may also be necessary in patients with refractory fluid overload or significant hyponatremia. An important caveat to the use of aldosterone antagonists in CRS is the risk of hyperkalemia in patients with renal impairment; these agents should generally be avoided in patients with GFR <30 mL/min.

Major drawbacks to the use of LD include neurohormonal activation, ototoxicity, electrolyte abnormalities (particularly hypokalemia and hypomagnesemia), dysrhythmias, and intravascular volume depletion with resultant worsening renal function and/or hypotension in patients who are preload-dependent or receiving concomitant vasodilator therapy.

A novel approach to diuretic use involves the co-administration of loop diuretics and hypertonic saline solution (HSS). Small studies in patients with ADHF have demonstrated that, compared to intravenous bolus loop diuretics with a low sodium diet, administration

because organic acids that accumulate in the uremic state compete for the same transporters;

Through intravascular volume depletion, LD may result in activation of the RAAS. This leads to increased sodium absorption by the proximal and distal tubule. This issue is compounded by the fact that post-diuretic rebound sodium avidity occurs between bolus doses of LD, negating much of the natriuretic benefit achieved. Strict dietary sodium restriction and administration of RAAS antagonists (i.e. ACE inhibitors and ARBs) may help to prevent this. Historically, it has been believed that continuous infusions of diuretics may also be effective in minimizing rebound sodium absorption; the recent DOSE (Diuretic Strategies in Patients with Acute Decompensated Heart Failure) trial suggests that there may be no difference in diuretic efficacy between intermittent intravenous bolus dosing and

The "braking phenomenon" is a short-term effect, whereby the nephron becomes less sensitive to LD after an initial dose. This is thought to result from upregulation of the Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle. Higher doses of LD may be necessary to overcome this. With chronic LD administration, distal tubule hypertrophy occurs. This allows increased distal sodium reabsorption, tending to negate the inhibition of

A strategy of combination diuretic administration, with the addition of a thiazide diuretic such as metolazone 5-10 mg 30 minutes prior to LD administration can help to prevent sodium retention by this mechanism. Thiazides inhibit the NaCl cotransporter in the distal convoluted tubule. Caution is needed, however, as combination diuretic therapy can result in profound electrolyte abnormalities. Serum levels of potassium and magnesium must be closely monitored and infrequent metolazone dosing (i.e. three times per week) or coadministration of a potassium-sparing diuretic may be necessary to prevent life-threatening

Finally, sodium and water retention may be upregulated in the distal nephron in patients with CRS, mediated by elevated levels of aldosterone and vasopressin, respectively. Administration of aldosterone antagonists or other potassium-sparing diuretics will minimize sodium retention in this situation; the new vasopressin antagonists have a role in preventing excessive absorption of free water (see section 3.6). Free water restriction may also be necessary in patients with refractory fluid overload or significant hyponatremia. An important caveat to the use of aldosterone antagonists in CRS is the risk of hyperkalemia in patients with renal impairment; these agents should generally be avoided in patients with

Major drawbacks to the use of LD include neurohormonal activation, ototoxicity, electrolyte abnormalities (particularly hypokalemia and hypomagnesemia), dysrhythmias, and intravascular volume depletion with resultant worsening renal function and/or hypotension in patients who are preload-dependent or receiving concomitant vasodilator

A novel approach to diuretic use involves the co-administration of loop diuretics and hypertonic saline solution (HSS). Small studies in patients with ADHF have demonstrated that, compared to intravenous bolus loop diuretics with a low sodium diet, administration

increased doses of LD may be required to overcome this problem.

sodium reabsorption that has occurred in the loop of Henle.

continuous infusions (Felker et al., 2011).

hypokalemia.

GFR <30 mL/min.

therapy.

of intermittent boluses of HSS with loop diuretics and moderate dietary sodium restriction resulted in more rapid diuresis, normalization of neurohormonal activity, shorter hospitalizations, and less renal dysfunction (Licata et al., 2003; Paterna et al., 2000). After discharge, these results were maintained by continuing moderate sodium restriction (<2.8 g/day) with strict fluid restriction (<1 L/day), resulting in fewer readmissions and improved survival compared to continued strict sodium (<2 g/day) and similar fluid restriction. The mechanism by which HSS provides these benefits is unclear, but may be related to the osmotic load drawing interstitial fluid into the intravascular space, leading to neurohormonal blockade, reduced vascular resistance, improved cardiac output, and reduced interstitial edema. In addition, the sodium load in the kidney may induce a sort of transient diabetes insipidus, resulting in rapid diuresis (Di Pasquale et al., 2007). Further research and larger scale studies are required to confirm the benefits of HSS in patients with CRS.

