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.