@article{01e55c67e23743f49fbd78fc8f7518a7,
title = "Association of GSTM1 Deletion With Progression of CKD in Children: Findings From the Chronic Kidney Disease in Children (CKiD) Study",
abstract = "Rationale & Objective: Loss of function of the product of the GSTM1 gene has been implicated in rapid progression of adult chronic kidney disease (CKD). Its role in pediatric CKD has not been previously described. Study Design: Secondary analysis of a prospective observational cohort examining the association between deletions in GSTM1 and progression of CKD. Setting & Participants: We used data and samples from the prospective Chronic Kidney Disease in Children (CKiD) cohort aged 1-16 years at enrollment with CKD. Exposure: We defined the exposure as fewer than 2 GSTM1 alleles on real-time polymerase chain reaction amplification. Outcome: The primary outcome was a composite of 50% decrease in estimated glomerular filtration rate (eGFR) or start of kidney replacement therapy. Secondary outcomes included remission of proteinuria in children with glomerular disease and cardiovascular complications. Analytical Approach: The primary analysis was by Cox proportional hazards model. Analysis was adjusted for age, sex, race, ethnicity, body mass index category, diagnosis category, and eGFR. Results: The analysis included 674 children. Their mean age at most recent visit was 11.9 years; 61% were male, and 20% were Black. There were 241 occurrences of the primary outcome at the time of analysis. After adjustment for baseline characteristics, the risk of progression of CKD for exposed children was 1.94 (95% CI, 1.27-2.97). The effect size was similar with either 1 or 2 deletions (autosomal dominant inheritance). The relationships between number of functional GSTM1 alleles and prespecified secondary outcomes were not statistically significant after adjustment. Limitations: Missing data, especially for secondary outcomes, and relatively small sample size compared to genetic studies in adults. Conclusions: GSTM1 deletion is associated with more rapid progression of pediatric CKD after adjustment in this large prospective cohort. No statistically significant associations were seen with secondary outcomes. If replicated, these findings may inform development of interventions for CKD in children.",
keywords = "CKD progression, CKiD, Children, GSTM1, GSTM1 null genotype, chronic kidney disease (CKD), gene polymorphism, genetic predisposition to disease, genetics, glutathione S-transferase, oxidative stress, pediatric nephrology, risk factor",
author = "Levy, {Rebecca V.} and Reidy, {Kimberly J.} and Le, {Thu H.} and Victor David and Cheryl Winkler and Yunwen Xu and Bradley Warady and Susan Furth and Frederick Kaskel and Melamed, {Michal L.}",
note = "Funding Information: CKiD ( http://www.statepi.jhsph.edu/ckid ) is funded by the National Institute of Diabetes and Digestive and Kidney Diseases , with additional funding from the National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute ( U01-DK-66143 , U01-DK-66174 , U01DK-082194 , U01-DK-66116 ). Dr Levy is supported by NIDDK T32-DK007110. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health , under contract HHSN26120080001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Funding Information: Rebecca V. Levy, BM, BCh, MSc, Kimberly J. Reidy, MD, Thu H. Le, MD, Victor David, MS, Cheryl Winkler, PhD, Yunwen Xu, MHS, Bradley Warady, MD, Susan Furth, MD, PhD, Frederick Kaskel, MD, PhD, and Michal L. Melamed, MD, MHS. CKiD study design: BW, SF, FK; study design: RVL, KJR, CW, FK, MLM; data analysis/interpretation: VD, CW; statistical analysis: RVL, YX; supervision/mentorship: KJR, THL, CW, FK, MLM. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. CKiD (http://www.statepi.jhsph.edu/ckid) is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, U01-DK-66116). Dr Levy is supported by NIDDK T32-DK007110. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. The authors declare that they have no other relevant financial interests. Data in this manuscript were collected by the CKiD prospective cohort study with clinical coordinating centers at Children's Mercy Hospital and the University of Missouri?Kansas City and Children's Hospital of Philadelphia, Central Biochemistry Laboratory at the University of Rochester Medical Center, and data coordinating center at the Johns Hopkins Bloomberg School of Public Health. Thanks to the CKiD data coordinating center, especially including Judith Jerry, Christopher Pierce, and Derek Ng for logistic and biostatistical support. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Materials from the CKiD cohort including codebooks and data dictionaries are currently available at https://repository.niddk.nih.gov/studies/ckid/. Individual participant data are available after deidentification to investigators after approval of a methodologically sound ancillary proposal. Study protocol and analytic code will be available from the corresponding author immediately after publication for a period of 3 years for any purpose. Received March 8, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form October 14, 2021. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jul,
doi = "10.1053/j.ajkd.2021.10.007",
language = "English (US)",
volume = "80",
pages = "79--86",
journal = "American Journal of Kidney Diseases",
issn = "0272-6386",
publisher = "W.B. Saunders Ltd",
number = "1",
}