Clinical and molecular epidemiology of acute kidney injury after lung transplant

项目摘要/摘要 急性肾损伤(AKI)是指肾功能在几天内迅速丧失，高达70%的肺移植患者会发生这种情况。 术后受者远比心脏手术后更常见，尽管有更年轻的 几乎没有预先存在的慢性肾脏疾病(CKD)。而移植后的AKI与随后的 慢性肾脏病与死亡率，尚不清楚AKI是独立影响预后，还是仅仅是肺部的一种附带现象 同种异体移植功能障碍和其他早期移植并发症。移植后急性心肌梗死的流行病学知识 仅限于相对较小的、回溯性的单中心研究，对AKI风险因素的评估有限。 阐明AKI对预后的独立影响，并确定AKI的高危患者，特别是 严重的形式与慢性肾脏病和死亡率有更强的联系，这是至关重要的，因为肾脏保护策略 液体注射对同种异体移植物有风险。血液和尿液生物标记物已显示出对AKI的预测作用 在危重疾病和心脏手术人群中，但尚未在肺移植患者中进行研究。这些 预测性标记物也可能阐明这一人群AKI高发病率背后的机制。 肺移植结果组(LTOG)是由美国国立卫生研究院资助的多中心前瞻性队列研究，始于 2002年，由我们的机构协调设计，旨在研究小儿麻痹症的临床和分子流行病学 移植物功能障碍(PGD)是一种急性肺移植损伤综合征。有了2000年的注册，LTOG是独一无二的 适用于支持AKI流行病学的辅助多中心研究。我们进行了临床和临床试验研究 一小部分LTOG受试者中AKI的血浆生物标记物危险因素。基于这些研究和现有的 文献中，我们假设不同的临床和分子特征与AKI有关 肺移植后，与AKI发病机制有关。我们进一步假设这些 特征可用于预测AKI风险，以确定降低风险策略的候选者。 利用LTOG的健壮多中心结构进行规模是迄今为止最大的3倍的研究， 我们在肺移植人群中提出了以下目标：1)确定临床危险因素和 AKI的结果，2)确定已建立的和新的血浆和尿液生物标记物的相关性 AKI，以及3)推导和验证AKI的预测模型。这项建议充分利用了这项研究 已经对LTOG进行了投资，以产生继肺之后对AKI的第一个全面研究 移植以建立AKI对预后的独立影响，确定可修改的AKI危险因素， 确定与AKI相关的血浆和尿液分子标志物，并启用AKI预测。已完成的 AIMS将在LTOG内创建一个灵活的基础设施，以支持当前和新的肾脏保护试验 针对高危患者的移植围手术期管理策略，最终目标是减少慢性肾脏病 负担，最大限度地提高肺移植的长期成功。此外，我们的探索性研究发现 新的AKI生物标志物可能会检测到新的预测因子，并为未来的研究指明有针对性的AKI机制。

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI), rapid loss of renal function over several days, occurs in up to 70% of lung transplant recipients postoperatively, far more common than after cardiac surgery despite a younger population with almost no pre-existing chronic kidney disease (CKD). While post-transplant AKI is associated with subsequent CKD and mortality, it is unclear if AKI impacts outcomes independently or is simply an epiphenomenon of lung allograft dysfunction and other early transplant complications. Knowledge of post-transplant AKI epidemiology is limited to relatively small, retrospective, single-center studies with limited assessment of AKI risk factors. Clarifying AKI’s independent impact on outcomes and identifying patients at high risk of AKI, particularly the severe forms more strongly linked to CKD and mortality, is critical since renal-protective strategies such as fluid administration carry risk to the allograft. Blood and urine biomarkers have shown predictive utility for AKI in critical illness and cardiac surgery populations but have not been studied in lung transplant patients. These predictive markers may also shed light on mechanisms underlying the high rate of AKI in this population. The Lung Transplant Outcomes Group (LTOG) is an NIH-funded multicenter prospective cohort started in 2002, coordinated by our institution and designed to study the clinical and molecular epidemiology of primary graft dysfunction (PGD), an acute lung allograft injury syndrome. With enrollment >2000, the LTOG is uniquely suited to support an ancillary, multicenter study of AKI epidemiology. We conducted pilot studies of clinical and plasma biomarker risk factors for AKI in a small group of LTOG subjects. Based on these studies and existing literature, we hypothesize that distinct clinical and molecular characteristics are associated with AKI after lung transplantation, with implications for AKI pathogenesis. We further hypothesize that these characteristics can be used to predict AKI risk to identify candidates for risk reduction strategies. Utilizing the robust multicenter structure of the LTOG to conduct a study 3 times the size of the largest to date, we propose the following aims in the lung transplant population: 1) Determine clinical risk factors for and outcomes of AKI, 2) Determine the association of established and novel plasma and urine biomarkers with AKI, and 3) Derive and validate predictive models for AKI. This proposal leverages the research investments already made in the LTOG in order to produce the first comprehensive study of AKI after lung transplant to establish the independent impact of AKI on outcomes, determine modifiable AKI risk factors, identify plasma and urine molecular markers associated with AKI, and enable AKI prediction. Completion of the aims will create a flexible infrastructure within the LTOG to support trials of current and novel renal-protective peri-transplant management strategies targeted to high-risk patients, with the ultimate goals of reducing CKD burden and maximizing the long-term success of lung transplant. In addition, our exploratory studies to identify novel AKI biomarkers may detect new predictors and point toward targetable AKI mechanisms for future study.