Acute Kidney Injury in Children with Chronic Kidney Disease

慢性肾病儿童的急性肾损伤

• 批准号: 10638267
• 负责人: Jason Henry Greenberg
• 金额: $ 36.5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10638267
• 关键词: Acceleration; Acute Renal Failure with Renal Papillary Necrosis; Address; Adult; Albumins; Albuminuria; Biological; Biological Markers; Blood Pressure; CCL2 gene; Characteristics; Child; Childhood; Childhood Injury; Chronic Kidney Failure; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cohort Studies; Creatinine; Data; Disease Progression; Early Diagnosis; Electronic Health Record; End stage renal failure; Epidermal Growth Factor; Etiology; Event; Fibrosis; Foundations; Functional disorder; Future; Growth; Health; Height; Incidence; Inflammation; Injury; Intervention; Intervention Studies; Kidney; Life; Link; Measurement; Measures; Modeling; Molecular; Natural regeneration; Outcome; Participant; Pathogenesis; Pathway interactions; Pediatric Research; Persons; Prospective cohort; Proteinuria; Public Health; Quality of life; Recording of previous events; Renal function; Renal tubule structure; Research; Risk; Risk Factors; Role; Serum; Severities; Site; Tubular formation; Urine; Visit; alpha-1-microglobulin; clinical decision-making; clinical trial enrollment; cohort; comorbidity; epidemiology study; follow-up; high risk; improved; insight; modifiable risk; mortality; mortality risk; nephrogenesis; post gamma-globulins; preclinical study; prevent; progression risk; rat KIM-1 protein; renal damage; research study; risk prediction model; therapeutic target; years of life lost

Project Summary: Acute kidney injury (AKI) is defined as an abrupt loss of kidney function and is very common in children with chronic kidney disease (CKD). AKI is associated with high mortality rates in children and is thought to be a risk factor for a permanent loss of kidney function and development of end stage kidney disease. These elevated risks require urgent focus on AKI in children with CKD to better characterize the modifiable risk factors of AKI as well as understand the relationship between AKI and kidney health. Improving the understanding of the risk factors and pathogenesis of AKI will provide a basis for interventional studies to prevent AKI, limit progression of CKD, and improve long-term outcomes. To study AKI in children with CKD and address a substantial gap in pediatric research, we have developed research studies with the 1100 participants of the CKD in Children (CKiD) cohort, the largest cohort of children with CKD. The yearly study visits with kidney function, blood pressure, and albuminuria measurements for all CKiD participants minimizes the bias and confounding of previous research which retrospectively examined kidney function assessments performed only when clinically indicated. As the kidney tubules are critical to life and essential to supporting multiple critical functions in a growing child, we will conduct a global assessment of kidney health using biomarkers of both glomerular and tubular health. To characterize tubular health including tubular regeneration, injury, dysfunction, and inflammation before and after AKI, we will measure 4 urine biomarkers (epidermal growth factor, kidney injury molecule-1, monocyte chemoattractant protein-1, α-1 microglobulin). They will add substantially to the examination of key pathways that may contribute to CKD progression after AKI. In preliminary data, we observed that after multivariable adjustment, each of these tubular biomarkers is associated with a subsequent decline in kidney function. We also observed at two CKiD sites, that 25 of 83 children (30%) developed at least one episode of AKI and that those with AKI were more than twice as likely to develop CKD progression. The specific aims are: 1) Determine the relationship between characteristics of glomerular and tubular health with the risk of AKI; 2) Determine the association between AKI with the subsequent change of GFR, blood pressure, albuminuria, growth, and tubular health biomarkers; 3) Develop and validate a risk prediction model for future progression of CKD in children combining CKD risk factors, prior AKI characteristics, and biomarkers of tubule health. Our research will represent a foundational epidemiologic study of AKI and may better explain the highly variable long-term outcomes in children with CKD. Completion of our research will provide new insights to identify therapeutic targets and support future interventional studies of AKI in CKD. Furthermore, a validated risk prediction model and understanding of the relationship between AKI and long-term outcomes may provide for the early detection and prompt treatment of GFR decline after AKI.

项目摘要：急性肾脏损伤（AKI）被定义为肾功能的突然丧失，并且在患有慢性肾脏疾病（CKD）的儿童中非常普遍。 AKI与儿童的死亡率高有关，被认为是肾功能永久丧失和末期肾脏疾病发展的危险因素。这些升高的风险需要紧急关注CKD儿童的AKI，以更好地表征AKI的可修改风险因素，并了解AKI和肾脏健康之间的关系。提高对AKI风险因素和发病机理的理解将为介入研究提供基础，以防止AKI，限制CKD的进展并改善长期结局。 为了研究CKD儿童的AKI并解决小儿研究的巨大差距，我们与CKD的1100名参与者（CKID）同伙（CKID）共同开发了研究，这是CKD的最大儿童。所有CKID参与者的肾功能，血压和蛋白尿测量的年度研究访问最小化了先前的研究的偏见和混淆，这些研究回顾性地检查了肾脏的功能，因为肾脏块茎对生命至关重要，对于在成长中的孩子中支持多个关键功能至关重要，我们将使用Biomarkers of Glomarker of Glomardormart of Glomarker and to glomarkers and Chembers negral of Bigrand Chimpt。为了表征肾小管健康，包括管状再生，损伤，功能障碍和AKI之前和之后的注射，我们将测量4种尿液生物标志物（表皮生长因子，肾脏损伤分子-1，单核细胞介绍剂蛋白-1，α-1微球蛋白）。它们将大大增加对AKI后CKD进展的关键途径的检查。在初步数据中，我们观察到，经过多变量的调整，这些管状生物标志物中的每一个都与随后的肾脏功能下降有关。我们还在两个CKID站点观察到，83名儿童（30％）中有25个发表了AKI的一集，而患有AKI的孩子则产生了CKD进展的可能性是两倍以上。具体目的是：1）确定肾小球和管状健康特征与AKI风险之间的关系； 2）确定AKI与随后的GFR，血压，蛋白尿，生长和管状健康生物标志物之间的关联； 3）在结合CKD风险因素，先前的AKI特征和小管健康生物标志物的儿童中，开发和验证CKD未来进展的风险预测模型。我们的研究将代表AKI的基础流行病学研究，并可以更好地解释CKD儿童的长期长期结局。我们的研究完成将提供新的见解，以确定治疗靶标并支持CKD中AKI的未来介入研究。此外，经过验证的风险预测模型以及对AKI与长期结局之间关系的理解可能会提供AKI后GFR下降的早期检测和迅速治疗。