CRAS – pathophysiology 1
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
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
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
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
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
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
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
Distribution of Aetiologies of Anaemia: Patients with Advanced CHF 20 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
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
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