Serially assessed bisphenol A and phthalate exposure and association with kidney function in children with chronic kidney disease in the US and Canada: A longitudinal cohort study

Author summaryWhy was this study done? The prevalence of chronic kidney disease has been steadily increasing over the last 40 years. While there are several known risk factors, such as diabetes and hypertension, few are potentially modifiable. Recent work has suggested kidney function may be affected by exposure to environmental chemicals such as bisphenols and phthalates, which are synthetic compounds used in the manufacturing of plastics and other consumer products. However, these chemicals are non-persistent, and no longitudinal studies to our knowledge have been conducted to investigate their potential impact on kidney function over time. What did the researchers do and find? In urine samples collected annually over 5 years from 618 children and adolescents with chronic kidney disease, we measured bisphenol A, phthalates, and biomarkers of tubular injury and oxidative stress. Clinical renal function outcomes were also monitored and collected over 5 years. We found that bisphenol A and phthalates were associated with increased tubular injury and oxidative stress biomarkers. Although phthalic acid was associated with lower estimated glomerular filtration rate over time, neither bisphenol A nor other phthalates were associated with clinical renal outcomes. What do these findings mean? Bisphenol A and phthalates were not associated with clinical renal function outcomes, but showed consistent positive associations with tubular injury and oxidative stress, which may signal the potential for clinical events to manifest with prolonged follow-up. These findings raise concern about the potential for clinically relevant changes to renal function to develop over time in relation to environmental exposures at current levels. This study suggests that exposure to environmental chemicals may be a potentially modifiable risk factor for the progression of chronic kidney disease. Background Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. Methods and findings Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2 '-deoxyguanosine [8-OHdG] and F-2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F-2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMIz-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F-2-isoprostane levels over time. For example, a 1-SD increase in n-ary sumation di-n-octyl phthalate metabolites was associated with increases in NGAL (beta = 0.13 [95% CI: 0.05, 0.21],p= 0.001), KIM-1 (beta = 0.30 [95% CI: 0.21, 0.40],p <0.001), 8-OHdG (beta = 0.10 [95% CI: 0.06, 0.13],p <0.001), and F-2-isoprostane (beta = 0.13 [95% CI: 0.01, 0.25],p= 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m(2)(95% CI: -0.75, -0.01;p= 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. Conclusions Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.