Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD

Arthur M. Lee, Yunwen Xu, Stephen R. Hooper, Alison G. Abraham, Jian Hu, Rui Xiao, Matthew B. Matheson, Celina Brunson, Eugene P. Rhee, Josef Coresh, Ramachandran S. Vasan, Sarah Schrauben, Paul L. Kimmel, Bradley A. Warady, Susan L. Furth, Erum A. Hartung, Michelle R. Denburg

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD. Methods We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30–90 ml/min per 1.73 m2 (n5569). NiCK is a single-center cross-sectional study of participants aged 8–25 years with eGFR,90 ml/min per 1.73 m2 (n560) and matched healthy controls (n567). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR. Results There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide—and with intelligence: g-glutamyl amino acids and aconitate. Conclusions Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome–derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis. CJASN 19: 13–25, 2024. doi:

Original languageEnglish (US)
Pages (from-to)13-25
Number of pages13
JournalClinical Journal of the American Society of Nephrology
Issue number1
StatePublished - Jan 2024
Externally publishedYes

ASJC Scopus subject areas

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


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