Identification and Validation of Biological Sub-phenotypes of Sepsis-induced Acute Kidney Injury: A Precision Medicine Approach to Improve Clinical Outcomes

项目总结/摘要 急性肾损伤（阿基）是脓毒症中最常见的器官衰竭形式，并且脓毒症诱导的阿基是 与住院时间延长、需要急性透析、持续性阿基和死亡相关。尽管如此 公共卫生的影响，没有有效的药物治疗存在治疗脓毒症诱导的阿基。一 原因可能是阿基中存在异质性，从而掩盖了独特的病理生理过程 特定于某些阿基人群。申请人是一个早期的职业调查员谁产生了初步的 数据表明，两种新的阿基亚表型存在于较大的异质性阿基临床表型中， 人口我们的研究小组证明，这些阿基亚表型对临床结局具有不同的风险。 和对加压素治疗的反应，独立于传统的阿基风险分层标准。我们还发现了一个 3-可变模型，包括内皮功能障碍和炎症的血浆标志物，以确定这两个 阿基亚表型。这些发现随后被一个独立的研究小组重复。通过 在这一系列工作中，我们一致表明，在脓毒症诱导的阿基中，这两种阿基亚表型 可重复性、预后性和预测性。将这些发现转化为临床研究的重要后续步骤 包括：1）扩大候选生物标志物的库，以鉴定这些或替代的阿基亚表型， 急诊室（ER）是实施预防或治疗阿基策略的早期关键时间; 2） 评估阿基亚表型对静脉输液量的反应，这是一种几乎所有患者都接受的治疗方法。 患有脓毒症诱导的阿基的患者;以及3）探测阿基亚表型是否在以下方面不同： 病理生理机制我们将在两项正在进行的NIH资助的研究中完成拟议的目标，1） 晶体自由或血管加压药早期复苏脓毒症（CLOVERS）和2）肾脏精准医学 项目（KPMP）。 在目标1中，我们将使用在ER中收集的生物标本鉴定脓毒症诱导的阿基亚表型， 确定与CLOVERS临床结局的相关性。我们将采用两种创新方法， 鉴定阿基子表型（无监督聚类和先前开发的3变量模型）。 在目标2中，我们将确定脓毒症诱导的阿基亚表型是否对限制性免疫应答不同。 液体/早期血管加压剂与自由液体/晚期血管加压剂复苏策略。 在目标3中，我们将从肾活检组织和尿蛋白中识别与肾活检相关的组织学病变。 KPMP中阿基期间采集的生物标本中脓毒症诱导的阿基亚表型。 我们的团队在阿基、败血症、分子流行病学和 介入性临床试验使我们能够将临床护理与潜在的分子机制结合起来， 为脓毒症诱导的阿基患者的研究和护理提供“精确”方法。

PROJECT SUMMARY/ABSTRACT Acute kidney injury (AKI) is the most common form of organ failure in sepsis and sepsis-induced AKI is associated with prolonged hospitalization, need for acute dialysis, persistent AKI, and death. Despite this public health impact, no effective pharmacotherapy exists for the treatment of sepsis -induced AKI. One reason may be that heterogeneity is present within AKI, thereby concealing unique pathophysiologic processes specific to certain AKI populations. The applicant is an early career investigator who has generated preliminary data demonstrating that two novel AKI sub-phenotypes are present within the larger heterogeneous AKI clinical population. Our group demonstrated that these AKI sub-phenotypes have differing risk for clinical outcomes and response to vasopressin therapy, independent of traditional criteria to risk stratify AKI. We also identified a 3-variable model that included plasma markers of endothelial dysfunction and inflammation to identify the two AKI sub-phenotypes. These findings were subsequently replicated by an independent research group. Through this body of work, we have consistently shown in sepsis-induced AKI that these two AKI sub-phenotypes are reproducible, prognostic and predictive. Important next steps for translating these findings to the bedside include: 1) expanding the pool of candidate biomarkers to identify these or alternative AKI sub-phenotypes in the emergency room (ER), an earlier and critical time to implement strategies to prevent or treat AKI; 2) evaluating response of AKI sub-phenotypes to volume of intravenous fluids, a therapy given to almost all patients with sepsis-induced AKI; and 3) probing whether the AKI sub-phenotypes different in terms of pathophysiologic mechanisms. We will complete the proposed Aims in two ongoing NIH-funded studies, 1) Crystalloid Liberal or Vasopressor Early Resuscitation in Sepsis (CLOVERS) and 2) Kidney Precision Medicine Project (KPMP). In Aim 1, we will identify sepsis-induced AKI sub-phenotypes using biospecimens collected in the ER and determine associations with clinical outcomes in CLOVERS. We will apply two innovative approaches to identify AKI sub-phenotypes (an unsupervised clustering and a previously developed 3-variable model). In Aim 2, we will determine whether sepsis-induced AKI sub-phenotypes respond differently to a restrictive fluid/early vasopressor versus a liberal fluid/late vasopressor resuscitation strategy. In Aim 3, we will identify histological lesions from kidney biopsy tissue and urinary proteins associated with sepsis-induced AKI sub-phenotypes in biospecimens collected during AKI in KPMP. The outstanding qualifications of our team in the field of AKI, sepsis, molecular epidemiology, and interventional clinical trials uniquely position us to align clinical care with underlying molecular mechanisms to inform a ‘precision’ approach to the study and care of patients with sepsis-induced AKI.