Metabolite biomarkers of ckd progression in children

Michelle R. Denburg, Yunwen Xu, Alison G. Abraham, Josef Coresh, Jingsha Chen, Morgan E. Grams, Harold I. Feldman, Paul L. Kimmel, Casey M. Rebholz, Eugene P. Rhee, Ramachandran S. Vasan, Bradley A. Warady, Susan L. Furth, Alison Abraham, Amanda Anderson, Shawn Ballard, Joseph Bonventre, Clary Clish, Heather Collins, Steven CocaJosef Coresh, Rajat Deo, Michelle Denburg, Ruth Dubin, Harold I. Feldman, Bart S. Ferket, Meredith Foster, Susan Lynn Furth, Peter Ganz, Daniel Gossett, Morgan Grams, Jason Greenberg, Orlando M. Gutiérrez, Tom Hostetter, Lesley A. Inker, Joachim Ix, Paul L. Kimmel, Jon Klein, Andrew S. Levey, Joseph Massaro, Gearoid McMahon, Theodore Mifflin, Girish N. Nadkarni, Chirag Parikh, Vasan S. Ramachandran, Casey Rebholz, Eugene Rhee, Brad Rovin, M. Sarnak, Venkata Sabbisetti, Jeffrey Schelling, Jesse Seegmiller, Michael G. Shlipak, Haochang Shou, Adriene Tin, Sushrut Waikar, Bradley Warady, Krista Whitehead, Dawei Xie

Research output: Contribution to journalArticlepeer-review

Abstract

Background and objectivesMetabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression. Design, setting, participants, & measurementsWe evaluated an untargeted metabolomics quantification of stored plasma samples from645 Chronic Kidney Disease in Children (CKiD) participants.Metaboliteswere standardized and logarithmically transformed. Cox proportional hazards regression examined the association between 825 nondrug metabolites and progression to the composite outcome of KRT or 50% reduction of eGFR, adjusting for age, sex, race, bodymass index,hypertension, glomerular versus nonglomerulardiagnosis,proteinuria, andbaseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR. Results Baseline characteristicswere 391 (61%)male;median age 12 years;median eGFR 54ml/min per 1.73m2; 448 (69%) nonglomerular diagnosis. Over a median follow-up of 4.8 years, 209 (32%) participants developed the composite outcome. Unique association signals were identified in subgroups of baseline eGFR. Among participants with baseline eGFR $60 ml/min per 1.73 m2, two-fold higher levels of seven metabolites were significantly associated with higher hazards of KRT/halving of eGFR events: Three involved in purine and pyrimidine metabolism (N6-carbamoylthreonyladenosine, hazard ratio, 16; 95% confidence interval, 4 to 60; 5,6- dihydrouridine, hazard ratio, 17; 95% confidence interval, 5 to 55; pseudouridine, hazard ratio, 39; 95% confidence interval, 8 to 200); two amino acids, C-glycosyltryptophan, hazard ratio, 24; 95% confidence interval 6 to 95 and lanthionine, hazard ratio, 3; 95%confidence interval, 2 to 5; the tricarboxylic acid cycle intermediate 2-methylcitrate/ homocitrate, hazard ratio, 4; 95%confidence interval, 2 to 7; and gulonate, hazard ratio, 10; 95%confidence interval, 3 to Among those with baseline eGFR,60 ml/min per 1.73 m2, a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9). Conclusions Untargeted plasma metabolomic profiling facilitated discovery of novel metabolite associations with CKD progression in children that were independent of established clinical predictors and highlight the role of select biologic pathways.

Original languageEnglish (US)
Pages (from-to)1178-1189
Number of pages12
JournalClinical Journal of the American Society of Nephrology
Volume16
Issue number8
DOIs
StatePublished - Aug 2021

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation

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