Kidney Health Biomarker Panels for Drug Toxicity and Prognosis in HIV Infection

 描述(由申请人提供)：虽然艾滋病毒感染者的预期寿命更长，但人们正在经历越来越多的慢性肾脏疾病(CKD)负担。慢性肾脏病在HIV感染者中的发病年龄比未感染者年轻得多，并与心血管疾病、心力衰竭和死亡率的高得多的风险有关。富马酸替诺福韦(TDF)的广泛使用加剧了本已增加的肾脏疾病及其并发症的风险。富马酸替诺福韦目前在美国约三分之二的艾滋病毒感染者中使用，与替代疗法相比，这种药物独立地导致慢性肾脏病的风险增加一倍。在美国和全世界，含有TDF的疗法都是艾滋病毒长期治疗的一线药物。尽管慢性肾脏病作为艾滋病毒的并发症和TDF的肾脏风险很重要，但自艾滋病毒流行以来，目前肾脏疾病筛查和诊断的做法基本上没有变化。因此，我们缺乏有效的策略来检测TDF造成的早期肾脏损害，将TDF引起的肾脏损害与其他CKD危险因素区分开来，或者准确地量化CKD的发生和发展的风险。在我们最初的资助期间，我们的研究团队展示了几种肾脏损伤的尿液生物标志物在检测和量化亚临床肾脏损伤、表征特定风险因素的影响以及预测随后的肾功能下降方面的显著潜力。这一新方法可以极大地改变艾滋病毒感染者肾脏疾病的筛查、诊断和治疗过程。在这一更新的R01申请中，我们有一个改变实践的目标，即开发和验证两个不同的多重尿液生物标志物小组：替诺福韦损伤小组和CKD风险小组。我们将评估15种候选尿液生物标志物，它们可以量化肾脏不同区域内的损害和功能障碍，我们将选择最佳组合，以最大限度地提高：1)在早期阶段检测肾脏异常；2)识别TDF特异性损害；以及3)肾脏疾病风险的预后。为了完成我们的生物标记物组合的开发和验证阶段，我们将通过五项多中心研究进行研究，这些研究拥有可用的生物样本，并欢迎我们在这项提议上的合作：暴露前预防倡议试验(Iprex)、妇女机构间艾滋病毒研究(WIHS)、多中心艾滋病队列研究(MACS)、艾滋病肾病活组织检查(Bean)和了解有效治疗时代艾滋病毒/艾滋病自然史的研究(SUN)。我们的多学科专家调查团队将确保这一项目的成功。在其结论中，我们将设计一项随机临床试验，以确定我们检测、诊断和分期肾脏疾病的先进方法是否可以在不牺牲临床有效性的情况下提高艾滋病毒治疗的安全性。

 DESCRIPTION (provided by applicant): Although HIV-infected individuals are achieving greater life-expectancy, the population is experiencing a growing burden of chronic kidney disease (CKD). CKD develops at much younger ages in HIV-infected than uninfected persons, and is associated with substantially higher risks for cardiovascular disease, heart failure, and mortality. These already elevated risks of kidney disease and its complications are amplified by the widespread use of tenofovir disoproxil fumarate (TDF), which is currently used by approximately two-thirds of HIV-infected persons in the US, and is independently associated with a doubling in risk for CKD compared with alternative regimens. Both in the United States and worldwide, TDF-containing therapies are first-line for long- term therapy of HIV. Despite the importance of CKD as a complication of HIV and the kidney risks of TDF, current practices for kidney disease screening and diagnosis remain essentially unchanged since the beginning of the HIV epidemic. As a consequence we lack effective strategies to detect early kidney damage from TDF, to distinguish kidney damage caused by TDF from other CKD risk factors, or to quantify risk accurately for the onset and progression of CKD. During our initial funding period, our research team demonstrated the remarkable potential of several urine biomarkers of kidney injury to detect and quantify subclinical kidney damage, to characterize the influence of specific risk factors, and to forecast subsequent declines in kidney function. This novel approach could dramatically transform the process of screening, diagnosing and treating kidney disease in HIV-infected persons. In this renewal R01 application, we have the practice-changing objectives of developing and validating two distinct multiplex urine biomarker panels: the Tenofovir Injury Panel and the CKD Risk Panel. We will evaluate 15 candidate urine biomarkers that quantify damage and dysfunction within distinct compartments of the kidney, and we will select the optimal combinations to maximize: 1) detection of kidney abnormalities at their earliest stages; 2) discernment of TDF specific damage; and 3) prognosis of kidney disease risk. To accomplish both development and validation stages for our biomarker combinations, we will conduct our research across five multi-center studies that have available biological specimens and that have welcomed our collaboration on this proposal: the Preexposure Prophylaxis Initiative trial (iPrEx), the Women's Interagency HIV Study (WIHS), the Multicenter AIDS Cohort Study (MACS), the Biopsy Examination of AIDS Nephropathy (BEANS), and the Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN). Our multi-disciplinary team of expert investigators will ensure the success of this project. At its conclusion we will design a randomized clinical trial to determine whether our advanced methods to detect, diagnose and stage kidney disease can improve the safety of HIV therapy without sacrificing its clinical effectiveness.