Detecting Endothelial Dysfunction in Renal Failure

描述（由申请人提供）：心血管内皮细胞功能障碍（ECD）并发症已成为终末期肾病（ESRD）最严重的危及生命的并发症。使用肱动脉血流介导扩张（FMD）的超声测量或侵入性测量来检测ECO，可能与全球普遍存在的微血管ECD（潜在的进行性心血管疾病（CVD））无关。基于文献的观察，我们开发了皮肤激光多普勒血流法结合局部热充血测量，可以区分对照组和已知ECD的ESRD患者，并可以检测临床无症状ECD。我们假设后一种患者以及许多晚期慢性肾脏疾病（CKD）患者发展为CVD临床表现的风险增加。利用前臂局部热充血（加热至41摄氏度）和点激光多普勒监测时间依赖性和激光多普勒灌注成像（扫描仪）的空间依赖性，我们将定义与一氧化氮（NO）生物利用度密切相关的皮肤血流模式和参数，从而与微血管内皮功能密切相关。为了验证这些假设，我们将研究控制组、ESRD组和CKD组（K/DOQI3和4）受试者局部热反应的关系。使用皮内微透析，我们将获得NOS抑制剂硝基- l -精氨酸（NLA）的剂量反应，酮罗拉酸有和没有前列腺素抑制。我们将特别验证一种假设，即在伴有或不伴有明显心血管疾病的ESRD和CKD患者中，异常的激光多普勒充血测量反映了异常的NO生物利用度。我们将使用超声和标准反应性充血血流刺激来比较ECD和FMD反应的皮肤微血管参数。我们将研究基于激光充血的ECD检测对无明显心血管疾病或糖尿病的ESRD和CKD患者CVD发展的临床预测价值。该研究将证明我们在ESRD和CKD中无创监测ECD的能力，并根据ECD结果做出临床预测。这些数据将构成未来无创预后检测和ECD风险患者治疗的基础，并可提供遵循治疗方式的手段。

DESCRIPTION (provided by applicant): Cardiovascular complications of endothelial cell dysfunction (ECD) have emerged as the most serious life threatening accompaniment of end-stage renal disease (ESRD). Macrovascular detection of ECO using, ultrasound measures of flow mediated dilation (FMD) in brachial arteries or invasive measures may not relate to globally pervasive microvascular ECD underlying progressive cardiovascular disease (CVD). Based on observations from the literature, we developed cutaneous laser-Doppler flowmetry methods combined with localized thermal hyperemia measurements which can distinguish among controls and ESRD patients with known ECD, and can detect clinically silent ECD. We hypothesize that the latter patients and indeed many patients with advance chronic kidney disease (CKD) are at increased risk for developing clinical manifestations of CVD. Using local forearm thermal hyperemia (heating to 41 degrees C) and point laser-Doppler monitor for time dependence and laser Doppler perfusion imaging (scanner) for spatial dependence, we will define patterns and parameters of cutaneous flow which relate closely to nitric oxide (NO) bioavailability and therefore to microvascular endothelial function. To test these hypotheses we will study the relation of local thermal responses in control, in ESRD, and in CKD (K/DOQI3 and 4) subjects. Using intradermal microdialysis we will obtain a dose-response to the NOS inhibitor nitro-L-arginine (NLA), with and without prostaglandin inhibition with ketorolac. We will specifically test the hypothesis that abnormal laser-Doppler hyperemia measurements reflect abnormal NO bioavailability in ESRD and CKD patients with and without evident CVD. We will compare cutaneous microvascular parameters of ECD to FMD responses using ultrasound and standard reactive hyperemia flow stimuli. We will study the clinical predictive value of laser-hyperemia based ECD testing for the development of CVD in ESRD and CKD patients without evident cardiovascular disease or diabetes. The research will demonstrate our ability to noninvasively monitor ECD in ESRD and CKD, and to make clinical predictions based on ECD results. These data will form the basis of future noninvasive prognostic testing and treatment of patients at risk for ECD and can provide a means to follow treatment modalities.