CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos 1

Learning Objectives Discuss the definition of CRAS Review the prevalence of cardio-renal anemia syndrome (CRAS) Understand the consequences of CRAS for patients Discuss the pathophysiology of CRAS 2

Definitions of CRAS 3

Recommendations for NHLBI in Cardio-Renal Interactions Related to Heart Failure “The result of interactions between the kidneys and other circulatory compartments that increase circulating volume and symptoms of heart failure and disease progression are exacerbated. At its extreme, cardio-renal dysregulation leads to what is termed ‘cardio-renal syndrome’ in which therapy to relieve congestive symptoms of heart failure is limited by further decline in renal function” NHLBI Working Group. Cardio-renal connections in heart failure and cardiovascular disease: executive summary Available at: http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm. 4

Features of the Cardio-Renal Syndrome Cardiorenal failure Mild: HF + eGFR 30–59 mL/min/1.73 m2 Moderate: HF + eGFR 15–29 mL/min/1.73 m2 Severe: HF + eGFR <15 mL/min/1.73 m2 or dialysis Worsening renal function during treatment of ADHF Change in creatine >0.3 mg/dL or >25% baseline Diuretic resistance Persistent congestion despite >80 mg furosemide/day >240 mg furosemide/day Continuous furosemide infusion Combination diuretic therapy (loop diuretic + thiazide + aldosterone antagonist) Liang KV et al. Crit Care Med 2008;36 (Suppl):S75–88 5

Cardio-Renal Syndrome (CRS) General CRS definition: ‘Pathophysiologic disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ induces acute or chronic dysfunction in the other’1 CRS Type I (Acute Cardiorenal Syndrome) Abrupt worsening of cardiac function leading to acute kidney injury CRS Type II (Chronic Cardiorenal Syndrome) Chronic abnormalities in cardiac function (e.g. chronic congestive heart failure) causing progressive and permanent chronic kidney disease CRS Type III (Acute Renocardiac Syndrome) Abrupt worsening of renal function (e.g. acute kidney ischaemia or glomerulonephritis) causing acute cardiac disorders (e.g. heart failure, arrhythmia, ischemia) CRS Type IV (Chronic Renocardiac Syndrome) Chronic kidney disease (e.g. chronic glomerular disease) contributing to decreased cardiac function, cardiac hypertrophy and/or increased risk of adverse cardiovascular events CRS Type V (Secondary Cardiorenal Syndrome) Systemic condition (e.g. DM, sepsis) causing both cardiac and renal dysfunction 1. Ronco C et al. Eur Heart J 2009;Dec 25 [epub ahead of print] 6

There are Numerous Definitions of CRAS “We propose that there is a vicious circle established whereby CHF (congestive heart failure) and CRF (chronic renal failure) both cause anemia and the anemia then worsens both the CHF and the CRF, causing more anemia and so on”1 “The cardio-renal anemia syndrome is a set of complex and interrelated phenomena that are poorly understood”2 “This combination of anemia, CKD and CHF has been called the cardio-renal anemia syndrome. The three seem to interact, each causing or worsening of the other two”3 Anemia CHF CKD CKD, chronic kidney disease; CHF, chronic heart failure 1. Silverberg D et al. Clin Nephrol 2002;58(suppl 1):372–45; 2. Jurkovitz C et al. Curr Opin Nephrol Hypertens 2006;15:117–122; 3. Silverberg D et al. Clin Exp Nephrol 2009;13:101–106 7

The Definition of CRAS Differs Depending on your Viewpoint (1) Nephrologists CKD Anemia CHF CKD Any degree of anemia Any degree of heart failure CKD Severe anemia Severe heart failure Renal failure Severe anemia Cardiovascular events Renal failure Anemia Cardiovascular disease 8

The Definition of CRAS Differs Depending on your Viewpoint (2) Cardiologists CHF Anemia CKD CHF Any degree of anemia Any degree of renal insufficiency CHF Severe anemia Renal failure Cardiovascular disease Severe anemia Renal failure Cardiovascular disease Anemia Renal insufficiency 9

