is a limited number of studies of longitudinal metabolomics, and virtually none in pediatric CKD. Methods The Chronic Kidney Disease in Children (CKiD) study is a multi-institutional, prospective cohort that enrolled children aged six-months to 16-years with estimated glomerular filtration rate (eGFR) 30-90ml/min/1.73m2. Untargeted metabolomics profiling was performed on plasma samples from the baseline, two-, and four-year study visits. There were technologic updates in the metabolomic profiling platform used between the baseline and follow-up assays. Statistical approaches were adopted to avoid direct comparison of baseline and follow-up measurements. To identify metabolite associations with eGFR or urine protein:creatinine (UPCR) among all three timepoints, we applied linear mixed effects (LME) models. To identify metabolites associated with time, we applied LME models to the two- and four-year follow-up data. We applied linear regression analysis to examine associations between change in metabolite level over time (∆level) and change in eGFR (∆eGFR) and UPCR (∆UPCR). We reported significance based on both the False Discovery Rate (FDR) <0.05 and p<0.05. Results There were 1156 person-visits (N: baseline=626, 2-year=254, 4-year=276) included. There were 622 metabolites with standardized measurements at all three timepoints. In LME modeling, 406 and 343 metabolites associated with eGFR and UPCR at FDR<0.05 respectively. Among 530 follow-up person-visits, 158 metabolites showed differences over time at FDR<0.05. For participants with complete data at both follow-up visits (N=123), we report 35 metabolites with ∆level∼∆eGFR associations significant at FDR<0.05. There were no metabolites with significant ∆level∼∆UPCR associations at FDR<0.05. We report 16 metabolites with ∆level∼∆UPCR associations at p<0.05 and associations with UPCR in LME modeling at FDR<0.05. Conclusion We characterized longitudinal plasma metabolomic patterns associated with eGFR and UPCR in a large pediatric CKD population. Many of these metabolite signals have been associated with CKD progression, etiology, and proteinuria in previous CKD Biomarkers Consortium studies. There were also novel metabolite associations with eGFR and proteinuria detected. Copyright © 2024 by the American Society of Nephrology...

中文翻译：

---

小儿慢性肾病的纵向血浆代谢组模式及其与肾功能和蛋白尿的关系

纵向代谢组学的研究数量有限，而且几乎没有针对儿科 CKD 的研究。方法 儿童慢性肾脏病 (CKiD) 研究是一项多机构前瞻性队列研究，招募了 6 个月至 16 岁的儿童，估计肾小球滤过率 (eGFR) 为 30-90ml/min/1.73m2。对基线、两年和四年研究访视的血浆样本进行了非靶向代谢组学分析。基线和后续检测之间使用的代谢组学分析平台进行了技术更新。采用统计方法来避免直接比较基线和后续测量结果。为了确定所有三个时间点中代谢物与 eGFR 或尿蛋白：肌酐 (UPCR) 的关联，我们应用了线性混合效应 (LME) 模型。为了识别与时间相关的代谢物，我们将 LME 模型应用于两年和四年的随访数据。我们应用线性回归分析来检查代谢物水平随时间的变化 (Δlevel) 与 eGFR (ΔeGFR) 和 UPCR (ΔUPCR) 的变化之间的关联。我们根据错误发现率 (FDR) <0.05 和 p<0.05 报告显着性。结果 共纳入 1156 人次就诊（N：基线 = 626，2 年 = 254，4 年 = 276）。有 622 种代谢物在所有三个时间点都有标准化测量。在 LME 模型中，FDR<0.05 时分别有 406 种和 343 种代谢物与 eGFR 和 UPCR 相关。在 530 名随访人员中，158 种代谢物随着时间的推移显示出 FDR <0.05 的差异。对于两次随访时均具有完整数据的参与者 (N=123)，我们报告了 35 种代谢物，其与 Δlevel∼ΔeGFR 相关性在 FDR<0.05 时显着。在 FDR<0.05 时，没有代谢物与显着的 Δlevel∼ΔUPCR 关联。我们报告了 16 种代谢物，其与 Δlevel∼ΔUPCR 的关联性为 p<0.05，并且在 LME 模型中与 UPCR 的关联性为 FDR<0.05。结论 我们对大量儿童 CKD 人群中与 eGFR 和 UPCR 相关的纵向血浆代谢组模式进行了分析。在之前的 CKD 生物标志物联盟研究中，许多代谢信号与 CKD 进展、病因和蛋白尿有关。还检测到与 eGFR 和蛋白尿相关的新代谢物。版权所有 © 2024 美国肾脏病学会...