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: 10231197
• 负责人: Michael G. S. Shashaty
• 金额: $ 65.21万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231197
• 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; Complication; Critical Illness; Cystic Fibrosis; Data; Diagnosis; Dialysis procedure; Enrollment; Epidemiology; Functional disorder; Funding; Future; Goals; Hour; Human; Incidence; Infrastructure; Injury; Injury to Kidney; 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; comorbidity; 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 急性肾脏损伤（AKI），几天内肾功能的迅速丧失，最多发生在70％的肺移植中 目前的接收者，比心脏手术目的地之后更常见的是年轻人 几乎没有先前存在的慢性肾脏疾病（CKD）。而移植后AKI与后续 CKD和死亡率，尚不清楚AKI是独立影响结果还是仅仅是肺的表皮 同种异体移植功能障碍和其他早期移植并发症。移植后AKI流行病学知识 仅限于相对较小的回顾性单中心研究，对AKI风险因素的评估有限。 阐明AKI对结果的独立影响，并确定具有AKI高风险的患者，尤其是 严重的形式与CKD和死亡率更加紧密，至关重要，因为肾脏保护策略，例如 流体给药带来同种异体移植的风险。血液和尿液生物标志物已显示出对AKI的预测效用 在重症疾病和心脏手术群体中，但尚未在肺移植患者中进行研究。这些 预测标记还可能阐明该人群中AKI率高的机制。 肺移植结果组（LTOG）是NIH资助的多中心前瞻性队列 2002年，由我们的机构协调，旨在研究原发性的临床和分子流行病学 移植功能障碍（PGD），一种急性肺同种异体损伤综合征。在注册> 2000中，LTOG是独特的 适合支持AKI流行病学的辅助，多中心研究。我们对临床和 一小组LTOG受试者中AKI的血浆生物标志物风险因素。基于这些研究和现有 文献，我们假设不同的临床和分子特征与AKI有关 肺移植后，对AKI发病机理有影响。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人。 利用LTOG的稳健多中心结构进行研究，是迄今为止最大的大小的3倍 我们在肺移植人群中提出以下目标：1）确定和确定的临床风险因素和 AKI的结果，2）确定已建立和新的血浆和尿液生物标志物的关联 使用AKI，3）得出AKI的预测模型并验证了预测模型。该建议利用研究 已经在LTOG中进行的投资是为了在肺后进行AKI的首次全面研究 移植以建立AKI对结果的独立影响，确定可修改的AKI风险因素， 识别与AKI相关的血浆和尿液分子标记，并实现AKI预测。完成 AIMS将在LTOG中创建灵活的基础架构，以支持当前和新型肾脏保护的试验 针对高风险患者的移植跨植物管理策略，其最终目标是减少CKD 负担和最大化肺移植的长期成功。此外，我们的探索性研究以确定 新型的AKI生物标志物可以检测新的预测因子，并指向未来研究的目标AKI机制。

项目成果

Development and validation of a population pharmacokinetic model to guide perioperative tacrolimus dosing after lung transplantation.

开发和验证群体药代动力学模型以指导肺移植后围术期他克莫司给药。

• DOI: 10.1101/2023.06.26.23291248
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Miano,ToddA;Feng,Rui;Griffiths,Stephen;Kalman,Laurel;Oyster,Michelle;Cantu,Edward;Yang,Wei;Diamond,JoshuaM;Christie,JasonD;Scheetz,MarcH;Shashaty,MichaelGS
• 通讯作者: Shashaty,MichaelGS