Inflammation mediates the association of heavy metal exposures with kidney function: Evidence from a longitudinal...

The kidney is a primary organ of heavy metal accumulation, and metal toxicity poses a great challenge to kidney health. We conducted a repeated-measure study to examine the longitudinal associations between blood heavy metal concentrations and kidney function biomarkers, including the urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and N-acetyl-β-d-glucosaminidase (NAG). Using linear mixed models, we found that chromium (Cr) and lead (Pb) were associated with impaired kidney function across multiple biomarkers. Manganese (Mn) levels were linked to lower UACR (β = -0.187, 95% CI: -0.321 to -0.047), suggesting a potential protective effect on albuminuria at moderate exposure levels; however, at higher levels, Mn was associated with lower eGFR, consistent with a nonlinear or biphasic effect on kidney function. The nonlinear and joint effect analyses showed similar findings, assessed by categorical analyses and Bayesian kernel machine regression (BKMR). Based on bioinformatics analysis, the inflammatory response is identified as the shared biological pathway for metals contributing to kidney disease. Therefore, we examined nine inflammatory indicators and used cluster analysis to describe participants' general inflammatory status. Elevated Cr levels were associated with higher interleukin-1 beta (IL-1β) and high-sensitivity C-reactive protein (hs-CRP), which partially mediated the Cr-UACR association. In contrast, Mn showed anti-inflammatory associations and may exert a potential protective effect on kidney function partly through downregulating hs-CRP, with significant indirect effects for UACR and eGFR-MDRD. Moreover, inflammatory status modified the hs-CRP-UACR association, with higher inflammatory status strengthening hs-CRP-related kidney damage.