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

 描述(由申请人提供)：急性肾损伤(AKI)在艾滋病毒感染者中非常常见，每6名患者中就有1名患者受到影响。Aki极大地增加了 艾滋病毒感染者中的心血管疾病、终末期肾病和死亡率。为了应对艾滋病毒感染人群中AKI及其不良后果的不成比例的风险，需要制定战略来确定AKI及其后果风险最高的患者。这些方法需要为艾滋病毒感染者量身定做，因为他们患急性肾功能衰竭和进行性肾脏疾病的危险因素与普通人群不同。然而，对AKI的干预失败了，部分原因是AKI诊断依赖于血清肌酐，只有在发生实质性肾脏损害后，血清肌酐才会上升。尽管新的尿液生物标记物有望用于AKI的早期诊断，但目前它们的临床应用受到目前用于测量它们的技术的严重阻碍，这些技术速度慢，检测范围有限，并且孤立地测量生物标记物。约翰霍普金斯大学HIV临床队列(JHHCC)提供了一个独特的机会来研究新的肾脏损伤生物标记物与AKI的关系以及HIV感染人群中相关的不良健康后果。JHCC有一个特征良好的艾滋病毒感染患者群体，以及一个高度集成的系统，能够收集动态和住院数据以及生物显微镜，这在AKI研究中是必不可少的。在这项建议中，我们将利用JHCC内的广泛资源来实现以下目标：1)确定动态肾脏损害与住院的临床AKI和AKI后进展性肾脏疾病的相关性；2)调查住院的HIV感染者中亚临床和临床AKI的患病率及其与住院后进展性肾脏疾病的相关性；以及3)开发和验证一个预测模型，该模型集成了一组互补的、信息丰富的尿液生物标志物和临床变量，将区分AKI事件和随后的进展性肾脏疾病的风险。在AIMS 1和AIMS 2中，我们将在门诊和住院期间连续检测肾内皮细胞和肾小管间质损伤、炎症和纤维化的尿液生物标记物。然后，我们将利用AIMS 1和2中观察到的相关性来指导临床适用的尿液生物标记物多元化小组的发展。这一小组将与临床变量相结合，以开发一个模型，以区分艾滋病毒感染者中AKI和随后的肾脏疾病进展的风险。这项研究将极大地提高我们对亚临床和临床AKI及其对HIV感染者不良健康后果的贡献的了解。我们的研究将产生一个包含多重HIV-AKI风险小组的预测模型，然后可以在临床试验中测试该模型作为筛查工具，将AKI的早期治疗或AKI后的强化治疗与当前的护理标准进行比较，以及作为AKI早期治疗候选者的替代终点。

 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.