The Role of Bortezomib in Pediatric Renal Transplant Recipients With Antibody Mediated Rejection.

Abstract

Purpose: Bortezomib, a proteasome inhibitor has been used successfully to treat early antibody-mediated rejection(AMR) in adults. It is not known whether Bortezomib is safe and effective in pediatric kidney transplant recipients. It is also not known if it is effective in late AMR secondary to non-adherence. We utilized Bortezomib in IVIG/Rituximab resistant AMR. Methods: 8 patients with a mean age of 15.5 years(range 5-20 years), were treated with a bortezomib protocol that we adopted for pediatric kidney transplant patients using 4 doses of bortezomib(1.3 mg/m2 per dose × 4) per course at standard labeled doses. The bortezomib protocol also included a total of 7 rounds of plasma exchange and one round of rituximab at the beginning of the course and a round of high dose IVIG at the end. 1 patient had early acute AMR and 1 other patient had plasma cell rich Acute Cellular Rejection(ACR) on biopsy without DSA's. The remaining 6 patients had a combination of late AMR+/- ACR. Patients were monitored by serial donor specific anti-HLA antibody (DSA) determinations [Luminex/Labscreen beads] and quantified by conversion to fluorescence intensity to molecules of equivalent soluble fluorescence (MESF). Results: Of the 8 patients treated with bortezomib, no effect was observed in the patient with plasma cell rich ACR on biopsy. 1 patient suffered graft loss. In the serum at the time of pre-treatment biopsy, the mean sum of pre-treatment MFI of DSA's in the 7 patients was 25,579 (range 7457 - 43457). The same post-treatment was 24,663(range 4436-50082). In patients with coexisting ACR, 5 out of the 8 patients had an improvement in their Banff grade. Of the 7 patients that had C4d+ biopsies, 3 had reductions in their C4d staining. At the beginning of treatment the mean eGFR by the Schwartz method of 68.26 ml/min/1.73m2 (range 11.3 - 112) and post-treatment the mean was 80.41 ml/min/1.73m2( range 18 - 102.5). None of the patients experienced serious adverse events like peripheral neuropathy as defined by a predetermined protocol. Conclusion: We conclude that Bortezomib may have a modest effect in patients that showed denovo DSA's with AMR on biopsy due to non-adherence as determined by the % tacrolimus co-efficient of variation of by self-report due to a structured interview. In our experience the eGFR remained stable and there was a modest decrease in the MFI of DSA's and C4d staining. Bortezomib was not effective in treating plasma cell rich ACR.