Therapeutic Strategies for Heart Failure in Cardiorenal Syndromes

IN PRACTICE Therapeutic Strategies for Heart Failure in Cardiorenal Syndromes Andrew A. House, MD, MSc,1 Mikko Haapio, MD,2 Johan Lassus, MD,3 Rinaldo Bellomo, MD,4 and Claudio Ronco, MD5,6 Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or long-term dysfunction in one organ may induce acute or long-term dysfunction of the other. The management of cardiovascular diseases and risk factors may influence, in a beneficial or harmful way, kidney function and progression of kidney injury. In this review, we assess therapeutic strategies and discuss treatment options for the management of patients with heart failure with decreased kidney function and highlight the need for future high-quality studies in patients with coexisting heart and kidney disease. Am J Kidney Dis 56:759-773. © 2010 by the National Kidney Foundation, Inc. INDEX WORDS: Heart failure; worsening kidney function; acute kidney injury; chronic kidney disease; cardiorenal syndrome; renocardiac syndrome; kidney function.

CASE PRESENTATION A 60-year-old man with coronary artery disease (previous anterior myocardial infarction and coronary artery bypass grafting) and heart failure was admitted because of worsening peripheral edema. Medical history included atrial fibrillation, type 2 diabetes, and obstructive pulmonary disease. An implantable defibrillator had been placed previously for documented sustained ventricular tachycardia. The cardiac left ventricle was dilated with an ejection fraction of 25% on echocardiography (normally ⬎60%). During the preceding 6 months, the patient had been hospitalized twice for worsening heart failure. He was on high-dose diuretic therapy (furosemide, 500 mg/d orally) and a ␤-blocker (bisoprolol), angiotensin-converting enzyme (ACE) inhibitor (enalapril), low-dose aspirin, a statin, and insulin, as well as inhaled corticosteroids and bronchodilators. On admission, increased jugular venous pressure with bilateral lower-limb pitting edema was detected. The patient reported dyspnea on exertion and weight gain (⫹6 kg) since the last hospitalization. Serum creatinine level, previously stable at approximately 1.8 mg/dL (159 ␮mol/L; estimated glomerular filtration rate [eGFR], 40 mL/min/1.73 m2 [0.7 mL/s/1.73 m2]) was now 2.8 mg/dL (240 ␮mol/L). A furosemide infusion was started with increasing doses (up to 15 mg/h); however, diuresis remained poor (900 mL/24 h). After 6 days in the hospital without satisfactory clinical improvement and with increasing weight (⫹3 kg), increasing N-terminal pro–B-type natriuretic peptide level (from 7,500 to 12,000 pg/mL), and worsening kidney function (serum creatinine increase to 3.8 mg/dL [336 ␮mol/L]), the patient was referred to a tertiary hospital for consultation.

INTRODUCTION Cardiac diseases are associated independently with a decrease in kidney function and progression of existing kidney diseases.1 Conversely, chronic kidney disease (CKD) represents an independent risk factor for cardiovascular events and outcomes.2 In both the acute setting and more long-term phase, even small

decreases in GFR are associated with adverse outcome.3,4 In patients with acute decompensated heart failure (ADHF), an acute increase in serum creatinine level ⬎0.3 mg/dL (⬎26.5 ␮mol/L) is associated with increased mortality, longer hospital stays, and more frequent readmissions.5 An acute increase in serum creatinine level accompanies 21%-45% of hospitalizations for ADHF, depending on the time frame and magnitude of creatinine level increase.6-9 Decreased kidney function also is present as a significant comorbid condition in approximately 50% of patients with chronic heart failure.10 Clinical outcomes in heart failure populations are poor, and concomitant decreased kidney function with eGFR ⬍60 mL/ min/1.73 m2 significantly increases the risk of mortality.10,11 This has led to justifiable concern regarding our ability to not only prevent From the 1London Health Sciences Centre, Division of Nephrology, London, Canada; Divisions of 2Nephrology and 3Cardiology, HUCH Meilahti Hospital, Helsinki, Finland; 4Department of Intensive Care, Austin Hospital, Melbourne, Australia; 5Department of Nephrology, St. Bortolo Hospital; and 6International Renal Research Institute Vicenza, Vicenza, Italy. Received February 12, 2010. Accepted in revised form April 14, 2010. Originally published online as doi:10.1053/ j.ajkd.2010.04.012 on June 17, 2010. Address correspondence to Andrew A. House, MD, MSc, London Health Sciences Centre, Division of Nephrology, London, Canada. E-mail: [email protected] © 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5604-0019$36.00/0 doi:10.1053/j.ajkd.2010.04.012

American Journal of Kidney Diseases, Vol 56, No 4 (October), 2010: pp 759-773

759

760 Box 1. Classification and Definitions of Cardiorenal Syndromes ●

●

●

●

●

●

General Definition of Cardiorenal Syndromes Disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Acute Cardiorenal Syndrome (type 1) Acute worsening of cardiac function leading to decreased kidney function. Chronic Cardiorenal Syndrome (type 2) Long-term abnormalities in cardiac function leading to decreased kidney function. Acute Renocardiac Syndrome (type 3) Acute worsening of kidney function causing cardiac dysfunction. Chronic Renocardiac Syndrome (type 4) Long-term abnormalities in kidney function leading to cardiac disease. Secondary Cardiorenal Syndromes (type 5) Systemic conditions causing simultaneous dysfunction of the heart and kidney.

and manage these challenging conditions, but also cope with the huge demands on economic resources and health care workers. The purpose of this article is to review possible therapeutic strategies in the management of patients with heart failure with decreased kidney function and highlight the need for future high-quality studies in this field to guide us. It is important to understand that the management of cardiovascular diseases and risk factors may influence, in a beneficial or harmful way, kidney function and progression of kidney injury. Anticipating and adapting to these influences may help optimize the function of both the heart and kidneys and improve patient outcomes.

CLASSIFICATION OF CARDIORENAL SYNDROMES The triad of concomitant decreased kidney function, therapy-resistant heart failure with congestion (ie, diuretic resistance), and worsening kidney function during heart failure therapy commonly has been termed cardiorenal syndrome (CRS).12,13 However, the need for a more precise definition of CRS recently has emerged and a new classification (Box 1) has been developed to encourage more thorough appreciation and understanding of the underlying mechanisms of the syndromes.14 This hopefully will lead to new clinical and therapeutic management strategies.

House et al

The recent work of the international Acute Dialysis Quality Initiative panel resulted in a comprehensive consensus statement about CRSs; their classification, epidemiology, prevention, and management; and use of biomarkers in the syndromes.15 The present case example and review focuses on types 1 and 2 (acute and chronic CRS) of the new classification, emphasizing practical management of patients with heart failure with worsening kidney function.