The Definition of CRAS for 2010 CRAS is a pathophysiologic process involving the progressive deterioration of heart and kidney function linked with worsening anemia CRAS is a vicious cycle where worsening of one factor negatively impacts on the other two conditions and itself, resulting in progressive deterioration CRAS is a combination of heart failure, kidney failure and anemia Any degree of heart failure Any degree of anemia Any degree of kidney failure What defines the above factors? See presentations by Piotr Ponikowski, Angel de Francisco and Bernard Canaud 10

Multidisciplinary Teams should Aim to Prevent CRAS Development Any patient diagnosed with CHF should be monitored for renal failure and anemia Any patient diagnosed with CKD should be monitored for heart failure and anemia Multidisciplinary management strategies are needed to ensure patients are diagnosed and treated early so that CRAS does not progress 11

Prevalence of CRAS 12

The Prevalence of CRAS is Dependant upon your Definition of CKD, CHF and Anemia CHF + CKD CHF CKD CRAS Anemia Anemia + CHF Anemia + CKD 13

The EuroHeart Failure survey programme – a survey on the quality of care among patients with heart failure in Europe 500 400 N=5249 men 33% with Hb <12 g/dL 300 Number of patients 200 100 4–4.4 5–5.4 6–6.4 7–7.4 8–8.4 9–9.4 10–10.4 11–11.4 12–12.4 13–13.4 14–14.4 15–15.4 16–16.4 17–17.4 18–18.4 19–19.4 20–20.4 Hb (g/dL) A total of 9971 patients had a value for Hb reported, which was ≤11 g/dL in 18% of men and 23% of women Cleland JG et al. Eur Heart J 2003;24:442–463 14

CRAS in US and European HF Surveys 60 50 40 Patients (%) 30 20 10 ADHERE 105,000 patients EuroHF Survey II Renal failure Anemia Galvao M et al. J Card Fail 2006;12:100–107; Nieminen MS et al. Eur J Heart Fail 2008;10:140–148 15

Prevalence Data for CRAS are Varied Anemia is common in patients with heart failure (HF) – prevalence ranges from 4–55%1 In patients with CHF NYHA functional class IV, the prevalence of anemia when defined as <12g/dL and ≤11g/dL was 79.1%3 and 14.4%, respectively4 The prevalence of renal impairment plus anemia (≤11g/dL) in New York heart association (NYHA) functional class IV HF patients is 6.3%4 The prevalence of chronic renal insufficiency (CRI) in new onset HF patients is 8.8%2 and the prevalence of renal insufficiency in acutely decompensated HF patients is 30%5 The prevalence of CHF in endstage renal disease is 63.7%6 1. Lang C & Mancini D. Heart 2007;93:665–671; 2. Ezekowitz J et al. Circulation 2003;107:223–225; 3. Silverberg D et al. J Am Coll Cardiol 2000;35:1737–1744; 4. Cromie N et al. Heart 2002;87:377–378; 5. Fonarow G et al. JAMA 2005;293:572–580; 6. Avorn J et al. Arch Intern Med 2002;162:2002–2006 16

New-onset HF Patients with both CKD and Anemia Population-based cohort of 12,065 patients with new-onset CHF Database analysis from 138 acute-care Canadian hospitals April 1993–March 2001 Analysis of prevalence and cause of anemia 14% 3% 6% 77% CHF + anemia alone (n=1696) CHF + anemia + CKD (n=387) CHF + CKD alone (n=674) CHF alone (n=9308) Adapted from Ezekowitz J et al. Circulation 2003;107:223–225 17

Fourteen Per Cent of NYHA Class II–IV HF Patients have both CKD and Anemia Multivariable analysis of data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Program 2653 patients with NYHA class II–IV 14% 11.5% 22% 52.5% CHF + anemia* alone (n=304) CHF + anemia* + CKD** (n=373) CHF + CKD** alone (n=583) CHF alone (n=1393) *Hb <12 g/dL in women, <13 g/dL in men; **eGFR <60 mL/min/1.73 m2 Adapted from O’Meara E et al. Circulation 2006;113:986–994 18

Twenty-two Per Cent of HF Patients with LVEF <45 have both CKD and Anemia Prospective, single-center, observational study 955 consecutive patients with HF (LVEF <45%) Median follow-up 531 days Investigation of the presence of anemia and its cause 10% 22% 32% 36% CHF + anemia* alone (n=94) CHF + anemia* + CKD** (n=211) CHF + CKD** alone (n=307) CHF alone (n=343) LVEF, left ventricular ejection fraction *Hb <12 g/dL in women, <13 g/dL in men; **eGFR <60 mL/min/1.73 m2 Adapted from de Silva R et al. Am J Cardiol 2006;98:391–398 19

