Detecting Endothelial Dysfunction in Renal Failure

检测肾衰竭中的内皮功能障碍

• 批准号: 7230178
• 负责人: JULIAN M STEWART
• 金额: $ 19.18万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230178
• 关键词: Acetylcholine; Advocate; Affect; Age; Algorithms; Arginine; Arteries; Biological Availability; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Classification; Clinical; Cross-Sectional Studies; Cutaneous; Data; Dependence; Detection; Development; Diabetes Mellitus; Discriminant Analysis; Dose; End Point; End stage renal failure; Endothelial Cells; Forearm; Functional disorder; Future; Gender; Goals; Grouping; Heating; Hyperemia; Image; Incidence; Invasive; Ketorolac; Ketorolac Tromethamine; Kidney Diseases; Kidney Failure; Laser-Doppler Flowmetry; Lasers; Life; Literature; Localized; Longitudinal Studies; Measurement; Measures; Mediating; Methods; Microdialysis; Modality; Monitor; Nitric Oxide; Patients; Pattern; Perfusion; Population; Predictive Value; Prostaglandin Inhibition; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Purpose; Research; Research Personnel; Risk; Risk Assessment; Staging; Standards of Weights and Measures; Stimulus; Subgroup; Testing; Time; Treatment Protocols; Ultrasonography; base; body system; brachial artery; cardiovascular disorder risk; cerebrovascular; cyclooxygenase 1; cyclooxygenase 2; disorder control; falls; inhibitor/antagonist; instrumentation; kidney vascular structure; pre-clinical; prognostic; programs; prophylactic; reactive hyperemia; response; vasoconstriction; Acetylcholine; Advocate; Affect; Age; Algorithms; Arginine; Arteries; Biological Availability; Cardiovascular Diseases; Cardiovascular system; Chronic Kidney Failure; Classification; Clinical; Cross-Sectional Studies; Cutaneous; Data; Dependence; Detection; Development; Diabetes Mellitus; Discriminant Analysis; Dose; End Point; End stage renal failure; Endothelial Cells; Forearm; Functional disorder; Future; Gender; Goals; Grouping; Heating; Hyperemia; Image; Incidence; Invasive; Ketorolac; Ketorolac Tromethamine; Kidney Diseases; Kidney Failure; Laser-Doppler Flowmetry; Lasers; Life; Literature; Localized; Longitudinal Studies; Measurement; Measures; Mediating; Methods; Microdialysis; Modality; Monitor; Nitric Oxide; Patients; Pattern; Perfusion; Population; Predictive Value; Prostaglandin Inhibition; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Purpose; Research; Research Personnel; Risk; Risk Assessment; Staging; Standards of Weights and Measures; Stimulus; Subgroup; Testing; Time; Treatment Protocols; Ultrasonography; base; body system; brachial artery; cardiovascular disorder risk; cerebrovascular; cyclooxygenase 1; cyclooxygenase 2; disorder control; falls; inhibitor/antagonist; instrumentation; kidney vascular structure; pre-clinical; prognostic; programs; prophylactic; reactive hyperemia; response; vasoconstriction

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.

描述（由申请人提供）：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）的最严重威胁生命的伴奏。使用臂动脉中流动介导的扩张（FMD）的超声测量对ECO的大血管检测或侵袭性措施可能与全球普遍存在的微血管ECD无关。根据文献的观察，我们开发了皮肤激光多普勒流量指标，结合了局部热充血性血症测量值，这些测量可以区分具有已知ECD的对照和ESRD患者，并且可以检测到临床上沉默的ECD。我们假设后者的患者乃至许多患有慢性肾脏病疾病的患者（CKD）的患者有增加CVD临床表现的风险。使用局部前臂热高血炎（加热至41度C）和点激光多普勒监测器，以进行时间依赖性和激光多普勒灌注成像（SCANNER），以实现空间依赖性，我们将定义皮肤流动的模式和参数，这些模式和参数与硝酸氧化物（NO）生物氧化（NO）的最终功能密切相关。为了检验这些假设，我们将研究对照，ESRD和CKD（K/DOQI3和4）受试者中局部热反应的关系。使用皮内微透析，我们将对NOS抑制剂硝基-L-精氨酸（NLA）获得剂量反应，并具有和没有前列腺素抑制酮洛拉克的前列腺素抑制作用。我们将明确检验以下假设：异常激光多普勒充血测量结果反映了有或没有明显CVD的ESRD和CKD患者的异常无生物利用度。我们将使用超声和标准反应性高血部流动刺激将ECD的皮肤微血管参数与FMD反应进行比较。我们将研究基于激光杂种血症的ECD测试对ESRD和CKD患者的CVD发展的临床预测值，而没有明显的心血管疾病或糖尿病。该研究将证明我们在ESRD和CKD中非侵入性监测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的非侵入性预后测试和对ECD风险的患者的治疗，并可以提供遵循治疗方式的手段。