Acute Kidney Injury in Children with Chronic Kidney Disease

项目概述：急性肾损伤(AKI)被定义为肾功能的突然丧失，在慢性肾脏疾病(CKD)的儿童中非常常见。AKI与儿童的高死亡率有关，被认为是永久丧失肾功能和发展为终末期肾脏疾病的危险因素。这些增加的风险要求迫切关注CKD儿童的AKI，以更好地表征AKI的可改变的危险因素，并了解AKI与肾脏健康之间的关系。提高对AKI危险因素和发病机制的认识，将为介入研究预防AKI，限制CKD进展，改善远期预后提供基础。 为了研究慢性肾脏病儿童的AKI，并解决儿科研究中的一个重大空白，我们与儿童慢性肾脏病(CKD)队列的1100名参与者开展了研究，CKiD是CKD儿童的最大队列。每年对所有CKiD参与者进行肾功能、血压和蛋白尿测量的研究访问，最大限度地减少了先前研究的偏差和混淆，这些研究回顾了仅在临床指示时进行的肾功能评估。由于肾小管对生命至关重要，对支持成长中儿童的多种关键功能至关重要，我们将使用肾小球和肾小管健康的生物标志物对肾脏健康进行全球评估。为了解肾小管损伤前后肾小管再生、损伤、功能障碍及炎症反应情况，我们检测了4种尿液生物标志物(表皮生长因子、肾损伤分子-1、单核细胞趋化蛋白-1、α-1微球蛋白)。它们将大大增加对可能有助于AKI后CKD进展的关键通路的检查。在初步数据中，我们观察到，在多变量调整后，这些管状生物标志物中的每一个都与随后的肾功能下降有关。我们还在两个CKiD点观察到，83名儿童中有25名(30%)至少发生一次AKI，AKI患者发生CKD进展的可能性是后者的两倍以上。具体目标是：1)确定肾小球和肾小管健康特征与AKI风险之间的关系；2)确定AKI与GFR、血压、蛋白尿、生长发育和肾小管健康生物标志物随后变化的关系；3)结合CKD危险因素、既往AKI特征和肾小管健康生物标志物，开发并验证儿童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，并可能更好地解释CKD儿童的高度可变的长期结果。我们研究的完成将为确定治疗靶点提供新的见解，并支持未来对慢性肾脏病AKI的干预研究。此外，一个有效的风险预测模型和对急性肾损伤与长期预后之间关系的了解可能有助于早期发现和及时治疗急性肾损伤后肾功能减退。

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.