Editorial Staying in the Pink of Health for Patients with Cardiorenal Anemia Requires a Multidisciplinary Approach

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1 Editorial Staying in the Pink of Health for Patients with Cardiorenal Anemia Requires a Multidisciplinary Approach Anemia and Heart Failure Ragavendra R. Baliga, MD, MBA James B. Young, MD Consulting Editors Anemia in heart failure is not only debilitating but also associated with higher morbidity, mortality, and greater total health care costs 1 in an everaging population. It is common in patients who have heart failure, with a prevalence ranging from 4% to 55%. 2 Most studies indicate that the prevalence of anemia is higher in patients with heart failure who are more symptomatic or have comorbid conditions, such as kidney disease, diabetes mellitus, and advanced age, when compared with ambulatory and less-symptomatic patients. 3,4 The relative risk of death increases by a factor of 1.6 in anemic patients with heart failure who also have chronic kidney disease. The pathophysiology of cardiorenal failure is multifactorial. 5 A recent consensus conference on cardiorenal syndromes 6 described 5 subtypes with distinct pathophysiologies (Fig. 1), 7 prevention, and management strategies (Fig. 2): dysfunction. This has been reported in 63% of patients hospitalized with congestive heart failure. In this subset, serum creatinine may not entirely reflect underlying renal function. Type 3, or acute renocardiac syndrome, is acute worsening of kidney function, leading to heart injury or dysfunction. The effects on heart function are due to factors in addition to volume overload (eg, acute kidney injury, glomerulonephritis, and renal ischemia). Type 4, or chronic renocardiac syndrome, is a situation in which chronic kidney disease leads to heart injury, disease, or dysfunction (eg, chronic glomerulonephritis). Type 5, or secondary cardiorenal syndrome, includes systemic conditions leading to injury or dysfunction of heart and kidney (eg, diabetes mellitus, sepsis, systemic lupus erythematosus, or amyloidosis). Type 1, or acute cardiorenal syndrome, is acute worsening of heart function leading to kidney injury or dysfunction. Approximately 27% to 40% of the patients with acute decompensated heart failure seem to develop acute kidney injury. This type is associated with the poorest prognosis. Type 2, or chronic cardiorenal syndrome, includes patients with chronic abnormalities in heart function leading to kidney injury or Heart Failure Clin 6 (2010) xi xvi doi: /j.hfc /10/$ see front matter ª 2010 Elsevier Inc. All rights reserved. Patients may move from one subtype to another depending on the nature of primary insult. The recognition of these 5 distinct subtypes of cardiorenal failure should facilitate better understanding not only of these conditions but also of accompanying comorbidities, such as anemia. The etiology and pathophysiology of anemia in heart failure is also multifactorial 8 and is due to a complex interaction 9 between cardiac function, renal dysfunction, neurohormonal and inflammatory heartfailure.theclinics.com

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3 Fig. 1. Subtypes of cardiorenal syndrome. (From Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31(6):703 11; with permission.) Editorial xiii

