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 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 OBJECTIVES: Metabolomics facilitates the discovery of biomarkers and potential therapeutic targets for CKD progression.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated an untargeted metabolomics quantification of stored plasma samples from 645 Chronic Kidney Disease in Children (CKiD) participants. Metabolites were 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, body mass index, hypertension, glomerular versus nonglomerular diagnosis, proteinuria, and baseline eGFR. Stratified analyses were performed within subgroups of glomerular/nonglomerular diagnosis and baseline eGFR.

RESULTS: Baseline characteristics were 391 (61%) male; median age 12 years; median eGFR 54 ml/min per 1.73 m 2; 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 m 2, 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 29. Among those with baseline eGFR <60 ml/min per 1.73 m 2, 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
Externally publishedYes

Bibliographical note

Funding Information:
A.G. Abraham reports receiving honoraria from the National Institutes of Health (NIH) for serving on a data monitoring board, on the Rare Kidney Stone disease study data monitoring board, and as an Associate Editor of American Journal of Epidemiology; and reports being funded through the National Institute on Aging, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute (NHLBI). B.A. Warady reports consultancy agreements with Akebia, Amgen, Baxter, Bayer, GlaxoS-mithKline, Reata, and Relypsa; reports receiving research funding from Baxter Healthcare; reports receiving honoraria from Akebia, GlaxoSmithKline, Reata, Relypsa, and University of Missouri; and reports serving as a scientific advisor or member of National Kidney Foundation (NKF), North American Pediatric Renal Trials and Collaborative Studies, and Nephrologists Transforming Dialysis Safety (NTDS) Board of Directors. C. Rebholz reports serving as an Editorial Board member for Diabetes Care and as an Editorial Fellow for JASN. H.I. Feldman reports consultancy agreements with DLA Piper, InMed Inc., Kyowa Hakko Kirin Co, Ltd. (ongoing), and NKF (ongoing); reports receiving honoraria from Rogosin Institute (invited speaker); reports serving as scientific advisor or member of the American Journal of Kidney Disease, Editor-in-Chief Steering Committee, Chronic Renal Insufficiency Cohort Study, Editor-in-Chief; and the NKF (member of Advisory Board). J. Coresh reports consultancy agreements with Healthy.io, Kaleido, and Ultragenyx; ownership interest in Health.io; receiving research funding from National Institutes of Health and the NKF (which receives industry support); and reports serving as a scientific advisor or member of Healthy.io and NKF. M. Grams reports receiving honoraria from academic institutions for giving grand rounds and ASN for Young Investigator Award; reports serving as a scientific advisor or member of American Journal of Kidney Diseases, CJASN, JASN Editorial Fellowship Committee, NKF Scientific Advisory Board, Kidney Disease: Improving Global Outcomes (KDIGO) Executive Committee, and United States Renal Data System Scientific Advisory Board; reports other interests/relationships with the NKF, which receives funding from Abbvie, Relypsa, and Thrasos; and reports receiving travel support from Dialysis Clinic, Inc (DCI) to speak at the annual meeting and KDIGO for participation in scientific meetings and the executive committee. M.R. Denburg reports receiving research funding from Mallinckrodt and serving on the NKF Delaware Valley Medical Advisory Board; reports grants from Mallinckrodt Pharmaceuticals, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Complementary and Integrative Health (NCCIH), Patient-Centered Outcomes Research Institute (PCORI), The Children’s Hospital of Philadelphia, outside the submitted work; and their spouse reports consultancy agreements with Trisalus Life Sciences, ownership interest in Precision Guided Interventions and In-Bore, and serving on the Trisalus Life Sciences Scientific Advisory Board. P.L. Kimmel reports serving as and receiving royalties as Co-Editor of Chronic Renal Disease Academic Press and Psychosocial Aspects of Chronic Kidney Disease Academic Press. R.S. Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine; and reports reports consultancy agreements with NIDDK. All remaining authors have nothing to disclose.

Funding Information:
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The CKiD study is funded by the NIH: NIDDK, National Institute of Child Health and Human Development (NICHD), and the NHLBI. The views expressed in this article are those of the authors and do necessarily represent the official view of the NIDDK, the NIH, the Department of Health and Human Services, or the government of the United States.

Funding Information:
This work was supported by NIDDK grants U01DK085689, U01DK103225, and K23DK093556.

Funding Information:
This work was supported by NIDDK grants U01DK106982, U01DK085689, U01DK103225, and K23DK093556.

Publisher Copyright:
© 2021 by the American Society of Nephrology.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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