Biomarkers of Kidney Injury to Predict AKI Onset and Progression in HIV Infection

肾损伤的生物标志物可预测 AKI 的发生和 HIV 感染的进展

• 批准号: 9099842
• 负责人: Michelle M Estrella
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099842
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Affect; Albuminuria; Biological Markers; CCL2 gene; Cardiovascular Diseases; Caring; Cessation of life; Chronic; Clinical; Clinical Trials; Collagen Type IV; Collection; Creatinine; Data; Development; Diagnosis; Disease Progression; End stage renal failure; Fibrosis; Functional disorder; General Population; HIV; HIV Infections; Health; Hospitalization; Hospitals; Individual; Inflammation; Injury; Injury to Kidney; Inpatients; Interleukin-18; Intervention; Kidney; Kidney Diseases; LCN2 gene; Measures; Methods; Modeling; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Outpatients; Patients; Persons; Phase; Population; Prevalence; Recovery; Renal function; Research Infrastructure; Resources; Risk; Risk Factors; Serum; Surrogate Endpoint; System; Techniques; Testing; Therapeutic; Urine; Visit; Work; adverse outcome; alpha-1-microglobulin; cardiovascular disorder risk; clinical application; cohort; follow-up; high risk; mortality; novel; predictive modeling; prognostic value; screening; tool; trial comparing; urinary

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is extremely common among HIV-infected individuals, affecting 1 in 6 patients. AKI substantially increases the risk for cardiovascular disease, end-stage renal disease and mortality among HIV-infected persons. To address the disproportionate risk of AKI and its adverse consequences in the HIV- infected population, strategies are needed to identify patients at highest risk of AKI and its consequences. These methods need to be tailored for HIV-infected persons as their risk factors for AKI and progressive kidney disease are distinct from the general population. Interventions for AKI have failed, however, in part due to the reliance for AKI diagnosis on serum creatinine which rises only after substantial kidney damage has already occurred. Despite the promise of novel urine biomarkers for early AKI diagnosis, at present, their clinical application is considerably hampered by the techniques currently used to measure them which are slow, have constrained detectable ranges, and measure biomarkers in isolation. The Johns Hopkins HIV Clinical Cohort (JHHCC) represents a unique opportunity to examine the associations of novel kidney injury biomarkers with AKI and related adverse health outcomes in the HIV- infected population. The JHHCC has a well-characterized population of HIV-infected patients and a highly integrated system that enables the collection of ambulatory and inpatient data as well as biospecimens which are imperative in the study of AKI. In this proposal, we will leverage the extensive resources within the JHHCC to achieve the following Aims: 1) to determine the association of ambulatory kidney damage with incident hospitalized clinical AKI and progressive kidney disease after AKI; 2) to investigate the prevalence of subclinical and clinical AKI among hospitalized HIV-infected individuals and their associations with progressive kidney disease after hospitalization; and 3) to develop and validate a predictive model which integrates a multiplex panel of complementary, informative urine biomarkers and clinical variables that will distinguish risk for incident AKI and subsequent progressive kidney disease. We will measure urine biomarkers of kidney endothelial and tubulointerstitial injury, inflammation and fibrosis at ambulatory visits and serially during hospitalizations in Aims 1 and 2. We will then utilize the observed associations in Aims 1 and 2 to guide the development of a clinically adaptable multiplex panel of urine biomarkers. This panel will be combined with clinical variables to develop a model that distinguishes the risk of AKI and subsequent kidney disease progression among HIV-infected persons. This study will greatly enhance our understanding of subclinical and clinical AKI and their contribution to adverse health outcomes among HIV-infected persons. Our study will yield a predictive model which incorporates the multiplex HIV-AKI Risk Panel which could then be tested as a screening tool in clinical trials comparing early management of AKI or intensive management after AKI with the current standards of care as well as a surrogate endpoint for early phase therapeutic candidates for AKI.

 描述（由应用提供）：在感染HIV的个体中，急性肾脏损伤（AKI）极为常见，影响了6例中有1例。 AKI大大增加了 艾滋病毒感染者的心血管疾病，终末期肾脏疾病和死亡率。为了解决AKI的不成比例风险及其在艾滋病毒感染人群中的不利后果，需要采取策略来识别患有AKI及其后果风险最高的患者。这些方法需要针对感染HIV的人量身定制，因为其AKI和进行性肾脏疾病的风险因素与一般人群不同。但是，AKI的干预措施失败了，部分原因是AKI诊断对血清Crectioninine的依赖，该诊断仅在发生了大量肾脏损伤后才上升。尽管有新型尿液生物标志物对早期AKI诊断有望，但目前，他们的临床应用被当前用于测量缓慢的技术的技术妨碍了它们的临床应用，具有约束的可检测范围，并隔离了生物标志物。约翰·霍普金斯（Johns Hopkins）艾滋病毒临床队列（JHHCC）代表了一个独特的机会，可以检查新型肾脏损伤生物标志物与HIV感染人群中AKI和相关不良健康结果的关联。 JHHCC具有良好的HIV感染患者人群，并且具有高度综合的系统，该系统可以收集卧床和住院数据，以及在AKI研究中必须进行的生物测量。在此提案中，我们将利用JHHCC内的广泛资源来实现以下目的：1）确定ABS肾脏损害与AKI后住院的临床AKI和进步性肾脏疾病的关联； 2）调查住院的HIV感染者及其与住院后进行性肾脏疾病的关联中亚临床和临床AKI的患病率； 3）开发和验证一个预测模型，该模型整合了一个完整的，信息丰富的尿液生物标志物和临床变量的多重小组，该模型将区分出现AKI的风险和随后的进行性肾脏疾病。我们将在AIMS 1和2中的住院期间测量肾脏内皮和肾小管间质损伤，感染和纤维化的尿液生物标志物，并在住院期间连续进行连续。然后，我们将在AIMS 1和2中使用观察到的关联来指导URINE Biomarkers的临床适应性多发性小组的发展。该小组将与临床变量结合使用，以开发一个模型，该模型区分了AKI的风险以及随后感染HIV的人群的肾脏疾病进展。这项研究将大大增强我们对亚临床和临床AKI的理解及其对艾滋病毒感染者不良健康结果的贡献。我们的研究将产生一个预测模型，该模型结合了多重HIV-AKI风险面板，然后在AKI与当前的护理标准以及AKI早期阶段治疗候选者的替代端点后，可以在临床试验中对筛查工具进行测试，以比较AKI或强化管理的早期管理。