CRAS Definition, Epidemiology and

Pathophysiology

Gerasimos Filippatos
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
Definitions of CRAS
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.
Features of the Cardio-Renal Syndrome

Cardiorenal failure
Mild: HF + eGFR 3059 mL/min/1.73 m2
Moderate: HF + eGFR 1529 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):S7588

 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 other1
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]
 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
Anemia
and so on1

The cardio-renal anemia syndrome

is a set of complex and interrelated
phenomena that are poorly understood2 CHF CKD

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 two3

CKD, chronic kidney disease; CHF, chronic heart failure

1. Silverberg D et al. Clin Nephrol 2002;58(suppl 1):37245; 2. Jurkovitz C et al. Curr Opin Nephrol Hypertens 2006;15:117122;
3. Silverberg D et al. Clin Exp Nephrol 2009;13:101106
The Definition of CRAS Differs Depending on
your Viewpoint (1)

Nephrologists

CKD Anemia CHF

Any degree of Any degree of

CKD
anemia heart failure

Severe
CKD Severe anemia
heart failure

Cardiovascular
Renal failure Severe anemia
events

Cardiovascular
Renal failure Anemia
disease
The Definition of CRAS Differs Depending on
your Viewpoint (2)

Cardiologists

CHF Anemia CKD

Any degree of Any degree of

CHF
anemia renal insufficiency

CHF Severe anemia Renal failure

Cardiovascular
Severe anemia Renal failure
disease

Cardiovascular
Anemia Renal insufficiency
disease
 The Definition of CRAS for 2010

1. 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

Any degree of Any degree of Any degree of

heart failure kidney failure anemia

What defines the above factors?

See presentations by Piotr Ponikowski, Angel de Francisco
and Bernard Canaud
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
Prevalence of CRAS
The Prevalence of CRAS is Dependant upon
your Definition of CKD, CHF and Anemia

CHF + CKD

CHF CKD

CRAS

Anemia Anemia
+ Anemia +
CHF CKD
The EuroHeart Failure survey programme a
survey on the quality of care among patients
with heart failure in Europe

500
Number of patients

N=5249 men
400

300 33% with Hb <12 g/dL

200

100

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;24:442463
CRAS in US and European HF Surveys

60

50
Patients (%)

40

30

20

10

0
ADHERE 105,000 patients EuroHF Survey II

Renal failure Anemia

Galvao M et al. J Card Fail 2006;12:100107; Nieminen MS et al. Eur J Heart Fail 2008;10:140148
 Prevalence Data for CRAS are Varied

Anemia is common in patients with heart failure (HF) prevalence

ranges from 455%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;93:665671; 2. Ezekowitz J et al. Circulation 2003;107:223225;
3. Silverberg D et al. J Am Coll Cardiol 2000;35:17371744; 4. Cromie N et al. Heart 2002;87:377378; 5. Fonarow G et al. JAMA 2005;293:572580;
6. Avorn J et al. Arch Intern Med 2002;162:20022006
New-onset HF Patients with both CKD and Anemia

Population-based cohort
of 12,065 patients with 14%
new-onset CHF 3%
Database analysis from 138 6%
acute-care Canadian hospitals
April 1993March 2001
77%
Analysis of prevalence and
cause of anemia

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;107:223225

 Fourteen Per Cent of NYHA Class IIIV HF
Patients have both CKD and Anemia

Multivariable analysis of data

from the Candesartan in Heart 11.5%
Failure: Assessment of
Reduction in Mortality and
14%
Morbidity (CHARM) Program
2653 patients with NYHA 52.5%
class IIIV
22%

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 Adapted from OMeara E et al. Circulation 2006;113:986994
 Twenty-two Per Cent of HF Patients with LVEF
<45 have both CKD and Anemia

Prospective, single-center,
observational study 10%
955 consecutive patients with
HF (LVEF <45%)
36%
Median follow-up 531 days 22%
Investigation of the presence of
anemia and its cause

32%

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 Adapted from de Silva R et al. Am J Cardiol 2006;98:391398
Prevalence of CRAS may be Greater than
Current Estimates

about half the patients admitted to hospital with a

primary diagnosis of CHFhave anemiaand 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):viii7viii12
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
Consequences of CRAS
 Anemia, CHF and CKD have an Additive Effect
on Mortality

Anemia is responsible for increased disease

progression, hospitalization, morbidity and
mortality in patients with CHF13 and CKD48

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;28:454458; 2. He WS & Wang LX. Congest Heart Fail 2009;15:123130; 3. Lindenfeld J. Am Heart J 2005;149:391401;
4. Xia H et al. J Am Soc Nephrol 1999;10:13091316; 5. Levin A et al. Nephrol Dial Transplant 2003;18(suppl 4):358:393394;
6. Herzog CA et al. J Card Fail 2004;10:467472; 7. Ma JZ et al. J Am Soc Nephrol 1999,10:610619; 8. Thorp M et al. Nephrology 2009;14:240246;
9. Efstratiadis G et al. Hippokratia 2008;12:1116; 10. Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7viii12
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) 6/18 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
OMeara (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;52:81827

 Relationship Between Baseline Hemoglobin and
Annual Mortality in HF. A Systematic Review and
Meta-analysis
40

35

30
Mortality per year (%)

25

20

15

10

5
R = -0.396, P = 0.025
0
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;52:81827
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
Predicted probability
of in-hospital death

0.08

0.07

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 (520 g/dL)

Young JB et al. Am J Cardiol 2008;101:223230
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
40
2-year mortality (%)

