Urinary nitrogen flame retardants and renal dysfunction: Population evidence with ferroptosis-related mediation

Nitrogen flame retardants (NFRs) are a class of emerging environmental pollutants with nephrotoxic effects, yet their mechanistic contributions to kidney stone formation remain unclear. In this case-control study of 123 patients with kidney stones and 77 healthy adults in China, we quantified seven urinary NFRs and assessed their associations with renal biomarkers. Kidney stones patients had significantly elevated total urinary NFR levels (median: 94.3 vs 28.9 ng/mL). Melamine (MEL) predominated in cases, while cyanuric acid (CYA) was most abundant in controls. MEL and ammelide (AMD) were positively associated with serum proteins and inversely associated with urinary markers of tubular and glomerular injury. Notably, AMD showed the strongest and most consistent associations with multiple renal injury markers, suggesting a potent and previously underrecognized nephrotoxic effect. Mixture modeling further revealed that combined NFR exposures exerted consistent joint effects on renal function. Crucially, mediation analyses showed that the associations between CYA and renal injury biomarkers were fully mediated by ferroptosis-related oxidative stress markers—ferrous iron and malondialdehyde. Furthermore, we report the first detection of 2,4,6-trimethoxy-1,3,5-triazine in human urine. These findings provide epidemiological evidence linking internal NFR exposure to early renal damage and suggest ferroptosis as a plausible mechanism with implications for mixture risk assessment. • Kidney stones patients exhibited higher urinary NFRs levels compared to controls. • MEL predominated in patients, while CYA was most prevalent in healthy individuals. • MEL and AMD positively correlated with blood biomarkers but inverse with urinary. • AMD is a key predictor of multiple renal injury biomarkers. • The effect of CYA on kidney injury is primarily mediated by Fe 2+ and MDA.