The controversial role of Bortezomib in the treatment of AMR E.Theodoropoulou1, H.Gakiopoulou2, G.Vlachopanos1, A.Iniotaki1, E.Patsouris2, J.Boletis1, G.Zavvos1 1 Transplantation Unit, Laiko Hospital, Athens, Greece 2 First Department of Pathology, School of Medicine, University of Athens, Greece Objectives To date, no effective immunosuppressive standard protocol has been established for the prevention or treatment of alloantibody production in antibody mediated rejection (AMR) of renal transplants. Bortezomib (BZ), a proteasome inhibitor inducing plasma cell apoptosis, has been considered to represent a promising drug with anti-humoral activity in the situation of an already established humoral alloimmune response after renal transplantation. We present two patients with AMR who were treated with BZ. Methods The two patients underwent a renal biopsy, 2 and 3 years after transplantation, respectively. Both presented with a slight deterioration of renal function while the second one also showed proteinuria. Both patients had circulating DSAs (Donor Specific Antibodies) and both had been switched to everolimus, the first because of an increased chronicity index in zero hour biopsy and the second because of a history of renal cell carcinoma. Interestingly, the first patient developed DSAs after switching to everolimus. A diagnosis of AMR (Banff 1997/2009 updates) was made based on the renal biopsy findings [morphologic evidence and diffuse C4d staining (C4d3)] together with the presence of DSAs. Following the biopsy results, both patients were re-switched to CNIs (tacrolimus) and were treated with BZ (1.3 mg/m2 in days 1, 4, 8, 11 every 21 days X 4 cycles). In the second patient, BZ treatment was supplemented with rituximab, immunoadsorptions (IA) and iv immunoglobulin. PRAs (Panel Reactive Antibodies) were measured before and after every treatment. Patients’ follow up is 10 months and 17 months, respectively. Results After treatment, renal function of both patients returned near the pre-biopsy levels and the proteinuria of the second patient decreased significantly. The first patient who was treated with BZ alone showed no decrease of the titers of DSAs and interestingly, a second and later a third DSA appeared while under treatment, with no clinical deterioration. The second patient showed a transient decrease of DSA titers after treatment with BZ (4 cycles), rituximab(1 dose of 375mg/m2), 9 sessions of IA, iv immunoglobulin and switch to CNI. However, the titers subsequently increased with a concurrent increase in proteinuria and stable renal function. A second renal transplant biopsy was then performed which demonstrated morphologic evidence of acute and chronic tissue injury with diffuse C4d staining. A 15% increase of interstitial fibrosis and tubular atrophy was also noted. The patient underwent 9 sessions of IA with concurrent administration of iv immunoglobulin. The patient responded to treatment with reduction of proteinuria and DSA titers. In the last follow up, a new rise of DSA titers was noted, reaching the pretreatment levels. Notably, the patient developed severe peripheral neuropathy after the fourth cycle of BZ. Conclusions Although BZ seems a promising tool in the treatment of AMR, our preliminary cases failed to demonstrate any effect on anti-HLA antibodies in more than one year renal transplant recipients which is in keeping with the results of Sberro-Soussan et al who used BZ as a solo therapy in 4 patients with AMR and at least 1 year out from transplantation. The efficacy of BZ in the management of AMR does not seem to overcome the known therapeutic limitations regarding long-lived antibody levels (further than one year post-transplant). However, BZ’s role may be better elucidated as more clinical data and well-designed clinical trials become available.