INTRODUCTION Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD. OBJECTIVES The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data. METHODS Untargeted ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th-95th percentile: 66.0-119.6 mL/min/1.73 m2). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th-95th percentile: 43.5-105.0 mL/min/1.73 m2). All analyses used Bonferroni-corrected alpha thresholds. RESULTS Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of C10H12O2 and C10H14O2(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites. CONCLUSION The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers.

中文翻译：

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Bogalusa心脏研究和动脉粥样硬化参与者的多民族研究中血液代谢产物与肾功能之间的新型关联。

简介慢性肾脏病（CKD）是全球主要的公共卫生挑战，因为它的高全球患病率以及心血管疾病和发展为终末期肾病的相关风险。尽管已知CKD患者会发生许多新陈代谢变化，但确定新的代谢物与肾功能的关联可能会增强我们对与CKD相关的生理途径的了解。目的本研究的目的是通过仔细确定的代谢组学，肾脏功能和协变量数据，阐明两个基于社区的队列参与者中与肾脏功能相关的新型代谢物。方法采用非靶向超高效液相色谱-串联质谱法检测和定量血液代谢产物。我们使用多元调整的线性回归分析了1243名Bogalusa心脏研究（BHS）参与者中单一代谢物与基于肌酐的估计肾小球滤过率（eGFRcr）之间的关联（中位eGFRcr：94.4，5-95％百分数：66.0-119.6 mL / min / 1.73平方米）。使用金标准测量的肾小球滤过率（mGFR）在260名多民族动脉粥样硬化研究（MESA）参与者中测试了通过统计学显着性和一致的作用方向确定的复制（中位mGFR：72.0，5-95％百分数：43.5-105.0 mL /min/1.73 m2）。所有分析均使用Bonferroni校正的alpha阈值。结果确定了51种与肾脏功能有关的新代谢产物，其中包括12种以前不相关的子途径：N6-羧甲基赖氨酸，胍糖，喹啉酸酯，γ-CEHC-葡糖醛酸，视黄醇，甲基丙二酸酯，3-羟基-3-甲基戊二酸酯，3-氨基异丁酸酯，N-甲基哌酸酯，硫酸氢醌和C10H12O2和C10H14O2的甘氨酸共轭物（1）。显着的代谢物通常与肾脏功能成反比，并且与非显着的代谢物相比，质荷比更小。结论鉴定出的51种新型代谢物可作为早期，临床相关的肾功能生物标志物。