Detecting Endothelial Dysfunction in Renal Failure

描述（由申请方提供）：内皮细胞功能障碍（ECD）的心血管并发症已成为终末期肾病（ESRD）最严重的危及生命的并发症。使用超声测量肱动脉中的血流介导的扩张（FMD）或侵入性测量进行ECO的大血管检测可能与全球普遍存在的微血管ECD相关，而微血管ECD是进行性心血管疾病（CVD）的基础。根据文献观察，我们开发了皮肤激光多普勒血流测量方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的ECD。我们假设，后者的患者，实际上是许多晚期慢性肾脏病（CKD）患者的风险增加，发展为心血管疾病的临床表现。使用局部前臂热充血（加热到41摄氏度）和点激光多普勒监测器的时间依赖性和激光多普勒灌注成像（扫描仪）的空间依赖性，我们将定义模式和参数的皮肤流量密切相关的一氧化氮（NO）的生物利用度，因此微血管内皮功能。为了检验这些假设，我们将研究对照组、ESRD组和CKD（K/DOQI 3和4）受试者中局部热反应的关系。使用皮内微透析，我们将获得一氧化氮合酶抑制剂硝基-L-精氨酸（NLA）的剂量反应，有和没有前列腺素抑制酮咯酸。我们将专门检验这一假设，即异常激光多普勒充血测量反映了ESRD和CKD患者（有或无明显CVD）的NO生物利用度异常。我们将使用超声和标准反应性充血血流刺激比较ECD与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患者发生CVD的临床预测价值。该研究将证明我们有能力无创监测ESRD和CKD的ECD，并根据ECD结果进行临床预测。这些数据将成为未来对有ECD风险的患者进行无创预后检测和治疗的基础，并可提供遵循治疗方式的方法。

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.