Association between melamine and phthalates and urinary renal injury markers among children aged 4 years

Abstract Background and Aims Chronic kidney disease (CKD) is a global public health issue and the prevalence and incidence of CKD and end-stage renal disease (ESRD) in Taiwan are among the highest in the world. The pathophysiology of renal function downhill is complex and multifactorial, and previous studies suggest that we should be concerned about the effects of low-dose environmental exposure to melamine and phthalate in increasing the risk of renal injury in susceptible populations such as children. However, the sex difference in renal injury related to environmental exposure among children is unknown. The aim of this study is to investigate the relationship between early renal injury biomarkers and melamine and phthalate exposure among boys and girls aged 4 years in Taiwan. Method In total, 1,676 pregnant women were enrolled in the original Taiwan Maternal and Infant Cohort Study (TMICS), a multicenter birth cohort study conducted at 9 hospitals in northern, central, southern, and eastern Taiwan from October 2012 to May 2015. Of those, 694 children aged 4 years participated in follow-up questionnaire interviews, received physical examinations and blood and urine tests from August 2016 to February 2020. After excluding 142 participants with missing data, the final statistical analysis of follow-up data included 552 children. One-spot overnight urine specimens were used to simultaneously measure melamine, 11 phthalate metabolites, and two markers of renal injury, microalbumin and N-acetyl-beta-D-glucosaminidas (NAG). Average daily intake (ADI) levels of melamine and six parental phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), and DEP (Diethyl phthalate), were estimated using a creatinine excretion-based model from urine melamine and phthalate metabolites. We used a weighted quantile sum (WQS) regression model to select the most important exposure variables of ADI levels of phthalates and melamine associated with urine microalbumin to creatinine ratio (ACR) and NAG; Furthermore, to examine effects of those most important exposure variables on ACR and NAG in multivariable linear regression models. The significance was set as two-sided p < 0.05. Results Of them, 319 (57.8%) and 223(42.2%) were boys and girls, respectively, with a median age of 4.0±0.8 years old. Median ADI levels (µg/kg bw/day) were 5.73 for DEHP, 1.75 for DEP, 3.23 for DnBP, 0.07 for BBzP, 1.37 for DiBP, and 1.18 for melamine and there is not significantly different between boys and girls. Using the WQS regression model to examine the association between ADI levels of melamine and phthalates and urine ACR and NAG, we found that a significant and positive association between the WQS score and ACR (β1 = 0.083, p = 0.023). ADI levels of melamine had the highest weight (0.650). Furthermore, we found that the highest (quartile 4) of ADI levels of melamine had the significantly higher ACR in all children (adjusted β = 0.131, p = 0.036), compared to other quartiles (quartile 1, 2 and 3). In subgroup analysis, the significant association between melamine intake and urine ACR was found in boys (adjusted β = 0.249, p = 0.003), not in girls. Conclusion Environmental exposure to melamine may be associated with urine ACR among children aged 4 years in Taiwan, and boys may be easily affected by melamine exposure.