CLINICAL MANIFESTATIONS AND PATHOPHYSIOLOGY Acute CRS A common clinical scenario of acute CRS (type 1) is a patient admitted for ADHF and experiencing worsening kidney function during hospitalization. The diagnosis of worsening kidney function or acute kidney injury is based on an acute increase in serum creatinine level and/or oliguria.16,17 ADHF may be characterized by rapid worsening of heart failure symptoms and signs (shortness of breath, pulmonary rales, congestion on chest radiograph, increased jugular venous pressure, and peripheral edema). However, ADHF is a very heterogeneous condition with various clinical presentations and multiple precipitating factors. Many patients with ADHF have preserved left ventricular ejection fraction, and in approximately one-third, ADHF is precipitated by acute coronary syndrome.18,19 Hemodynamic derangements are highly variable, ranging from acute pulmonary edema with hypertension to severe peripheral fluid overload to cardiogenic shock and hypotension.20-22 Although hypotension and decreased cardiac output (with activation of the sympathetic nervous system and renin-angiotensin-aldosterone system [RAAS]) have been the traditional explanations for the pathophysiologic process behind worsening kidney function in this setting, recent evidence has implicated high venous pressure and increased intra-abdominal pressure leading to renal venous congestion as equal and perhaps more important contributors to impairment of kidney function.23,24 Increased levels of circulatory cytokines signaling injury from the heart to the kidneys also may take part in the process of acute kidney injury.25 Persistent renal vasoconstriction from

Management of Cardiorenal Syndromes Types 1 and 2

761

Figure 1. Cardiorenal syndrome (CRS) type 1. Pathophysiologic interactions between heart and kidney in type 1 or “acute CRS” (abrupt worsening of cardiac function; eg, acute cardiogenic shock or acute decompensation of chronic heart failure) leading to kidney injury. Abbreviations: ACE, angiotensin-converting enzyme; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CO, cardiac output; GFR, glomerular filtration rate; H2O, water; KIM, kidney injury molecule; Na, sodium; N-GAL, neutrophil gelatinase-associated lipocalin; RAA, renin angiotensin aldosterone. Reproduced from Ronco et al27 with permission of Elsevier.

tubuloglomerular feedback and various vasoactive substances (adenosine and endothelin), decreased renal responsiveness to natriuretic peptides, and impaired autoregulation of GFR may all have a part (particularly in the setting of RAAS blockade).26 The emergence of diuretic resistance is multifactorial and includes decreased solute delivery to tubules caused by decreased renal blood flow, decreased GFR, hypoalbuminemia, and the phenomenon of diuretic “braking” caused by enhanced sodium reabsorption and distal tubular hypertrophy.12 Figure 1 shows an overview of the potential pathophysiologic mechanisms responsible for type 1 CRS.

Chronic CRS Concomitant decreased kidney function in patients with heart failure is very common, with a negative influence of long-term cardiac dysfunction on kidney function (type 2 CRS). The prevalence of GFR ⬍60 mL/min/1.73 m2 (CKD stage 3 or higher) is overrepresented in chronic heart failure and may be as high as 30%-40%.28-30 However, in patients hospitalized for ADHF, the prevalence of GFR ⬍60 mL/min/1.73 m2 on admission is up to 70%,10,31-33 likely reflecting a combination of patients with CKD and those with superimposed acute kidney injury. In a patient with chronic heart failure, clinical manifestations of CRS often include increased

762

House et al

Figure 2. Cardiorenal syndrome (CRS) type 2. Pathophysiologic interactions between heart and kidney in type 2 or “chronic CRS” (long-term abnormalities in cardiac function; eg, chronic heart failure) causing progressive chronic kidney disease (CKD). Abbreviations: Ca, calcium; H2O, water; LVH, left ventricular hypertrophy; Na, sodium; Phos, phosphorus; RAA, renin angiotensin aldosterone. Reproduced from Ronco et al27 with permission of Elsevier.

arterial blood pressure, gradually worsening kidney function with heightened susceptibility to complications of therapy (worsening GFR and electrolyte disturbance), and diuretic resistance with peripheral edema.34-36 Decreased kidney function seems to be one of the most powerful predictors of impaired prognosis in heart failure.10,28,37 In the pathogenesis of chronic CRS, there are several proposed mechanisms: chronic overactivation of the RAAS and sympathetic nervous system and increased levels of inflammatory substances and markers of cardiac stress in both

the circulation and target organs.25,38-41 Longterm upregulation of endothelin 1 followed by strengthened action of transforming growth factor ␤ and nuclear factor-␬B are capable of causing the initiation and progression of renal fibrosis and glomerulosclerosis.42 A visual representation of these potential mechanisms is shown in Fig 2.

MANAGEMENT Many mainstay therapies in use for decades in the management of ADHF have not been subjected to the scrutiny of proper randomized con-

Management of Cardiorenal Syndromes Types 1 and 2

trolled trials. Treatment includes cautious and combined use of appropriate drugs or interventions to relieve congestive and/or ischemic symptoms; strict fluid management, depending on the hemodynamic and circulatory status of the patient; and following up clinical response to treatment. In more severe cases, hemodynamic monitoring may be considered,20-22 although use of pulmonary artery catheters has not improved clinical or renal outcomes.43 Interruption of the sympathetic nervous system and RAAS when possible represents the most important goal in the management of type 2 CRS. To achieve this, treatment strategies often need to include the use of multiple pharmaceutical regimens with close monitoring of possible side effects and recurrent adjustment of dosing. Table 1 lists some of the more commonly used agents with indications, expected actions, and potential problems. Therapies listed under categories for type 1 or 2 CRS are not meant to be mutually exclusive because patients often move between these clinical categories. Pharmacologic Therapies for Type 1 CRS Diuretics and Vasodilators As mentioned, management and prevention of type 1 CRS in the setting of ADHF or cardiogenic shock is largely empiric because many traditional therapies to relieve congestive and/or ischemic symptoms (diuretics, vasodilators, and morphine)22 have not been studied rigorously. Although strategies to improve cardiac output and renal perfusion pressure are important, recent evidence implicating high venous pressure, increased intra-abdominal pressure, and renal congestion44 heightens the importance of diuretics and vasodilators in early management. Although diuretics have been used for decades to facilitate prompt relief of symptoms of ADHF, management often is complicated by insidiously worsening kidney function.45 High doses of diuretics have been associated with worse clinical outcomes in some studies,46,47 but not others,43,44,48 although disease severity likely serves as a serious confounder. The goal of diuretic use should be to deplete extracellular fluid volume at a rate that allows refilling from the interstitium to the intravascular compartment, recognizing that diuretics poten-

