AKI: Biomarker Guided Therapies

急性肾损伤（AKI）是一种常见的临床问题，其定义是由于损伤或侮辱导致肾脏功能或结构改变而导致血清肌酐（SCr）突然（< 48小时）升高。尽管在重症儿童的护理方面取得了重大进展，但发展为AKI的儿童的死亡率并没有改善。利用基因组学和蛋白质组学技术，我们发现中性粒细胞明胶酶相关脂钙蛋白（NGAL）是一种生物标志物，在肾损伤后很早就在肾脏中大量产生。我们为这些补充研究制定了三个目标：NGAL定向治疗以预防AKI， NGAL定向治疗以优化对AKI患者的支持，以及生物标志物/蛋白质组学分析以预测或早期检测CKD发展。因此，这项建议的具体目标是：目标1。预防AKI -该目的将根据血浆NGAL护理点检测，确定对有AKI风险的儿童给予非诺多泮是否会预防CPB后AKI的发生。AKI将根据修改后的儿科RIFLE （pRIFLE）标准确定。使用pRIFLE， AKI将定义为手术后48小时内6小时内肌酐清除率较术前基线水平下降≥25%或尿量< 0.5 ml/kg/hr。目标2。预防AKI的急性并发症——这一目标将确定持续升高的NGAL是否可以预测哪些危重儿童最终会出现显著（bbb10 %）的ICU积液阳性超过24小时，从而优化透析启动。目的3：预测AKI的长期后果-该目的将评估尿蛋白组学特征，以发现新的生物标志物，以预测AKI的恢复和/或AKI向CKD的过渡。多学科的研究团队，包括儿科肾病学家、重症医师、心脏病学家和生物统计学家，将广泛使用蛋白质组学核心（Core B）和生物标志物核心（Core C）来成功完成这个项目。

Acute Kidney Injury (AKI) is a common clinical problem defined by an abrupt (< 48 hour) increase in serum creatinine (SCr) resulting from an injury or insult causing a functional or structural change in the kidney. Despite significant advancements in the care of the critically ill child, mortality rates in children who develop AKI have not improved. Using genomic and proteomic technologies, we identified neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker that is produced in high levels in the kidney very early after kidney injury. We have developed three aims for these complementary studies: NGAL directed therapy to prevent AKI, NGAL directed therapy to optimize support for patients who develop AKI and biomarker/proteomic profiling to predict or detect CKD development early. Accordingly the specific aims of this proposal are: Aim 1. Prevent AKI - this aim will determine if the administration of fenoldopam to children at risk for AKI, based upon plasma NGAL point of care testing, will prevent the occurrence of AKI following CPB. AKI will be determined based on the modified pediatric RIFLE (pRIFLE) criteria. Using pRIFLE, AKI will be defined as an estimated creatinine clearance decrease by ≥ 25% from preoperative baseline level or urine output < 0.5 ml/kg/hr for 6 hours within 48h of surgery. Aim 2. Prevent acute complications of AKI - this aim will determine if persistently elevated NGAL can predict which critically ill children will ultimately develop significant (>10%) positive ICU fluid accumulation for more than 24 hours and thereby optimize dialysis initiation. Aim 3: Predict long term consequences of AKI - this aim will assess urinary proteomic profiles for discovery of novel biomarkers to predict the AKI recovery and/or transition of AKI to CKD. The multidisciplinary team of investigators, including pediatric nephrologists, intensivists, cardiologists, and biostatisticians will extensively employ the Proteomics Core (Core B) and the Biomarker Core (Core C) for the successful completion of this project.