Review of Knowledge of Uranium-Induced Kidney Toxicity for the Development of an Adverse Outcome Pathway to Renal Impairment.

An adverse outcome pathway (AOP) is a conceptual construct of causally and sequentially linked events, which occur during exposure to stressors, with an adverse outcome relevant to risk assessment. The development of an AOP is a means of identifying knowledge gaps in order to prioritize research assessing the health risks associated with exposure to physical or chemical stressors. In this paper, a review of knowledge was proposed, examining experimental and epidemiological data, in order to identify relevant key events and potential key event relationships in an AOP for renal impairment, relevant to stressors such as uranium (U). Other stressors may promote similar pathways, and this review is a necessary step to compare and combine knowledge reported for nephrotoxicants. U metal ions are filtered through the glomerular membrane of the kidneys, then concentrate in the cortical and juxtaglomerular areas, and bind to the brush border membrane of the proximal convoluted tubules. U uptake by epithelial cells occurs through endocytosis and the sodium-dependent phosphate co-transporter (NaPi-IIa). The identified key events start with the inhibition of the mitochondria electron transfer chain and the collapse of mitochondrial membrane potential, due to cytochrome b5/cytochrome c disruption. In the nucleus, U directly interacts with negatively charged DNA phosphate, thereby inducing an adduct formation, and possibly DNA strand breaks or cross-links. U also compromises DNA repair by inhibiting zing finger proteins. Thereafter, U triggers the Nrf2, NF-κB, or endoplasmic reticulum stress pathways. The resulting cellular key events include oxidative stress, DNA strand breaks and chromosomal aberrations, apoptosis, and pro-inflammatory effects. Finally, the main adverse outcome is tubular damage of the S2 and S3 segments of the kidneys, leading to tubular cell death, and then kidney failure. The attribution of renal carcinogenesis due to U is controversial, and specific experimental or epidemiological studies must be conducted. A tentative construction of an AOP for uranium-induced kidney toxicity and failure was proposed.