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: 10214194
• 负责人: Orlando M Gutierrez
• 金额: --
• 依托单位: VETERANS MEDICAL RESEARCH FDN/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: 2021-04-01 至 2021-04-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214194
• 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.

项目总结 急性肾损伤(AKI)在住院患者中很常见，费用高昂，而且与死亡率密切相关。 它现在也被广泛认为是进行性慢性肾脏疾病(CKD)的驱动因素。Aki发生 常见的临床情况包括败血症、心力衰竭和冠状动脉搭桥术后。 (CABG)手术，但尚不清楚为什么一些人在这些环境中患上AKI，而另一些人则不是。我们 假设肾功能异常不能被肌酸或蛋白尿捕获 那些倾向于AKI的人存在风险。在Sprint试验的初步研究中，我们已经表明， 基线时的肾小管功能可预测AKI的未来发展，独立于肌酐、蛋白尿或 其他AKI风险因素。如果得到证实，这一发现可能会提供一个范式转变，因为它将允许识别 在事件发生前有AKI风险的明显健康的个人，使策略能够最大限度地减少 AKI风险，如药物、水化方案和手术方法的改变。这一知识 也可能为推动AKI事件的潜在病理机制提供关键的新见解。通过利用 中风(方面)队列中地理和种族差异的30239个主题原因，这 应用程序寻求利用临床上收集的参与者的血液和尿液样本 稳定的门诊患者来描述他们的肾小管健康状况。我们将确定哪些方面的参与者 随后经历脓毒症、心力衰竭或冠状动脉旁路移植术，并将提取每日住院患者的肌酐 在这些入院期间的数据以确定AKI的存在和严重程度。然后我们将确定小管是否 在这些临床方案(目标1)中，相对健康时的功能障碍可预测AKI。接下来，我们将构建一个 简约的生物标记物小组将在这些环境中预测AKI，为未来的临床奠定基础 执行(目标2)。最后，我们将在10年的随访后重新检查这些生物标志物的变化， 并确定与对照组相比，AKI幸存者的肾小管损伤或功能障碍是否有不同的改变。 这一生物标志物特征可使临床医生确定门诊(无目击)AKI发作 可能是慢性肾脏病发展或进展的基础(目标3)。我们的努力将直接连接基线小管 与未来的AKI风险有关，为缓解或预防AKI的创新疗法奠定了基础。