Urinary polycyclic aromatic hydrocarbons in a longitudinal cohort of children with chronic kidney disease: A case of reverse causation?

Background: Air pollution, which results in the formation of polycyclic aromatic hydrocarbons (PAH), has been identified as a cause of renal function decline and a contributor to chronic kidney disease (CKD). However, the results of cross-sectional studies investigating personal, integrated biomarkers of PAHs have been mixed. Longitudinal studies may be better suited to evaluate environmental drivers of kidney decline. The purpose of this study was to examine associations of serially measured urinary PAH metabolites with clinical and subclinical measures of kidney function over time among children with CKD. Methods: This study was conducted among 618 participants in the CKD in Children study, a cohort study of pediatric CKD patients from the US and Canada, between 2005 and 2015. In serially collected urine samples over time, nine PAH metabolites were measured. Clinical outcomes measured annually included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Subclinical biomarkers of tubular injury (kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)) and oxidant stress (8-hydroxy-2'- deoxyguanosine (8-OHdG) and F2-isoprostane) were assayed in urine samples. Results: Children were followed over an average of 3.0 years (standard deviation (SD)=1.6) and 2469 study visits (mean=4.0, SD=1.6). Hydroxynaphthalene (NAP) or hydroxyphenanthrene (PHEN) metabolites were detected in >99% of samples and NAP concentrations were greater than PHEN concentrations. PHEN metabolites, driven by 3-PHEN, were associated with increased eGFR and reduced proteinuria, diastolic blood pressure z-score, and NGAL concentrations over time. However, PAH metabolites were consistently associated with increased KIM-1 and 8-OHdG concentrations. Conclusions: Among children with CKD, these findings provoke the potential explanation of reverse causation where renal function affects measured biomarker concentrations even in the setting of a longitudinal study. Additional work is needed to determine if elevated KIM-1 and 8-OHdG excretion reflects site-specific injury to the proximal tubule mediated by low-grade oxidant stress.