Download Anemia - Jantung Sehat

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
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 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
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
and so on”1
“The cardio-renal anemia syndrome
is a set of complex and interrelated
phenomena that are poorly understood”2
Anemia
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 two”3
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
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
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
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
heart failure
Any degree of
kidney failure
Any degree of
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
+
CHF
Anemia
Anemia
+
CKD
The EuroHeart Failure survey programme – a
survey on the quality of care among patients
with heart failure in Europe
Number of patients
500
400
N=5249 men
33% with Hb <12 g/dL
300
200
100
0
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
CRAS in US and European HF Surveys
60
Patients (%)
50
40
30
20
10
0
ADHERE 105,000 patients
Renal failure
EuroHF Survey II
Anemia
Galvao M et al. J Card Fail 2006;12:100–107; Nieminen MS et al. Eur J Heart Fail 2008;10:140–148
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
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
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
11.5%
14%
52.5%
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 O’Meara E et al. Circulation 2006;113:986–994
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%
36%
22%
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;98:391–398
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
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
Relationship Between Anemia and Mortality in HF:
A Systematic Review and Meta-analysis
Study ID `
Al Ahmad (2001)
Tanner (2002)
McClellan (2002)
Horwich (2002)
Szachniewi (2003)
Kerzner (2003)
Kalra (2003)
Mozaffarian (2003)
Kosiborod (2003)
Van der Meer (2004)
Anand (2004)
Sharma (2004)
Ralli (2005)
Kosiborod (2005)
Rosolova (2005)
Gardner (2005)
Maggioni-V (2005)
Maggioni-I (2005)
Ezekowitz (2005)
Varadarajan (2006)
Elabbassi (2006)
Maraldi (2006)
DeSilva (2006)
Berry (2006)
Go (2006)
Komajda (2006)
Newton (2006)
Formiga (2006)
Terrovitis (2006)
O’Meara (2006)
Felker (2006)
Shamagian (2006)
Schou (2007)
Overall (I-squared = 92.4%, p=0.000)
Odds ratio (95% CI)
1.87 (1.46, 2.41)
0.46 (0.17, 1.28)
1.61 (1.17, 2.21)
1.82 (1.36, 2.43)
3.26 (1.11, 9.63)
1.61 (1.03, 2.53)
1.60 (0.98, 2.61)
1.57 (1.16, 2.12)
1.82 (1.52, 2.17)
3.00 (0.87, 10.30)
2.01 (1.27, 3.19)
1.25 (0.98, 1.60)
3.00 (1.55, 5.80)
1.49 (1.44, 1.55)
1.88 (1.27, 2.80)
1.23 (0.46, 3.34)
1.85 (1.49, 2.29)
2.29 (1.76, 2.99)
2.44 (1.79, 3.33)
1.67 (1.41, 1.98)
2.98 (1.69, 5.26)
1.72 (1.07, 2.75)
2.36 (1.65, 3.38)
2.47 (1.73, 3.54)
2.40 (2.32, 2.48)
1.94 (1.59, 2.36)
1.82 (1.28, 2.59)
1.83 (0.73, 4.60)
7.05 (2.15, 23.08)
2.13 (1.75, 2.58)
2.52 (2.24, 2.83)
3.97 (1.94, 8.13)
2.24 (1.29, 3.88)
1.96 (1.74, 2.21)
.4
.5
1
Lower risk of anemia
2
4
8
Events, anemic n/N
98/279
5/51
191/296
109/271
6/18
102/236
70/96
96/215
423/1093
6/18
30/108
101/513
29/108
8867/21290
70/136
6/38
134/453
97/375
223/305
713/1122
29/127
46/253
71/305
125/231
13233/25452
237/475
117/215
13/44
12/16
231/677
1135/1937
33/95
29/95
26687/56943
Events, non anemic n/N
1363/6081
27/142
179/337
213/790
21/158
42/131
273/435
311/915
306/1188
8/56
129/804
414/2531
17/156
9415/29115
134/372
19/144
845/4557
269/2036
256/486
574/1124
28/310
36/314
74/650
93/288
10668/34320
856/2521
124/313
11/59
43/144
387/1976
1085/3014
13/110
41/250
28274/95827
10
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
40
Mortality per year (%)
35
30
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;52:818–27
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
Predicted probability
of in-hospital death
0.09
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 (5–20 g/dL)
Young JB et al. Am J Cardiol 2008;101:223–230
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
2-year mortality (%)
45
45.6
40
38.4
35
34.6
30
25
27.3
26.6
20
15
16.1
16.4
10
5
7.7
0
No
anemia
CHF or CKI
Anemia
CHF
CKI
CHF and
anemia
CKI and
anemia
CHF and
CKI
Anemia,
CHF and
CKI
Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12
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
2-year incidence of
ESRD (%)
6
5.9
5.4
4
3.5
2.6
2
0
0.1
0.2
0.2
No
anemia,
CHF or
CKI
Anemia
CHF
0.3
CKI
CHF
and anemia
CKI
and
anemia
CHF
and CKI
Anemia,
CHF and
CKI
Silverberg D et al. Nephrol Dial Transplant 2003;18(suppl 8):viii7–viii12
The Prognostic Value of Anemia
in Patients with Diastolic Heart Failure
Survival distribution function (%)
1.0
0.8
No Anemia (n=132)
0.6
Anemia (n=162)
0.4
0.2
0
0
10
20
30
40
50
60
70
Survival time (months)
Tehrani F et al. Texas Heart J 2009;36:220–225
Anemia in Diastolic HF
1
No anemia/PSF
0.9
No anemia/ISF
Survival probability
0.8
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;151:457–462
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;10:455–464; 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
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
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
EPO and Iron Deficiency can Cause Anemia in
Patients with CKD
• Causes of anemia in CKD1–4
– Erythropoietin (EPO)
deficiency/resistance
– Iron deficiency
CKD
Reduced
erythropoiesis
↓ Hct
• Anemia can worsen kidney
function through:
– Renal ischemia
– Vasoconstriction
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
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;10:455–464; 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
Mechanisms of Anemia in CHF
• Hemodilution
– Plasma Volume 
• Forward failure
– BM dysfunction
• Iron deficiency
– Fe2+ uptake 
– Malabsorption
– Chronic bleeding (Aspirin)
BM, bone marrow; EPO, erythropoietin; ACEi,
angiotensin-converting enzyme inhibitor
• 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
Distribution of Various Etiologies of Anemia
among Patients with Advanced Congestive
Heart Failure
100
Iron deficiency
Anemia of chronic disease
Patients (%)
80
Hemodilution
73.0%
Drug induced
60
40
20
18.9%
5.4%
2.7%
0
Nanas JN et al. J Am Coll Cardiol 2006;48:2485–2489
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
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
Pathophysiology of CRAS
Sympathetic nervous system
Renin-angiotensin system
CKD
CHF
Reduced
erythropoiesis
↓ 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
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