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

Abstract

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 F2-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 F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-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 F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 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 m2 (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.

Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: HT reports NIDDK grants and consultancy agreements with Retrophin, Goldfinch Bio, Chemocentryx and Otsuka Pharmaceutical.

Figures

Fig 1. Associations between ln-transformed chemical exposures and ln-transformed biomarkers of tubular injury by study visit.

Outcome estimates were derived from adjusted linear mixed-effects (LME) models and correspond to a 1–standard deviation change in each ln-transformed chemical exposure. Numerical estimates are shown in S3 Table. The horizontal dashed line indicates 0. Black dots indicate that the estimate had a p-value < 0.05; white dots indicate a p-value ≥ 0.05. B, baseline; BPA, bisphenol A; DEHP, di(2-ethylhexyl) phthalate; DOP, di-n-octyl phthalate; HMW, high molecular weight phthalates; KIM1, kidney injury molecule-1; LMW, low molecular weight phthalates; Ngal, neutrophil gelatinase-associated lipocalin; PA, phthalic acid; Y[number], year [number].

Fig 2. Associations between ln-transformed chemical exposures and ln-transformed oxidative stress biomarkers by study visit.

Outcome estimates were derived from adjusted linear mixed-effects (LME) models and correspond to a 1–standard deviation change in each ln-transformed chemical exposure. Numerical estimates are shown in S4 Table. The horizontal dashed line indicates 0. Black dots indicate that the estimate had a p-value < 0.05; white dots indicate a p-value ≥ 0.05. 8-OHDG: 8-hydroxy-2′-deoxyguanosine; B, baseline; BPA, bisphenol A; DEHP, di(2-ethylhexyl) phthalate; DOP, di-n-octyl phthalate; HMW, high molecular weight phthalates; LMW, low molecular weight phthalates; PA, phthalic acid; Y[number], year [number].