Mechanisms of erythropoietin induced hypertension

促红细胞生成素诱发高血压的机制

• 批准号: 10425327
• 负责人: RAJIV AGARWAL
• 金额: --
• 依托单位: RLR VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425327
• 关键词: Adverse effects; Aftercare; Aldosterone; Anemia; Angiotensins; Animals; Aranest; Arginine; Biological Markers; Blood Pressure; Blood Vessels; Blood flow; Breathing; Cardiovascular system; Chronic Kidney Failure; Clinic; Data; Databases; Diastolic blood pressure; Dilatation - action; Dissection; Endothelin; Endothelin-1; Endothelium; Equipment; Erythropoietin; Event; Excretory function; Failure; Forearm; Future; Gold; Hemoglobin; Human; Hypertension; Hypoxia; Hypoxia Inducible Factor; Incidence; Informatics; Infrastructure; Iron; Laboratories; Measurement; Measures; Mediating; Methods; Molecular; Monitor; Nitrates; Nitric Oxide; Nitric Oxide Pathway; Nitrites; Oral; Oxygen; Patients; Pattern; Plasma; Play; Plethysmography; Randomized; Randomized Controlled Trials; Renin; Renin-Angiotensin System; Renin-Angiotensin-Aldosterone System; Research Design; Role; Sample Size; Sodium; System; Testing; Time; Tissues; Urine; Waiting Lists; cardiovascular risk factor; contextual factors; endothelial dysfunction; experience; experimental study; high risk; improved; innovation; iron deficiency; novel; novel therapeutics; open label; peripheral blood vessel; randomized trial; response; screening; side effect; stroke risk; supplemental oxygen; trial design; urinary

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.

高血压是促红细胞生成素的一种常见但经常被忽视和低估的不良反应 (EPO)疗法虽然EPO在1989年被批准用于治疗慢性肾病患者的贫血， 慢性肾脏病（CKD），直到最近才有试验指出， 血红蛋白。新的治疗方法，如缺氧诱导因子（HIF）稳定剂即将问世。它仍然是 与EPO相比，这些新药是否会降低或增加高血压的风险。 因此，了解EPO致高血压的机制是当务之急。内皮功能失调的 EPO诱导的高血压的发生的中心是由氧张力的失调感觉， 外周血管我们假设与未治疗的对照组相比，贫血患者的EPO治疗 CKD患者的舒张压会升高。12周时舒张压升高的幅度， 通过24小时动态血压监测，将与两个因素有关。首先，内皮功能障碍， 内皮功能从基线到4周的恶化，其次是前臂血流的调节 对呼吸氧的反应以及从基线到4周该测量的变化。的因素 将通过询问一氧化氮途径（24小时尿硝酸盐）来探索潜在的内皮功能障碍 和亚硝酸盐和血浆ADMA），内皮素活化（血浆内皮素1浓度），以及 肾素血管紧张素系统（坐位血浆醛固酮、肾素活性和24小时尿钠排泄率）。我们 将采用随机对照试验设计，对80名患者开放标签给予EPO或不给予EPO 并比较12周治疗后的反应。两组均采用口服铁剂 来补充缺铁未接受治疗的"等待名单"对照组将在12周后接受治疗， 在用EPO治疗12周后检查舒张压，并检查其与 内皮功能障碍和前臂血流调节失败，使用配对试验与基线 结果作为自己的控制。初步数据显示，我们的样本量有能力检测到5 mmHg 组间舒张压的变化。对于内皮功能障碍，大多数研究的把握度为1 - 2%， 较基线的变化。我们的研究能够检测到低至0.45%的效应量。因此，我们有 有足够的能力来观察观察到的效果。最后，随机化的可行性在什么时候 通过VINCI数据库的筛选支持了似乎是大量的。这项研究有 通过精确量化EPO的副作用，提高我们对EPO常见副作用的理解的潜力 血压变化的幅度，其对内皮功能的影响，并发现这些不良反应的生物标志物， 方面的影响.因此，我们可以在未来稳健地比较EPO与HIF稳定剂的这些作用。