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 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).
Table 1. Clinical Parameters before, during, and after Bortezomib Administration.
| Parameters | Normal range | Before rejection | Detection | Bortezomib administration | Day 90 | Day 180 | Day 365 | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Day 10 | Day 13 | Day 17 | Day 20 | |||||||
| SCr (mg/dL) | 0.6–1.2 | 1.1 | 1.89 | 1.6 | 1.8 | 1.6 | 1.5 | 1.7 | 1.5 | 1.55 |
| eGFR (mL/min) | >90 | 80 | 40 | 48 | 42 | 48 | 53 | 47 | 53 | 50 |
| Proteinuria (mg/24 hr) | 28–141 | 30 | 94 | - | - | - | 0177 | 48 | 74 | 46 |
| WCC (cell×103/µL) | 4.8–10.8 | - | 7.0 | 8.2 | 9.3 | 6.5 | 6.3 | 6.9 | 13.0 | 7.58 |
| NLR (#) | / | - | 1.9 | 7.8 | 4.6 | 2.1 | 1.9 | 1.3 | 3.9 | 2.0 |
| CRP (mg/L) | <0.5 | - | - | - | - | 0.03 | 0.03 | - | - | - |
| Anti-HLA Class I Abs (%) | / | 0 | 11 | 0 | - | - | - | 0 | 0 | 0 |
| Anti-HLA Class II Abs (%) | / | 0 | 26 | 0 | - | - | - | 0 | 0 | 0 |
| DSA B58 (MFI) | / | - | 2755 | - | - | - | - | - | - | - |
| DSA DQ9 (MFI) | / | - | 3800 | - | - | - | - | - | - | - |
| Anti-AT1R Abs (U/l) | / | - | >50 | - | - | - | 14 | - | 0 | 0 |
| Prednisone (mg/day) | / | 5 | 5 | 20 | 20 | 20 | 20 | 10 | 10 | 10 |
| Sodium mycophenolate (mg/day) | / | 1440 | 1440 | 1440 | 1440 | 1440 | 1440 | 1440 | 1440 | 1440 |
| Tacrolimus (mg/day) | / | 3 | 3 | 5 | 5 | 5 | 5 | 6.5 | 5.5 | 5.5 |
| Tacrolimus C0 (ng/mL) | / | 6.1 | 3.2 | 5.6 | 6.8 | 4.4 | 5.2 | 8.3 | 5.7 | 4.6 |
| Diuresis (mL/24 hr) | / | - | 3500 | 4500 | - | 3000 | 3300 | 3500 | 3300 | 4000 |
Abs, antibodies; AT1R, anti-angiotensin II type 1 receptor; C0, trough level; CRP, C-reactive protein; DSA, donor-specific antibodies; eGFR, estimated glomerular filtration rate; HLA, human leukocyte antigen; MFI, mean fluorescence intensity; NLR, neutrophil-to-lymphocyte ratio; WCC, white cell count.
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.
Footnotes
The authors have no financial conflicts of interest.
References
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