CRAS – pathophysiology

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

The Pathophysiology of CRAS

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 Renal ischaemiaVasoconstriction

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

IschaemiaHaemodilution

EPOCytokines

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

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

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

EPOCytokines

Pathophysiology of CRAS

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

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

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

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=haematocrit

Hct Renal ischaemiaVasoconstriction

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

EPO

Pathophysiology of CRAS

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 Renal ischaemiaVasoconstriction

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

EPO

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

– 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

Nanas JN et al. J Am Coll Cardiol 2006;48:2485–2489

Iron deficiency

Anaemia of chronic disease

Haemodilution

Drug induced

0

20

40

60

80

100

Pati

en

ts (

%)

73.0%

18.9%

5.4% 2.7%

Distribution of Aetiologies of Anaemia: Patients with Advanced CHF

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

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

Hct

Reduced haematopoiesis

IschaemiaHaemodilution

Cytokines

Pathophysiology of CRAS

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 Renal ischaemiaVasoconstriction

Reduced haematopoiesis

Sympathetic nervous systemRenin-angiotensin system

EPO

IschaemiaHaemodilution

Cytokines