Prevalence of CRAS may be Greater than Current Estimates “…about half the patients admitted to hospital with a primary diagnosis of CHF…have anemia…and the great majority will also have CKI (chronic kidney insufficiency)”1 Silverberg et al. noted the majority of CKI patients with anemia also had CHF2 1. Silverberg DS et al. Semin Nephrol 2006;26:296; 2. Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 20

Prevalence Data for CRAS are Limited Very few studies have specifically assessed the prevalence of CRAS within the CKD and CHF populations Exclusion criteria for clinical trials often remove patients with CRAS and so a true prevalence of the disorder is unknown 21

Consequences of CRAS 22

Anemia, CHF and CKD have an Additive Effect on Mortality Anemia is responsible for increased disease progression, hospitalization, morbidity and mortality in patients with CHF1–3 and CKD4–8 There is an additive effect of anemia, CKD and CHF affecting mortality risk6,9,10 and progression to ESRD9,10 ESRD, end-stage renal disease 1. Vasu S et al. Clin Cardiol 2005;28:454–458; 2. He WS & Wang LX. Congest Heart Fail 2009;15:123–130; 3. Lindenfeld J. Am Heart J 2005;149:391–401; 4. Xia H et al. J Am Soc Nephrol 1999;10:1309–1316; 5. Levin A et al. Nephrol Dial Transplant 2003;18(suppl 4):358:393–394; 6. Herzog CA et al. J Card Fail 2004;10:467–472; 7. Ma JZ et al. J Am Soc Nephrol 1999,10:610–619; 8. Thorp M et al. Nephrology 2009;14:240–246; 9. Efstratiadis G et al. Hippokratia 2008;12:11–16; 10. Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 23

Relationship Between Anemia and Mortality in HF: A Systematic Review and Meta-analysis Study ID ` Odds ratio (95% CI) Events, anemic n/N Events, non anemic n/N Al Ahmad (2001) 1.87 (1.46, 2.41) 98/279 1363/6081 Tanner (2002) 0.46 (0.17, 1.28) 5/51 27/142 McClellan (2002) 1.61 (1.17, 2.21) 191/296 179/337 Horwich (2002) 1.82 (1.36, 2.43) 109/271 213/790 Szachniewi (2003) 3.26 (1.11, 9.63) 6/18 21/158 Kerzner (2003) 1.61 (1.03, 2.53) 102/236 42/131 Kalra (2003) 1.60 (0.98, 2.61) 70/96 273/435 Mozaffarian (2003) 1.57 (1.16, 2.12) 96/215 311/915 Kosiborod (2003) 1.82 (1.52, 2.17) 423/1093 306/1188 Van der Meer (2004) 3.00 (0.87, 10.30) 8/56 Anand (2004) 2.01 (1.27, 3.19) 30/108 129/804 Sharma (2004) 1.25 (0.98, 1.60) 101/513 414/2531 Ralli (2005) 3.00 (1.55, 5.80) 29/108 17/156 Kosiborod (2005) 1.49 (1.44, 1.55) 8867/21290 9415/29115 Rosolova (2005) 1.88 (1.27, 2.80) 70/136 134/372 Gardner (2005) 1.23 (0.46, 3.34) 6/38 19/144 Maggioni-V (2005) 1.85 (1.49, 2.29) 134/453 845/4557 Maggioni-I (2005) 2.29 (1.76, 2.99) 97/375 269/2036 Ezekowitz (2005) 2.44 (1.79, 3.33) 223/305 256/486 Varadarajan (2006) 1.67 (1.41, 1.98) 713/1122 574/1124 Elabbassi (2006) 2.98 (1.69, 5.26) 29/127 28/310 Maraldi (2006) 1.72 (1.07, 2.75) 46/253 36/314 DeSilva (2006) 2.36 (1.65, 3.38) 71/305 74/650 Berry (2006) 2.47 (1.73, 3.54) 125/231 93/288 Go (2006) 2.40 (2.32, 2.48) 13233/25452 10668/34320 Komajda (2006) 1.94 (1.59, 2.36) 237/475 856/2521 Newton (2006) 1.82 (1.28, 2.59) 117/215 124/313 Formiga (2006) 1.83 (0.73, 4.60) 13/44 11/59 Terrovitis (2006) 7.05 (2.15, 23.08) 12/16 43/144 O’Meara (2006) 2.13 (1.75, 2.58) 231/677 387/1976 Felker (2006) 2.52 (2.24, 2.83) 1135/1937 1085/3014 Shamagian (2006) 3.97 (1.94, 8.13) 33/95 13/110 Schou (2007) 2.24 (1.29, 3.88) 29/95 41/250 Overall (I-squared = 92.4%, p=0.000) 1.96 (1.74, 2.21) 26687/56943 28274/95827 .4 .5 1 2 4 8 10 Lower risk of anemia Higher risk of anemia Groenveld HF et al. J Am Coll Cardiol 2008;52:818–27 24

