Impact of Acute Kidney Injury on Kidney Disease Progression

描述（由申请人提供）： 这一特殊的拨款申请是为了响应寻求建立急性肾损伤（阿基）自然史联盟的资助机会公告而提交的，该联盟的主要目标是在阿基患者完成其疾病的急性期后跟踪其自然史，以与同期相关对照患者进行比较。阿基是住院患者常见的严重并发症。根据大型医疗保险数据库的信息，阿基的发病率在过去几十年中急剧增加，表明病例数量每年增加11%。虽然阿基的院内并发症已得到广泛研究，但阿基的长期后遗症，特别是其对导致终末期肾病的CKD发展和进展的贡献，尚未得到彻底评价。本提案的具体目的如下：具体目的#1：在危重患者的长期前瞻性队列研究中检查既往阿基病史对慢性肾脏疾病（CKD）进展的独立风险。我们假设，在入住重症监护室（ICU）的受试者中，与未诊断阿基的受试者相比，诊断阿基与CKD进展率较高（急性疾病恢复后）相关。具体目标2：在一项针对危重患者的长期前瞻性队列研究中，检查阿基既往史对氧化应激增加、慢性炎症和进行性心血管疾病发展的独立风险。我们假设，与ICU中未诊断为阿基的患者相比，阿基导致氧化应激负荷增加，并导致ICU中受影响患者的慢性炎症反应和心血管风险状况恶化。具体目标3：a）比较生物标志物组在高风险危重患者中阿基早期诊断中的相对和组合预测能力; B）确定相同生物标志物组是否预测阿基的严重程度（需要肾脏替代治疗、无透析存活率）和其他临床相关结局（死亡率和ICU/住院时间）。我们假设：1）在ICU中的患者的易感群体中基于AKIN标准诊断阿基时，包括在招募时获得的肾特异性损伤标志物（例如尿IL-18、NGAL、F2-异前列烷和血清/尿胱抑素C）的生物标志物组将上级单一标志物; ii）相同的生物标志物组在预测阿基的严重程度和其他临床相关结果方面上级单一标志物。为了实现拟定的目标，我们将从一个独特的新资源中招募500名受试者，即急性肺损伤诊断（VALID）研究中生物标志物的验证，这是一个大型（2550名受试者）前瞻性观察性队列，在整个ICU和剩余住院期间对异质性危重患者人群进行随访。

DESCRIPTION (provided by applicant): This particular grant application is submitted in response to the funding opportunity announcement that seeks to establish an Acute Kidney Injury (AKI) Natural History Consortium with the primary objective of following the natural history of patients with AKI after they finish the acute phase of their illness for comparison with concurrent relevant control patients. AKI is a common and serious complication in hospitalized patients. The incidence of AKI has increased dramatically over the past several decades based on information from large Medicare databases suggesting an increase in the number of cases by 11% per year. Whereas in-hospital complications of AKI have been extensively studied, the long-term sequelae of AKI, specifically its contribution to the development and progression of CKD leading to end-stage renal disease, have not been thoroughly evaluated. The specific aims of this proposal are as follows: SPECIFIC AIM #1: To examine the independent risk of prior history of AKI on chronic kidney disease (CKD) progression in a long-term prospective cohort study of critically ill patients. We hypothesize that the diagnosis of AKI is associated with a higher rate of progression of CKD (after the recovery of the acute illness) compared to no diagnosis of AKI in subjects admitted to intensive care unit (ICU). SPECIFIC AIM #2: To examine the independent risk of a prior history of AKI on the development of increased oxidative stress, chronic inflammation and progressive cardiovascular disease in a long-term prospective cohort study of critically ill patients. We hypothesize that AKI causes an increased oxidative stress burden and contributes to the chronic inflammatory response and worsened cardiovascular risk profiles of affected patients in the ICU compared to those without the diagnosis of AKI in the ICU. SPECIFIC AIM #3: a) To compare the relative and combined predictive capacities of a biomarker panel in the early diagnosis of AKI in high-risk critically ill patients; b) To determine if the same biomarker panel predicts the severity of AKI (need for renal replacement therapy, dialysis-free survival) and other clinically-relevant outcomes (mortality and ICU/hospital length of stay). We hypothesize that: 1) a biomarker panel that includes kidney specific markers of injury, such as urine IL-18, NGAL, F2- isoprostanes, and serum/urine cystatin C obtained at the time of enrollment will be superior to a single marker in diagnosing AKI based on AKIN criteria in a susceptible population of patients in the ICU; ii) Same biomarker panel will be superior to a single marker in predicting severity of AKI and other clinically-relevant outcomes. In order to achieve the proposed aims, we will recruit 500 subjects from a unique and novel resource, the Validation of biomarkers in Acute Lung Injury Diagnosis (VALID) study, a large (2550 subject) prospective observational cohort of a heterogeneous critically ill population followed throughout their ICU and remaining hospital stay.