Bortezomib in Kidney Transplant: Current Use and Perspectives

Abstract

Background: Despite major advances in transplant medicine, antibody-mediated rejection (AMR) continues to have severe clinical implications and adversely affect graft survival. Therefore, the search for alternative drugs to treat AMR is widely pursued. The first-in-class proteasome inhibitor bortezomib (BZ) is a selective inhibitor of the 26S proteasome, which was initially approved for the treatment of malignant plasma cell disorders. Methods: This review encompasses how our understanding of inhibiting proteasome pathway created the basis of BZ research and important milestones accomplished in AMR treatment in the transplant setting. It further discusses at length the results of clinical studies, the tolerability profile, drug-drug interactions and the perspectives of BZ use in desensitization protocols. Results: Proteasome inhibition can downregulate NF-kappa B activity

decrease cell proliferation/differentiation

induce apoptosis via cell cycle arrest, endoplasmic reticulum stress and caspase induction due the accumulation of unfolded or misfolded proteins

and downregulate antigen presentation, cell-cell interaction, and cell migration. Proteasome inhibition is more evident in cells with high rate of protein synthesis and secretion, like plasma cells. These cells play a critical role in the production of antibodies during AMR. Conclusions: There is accumulating evidence that the proteasome inhibitor BZ may substantially affect the function and integrity of alloantibody-secreting plasma cells in AMR after organ solid transplant, as well as the activation, proliferation and differentiation of T-and B-lymphocytes. Recent clinical studies have provided evidence that BZ has the capability to downregulate circulating antibodies and treat AMR episodes. Additional randomized-controlled studies are required to assess the impact of BZ during short and long follow-ups.