Related Experiment Video
Updated: Jul 12, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD
Arthur M Lee1, Yunwen Xu2, Stephen R Hooper3
1Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Insights
Metabolites linked to gut health, energy, and toxins impact children's brain function in chronic kidney disease (CKD). This study identifies key metabolic markers for neurocognitive dysfunction in pediatric CKD patients.
Area of Science:
- Pediatric Nephrology
- Neuroscience
- Metabolomics
Background:
- Children with chronic kidney disease (CKD) face risks of impaired neurocognitive functioning.
- Investigating metabolic profiles can reveal underlying causes of cognitive deficits in pediatric CKD.
Purpose of the Study:
- To identify specific metabolites associated with neurocognitive performance in children with CKD.
- To explore the relationship between metabolic alterations and various domains of neurocognition.
Main Methods:
- Utilized data from the CKiD and NiCK studies, analyzing plasma and serum samples from children with CKD and healthy controls.
- Employed untargeted metabolomic quantification and assessed neurocognitive domains including intelligence, attention, working memory, and executive function.
- Applied linear regression and mixed-effects models, adjusting for relevant clinical factors and eGFR.
Main Results:
- Identified multiple significant associations between specific metabolites and neurocognitive outcomes across analytic samples.
- Observed elevated levels of most associated metabolites in children with CKD compared to controls.
- Highlighted associations with executive function (phenylacetylglutamine, indoleacetylglutamine, trimethylamine N-oxide) and intelligence (γ-glutamyl amino acids, aconitate).
Conclusions:
- Several metabolites are linked to neurocognitive dysfunction in pediatric CKD.
- Findings suggest implications of gut microbiome, mitochondrial dysfunction, altered energy metabolism, and redox homeostasis.
- Metabolomic analysis offers insights into the complex pathophysiology of cognitive impairment in pediatric CKD.
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 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). 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: γ -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.
Podcast:
This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_11_17_CJN0000000000000318.mp3.
Related Concept Videos
01:24Chronic Kidney Disease II: Clinical Manifestations
01:28Chronic Kidney Disease III: Interprofessional Care
01:25Chronic Kidney Disease I: Introduction
01:18Chronic Kidney Disease IV: Nursing Management
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention
01:29Renal Regulation of Acid-Base Balance
In the kidneys, cells within the proximal convoluted tubules (PCT) and the collecting ducts secrete hydrogen ions (H+) into the tubular fluid. Specifically, in the PCT, Na+/H+ antiporters secrete H+ while reabsorbing Na+.
However, the intercalated cells in...