Heavy metals and elderly kidney health: A multidimensional study through Enviro-target Mendelian Randomization

Chronic Kidney Disease (CKD), closely linked to environmental factors, poses a significant public health challenge. This study, based on 529 triple-repeated measures from key national environmental pollution area and multiple gene-related public databases, employs various epidemiological and bioinformatics models to assess the impact of combined heavy metal exposure (Chromium [Cr], Cadmium [Cd], and Lead [Pb]) on early renal injury and CKD in the elderly. Introducing the novel Enviro-Target Mendelian Randomization method, our research explores the causal relationship between metals and CKD. The findings indicate a positive correlation between increased levels of metal and renal injury, with combined exposure caused renal damage more significantly than individual exposure. The study reveals that metals primarily influence CKD development through oxidative stress and metal ion resistance pathways, focusing on three related genes (SOD2, MPO, NQO1) and a transcription factor (NFE2L2). Metals were found to regulate oxidative stress levels in the body by increasing the expression of SOD2, MPO, NQO1, and decreasing NFE2L2, leading to CKD onset. Our research establishes a new causal inference framework linking environmental pollutants-pathways-genes-CKD, assessing the impact and mechanisms of metal exposure on CKD. Future studies with more extensive in vitro evidence and larger population are needed to validate.