Iodinated contrast media nephrotoxicity: evolving mechanisms from osmotic stress to molecular pathways

Iodinated contrast media represent exogenous chemical stressors that can induce renal tubular toxicity, particularly in individuals with preexisting renal dysfunction. Contrast-induced acute kidney injury (CI-AKI) is increasingly recognized as a form of chemically mediated tubular epithelial cell injury rather than a purely hemodynamic phenomenon. Despite the clinical transition from high-osmolar to low- and iso-osmolar contrast media, nephrotoxicity persists, underscoring the limitations of osmolality-centered paradigms and the need for a mechanistic toxicology framework. This narrative review integrates experimental, translational, and clinical evidence to illuminate the toxicological mechanisms underlying contrast media induced renal tubular epithelial cell (RTEC) injury. By synthesizing classical physicochemical determinants-including osmolality, ionicity, and viscosity-with emerging molecular insights, we identify viscosity-dependent tubular flow perturbation, prolonged intrarenal retention, mitochondrial dysfunction, and oxidative stress as the key upstream toxic events. These converge on a complex network of regulated cell death pathways, including apoptosis, ferroptosis, and pyroptosis, with RTEC as the primary toxicological target. This perspective supports improved understanding of CI-AKI pathogenesis and mechanism-based prevention strategies.