Effects of Environmental Heavy Metal Interactions on Renal Impairment: Epidemiological Evidence from Rural Northeastern China

Chronic kidney disease, common in older individuals, causes a considerable disease burden worldwide. Although heavy metal exposure is associated with renal impairment, the effects of heavy metal mixtures and metal–metal interactions on renal impairment warrant investigation. We recruited 1674 participants living in northeastern China for a cross-sectional survey (2016–2019). We gathered data on urinary Cr, Cd, Pb, and Mn; β2-microglobulin (β2-MG); and the renal function biomarker N-acetyl-β-D-glycosaminidase (NAG). We also estimated glomerular filtration rates (eGFRs) using the Modification of Diet in Renal Disease equation (eGFR-MDRD) and the Chronic Kidney Disease Epidemiology Collaboration equation (eGFR-EPI). Generalized linear models were used to explore the association of each metal with the renal function biomarkers. We used quantile g-computation and Bayesian kernel machine regression (BKMR) to explore the overall effects of the metal mixtures and BKMR and multivariate linear regression to investigate the effects of metal–metal interactions on renal function. Metal mixture levels were positively associated with NAG, eGFR-EPI, and eGFR-MDRD but not β-2MG levels. Cd–Cr, Cd–Mn, and Cd–Pb were antagonistically associated with NAG overall. In women, the association of β-2MG with Cd–Mn, Cd–Pb, and Cd–Cr was synergistic, whereas that with Cr–Mn was antagonistic. In men, the association of eGFR-MDRD with Cd–Pb was antagonistic but that with Cd–Cr was synergistic. Overall and in women, the association of eGFR-MDRD with Cd–Cr was antagonistic. Finally, the association of eGFR-EPI with Cd–Cr was synergistic, but that with Cd–Pb was antagonistic. For β-2MG, there was a three-way Cd–Cr–Pb synergistic interaction in men and a four-way Cd–Cr–Mn–Pb interaction in women. Exposure to heavy metals is associated with renal function biomarkers, and metal–metal interactions exert synergistic or antagonistic effects on this association. Additional epidemiological studies considering the combined effects and interactions of multiple pollutants simultaneously are warranted. Graphical Abstract