Metabolite Biomarkers of CKD Progression in Children

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 m2; 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 29. 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.

Keywords: biomarkers; children; chronic kidney disease; metabolism; pediatric nephrology; progression of chronic renal failure.

Copyright © 2021 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Volcano plot of 825 known, nondrug metabolites for all 645 participants. Fully adjusted included baseline covariates of age, sex, race, BMI Z-score, hypertension, CKD diagnosis (glomerular versus nonglomerular), log base 2 transformed UPCR and eGFR; partially adjusted included all baseline covariates excluding log base 2 transformed UPCR and eGFR. BMI, body mass; FDR, false discovery rate; UPCR, urine protein-creatinine ratio.

Figure 2.

Volcano plot of 825 known, nondrug metabolites for participants by baseline eGFR. Fully adjusted included baseline covariates of age, sex, race, BMI Z-score, hypertension, CKD diagnosis (glomerular versus nonglomerular), log base 2 transformed UPCR and eGFR; partially adjusted included all baseline covariates excluding log base 2 transformed UPCR and eGFR.