Mechanisms of EPO-induced Hypertension

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Hypertension is a common but frequently overlooked and underreported adverse effect of erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks associated with normalization of hemoglobin. The risk of strokes is strongly related to poorly controlled hypertension. Blood...

Hypertension is a common but frequently overlooked and underreported adverse effect of erythropoietin (EPO) therapy. Recent trials have noted substantial cardiovascular risks associated with normalization of hemoglobin. The risk of strokes is strongly related to poorly controlled hypertension. Blood pressure was not measured the way it usually is in hypertension trials, so the investigators cannot be completely confident that the risk of strokes in this large randomized trial was not related to EPO-induced hypertension. New therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon but it remains to be seen whether these new drugs would have a lower or a higher risk for hypertension compared to EPO. Accordingly, understanding the mechanism of EPO-induced hypertension is urgent. The investigators hypothesize that compared to untreated controls, EPO therapy in anemic patients with chronic kidney disease (CKD) will raise diastolic blood pressure. The magnitude of increase in diastolic BP at 12 weeks after treatment will be related to two factors. First, endothelial dysfunction and worsening of endothelial function from baseline to 4 weeks and second, the modulation of forearm blood flow in response to breathing oxygen and the change in this measure from baseline to 4 weeks. If the investigators understood the time course, the magnitude, and the mechanisms of exercise-induced hypertension (EIH) the investigators will better be able to design studies to compare the vascular effects of EPO and HIF stabilizers in the future. Thus, this study has the potential of improving the investigators' understanding of a common side effect of EPO by precisely quantifying the magnitude of BP change, its effects on endothelial function, and discovering the biomarkers of these adverse effects. Thus, the investigators can in the future robustly compare these effects of EPO with HIF stabilizers. This study is innovative because it will focus on the potential mechanisms by which EPO induces an increase in BP. The time-course and magnitude of change in BP will be assessed using the gold-standard measurement of 24 hour ambulatory BP recordings. The more frequent clinic BP recordings using validated methods will better allow us to track changes in BP over time. The investigators' lab is uniquely qualified to carry out these experiments due to a large experience with such types of studies. The investigators will examine endothelial function using a reference method -- that of flow-mediated dilatation -- which is established in the investigators' laboratory. The investigators will directly test the hypothesis whether hypoxia-sensitivity of the vascular tissue is responsible for the BP increase.

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