Diagnostic and Prognostic Relevance of Acute Kidney Injury Biomarkers in the ICU

描述（由申请人提供）：指导患者为导向的研究职业发展奖（K23）将使博士爱德华D。Siew将发展成为急性肾损伤（阿基）临床和转化研究的独立研究者，并建立一个专注于危重病相关肾损伤的独立研究项目。通过在临床蛋白质组学，先进流行病学和生物统计学方面精心构建的教学活动计划的可用性;当地和国际专家的密集指导;以及在设计，实施和解释来自大型危重病成人前瞻性队列的数据方面的直接经验，萧博士将利用这个奖项成为阿基研究中训练有素的研究员。该提案的主要科学目的是检查损伤生物标志物对危重患者阿基早期检测和预后的独立和附加影响，并将新兴蛋白质组学技术应用于发现能够在早期诊断时预测损伤进展的新型蛋白质标志物。尽管在提供护理方面取得了进展，但阿基仍然是危重患者中常见的毁灭性事件，也是发病率和死亡率的独立预测因素。将有希望的干预措施转化为改善阿基结局的尝试有限，迟来的和不可靠的损伤标志物（即血清肌酐和尿量的变化）提供的关于持续损伤的时间和机制的信息很少。这些局限性在混合ICU患者人群中进一步放大，其中损伤的时间和程度更难以定义。使用一个大型的、表型良好的危重成人前瞻性队列（急性肺损伤诊断生物标志物验证/VALID研究），该提案将检验以下假设：由肾损伤特定指标组成的生物标志物组对混合成人ICU人群中阿基的早期诊断和预后具有独立和附加价值（特定目的1a和1b）。候选人将学习应用新兴的蛋白质组学技术，如液相色谱串联质谱（LC-MS-MS），以发现和验证能够在初始阿基诊断时预测损伤进展的新的潜在蛋白质靶点（具体目标2）。拟议的研究计划将进一步确定有前途的候选标志物在提供额外的病理生理学见解，增强风险分层和促进临床试验招募方面的作用。此外，本提案中包含的研究还将为该候选人提供技能和经验，使其成为一名成功的独立研究者，能够为改善该疾病患者的护理做出重大贡献。 公共卫生相关性：在改善危重患者急性肾损伤（阿基）结局方面的进展受到了迟发性和不可靠损伤标志物（即血清肌酐、尿量）使用的限制。拟定的职业发展奖申请旨在利用2550例重症成人患者的大型充分表征队列的优势（VALID -HL 081332）。总体目标是验证能够提高阿基诊断和预后的准确性和及时性的候选损伤生物标志物，并将新兴的蛋白质组学技术应用于识别有进行性损伤风险的患者。

DESCRIPTION (provided by applicant): The Mentored Patient-Oriented Research Career Development Award (K23) will enable Dr. Edward D. Siew to develop into an independent investigator in the clinical and translational study of acute kidney injury (AKI) and establish an independent research program focused on critical illness-associated kidney injury. Through the availability of a carefully constructed program of didactic activities in clinical proteomics, advanced epidemiology, and biostatistics; intensive mentorship by local and international experts; and direct experience in the design, implementation, and interpretation of data derived from a large prospective cohort of critically ill adults, Dr. Siew will use this award to become a highly trained investigator in AKI research. The primary scientific aims of this proposal are to examine the independent and additive impact of biological markers of injury for the early detection and prognosis of AKI in the critically ill and to apply emerging proteomic technology towards the discovery of novel protein markers able to predict progression of injury at the time of early diagnosis. Despite advances in the provision of care, AKI remains a common and devastating occurrence in the critically ill and an independent predictor of morbidity and mortality. Attempts at translating promising interventions into improved outcomes in AKI have been limited belated and unreliable markers of injury (i.e. changes in serum creatinine and urine output) that provide little information on the timing and mechanisms of ongoing injury. These limitations are further magnified in a mixed ICU patient population where the timing and extent of injury is more difficult to define. Using a large, well- phenotyped prospective cohort of critically ill adults (The Validation of Biomarkers for Acute Lung Injury Diagnosis/VALID Study), this proposal will test the hypothesis that a biomarker panel consisting of specific indicators of kidney injury will have independent and additive value for the early diagnosis and prognosis of AKI in a mixed adult ICU population (Specific Aims 1a and 1b). The candidate will learn to apply emerging proteomic techniques such as liquid- chromatography tandem mass-spectrometry (LC-MS-MS) towards discovering and verifying new potential protein targets able to predict progression of injury at the time of initial AKI diagnosis (Specific Aim 2). The proposed research plan will further define the role of promising candidate markers in providing additional pathophysiologic insight, enhancing risk stratification, and facilitating clinical trial enrollment. Further, the research included in this proposal will also provide this candidate with the skill set and experience to develop into a successful independent investigator able to make significant contributions toward improving the care of patients with this disease. PUBLIC HEALTH RELEVANCE: Progress towards improving outcomes in acute kidney injury (AKI) in the critically ill has been limited by the use of belated and unreliable markers of injury (i.e. serum creatinine, urine output). The proposed career development award application seeks to leverage the strengths of a large well-characterized cohort of 2550 critically ill adult patients (VALID - HL081332). The overarching aims are to validate candidate biological markers of injury able to improve the accuracy and timeliness of AKI diagnosis and prognosis as well as to apply emerging proteomic technology towards identifying patients at risk for progressive injury.