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: 10449922
• 负责人: Orlando M Gutierrez
• 金额: $ 75.36万
• 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/10449922
• 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.

项目摘要 急性肾脏损伤（AKI）在住院的患者中很常见，昂贵，并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脏疾病（CKD）的驱动力。 Aki发生 经常在常见的临床情况下，包括败血症，心力衰竭和冠状动脉搭桥后 （CABG）手术，但目前尚不清楚为什么有些人在这些环境中发展AKI而另一些人则没有。我们 假设肌酐或蛋白尿未捕获的肾脏功能异常可能会识别 那些易受AKI风险的人。在Sprint试验的初步研究中，我们表明 基线肾小管功能预测AKI的未来发展，独立于肌酐，蛋白尿或 其他AKI风险因素。如果得到确认，这一发现可以提供范式转移，因为它可以识别 显然，在发生事件发生之前有AKI风险的健康个人，从而使策略最小化 AKI风险，例如药物改变，水合方案和外科手术方法的风险。这个知识 还可能对推动AKI事件的潜在病理机制有关键的新见解。通过利用 大量的30,239个主题是中风（有关）队列中的地理和种族差异的原因， 当参与者在临床上，应用程序旨在利用收集的血液和尿液标本 稳定的门诊病人可以表征其肾小管健康。我们将确定参与者 随后会体验败血症，心力衰竭或CABG，并将每天抽象住院医院肌酐 这些入院期间的数据以确定AKI的存在和严重性。然后，我们将确定是否小管 在相对健康时，功能障碍在这些临床情况下预测了AKI（AIM 1）。接下来，我们将建立一个 在这些环境中可以预测AKI的简约生物标志物面板，为将来的临床奠定了基础 实施（目标2）。最后，经过10年的随访，我们将重新检查这些生物标志物的变化， 并确定在AKI与对照的幸存者中，小管损伤或功能障碍是否差异改变。 该生物标志物签名可能允许临床医生确定门诊（不愿意）AKI情节是否 可能是CKD的发展或发展的基础（AIM 3）。我们的努力将直接连接基线小管 具有未来AKI风险的功能，为减轻或预防AKI的创新疗法奠定了基础。