Red cell dynamics and haemodynamics in cardiorenal failure

Abstract

The combination of chronic heart failure (CHF) and chronic kidney disease (CKD) is prevalent and associated with a higher mortality and morbidity than can be expected solely on the combination of both conditions. This combination leads to a “dangerous liaison”, also called the cardiorenal syndrome, in which failure of the one organ accelerates the progression of structural damage and failure of the other organ. The responsible pathophysiological interactions that couple CHF and CKD are still incompletely identified. These underlying pathophysiological mechanisms can be differentiated in non-haemodynamic and haemodynamic interactions between heart and kidney. This thesis addressed red cell dynamics, the production and decay of the circulating erythrocyte, regarding the non-haemodynamic coupling. The important role of red cell dynamics shows by the high prevalence of anaemia. Potential causative mechanisms affect the erythropoiesis, such as an impaired erythropoietin (EPO) production, a disordered iron metabolism and a decreased responsiveness of the bone marrow for EPO (EPO resistance). Other causative mechanisms affect the life span of the red cell, such as inflammation. In this thesis we investigated the role of erythropoietin, focused on the differentiation between its erythropoietic and its non-erythropoietic effects. For this purpose we designed the EPOCARES study (the role of Erytropoietin in the CArdioREnal Syndrom), in which chronic, stable, ambulant patients with both CHF and CKD with a mild anaemia under oral iron supplementation were randomised into three groups. One group received a low fixed EPO dose to increase the haemoglobin level. The second group also received a low fixed EPO dose, but the haemoglobin levels in these patients were maintained at baseline level by sequential blood withdrawal. The third group received no EPO (control group). Data from this trial are used to address questions in this thesis. We demonstrate that only those patients whose haemoglobin level was let to increase experienced an improved quality of life and cardiac function. Moreover, we show a negative association between a measurement of heterogeneity in circulating red cells (RDW), which is associated with adverse prognosis, with quality of life and physical fitness. This association seems to be determined by functional iron availability, red cell turnover and inflammation. Hence, the positive effects of a low, fixed dose of ESA on cardiac function and quality of life in cardiorenal patients is dependent upon red cell levels, given the fact that there was no improvement in the phlebotomy group. Together with the negative correlation between RDW and quality of life this underscores the central role of red cell dynamics in cardiorenal patients. Regarding the haemodynamic coupling between heart and kidney failure we addressed atherosclerotic renal artery stenosis (ARAS) and stabilization of glomerular filtration rate (GFR) upon changes in blood pressure. We found a prevalence of 57% of ARAS in cardiorenal failure and this was not associated with cardiac function or the presence and extent of myocardial fibrosis. Furthermore, we only found a very weak association between changes in blood pressure and stabilization of GFR, even in the presence of ARAS.