Circulating cells in heart and renal failure

Abstract

The presence of combined chronic heart failure and chronic kidney disease, i.e. the cardiorenal syndrome (CRS), is a rising problem with high cardiovascular morbidity and mortality. In CRS, disease progression in both organs is amplified. In this thesis, we aimed to gain insight into pathophysiologic mechanisms of CRS by analyzing gene expression profiles of circulating monocytes, as biosensors of the altered systemic environment. The observed gene expression differences between CRS patients and healthy controls were modest, but pointed at modulated inflammation and oxidative stress, two of the systems that have previously been proposed as important connectors between the heart and the kidney. Erythropoietin (EPO) treatment, well-known for its erythropoiesis stimulating effect, has also shown beneficial effects on the cardiovascular system in some, but not all studies. Mechanisms underlying EPO effects are not fully understood. Effects of short-term EPO treatment on monocyte transcriptomes were evaluated in CRS patients to identify underlying mechanisms of non-hematopoietic EPO actions. Limited effects of low EPO dose to treat renal anemia were observed. Of note, at this regular EPO dose no harmful effects could be detected. Furthermore, we characterized endothelial progenitor cell (EPC) levels and function, as key players of endothelial repair, in several conditions with increased cardiovascular disease. Decreased levels of circulating EPC were demonstrated during aging in healthy subjects, in children with end-stage chronic kidney disease, in adults with predialysis chronic kidney disease and a history of cardiovascular disease and in CRS patients. Our data suggest that renal dysfunction in particular in presence of other cardiovascular risk factors (e.g. inflammation) is associated with decreased EPC levels and may contribute to accelerated atherosclerosis. Our findings open a new field of possible interventions to reduce cardiovascular risk in these populations. The mechanisms underlying reduced EPC availability in these conditions remain to be clarified in order to design effective treatment strategies. Since beneficial effects of EPO on EPC mobilization have previously been shown in experimental studies, short- and long-term effects of EPO treatment on EPC were evaluated in CRS patients. In line with limited short-term EPO effects on monocyte gene expression profiles, no changes in EPC levels or function were observed. After 52 weeks however, EPO stabilized EPC levels, while levels decreased in patients without EPO therapy. These data suggest that reduction of circulating EPC levels in CRS patients, which may contribute to the increased CVD risk, can be decelerated by long-term EPO treatment.