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

脓毒症引起的急性肾损伤的生物亚表型的鉴定和验证：改善临床结果的精准医学方法

• 批准号: 10674050
• 负责人: Pavan Kumar Bhatraju
• 金额: $ 47.62万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10674050
• 关键词: Accident and Emergency department; Acute; Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Biological; Biological Markers; Biopsy; Blood; Blood capillaries; Cessation of life; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Critical Care; Critical Illness; Data; Dialysis procedure; Funding; Genetic Risk; Heterogeneity; Histologic; Histology; Histopathology; Hospital Mortality; Hospitalization; Hour; IV Fluid; Inflammation; Intervention; Kidney; Lesion; Liquid substance; Measures; Modeling; Molecular; Molecular Epidemiology; Multicenter Trials; Nephrology; Organ failure; Outcome; Patient Care; Patients; Pattern; Pharmacotherapy; Phenotype; Plasma; Population; Positioning Attribute; Process; Prospective Studies; Proteins; Proteomics; Public Health; Qualifying; Randomized; Recovery; Renal Replacement Therapy; Reproducibility; Research; Research Personnel; Resuscitation; Risk; SP1 gene; Sample Size; Sepsis; Septic Shock; Structure; Syndrome; Testing; Therapeutic; Time; Tissues; Translating; United States National Institutes of Health; Urine; Validation; Vasoconstrictor Agents; Vasopressins; aptamer; candidate marker; career; clinical care; clinical risk; crystalloid; disorder risk; endothelial dysfunction; high risk; improved; innovation; kidney biopsy; multidisciplinary; novel; personalized approach; pre-clinical; precision medicine; prevent; prognostic; prospective; response; risk stratification; treatment response; trial enrollment; urinary

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.

项目摘要/摘要 急性肾损伤(AKI)是脓毒症中最常见的器官衰竭形式，脓毒症所致的AKI是 与长时间住院、需要急性透析、持续性急性心肌梗死和死亡有关。尽管如此 对公众健康的影响，目前还没有有效的药物疗法来治疗脓毒症所致的AKI。一 原因可能是AKI内部存在异质性，从而隐藏了独特的病理生理过程 特定于某些AKI人群。申请者是一名早期职业调查员，他已经生成了初步的 数据显示，在较大的异质性AKI临床中存在两种新的AKI亚型 人口。我们的小组证明，这些AKI亚型对临床结果有不同的风险。 以及对加压素治疗的反应，独立于传统的AKI危险分层标准。我们还确定了一个 包括内皮功能障碍和炎症的血浆标志物以确定两者的3变量模型 Aki亚型。随后，一个独立的研究小组重复了这些发现。穿过 这项工作，我们在脓毒症诱导的AKI中一直表明，这两个AKI亚型是 可重复性、预测性和预测性。将这些发现转化到床边的下一步重要步骤 包括：1)扩大候选生物标志物的库，以识别这些或替代的AKI亚型 急诊室(ER)，这是实施预防或治疗AKI策略的更早和关键时刻；2) 评估AKI亚型对静脉输液量的反应，这是一种几乎适用于所有患者的治疗方法 脓毒症引起的AKI患者；3)探讨AKI亚型在以下方面的不同 病理生理机制。我们将在NIH资助的两项正在进行的研究中完成拟议的目标，1) 脓毒症(三叶草)的晶体游离或血管升压剂早期复苏和2)肾脏精准医学 项目(KPMP)。 在目标1中，我们将使用收集在内质网和内质网中的生物标本来鉴定脓毒症诱导的AKI亚型。 确定三叶草与临床结果之间的关系。我们将运用两个创新方法来 确定AKI亚型(无监督聚类和之前开发的三变量模型)。 在目标2中，我们将确定脓毒症诱导的AKI亚型是否对限制性 液体/早期升压药与自由液体/晚期升压药复苏策略。 在目标3中，我们将从肾活检组织和与以下相关的尿蛋白中鉴定组织学损害 KPMP在AKI期间收集的生物标本中脓毒症诱导的AKI亚型。 我们团队在AKI、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相结合，从而 告知一种“精确”的方法来研究和护理脓毒症所致AKI患者。