763

tially aggravate electrolyte imbalances, contract the effective circulating volume, and may contribute to activation of unfavorable neurohormonal responses. Loop diuretics, such as furosemide, are preferred over agents such as thiazides, which often have limited efficacy in more advanced stages of decreased kidney function.49 However, the optimal dose, frequency, and route of loop diuretics have not been well studied. The ongoing DOSE-AHF (Diuretic Optimal Strategy Evaluation in Acute Heart Failure) study is designed to examine optimal furosemide use in patients with ADHF, enrolling 300 patients in a 2⫻2 factorial design comparing high- versus low-dose furosemide and infusion versus bolus.36 This study will include change in serum creatinine levels and patient symptoms as important clinical outcomes. Nitroglycerin is a nitric oxide donor often used to relieve symptoms and improve hemodynamics in patients with ADHF. At lower doses, it dilates venules, decreases cardiac filling pressures, and decreases myocardial oxygen demand. At higher doses, it decreases afterload and augments cardiac output.50 Hypotension and nitrate tolerance are limiting features. Although randomized trials in heart failure are lacking, clinical experience supports its utility, as do novel bedside measurements of tissue perfusion.50,51 Sodium nitroprusside acts through cyclic guanosine monophosphate in vascular smooth muscle to cause significant arterial and venous vasodilation.51 As with nitroglycerin, its use often is reserved for patients with normal or increased blood pressure with evidence of increased preload, afterload, and pulmonary and venous congestion. Nitroprusside has long been recognized as being potentially hazardous in patients with decreased kidney function because of the accumulation of thiocyanate.52 However, its use in patients presenting with ADHF in a nonrandomized trial was associated with improved outcomes and stable kidney function,53 a study that included patients with varying degrees of decreased kidney function and some with overt hypotension. Nesiritide, a recombinant form of human Btype natriuretic peptide, decreases preload, afterload, and pulmonary vascular resistance; increases cardiac output in ADHF; and causes

764

House et al Table 1. Regimens for Management of Cardiorenal Syndromes Types 1 and 2 Drug

Loop diuretics

ACE inhibitors or ARBs

Indicationa

Intended Action and Effects

1

Diuretics Natriuresis, decrease in fluid overload, sodium and water elimination

2

Control of hypertension, diuresis, and extracellular fluid volume

1

Management of acute low cardiac output, afterload and preload reduction Management of CHF, increase in cardiac output (in low-output states)

2

Spironolactone, eplerenone

␤-Blockers

1-2

1 2

Aspirin

1-2

Clopidogrel

1-2

Low-molecular-weight heparins

1-2

Nitroglycerin

1 2

Nitroprusside

1

Nesiritide

1

Inotropes

1-2

Levosimendan

1-2

Aldosterone Blockade Control of hypertension, diuresis, and extracellular fluid volume Not recommended or extreme caution required in low-cardiac-output state Control of hypertension or arrhythmias, management of ischemic heart disease, possible favorable renal effects (carvedilol) Antithrombotic Agents Secondary prevention of thromboembolic cardiovascular events Prevention of thromboembolic cardiovascular events, stent patency Prevention of thromboembolic cardiovascular events

Vasodilators Venodilation, decreased cardiac ischemia, decreased afterload With hydralazine, used as an alternative to RAAS blockade Arterial and venous dilation, decreased preload, afterload Decrease in preload, afterload, and pulmonary vascular resistance; increase in cardiac output in ADHF Extreme cases of low cardiac output, increase cardiac output Increase cardiac output, improve hemodynamics, renal perfusion, and diuresis

Potential Side Effects and Problems

Neurohormonal activation, electrolyte imbalance, and worsening kidney function Worsening kidney function, hyperuricemia, electrolyte imbalance, diuretic resistance Decrease in GFR and increase in serum creatinine, hypotension, hyperkalemia Hypotension, hyperkalemia, increase in serum creatinine Hyperkalemia (especially with ACE inhibitors or ARBs), worsening kidney function Cardiogenic shock, worsening kidney function Toxic effects due to accumulation of certain agents in patients with decreased GFR (atenolol, sotalol) Risk of minor bleeding, possible interference with GFR with higher aspirin doses Efficacy in patients with CKD uncertain, risk of bleeding Possible accumulation due to altered pharmacokinetics with decreased kidney function (risk of bleeding) Hypotension, tolerance Hypotension, tolerance Hypotension, thiocyanate toxicity (particularly with decreased GFR) Possible decrease in kidney function, hypotension Possible increase in myocardial injury, arrhythmias, worsened outcome Hypotension, unclear efficacy

(Continued on following page)

effective diuresis, quickly relieving dyspnea in acute heart failure states.54 However, there have been mixed results in studies investigating the

safety and renal effects of nesiritide. A metaanalysis of randomized double-blind controlled trials reported that the use of nesiritide for ADHF

Management of Cardiorenal Syndromes Types 1 and 2

765

Table 1 (Cont’d). Regimens for Management of Cardiorenal Syndromes Types 1 and 2 Drug

Indicationa

Intended Action and Effects

Potential Side Effects and Problems

Miscellaneous Therapies ESAs

2

RRT: ultrafiltration

1-2

RRT: hemo(dia)filtration

1-2

Cardiac resynchronization

2

Correction of anemia, improved cardiac function, decrease in left ventricular size Removal of excess fluid in patients with diuretic resistance

Removal of excess fluid, clearance of uremic toxins, correction of electrolyte abnormalities and acidbase balance Long-term extremely low cardiac output with right and left ventricular dyssynchrony

Risk of thrombosis, stroke; concerns in patients with active malignancies Technical and economic requirements, hypotension, postpuncture complications, sepsis Technical and economic requirements, hypotension, postpuncture complications, sepsis Technical and manpower expertise requirements

Abbreviations: ACE, angiotensin-converting enzyme; ADHF, acute decompensated heart failure; ARB, angiotensin receptor blocker; CHF, congestive heart failure; CKD, chronic kidney disease; ESA, erythropoiesis-stimulating agent; GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system; RRT, renal replacement therapy. a Type of cardiorenal syndrome for which therapy is appropriate.

did not avoid type 1 CRS and increased the risk of worsening kidney function, as well as mortality, in the active treatment groups.55 However, in a separate randomized, double-blind, and placebocontrolled trial of ADHF with pre-existing decreased kidney function, no adverse impact on kidney function was observed.56 The conclusive answer to the safe use of nesiritide is undetermined; however, a large 7,000-patient multicenter study (ASCEND-HF [Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure]) is underway to establish its role.57 Inotropes