Baseline Hb levels (g/dL) Relationship Between Baseline Hemoglobin and Annual Mortality in HF. A Systematic Review and Meta-analysis 40 35 30 25 20 Mortality per year (%) 15 10 5 R = -0.396, P = 0.025 11.5 12.0 12.5 13.0 13.5 14.0 14.5 Baseline Hb levels (g/dL) Groenveld HF et al. J Am Coll Cardiol 2008;52:818–27 25

Predicted probability of in-hospital death Relation of Low Hemoglobin and Anemia to Morbidity and Mortality in Patients Hospitalized With Heart Failure (Insight from the OPTIMIZE-HF Registry) 0.11 0.10 0.09 0.08 0.07 Predicted probability of in-hospital death 0.06 0.05 0.04 0.03 0.02 0.01 0.10 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Admission Hb (5–20 g/dL) Young JB et al. Am J Cardiol 2008;101:223–230 26

Patients with CRAS have a 2-year Mortality Rate of ~46% 1,136,201 patients in the 5% Medicare database Anemia, CKD and CHF contribute significantly to mortality rates 50 45 45.6 Anemia, CHF and CKI 40 38.4 CHF and CKI 35 34.6 CHF and anemia 30 2-year mortality (%) 25 27.3 CKI and anemia 26.6 CHF 20 15 16.1 Anemia 16.4 CKI 10 7.7 No anemia CHF or CKI 5 Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 27

Patients with CRAS have a 2-year ESRD Incidence Rate of ~6% 1,136,201 patients in the 5% Medicare database Anemia, CKD and CHF contribute significantly to the incidence of ESRD 6 5.9 Anemia, CHF and CKI 5.4 CKI and anemia 4 2-year incidence of ESRD (%) 3.5 CHF and CKI 2.6 CKI 2 CHF and anemia 0.3 No anemia, CHF or CKI 0.1 Anemia 0.2 CHF 0.2 Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 28

Survival distribution function (%) Survival time (months) The Prognostic Value of Anemia in Patients with Diastolic Heart Failure 1.0 0.8 No Anemia (n=132) 0.6 Survival distribution function (%) Anemia (n=162) 0.4 0.2 10 20 30 40 50 60 70 Survival time (months) Tehrani F et al. Texas Heart J 2009;36:220–225 29

Anemia in Diastolic HF 1 No anemia/PSF 0.9 No anemia/ISF 0.8 0.7 0.6 Survival probability 0.5 0.4 Anemia/ISF Anemia/PSF 0.3 0.2 0.1 1 2 3 4 5 6 7 Years Felker GM et al. Am Heart J 2006;151:457–462 30

Pathophysiology of CRAS 31

CRAS is a Vicious Cycle Deteriorating kidney function worsens anemia and heart function, which further impacts on kidney function The same is true of worsening anemia and deteriorating heart function Anemia CKD CHF 32

The Pathophysiology of CRAS Anemia Reduced erythropoiesis CKD CHF Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431–438; Felker GM et al. J Am Coll Cardiol 2004;44:959–966; van der Meer P et al. Eur Heart J 2004;25:285–291; Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:15–30 33

