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 sub-types of AMR is still lacking. After an experience previously reported in this journal,1 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. Postopera-tive 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/m² of body surface area, on days 1, 4, 8, and 11, to directly inhibit antibody production th-rough plasma cell depletion.2 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.3 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.4 Anti-AT1R antibodies can act independently or synergistically with other effectors of the rejection pathway.5

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 under-immunosuppressed kidney transplant recipients.5 De novo anti-AT1R antibodies have been also detected after episodes of allosensitization,6 being consistently associated with rejection and poor graft and patient survivals.7 However, testing for non-anti-HLA antibodies is not routinely performed, such that their real incidence and prevalence in the transplant population are basically unknown.7

What may trigger the development of anti-AT1R antibodies after transplantation is still under investigation. Several factors have been proposed: 1) genetic polymorphisms affecting the structure of AT1R extra-cellular domain; 2) genetic polymorphisms altering the geometric shape of the receptor; 3) antigenic exposure secondary to death perturbations; and 4) cell damage caused by alloimmune response, which modifies AT1R expression into the graft exposing previously hidden epitopes.5

Meanwhile, several therapeutic options have been proposed to treat early-onset anti-HLA AMR. Some combination strategies have shown good results in the short term, although no clear benefit of one specific regimen has been demonstrated, and long-term results are sub-optimal. Experience with late-onset non-anti-HLA AMR is even more limited.8 Inhibition of B-cells and antibody production by administration of anti-CD20 monoclonal antibodies (e.g., rituximab) or proteasome inhibitors (e.g., bortezomib) may represent a promising option together with apheretic techniques and intravenous immunoglobulins.9

Optimal treatment of late-onset acute AMR is still a matter of debate. Reports on anti-AT1R AMR are anecdotal: some authors support the role of apheresis combined with intravenous normal human immunoglobulins, rituximab, and high-dose AT1R-blockers.10 This journal has already published a first successful experience with bortezomib.1 Our experience with a multimodality treatment, including bortezomib, confirms its efficiency in stably clearing not only anti-HLA but also anti-AT1R antibodies, halting renal function deterioration even in the longer term.

Further investigations are warranted to better address the role of proteasome inhibition in the setting of anti-HLA and non-anti-HLA AMR and to assess the contribution of bortezomib to overall efficacy.