Mechanisms of erythropoietin induced hypertension

高血压是一种常见的但经常被忽视和低估的不良反应促红细胞生成素

Hypertension is a common but a frequently overlooked and underreported adverse effect of erythropoietin (EPO) therapy. Although EPO was approved in 1989 for treatment of anemia in patients with chronic kidney disease (CKD), only recently have trials noted substantial cardiovascular risks associated with normalization of hemoglobin. New therapies, such as hypoxia-inducible factor (HIF) stabilizers are on the horizon. 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. Endothelial dysfunction is central to the genesis of EPO-induced hypertension as is the dysregulated sensing of oxygen tension by the peripheral blood vessels. We hypothesize that compared to untreated controls, EPO therapy in anemic patients with CKD will raise diastolic blood pressure. The magnitude of increase in diastolic BP at 12 weeks, as measured by 24h ambulatory BP monitoring, 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. The factors underlying endothelial dysfunction will be explored by interrogating the nitric oxide pathway (24h urine nitrate and nitrite and plasma ADMA), endothelin activation (plasma endothelin 1 concentration), and changes in the renin angiotensin system (seated plasma aldosterone, renin activity, and 24h urine sodium excretion rate). We will use a randomized controlled trial design, with open-label administration of EPO or nothing to 80 patients in each group and comparing the responses over 12 weeks of treatment. Oral iron will be used in both groups to replete iron deficiency. The untreated “waitlisted” controls will then be treated after 12 weeks and we will examine the diastolic BP after a further 12 weeks of treatment with EPO and examine its relationship with endothelial dysfunction and failure to regulate forearm blood flow using paired testing with their baseline results as their own control. Preliminary data show that our sample size has the ability to detect 5 mmHg change in diastolic BP between groups. For endothelial dysfunction, most studies are powered to detect 1-2% change from baseline. Our study has the ability to detect an effect size that is as little as 0.45%. Thus, we have adequate power to see the observed effects. Finally, the feasibility of randomizing in a timely manner of what appear to be large numbers is supported by screening through the VINCI databases. This study has the potential of improving our 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, we can in the future robustly compare these effects of EPO with HIF stabilizers.