INVOLVEMENT OF SUCCINATE DEHYDROGENASE (SDH) IN DECEASED RENAL TRANSPLANT DONORS' INFAMMATION AND FIBROSIS

Abstract Background and Aims Succinate is a Krebs cycle intermediate that is converted to fumarate by succinate dehydrogenase (SDH). SDH is part of the electron-transport chain of inner mitochondrial membrane (complex II) and its activity depends indirectly on the oxygen availability. Low oxygen states, such as ischemia, can increase circulating succinate levels due to low SDH activity. In renal transplantation, ischemia and hypoxia can increase renal succinate formation and induce the infiltration of immune cells producing TNF-α, increasing inflammation, renal epithelial apoptosis, as well as leukocyte recruitment, binding and migration, which can lead to renal graft damage. Method Samples of pre-implantation renal tissue, 17 from living donors and 40 from deceased donors were analyzed by Real-time PCR. Results In kidneys from deceased donors SDH expression is downregulated before transplantation and it lasts for at least the first year. Low SDH gene expression at 4 months after kidney transplant is positively correlated with graft renal function (CKD-EPI) at 12 and 24 months (p=0.046, r= 0.6511 and p= 0.0351, r= 0.4731; respectively). In kidneys from deceased and living donors, SDHD is negatively associated with monocyte recruitment (MCP-1) and activation (IL-1β) and positively with the expression of SOD1. Moreover, only in deceased donors, SDHD gene expression correlates inversely with pro-fibrotic (TGF-β1 and vimentin) and inflammatory (TNF-α) molecules, as well as with M1 (CD80, CD86) and M2 (CD163) macrophage markers, all of which are found to be higher expressed in deceased donor kidneys than in living donor ones. Conclusion Our results indicate that low gene expression of SDH in kidneys from deceased donors could result in reduced activity of SDH that would reduce the ability to transform succinate to fumarate resulting in succinate accumulation, increasing inflammation and reparation through fibrosis worsening transplant outcome.