Mechanisms of erythropoietin induced hypertension

高血压是一种常见的促红细胞生成素的副作用，但经常被忽视和低估。 (EPO)疗法。虽然EPO在1989年被批准用于治疗慢性肾脏病患者的贫血 疾病(CKD)，直到最近才有试验注意到与正常的 血红蛋白。新的治疗方法，如低氧诱导因子(HIF)稳定剂即将问世。它仍然存在 与促红细胞生成素相比，这些新药患高血压的风险是低还是高。 因此，了解EPO诱发高血压的机制迫在眉睫。内皮功能障碍是 促红细胞生成素诱导的高血压的发生的中心是氧分压的异常感应。 周围血管。我们假设，与未经治疗的对照组相比，贫血患者的EPO治疗 合并CKD会使舒张压升高。12周时舒张压升高的幅度，如 测得的24小时动态血压，将与两个因素有关。首先，内皮功能障碍和 从基线到4周的内皮功能恶化；第二，前臂血流的调节 在应对吸氧和这一指标的变化时从基线到4周。影响因素 潜在的内皮功能障碍将通过询问一氧化氮途径(24小时尿硝酸盐)来探索 和亚硝酸盐和血浆ADMA)、内皮素激活(血浆内皮素1浓度)，以及 肾素血管紧张素系统(静息血浆醛固酮、肾素活性、24小时尿钠排泄率)。我们 将使用随机对照试验设计，对80名患者开放标签给药或不给药 并比较治疗12周后的反应。两组均使用口服铁剂。 以补充铁的缺乏。未经治疗的“等待名单”对照组将在12周后接受治疗，我们将 再用促红细胞生成素治疗12周后检查舒张压，并检查其与 与基线配对测试的内皮功能障碍和前臂血流调节失败 结果作为自己的对照。初步数据显示，我们的样本量有能力检测到5毫米汞柱 两组间舒张压的变化。对于内皮功能障碍，大多数研究的动力是检测到1-2% 从基线更改。我们的研究有能力检测到低至0.45%的影响大小。因此，我们有 有足够的能量来观察观察到的效果。最后，适时随机化的可行性是什么 通过Vinci数据库的筛选支持了大量的数字。这项研究具有 通过精确量化EPO的一种常见副作用来提高我们对EPO的理解的潜力 血压变化的幅度、对内皮功能的影响以及这些不利因素的生物标志物的发现 效果。因此，我们可以在未来有力地比较EPO和HIF稳定剂的这些作用。

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.