When kidney function is endangered by acute myocardial ischemia with low output and emerging inflammatory processes with cytokine activation, all efforts are to be made to limit the myocardial damage to preserve organ oxygen supply and restrain the emergence of the inflammatory cascade. In extreme cases of low cardiac output, positive inotropes, such as dobutamine or phosphodiesterase inhibitors, may be required,11,22 although their use may accelerate some pathophysiologic mechanisms, increase myocardial injury and arrhythmias, and potentially worsen outcomes. Cuffe et al58 reported results of the randomized OPTIME-CHF (Out-

comes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) of milrinone in patients with ADHF, which showed a higher incidence of hypotension, more arrhythmias, no benefit on mortality or hospitalization, and a suggestion in post hoc analysis that milrinone may increase mortality in patients with ischemic cardiomyopathy.59 Effects of this therapy on kidney function were not reported. Levosimendan, a phosphodiesterase inhibitor with lusitropic activity (calcium sensitizer), improves hemodynamics and renal perfusion and in a small randomized trial was found to improve eGFR at 72 hours by 45.5% versus 0.1% (P ⬍ 0.001) compared with dobutamine.60 This result was not confirmed in the larger SURVIVE (Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support) study,61 and although levosimendan appears in the European Society of Cardiology guidelines for management of heart failure,22 the drug currently is not available in North America and its precise role in the treatment or avoidance of CRS is unclear. Other Pharmacologic Regimens

A number of novel therapies have held promise in preclinical and early clinical trials to pre-

766

vent morbidity (including type 1 CRS) and mortality in patients with ADHF. However, subsequent randomized trials have failed to show a benefit of antagonism of receptors for endothelin,62,63 adenosine,64 and vasopressin.65 Pharmacologic Therapies for Type 2 CRS RAAS Blockade Blockade of the RAAS is part of the cornerstone of management of patients with heart failure. However, studies in chronic congestive heart failure typically have excluded patients with significant decreased kidney function66 or removed patients from study based on changes in kidney function during run-in periods of RAAS blockade.67 However, retrospective analyses have found that a substantial proportion of patients with decreased kidney function (creatinine clearance or GFR ⬍60 mL/min/1.73 m2) were included. Based on these studies, the effects of RAAS blockade in patients with heart failure have been equally beneficial in those with and without CKD.30,68 A particularly vexing problem in the clinical management of both types 1 and 2 CRS occurs when drugs that interfere with the RAAS lead to significant perturbations of kidney function or potassium levels. However, there is evidence of renoprotective effects of ACE inhibitors or angiotensin receptor blockers even with considerably decreased kidney function.69 Up to a 30% increase in creatinine level that stabilizes within 2 months was associated with improved long-term preservation of kidney function in a systematic review of 12 randomized controlled studies,70 although these were studies of patients with primary kidney diseases and not patients with heart failure. In heart failure trials, the percentage of patients with an increase in serum creatinine level has been 10%-35% depending on the population studied, but it is of note that discontinuation rates because of creatinine level increase have been highly variable.71 Typically, it has been recommended that ACE inhibitors and angiotensin receptor blockers may be used cautiously provided serum creatinine level does not continue to increase beyond 30% and potassium level remains consistently ⬍5.0 mEq/L. For patients who are hypovolemic or have low systemic vascular resis-

House et al

tance, decreasing, withholding, or delaying the use of RAAS blockade may be required to maintain GFR.35 Furthermore, both diuretics and advancing age represent risk factors for significant deterioration in kidney function in conjunction with RAAS inhibition.72 Aldosterone Blockade

Drugs such as spironolactone and eplerenone have improved morbidity and mortality in patients with left ventricular ejection fraction ⬍35% despite conventional therapy73 or those with ejection fraction ⬍40% after acute myocardial infarction.74 However, concerns have been raised about the use of aldosterone blockade in the management of patients with heart failure in conjunction with ACE inhibition because since publication of the RALES (Randomized Aldactone Evaluation Study),73 prescriptions for spironolactone and rates of hospitalizations and mortality related to hyperkalemia increased sharply, and it was estimated that approximately 37,000 excess hospitalizations and 4,200 deaths annually in the United States might be related to its use.75 Proper patient selection, including patients with decreased left ventricular ejection fraction and excluding those with moderate CKD (serum creatinine ⱖ2.5 mg/dL [ⱖ220 ␮mol/L]) or hyperkalemia with potassium level ⬎5.0 mEq/L, which were exclusion criteria in RALES, could lower the risk of potentially life-threatening hyperkalemia.76 ␤-Blockers ␤-Blocker therapy has an important role in interrupting the sympathetic nervous system in patients with congestive heart failure and/or ischemic heart disease, and their use generally is considered to be neutral to kidney function. Certain ␤-blockers may be relatively contraindicated because of altered pharmacokinetics, and acute administration of ␤-blockers in the setting of type 1 CRS generally is not advised until hemodynamic stabilization has occurred. Particular concern applies to ␤-blockers excreted by the kidney, such as atenolol, nadolol, or sotalol,77 and it may be prudent to avoid such agents in patients with type 2 CRS with more significantly decreased kidney function. These considerations should not inhibit the slow, careful, and titrated introduction of appropriate treatment with ␤-blockers later on in the more stable phase of

Management of Cardiorenal Syndromes Types 1 and 2

cardiac failure. In addition, ␤-blockers can be used to treat ischemic heart disease and decrease heart rate in rapid atrial fibrillation in patients with heart failure, with metoprolol also having a safe pharmacokinetic profile in patients with CKD.78,79 Moreover, carvedilol, a ␤-blocker with ␣1-blocking effects, has had favorable renal effects in some subgroups with heart and kidney disease and hence may have a benefit over older formulations of ␤-blockers.80 Antithrombotic Therapy

Other agents used in the management of congestive heart failure, particularly secondary to ischemic heart disease, typically will include antiplatelet agents that potentially could aggravate type 2 CRS. Although aspirin potentially can interfere with GFR through its actions on cyclooxygenase and renal prostaglandins, at low doses, it has long been considered safe in patients with kidney disease. This was confirmed in the first UK Heart and Renal Protection Study,81 which showed that daily low-dose aspirin (100 mg) did not lead to an important decrease in GFR or increase the risk of need for renal replacement therapy. The risk of major bleeding was not increased, although these patients had an increased risk of minor bleeding. Clopidogrel was studied as an intervention in the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial,82 in which the beneficial effect of adding clopidogrel to treatment for aspirin-treated patients with acute coronary syndrome and varying degrees of decreased kidney function was shown. In contrast, a study comparing long-term clopidogrel use versus placebo after elective percutaneous intervention (the CREDO [Clopidogrel for the Reduction of Events During Observation] trial), found that participants with mild to moderate CKD had no benefit from clopidogrel therapy compared with those with normal kidney function.83 Thus, the efficacy of clopidogrel in patients with decreased kidney function is uncertain and needs further confirmation. Other antithrombotic agents, such as lowmolecular-weight heparins, particularly in the setting of acute coronary syndrome, may be associated with major bleeding episodes and dosing needs to be adjusted or substituted for

