CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos

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

NHLBI Working Group. Cardio-renal connections in heart failure and cardiovascular disease: executive summaryAvailable at: http://www.nhlbi.nih.gov/meetings/workshops/cardiorenal-hf-hd.htm.

“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

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

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

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

CHF CKD

Anemia

CKD, chronic kidney disease; CHF, chronic heart failure

The Definition of CRAS Differs Depending on your Viewpoint (1)

Nephrologists

CKDAny degree of

anemiaAny degree of

heart failure

CKD Severe anemiaSevere

heart failure

Renal failure Severe anemiaCardiovascular

events

Renal failure AnemiaCardiovascular

disease

CKD Anemia CHF

The Definition of CRAS Differs Depending on your Viewpoint (2)

Cardiologists

CHFAny degree of

anemiaAny degree of

renal insufficiency

CHF Severe anemia Renal failure

Cardiovascular disease

Severe anemia Renal failure

Cardiovascular disease

Anemia Renal insufficiency

CHF Anemia CKD

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

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

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

AnemiaAnemia

+CKD

Anemia +

CHF

CRAS

CHF + CKD

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

Nu

mb

er o

f p

atie

nts

Hb (g/dL)

500

400

300

200

100

04–4.4

5–5.46–6.4

7–7.48–8.4

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

The EuroHeart Failure survey programme – a survey on the quality of care among patients with heart failure in Europe

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;10:140–148

60

50

40

30

20

10

0ADHERE 105,000 patients EuroHF Survey II

Renal failure Anemia

Pat

ien

ts (

%)

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

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)

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 O’Meara 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 m2

14%

11.5%

22%

52.5%

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 m2

10%

22%

32%

36%

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

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 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

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

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

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

Groenveld HF et al. J Am Coll Cardiol 2008;52:818–27

30

25

20

15

10

5

011.5

35

40

Mo

rtal

ity

per

yea

r (%

)

12.0 12.5 13.0 13.5 14.0 14.5

Baseline Hb levels (g/dL)

R = -0.396, P = 0.025

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;101:223–230

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0.10

Pre

dic

ted

pro

bab

ility

o

f in

-ho

spit

al d

eath

Admission Hb (5–20 g/dL)

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

34.6

CHF andanemia

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

0

5

10

15

20

25

30

35

40

45

50

7.7

Noanemia

CHF or CKI

16.1

Anemia

26.6

CHF

27.3

CKI andanemia

38.4

CHF andCKI

45.6

Anemia,CHF and

CKI

2-ye

ar m

ort

alit

y (%

)

Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12

16.4

CKI

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

0

2

4

6

5.4

CKI and

anemia

3.5

CHF and CKI

5.9

Anemia,CHF and

CKI

2-ye

ar in

cid

ence

of

ES

RD

(%

)

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

The Prognostic Value of Anemiain Patients with Diastolic Heart Failure

Tehrani F et al. Texas Heart J 2009;36:220–225

0

0

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n (

%)

10

Survival time (months)

0.2

0.6

0.4

0.8

1.0

20 30 40 50 60 70

No Anemia (n=132)

Anemia (n=162)

Anemia in Diastolic HF

Felker GM et al. Am Heart J 2006;151:457–462

0.3

0.1

00

Su

rviv

al p

rob

abili

ty

1

Years

2 3 4 5 6 7

0.2

0.6

0.4

0.5

0.9

0.7

0.8

1

Anemia/ISF

No anemia/PSF

Anemia/PSF

No anemia/ISF

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

Anemia

CKD CHF

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

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 systemRenin-angiotensin system

CKD CHF

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


Anemia



CKD CHF



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


Renal ischemiaVasoconstriction

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;117:296–3053. 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


Anemia




CKD CHF↓ EPO



↓ Hct

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 – EPO activity in BM

• Chronic kidney failure– Production of EPO – Loss in urine

Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–1744BM, bone marrow; EPO, erythropoietin; ACEi, angiotensin-converting enzyme inhibitor

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

0

20

40

60

80

100

Pat

ien

ts (

%)

73.0%

18.9%

5.4% 2.7%

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


IschemiaHemodilution

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


Anemia




IschemiaHemodilution

CKD CHF↓ EPO

↓ Hct

↑ Cytokines etc



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

Documents

CRAS – Definition, Epidemiology and Pathophysiology Gerasimos Filippatos