Urinary Polycyclic Aromatic Hydrocarbons in a Longitudinal Cohort of Children with CKD: A Case of Reverse Causation?

Abstract

Background: Air pollution, which results in the formation of polycyclic aromatic hydrocarbons (PAHs), has been identified as a cause of renal function decline and a contributor to 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 Chronic Kidney Disease in Children study, a cohort study of pediatric patients with CKD from the United States and Canada, between 2005 and 2015. In serially collected urine samples over time, nine PAH metabolites were measured. Clinical outcomes measured annually included eGFR, proteinuria, and BP. 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 (SD) of 3.0 (1.6) years and 2469 study visits (mean±SD, 4.0±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 BP 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.

Keywords: children; chronic kidney disease; kidney; polycyclic aromatic hydrocarbon; renal function; reverse causation.

Conflict of interest statement

M. Liu reports having consultancy agreements with Adaptimmune and serving as executive director of the International Chinese Statistical Association. H. Trachtman reports having consultancy agreements with Akebia, Alexion, Astellas (inactive), Bristol Meyers Squibb, Chemocentryx, Complexa (inactive), Goldfinch Bio, Kaneka (inactive), Natera (RenaSight), Otsuka, and Travere Therapeutics; receiving research funding from Alexion (support for clinical work), and Goldfinch and Travere Therapeutics (support for trial design); receiving honoraria from Astellas and Reata (for attendance at glomerular disease panels); serving on the steering committees of the Bristol-Myers Squibb abatacept trial, Goldfinch Bio, and Travere Therapeutics DUPLEX Trial; serving on the data and safety monitoring boards of the bumetanide-seizure trial (completed), Chemocentryx ANCA-associated vasculitis trial, Otsuka trials of tolvaptan in children (as chair), and RIVUR Trial (completed); serving on the editorial boards of Glomerular Disease and Kidney360, on the Kidney Health Initiative Board of Directors, and as a committee member of the Medicare Evidence Development and Coverage Advisory Committee; and partnering with NephCure Kidney International in efforts to promote pediatric participation in clinical trials for glomerular disease. L. Trasande reports receiving honoraria from Audible, Houghton Mifflin, Kobunsha, and Paidos; serving in an advisory or leadership role for Beautycounter, Endocrine Society, and Grassroots Environmental Education; receiving research funding from the Centers for Disease Control and Prevention, Helmsley Foundation, and National Institutes of Health (NIH); and having ownership interest in Footprint US. B.A. Warady reports having consultancy agreements with Amgen, Bayer, Lightline Medical, Reata, Relypsa, and UpToDate; receiving honoraria from Amgen, Bayer, Reata, Relypsa, and UpToDate; receiving research funding from Baxter Healthcare; and serving in an advisory or leadership role for Midwest Transplant Network (on the governing board), National Kidney Foundation, Nephrologists Transforming Dialysis Safely (on the board of directors), and North American Pediatric Renal Trials and Collaborative Studies. Y. Wu reports having ownership interest in Alibaba, AMD, Apple, Nvidia, Meta, and Tesla. All remaining authors have nothing to disclose.

Copyright © 2022 by the American Society of Nephrology.

Figures

Graphical abstract

Figure 1.

Associations between PAH metabolites and kidney injury and oxidative stress biomarkers varied over time for KIM-1 and 8-OHdG. Estimates were derived from adjusted linear mixed-effects models and correspond to a 1-SD change in each ln-transformed chemical exposure. KIM-1, kidney injury molecule-1; NAP, hydroxynaphthalene; NGAL, neutrophil gelatinase-associated lipocalin; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; OH-PAH, hydroxylated PAH; PHEN, hydroxyphenanthrene.