Phthalate exposure is associated with increased CVD risk in CKD: evidence from NHANES and network toxicology analysis

Chronic kidney disease (CKD) is a global health burden, with cardiovascular disease (CVD) representing the primary cause of mortality in this population. In this cross-sectional study, we analyzed data from 2,227 participants in the National Health and Nutrition Examination Survey (NHANES, 2003-2018) to investigate the relationship between phthalate exposure and self-reported CVD among CKD patients. Logistic regression identified four phthalate metabolites exposure, including MBP, MEHHP, MEOHP and MECPP significantly increases CVD risk across all three logistic regression models. As phthalate exposure typically occurs as a mixture in real life, we employed advanced mixture analysis methods: the Weighted Quantile Sum (WQS) model, Quantile G-Computation (qgcomp) model, and Bayesian Kernel Machine Regression (BKMR) model. All the three models consistently demonstrated a positive association between phthalate mixtures and CVD in CKD patients. Furthermore, network toxicology analysis revealed that PPARG, CASP9 and CTSS play important roles in mediating the pathogenic mechanisms linking phthalate exposure to both CKD and CVD. These findings suggest that phthalate exposure is associated with adverse effects on cardiovascular health in CKD patients. As common hub genes linking CKD and CVD, PPARG, CASP9, and CTSS may contribute to the toxic effects of phthalate exposure on both diseases, suggesting as potential therapeutic targets. However, given the cross-sectional nature of NHANES data, causal inferences cannot be made, and the potential for reverse causality and residual confounding should be considered.