OPTIONS AND OUTCOMES IN THE SENSITIZED KIDNEY RECIPIENT

S. Raghavaiah¹, T.S. Diwan¹, M.D. Stegall¹, J.M. Burns², J.M. Gloor^3
1Of Surgery, Division Of Transplantation, Mayo Clinic, Rochester/UNITED STATES OF AMERICA, ²Liver Transplantation Surgery, Mayo Clinic, Rochester/UNITED STATES OF AMERICA, ³Internal Medicine, Division Of Nephrology And Hypertension, Mayo Clinic, Rochester/UNITED STATES OF AMERICA

Body: Introduction: Alloantibody secreting plasma cells (PCs) are insensitive to current immunosuppression. Thus our current “desensitization” protocols using multiple plasma exchanges (PEs) generally are unsuccessful in renal allograft candidates with very high levels of donor-specific alloantibody (DSA). The aim of this study was to determine if proteasome inhibition with bortezomib would deplete PCs in vivo and thus increase rate of transplantation in candidates with very high DSA at baseline. Methods: Renal allograft candidates included had a baseline T and/or B cell flow-cytometric crossmatch channel shift (BFXM) >450, MESF=30,000). Patients were consecutively stratified to either PE alone (n=8) or one of two regimens (4 or 16 doses of 1.3 mg/m2) followed by PE (n=9). Groups were comparable with respect to demographics, baseline BFXM and DSA specificities. The number of bone marrow derived donor-specific PCs was determined pre and post-bortezomib treatment using an AlloELISPOT assay ⁽¹⁾. PE was performed daily for at least 7 days in all patients with the goal of achieving a BFXM <300—our criteria for proceeding to kidney transplantation. Results: Compared to pre-treatment, all bortezomib patients receiving 16 doses showed a decrease in Allo-specific PCs and 3 of 4 receiving 4 doses showed a decrease. (fig 1) Treatment was well-tolerated and total serum immunoglobulin was unaffected. In this cohort with very high DSA that commonly fail PE, no patient in the control group achieved a BFXM <300, while 4 patients in the bortezomib group achieved a BFXM <300 (p=0.039) even though the number of PEs was greater in the control group (11.63 + 3.9 control, vs 7.5 + 1.7 Bortezomib, p=.04). Further evidence of the impact of proteasome inhibition on DSA was the finding that the bortezomib group also had an overall greater response to PE: the decrease in BFXM pre/post PE was 258.63 + 112 in the bortezomib group v/s 112.23 + 92.67 in controls (p=.016).(Fig 2) Conclusion: Proteasome inhibition depletes allospecific PCs in-vivo and improves the efficacy of PE in patients with very high levels of DSA at baseline. Longer treatments appear more effective and are well tolerated. Reference: Am J Transplant 2008; 8: 133 – 143
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Disclosure: All authors have declared no conflicts of interest.