4 xiv Syndromes Acute cardio-renal (type 1) Chronic cardio-renal (type 2) Acute reno-cardiac (type 3) Chronic reno-cardiac (type 4) Secondary CRS (type 5) Organ failure sequence Editorial Definition Acute worsening of heart function (AHF ACS) leading to kidney injury and/or dysfunction Chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction Acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction Chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction Systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney Primary Acute heart failure (AHF) or acute coronary syndrome (ACS) or cardiogenic shock Chronic heart disease (LV remodelling and dysfunction, diastolic dysfunction, chronic abnormalities in cardiac function, cardiomyopathy) AKI CKD Systemic disease (sepsis, amyloidosis, etc.) Criteria for primary ESC, AHA/ACC ESC, AHA/ACC RIFLE AKI N KDOQI Disease-specific criteria Secondary AKI CKD AHF, ACS, arrhythmias, shock CHD (LV remodelling and dysfunction, diastolic dysfunction, abnormalities in cardiac function), AHF, ACS AHF, ACS, AKI, CHD, CKD Criteria for secondary RIFLE AKIN KDOQI ESC, AHA/ACC ESC, AHA/ACC ESC, AHA/ACC, RIFLE/AKIN ESC, AHA/ACC KDOQI Cardiac biomarkers Troponin, CK-MB, BNP, NTproBNP, MPO, IMA BNP, NT-proBNP, C-reactive protein BNP, NT-proBNP BNP, NT-proBNP, C-reactive protein C-reactive protein, procalcitonin, BNP Renal biomarkers Serum cystatine C, creatinine, NGAL. Urinary KIM-1, IL-18, NGAL, NAG Serum creatinine, cystatin C, urea, uric acid, C-reactive protein, decreased GFR Serum creatinine, cystatin C, NGAL. Urinary KIM-1, IL-18, NGAL, NAG Serum creatinine, cystatin C, urea, uric acid, decreased GFR Creatinine, NGAL, IL-18, KIM-1, NAG Prevention strategies Acutely decompensated heart failure and acute coronary syndromes are A common pathophysiology (neurohumoral, inflammatory, oxidative Acute sodium and volume overload are part of the pathogenesis. The chronic processes of cardiac and renal fibrosis, left ventricular hypertrophy, Potential systemic factors negatively impact function of both organs

5 Syndromes Acute cardio-renal (type 1) Chronic cardio-renal (type 2) Acute reno-cardiac (type 3) Chronic reno-cardiac (type 4) Secondary CRS (type 5) Management strategies most common scenarios Inciting event may be acute coronary ischaemia, poorly controlled blood pressure, and noncompliance with medication and dietary sodium intake Randomized trials improving compliance with heart failure care management have reduced rates of hospitalization and mortality, and a reduction in the rates of acute cardio-renal syndrome (type 1) can be inferred Specific depends on precipitating factors General supportive oxygenate, relieve pain & pulmonary congestion, treat arrhythmias appropriately, differentiate left from right heart failure, treat low cardiac output or congestion according to ESC guidelines (a) ; avoid nephrotoxins, closely monitor kidney function. injury) could be at work to create organ dysfunction. Drugs that block the renin angiotensin system reduce the progression of both heart failure and CKD It is unknown whether other classes of drugs can prevent chronic cardio-renal syndrome (type 2) Treat CHF according to ESC guidelines a, exclude precipitating pre-renal AKI factors (hypovolaemia and/or hypotension), adjust therapy accordingly and avoid nephrotoxins, while monitoring renal function and electrolytes. Extracorporeal ultrafiltration It is unknown whether sodium and volume overload is prevented with different forms of renal replacement therapy and if this will result in lower rates of cardiac decompensation Follow ESC guidelines for acute CHF a specific management may depend on underlying aetiology, may need to exclude renovascular disease and consider early renal support, if diuretic resistant vascular stiffness, chronic Na and volume overload, and other factors (neurohumoral, inflammatory, oxidative injury) could be at work to create organ dysfunction A reduction in the decline of renal function and albuminuria has been associated with a reduction in cardiovascular The role of chronic uraemia, anaemia, and changes in CKD-mineral and bone disorder on the cardiovascular system is known in chronic reno-cardiac syndrome Follow KDOQI guidelines for CKD management, exclude precipitating causes (cardiac tamponade). Treat heart failure according to ESC guidelines a, consider early renal replacement support acutely. It is uncertain if reduction/elimination of the key factors (immune, inflammatory, oxidative stress, thrombosis) will prevent both cardiac and renal decline. Specific according to etiology. General see CRS management as advised by ESC guidelines* 2008 Fig. 2. Cardiorenal syndromes: classification, definitions, and work group statements. ACC, American College of Cardiology; ACS, acute coronary syndrome; ADHF, acute de-compensated heart failure; ADQI, Acute Dialysis Quality Initiative; AHA, American Heart Association; AHF, acute heart failure; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CHF, chronic heart failure; CKD, chronic kidney disease; KDOQI, Kidney Disease Outcome Quality Initiative; KIM-1, kidney injury molecule-1; MPO, myeloperoxidase; NAG, N-acetyl-b-(D)glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; NKF, National Kidney Foundation; RIFLE, risk, injury, failure, loss of kidney function, and end-stage kidney disease; WRF, worsening renal function. a As advised by European Society of Cardiology guidelines (From Ronco C, McCullough P, Anker SD, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 2010;31(6):703 11; with permission.) Editorial xv

