Detecting Endothelial Dysfunction in Renal Failure

描述(由申请人提供)：血管内皮细胞功能障碍(ECD)的心血管并发症已成为终末期肾病(ESRD)最严重的生命威胁。使用ECO检测大血管、超声测量肱动脉血流介导的扩张(FMD)或侵入性测量可能与全球普遍存在的进展性心血管疾病(CVD)背后的微血管ECD无关。在文献观察的基础上，我们开发了结合局部热充血测量的皮肤激光多普勒血流测量方法，该方法可以区分已知ECD的对照组和ESRD患者，并可以检测到临床上无症状的ECD。我们假设后者患者和许多慢性肾脏疾病(CKD)进展期患者发生CVD临床表现的风险增加。使用局部前臂热充血(加热至41摄氏度)和点激光多普勒监测的时间相关性和激光多普勒血流成像(扫描仪)的空间相关性，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，我们将研究对照组、ESRD和CKD(K/DOQI3和4)受试者的局部热反应之间的关系。利用皮内微透析，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，在前列腺素被酮咯酸抑制或不被抑制的情况下。我们将专门测试这一假设，即异常的激光多普勒充血测量反映了有或没有明显CVD的终末期肾病和CKD患者的异常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的皮肤微血管参数与FMD反应。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终末期肾病和慢性肾脏病患者发生心血管疾病的临床预测价值。这项研究将展示我们在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，并可提供一种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.