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（由申请人提供）：急性肾损伤（阿基）在HIV感染者中极为常见，每6名患者中就有1名受到影响。阿基会显著增加以下风险： 心血管疾病、终末期肾病和艾滋病毒感染者的死亡率。为了解决艾滋病毒感染人群中阿基及其不良后果的不成比例的风险，需要采取策略来识别阿基及其后果风险最高的患者。这些方法需要针对艾滋病毒感染者量身定制，因为他们的阿基和进行性肾脏疾病的风险因素与一般人群不同。然而，阿基的干预措施失败了，部分原因是阿基诊断依赖于血清肌酐，血清肌酐仅在发生严重肾损伤后才升高。尽管新的尿生物标志物有希望用于早期阿基诊断，但目前，它们的临床应用受到目前用于测量它们的技术的极大阻碍，这些技术是缓慢的，具有受限的可检测范围，并且单独测量生物标志物。 约翰霍普金斯HIV临床队列研究（JHHCC）提供了一个独特的机会，可以在HIV感染人群中研究新型肾损伤生物标志物与阿基和相关不良健康结局的相关性。JHHCC拥有特征良好的HIV感染患者人群和高度集成的系统，能够收集阿基研究中必不可少的门诊和住院数据以及生物标本。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）确定非卧床肾损伤与住院临床阿基事件和阿基后进行性肾脏疾病的相关性; 2）调查住院HIV感染者中亚临床和临床阿基的患病率及其与住院后进行性肾脏疾病的相关性;和3）开发和验证一种预测模型，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，将区分突发阿基和随后进行性肾病的风险。我们将在门诊访视时和目的1和2中住院期间连续测量肾脏内皮和肾小管间质损伤、炎症和纤维化的尿液生物标志物。然后，我们将利用目标1和2中观察到的相关性来指导临床适应性多重尿液生物标志物组的开发。该小组将与临床变量相结合，以开发一种区分艾滋病毒感染者中阿基和随后肾脏疾病进展风险的模型。这项研究将大大提高我们对亚临床和临床阿基及其对HIV感染者不良健康结局的影响的理解。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，然后可以在临床试验中作为筛选工具进行测试，将阿基的早期管理或阿基后的强化管理与当前的护理标准以及阿基早期治疗候选者的替代终点进行比较。