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CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos.

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Presentation on theme: "CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos."— Presentation transcript:

1 CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos

2 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

3 Definitions of CRAS

4 NHLBI Working Group. Cardio-renal connections in heart failure and cardiovascular disease: executive summary Available at: 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 Recommendations for NHLBI in Cardio-Renal Interactions Related to Heart Failure

5 Features of the Cardio-Renal Syndrome Cardiorenal failure –Mild: HF + eGFR 30–59 mL/min/1.73 m 2 –Moderate: HF + eGFR 15–29 mL/min/1.73 m 2 –Severe: HF + eGFR <15 mL/min/1.73 m 2 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

6 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 1. Ronco C et al. Eur Heart J 2009;Dec 25 [epub ahead of print] 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

7 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 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 CHFCKD Anemia CKD, chronic kidney disease; CHF, chronic heart failure

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

9 The Definition of CRAS Differs Depending on your Viewpoint (2) Cardiologists CHF Any degree of anemia Any degree of renal insufficiency CHFSevere anemiaRenal failure Cardiovascular disease Severe anemiaRenal failure Cardiovascular disease AnemiaRenal insufficiency CHFAnemiaCKD

10 The Definition of CRAS for 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 2.CRAS is a combination of heart failure, kidney failure and anemia What defines the above factors? See presentations by Piotr Ponikowski, Angel de Francisco and Bernard Canaud Any degree of heart failure Any degree of anemia Any degree of kidney failure

11 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

12 Prevalence of CRAS

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

14 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 N=5249 men 33% with Hb <12 g/dL Number of patients Hb (g/dL) –4.4 5–5.4 6–6.4 7–7.4 8–8.49–9.4 10– – –12.413– – –15.416– –17.418–18.419– –20.4 The EuroHeart Failure survey programme – a survey on the quality of care among patients with heart failure in Europe

15 CRAS in US and European HF Surveys Galvao M et al. J Card Fail 2006;12:100–107; Nieminen MS et al. Eur J Heart Fail 2008;10:140– ADHERE 105,000 patientsEuroHF Survey II Renal failureAnemia Patients (%)

16 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%, respectively 4 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

17 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 Adapted from Ezekowitz J et al. Circulation 2003;107:223–225 14% 3% 6% 77% CHF + anemia alone (n=1696) CHF + anemia + CKD (n=387) CHF + CKD alone (n=674) CHF alone (n=9308)

18 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 Adapted from OMeara E et al. Circulation 2006;113:986–994 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 m 2 14% 11.5% 22% 52.5%

19 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 Adapted from de Silva R et al. Am J Cardiol 2006;98:391–398 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 m 2 10% 22% 32% 36%

20 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 CHF 2 1. Silverberg DS et al. Semin Nephrol 2006;26:296; 2. Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12

21 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

22 Consequences of CRAS

23 Anemia, CHF and CKD have an Additive Effect on Mortality Anemia is responsible for increased disease progression, hospitalization, morbidity and mortality in patients with CHF 1–3 and CKD 4–8 There is an additive effect of anemia, CKD and CHF affecting mortality risk 6,9,10 and progression to ESRD 9,10 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 ESRD, end-stage renal disease

24 Relationship Between Anemia and Mortality in HF: A Systematic Review and Meta-analysis Study ID `Odds ratio (95% CI)Events, anemic n/NEvents, non anemic n/N Al Ahmad (2001)1.87 (1.46, 2.41)98/ /6081 Tanner (2002)0.46 (0.17, 1.28)5/5127/142 McClellan (2002)1.61 (1.17, 2.21)191/296179/337 Horwich (2002)1.82 (1.36, 2.43)109/271213/790 Szachniewi (2003)3.26 (1.11, 9.63)6/1821/158 Kerzner (2003)1.61 (1.03, 2.53)102/23642/131 Kalra (2003)1.60 (0.98, 2.61)70/96273/435 Mozaffarian (2003)1.57 (1.16, 2.12)96/215311/915 Kosiborod (2003)1.82 (1.52, 2.17)423/ /1188 Van der Meer (2004)3.00 (0.87, 10.30)6/188/56 Anand (2004)2.01 (1.27, 3.19)30/108129/804 Sharma (2004)1.25 (0.98, 1.60)101/513414/2531 Ralli (2005)3.00 (1.55, 5.80)29/10817/156 Kosiborod (2005)1.49 (1.44, 1.55)8867/ /29115 Rosolova (2005)1.88 (1.27, 2.80)70/136134/372 Gardner (2005)1.23 (0.46, 3.34)6/3819/144 Maggioni-V (2005)1.85 (1.49, 2.29)134/453845/4557 Maggioni-I (2005)2.29 (1.76, 2.99)97/375269/2036 Ezekowitz (2005)2.44 (1.79, 3.33)223/305256/486 Varadarajan (2006)1.67 (1.41, 1.98)713/ /1124 Elabbassi (2006)2.98 (1.69, 5.26)29/12728/310 Maraldi (2006)1.72 (1.07, 2.75)46/25336/314 DeSilva (2006)2.36 (1.65, 3.38)71/30574/650 Berry (2006)2.47 (1.73, 3.54)125/23193/288 Go (2006)2.40 (2.32, 2.48)13233/ /34320 Komajda (2006)1.94 (1.59, 2.36)237/475856/2521 Newton (2006)1.82 (1.28, 2.59)117/215124/313 Formiga (2006)1.83 (0.73, 4.60)13/4411/59 Terrovitis (2006)7.05 (2.15, 23.08)12/1643/144 OMeara (2006)2.13 (1.75, 2.58)231/677387/1976 Felker (2006)2.52 (2.24, 2.83)1135/ /3014 Shamagian (2006)3.97 (1.94, 8.13)33/9513/110 Schou (2007)2.24 (1.29, 3.88)29/9541/250 Overall (I-squared = 92.4%, p=0.000)1.96 (1.74, 2.21)26687/ / Lower risk of anemiaHigher risk of anemia Groenveld HF et al. J Am Coll Cardiol 2008;52:818–27

