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

项目总结/摘要： 感染性休克影响了10%的儿科重症监护病房的儿童，其中25%死亡。成果 在脓毒症相关急性肾损伤（SA-AKI）患者中尤其差， 由宿主对感染的免疫反应失调驱动的综合征，治疗选择有限 存在.根据现有的成人文献和初步数据的坚实基础，斯坦斯基博士的建议 旨在开发一种精确的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鉴定独特的SA-AKI亚表型， 在床边选择血管活性药物。这些研究的结果将指导未来的工作 确定儿科SA-AKI的治疗策略，并改善感染性休克儿童的预后 整体候选人：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）。她 在急性肾损伤和脓毒症领域具有良好的早期以患者为导向的研究记录 精准医学，侧重于确定表征综合征异质性的策略。斯坦斯基医生很久- 长期目标是成为一个独立的医生，科学家领先的精确医学知情病人为导向 研究以改善脓毒症和SA-AKI儿童的结局。因此，她的训练目标是其中的一部分， 奖项包括获得以下领域的先进知识：设计和以病人为导向的行为 研究（包括临床试验），实施科学和定性研究方法，先进的 生物统计学（包括聚类分析技术），以及精准医学、败血症和 SA-AKI为了实现这些目标，斯坦斯基博士的职业发展计划包括正式的课程， 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的儿科SA-AKI 临床亚表型，并描述其与结果和血清生物标志物谱的相关性，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， 脓毒性休克和SA-AKI患儿的血管活性选择。此应用程序利用了 CCHMC的研究基础设施，以及强大的专家指导，顾问和 合作者团队具体来说，斯坦斯基博士对现有大型患者数据集和生物储存库的访问 进行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Stanski博士处于有利地位，以实现她的长期目标 研究的独立性，所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，需要改善儿科感染性休克的结局。

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.