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.

项目概要/摘要 急性肾损伤是肝硬化的一种破坏性并发症（Cirr-AKI）。 建议所有患者接受 1 g/kg/天的静脉注射白蛋白，持续两天，无论其表现如何。 然而，Cirr-AKI 呈现出异质性，通常具有重叠的损伤原因和不断变化的临床症状 因此，这种“一刀切”的方法可能会伤害已有血管内超负荷的患者。 和/或分子特征表明肺血管渗漏的高风险。此外，没有指导。 停止白蛋白或如何定义“足够”的补充因此，存在着未满足的关键需求。 对 Cirr-AKI 患者进行个性化复苏，以改善临床结果并避免并发症 我们以并行和互补的目标来应对这一挑战。 研究表明，全身炎症和血管完整性破坏可能与 Cirr-AKI 的血流动力学功能障碍患者血管炎症较少可能更有可能做出反应。 与白蛋白相比，不易发生毛细血管渗漏导致的肺水肿等不良反应。 来自两个大型且先前发布的生物库的数据和样本，我们将建立 Cirr- 使用临床、生理和分子数据对既定治疗反应良好（或较差）的 AKI。 其次，我们的目标是使用护理点超声 (POCUS) 更好地定义血管内容量状态，这是一种 重症监护文献中公认的新兴技术是一种客观、可靠且廉价的工具 将该工具添加到当前 Cirr-AKI 护理标准中可以最大限度地提高血管内容量。 达到血容量正常和/或减少静脉注射白蛋白给药量的机会 我们将进行一项试点试验，评估 POCUS 指导的治疗方案的效果。 影响肾脏结果并影响 Cirr-AKI 中静脉注射白蛋白处方的实践模式。 这些目标的成功实现将为诊断、治疗监测和治疗指明新的方向。 针对 Cirr-AKI 的定制干预措施与试验设计、血管生物学和培养培训相结合。 Cirr-AKI 研究领导者的国家网络，K23 的支持将提供适用于 涵盖更广泛的肾损伤领域的临床试验工作，为独立的研究提供了跳板 肾脏病学领域的学术生涯，并在未来的 R01 奖项中建立多中心协作网络。