767

unfractionated heparin to account for decreased kidney function.84,85 Anemia Management

Congestive heart failure is associated with anemia, and anemia as its sequelae may aggravate heart failure and kidney function, leading to an unwanted spiral of progression of disease and worsening symptoms.86 Furthermore, erythropoietin receptor activation in the heart may be protective for apoptosis, fibrosis, and inflammation,87,88 which provides the rationale for using erythropoiesis-stimulating agents (ESAs) in patients with heart failure.86 In keeping with such experimental data, preliminary clinical studies show that administration of ESAs to patients with chronic heart failure, CKD, anemia, and type 2 CRS leads to improved cardiac function, decrease in left ventricular size, and decrease in B-type natriuretic peptide level.89 However, a recent randomized trial in patients with symptomatic heart failure failed to show a significant improvement in symptoms, quality of life, exercise duration, or other clinical parameters.90 Despite the apparent benefit to anemia management in patients with CKD of ESAs in observational studies,91 disappointing results of the recent CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency), CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment With Epoetin Beta), and TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) studies,92-94 as well as a previous study in dialysis patients with known cardiac disease,95 have required re-examination of hemoglobin targets in patients with CKD. In particular, concern has been raised about the safety of increasing hemoglobin to levels considered “normal,” and ongoing clinical trials are required to establish whether ESAs have a role in the management of congestive heart failure and type 2 CRS. Given concerns about ESAs, there is increasing interest in the use of parenteral iron to correct anemia in patients with congestive heart failure. A number of studies have shown improvement in such parameters as symptoms of heart failure, oxygen utilization during exercise, and left ventricular ejection fraction, as well as B-type natriuretic peptide levels and kidney function.96-98 In one randomized controlled trial, FERRIC-HF (Ferric Iron Sucrose in Heart Failure), clinical

768

outcomes improved without a significant between-group difference in change in hemoglobin levels, suggesting that the effects of iron may be at the cellular level independent of its effects on hemoglobin level.99 In the FAIR-HF (Ferinject Assessment in Patients With Iron Deficiency and Chronic Heart Failure), 459 patients with both congestive heart failure and iron deficiency with or without anemia were randomly assigned to treatment with ferric carboxymaltose or placebo, and the active treatment group experienced an improvement in the New York Heart Association (NYHA) class of heart failure symptoms, Patient Global Assessment, 6-minute walk test, and quality of life during the 24-week study.100 Of relevance to type 2 CRS, the ferric-carboxymaltose group had a higher GFR at the study conclusion, adjusted for baseline differences, of 3.8 mL/min/ 1.73 m2. Statins

Use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins has become an integral part in the primary and secondary prevention of further cardiac damage in all patients at risk of cardiac disease. However, 2 high-profile negative trials in dialysis patients treated with atorvastatin101 or rosuvastatin102 have questioned the benefit of statins in patients with varying degrees of decreased kidney function. In a recent meta-analysis, Strippoli et al103 found that statins led to significant decreases in cardiovascular end points in patients with CKD, although all-cause mortality was not improved. Intriguingly, a small number of studies were available to look at nephroprotection, and proteinuria seemed to be improved by a modest 0.73 g/d of protein excretion without significant improvement in GFR. Importantly, statins did not seem to have higher adverse-event rates in patients with kidney disease. Nonpharmacologic Therapies Noninvasive Positive Pressure Ventilation Noninvasive methods of ventilation, such as continuous positive airway pressure or noninvasive intermittent positive pressure ventilation, have been suggested in small studies to improve oxygenation and gas exchange and increase intrathoracic pressure, leading to improved cardiac output and improved sense of dyspnea in patients

House et al

with heart failure. These therapies were compared with standard oxygen therapy and applied for a minimum of 2 hours in a randomized trial of more than 1,000 patients presenting with acute cardiogenic pulmonary edema.104 Although patients receiving either continuous positive airway pressure or noninvasive intermittent positive pressure ventilation had greater decreases in dyspnea, heart rate, acidosis, and hypercapnea than those receiving only supplemental oxygen, there was no difference in 7- or 30-day mortality or rates of intubation or critical care admission. There were no important differences noted between the 2 modes of noninvasive ventilation. Ultrafiltration and/or Renal Replacement Therapy

When fluid balance and congestive symptoms become increasingly difficult to manage using conventional medical therapies, intermittent (isolated) ultrafiltration or hemo(dia)filtration have been used to decrease excessive fluid overload and, in the case of significantly decreased kidney function, also correct abnormalities in electrolyte levels and acid-base status.105,106 In the RAPIDCHF (Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure) study, 20 patients with ADHF received ultrafiltration compared with 20 patients receiving usual care.107 The ultrafiltration group had a negative fluid balance of 4.65 versus 2.84 L within the first 24 hours (P ⫽ 0.001) with a dramatic improvement in heart failure symptoms, 81.3% versus 43.8% at 48 hours (P ⫽ 0.023), but no difference in change in creatinine levels. The UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure) trial investigators examined this strategy in 100 patients with hypervolemic congestive heart failure compared with 100 usual-care patients.108 Weight loss was greater in the ultrafiltration group at 5.0 versus 3.1 kg (P ⫽ 0.001). They also found decreased need for vasoactive drugs, 3.1% versus 12.0% (P ⫽ 0.015), with fewer rehospitalizations and emergency department visits in the ultrafiltration group, but no difference in mortality. The improved weight loss and symptoms did not come at the expense of kidney function because a similar proportion experienced worsening kidney function, 26.5% versus 20.3% at 48 hours (P ⫽ 0.43). The CARRESS-HF (Cardiore-

Management of Cardiorenal Syndromes Types 1 and 2

nal Rescue Study in Acute Decompensated Heart Failure) trial currently is being undertaken to further define the use of this therapy in patients with ADHF and acute CRS/worsening kidney function.36 Further development and wider application to clinical use of simple bedside ultrafiltration devices could provide an alternative to medication in resistant cases of chronic CRS with fluid overload. Cardiac Resynchronization and Augmentative Therapies

In patients with severe heart failure with disabling symptoms, cardiac resynchronization therapy with an implantable device synchronizing contraction of the right and left ventricles may be considered. Interestingly, in the MIRACLE (Multicenter Insync Randomized Clinical Evaluation) study of patients with heart failure with NYHA classes III-IV, this therapy improved not only left ventricular function, but also eGFR in patients with moderate baseline CKD.109 When patients with ADHF or cardiogenic shock and acute CRS continue to deteriorate despite maximal medical therapy, select patients may require more invasive means, such as intraaortic balloon pulsation, ventricular assist devices, or artificial hearts, as a bridge to recovery of cardiac function or transplant, with improvement in renal perfusion and function.110-113

