Jovia L Nierenberg1, Jiang He1,2, Changwei Li1,3, Xiaoying Gu1,4, Mengyao Shi1, Alexander C Razavi1, Xuenan Mi1, Shengxu Li1, Lydia A Bazzano1, Amanda H Anderson1, Hua He1, Wei Chen1, Jason M Kinchen5, Casey M Rebholz6,7, Josef Coresh6,7, Andrew S Levey8, Lesley A Inker8, Michael Shlipak9, Tanika N Kelly10. 1. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2000, New Orleans, LA, 70112, USA. 2. Department of Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA. 3. Department of Epidemiology & Biostatistics, University of Georgia College of Public Health, Athens, GA, USA. 4. Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China. 5. Metabolon, Inc., Morrisville, NC, USA. 6. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. 7. Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA. 8. Division of Nephrology, Tufts Medical Center, Boston, MA, USA. 9. Department of General Internal Medicine, University of California San Francisco, San Francisco, CA, USA. 10. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, Suite 2000, New Orleans, LA, 70112, USA. tkelly@tulane.edu.
Abstract
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.
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 CKDpatients, 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.
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