Biomarker-Based Diagnostic Algorithms To Prevent, Detect And Guide Treatment Of Kidney Disease In Persons Living With HIV

摘要 我们预防、检测和监测HIV感染者（PLWH）肾脏疾病的策略 远远落后于过去几十年来艾滋病毒治疗和管理方面令人难以置信的进步。 尽管它们在诊断慢性肾脏疾病（CKD）方面被证明是有局限性的，但血清肌酐和 尿蛋白浓度仍然是PLWH肾脏健康监测的主要内容。虽然临床肾 诊断测试停滞不前，PLWH面临越来越多的肾脏损害，包括 代谢和血管风险因素、慢性炎症、直接病毒毒性和潜在肾毒性 药物治疗因此，CKD已加速成为PLWH发病率和死亡率的原因。 在过去的十年中，我们在PLWH方面的开创性工作表明，肾小管健康的生物标志物产生 比常规肾脏健康检查获得的诊断和预后信息更多 评估。此竞争性续约申请将建立在此之前的工作，以完成我们的使命， 从根本上改变了肾脏疾病的检测、诊断和监测方式。这一战略建议 解决了CKD诊断和治疗中最具挑战性的方面，并将提供证据 需要将基于肾脏生物标志物的诊断算法推进临床实践。 我们的目标的成功完成和临床翻译将使临床医生实现以下主要目标 目标. 1)在血清肌酐急性升高的PLWH中，我们将能够区分是否或 不是个人有真正的肾损伤，并确定损伤的模式，预测的可能性， 在后续随访期间肾功能恢复或恶化（目标1）。2)对于每个可变肾脏 疾病风险因素，我们将能够监测风险改善和恶化的影响， 使用一组定制的替代生物标志物对肾脏进行因子控制（目标2a）。3)我们会利用一段时间- 更新的算法，将整合风险因素和肾脏生物标志物的动态变化， 对于每个PLWH个体，快速进展性肾脏疾病风险的纵向变化（目标2b）。4)为 许多PLWH有无数的风险，威胁或降低风险的进行性肾脏疾病，我们将 利用一种新的基于生物标志物的监测算法，根据其 导致观察到的肾损伤模式和严重程度的贝叶斯概率。尽管这些雄心勃勃的 目标，这项建议是可行和有效的，因为我们将使用生物标本和临床数据， 或将在多中心艾滋病队列研究（MACS）、妇女跨机构艾滋病毒研究（MACS）中的艾滋病毒感染者中收集。 研究（WIHS）、MACS-WIHS联合队列研究（MWCCS）和急性肾损伤的预测因素 研究（巴黎）队列。研究人员是一个多学科的专家团队，他们带来了巨大的 热情，经验和承诺的建议，并将保证其成功。

ABSTRACT Our strategies for preventing, detecting, and monitoring kidney disease in people living with HIV (PLWH) have lagged far behind the incredible advances in HIV treatment and management over the past decades. Despite their proven limitations for diagnosing chronic kidney disease (CKD), the serum creatinine and the urine protein concentration remain the mainstays of kidney health monitoring for PLWH. While clinical kidney diagnostic testing has stagnated, PLWH face an increasing myriad of insults to the kidneys, including metabolic and vascular risk factors, chronic inflammation, direct viral toxicity, and potentially nephrotoxic medications. Consequently, CKD has accelerated as a cause of morbidity and mortality in PLWH. Over the past decade, our pioneering work in PLWH has shown that biomarkers of tubule health yield significantly more diagnostic and prognostic information than could be obtained by conventional kidney health assessments. This competitive renewal application will build upon this prior work to fulfill our mission of fundamentally changing how kidney disease is detected, diagnosed and monitored. This proposal strategically addresses the most challenging aspects of CKD diagnosis and treatment, and will provide the evidence needed to advance kidney biomarker-based diagnostic algorithms into clinical practice. Successful completion and clinical translation of our Aims will allow clinicians to achieve the following major goals. 1) Among PLWH with acute elevations of the serum creatinine, we will be able to distinguish whether or not the individual has true kidney injury and to identify the patterns of injury that forecast the likelihood of kidney function recovering or worsening during subsequent follow-up (Aim 1). 2) For each modifiable kidney disease risk factor in PLWH, we will be able to monitor the impact of improvements and deteriorations in risk factor control on the kidney, using a tailored set of surrogate biomarkers (Aim 2a). 3) We will use a time- updated algorithm that will integrate dynamic changes in risk factors and kidney biomarkers to prognosticate longitudinal changes in risk for rapidly progressive kidney disease, for each individual PLWH (Aim 2b). 4) For the many PLWH with myriad exposures that threaten or lower risk for progressive kidney disease, we will utilize a novel biomarker-based monitoring algorithm to identify and prioritize each risk factor based on its Bayesian probability of causing the observed pattern and severity of kidney damage. Despite these ambitious goals, this proposal is both feasible and efficient as we will use biospecimens and clinical data that have been or will be collected among PLWH in the Multicenter AIDS Cohort Study (MACS), the Women’s Interagency HIV Study (WIHS), the MACS-WIHS Combined Cohort Study (MWCCS), and the Predictors of Acute Renal Injury Study (PARIS) cohorts. The study investigators are a multi-disciplinary team of experts who bring enormous enthusiasm, experience and commitment to the proposal and will guarantee its success.