Cadmium exposure and advanced cardiovascular-kidney-metabolic syndrome: An integrated multi-organ perspective based on epidemiology and adverse outcome pathways

While metal exposures are linked to cardiovascular and renal diseases, their role in cardiorenal comorbidity remains poorly understood. Using the American Heart Association's Cardiovascular-Kidney-Metabolic Syndrome (CKM syndrome) framework, we combined population epidemiology and Adverse Outcome Pathway (AOP) analysis to explore how cadmium exposure influences CKM progression and advanced-stage outcomes. Data from 5865 adults aged 30-79 years in the National Health and Nutrition Examination Surveys (NHANES) were analyzed to investigate serum metal exposure patterns and CKM syndrome progression. Logistic regression showed that higher blood cadmium levels were associated with CKM progression (OR = 1.21, 95 % CI = 1.05-1.40), highlighting cadmium as a key risk factor. Subsequent Cox proportional hazards regression analyses demonstrated amplified effects of cadmium exposure on all-cause mortality in advanced-stage CKM patients (HR = 1.30, 95 % CI = 1.09-1.56). To mechanistically characterize Cd-induced CKM syndrome progression and advanced-stage outcomes, we constructed a Chemical-Gene-Phenotype-Disease (CGPD) network through integrative mining of the Comparative Toxicogenomics Database (CTD) and GeneCards databases. This was synergistically combined with AOP-Wiki and PubMed databases to establish an AOP framework. This investigation represents the first study combining population epidemiology with AOP methodology to delineate the multi-organ interaction mechanisms between metal exposure (Cd) and CKM syndrome. This study not only furnishes a novel evidence base for risk assessment of metal exposure, but also establishes a paradigmatic reference for constructing adverse outcome pathway (AOP) frameworks across multiple organ systems, demonstrating significant public health implications.