Anemia and response to erythropoietin in the cardiorenal syndrome

Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease and death. Whereas cardiovascular disease is common in CKD, patients with cardiac failure often have renal dysfunction. The combination of kidney disease and heart failure is currently known as the cardiorenal syndrome (CRS). Anemia is common in CRS and is associated with increased mortality risk. A main causative factor is an inadequate bone marrow response to endogenous and/or exogenous EPO has (EPO resistance). The role of treatment of anemia with recombinant human EPO has been the subject of many studies recently. Large-scale trials failed to demonstrate a beneficial effect of EPO when targeting normalization of Hb in CKD patients. This could be related to the Hb levels attained, or alternatively to unwanted nonhematopoietic effects of (high dosages of) EPO. Also patient-related factors may play a role, since it is known that EPO resistance in itself is associated with worse outcomes. In this thesis, we investigate mechanisms of EPO resistance and the role of hepcidin herein. Furthermore, we study various aspects of hemoglobin variability in four different patient groups: hemodialysis and peritoneal patients treated with EPO, predialysis patients treated with EPO and predialysis patients not treated with EPO. Lastly, the role of circadian (mis)alignment of melatonin, EPO, IGF-1 and pro-inflammatory cytokines in the pathophysiology of anemia in CKD is investigated. The overall conclusion of this thesis is that EPO treatment should be tailored to the individual patient. However, no evidence is available as to which patients will encounter benefits or complications from EPO.