1. CRAS – Definition, Epidemiology and Pathophysiology
Gerasimos Filippatos 1

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 2

3. Definitions of CRAS 3

4. 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: 4

5. 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

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
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

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
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

8. 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

9. 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

10. 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

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 11

12. Prevalence of CRAS 12

13. 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

14. 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

15. CRAS in US and European HF Surveys60 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

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%, 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

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
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

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
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

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
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

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 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

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 21

22. Consequences of CRAS 22

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 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

24. 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

25. 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 = , 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. Pathophysiology of CRAS31

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
CKD
CHF 32

33. 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

34. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

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 42