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: 8922736
• 负责人: Michelle M Estrella
• 金额: $ 75.91万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8922736
• 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; 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; cardiovascular disorder risk; clinical application; cohort; follow-up; high risk; mortality; novel; predictive modeling; prognostic value; public health relevance; 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（由申请人提供）：急性肾损伤 (AKI) 在 HIV 感染者中极为常见，每 6 名患者中就有 1 人患有 AKI，严重增加了患 AKI 的风险。 HIV 感染者的心血管疾病、终末期肾病和死亡率 为了解决 HIV 感染人群中 AKI 及其后果的过高风险，需要制定策略来识别 AKI 及其后果风险最高的患者。需要针对 HIV 感染者进行定制，因为他们的 AKI 和进行性肾病的危险因素与普通人群不同。然而，AKI 干预措施失败的部分原因是 AKI 诊断依赖于血清肌酐，而血清肌酐仅在感染后才会升高。尽管新型尿液生物标志物有望用于早期 AKI 诊断，但目前其临床应用受到目前用于测量这些生物标志物的技术的严重阻碍，这些技术速度慢、可检测范围有限且单独测量生物标志物。约翰·霍普金斯大学 HIV 临床队列 (JHHCC) 提供了一个独特的机会，可以研究新型肾损伤生物标志物与 HIV 感染人群中 AKI 及相关不良健康结果的关联。JHHCC 拥有一个特征明确的 HIV 感染人群。患者和高度集成的系统，能够收集 AKI 研究中必不可少的门诊和住院数据以及生物样本。 在本提案中，我们将利用 JHHCC 内的广泛资源来实现以下目标：1)确定动态肾损伤与住院临床 AKI 和 AKI 后进行性肾病的关联 2) 调查住院 HIV 感染者中亚临床和临床 AKI 的患病率及其与 AKI 后进行性肾病的关系；住院治疗；3) 开发和验证一个预测模型，该模型整合了一组互补的、信息丰富的尿液生物标志物和临床变量，以区分 AKI 事件和随后进行性肾病的风险。我们将测量肾内皮和肾小管间质损伤的尿液生物标志物。目标 1 和 2 中门诊就诊时以及住院期间的炎症和纤维化。然后，我们将利用目标 1 和 2 中观察到的关联来指导临床适应性的开发该组将与临床变量相结合，开发一个区分 HIV 感染者 AKI 和随后肾脏疾病进展的风险的模型。这项研究将极大地增强我们对亚临床和临床 AKI 及其贡献的理解。我们的研究将产生一个预测模型，其中包含多重 HIV-AKI 风险小组，然后可以在临床试验中将其作为筛选工具进行测试，比较 AKI 的早期治疗或 AKI 后的强化治疗与早期治疗。当前的护理标准以及 AKI 早期治疗候选者的替代终点。