Personalizing Therapies for Acute Kidney Injury in Cirrhosis

肝硬化急性肾损伤的个体化治疗

• 批准号: 10371378
• 负责人: Andrew S Allegretti
• 金额: $ 19.79万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371378
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adverse effects; Affect; Albumins; Algorithms; Angiopoietin-2; Assessment tool; Award; Biological; Biology; Blinded; Blood Vessels; Blood capillaries; Cirrhosis; Clinical; Clinical Data; Clinical Trials; Complication; Creatinine; Critical Care; Critical Illness; Data; Development; Diagnosis; Dose; Endothelium; Enrollment; Event; Extravasation; FDA approved; Fostering; Functional disorder; Future; Guidelines; Hepatology; Individual; Inflammation; Infrastructure; Injury; Injury to Kidney; Intervention; Intravenous; Investigation; K-Series Research Career Programs; Kidney; Literature; Lung; Measurement; Measures; Methodology; Molecular; Monitor; Multicenter Trials; Nephrology; Outcome; Pathway interactions; Patients; Pattern; Perfusion; Physiological; Pilot Projects; Population; Publishing; Pulmonary Edema; Randomized; Renal function; Research; Research Support; Respiratory Failure; Resuscitation; Sampling; Serum; Syndrome; Techniques; Therapeutic; Time; Training; Treatment Protocols; Universities; Work; biobank; care providers; career; comparison group; hemodynamics; high risk; high risk population; improved; improved outcome; insight; molecular marker; open label; personalized medicine; pilot trial; point of care; prognostic; response; skills; standard care; standard of care; systemic inflammatory response; therapy outcome; tool; treatment response; trial design; ultrasound; vascular inflammation

PROJECT SUMMARY/ABSTRACT Acute kidney injury is a devastating complication of cirrhosis (Cirr-AKI). Current Cirr-AKI guidelines recommend all patients receive 1 g/kg/day of IV albumin for two days regardless of presenting features. However, Cirr-AKI presents heterogeneously, often with overlapping causes of injury and evolving clinical courses. Thus, this “one size fits all approach” may harm patients with pre-existing intravascular overload and/or molecular features suggesting high risk of lung vascular leakage. Moreover, there is no guidance when to stop albumin or how to define “adequate” repletion. Therefore, there is a critical unmet need for personalizing resuscitation among Cirr-AKI patients to improve clinical outcomes and avoid complications of volume overload. We approach this challenge with parallel and complementary aims. First, several studies have shown that systemic inflammation and disruption of vascular integrity may be implicated in the hemodynamic dysfunction of Cirr-AKI. Patients with less vascular inflammation may be more likely to respond to albumin and less likely to be suffer adverse effects such as pulmonary edema due to capillary leak. Using data and samples from two large and previously published biobanks, we will establish subphenotypes of Cirr- AKI that respond well (or poorly) to established treatments using clinical, physiological, and molecular data. Second, we aim to better define intravascular volume status using Point of Care Ultrasound (POCUS), an emerging technique well-established in the critical care literature as an objective, reliable, and inexpensive tool to gauge intravascular volume. Addition of this tool to current standard of care for Cirr-AKI may maximize the chance of reaching euvolemia and/or reduce IV albumin administration to those already adequately resuscitated or overloaded. We will perform a pilot trial assessing how a POCUS-guided treatment protocol affects kidney outcomes and influences practice patterns around IV albumin prescription in Cirr-AKI. Successful execution of these aims will illuminate new directions for diagnosis, therapeutic monitoring, and tailored interventions for Cirr-AKI. In concert with training in trial design, vascular biology, and fostering a national network of leaders in Cirr-AKI research, support from the K23 will enable a skill set that is applicable to clinical trial work across the broader landscape of kidney injury, provide a springboard to an independent academic career in nephrology, and build towards a multicenter collaborative network in a future R01 award.

项目总结/摘要 急性肾损伤是肝硬化（Cirr-AKI）的一种毁灭性并发症。当前Cirr-AKI指南 建议所有患者接受1 g/kg/天IV白蛋白治疗，持续2天，无论其表现特征如何。 然而，Cirr-AKI呈现异质性，通常具有重叠的损伤原因和不断发展的临床 课程因此，这种“一刀切的方法”可能会损害预先存在血管内负荷过重的患者 和/或提示肺血管渗漏高风险的分子特征。此外，没有指导， 停止使用白蛋白或如何定义“充分”的饱食。因此，有一个关键的未满足的需求， 在Cirr-AKI患者中进行个性化复苏，以改善临床结局并避免 容量过载。我们以平行和互补的目标应对这一挑战。首先，几项研究 已经表明，全身炎症和血管完整性的破坏可能与 Cirr-AKI血流动力学功能障碍。血管炎症较少的患者可能更有可能做出反应 且不太可能遭受诸如由于毛细血管渗漏导致的肺水肿的副作用。使用 数据和样本从两个大的和以前发表的生物库，我们将建立Cirr的亚表型， 使用临床、生理和分子数据对已建立的治疗反应良好（或不良）的阿基。 其次，我们的目标是使用床旁超声（POCUS）更好地定义血管内容量状态， 一种在重症监护文献中作为客观、可靠和廉价工具得到充分确立的新兴技术 来测量血管内容量。将该工具添加到Cirr-AKI的当前护理标准中可以最大限度地提高 达到正常血容量的机会和/或减少IV白蛋白给药， 复苏或超载。我们将进行一项试点试验，评估POST-guided治疗方案 影响肾脏结局并影响Cirr-AKI患者IV白蛋白处方的实践模式。 这些目标的成功实现将为诊断、治疗监测和 针对Cirr-AKI的定制干预措施。与试验设计、血管生物学和培养 Cirr-AKI研究领导者的国家网络，K23的支持将使适用于以下方面的技能集成为可能： 临床试验工作跨越更广泛的肾损伤景观，提供了一个跳板， 在肾脏病学的学术生涯，并建立一个多中心的合作网络，在未来的R 01奖。