#### **3.2 Renin-angiotensin-aldosterone system antagonists**

Inhibitors of the renin-angiotensin system, including ACE inhibitors and ARBs have proven survival benefit in patients with left ventricular dysfunction (The SOLVD Investigators, 1991; The SOLVD Investigators, 1992), and have also been shown to slow the rate of decline of renal function in patients with diabetic chronic kidney disease (Lewis et al., 1993). It stands to reason, therefore, that these agents would be beneficial in the CRS, although largescale clinical trials in the HF population have typically excluded patients with significant renal dysfunction.

The CHARM studies investigated the effects of candesartan compared with placebo in a broad population of patients with HF. Patients with serum creatinine >3.0 mg/dL were excluded, but among the study population, there was no statistically significant interaction between eGFR and treatment effect, suggesting a mortality benefit of ARBs in patients with HF and mild-to-moderate renal dysfunction that is equivalent to that seen in patients with HF and preserved renal function (Hillege et al., 2006). An analysis of CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) which demonstrated a mortality benefit of enalapril compared to placebo in patients with HF, found a greater benefit in patients with baseline serum creatinine above the median (123 umol/L) than in those with serum creatinine below the median (Swedberg et al., 1990). A retrospective analysis of the Minnesota Heart Survey stratified 4573 patients hospitalized with HF by GFR, and revealed that patients at all stages of CKD had reduced in-hospital mortality when an ACE inhibitor or ARB was used in hospital, and reduced one-year mortality when discharged on an ACE inhibitor or ARB (Berger et al., 2007). This same analysis, however, demonstrated that patients with severe renal dysfunction were far less likely to receive either agent than those with normal renal function.

In HF, elevated angiotensin II levels cause efferent arteriolar vasoconstriction, elevating glomerular filtration pressure and preserving GFR. Inhibition of this process with ACE inhibitors or ARBs may result in an initial decline in GFR, but in the long term protects the glomerulus from high filtration pressures and may help to preserve long-term renal function (Heywood, 2004). Although there appear to be benefits of using these agents in the CRS population, caution must be taken when initiating ACE inhibitors and ARBs in patients with renal dysfunction, particularly with regard to volume status and avoidance of NSAIDs.

Sub-Types and Therapeutic Management of the Cardiorenal Syndrome 135

improvement in both creatinine clearance and hemoglobin levels, while those patients who did not receive β-blockers had worsening renal function and anemia over the same time period (Khan et al., 2006). In patients with HF and normal renal function at baseline, lack of treatment with a β-blocker was associated with increased risk of developing renal failure over 20 years of follow-up (Tanaka et al., 2007). In hemodialysis patients with dilated left ventricles, treatment with metoprolol resulted in reduced ventricular dimensions, increased fractional shortening, and reduced levels of natriuretic peptides (Hara et al., 2001). A randomized trial of 114 hemodialysis patients with dilated cardiomyopathy showed that carvedilol, compared to placebo, was associated with improved ejection fraction, improved survival, and fewer HF hospitalizations (Cice et al., 2003). Although large-scale clinical trials in this population are lacking, the weight of evidence suggests that treatment with βblockers in the CRS population is likely to be associated with reductions in mortality and

Inotropic medications such as dobutamine and milrinone are frequently used in patients with ADHF, particularly in the setting of the CRS where low cardiac output is felt to be a major contributor to rapidly declining renal function. Both agents are vasodilating inotropes, but they have different mechanisms of action. Dobutamine is an adrenergic agonist that affects inotropy and chronotropy via β-1 activity and peripheral vasodilation via β-2 activity. Milrinone is an inhibitor of type III phosphodiesterase and results in increased intracellular cyclic adenosine monophosphate (cAMP). This, in turn, results in increased inotropy (without chronotropy) as well as peripheral vasodilation. Although both agents have attractive hemodynamic profiles in the treatment of CRS, evidence suggests that they should not be part of standard therapy in this condition. OPTIME-CHF (Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) compared intravenous milrinone to placebo in patients with ADHF not requiring inotropic therapy for shock or other indications. There was no difference between the two groups in the primary endpoint of total number of days in hospital by 60 days after randomization. There was also no difference in the rate of progression of HF, but the patients treated with milrinone had higher rates of treatment failure, largely driven by higher rates of

The ADHERE registry compared outcomes of patients with ADHF treated with vasodilating medications (nitroglycerin, nesiritide) and inotropic agents (dobutamine, milrinone). Even after adjustment for baseline variables including age, gender, blood pressure, BUN, creatinine, sodium, heart rate, and symptom severity, odds ratios for mortality between individual inotropes and individual vasodilators ranged from 1.45 to 2.17. Inotropic agents, therefore, are recommended by major society guidelines only for short-term use in patients with cardiogenic shock or refractory volume overload with diuretic resistance, and not recommended for routine use in hospitalized patients with ADHF. In addition, patients receiving these agents must be carefully monitored for hypotension and arrhythmias, and it should be recognized that the use of these agents is associated with a worse prognosis.