CONCLUSIONS AND RECOMMENDATIONS The various subtypes of CRS present unique challenges because therapies directed at one organ may have beneficial or detrimental effects on the other. Better understanding of the bidirectional pathways by which the heart and kidneys influence each other’s function is necessary to tailor therapy appropriate to the situation. It is clear that impairment of kidney function influences therapeutic decision making. For example, the proportion of individuals with CKD receiving appropriate risk-factor modification and/or interventional strategies is lower than in the general population, a concept termed “therapeutic nihilism.”114 Many studies have shown that these therapeutic choices are influenced strongly by kidney function.115-117 In patients with endstage renal disease, who are at extreme risk of cardiovascular events, ⬍50% are on combina-

769

tion therapy with aspirin, ␤-blockers, ACE inhibitors, and statins.118 In this article, we provide an overview of the rationale for the use of a number of treatments for patients with acute and chronic CRS (namely, types 1 and 2). Admittedly, most clinical trials performed in this area have systematically excluded patients with significant CKD (stage 3 or greater); hence, many recommendations are opinion based, rather than guided by evidence from large-scale randomized trials. The complexity of care necessary to offer best therapy to patients with the various types of CRS demands a multidisciplinary approach, combining the expertise of cardiology, nephrology, and critical care. In addition, by using an agreed-upon definition of each type of CRS, physicians can prescribe treatments and interventions that are focused and pathophysiologically sound. Using a consensus definition will allow the development of randomized controlled trials of interventions to improve morbidity and mortality in these increasingly common conditions and better inform clinical care.

CASE REVIEW Returning to the case, the patient was admitted to the intensive care unit for close clinical and hemodynamic monitoring. Treatment was started with a levosimendan infusion (without bolus to avoid severe hypotension) titrated slowly to a dose of 0.2 ␮g/kg/min. During the 24-hour infusion, there was clear improvement in diuresis (4,000 mL/24 h) and relief of dyspnea. Because of severe volume overload, fluid removal using daily isolated ultrafiltration was initiated after the levosimendan infusion, and during this time, no furosemide was given. Serum creatinine level returned to approximately 1.7 mg/dL (150 ␮mol/L) within a few days. Diuresis was maintained (urine output, ⬃2,000 mL/24 h), and weight decreased by 6 kg. After 5 days in the intensive care unit, the patient was transferred back to a regular ward on treatment with a ␤-blocker (bisoprolol, 2.5 mg twice daily), ACE inhibitor (enalapril, 2.5 mg twice daily), spironolactone (12.5 mg/d), digoxin (0.125 mg/d), and furosemide boluses intravenously. Unfortunately, the in-hospital stay was prolonged because of an infection with recurrent cycles of cardiac and kidney codysfunction.

770

House et al

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: Dr House has received support for research, speaking engagements, and continuing medical education events from Ortho-Biotech, Amgen, Novartis, Astellas, Wyeth, Roche, and Gambro. Dr Haapio has received support for speaking engagements or continuing medical education events from Abbott, Amgen, Astellas, Fresenius Medical Care, Roche, and ILS Laboratories Scandinavia. Dr Lassus has received support for speaking engagements and continuing medical education events from Bayer, Merck-Serono, Orion-Pharma, and Pfizer. Dr Bellomo has received consultant fees from Gambro Pty Ltd, Abbott Diagnostics, Inverness Medical, and Philips Medical. Dr Ronco has received support for speaking engagements from Abbott and is a consultant for Biosite and Gambro.

REFERENCES 1. Elsayed EF, Tighiouart H, Griffith J, et al. Cardiovascular disease and subsequent kidney disease. Arch Intern Med. 2007;167(11):1130-1136. 2. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003;42(5):1050-1065. 3. Coca SG, Peixoto AJ, Garg AX, Krumholz HM, Parikh CR. The prognostic importance of a small acute decrement in kidney function in hospitalized patients: a systematic review and meta-analysis. Am J Kidney Dis. 2007;50(5):712720. 4. de Silva R, Nikitin NP, Witte KK, et al. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: contributing factors and relationship to prognosis. Eur Heart J. 2006;27(5):569-581. 5. Damman K, Jaarsma T, Voors AA, et al. Both in- and out-hospital worsening of renal function predict outcome in patients with heart failure: results from the Coordinating Study Evaluating Outcome of Advising and Counseling in Heart Failure (COACH). Eur J Heart Fail. 2009;11(9):847854. 6. Chittineni H, Miyawaki N, Gulipelli S, Fishbane S. Risk for acute renal failure in patients hospitalized for decompensated congestive heart failure. Am J Nephrol. 2007;27(1):55-62. 7. Krumholz HM, Chen YT, Vaccarino V, et al. Correlates and impact on outcomes of worsening renal function in patients ⬎ or ⫽65 years of age with heart failure. Am J Cardiol. 2000;85(9):1110-1113. 8. Smith GL, Vaccarino V, Kosiborod M, et al. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail. 2003;9(1):13-25. 9. Forman DE, Butler J, Wang Y, et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol. 2004;43(1):61-67.

10. Smith GL, Lichtman JH, Bracken MB, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47(10):19871996. 11. Shlipak MG, Massie BM. The clinical challenge of cardiorenal syndrome. Circulation. 2004;110(12):15141517. 12. Tang WH, Mullens W. Cardiorenal syndrome in decompensated heart failure. Heart. 2010;96(4):255-260. 13. Liang KV, Williams AW, Greene EL, Redfield MM. Acute decompensated heart failure and the cardiorenal syndrome. Crit Care Med. 2008;36(1 suppl):S75-88. 14. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong. Intensive Care Med. 2008;34(5):957-962. 15. Ronco C, McCullough P, Anker SD, et al. Cardiorenal syndromes: report from the consensus conference of the Acute Dialysis Quality Initiative. Eur Heart J. 2010;31(6): 703-711. 16. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative Workgroup. Acute renal failure—definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204212. 17. Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. 18. Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J. 2005;149(2):209-216. 19. Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart failure survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725-2736. 20. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53(15):e1-90. 21. Jessup M, Costanzo MR. The cardiorenal syndrome: do we need a change of strategy or a change of tactics? J Am Coll Cardiol. 2009;53(7):597-599. 22. European Society of Cardiology, Heart Failure Association of the ESC (HFA), European Society of Intensive Care Medicine (ESICM), et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur J Heart Fail. 2008;10(10):933-989.