35 38.4
34.6
30
25 26.6 27.3
20
15 16.1 16.4
10
5 7.7
0
No Anemia CHF CKI CHF and CKI and CHF and Anemia,
anemia anemia anemia CKI CHF and
CHF or CKI CKI

Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7viii12

 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
2-year incidence of

5.4
ESRD (%)

4
3.5

2 2.6

0.1 0.2 0.2 0.3

0
No Anemia CHF CKI CHF CKI CHF Anemia,
anemia, and anemia and and CKI CHF and
CHF or anemia CKI
CKI
Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7viii12
The Prognostic Value of Anemia
in Patients with Diastolic Heart Failure

1.0
Survival distribution function (%)

0.8
No Anemia (n=132)
0.6

Anemia (n=162)
0.4

0.2

0 10 20 30 40 50 60 70
Survival time (months)
Tehrani F et al. Texas Heart J 2009;36:220225
 Anemia in Diastolic HF

1
0.9 No anemia/PSF
No anemia/ISF
0.8
Survival probability

0.7
0.6
0.5
0.4
Anemia/ISF Anemia/PSF
0.3
0.2
0.1
0
0 1 2 3 4 5 6 7
Years
Felker GM et al. Am Heart J 2006;151:457462
Pathophysiology of CRAS
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

CKD CHF

Anemia
The Pathophysiology of CRAS

CKD CHF

Reduced
erythropoiesis

Anemia
Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431438;
Felker GM et al. J Am Coll Cardiol 2004;44:959966; van der Meer P et al. Eur Heart J 2004;25:285291;
Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:1530
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:13

The sympathetic nervous system
The renin-angiotensin system
Inflammation
Reactive oxygen species
Nitric oxide balance

1. Efstratiadis G et al. Hippokratia 2008;12:1116; 2. Jie KE et al. Am J Physiol Renal Physiol 2006;291:F932F944;
3. Ronco C et al. Blood Purif 2009;27:114126
Pathophysiology of CRAS

Sympathetic nervous system

Renin-angiotensin system

CKD CHF

Reduced
erythropoiesis

Anemia
Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431438;
Felker GM et al. J Am Coll Cardiol 2004;44:959966; van der Meer P et al. Eur Heart J 2004;25:285291;
Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:1530
 EPO and Iron Deficiency can Cause Anemia in
Patients with CKD

Causes of anemia in CKD14

Erythropoietin (EPO)
CKD deficiency/resistance
Iron deficiency
Anemia can worsen kidney
Reduced function through:
erythropoiesis
Renal ischemia
Hct Vasoconstriction
Renal ischemia
Vasoconstriction

Anemia

Hct, hematocrit
1. Kazory A & Ross EA. J Am Coll Cardiol 2009;53:639647; 2. Akram K & Pearlman BL. Int J Cardiol 2007;117:296305
3. Elliot J et al. Adv Chronic Kidney Dis 2009;16:94100; 4. Fishbane S et al. Clin J Am Soc Nephrol 2009;4:5761
Pathophysiology of CRAS

Sympathetic nervous system

Renin-angiotensin system

CKD CHF

Reduced
erythropoiesis

Hct
Renal ischemia
Vasoconstriction

Anemia
Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431438;
Felker GM et al. J Am Coll Cardiol 2004;44:959966; van der Meer P et al. Eur Heart J 2004;25:285291;
Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:1530
 Mechanisms of Anemia in CHF

Hemodilution Chronic immune activation

Plasma Volume TNF
Production of EPO
EPO activity in BM
Forward failure
BM dysfunction
Drugs
ACEi: EPO synthesis
Iron deficiency
EPO activity in BM
Fe2+ uptake
Malabsorption
Chronic bleeding (Aspirin) Chronic kidney failure
Production of EPO
Loss in urine

BM, bone marrow; EPO, erythropoietin; ACEi,

angiotensin-converting enzyme inhibitor Silverberg DS et al. J Am Coll Cardiol 2000;35:17371744
Distribution of Various Etiologies of Anemia
among Patients with Advanced Congestive
Heart Failure

100
Iron deficiency
Anemia of chronic disease

80 Hemodilution
73.0%
Drug induced
Patients (%)

60

40

18.9%
20

5.4% 2.7%
0

Nanas JN et al. J Am Coll Cardiol 2006;48:24852489

Increased Levels of Inflammatory Cytokines and Iron
deficiency can Cause Anemia in Patients with CHF

Causes of anemia in CHF15

Increased cytokine levels
Iron deficiency CHF

Anemia can worsen heart

function through: Reduced
erythropoiesis
Ischemia
Hemodilution Hct
Ischemia
Hemodilution

Anemia

1. Akram K & Pearlman BL. Int J Cardiol 2007;117:296305; 2. Morelli S et al. Acta Cardiol 2008;63:565570; 3. Kazory A & Ross EA. J Am Coll Cardiol
2009;53:639647; 4. Anand IS. J Am Coll Cardiol 2008;52:501511; 5. Caramelo C et al. Rev Esp Cardiol 2007;60:848860
Pathophysiology of CRAS

Sympathetic nervous system

Renin-angiotensin system

CKD CHF

Reduced
erythropoiesis

Hct
Renal ischemia Ischemia
Vasoconstriction Hemodilution

Anemia
Mak G et al. Curr Treat Options Cardiovasc Med 2008;10:455464; Murphy CL & McMurray JJV. Heart Fail Rev 2008;13:431438;
Felker GM et al. J Am Coll Cardiol 2004;44:959966; van der Meer P et al. Eur Heart J 2004;25:285291;
Malyszko J & Mysliwiec M. Kidney Blood Press Res 2007;30:1530
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