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Pathophysiology
Gerasimos Filippatos
Learning Objectives
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)
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
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
Cardiovascular
Severe anemia Renal failure
disease
Cardiovascular
Anemia Renal insufficiency
disease
The Definition of CRAS for 2010
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
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
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
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
*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%
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
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
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
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
6
5.9
2-year incidence of
5.4
ESRD (%)
4
3.5
2 2.6
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
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
CKD CHF
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
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
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
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
100
Iron deficiency
Anemia of chronic disease
80 Hemodilution
73.0%
Drug induced
Patients (%)
60
40
18.9%
20
5.4% 2.7%
0
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
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