Iron chelation prior to static cold storage decreases lipid peroxidation and improves gluconeogenesis during NMP in isolated porcine kidneys

Abstract

Despite alternative graft preservation techniques, static cold storage (SCS) remains the most widely used kidney preservation method. Nevertheless, the molecular mechanisms of SCS’ drawbacks remain poorly understood. One of the mechanisms that drives delayed graft function (DGF) and poorer transplant outcomes is suggested to entail increased oxidative stress due to prolonged cold ischemia, thus driving lipid peroxidation and ferroptosis via iron-mediated Fenton chemistry. Here, we investigate whether iron chelation with deferasirox can prevent the Fenton reaction and thereby mitigate lipid peroxidation and improve kidney preservation. Porcine kidneys underwent 24 h of SCS in University of Wisconsin (UW) solution with or without deferasirox (60 µmol), followed by 3 h of normothermic machine perfusion (NMP). Deferasirox-treated kidneys exhibited significantly lower lipid peroxidation, as evidenced by reduced 4-hydroxy-nonenal (4HNE)-protein adduct levels, without altering antioxidative capacity manifested by glutathione peroxidase 4 (GPx4) expression. Metabolic stability was enhanced, with increased glucose availability and a higher glucose-to-lactate ratio, suggesting improved oxidative phosphorylation. Adenosine triphosphate (ATP) levels remained stable, indicating no adverse mitochondrial effects. Additionally, deferasirox reduced kidney weight gain, which may reflect lower edema formation, and strongly improved glomerular integrity and reduced tubular dilation. By reducing lipid peroxidation and maintaining metabolic function, deferasirox may help mitigate ischemia-reperfusion injury (IRI), enhance early graft function, and improve transplant outcomes. These findings strengthen the role of iron in cold-induced oxidative damage, and imply that iron chelation is a promising adjunct to improve graft preservation.