Management of Cardiorenal Syndromes Types 1 and 2 23. Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail. 2007;9(9):872-878. 24. Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol. 2008;51(3):300-306. 25. Chen D, Assad-Kottner C, Orrego C, Torre-Amione G. Cytokines and acute heart failure. Crit Care Med. 2008; 36(1 suppl):S9-16. 26. Smilde TD, Damman K, van der Harst P, et al. Differential associations between renal function and ”modifiable” risk factors in patients with chronic heart failure. Clin Res Cardiol. 2009;98(2):121-129. 27. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol. 2008; 52(19):1527-1539. 28. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000; 35(3):681-689. 29. Ezekowitz J, McAlister FA, Humphries KH, et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol. 2004;44(8): 1587-1592. 30. Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113(5):671678. 31. Heywood JT, Fonarow GC, Costanzo MR, et al. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail. 2007;13(6):422-430. 32. Tavazzi L, Maggioni AP, Lucci D, et al. Nationwide survey on acute heart failure in cardiology ward services in Italy. Eur Heart J. 2006;27(10):1207-1215. 33. Lassus J, Harjola VP, Sund R, et al. Prognostic value of cystatin C in acute heart failure in relation to other markers of renal function and NT-proBNP. Eur Heart J. 2007;28(15):1841-1847. 34. Liu PP. Cardiorenal syndrome in heart failure: a cardiologist’s perspective. Can J Cardiol. 2008;24(suppl B):25B-9B. 35. Heywood JT. The cardiorenal syndrome: lessons from the ADHERE database and treatment options. Heart Fail Rev. 2004;9(3):195-201. 36. Shah RV, Givertz MM. Managing acute renal failure in patients with acute decompensated heart failure: the cardiorenal syndrome. Curr Heart Fail Rep. 2009;6(3):176-181. 37. Damman K, Navis G, Voors AA, et al. Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail. 2007;13(8):599-608. 38. Tojo A, Onozato ML, Kobayashi N, Goto A, Matsuoka H, Fujita T. Angiotensin II and oxidative stress in Dahl salt-sensitive rat with heart failure. Hypertension. 2002; 40(6):834-839.

771 39. Bonventre JV, Zuk A. Ischemic acute renal failure: an inflammatory disease? Kidney Int. 2004;66(2):480-485. 40. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B. The severe cardiorenal syndrome: ’Guyton revisited’. Eur Heart J. 2005;26(1):11-17. 41. Schrier RW. Role of diminished renal function in cardiovascular mortality: marker or pathogenetic factor? J Am Coll Cardiol. 2006;47(1):1-8. 42. Onozato ML, Tojo A, Kobayashi N, Goto A, Matsuoka H, Fujita T. Dual blockade of aldosterone and angiotensin II additively suppresses TGF-beta and NADPH oxidase in the hypertensive kidney. Nephrol Dial Transplant. 2007;22(5):1314-1322. 43. Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51(13):1268-1274. 44. Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol. 2009;53(7):589-596. 45. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med. 2004;32(8): 1669-1677. 46. Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J. 2004;147(2):331-338. 47. Metra M, Nodari S, Parrinello G, et al. Worsening renal function in patients hospitalised for acute heart failure: clinical implications and prognostic significance. Eur J Heart Fail. 2008;10(2):188-195. 48. Cowie MR, Komajda M, Murray-Thomas T, Underwood J, Ticho B; POSH Investigators. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the Prospective Outcomes Study in Heart Failure (POSH). Eur Heart J. 2006;27(10):1216-1222. 49. Madkour H, Gadallah M, Riveline B, Plante GE, Massry SG. Comparison between the effects of indapamide and hydrochlorothiazide on creatinine clearance in patients with impaired renal function and hypertension. Am J Nephrol. 1995;15(3):251-255. 50. den Uil CA, Lagrand WK, Spronk PE, et al. Lowdose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure. Eur J Heart Fail. 2009;11(4): 386-390. 51. den Uil CA, Lagrand WK, Valk SD, Spronk PE, Simoons ML. Management of cardiogenic shock: focus on tissue perfusion. Curr Probl Cardiol. 2009;34(8):330-349. 52. Schulz V, Bonn R, Kindler J. Kinetics of elimination of thiocyanate in 7 healthy subjects and in 8 subjects with renal failure. Klin Wochenschr. 1979;57(5):243-247. 53. Mullens W, Abrahams Z, Francis GS, et al. Sodium nitroprusside for advanced low-output heart failure. J Am Coll Cardiol. 2008;52(3):200-207. 54. Reichert S, Ignaszewski A. Molecular and physiological effects of nesiritide. Can J Cardiol. 2008;24(suppl B):15B-8B. 55. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients

772 with acutely decompensated heart failure. Circulation. 2005;111(12):1487-1491. 56. Witteles RM, Kao D, Christopherson D, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol. 2007;50(19):1835-1840. 57. Hernandez AF, O’Connor CM, Starling RC, et al. Rationale and design of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND-HF). Am Heart J. 2009;157(2):271-277. 58. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002; 287(12):1541-1547. 59. Felker GM, Benza RL, Chandler AB, et al. Heart failure etiology and response to milrinone in decompensated heart failure: results from the OPTIME-CHF study. J Am Coll Cardiol. 2003;41(6):997-1003. 60. Yilmaz MB, Yalta K, Yontar C, et al. Levosimendan improves renal function in patients with acute decompensated heart failure: comparison with dobutamine. Cardiovasc Drugs Ther. 2007;21(6):431-435. 61. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA. 2007;297(17):1883-1891. 62. Kirkby NS, Hadoke PW, Bagnall AJ, Webb DJ. The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol. 2008;153(6):1105-1119. 63. Coletta AP, Cleland JG. Clinical trials update: highlights of the scientific sessions of the XXIII Congress of the European Society of Cardiology—WARIS II, ESCAMI, PAFAC, RITZ-1 and TIME. Eur J Heart Fail. 2001;3(6):747-750. 64. Bax JJ, Casadei B, Di Mario C, et al. Highlights of the 2009 scientific sessions of the European Society of Cardiology. J Am Coll Cardiol. 2009;54(25):2447-2458. 65. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA. 2007;297(12):1332-1343. 66. Coca SG, Krumholz HM, Garg AX, Parikh CR. Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA. 2006;296(11): 1377-1384. 67. Saltzman HE, Sharma K, Mather PJ, Rubin S, Adams S, Whellan DJ. Renal dysfunction in heart failure patients: what is the evidence? Heart Fail Rev. 2007;12(1):37-47. 68. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW. Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation. 2004;109(8):1004-1009. 69. Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med. 2006;354(2):131-140. 70. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: Is this a cause for concern? Arch Intern Med. 2000;160(5):685-693.

