#6546 RENAL TUBULAR TOXICITY OF ORGANOPHOSPHATE FLAME RETARDANTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Tsai Kai-Fan , Lee Wen-Chin , Lee Chien-Te , Kung Chia-Te 
Published: June 2023

Abstract

Background and Aims
Organophosphate flame retardants (OPFRs) are widely utilized flame retardants and considered less harmful than legacy brominated flame retardants. However, owing to their widespread utilization, OPFRs have led to extensive and persistent human exposure, with potentially hazardous effects on human health such as nephrotoxicity. Experimental and clinical studies have revealed that OPFR exposure is associated with renal tubular toxicity and renal impairment. However, the nephrotoxic mechanisms of OPFRs have not yet been clarified, and their impact on renal tubular injury has less been evaluated in patients with chronic kidney disease (CKD). In this cross-sectional observational study, we assessed the urinary OPFR concentrations in CKD patients to evaluate the associations between OPFR exposure and renal tubular injury in this population.

Method
Adult CKD patients in Taiwan (≥ 20 years of age and with non-dialysis-dependent CKD stage 3–5) were recruited from the Kaohsiung Chang Gung Memorial Hospital between January 2020 and May 2021. The first-void urine samples in the morning were collected to measure the concentrations of 10 common OPFR compounds using an ultra-performance liquid chromatography-tandem mass spectrometry (Waters, Milford, MA, USA). The urinary novel renal biomarkers were also measured using enzyme-linked immunosorbent assays (kidney injury molecule-1 [KIM1] and 8-hydroxy-2-deoxyguanosine [8-OHdG]; Abcam, Trumpington, Cambridge, UK). OPFRs with concentrations below a limit of quantitation (LOQ) were considered undetectable, and LOQ/√2 was assigned to the non-detected samples for analysis. The associations between urinary renal biomarkers and ΣOPFR concentrations (i.e., the sum of 10 OPFR compounds) were assessed via Spearman's correlation analysis. Simple linear regression analyses were conducted to evaluate the correlations between urinary renal biomarkers, ΣOPFR concentrations, and baseline patient characteristics. The effects of OPFR exposure on the urinary concentrations of KIM-1 and 8-OHdG in the enrolled CKD patients were examined in multiple linear regression analyses, adjusting for age, sex, body mass index, diabetes, hypertension, renal function, proteinuria, and covariates with a p-value &lt; 0.1 in univariate analyses via the enter method.

Results
In this study, 163 CKD patients were enrolled for analysis (stage 3: n = 79 [49.47%]; stage 4: n = 48 [29.45%]; stage 5: n = 36 [22.08%]). The overall detection frequency of urinary OPFRs was 98.77% in the study cohort, with a median ΣOPFR of 2.04 μg/g Cr (interquartile range [IQR], 0.84–4.27). The median urinary KIM-1 and 8-OHdG concentrations were 185.89 ng/g Cr (IQR, 83.05–441.60) and 71.23 μg/g Cr (IQR, 37.87–149.73), respectively. In our analysis, urinary ΣOPFR concentrations were positively correlated with urinary KIM-1 and 8-OHdG concentrations (rs = 0.267 for KIM-1, p = 0.001; rs = 0.281 for 8-OHdG, p &lt; 0.001) (Figure 1). In the multiple linear regression analyses, urinary ΣOPFR concentration was identified as an independent predictor positively associated with urinary renal biomarkers in the enrolled patients, with a 0.260 log ng/g Cr (95% confidence interval [CI], 0.140–0.380, p &lt; 0.001) increase in urinary KIM1 and a 0.227 log μg/g Cr elevation (95% CI, 0.124–0.330, p &lt; 0.001) in urinary 8-OHdG by per log μg/g Cr ΣOPFR (Figure 2).

Conclusion
OPFR exposure is common and associated with renal tubular injury as well as increased oxidative stress in CKD patients, which highlights its nephrotoxic potential in this vulnerable population.