Fig. 8.

Current working hypothesis. Omeprazole promotes necrotic cell death in cultured proximal tubular cells. This is associated to an early decrease in ATP levels and an early increase in mitochondrial ROS production, suggesting mitochondrial injury. ROS are instrumental in promoting necrotic cell death, which is inhibited by N-acetyl-cysteine (NAC). However, interventions over apoptosis, ferroptosis and necroptosis were not protective. Omeprazole-induced necrosis may lead to the release of cell debris that may facilitate the development of an immune response underlying the observations of acute tubulointerstitial nephritis cases reported in omeprazole-treated patients. Additionally, omeprazole caused subclinical nephrotoxicity in mice. This is consistent with the low nephrotoxic potential of omeprazole in humans. In this regard, omeprazole nephrotoxicity may be increased by additional environmental factors, including comorbidities and concomitant medications. Among them, a frequent association is oral anticoagulants that may lead to proximal tubular cell iron overload. In cultured cells, iron overload facilitated omeprazole nephrotoxicity. The combination of these additional factors may explain why glomerular filtration rate is lost at a faster rate in patients on chronic omeprazole therapy.