Dopamine is an endogenous catecholamine that binds dopamine receptors (D1-D5) as well as α and β adrenergic receptors with varying affinity depending on the dose administered. At low doses (2-5 mcg/kg/min), it primarily binds dopaminergic receptors and causes

morbidity.

**3.4 Inotropic agents** 

hypotension and atrial arrhythmias.

Volume depletion increases the risk of significant renal dysfunction associated with ACE inhibitors and ARBs. Increases in creatinine of up to 30% are acceptable, and may identify a group of patients most likely to benefit from angiotensin inhibition (Koniari et al., 2010). HF patients who are unable to tolerate ACE inhibitor therapy because of hypotension, renal dysfunction, or hyperkalemia have a particularly high one-year mortality rate, in excess of 50% (Kittleson et al., 2003).

#### **3.3 -adrenergic receptor blockers**

β-blockers are considered standard therapy in patients with HF and systolic dysfunction. They exert a number of beneficial effects, including prevention of ventricular arrhythmias, prevention of ventricular remodeling, reduction in myocardial oxygen demand, increased myocardial oxygen supply, and inhibition of other deleterious neurohormonal pathways. Their significant mortality benefit in patients with HF is well established through large clinical trials. Unfortunately, the majority of these studies excluded patients with significant renal dysfunction, but retrospective analyses of trials data have offered insight into the benefits in patients with mild-to-moderate renal impairment. COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival Study), for example, demonstrated a 35% reduction in the risk of death in patients with severe HF treated with carvedilol compared to placebo, but excluded patients with a serum creatinine greater than 2.8 mg/dL. Similarly, the CAPRICORN (Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction) trial showed a 23% reduction in all-cause mortality in patients with EF ≤40% after myocardial infarction treated with carvedilol compared with placebo, but excluded patients with significant renal impairment (Dargie, 2001). A post-hoc analysis of individual patient data from these two trials, however, demonstrated that in patients with HF and mild-tomoderate CKD, carvedilol was safe and efficacious, associated with reductions in all-cause mortality, cardiovascular mortality, and HF hospitalization (Wali et al., 2011). CIBIS-II (The Cardiac Insufficiency Bisoprolol Study II) demonstrated a 34% reduction in mortality in patients with HF treated with bisoprolol compared to placebo, and excluded patients with serum creatinine ≥300 umol/L (3.4 mg/dL) (CIBIS-II Investigators and Committees, 1999). A post-hoc analysis of this trial showed that although patients with GFR <60 mL/min had higher overall mortality than those with GFR ≥60 mL/min, the benefit of bisoprolol was similar in both groups (Erdmann et al., 2001). The relative risk of mortality in the group with GFR <60 mL/min treated with bisoprolol compared to placebo was 0.66, and there was a non-significant trend towards an even greater benefit in the small number of patients with GFR <30 mL/min.

An analysis of MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II), which demonstrated a 31% reduction in the risk of all-cause mortality with the addition of an implantable cardioverter-defibrillator to medical therapy in patients with ischemic cardiomyopathy and EF ≤30%, examined the predictors of sudden cardiac death (SCD) in the subset of patients in the medical arm of the study with impaired renal function, defined as GFR ≤75 mL/min. β-blocker therapy was a negative predictor of SCD, with a hazard ratio of 0.61 (Chonchol et al., 2007).

Smaller studies have examined the benefits of β-blocker therapy in patients with end-stage renal failure. In a non-randomized study of 134 patients with HF and either chronic renal impairment, anemia, or both, treatment with β-blockers for 12 months was associated with improvement in both creatinine clearance and hemoglobin levels, while those patients who did not receive β-blockers had worsening renal function and anemia over the same time period (Khan et al., 2006). In patients with HF and normal renal function at baseline, lack of treatment with a β-blocker was associated with increased risk of developing renal failure over 20 years of follow-up (Tanaka et al., 2007). In hemodialysis patients with dilated left ventricles, treatment with metoprolol resulted in reduced ventricular dimensions, increased fractional shortening, and reduced levels of natriuretic peptides (Hara et al., 2001). A randomized trial of 114 hemodialysis patients with dilated cardiomyopathy showed that carvedilol, compared to placebo, was associated with improved ejection fraction, improved survival, and fewer HF hospitalizations (Cice et al., 2003). Although large-scale clinical trials in this population are lacking, the weight of evidence suggests that treatment with βblockers in the CRS population is likely to be associated with reductions in mortality and morbidity.