Sympathetic nervous system Renin-angiotensin system Heart and Kidney Failure are Linked through the Sympathetic Nervous System Sympathetic nervous system Renin-angiotensin system CKD CHF The heart and kidney can directly interact through:1–3 The sympathetic nervous system The renin-angiotensin system Inflammation Reactive oxygen species Nitric oxide balance 1. Efstratiadis G et al. Hippokratia 2008;12:11–16; 2. Jie KE et al. Am J Physiol Renal Physiol 2006;291:F932–F944; 3. Ronco C et al. Blood Purif 2009;27:114–126 34

Pathophysiology of CRAS Sympathetic nervous system Renin-angiotensin system CKD CHF Reduced erythropoiesis Anemia Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431–438; Felker GM et al. J Am Coll Cardiol 2004;44:959–966; van der Meer P et al. Eur Heart J 2004;25:285–291; Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:15–30 35

EPO and Iron Deficiency can Cause Anemia in Patients with CKD Causes of anemia in CKD1–4 Erythropoietin (EPO) deficiency/resistance Iron deficiency Anemia can worsen kidney function through: Renal ischemia Vasoconstriction CKD ↓ EPO Reduced erythropoiesis ↓ Hct Renal ischemia Vasoconstriction Anemia Hct, hematocrit 1. Kazory A & Ross EA. J Am Coll Cardiol 2009;53:639–647; 2. Akram K & Pearlman BL. Int J Cardiol 2007;117:296–305 3. Elliot J et al. Adv Chronic Kidney Dis 2009;16:94–100; 4. Fishbane S et al. Clin J Am Soc Nephrol 2009;4:57–61 36

Pathophysiology of CRAS Sympathetic nervous system Renin-angiotensin system CKD CHF ↓ EPO Reduced erythropoiesis ↓ Hct Renal ischemia Vasoconstriction Anemia Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431–438; Felker GM et al. J Am Coll Cardiol 2004;44:959–966; van der Meer P et al. Eur Heart J 2004;25:285–291; Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:15–30 37

Mechanisms of Anemia in CHF Hemodilution Plasma Volume  Forward failure BM dysfunction Iron deficiency Fe2+ uptake  Malabsorption Chronic bleeding (Aspirin) Chronic immune activation TNF Production of EPO  EPO activity in BM  Drugs ACEi: EPO synthesis  Chronic kidney failure Loss in urine  BM, bone marrow; EPO, erythropoietin; ACEi, angiotensin-converting enzyme inhibitor Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–1744 38

Anemia of chronic disease Distribution of Various Etiologies of Anemia among Patients with Advanced Congestive Heart Failure 100 Iron deficiency Anemia of chronic disease Hemodilution 80 73.0% Drug induced 60 Patients (%) 40 18.9% 20 5.4% 2.7% Nanas JN et al. J Am Coll Cardiol 2006;48:2485–2489 39

Reduced erythropoiesis Increased Levels of Inflammatory Cytokines and Iron deficiency can Cause Anemia in Patients with CHF Causes of anemia in CHF1–5 Increased cytokine levels Iron deficiency Anemia can worsen heart function through: Ischemia Hemodilution CHF ↑ Cytokines etc Reduced erythropoiesis ↓ Hct Ischemia Hemodilution Anemia 1. Akram K & Pearlman BL. Int J Cardiol 2007;117:296–305; 2. Morelli S et al. Acta Cardiol 2008;63:565–570; 3. Kazory A & Ross EA. J Am Coll Cardiol 2009;53:639–647; 4. Anand IS. J Am Coll Cardiol 2008;52:501–511; 5. Caramelo C et al. Rev Esp Cardiol 2007;60:848–860 40

Pathophysiology of CRAS Sympathetic nervous system Renin-angiotensin system CKD CHF ↓ EPO Reduced erythropoiesis ↑ Cytokines etc ↓ Hct Renal ischemia Vasoconstriction Ischemia Hemodilution Anemia Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455–464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431–438; Felker GM et al. J Am Coll Cardiol 2004;44:959–966; van der Meer P et al. Eur Heart J 2004;25:285–291; Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:15–30 41

Conclusions CRAS is a vicious cycle involving the progressive deterioration of heart and kidney function linked with worsening anemia The prevalence of CRAS has not been adequately investigated, but it is likely to be greater than most current estimates Anemia, CHF and CKD have an Additive Effect on Mortality 42