Gene–metabolite–cardiac associations in the Chronic Kidney Disease in Children (CKiD) study
Year: 2026
Type: article
Abstract: BACKGROUND: Characterizing gene-metabolite-cardiac associations in childhood chronic kidney disease (CKD) has the potential to identify new research directions or therapeutic targets for mitigating the excessive cardiovascular risk in childhood CKD. METHODS: across 54 North American centers. Predictor and outcome variables included genotypes, metabolite levels, left ventricular mass index (LVMI) z-score, and left ventricular filling pressure (E/e'). Multivariable linear regression analyses assessed metabolite associations with either LVMI z-score or E/e', adjusting for age, sex, CKD duration, glomerular etiology, renin-angiotensin-aldosterone-system blockade, hypertension, anemia, dyslipidemia, eGFR, and proteinuria. Significance was based on the Benjamini-Hochberg False Discovery Rate <0.05. Metabolites associated with cardiac markers were carried forward for a metabolite-genome-wide association study (mGWAS). Linear regression calculated the residual metabolite variability not explained by age, sex, and eGFR. Linear regression assessed metabolite residual variability versus genetic variant dosage at the Bonferroni-corrected genome-wide significance threshold (corrected for number of metabolites assessed). RESULTS: 556 unique participants with 574 metabolites and ~8.4 million SNPs were included. Sphingomyelin (d18:2/d18:1) and hypotaurine were associated with LVMI z-score. Isobutyrylglycine and 3beta-hydroxy-5-cholestenoate were associated with E/e'. Multiple genetic variants associated with these metabolites at p < 1.25E-8 (p < [5E-8]/4, Bonferroni-corrected genome-wide significance threshold). CONCLUSIONS: We identified metabolites associated with cardiac markers in children with CKD. We identified genetic associations with variability in these metabolites. Collectively, these gene-metabolite associations suggest roles for inflammation, increased oxidative stress, mitochondrial and energy dysmetabolism, and gut microbial dysbiosis in mediating cardiac pathology in childhood CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.
Source: Pediatric Nephrology
Authors: Arthur M. Lee, Mark M. Mitsnefes, Craig S. Wong, Jennifer Roem, Michael E. March, Hakon Hakonarson, Rui Xiao, Joseph T. Flynn, Susan L. Furth, Bradley A. Warady, Ramachandran S. Vasan, Paul L. Kimmel, Aditya Surapaneni, Eugene P. Rhee, Pascal Schlosser, Morgan E. Grams, Michelle R. Denburg, On behalf of the CKiD Study Investigators
Institutions: Children's Hospital of Philadelphia, University of Pennsylvania, Cincinnati Children's Hospital Medical Center, University of New Mexico Health Sciences Center, Johns Hopkins University, Seattle Children's Hospital, University of Washington, Children's Mercy Hospital, University of Missouri–Kansas City, The University of Texas at San Antonio, George Washington University, New York University, Harvard University, Massachusetts General Hospital, University of Freiburg, University Medical Center Freiburg
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,337
Funders: U.S. Department of Health and Human Services, Children's Hospital of Philadelphia, University of Missouri, University of Minnesota, Johns Hopkins University, Children's Mercy Hospital, Deutsche Forschungsgemeinschaft, National Institutes of Health, Johns Hopkins Bloomberg School of Public Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development
Awards: Chronic Kidney Disease (CKD) Biomarkers Consortium Data Coordinating Center, G2666731977, G3311351653, Identifying genetic drivers of circulating metabolites associated with cardiac risk in pediatric chronic kidney disease, Kausale Inferenz durch maschinelles Lernen: Nutzung multidimensionaler omicsDaten für ein besseres Verständnis komplexer Krankheiten, Chronic Kidney Disease Biomarkers Consortium (CKD BioCon) U01, CKD Biomarker Consortium-Phase 2: Risk Markers in Blood, Pediatric investigation for genetic factors linked to renal progression (PediGFR), Mentoring Early Career Researchers in Patient-Oriented Research in Kidney Disease, The Central Biochemistry Laboratory for the Chronic Kidney Disease in Children Cohort (CKiD), The Kidney Disease in Children Data Management and Analysis Center (KIDMAC), Chronic Kidney Disease in Children (CKiD), Chronic Kidney Disease in Children (CKiD V), A multi-omic investigation of uremic toxin sources and accumulation in children with kidney failure, The Penn-StARR Program for Research in Residency
OpenAlex ID: W7225318927