Developing a Precision Medicine Approach to Pediatric Sepsis-Associated Acute Kidney Injury: Identification of Unique Subphenotypes and Strategies for Bedside Implementation

开发针对小儿脓毒症相关急性肾损伤的精准医学方法：识别独特的亚表型和临床实施策略

• 批准号: 10721391
• 负责人: Natalja L. Stanski
• 金额: $ 19.23万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721391
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Admission activity; Adoption; Adult; Affect; Algorithms; Angiotensin II; Area; Award; Biological Markers; Biology; Biometry; Caring; Categories; Child; Childhood; Clinical; Clinical Data; Clinical Trials; Cluster Analysis; Consensus; Convulsive therapy; Critical Care; Critical Illness; Critically ill children; Data; Data Set; Databases; Development; Development Plans; Diagnosis; Disease; Disease Outcome; Failure; Foundations; Future; Goals; Granzyme; Heat shock proteins; Heterogeneity; Immune response; Incidence; Infection; Inflammatory; Interleukin-8; Intervention; Knowledge; Ligands; Literature; Maintenance; Maps; Measures; Medical center; Medicine; Mentors; Mentorship; Metalloproteases; Methodology; Morbidity - disease rate; Nature; Observational Study; Outcome; Patients; Pediatric Hospitals; Pediatric Intensive Care Units; Pharmaceutical Preparations; Phenotype; Physicians; Positioning Attribute; Prediction of Response to Therapy; Process; Prognosis; Qualitative Research; Recommendation; Renal Replacement Therapy; Renin; Research; Research Infrastructure; Research Methodology; Research Personnel; Residual state; Scientist; Sepsis; Septic Shock; Serum; Severity of illness; Subgroup; Supportive care; Syndrome; Techniques; Training; Universities; Validation; Vasopressins; Work; beta-Chemokines; biobank; biomarker signature; career development; cohort; college; design; effective therapy; experience; high risk; implementation science; improved outcome; mortality; mortality risk; new therapeutic target; novel; patient oriented; patient oriented research; patient subsets; pediatric sepsis; personalized approach; personalized management; phenotypic data; precision medicine; professor; prognostic; prospective; response; success; theories; therapy outcome; transcriptomics; translational scientist; treatment strategy; vasoactive agent

PROJECT SUMMARY/ABSTRACT: Septic shock impacts 10% of children admitted to the pediatric intensive care unit, 25% of whom die. Outcomes are particularly poor in those who suffer sepsis-associated acute kidney injury (SA-AKI), a heterogeneous syndrome driven by the dysregulated host immune response to infection, and for which limited treatment options exist. Informed by existing adult literature and a strong foundation of preliminary data, Dr. Stanski’s proposal seeks to develop a precision medicine approach to management of these high risk children with septic shock and SA-AKI, by leveraging clinical and biomarker data to identify unique SA-AKI subphenotypes that may inform vasoactive medication selection at the bedside. The results from these studies will guide future prospective work to identify treatment strategies for pediatric SA-AKI, and improve outcomes for children with septic shock as a whole. Candidate: Dr. Natalja Stanski is an Assistant Professor of Pediatric Critical Care Medicine at the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center (CCHMC). She has a strong early track record of patient-oriented research in the areas of acute kidney injury and sepsis precision medicine, focusing on identifying strategies to characterize syndrome heterogeneity. Dr. Stanski’s long- term goal is to become an independent physician-scientist leading precision-medicine informed patient-oriented research to improve outcomes for children with sepsis and SA-AKI. As such, her training goals as part of this award include gaining advanced knowledge in the following areas: design and conduct of patient-oriented research (including clinical trials), implementation science and qualitative research methodologies, advanced biostatistics (including techniques for cluster analysis), and content expertise in precision medicine, sepsis and SA-AKI. To accomplish these goals, Dr. Stanski’s career development plan includes formal coursework in advanced biostatistics, clinical trial management, implementation science and qualitative research; individualized expert mentoring; training by expert consultants; and completion of the proposed research aims. Research: The aims of this study are: 1) to use cluster analysis methodology to identify novel pediatric SA-AKI clinical subphenotypes and describe their associations with outcomes and serum biomarker profiles, and 2) to use Implementation Mapping to develop a rigorous, theory-based implementation plan for personalized vasoactive selection in children with septic shock and SA-AKI. This application leverages the outstanding research infrastructure at CCHMC, and the support of a formidable expert mentorship, consultant and collaborator team. Specifically, Dr. Stanski’s access to the existing large patient datasets and biorepositories necessary to conduct this important work makes her uniquely suited to complete her proposed research aims. The support and training provided by this K23 will leave Dr. Stanski well-positioned to achieve her long-term goal of research independence, and the preliminary data generated will provide the foundation for a feasible precision medicine approach to SA-AKI management that is needed to improve outcomes in pediatric septic shock.

项目摘要/摘要： 感染性休克影响了 10% 入住儿科重症监护室的儿童，其中 25% 死亡。 脓毒症相关急性肾损伤 (SA-AKI) 患者的健康状况尤其差，这是一种异质性的疾病。 由宿主对感染的免疫反应失调引起的综合征，其治疗选择有限 根据现有的成人文献和坚实的初步数据基础，斯坦斯基博士的提议是存在的。 寻求开发一种精准医学方法来管理这些感染性休克的高危儿童 和 SA-AKI，通过利用临床和生物标志物数据来识别可能提供信息的独特 SA-AKI 亚表型 这些研究的结果将指导未来的前瞻性工作。 确定儿科 SA-AKI 的治疗策略，并改善感染性休克儿童的预后 候选人：Natalja Stanski 博士是儿科重症监护医学助理教授。 辛辛那提大学医学院和辛辛那提儿童医院医疗中心 (CCHMC)。 在急性肾损伤和脓毒症领域以患者为中心的研究方面拥有良好的早期记录 精准医学，重点是确定表征综合征异质性的策略。 长期目标是成为一名独立的医师科学家，领导精准医学，知情，以患者为中心 旨在改善脓毒症和 SA-AKI 儿童治疗效果的研究因此，她的培训目标也是其中的一部分。 奖项包括获得以下领域的先进知识：以患者为中心的设计和实施 研究（包括临床试验）、实施科学和定性研究方法、高级 生物统计学（包括聚类分析技术）以及精准医学、脓毒症和 为了实现这些目标，斯坦斯基博士的职业发展计划包括以下方面的正式课程： 先进的生物统计学、临床试验管理、实施科学和定性研究； 个性化的专家指导；专家顾问的培训；以及完成拟议的研究目标。 研究：本研究的目的是：1) 使用聚类分析方法来识别新型儿科 SA-AKI 临床亚表型并描述其与结果和血清生物标志物谱的关联，以及 2) 使用实施映射来制定严格的、基于理论的个性化实施计划 感染性休克和 SA-AKI 儿童的血管活性选择​​该应用利用了杰出的技术。 CCHMC 的研究基础设施，以及强大的专家指导、顾问和支持 具体来说，斯坦斯基博士可以访问现有的大型患者数据集和生物存储库。 开展这项重要工作的必要性使她非常适合完成她提出的研究目标。 K23 提供的支持和培训将使斯坦斯基博士能够实现她的长期目标 研究独立性，产生的初步数据将为可行的精度提供基础 SA-AKI 管理的医学方法需要改善小儿感染性休克的结果。