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。 尽管已被证明在诊断慢性肾脏疾病(CKD)方面存在局限性，但血清肌酐和 尿蛋白浓度仍然是PLWH肾脏健康监测的主要指标。而临床肾脏 诊断检测已经停滞不前，PLWH面临着越来越多对肾脏的侮辱，包括 代谢和血管危险因素、慢性炎症、直接病毒毒性和潜在的肾毒性 药物。因此，慢性肾脏病加速成为PLWH发病和死亡的原因之一。 在过去的十年里，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了 与传统的肾脏健康相比，可以获得更多的诊断和预后信息 评估。此竞争性续订申请将建立在先前工作的基础上，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。这一建议具有战略意义 解决慢性肾脏病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记物的诊断算法推向临床实践。 我们的目标的成功完成和临床转化将使临床医生能够实现以下主要目标 目标。1)在伴有血清肌酐急性升高的PLWH中，我们将能够区分 不是真正有肾脏损伤的个体，要确定损伤的模式，以预测发生 随访期间肾功能恢复或恶化(目标1)。2)每个可修改的肾脏 疾病风险因素，我们将能够监测风险改善和恶化的影响 使用一套量身定制的替代生物标记物对肾脏进行因子控制(目标2a)。3)我们将利用时间- 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来预测 快速进展性肾脏疾病风险的纵向变化，每个PLWH个体(目标2b)。4)用于 许多PLWH与无数接触威胁或降低进行性肾脏疾病的风险，我们将 利用一种新的基于生物标志物的监测算法来识别每个风险因素并根据其 造成观察到的肾脏损害模式和严重程度的贝叶斯概率。尽管有这些雄心壮志 目标，这项建议是可行和有效的，因为我们将使用生物制品和已经被 或将在多中心艾滋病队列研究(MACS)中从PLWH中收集，即妇女机构间艾滋病毒 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。研究调查人员是一个多学科的专家团队，他们带来了巨大的 对这项提议的热情、经验和承诺将保证其成功。

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.