Kidney Tubule Dysfunction and Future Risk of Acute Kidney Injury

项目摘要 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。 它现在也被广泛认为是进行性慢性肾病（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旁路移植术后 冠状动脉旁路移植术（CABG）手术，但目前尚不清楚为什么有些人在这些设置中发展AKI，而其他人则没有。我们 假设未被肌酐或蛋白尿捕获的肾功能异常可以鉴定 易患AKI风险的人群。在SPRINT试验的初步研究中，我们已经表明， 基线时肾小管功能预测AKI未来发展，与肌酐、蛋白尿或 其他AKI风险因素。如果得到证实，这一发现可能提供一个范式转变，因为它将允许识别 在事件发生前处于AKI风险中的明显健康个体，使策略能够最大限度地减少 AKI风险，如药物、水合方案和手术方法的改变。这些知识 也可能为驱动AKI事件的潜在病理机制提供重要的新见解。通过利用 大型30，239例受试者卒中地理和种族差异原因（REGARDS）队列， 该应用旨在利用REGARDS参与者在临床上 稳定的门诊患者来表征他们的肾小管健康。我们将确定以下方面的参与者： 随后经历败血症、心力衰竭或冠状动脉旁路移植术，并将每日抽取住院患者的医院肌酸酐 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，我们将建立一个 简约的生物标志物面板，将预测AKI在这些设置，为未来的临床 （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， 并确定肾小管损伤或功能障碍是否在AKI幸存者与对照组中有差异性改变。 这种生物标志物特征可以让临床医生确定门诊（无人目击）AKI是否发作 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 这些药物的作用与未来AKI风险有关，为缓解或预防AKI的创新疗法奠定了基础。

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.