Consistency of metabolite associations with measured glomerular filtration rate in children and adults

Abstract

Abstract Background and hypothesis There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation. Methods We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study, and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform, and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR (r < −0.5), we assessed additional variation by age (height in children), sex, race, and BMI. Results A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race, and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates, and nucleotides were more often negatively correlated with mGFR compared to lipids, but there was no association with metabolite molecular weight, LC/MS platform, and measurement CV. Among 114 metabolites with strong negative associations with mGFR (r<−0.5), 27 were consistently not associated with age (height in children), sex, or race. Conclusions The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI, and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR.