Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD

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

doi:10.2215/cjn.0000000000000318

Cited by 2 publications

(5 citation statements)

References 91 publications

(142 reference statements)

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“…These compounds are believed to be mitochondrial toxins and have been previously associated with worse neurocognitive outcomes in children with CKD. 18,88,89 These novel signals support the impetus for research into how mitochondrial function may be impaired by kidney function decline.…”

Section: Discussionmentioning

confidence: 92%

“…We recently reported these metabolites were positively correlated with neurocognitive assessments in children with CKD. 18 These g-glutamyl amino acids are believed to be downstream products of g-glutamyl transpeptidase (GGT1) in glutathione metabolism, and GGT1 is abundantly expressed in the proximal tubule. [80][81][82] We previously hypothesized that elevated g-glutamyl amino acids levels suggest a protective metabolic adaptation against increased oxidative stress in children with CKD.…”

Section: Discussionmentioning

confidence: 99%

“…[80][81][82] We previously hypothesized that elevated g-glutamyl amino acids levels suggest a protective metabolic adaptation against increased oxidative stress in children with CKD. 18 It is interesting that these metabolite levels are more strongly linked to proteinuria than eGFR. This merits continued study as oxidative stress is gaining interest as a potentially modifiable target in many disease states.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13][14][15][16] Untargeted metabolomics studies in pediatric CKD have identified novel metabolite biomarkers of CKD progression, etiology, and neurocognition. 2,17,18 Our recently published study on neurocognition was one of the first and largest studies of repeated longitudinal untargeted metabolomic associations with a clinical outcome in pediatric CKD. 18 Studies with repeated longitudinal untargeted metabolomic profiling are limited, particularly in pediatrics.…”

Section: Introductionmentioning

confidence: 99%

“…2,17,18 Our recently published study on neurocognition was one of the first and largest studies of repeated longitudinal untargeted metabolomic associations with a clinical outcome in pediatric CKD. 18 Studies with repeated longitudinal untargeted metabolomic profiling are limited, particularly in pediatrics. [19][20][21] The CKD in Children (CKiD) cohort provides a unique opportunity to study longitudinal metabolomic patterns in children with CKD.…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD

Lee,

Xu,

et al. 2024

CJASN

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Introduction Understanding plasma metabolome patterns in relation to changing kidney function in pediatric chronic kidney disease (CKD) is important for continued research for identifying novel biomarkers, characterizing biochemical pathophysiology, and developing targeted interventions. There is a limited number of studies of longitudinal metabolomics, and virtually none in pediatric CKD. Methods The Chronic Kidney Disease in Children (CKiD) study is a multi-institutional, prospective cohort that enrolled children aged six-months to 16-years with estimated glomerular filtration rate (eGFR) 30-90ml/min/1.73m2. Untargeted metabolomics profiling was performed on plasma samples from the baseline, two-, and four-year study visits. There were technologic updates in the metabolomic profiling platform used between the baseline and follow-up assays. Statistical approaches were adopted to avoid direct comparison of baseline and follow-up measurements. To identify metabolite associations with eGFR or urine protein:creatinine (UPCR) among all three timepoints, we applied linear mixed effects (LME) models. To identify metabolites associated with time, we applied LME models to the two- and four-year follow-up data. We applied linear regression analysis to examine associations between change in metabolite level over time (∆level) and change in eGFR (∆eGFR) and UPCR (∆UPCR). We reported significance based on both the False Discovery Rate (FDR) <0.05 and p<0.05. Results There were 1156 person-visits (N: baseline=626, 2-year=254, 4-year=276) included. There were 622 metabolites with standardized measurements at all three timepoints. In LME modeling, 406 and 343 metabolites associated with eGFR and UPCR at FDR<0.05 respectively. Among 530 follow-up person-visits, 158 metabolites showed differences over time at FDR<0.05. For participants with complete data at both follow-up visits (N=123), we report 35 metabolites with ∆level∼∆eGFR associations significant at FDR<0.05. There were no metabolites with significant ∆level∼∆UPCR associations at FDR<0.05. We report 16 metabolites with ∆level∼∆UPCR associations at p<0.05 and associations with UPCR in LME modeling at FDR<0.05. Conclusion We characterized longitudinal plasma metabolomic patterns associated with eGFR and UPCR in a large pediatric CKD population. Many of these metabolite signals have been associated with CKD progression, etiology, and proteinuria in previous CKD Biomarkers Consortium studies. There were also novel metabolite associations with eGFR and proteinuria detected.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD

Lee,

Xu,

et al. 2024

CJASN

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Genome-wide Association Studies of Missing Metabolite Measures: Results From Two Population-based Studies

Faquih,

Imtiaz,

Talevi

et al. 2024

Preprint

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Metabolomic studies are increasingly used for both etiological and predictive research, but frequently report missing values. We hypothesized that interindividual genetic variation may account for part of this missingness. Therefore, we performed a GWAS of missingness in measured metabolite levels using an untargeted mass spectrometry-based platform in the Netherlands Epidemiology of Obesity Study (N=594) and the Rhineland Study (N=4,165). We considered metabolites missing in 10%-90% of individuals in both cohorts (N=224). GWAS meta-analyses of these metabolites' probability of missingness revealed 55 metabolome-wide significant associations, including 42 novel ones (p<1.58x10-10), involving 28 metabolites and 41 lead SNPs. Despite considerable pleiotropy, the majority of identified SNP-"missing metabolite" associations were biologically plausible, relating to beta-oxidation, bile acids, steroids, and xenobiotics metabolism. These findings suggest that missing values in metabolomics are nonrandom and partly reflect genetic variation, accounting for which is important for both clinical and epidemiological studies, especially nutritional and pharmacogenetics studies.

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Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD

Cited by 2 publications

References 91 publications

Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD

Longitudinal Plasma Metabolome Patterns and Relation to Kidney Function and Proteinuria in Pediatric CKD

Genome-wide Association Studies of Missing Metabolite Measures: Results From Two Population-based Studies

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