Tissue Oxygenation in Human Renovascular Hypertension

慢性肾脏疾病(CKD)在美国正在增加，特别是在老年人中。超过8个 美国有数百万人肾功能减退。即使是轻微的CKD也可归因于过度- 紧张和糖尿病预示着重大的心血管风险，包括心肌梗塞死亡。两者都有 病情的特点是肾脏内的小血管疾病。大肾动脉粥样硬化 血管可加速高血压，叠加小血管疾病，并产生肾脏损伤。 肾血管疾病既会激活氧化途径，又会产生纤维化。对这些的监管 人们对人类疾病的途径知之甚少。BOLD(血氧水平依赖)磁 磁共振(MR)提供了一种直接、非侵入性的脱氧血红蛋白测量方法。实验研究 表明BOLD MR水平与肾皮质和髓质内的局部氧分压直接相关。 我们的初步结果表明，在阻断脑缺血期间，BOLD MR测量的脱氧血红蛋白的变化 钠重吸收与动脉粥样硬化性肾血管病变中不可逆性肾功能障碍程度有关 疾病。在这些研究中要检验的总体假设是，脱氧血红蛋白信号 (BOLD磁共振方法学的基础)，它反映了区域性肾脏缺血，预测 动脉粥样硬化性血管疾病患者肾脏氧化和纤维化通路的激活。我们建议 利用这些方法作为阐明人类发病机制和指导治疗的手段 动脉粥样硬化性肾血管疾病。 我们的具体目标将检查年龄、种族和大血管肾血管疾病在 改变肾脏耗氧量以检查其在调节损伤途径中的作用的条件：目的 第一项研究将检查与年龄和种族相关的小血管变化的作用，以确定髓质和 速尿诱发BOLD MR的皮质改变及其与局部血流量的关系(测量) 通过多探测器CT)、氧化途径和纤维化生物标志物。目标2将考察一系列变化 速尿在狭窄和非狭窄肾脏中诱发的髓质和皮质BOLD磁共振成像 通过血管内血运重建术改变氧耗水平。目标3号将检查系列赛 狭窄和非狭窄肾脏在全身性降压过程中区域BOLD MR的变化 在不进行肾血管重建术的情况下使用降压治疗。 这些项目将提供从我们计划项目的其他研究到人类的关键扩展 与肾血管性高血压和损伤(Romero)、微血管损伤和修复机制有关 (Lerman)和肾纤维化反应中的细胞信号通路(Grande)。

Chronic kidney disease (CKD) is increasing in the U.S., particularly in older individuals. More than eight million people in the US have reduced kidney function. Even minor degrees of CKD attributed to hyper- tension and diabetes predict major cardiovascular risks, including death from myocardial infarction. Both conditions are characterized by small vessel disease within the kidney. Atherosclerosis of the larger renal vessels can accelerate hypertension, is superimposed upon small vessel disease and produces renal injury. Renovascular disease both activates oxidative pathways and produces fibrosis. The regulation of these pathways in human disease is poorly understood. BOLD (Blood Oxygen Level Dependent) magnetic resonance (MR) provides a direct, non-invasive measure of deoxygenated hemoglobin. Experimental studies indicate that BOLD MR levels relate directly to regional oxygen tension within kidney cortex and medulla. Our preliminary results indicate that deoxyhemoglobin changes measured by BOLD MR during blockade of sodium reabsorption are related to levels of irreversible kidney dysfunction in atherosclerotic renovascular disease. The overall hypothesis to be examined in these studies is that deoxygenated hemoglobin signals (the basis for BOLD magnetic resonance methodology), which reflect regional kidney ischemia, predict activation of oxidative and fibrogenic pathways in kidneys with atherosclerotic vascular disease. We propose to utilize these methods as a means of elucidating the pathogenesis and guiding therapy in human atherosclerotic renovascular disease. Our specific aims will examine the role of age, ethnicity and large-vessel renovascular disease under conditions that modify kidney oxygen consumption to examine their role in regulating injury pathways: Aim No. 1 will examine the role of small vessel changes related to age and ethnicity to determine medullary and cortical changes in BOLD MR induced by furosemide and their relationship to regional blood flow (measured by multi-detector CT), oxidative pathways and fibrogenic biomarkers. Aim No. 2 will examine serial changes in medullary and cortical BOLD MR induced by furosemide in stenotic and non-stenotic kidneys after changing levels of oxygen consumption with endovascular revascularization. Aim No. 3 will examine serial changes in regional BOLD MR in stenotic and non-stenotic kidneys during systemic blood pressure reduction using antihypertensive therapy without renalrevascularization. These projects will provide a critical extension into humans from the other studies of our program project related to mechanisms of renovascular hypertension and injury (Romero), microvascular injury and repair (Lerman) and pathways of cell signaling in renal fibrogenic responses (Grande).