Rapid and complete elimination of donor-specific anti-human leukocyte antigen antibodies (DSA) during antibody-mediated rejection (AMR) of renal transplantation is rarely achieved with traditional antihumoral therapies. Current antihumoral therapies do not target the mature antibody producing plasma cells. Bortezomib is a first in class proteosome inhibitor for the treatment of plasma cell derived tumors like multiple myeloma. Proteasome inhibitor-based therapy has been shown to effectively treat refractory AMR. Here, we report on our experience with plasma cell targeted therapy (bortezomib) as an antirejection strategy for refractory early and delayed AMR post renal transplantation.
Adult kidney transplant recipients with AMR, diagnosed by Banff criteria, received a bortezomib-based regimen after failing at least 2 traditional treatments for AMR. Bortezomib therapy was administered (1.3 mg/m2 IV D1,4,8,11) with plasmapheresis performed immediately before each dose of Bortezomib and a single dose of rituximab (375 mg/m2) given with the first bortezomib dose. Methylprednisolone was administered along with Bortezomib at 100 mg IV on D1,4 and 50 mg IV on D8,11. All patients received valganciclovir prophylaxis for prevention of herpes zoster and cytomegalovirus reactivation. Monitoring included serial donor-specific antihuman leukocyte antigen antibody (DSA) levels, serum creatinine levels, urine protein excretion and repeated allograft biopsies.
Ten episodes of AMR in eight renal transplant recipients were treated with bortezomib, rituximab, methylprednisone and plasmapheresis.
| . | N . |
|---|---|
| Patients, Episodes | 8, 10 |
| Median Age at Transplant, years (range) | 49 (25-65) |
| Non-Caucasian Race (%) | 6 (80%) |
| Living Donor Transplant (%) | 6 (80%) |
| Delayed Graft Function (%) | 1 (13%) |
| History of Non-Compliance (%) | 4 (50%) |
| Delayed Rejection (%) | 7 (88%) |
| Median Time Post-Transplant to Rejection, months (range) | 31 (5-168) |
| Biopsy, AMR (%) | 8 (80%) |
| Pre-Treatment SCr, median (mg/dL) | 2.0 (1.1-3.3) |
| Post-Treatment SCr at Nadir, median (mg/dL) | 1.9 (1.1-2.8) |
| Pre-Treatment proteinuria, median (g/24 hr) | 2.0 (0.4-2.5) |
| Post-Treatment proteinuria, median (g/24hr) | 1.3 (0.1-3.1) |
| Histologic Improvement * | 3 |
| Median follow-up time, months (range) | 15 (3-25) |
| Graft Survival (%) | 10 (100%) |
| Patient Survival (%) | 8 (100%) |
| . | N . |
|---|---|
| Patients, Episodes | 8, 10 |
| Median Age at Transplant, years (range) | 49 (25-65) |
| Non-Caucasian Race (%) | 6 (80%) |
| Living Donor Transplant (%) | 6 (80%) |
| Delayed Graft Function (%) | 1 (13%) |
| History of Non-Compliance (%) | 4 (50%) |
| Delayed Rejection (%) | 7 (88%) |
| Median Time Post-Transplant to Rejection, months (range) | 31 (5-168) |
| Biopsy, AMR (%) | 8 (80%) |
| Pre-Treatment SCr, median (mg/dL) | 2.0 (1.1-3.3) |
| Post-Treatment SCr at Nadir, median (mg/dL) | 1.9 (1.1-2.8) |
| Pre-Treatment proteinuria, median (g/24 hr) | 2.0 (0.4-2.5) |
| Post-Treatment proteinuria, median (g/24hr) | 1.3 (0.1-3.1) |
| Histologic Improvement * | 3 |
| Median follow-up time, months (range) | 15 (3-25) |
| Graft Survival (%) | 10 (100%) |
| Patient Survival (%) | 8 (100%) |
only 3 patients had post-treatment biopsy and all showed histologic improvement
Post treatment reduction in immunodominant DSA was observed and this data will be available at the meeting. None of the patients experienced peripheral neuropathy from bortezomib and only one patient had GI toxicity with nausea and diarrhea, which was transient. None of the patients had reactivation of herpes zoster infection.
In conclusion, bortezomib, rituximab, methylprednisone and plasma exchange therapy provided reversal of AMR rejection post renal transplantation with improvement in renal function, proteinuria and histology, at a median follow-up of 15 months.
No relevant conflicts of interest to declare.
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