Personalizing Therapies for Acute Kidney Injury in Cirrhosis

项目摘要/摘要 急性肾损伤是肝硬变(Cirr-AKI)的严重并发症。当前Cirr-AKI指南 建议所有患者接受1g/kg/天的静脉注射白蛋白，连续两天，无论症状如何。 然而，Cirr-AKI表现不均，通常有重叠的损伤原因和不断演变的临床。 课程。因此，这种“一刀切”的手术方式可能会伤害已有血管内负荷过重的患者。 和/或提示肺血管渗漏风险高的分子特征。此外，在什么情况下，没有指导 停止白蛋白或如何定义“充足的”补充。因此，存在着严重的未得到满足的需求 在Cirr-AKI患者中进行个性化复苏以改善临床结果并避免并发症 音量过载。我们以并行和互补的目标应对这一挑战。首先，几项研究 已表明全身性炎症和血管完整性的破坏可能与 CIRR-AKI的血流动力学障碍。血管炎症程度较轻的患者可能更有可能做出反应 对白蛋白和更少的不良影响，如因毛细血管渗漏而引起的肺水肿。vbl.使用 来自两个大型和以前发表的生物库的数据和样本，我们将建立CirR的亚型。 使用临床、生理和分子数据对已建立的治疗反应良好(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。 新兴技术作为一种客观、可靠和廉价的工具在重症监护文献中得到了广泛的认可 以测量血管内容量。将此工具添加到CIRR-AKI的当前护理标准中可能会使 达到优血症和/或减少静脉注射白蛋白给药的机会已经足够 复苏或超载。我们将进行一项试点试验，评估Pocus引导的治疗方案如何 影响肾脏预后并影响Cirr-AKI中静脉白蛋白处方的实践模式。 这些目标的成功实施将为诊断、治疗监测和 为Cirr-AKI量身定制的干预措施。与试验设计、血管生物学和培养 Cirr-AKI研究领域的全国领导者网络，来自K23的支持将使技能集适用于 跨肾损伤更广泛的临床试验工作，提供了一个独立的跳板 在肾脏病方面的学术生涯，并在未来的R01奖中朝着多中心合作网络的方向发展。

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.