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: 10663170
• 负责人: Andrew S Allegretti
• 金额: $ 19.61万
• 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/10663170
• 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; Event; Extravasation; FDA approved; Fostering; Functional disorder; Future; Guidelines; Hepatology; Individual; Inflammation; Infrastructure; Injury; Injury to Kidney; Intervention; Intravenous; K-Series Research Career Programs; Kidney; Literature; Lung; Measurement; Measures; Methodology; Molecular; Monitor; Multicenter Trials; Nephrology; Outcome; Pathway interactions; Patients; Pattern; Perfusion; Phenotype; Physiological; Pilot Projects; Population; Publishing; Pulmonary Edema; Randomized; Recommendation; Renal function; Research; 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; trial enrollment; 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.

项目摘要/摘要 急性肾脏损伤是肝硬化的毁灭性并发症（CIRR-AKI）。当前的CIRR-AKI指南 建议所有患者在两天内接受1 g/kg/天的IV白蛋白，而不论出现特征如何。 但是，Cirr-Aki表现出异质性，通常会因受伤和不断发展的临床原因重叠 课程。那就“一件尺寸适合所有方法”可能会损害先前存在血管内超负荷的患者 和/或分子特征表明肺血管泄漏的高风险。而且，当没有指导 停止白蛋白或如何定义“足够”替代品。因此，对 个性化CIRR-AKI患者之间的复苏，以改善临床结果并避免并发症 体积超负荷。我们以平行和互补的目的来应对这一挑战。首先，几项研究 已经表明，系统注射和血管完整性的破坏可能与 CIRR-AKI的血液动力学功能障碍。血管炎症较少的患者可能更有可能反应 对于白蛋白，由于毛细血管泄漏而导致的肺水肿等不良影响。使用 来自两个大型且先前发表的生物库的数据和样品，我们将建立CIRR-的亚表征 AKI对使用临床，物理和分子数据对建立的治疗做出良好反应（或不良）。 其次，我们的目标是使用护理点超声（POCUS）更好地定义血管内体积状态， 在重症监护文献中，新兴技术是一种客观，可靠和廉价的工具 衡量血管内体积。在CIRR-AKI的当前护理标准中添加此工具可能会使该工具最大化 达到舒适血症和/或将IV白蛋白施用到已经适当适当的人的机会 复苏或超负荷。我们将进行试点试验评估如何使用Pocus引导的治疗方案 影响肾脏的结果并影响CIRR-AKI中IV白蛋白处方的实践模式。 这些目标的成功执行将为诊断，治疗监测和 量身定制的CIRR-AKI干预措施。与试验设计，血管生物学的培训和培养 CIRR-AKI研究领导者国家领导者网络，K23的支持将使适用于 在肾脏损伤的更广泛景观中的临床试验工作，为独立的跳板提供了跳板 肾脏学的学术生涯，并建立在未来R01奖中的多中心协作网络中。