25 Relationship Between Baseline Hemoglobin and Annual Mortality in HF. A Systematic Review and Meta-analysis Groenveld HF et al. J Am Coll Cardiol 2008;52:818– Mortality per year (%) Baseline Hb levels (g/dL) R = , P = 0.025

26 Relation of Low Hemoglobin and Anemia to Morbidity and Mortality in Patients Hospitalized With Heart Failure (Insight from the OPTIMIZE-HF Registry) Young JB et al. Am J Cardiol 2008;101:223– Predicted probability of in-hospital death Admission Hb (5–20 g/dL)

27 34.6 CHF and anemia 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 No anemia CHF or CKI 16.1 Anemia 26.6 CHF 27.3 CKI and anemia 38.4 CHF and CKI 45.6 Anemia, CHF and CKI 2-year mortality (%) Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii CKI

28 2.6 CKI 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 CKI and anemia 3.5 CHF and CKI 5.9 Anemia, CHF and CKI 2-year incidence of ESRD (%) Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12 No anemia, CHF or CKI 0.1 Anemia 0.2 CHF 0.2 CHF and anemia 0.3

29 The Prognostic Value of Anemia in Patients with Diastolic Heart Failure Tehrani F et al. Texas Heart J 2009;36:220– Survival distribution function (%) 10 Survival time (months) No Anemia (n=132) Anemia (n=162)

30 Anemia in Diastolic HF Felker GM et al. Am Heart J 2006;151:457– Survival probability 1 Years Anemia/ISF No anemia/PSF Anemia/PSF No anemia/ISF

31 Pathophysiology of CRAS

32 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 CKDCHF

33 The Pathophysiology of CRAS Anemia Reduced erythropoiesis CKDCHF 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

34 Heart and Kidney Failure are Linked through the Sympathetic Nervous System 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 Sympathetic nervous system Renin-angiotensin system CKDCHF 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

35 Pathophysiology of CRAS Anemia Reduced erythropoiesis Sympathetic nervous system Renin-angiotensin system CKDCHF 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

36 EPO and Iron Deficiency can Cause Anemia in Patients with CKD Causes of anemia in CKD 1–4 –Erythropoietin (EPO) deficiency/resistance –Iron deficiency Anemia can worsen kidney function through: –Renal ischemia –Vasoconstriction Reduced erythropoiesis Renal ischemia Vasoconstriction CKD EPO Hct Anemia 1. Kazory A & Ross EA. J Am Coll Cardiol 2009;53:639–647; 2. Akram K & Pearlman BL. Int J Cardiol 2007;117:296– 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 Hct, hematocrit

37 Pathophysiology of CRAS Anemia Reduced erythropoiesis Sympathetic nervous system Renin-angiotensin system Renal ischemia Vasoconstriction CKDCHF EPO 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 Hct

38 Mechanisms of Anemia in CHF Hemodilution –Plasma Volume Forward failure –BM dysfunction Iron deficiency –Fe 2+ uptake –Malabsorption –Chronic bleeding (Aspirin) Chronic immune activation –TNF Production of EPO EPO activity in BM Drugs –ACEi: EPO synthesis –EPO activity in BM Chronic kidney failure –Production of EPO –Loss in urine Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–1744 BM, bone marrow; EPO, erythropoietin; ACEi, angiotensin-converting enzyme inhibitor

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

40 Increased Levels of Inflammatory Cytokines and Iron deficiency can Cause Anemia in Patients with CHF Causes of anemia in CHF 1–5 –Increased cytokine levels –Iron deficiency Anemia can worsen heart function through: –Ischemia –Hemodilution Reduced erythropoiesis Ischemia Hemodilution CHF Hct Cytokines etc 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

41 Pathophysiology of CRAS Anemia Reduced erythropoiesis Sympathetic nervous system Renin-angiotensin system Renal ischemia Vasoconstriction Ischemia Hemodilution CKDCHF EPO Hct Cytokines etc 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

42 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


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