HIV-Related Proteinuria and Endothelial Dysfunction

描述（由申请人提供）： 艾滋病毒感染者的肾脏和心血管疾病的报告越来越多，可能相互关联。总蛋白尿，一个广泛使用的肾脏疾病的初步筛选标志物，是非常常见的艾滋病毒感染者。在一般人群中，蛋白尿也与全身性内皮功能障碍相关，是未来心血管事件的预测因子。因此，我们推测内皮功能障碍可能与HIV感染人群中蛋白尿的高患病率有关。此外，由于蛋白酶抑制剂与内皮功能障碍有关，我们推测这类抗逆转录病毒药物可能特异性导致肾小球内皮疾病，最初表现为微量白蛋白尿。本研究的具体目的是（1）确定HIV感染患者蛋白尿和全身性内皮功能障碍之间的关系，（2）确定基于蛋白酶催化剂的HAART对HIV感染患者微量白蛋白尿的影响。为了实现目标1，我们建议对在印第安纳州大学医学中心接受治疗的HIV感染受试者进行一项前瞻性队列研究。具体而言，将在基线和两年后再次比较两个HIV感染组（持续性蛋白尿组与无蛋白尿组）的超声测量的肱动脉血流介导的扩张（内皮功能的生理测量）、脂质、胰岛素和葡萄糖水平、人体测量学、生活方式因素和血压。目标2将通过对AIDS临床试验组研究384的代谢子研究（由主要研究者的主要导师主持）进行二次分析来解决，该研究比较了基于蛋白酶的方案与基于非核苷逆转录酶的方案用于HIV感染患者的初始抗逆转录病毒治疗。在整个子研究期间定期采集的存档尿样将用于测量微量白蛋白尿水平。总之，这些研究的结果将成为未来针对HIV感染患者肾脏和心血管疾病的预防和治疗试验的基础。拟议的研究将促进主要研究者的临床研究职业发展，由独立研究者（主要导师：Michael P. Dub6）在HIV代谢和肾脏并发症，肾血管和肾小球病理学以及临床试验设计和实施领域进行监督。

DESCRIPTION (provided by applicant): Renal and cardiovascular diseases in HIV-infected patients are increasingly reported and may be interrelated. Total proteinuria, a widely used initial screening marker for renal disease, is extremely common in HIV-infected patients. In the general population, proteinuria is also associated with systemic endothelial dysfunction, a predictor of future cardiovascular events. Therefore, we hypothesize that endothelial dysfunction may be associated with the high prevalence of proteinuria in the HIV-infected population. Furthermore, because protease inhibitors are associated with endothelial dysfunction, we hypothesize that this class of antiretrovirals may specifically result in glomerular endothelial disease, manifested initially as microalbuminuria. The specific aims of this study are to (1) determine the relationships between proteinuria and systemic endothelial dysfunction in HIV-infected patients and (2) determine the effects of protease inhibitor-based HAART on microalbuminuria in HIV-infected patients. To address Aim #1, we propose to perform a prospective, cohort study of HIV-infected subjects cared for at the Indiana University Medical Center. Specifically, ultrasound-measured flow mediated dilation of the brachial artery (a physiologic measurement of endothelial function), lipids, insulin and glucose levels, anthropometrics, lifestyle factors, and blood pressures of two HIV-infected groups (those with persistent proteinuria vs. those without proteinuria) will be compared at baseline and again in two years. Aim #2 will be addressed by performing a secondary analysis of a metabolic substudy (chaired by the principal investigator's primary mentor) of AIDS Clinical Trials Group study 384, which compared the use of protease inhibitor-based regimens with nonnucleoside reverse transcriptase-based regimens for the initial antiretroviral treatment of HIV-infected patients. Archived urine samples obtained at regular intervals through the duration of this substudy will be used to measure microalbuminuria levels. Taken together, the results of these studies will form the basis for future prevention and therapeutic trials targeted at both renal and cardiovascular diseases in HIV-infected patients. The proposed research will foster the principal investigator's clinical research career development, as supervised by established independent investigators (primary mentor: Michael P. Dub6) in the fields of HIV metabolic and renal complications, renal vascular and glomerular pathology, and clinical trials design and implementation.