Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients.

Optimal induction regimens for patients at high risk for antibody and/or cell-mediated rejection have not been established. This pilot, prospective, randomized study evaluated addition of B cell/plasma cell-targeting agents to T cell-based induction with rabbit antithymocyte globulin (rATG) in high immunologic risk renal transplant recipients. Patients were randomized to induction with rATG, rATG + rituximab, rATG + bortezomib or rATG + rituximab + bortezomib. Inclusion criteria were: (1) current cytotoxic panel reactive antibody (PRA) ≥20% or peak cytotoxic PRA ≥50% or (2) T or B cell positive flow crossmatch with donor-specific antibody (DSA) or (3) historical positive serologic or cytotoxic crossmatch or DSA to donor or (4) prior allograft loss with more than one acute rejection. Median overall follow-up was 496 days: 1-year and overall acute rejection were 25% and 27.5%, and 25% of patients developed de novo DSA within 1 year. One-year and overall patient survival were 97.5% and 92.5%, and 1-year and overall death-censored allograft survival were 97.5% and 95%. Renal allograft function posttransplant was similar among all arms. Eight of nine cases of peripheral neuropathy were mild, whereas one case was moderate and required a narcotic prescription. In conclusion, addition of rituximab and/or bortezomib to rATG induction has an acceptable safety/toxicity profile in a high immunologic risk renal transplant population.

C4d deposition in lung allografts is associated with circulating anti-HLA alloantibody.

UNLABELLED: The complement activation demonstrated by vascular C4d deposition is used to diagnose antibody-mediated rejection (AMR) in renal allografts, but remains controversial in lung transplantation (LTX). METHODS: C4d deposition was assessed by immunohistochemistry in 192 lung transplant biopsies from 32 patients. ELISA analysis was performed on 415 serum samples in those 32 temporally and rejection-grade matched LTX patients; 16 patients developed HLA-Ab, while the other 16 patients remained negative. The specificity of C4d staining was further compared in 18 additional LTX patients without HLA-Ab or acute cellular rejection (ACR), but in the presence of CMV-pneumonitis or reperfusion injury. RESULTS: Specific subendothelial C4d deposition was seen in 5 of 16 (31%) patients with HLA-Ab and was absent in 16 patients without HLA-Ab (p<0.05). All patients with specific C4d deposition exhibited donor-specific HLA-Ab. There were 13 patients with bronchiolitis obliterans syndrome in the group of 16 HLA-Ab positive patients, versus 2/16 in ELISA-negative patients (p<0.005). One of 7 patients with CMV pneumonitis and 2 of 11 patients with reperfusion injury also showed C4d positivity (not statistically significant). CONCLUSIONS: In this study, specific subendothelial C4d deposition was a marker for the involvement of HLA-Ab in lung allograft rejection. The patchy nature, low sensitivity, and specificity of C4d staining might limit clinical use in protocol biopsies. However, in patients with decreasing pulmonary function, refractory ACR and/or HLA-Ab, specific C4d deposition may serve as a marker of coexistent AMR.