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Multicenter Study
. 2024 Jan 1;19(1):13-25.
doi: 10.2215/CJN.0000000000000318. Epub 2023 Oct 23.

Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD

Arthur M Lee  1 , Yunwen Xu  2 , Stephen R Hooper  3 , Alison G Abraham  4 , Jian Hu  5 , Rui Xiao  6   7 , Matthew B Matheson  2 , Celina Brunson  8 , Eugene P Rhee  9   10 , Josef Coresh  2   11 , Ramachandran S Vasan  12   13 , Sarah Schrauben  14   15 , Paul L Kimmel  16 , Bradley A Warady  17   18 , Susan L Furth  1   15   19   20 , Erum A Hartung  1   21 , Michelle R Denburg  1   15   20 ; CKD Biomarkers Consortium
Collaborators, Affiliations
Multicenter Study

Circulating Metabolomic Associations with Neurocognitive Outcomes in Pediatric CKD

Arthur M Lee et al. Clin J Am Soc Nephrol. .

Abstract

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.

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Conflict of interest statement

A.G. Abraham reports consultancy for Implementation Group, Inc.; research funding from NIH; honoraria from Elsevier; and advisory or leadership role as an Associate Editor of American Journal of Epidemiology and an Associate Editor of Population Health Metrics. J. Coresh reports employment with The Johns Hopkins University, Welch Center for Prevention, Epidemiology, and Clinical Research and research funding from the National Institutes of Health. M.R. Denburg reports research funding from Mallinckrodt; patents or royalties from InBore LLC; advisory or leadership role on the Editorial Board of Kidney International Reports and on KDIGO Executive Committee; and other interests or relationships with American Society of Pediatric Nephrology Research and Program Committees. M.R. Denburg's spouse reports consultancy for TriSalus Life Sciences; ownership interest in InBore LLC, Instylla, and Precision Guided Interventions LLC; and an advisory or leadership role for TriSalus Life Sciences Scientific Advisory Board. S.L. Furth reports consultancy for Genentech. E.A. Hartung reports advisory or leadership role for Polycystic Kidney Disease Foundation—Scientific Advisory Committee and PKD in Children Council/ARPKD Task Force (volunteer) and other interests or relationships as American Society of Pediatric Nephrology member and American Board of Pediatrics—Nephrology Subboard Member. P.L. Kimmel reports employment with National Institute of Diabetes and Digestive Kidney Diseases (NIDDK); royalties for co-editing Chronic Renal Disease and Psychosocial Aspects of Chronic Kidney Disease and royalties from Mayo Clinic Press for The Body's Keepers; patents or royalties from Elsevier; advisory or leadership role as an unpaid member of Board of Directors of Academy of Medicine of Washington, DC; and other interests or relationships as Co-Editor of Chronic Renal Disease (Academic Press) and Co-Editor of Psychosocial Aspects of Chronic Kidney Disease. As a Federal Employee at NIDDK, P.L. Kimmel's holdings are reviewed each year for potential conflicts of interest. At this time, P.L. Kimmel's only stock holding related in any fashion to health care is CVS and GE Healthcare. M.B. Matheson reports employment with Johns Hopkins Bloomberg School of Public Health and research funding from Toshiba Corporation. R.S. Vasan reports consultancy for NIDDK. B.A. Warady reports consultancy for Amgen, Bayer, GlaxoSmithKline, Light Line Medical, and UpToDate; research funding from Baxter Healthcare; honoraria from Amgen, Bayer, GlaxoSmithKline, and UpToDate; advisory or leadership role as Vice President of North American Pediatric Renal Trials and Collaborative Studies; and advisory or leadership roles on National Kidney Foundation Board of Directors, NTDS Board of Directors, and Midwest Transplant Network Governing Board. Y. Xu reports employment with Johns Hopkins School of Public Health. All remaining authors have nothing to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Neurocognitive assessments in CKiD and NiCK. There were slight differences in the number of CKiD participants with complete assessments per domain, denoted above each bar. Each point represents the median neurocognitive assessment z-score, and the whiskers represent the interquartile range. There were differences in neurocognitive assessment z-scores between all four sample groups on the basis of Kruskal–Wallis tests: intelligence (P = 0.027), working memory (P < 0.001), and parental rating of executive function (P < 0.001). Differences between CKD sample groups and the NiCK control group were assessed with Wilcoxon rank-sum tests. The CKiD baseline sample had lower intelligence (P = 0.0068) and executive function (P < 0.001). The CKiD follow-up sample had lower executive function (P < 0.001). The NiCK CKD sample had lower attention regulation (P = 0.028), working memory (P = 0.027), and executive function (P = 0.0012). The Wilcoxon rank-sum test showed significant difference in working memory between CKiD (baseline and follow-up) and NiCK (CKD and controls), P < 0.001. CKiD, Chronic Kidney Disease in Children; NiCK, Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease.
Figure 2
Figure 2
Significant metabolites in CKiD longitudinal internal replication. Associated neurocognitive domain is denoted by dot shape and color. Metabolites of interest are annotated. Notably, parental ratings of executive function associated with gut microbiome–derived phenylacetylglutamine. In analyses not adjusted for eGFR, executive function also associated with metabolites previously associated with pediatric CKD progression: N6-carbamoylthreonyladenosine, c-glycosyltryptophan, 5,6-dihydrouridine, and 2,3-dihydroxy-5-methylthio-4-pentenoate (DMTPA). CMPF, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate.
Figure 3
Figure 3
Significant metabolites in NiCK CKD external replication. Associated neurocognitive domain is denoted by dot shape and color. Metabolites of interest are annotated. Kynurenine and γ-glutamyl-amino acids positively associated with intelligence z-score.
See this image and copyright information in PMC

References

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