儿童至成年肥胖指标的变化轨迹对慢性肾病的影响及相关机制研究

The clinical manifestations of chronic kidney disease (CKD) mainly occur at middle and older ages, but the progress may begin at an early life. Previous studies have demonstrated that childhood obesity is associated with adult CKD. However, these studies are limited to white populations, and adiposity indexes were only measured once in childhood. .In the present project, we plan to follow up the subjects who were from the Beijing Blood Pressure Cohort study started in 1987 (n=3198, 6-18 years). We have conducted 10 follow-up surveys, which result in multiple measurements of adiposity indexes. We plan to invite all participants from the original studies to have a clinical examination during 2019-2020. During the follow-up survey, data on CKD, metabolic diseases, insulin, inflammatory biomarkers, and adipokines will be collected. .A mixed-effect model will be used to establish the growth curve of each adiposity index for each individual. The cumulative burden and variability during the follow-up, as well as the level and rate of change at each age, will be estimated. A latent class growth model will be used to identify different trajectories of each adiposity measure and classify individuals into distinct groups with similar underlying trajectories. One objective of this study is to examine the association of these variables with adult CKD risk. In addition, using mediation effect analysis, we will evaluate the mediation effect of metabolic diseases, insulin, inflammation, and adipokines on the association between childhood adiposity and adult CKD risk. The results from this project will provide strong evidence for early prevention of CKD.

慢性肾病（CKD）临床症状常出现在成人，但其病变过程在儿童时期已经开始。前期研究发现儿童肥胖可预测成年CKD发生风险，但这些研究局限于白种人，且儿童期肥胖指标仅测量一次。.本项目基于始于儿童的“北京儿童血压队列”研究（n=3198，6-18岁，1987年）。本队列前期已经进行10次阶段性随访，获得肥胖指标（体质指数及皮褶厚度）的多次测量数据。本项目拟于2019-2020年进行临床随访，内容包括评估CKD和代谢性疾病，并测定血中胰岛素、炎性因子及脂肪细胞因子的水平。基于队列基线及多次随访数据，本研究拟采用混合效应模型及潜类别增长模型估计肥胖指标在儿童至成年的累积效应、增长速度、变异大小及变化轨迹模式，分析这些因素对成年CKD的预测价值；并采用中介效应分析模型探讨胰岛素抵抗、炎性因子及脂肪细胞因子在儿童肥胖致成年CKD中的作用。研究结果为CKD的早期防治提供基于流行病学的循证依据。

慢性肾病（CKD）是一个沉默隐秘进展的长期病变过程，其病变过程在儿童时期已经开始。本项目通过对北京儿童血压队列的前瞻性随访，评估儿童至成年肥胖指标的变化对成年肾脏损害的影响，并探讨心血管代谢异常、炎症反应、胰岛素抵抗及脂肪细胞因子在儿童肥胖致成年肾脏损害中的作用。本项目采用尿微量白蛋白、肾小球滤过率、胱抑素C及尿酸评估成年肾脏早期损害。基于儿童至成年BMI的多时点测量数据，采用混合效应模型构建个体儿童至成年期的BMI生长曲线，通过计算曲线下面积（即AUC-BMI）评估儿童致成年BMI的累积负担。主要研究结果包括：1）随着儿童期BMI水平的提高，成年期尿酸及胱抑素C水平逐渐升高。2）AUC-BMI与成年尿微量白蛋白、肾小球滤过率及尿酸存在正向关联，但与胱抑素C无关联。调整高血压、糖尿病及血脂异常后，AUC-BMI仅与尿酸存在统计学关联。3）成年期尿微量白蛋白-偏高组的BMI在随访期间的增长速度较快，且BMI差异随着年龄逐渐增大；肾小球滤过率偏低组与肾小球滤过率正常组之间BMI变化曲线无明显差异；成年期尿酸偏高组的BMI在随访期间的增长速度较快，两组间BMI的差异随着年龄逐渐增大；成年期胱抑素C-偏高组的BMI在随访期间的增长速度较快，BMI差异随着年龄逐渐增大。4）儿童期BMI、成年期BMI及AUC-BMI均与成年CRP存在正向关联，而与成年胰岛素及脂联素未发现统计学关联。5）以儿童至成年持续体重正常组为参照，调整性别、年龄，儿童期体重正常-成年期肥胖组及儿童期至成年期持续肥胖组的CRP水平较高，而儿童期肥胖-成年期体重正常组的CRP水平未发现统计学差异。儿童至成年体重状态变化与成年胰岛素及脂联素均无统计学关联。慢性肾脏疾病已成为影响我国居民健康的重大公共卫生问题，且儿童肥胖患病率逐年升高。本项目研究结果提示儿童期肥胖的干预可能会减缓未来慢性肾病的发生风险，将为实现慢性肾病防治窗口子的“前移”和“下移”提供重要的流行病学证据。