TY - JOUR
T1 - Metabolite biomarkers of ckd progression in children
AU - Denburg, Michelle R.
AU - Xu, Yunwen
AU - Abraham, Alison G.
AU - Coresh, Josef
AU - Chen, Jingsha
AU - Grams, Morgan E.
AU - Feldman, Harold I.
AU - Kimmel, Paul L.
AU - Rebholz, Casey M.
AU - Rhee, Eugene P.
AU - Vasan, Ramachandran S.
AU - Warady, Bradley A.
AU - Furth, Susan L.
AU - Abraham, Alison Gump
AU - Anderson, Amanda
AU - Ballard, Shawn
AU - Bonventre, Joseph
AU - Clish, Clary
AU - Collins, Heather
AU - Coca, Steven
AU - Deo, Rajat
AU - Denburg, Michelle
AU - Dubin, Ruth
AU - Feldman, Harold I.
AU - Ferket, Bart S.
AU - Foster, Meredith
AU - Ganz, Peter
AU - Gossett, Daniel
AU - Grams, Morgan
AU - Greenberg, Jason
AU - Gutiérrez, Orlando M.
AU - Hostetter, Tom
AU - Inker, Lesley A.
AU - Ix, Joachim
AU - Kimmel, Paul L.
AU - Klein, Jon
AU - Levey, Andrew S.
AU - Massaro, Joseph
AU - McMahon, Gearoid
AU - Mifflin, Theodore
AU - Nadkarni, Girish N.
AU - Parikh, Chirag
AU - Ramachandran, Vasan S.
AU - Rhee, Eugene
AU - Rovin, Brad
AU - Sarnak, M.
AU - Sabbisetti, Venkata
AU - Schelling, Jeffrey
AU - Seegmiller, Jesse
AU - Shlipak, Michael G.
AU - Shou, Haochang
AU - Tin, Adriene
AU - Waikar, Sushrut
AU - Warady, Bradley
AU - Whitehead, Krista
AU - Xie, Dawei
N1 - Publisher Copyright:
© 2021 by the American Society of Nephrology.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112252965&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112252965&partnerID=8YFLogxK
U2 - 10.2215/CJN.00220121
DO - 10.2215/CJN.00220121
M3 - Article
C2 - 34362785
AN - SCOPUS:85112252965
SN - 1555-9041
VL - 16
SP - 1178
EP - 1189
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 8
ER -