TY - JOUR
T1 - Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD
AU - Lee, Arthur M.
AU - Xu, Yunwen
AU - Hooper, Stephen R.
AU - Abraham, Alison G.
AU - Hu, Jian
AU - Xiao, Rui
AU - Matheson, Matthew B.
AU - Brunson, Celina
AU - Rhee, Eugene P.
AU - Coresh, Josef
AU - Vasan, Ramachandran S.
AU - Schrauben, Sarah
AU - Kimmel, Paul L.
AU - Warady, Bradley A.
AU - Furth, Susan L.
AU - Hartung, Erum A.
AU - Denburg, Michelle R.
N1 - Publisher Copyright:
Copyright © 2023 by the American Society of Nephrology.
PY - 2024/1
Y1 - 2024/1
N2 - 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: https://doi.org/10.2215/CJN.0000000000000318
AB - 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: https://doi.org/10.2215/CJN.0000000000000318
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U2 - 10.2215/CJN.0000000000000318
DO - 10.2215/CJN.0000000000000318
M3 - Article
C2 - 37871960
AN - SCOPUS:85182397564
SN - 1555-9041
VL - 19
SP - 13
EP - 25
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 1
ER -