Kidney Tubule Dysfunction and Future Risk of Acute Kidney Injury

肾小管功能障碍和未来急性肾损伤的风险

• 批准号: 10376834
• 负责人: Orlando M Gutierrez
• 金额: $ 69.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-19 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376834
• 关键词: Acids; Acute Renal Failure with Renal Papillary Necrosis; Address; Admission activity; Automobile Driving; Award; Azotemia; Biological Markers; Blood; Cell physiology; Cells; Chronic Kidney Failure; Clinical; Coronary Artery Bypass; Creatinine; Data; Development; Disease Progression; Distal; Etiology; Event; Factor Analysis; Fibrosis; Functional disorder; Future; Generations; Health; Heart failure; Heterogeneity; Hospitalization; Hospitals; Hydration status; Impairment; Incidence; Individual; Injury; Innovative Therapy; Kidney; Knowledge; LCN2 gene; Lead; Link; Methods; Monitor; Morbidity - disease rate; Operative Surgical Procedures; Outpatients; Participant; Pathologic; Patients; Persons; Pharmaceutical Preparations; Prevention strategy; Proteins; Proteinuria; Protocols documentation; Reasons for Geographic And Racial Differences in Stroke; Regulation; Renal function; Renal tubule structure; Research; Resources; Risk; Risk Factors; Sample Size; Sampling; Sepsis; Severities; Specimen; Stress; Survivors; Testing; Time; Tubular formation; Urine; Visit; Work; adverse outcome; base; biomarker panel; biomarker signature; cell injury; clinical implementation; cohort; cost; experience; follow-up; high risk; insight; kidney biopsy; mortality; novel; predictive marker; prevent; programs; recruit; stressor; tool

PROJECT SUMMARY Acute kidney injury (AKI) is common in hospitalized patients, costly, and strongly associated with mortality. It is also now widely recognized to be a driver of progressive chronic kidney disease (CKD). AKI occurs frequently in common clinical scenarios including sepsis, heart failure, and after coronary artery bypass graft (CABG) surgery, but it is unclear why some individuals develop AKI in these settings while others do not. We hypothesize that abnormalities in kidney function that are not captured by creatinine or proteinuria may identify those predisposed to AKI risk. In preliminary studies in the SPRINT trial, we have shown that abnormalities in kidney tubule function at baseline predict future development of AKI, independent of creatinine, proteinuria, or other AKI risk factors. If confirmed, this finding could provide a paradigm shift as it would allow identification of apparently healthy individuals who are at risk of AKI before the event occurs, enabling strategies to minimize AKI risk such as alterations in medications, hydration protocols, and surgical approaches. This knowledge may also give critical new insights into potential pathological mechanisms driving AKI events. By leveraging the large 30,239 subject Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, this application seeks to utilize blood and urine specimens collected when REGARDS participants were clinically stable outpatients to characterize their kidney tubule health. We will identify REGARDS participants who subsequently experience sepsis, heart failure, or CABG, and will abstract daily in-patient hospital creatinine data during these admissions to ascertain AKI presence and severity. We will then determine whether tubule dysfunction at times of relative health predicts AKI in these clinical scenarios (Aim 1). Next, we will build a parsimonious biomarker panel that will predict AKI in these settings, setting the stage for future clinical implementation (Aim 2). Finally, we will re-examine changes in these biomarkers after 10 years of follow-up, and determine whether tubule injury or dysfunction is differentially altered in survivors of AKI versus controls. This biomarker signature may allow clinicians to determine whether outpatient (unwitnessed) AKI episodes may underlie the development or progression of CKD (Aim 3). Our efforts will directly link baseline tubule function with future AKI risk, setting the stage for innovative therapies to mitigate or prevent AKI.

项目概要 急性肾损伤（AKI）在住院患者中很常见，费用昂贵且与死亡率密切相关。 现在它也被广泛认为是进行性慢性肾病 (CKD) 的驱动因素。发生 AKI 常见于常见的临床情况，包括脓毒症、心力衰竭和冠状动脉搭桥术后 (CABG) 手术，但尚不清楚为什么有些人在这些情况下会发生 AKI，而另一些人则不会。我们 假设肌酐或蛋白尿未捕获的肾功能异常可能会识别 那些易患 AKI 风险的人。在 SPRINT 试验的初步研究中，我们发现异常 基线肾小管功能可预测 AKI 的未来发展，与肌酐、蛋白尿或 其他 AKI 危险因素。如果得到证实，这一发现可能会带来范式转变，因为它将允许识别 在事件发生之前，表面上健康的个体有 AKI 的风险，从而能够采取策略最大限度地减少 AKI 风险，例如药物、水合方案和手术方法的改变。这些知识 还可能为驱动 AKI 事件的潜在病理机制提供重要的新见解。通过利用 在 30,239 名受试者中风的地理和种族差异原因 (REGARDS) 队列中， 应用程序旨在利用 REGARDS 参与者临床时收集的血液和尿液样本 稳定的门诊患者来表征他们的肾小管健康状况。我们将确定问候参与者 随后出现败血症、心力衰竭或冠状动脉搭桥术，并将每天在住院医院抽取肌酐 入院期间的数据以确定 AKI 的存在和严重程度。然后我们将确定是否有肾小管 在这些临床情况下，相对健康时的功能障碍可预测 AKI（目标 1）。接下来，我们将构建一个 简约的生物标志物组合将预测这些情况下的 AKI，为未来的临床奠定基础 实施（目标 2）。最后，我们会在10年的随访后重新审视这些生物标志物的变化， 并确定 AKI 幸存者与对照组相比，肾小管损伤或功能障碍是否存在差异性改变。 这种生物标志物特征可以让临床医生确定门诊患者（无人目睹的）AKI 发作是否发生 可能是 CKD 发生或进展的基础（目标 3）。我们的努力将直接连接基线小管 与未来 AKI 风险发挥作用，为减轻或预防 AKI 的创新疗法奠定基础。