House et al 71. Shlipak MG. Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med. 2003; 138(11):917-924. 72. Knight EL, Glynn RJ, McIntyre KM, Mogun H, Avorn J. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the Studies of Left Ventricular Dysfunction (SOLVD). Am Heart J. 1999;138(5 pt 1):849-855. 73. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717. 74. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321. 75. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551. 76. Ko DT, Juurlink DN, Mamdani MM, et al. Appropriateness of spironolactone prescribing in heart failure patients: a population-based study. J Card Fail. 2006;12(3):205-210. 77. Yorgun H, Deniz A, Aytemir K. Cardiogenic shock secondary to combination of diltiazem and sotalol. Intern Med J. 2008;38(3):221-222. 78. Fernandez JS, Sadaniantz A. Medical and revascularization management in acute coronary syndrome in renal patients. Semin Nephrol. 2001;21(1):25-35. 79. Seiler KU, Schuster KJ, Meyer GJ, Niedermayer W, Wassermann O. The pharmacokinetics of metoprolol and its metabolites in dialysis patients. Clin Pharmacokinet. 1980; 5(2):192-198. 80. Bakris GL, Hart P, Ritz E. Beta blockers in the management of chronic kidney disease. Kidney Int. 2006; 70(11):1905-1913. 81. Baigent C, Landray M, Leaper C, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) Study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. Am J Kidney Dis. 2005;45(3):473-484. 82. Keltai M, Tonelli M, Mann JF, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil. 2007;14(2):312-318. 83. Best PJ, Steinhubl SR, Berger PB, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2008; 155(4):687-693. 84. Melloni C, Peterson ED, Chen AY, et al. CockcroftGault versus Modification of Diet in Renal Disease: importance of glomerular filtration rate formula for classification of chronic kidney disease in patients with non-ST-segment elevation acute coronary syndromes. J Am Coll Cardiol. 2008;51(10):991-996. 85. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA. 2005;294(24):3108-3116. 86. Silverberg DS, Wexler D, Iaina A, Steinbruch S, Wollman Y, Schwartz D. Anemia, chronic renal disease and

Management of Cardiorenal Syndromes Types 1 and 2 congestive heart failure—the cardio renal anemia syndrome: the need for cooperation between cardiologists and nephrologists. Int Urol Nephrol. 2006;38(2):295-310. 87. Fu P, Arcasoy MO. Erythropoietin protects cardiac myocytes against anthracycline-induced apoptosis. Biochem Biophys Res Commun. 2007;354(2):372-378. 88. Riksen NP, Hausenloy DJ, Yellon DM. Erythropoietin: ready for prime-time cardioprotection. Trends Pharmacol Sci. 2008;29(5):258-267. 89. Palazzuoli A, Silverberg DS, Iovine F, et al. Effects of beta-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. Am Heart J. 2007;154(4):645.e9-15. 90. Ghali JK, Anand IS, Abraham WT, et al. Randomized double-blind trial of darbepoetin alfa in patients with symptomatic heart failure and anemia. Circulation. 2008;117(4): 526-535. 91. Locatelli F, Pisoni RL, Combe C, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19(1):121-132. 92. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098. 93. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071-2084. 94. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. 95. Besarab A, Goodkin DA, Nissenson AR; Normal Hematocrit Cardiac Trial Authors. The Normal Hematocrit Study—follow-up. N Engl J Med. 2008;358(4):433-434. 96. Bolger AP, Bartlett FR, Penston HS, et al. Intravenous iron alone for the treatment of anemia in patients with chronic heart failure. J Am Coll Cardiol. 2006;48(6):1225-1227. 97. Toblli JE, Lombrana A, Duarte P, Di Gennaro F. Intravenous iron reduces NT-pro-brain natriuretic peptide in anemic patients with chronic heart failure and renal insufficiency. J Am Coll Cardiol. 2007;50(17):1657-1665. 98. Usmanov RI, Zueva EB, Silverberg DS, Shaked M. Intravenous iron without erythropoietin for the treatment of iron deficiency anemia in patients with moderate to severe congestive heart failure and chronic kidney insufficiency. J Nephrol. 2008;21(2):236-242. 99. Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency FERRIC-HF: a randomized, controlled, observer-blinded trial. J Am Coll Cardiol. 2008;51(2):103-112. 100. Anker SD, Comin Colet J, Filippatos G, et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009;361(25):2436-2448. 101. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353(3):238-248. 102. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360(14):1395-1407.

773 103. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008;336(7645):645-651. 104. Gray A, Goodacre S, Newby DE, et al. Noninvasive ventilation in acute cardiogenic pulmonary edema. N Engl J Med. 2008;359(2):142-151. 105. Udani SM, Murray PT. The use of renal replacement therapy in acute decompensated heart failure. Semin Dial. 2009;22(2):173-179. 106. Libetta C, Sepe V, Zucchi M, et al. Intermittent haemodiafiltration in refractory congestive heart failure: BNP and balance of inflammatory cytokines. Nephrol Dial Transplant. 2007;22(7):2013-2019. 107. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration versus usual care for hospitalized patients with heart failure: the Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol. 2005;46(11):2043-2046. 108. Costanzo MR, Guglin ME, Saltzberg MT, et al. Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure. J Am Coll Cardiol. 2007;49(6):675-683. 109. Boerrigter G, Costello-Boerrigter LC, Abraham WT, et al. Cardiac resynchronization therapy improves renal function in human heart failure with reduced glomerular filtration rate. J Card Fail. 2008;14(7):539-546. 110. Tokunaga S, Tominaga R, Nakano T, Fukae K, Takeshita A, Yasui H. Effects of intra-aortic balloon pumping on renal sympathetic nerve activity and renal circulation in dogs. J Cardiovasc Surg (Torino). 2000;41(5):669-674. 111. Norkiene I, Ringaitiene D, Rucinskas K, et al. Intraaortic balloon counterpulsation in decompensated cardiomyopathy patients: bridge to transplantation or assist device. Interact Cardiovasc Thorac Surg. 2007;6(1):66-70. 112. Butler J, Geisberg C, Howser R, et al. Relationship between renal function and left ventricular assist device use. Ann Thorac Surg. 2006;81(5):1745-1751. 113. Roussel JC, Senage T, Baron O, et al. CardioWest (Jarvik) total artificial heart: a single-center experience with 42 patients. Ann Thorac Surg. 2009;87(1):124-129; discussion 130. 114. McCullough PA. Cardiorenal risk: an important clinical intersection. Rev Cardiovasc Med. 2002;3(2):71-76. 115. Wright RS, Reeder GS, Herzog CA, et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med. 2002;137(7):563-570. 116. Beattie JN, Soman SS, Sandberg KR, et al. Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction. Am J Kidney Dis. 2001; 37(6):1191-1200. 117. Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol. 2003;42(9):1535-1543. 118. Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. J Am Coll Cardiol. 2003; 42(2):201-208.