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.

项目概要/摘要 急性肾损伤 (AKI) 是脓毒症中最常见的器官衰竭形式，脓毒症引起的 AKI 是 尽管如此，仍与长期住院、需要急性透析、持续 AKI 和死亡有关。 公共健康影响，目前尚无有效的药物疗法可治疗脓毒症引起的 AKI。 原因可能是 AKI 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 AKI 人群的申请人是一名早期职业研究者，已生成初步结果。 数据表明，在更大的异质性 AKI 临床中存在两种新的 AKI 亚表型 我们的小组证明这些 AKI 亚表型对临床结果具有不同的风险。 以及对加压素治疗的反应，独立于 AKI 风险分层的传统标准。 3 变量模型，包括内皮功能障碍和炎症的血浆标记物，以识别两者 AKI 亚表型随后被一个独立研究小组重复。 在这项工作中，我们在脓毒症诱发的 AKI 中一致证明，这两种 AKI 亚表型是 将这些发现转化为临床的重要后续步骤。 包括：1) 扩大候选生物标志物库，以识别这些或替代的 AKI 亚表型 急诊室 (ER)，尽早实施 AKI 预防或治疗策略的关键时刻 2) 评估 AKI 亚表型对静脉输液量的反应，这种治疗几乎适用于所有患者 脓毒症诱发的 AKI 患者；3) 探讨 AKI 亚型在以下方面是否存在差异： 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) 脓毒症中的晶体自由或血管加压药早期复苏 (CLOVERS) 和 2) 肾脏精准医学 项目（毕马威会计师事务所）。 在目标 1 中，我们将使用急诊室收集的生物样本来识别败血症诱发的 AKI 亚表型 确定与 CLOVERS 临床结果的关联我们将应用两种创新方法。 识别 AKI 亚表型（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 AKI 亚表型对限制性药物的反应是否不同 液体/早期血管加压药与自由液体/晚期血管加压药复苏策略。 在目标 3 中，我们将从肾活检组织和尿液相关蛋白中识别组织学病变 KPMP 中 AKI 期间收集的生物样本中脓毒症诱导的 AKI 亚表型。 我们团队在 AKI、脓毒症、分子流行病学和 介入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 为脓毒症引起的 AKI 患者的研究和护理提供“精确”方法。