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

基于生物标志物的诊断算法，用于预防、检测和指导 HIV 感染者肾脏疾病的治疗

• 批准号: 10666457
• 负责人: Michelle M Estrella
• 金额: $ 74.62万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666457
• 关键词: Abate; Acceleration; Acute; Address; Affect; Algorithms; Anti-Retroviral Agents; Bayesian Analysis; Benign; Biological Markers; Caring; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Cohort Studies; Computational algorithm; Creatinine; Data; Deterioration; Diagnosis; Diagnostic; Diagnostic tests; Dimensions; Early Diagnosis; Event; Face; Factor Analysis; Future; Goals; HIV; HIV Infections; Health; Individual; Inflammation; Influentials; Injury; Injury to Kidney; Intervention; Investigation; Kidney; Kidney Diseases; Learning; Maps; Measures; Mediating; Metabolic; Mission; Monitor; Morbidity - disease rate; Nephrons; Outcome; Patients; Pattern; Persons; Pharmaceutical Preparations; Phase; Population; Prevention; Prevention strategy; Preventive; Probability; Prognosis; Proteins; Renal function; Renal tubule structure; Research Personnel; Risk; Risk Factors; Risk Reduction; Safety; Serum; Severities; Site; Surrogate Markers; System; Tenofovir; Testing; The Multicenter AIDS Cohort Study; Time; Toxic effect; Tubular formation; Update; Urine; Viral; Women' s Interagency HIV Study; Work; aggressive therapy; biomarker identification; biomarker panel; candidate identification; cardiovascular disorder risk; clinical care; clinical practice; clinical risk; clinical translation; cohort; comorbidity; diagnostic algorithm; diagnostic biomarker; diagnostic strategy; disease diagnosis; experience; follow-up; functional decline; health assessment; hemodynamics; high risk; high risk population; improved; individualized prevention; modifiable risk; mortality; multidisciplinary; nephrotoxicity; novel marker; novel strategies; personalized predictions; predictive tools; prevent; prognostic; prognostic significance; prognostication; progression risk; renal damage; success; targeted treatment; tool; treatment response; treatment strategy; vascular risk factor

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.

抽象的 我们预防、检测和监测艾滋病毒感染者 (PLWH) 肾病的策略 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。 尽管已证明血清肌酐和肾病诊断在诊断慢性肾病 (CKD) 方面存在局限性，但 蛋白质尿浓度仍然是感染者临床肾脏健康监测的支柱。 诊断检测停滞不前，感染者的肾脏面临着越来越多的损害，包括 代谢和血管危险因素、慢性炎症、直接病毒毒性和潜在肾毒性 经检查，CKD 已成为 PLWH 发病率和死亡率的一个原因。 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 与传统肾脏健康相比，可以获得更多的诊断和预后信息 此竞争性更新申请将建立在之前的工作基础上，以完成我们的使命： 该提案从战略上改变了肾脏疾病的检测、诊断和监测方式。 解决 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到临床实践中。 我们的目标的成功完成和临床转化将实现以下主要目标 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 并非该人患有真正的肾损伤，并确定预测肾损伤可能性的损伤模式 在后续随访期间肾功能恢复或恶化（目标 2）对于每个可修改的肾脏。 PLWH 的疾病风险因素，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）。 更新的算法将整合危险因素和肾脏生物标志物的动态变化来进行预测 每个 PLWH 的快速进展性肾脏疾病风险的纵向变化（目标 2b）。 许多感染者接触过多种可能威胁或降低进展性肾病风险的感染者，我们将 利用基于生物标记的新型监测算法来识别每个风险因素并根据其优先顺序 尽管有这些雄心勃勃的目标，但造成观察到的肾脏损害模式和严重程度的贝叶斯概率。 目标，这个建议既可行又有效，因为我们将使用已经被研究过的生物样本和临床数据。 或将在多中心艾滋病队列研究 (MACS)、妇女机构间艾滋病毒研究中从 PLWH 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子 研究（巴黎）队列的研究人员是一个多学科的专家团队，他们带来了巨大的成果。 对提案的热情、经验和承诺将保证其成功。

项目成果

Tenofovir exposure alters associations of serum bicarbonate with chronic kidney disease risk in HIV-infected veterans.

替诺福韦暴露改变了感染艾滋病毒的退伍军人血清碳酸氢盐与慢性肾病风险的关联。

• 发表时间: 2016-04-24
• 作者: Kim, Julie E;Scherzer, Rebecca;Estrella, Michelle M;Ix, Joachim H;Shlipak, Michael G
• 通讯作者: Shlipak, Michael G

Associations of tumor necrosis factor alpha receptor type 1 with kidney function decline, cardiovascular events, and mortality risk in persons with coronary artery disease: Data from the Heart and Soul Study.

肿瘤坏死因子 α 受体 1 型与冠状动脉疾病患者肾功能下降、心血管事件和死亡风险的关联：来自心与灵魂研究的数据。

• DOI: 10.1016/j.atherosclerosis.2017.05.021
• 发表时间: 2017-08
• 期刊: Atherosclerosis
• 影响因子: 5.3
• 作者: Park M;Maristany D;Huang D;Shlipak MG;Whooley M
• 通讯作者: Whooley M

Urine Biomarkers of Kidney Tubule Health and Incident CKD Stage 3 in Women Living With HIV: A Repeated Measures Study.

HIV 感染女性肾小管健康和 CKD 第 3 期事件的尿液生物标志物：重复测量研究。

• 发表时间: 2021-05
• 影响因子: 3.9
• 作者: Ascher, Simon B;Scherzer, Rebecca;Estrella, Michelle M;Jotwani, Vasantha K;Shigenaga, Judy;Spaulding, Kimberly A;Ng, Derek K;Gustafson, Deborah;Spence, Amanda B;Sharma, Anjali;Cohen, Mardge H;Parikh, Chirag R;Ix, Joachim H;Shlipak, Michael G
• 通讯作者: Shlipak, Michael G

Kidney Disease, Income, and Life Expectancy.

肾脏疾病、收入和预期寿命。

• DOI: 10.1053/j.ajkd.2016.07.004
• 发表时间: 2016-11-01
• 期刊: American journal of kidney diseases : the official journal of the National Kidney Foundation
• 作者: Joshua Lang;M. Shlipak
• 通讯作者: M. Shlipak

Detection of chronic kidney disease with creatinine, cystatin C, and urine albumin-to-creatinine ratio and association with progression to end-stage renal disease and mortality.

• DOI: 10.1001/jama.2011.468
• 发表时间: 2011-04-20
• 期刊: JAMA
• 作者: Peralta, Carmen A.;Shlipak, Michael G.;Judd, Suzanne;Cushman, Mary;McClellan, William;Zakai, Neil A.;Safford, Monika M.;Zhang, Xiao;Muntner, Paul;Warnock, David
• 通讯作者: Warnock, David