Clinical and molecular epidemiology of acute kidney injury after lung transplant

肺移植术后急性肾损伤的临床和分子流行病学

• 批准号: 9751843
• 负责人: Michael G. S. Shashaty
• 金额: $ 67.94万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751843
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Age; Allografting; Back; Biological Markers; Blood; Calcineurin inhibitor; Cardiac Surgery procedures; Cessation of life; Characteristics; Chronic; Chronic Kidney Failure; Clinical; Clinical Data; Coagulation Process; Comorbidity; Complication; Critical Illness; Cystic Fibrosis; Data; Diagnosis; Dialysis procedure; Enrollment; Epidemiology; Functional disorder; Funding; Future; Goals; Hour; Human; Incidence; Infrastructure; Injury; Institution; Investments; Kidney; Kidney Transplantation; Knowledge; Lead; Life; Light; Link; Liquid substance; Literature; Low Prevalence; Lung; Lung Transplantation; Lung diseases; Mediator of activation protein; Medicare; Modeling; Molecular; Molecular Epidemiology; Multicenter Studies; Obesity; Outcome; Pathogenesis; Patients; Pennsylvania; Perioperative; Phase; Phenotype; Pilot Projects; Plasma; Plasma Proteins; Plasminogen Activator Inhibitor 1; Population; Populations at Risk; Positioning Attribute; Postoperative Period; Prevention strategy; Prospective cohort; Prospective cohort study; Protein C; Proteins; Proteomics; Pulmonary Emphysema; Pulmonary Fibrosis; Quality of life; Renal Replacement Therapy; Renal function; Reperfusion Injury; Reperfusion Therapy; Research; Resources; Risk; Risk Factors; Risk Reduction; Sampling; Savings; Severities; Site; Specimen; Structure; Syndrome; Testing; Therapeutic Trials; Thrombomodulin; Time; Transplant Recipients; Transplantation; United States National Institutes of Health; Universities; Urine; base; burden of illness; candidate marker; clinical epidemiology; clinical risk; cohort; cost; cystic fibrosis patients; design; disorder risk; effective therapy; endothelial dysfunction; flexibility; high risk; high risk population; improved; lung allograft; molecular marker; mortality; mortality risk; novel; operation; patient subsets; post-transplant; pre-clinical; predictive marker; predictive modeling; prevent; prospective; renal damage; renal ischemia; success; therapeutic target; translational study; transplant centers; treatment strategy

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.

项目摘要/摘要 急性肾损伤（阿基）是指肾功能在几天内迅速丧失，发生在高达70%的肺移植中。 接受者术后，远比心脏手术后更常见，尽管年轻人群， 几乎没有预先存在的慢性肾脏疾病（CKD）。虽然移植后阿基与随后的 CKD和死亡率，尚不清楚阿基是否独立影响结局或仅是肺损伤的附带现象。 同种异体移植物功能障碍和其他早期移植并发症。移植后阿基流行病学知识 仅限于相对较小的回顾性单中心研究，对阿基风险因素的评估有限。 阐明阿基对结局的独立影响，并识别阿基高风险患者，特别是 严重形式与CKD和死亡率密切相关，这是至关重要的，因为肾脏保护策略， 液体给药对同种异体移植物有风险。血液和尿液生物标志物显示出对阿基的预测效用 在危重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 预测标记物也可能揭示该人群中阿基高发病率的潜在机制。 肺移植结局组（LTOG）是一个由NIH资助的多中心前瞻性队列研究，始于年。 2002年，由我们的机构协调，旨在研究原发性肝癌的临床和分子流行病学， 移植物功能障碍（PGD），一种急性肺移植物损伤综合征。随着入学人数>2000，LTOG是唯一的 适用于支持阿基流行病学的辅助、多中心研究。我们进行了临床试验， 一小组LTOG受试者中阿基的血浆生物标志物风险因素。根据这些研究和现有的 根据文献，我们假设不同的临床和分子特征与阿基相关 肺移植后，与阿基发病机制的影响。我们进一步假设， 这些特征可用于预测阿基风险，以识别风险降低策略的候选者。 利用LTOG强大的多中心结构进行一项规模是迄今为止最大规模3倍的研究， 我们在肺移植人群中提出了以下目标：1）确定肺移植的临床危险因素， 阿基的结果，2）确定已建立的和新的血浆和尿液生物标志物之间的关联 3）推导并验证阿基的预测模型。该提案利用了研究 已经对LTOG进行了投资，以进行肺移植后阿基的首次全面研究。 移植以确定阿基对结局的独立影响，确定可改变的阿基风险因素， 鉴定与阿基相关的血浆和尿液分子标志物，并能够进行阿基预测。完成 目的是在LTOG内创建一个灵活的基础设施，以支持现有和新型肾脏保护药物的试验。 针对高风险患者的围移植期管理策略，最终目标是减少CKD 减轻负担，最大限度地提高肺移植的长期成功率。此外，我们的探索性研究，以确定 新的阿基生物标志物可以检测新的预测因子，并为未来的研究指明可靶向的阿基机制。