Bortezomib-Containing Multimodality Treatment for Antibody-Mediated Rejection with Anti-HLA and Anti-AT1R Antibodies after Kidney Transplantation

www.eymj.org To the Editor: For decades, the human leukocyte antigen (HLA) complex has been considered the primary target of antibody-mediated rejection (AMR), and treatment strategies have mainly focused on anti-HLA antibodies. Recently, other antibodies potentially causing organ damage and loss have been discovered. Conclusive evidence on treatment options for these subtypes of AMR is still lacking. After an experience previously reported in this journal, we describe a case of late-onset AMR, with mixed anti-HLA and anti-angiotensin II type 1 receptor (AT1R) antibodies, that was successfully treated with a multimodal approach, including the use of the proteasome inhibitor bortezomib. A 39-year-old Caucasian man received a live-related renal transplant in 2007. The donor and the recipient were blood group compatible with a 5 ABDRDQ-HLA-antigen mismatch. Pre-transplant panel reactivity antibody and direct microcytotoxicity cross-match were negative. For baseline immunosuppression, the patient received basiliximab, tacrolimus, enteric-coated mycophenolate sodium, and steroids. Postoperative course and follow up were uneventful. Seven years after transplantation, the patient was hospitalized with worsening graft function and low calcineurin inhibitor levels (Table 1), reflecting occasional non-compliance with immunosuppressants. Antibody screening showed anti-HLA sensitization, with de novo donor-specific antibodies (DSAs) against B58 and DQ9, and high titers of anti-AT1R antibodies (>50 U/L). Interestingly, both anti-HLA DSAs were unable to fix C1q, suggesting that anti-AT1R antibodies played a toxic role, in this specific setting. Histopathologic examination confirmed AMR. The patient received an initial multimodality treatment based on a combination of steroids, plasma exchange, and intravenous immunoglobulins. Then, bortezomib (Velcade®, Takeda, Osaka, Japan) was administered at 1.3 mg/m of body surface area, on days 1, 4, 8, and 11, to directly inhibit antibody production through plasma cell depletion. Following anti-rejection treatment, anti-HLA DSA and anti-AT1R antibodies promptly disappeared, and SCr stably decreased. One year later, the patient is doing fine, with stable graft function, no proteinuria, and undetectable DSA and anti-AT1R antibodies (Table 1). Despite surgical innovations and novel immunosuppressive regimens, long-term kidney allograft survival has not significantly improved during last decades, since we are now losing organs mainly due to AMR. Recently, in addition to anti-HLA antibodies, new antibodies have been discovered in transplant recipients experiencing rejection, supporting the hypothesis that anti-HLA antibodies may not be the only effectors of alloimmune humoral response. Among them, anti-AT1R antibodies seem to be particularly significant. AT1R is the main receptor for angiotensin II. Anti-AT1R antibodies can mimic angiotensin II and trigger multiple autoreactive and alloreactive responses, eventually leading to cell damage, apoptosis, and hypertension due to allosteric activation of AT1R. Anti-AT1R antibodies can act independently or synergistically with other effectors of the rejection pathway. Our patient experienced AMR seven years after transplantation due to non-compliance. An association between anti-HLA and anti-AT1R antibodies has been already described in unBortezomib-Containing Multimodality Treatment for Antibody-Mediated Rejection with Anti-HLA and Anti-AT1R Antibodies after Kidney Transplantation