Cardio Renal Anemia Syndrome – Definition, Epidemiology and Pathophysiology Faculty of Medicine Universitas Brawijaya
Jan 23, 2016
Cardio Renal Anemia Syndrome – Definition, Epidemiology and Pathophysiology
Faculty of Medicine
Universitas Brawijaya
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
Pathophysiology of CRAS
Anemia
Reduced erythropoiesis
Sympathetic nervous systemRenin-angiotensin system
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
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
Reduced erythropoiesis
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
Pathophysiology of CRAS
Anemia
Reduced erythropoiesis
Sympathetic nervous systemRenin-angiotensin system
Renal ischemiaVasoconstriction
CKD CHF↓ 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
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
Reduced erythropoiesis
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
Pathophysiology of CRAS
Anemia
Reduced erythropoiesis
Sympathetic nervous systemRenin-angiotensin system
Renal ischemiaVasoconstriction
IschemiaHemodilution
CKD CHF↓ 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
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