1. CRAS – pathophysiology1

2. CRAS is a Vicious Cycle
Deteriorating kidney function worsens anaemia and heart function, which further impacts on kidney function
The same is true of worsening anaemia and deteriorating heart function 2

3. The Pathophysiology of CRAS
Hct
Renal ischaemia
Vasoconstriction
Reduced haematopoiesis
Sympathetic nervous system
Renin-angiotensin system
Ischaemia
Haemodilution
EPO
Cytokines
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 3

4. 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
Reduced haematopoiesis
Cytokines
EPO
Sympathetic nervous system
Renin-angiotensin system
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 4

5. Pathophysiology of CRAS
Reduced haematopoiesis
Sympathetic nervous system
Renin-angiotensin system
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 5

6. EPO and Iron Deficiency can Cause Anaemia in Patients with CKD
Causes of anaemia in CKD1–4
Erythropoietin (EPO) deficiency/resistance
Iron deficiency
Anaemia can worsen kidney function through:
Renal ischemia
Vasoconstriction
Hct
Renal ischaemia
Vasoconstriction
Reduced haematopoiesis
EPO
Sympathetic nervous system
Renin-angiotensin system
Hct=haematocrit
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 6

7. Pathophysiology of CRAS
Hct
Renal ischaemia
Vasoconstriction
Reduced haematopoiesis
Sympathetic nervous system
Renin-angiotensin system
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 7

8. Mechanisms of Anaemia in CHF
Haemodilution
Plasma Volume 
Forward failure
BM dysfunction
Iron deficiency
Fe2+ uptake 
Malabsorption
Chronic bleeding (e.g., aspirin)
Chronic immune activation
TNF
Production of EPO 
EPO activity in BM 
Drugs
ACEi: EPO synthesis 
Chronic kidney failure
Loss in urine 
BM=bone marrow; EPO=erythropoietin; ACEi=angiotensin-converting enzyme inhibitor
Silverberg DS et al. J Am Coll Cardiol 2000;35:1737–1744 8

9. Distribution of Aetiologies of Anaemia: Patients with Advanced CHF20 40 60 80
100
Patients (%)
73.0%
18.9%
5.4%
2.7%
Iron deficiency
Anaemia of chronic disease
Haemodilution
Drug induced
Nanas JN et al. J Am Coll Cardiol 2006;48:2485–2489 9

10. Reduced haematopoiesis
Increased Levels of Inflammatory Cytokines and Iron Deficiency can cause Anaemia in Patients with CHF
Causes of anaemia in CHF1–5
Increased cytokine levels
Iron deficiency
Anaemia can worsen heart function through:
Ischaemia
Haemodilution
Ischaemia
Haemodilution
Hct
Reduced haematopoiesis
Cytokines
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 10

11. Pathophysiology of CRAS
Ischaemia
Haemodilution
Hct
Renal ischaemia
Vasoconstriction
Reduced haematopoiesis
EPO
Cytokines
Sympathetic nervous system
Renin-angiotensin system
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 11