6 xvi Editorial responses, hemodilution, iron deficiency, impaired ability to use available iron stores, 10 bone marrow suppression due to cytokines (eg, tumor necrosis factor a [TNF-a], interleukin [IL]-1, IL-6, and C-reactive protein), blunted bone marrow responsiveness to erythropoietin, impaired iron mobilization, and effects of medications. Aspirin and angiotensin-converting enzyme inhibitors 11 contribute to the anemia potentially through the actions of hematopoesis inhibitor, N-acetyl-serylaspartyl-lysyl-proline. 12 IL-6 stimulates the production of hepcidin in the hepatic cells, which blocks absorption of iron in duodenum and down-regulates ferroprotein expression, which in turn pr release of iron from total body stores. 13 In contrast, TNF-a and IL-6 inhibit erythropoietin production in the kidney by activating the GATA-binding protein, GATA2, and nuclear factor kb and also inhibits proliferation of bone marrow erythroid progenitor cells. 3,4,13 Some have used erythropoietin receptor stimulating agents or intravenous iron to correct the anemia of heart failure, but concern has arisen about the true effectiveness of this approach and morbidity associated with the therapy. The Reduction of Events with Darbopoeitin Alfa in Heart Failure is a largescale, phase III, placebo-controlled, randomized, morbidity and mortality clinical trial designed to clarify these issues and will likely be finished recruiting in 18 months. 14 To unravel these complex interactions in cardiorenal anemia, Anil Agarwal, MD, Stuart Katz, MD, and Ajay Singh, MD, have assembled a multidisciplinary team of experts in this field. In our opinion, their multidisciplinary approach is essential to ensure that patients with cardiorenal anemia stay in the pink of health. Ragavendra R. Baliga, MD, MBA Division of Cardiovascular Medicine The Ohio State University Columbus, OH, USA James B. Young, MD Division of Medicine and Lerner College of Medicine, Cleveland Clinic Cleveland, OH, USA addresses: Ragavendra.Baliga@osumc.edu (R.R. Baliga) YOUNGJ@ccf.org (J.B. Young) REFERENCES 1. Allen LA, Anstrom KJ, Horton JR, et al. Relationship between anemia and health care costs in heart failure. J Card Fail 2009;15(10): Tanner H, Moschovitis G, Kuster GM, et al. The prevalence of anemia in chronic heart failure. Int J Cardiol 2002;86(1): Anand IS. Anemia and chronic heart failure implications and treatment options. J Am Coll Cardiol 2008; 52(7): Dec GW. Anemia and iron deficiency new therapeutic targets in heart failure? N Engl J Med 2009; 361(25): Baliga RR, Young JB. Stiff central arteries syndrome: does a weak heart really stiff the kidney? Heart Fail Clin 2008;4(4):ix xii. 6. 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): Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol 2008;52(19): Nanas JN, Matsouka C, Karageorgopoulos D, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol 2006;48(12): Felker GM. Too much, too little, or just right?: untangling endogenous erythropoietin in heart failure. Circulation 2010; 121(2): Opasich C, Cazzola M, Scelsi L, et al. Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure. Eur Heart J 2005;26(21): Ishani A, Weinhandl E, Zhao Z, et al. Angiotensinconverting enzyme inhibitor as a risk factor for the development of anemia, and the impact of incident anemia on mortality in patients with left ventricular dysfunction. J Am Coll Cardiol 2005; 45(3): van der Meer P, Lipsic E, Westenbrink BD, et al. Levels of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysylproline partially explain the occurrence of anemia in heart failure. Circulation 2005;112(12): Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005;352(10): McMurray JJV, Anand IS, Diaz R, et al. Design of the reduction of with darbepoetin alfa in heart failure (RED-HF): a phase III, anaemia correction, morbidity-morality trial. Eur J Heart Fail 2009;11: