Do C1q-Positive Donor Specific Antibodies have Prognostic Effect in Patients with Resistant Antibody-Mediated Rejection Treated with Bortezomib? Single-Centre Experience

Abstract

Introduction and Aims Donor-specific antibodies (DSAs) examination is a crucial part of antibody-mediated rejection (AMR) diagnosis. C1q-positive (+) DSAs are associated with poor graft survival. We analyzed results of patients (pts) treated for acute resistant AMR by a bortezomib-based regimen with retrospectively performed C1q assay. The aim of this work was to analyze the treatment effect on DSA levels and potential effect of C1q+ DSAs on graft survival. Methods We retrospectively analyzed documentation of 772 pts who underwent renal transplantation (Tx) between 1/2012-6/2015. Novel therapeutic approach to resistant acute AMR in kidney transplant recipients was applied in 23 pts (3%) based on administration of bortezomib (B) [1 cycle of 4 doses of B (1.3 mg/m2)], small doses of i.v. steroids, plasmapheresis (PP) and a dose of rituximab (375mg/m2). This protocol was administered after conventional treatment had failed. Resistant AMR was defined as persisting deterioration or non-function of renal allograft in pts with histological verification of AMR, positive C4d staining and detection of DSA receiving standard antirejection treatment with PP + IVIG. C1q assay was performed 3 times – before Tx, at the time of diagnosis and after AMR treatment. Pts were followed for minimum of 24 months. Results Therapy of resistant acute AMR was administered to 23 pts after kidney Tx with median peak PRA 52%, actual PRA 36%, mean HLA mismatch in HLA-A 1.2 ± 0.4, HLA-B 1.7 ± 0.5, HLA-DR 1.3 ± 0, with median of 5.8 years on dialysis. 3 pts underwent 1st kidney Tx, while 20 pts reTx. All pts received induction therapy with antithymocyte globulin (n=22) or basiliximab (n=1), and maintenance immunosuppression with tacrolimus, mycophenolate mofetil/enteric-coated mycophenolate sodium and corticosteroids. Diagnosis of resistant acute AMR was made on 14th POD (7- 60 days). Using bortezomib regimen in treating resistant acute AMR led to decrease in DSA quantity in HLA especially in class I (p=0.005), class II (p = 0.015), but not in DQ (p= 0.2). No significant improvement of renal function was observed during the follow-up. The pts whose levels of serum creatinine increased more than 25% of baseline level in 6 months after administration of protocol with B, are progressors (n=11). The progressors graft survival was 57% in 2 years. The treatment protocol was not effective in decreasing C1q+ DSAs class I (p=0.25), class II (p=0.69), DQ (p=0.58). We detected C1q+ in 11 out of 11 progressors, compared with 3 out of 12 non-progressors (p<0.001). C1q+ DSAs correlated with C4d+ in graft biopsies at the time of AMR diagnosis (p=0.0012). Conclusions Bortezomib-based regimen was effective against class I and II DSAs, but it did not affect DQ DSAs. Pts with any C1q+ DSAs were more likely to have progressive graft dysfunction compared to those with C1q-negative DSAs. C1q positivity is a promising prognostic marker in pts with resistant AMR.