Donor shortage is responsible for the increase in the number of human leukocyte antigen-incompatible (HLAi) and ABO-incompatible (ABOi) living-donor kidney transplantation (LDKT) cases in Korea. For successful HLAi or ABOi LDKT, it is necessary to perform pretransplant desensitization; however, early antibody-mediated rejection (ABMR) is still the most important complication following HLAi or ABOi transplantation. ABMR is an immune response of alloantibodies against the transplanted organ, more specifically against mismatched classical HLA antigens of a donor, nonclassical major histocompatibility complex class I-related chain-A antibodies, non-HLA endothelial antigens, or mismatched ABO antigens [123]. Acute ABMR is a major cause for graft loss in kidney transplantation [1]. Here, we described a case of early acute ABMR after HLAi and ABOi LDKT, treated by a combination therapy of plasmapheresis, high-dose intravenous immunoglobulin (IV-Ig), and bortezomib.

More than 300 ABOi LDKTs have been performed annually in the recent years since its introduction in 2007 and account for approximately 25% of the total LDKTs in Korea [6]. Short-term ABOi LDKT and ABO-compatible LDKT outcomes are comparable. In Korea, HLAi LDKT has been successfully implemented since 2002, and its frequency was approximately equal to one-third of that of ABOi LDKT [7]. HLAi LDKT indicates LDKT after desensitization in recipients with significant DSA levels showing positive or negative crossmatching results. HLAi LDKT showed better patient survival as compared to HLA-compatible (HLAc) deceased-donor kidney transplantation [8], but exhibited lower graft survival as compared to HLAc LDKT in USA because of high ABMR risk despite appropriate desensitization [9].

Acute ABMR occurs in approximately 5% HLAc LDKT patients, but its incidence can increase to 50% in HLAi LDKT patients [10]. Acute ABMR can cause 1-year graft loss in 15%–20% patients and exhibits worse prognosis than that of acute T cell-mediated rejection. It occurs in the first few days per weeks after transplantation and is less responsive to anti-rejection therapy; therefore, it could easily cause chronic allograft dysfunction and graft loss. The 5-year graft survival rate was 60% and 92.5% among patients with and without ABMR, respectively. For long-term survival of the graft, its prevention and treatment is important [111], and it is also a major hurdle to overcome in LDKT. Similar to this case, early ABMR usually occurs within the first few days/weeks after HLAi or ABOi LDKT in sensitized patients [12]. Memory B-cells stimulated by alloantigen rapidly increase the preformed DSA levels, and the incidence of early ABMR is closely linked to the DSA level at that time. The incidence is as high as 40% in patients with high DSA levels, whereas it is <10% in those with low DSA levels [13]. Anti-ABO antibody titer higher than 1:32 is associated with a higher ABMR rate in ABOi KT. We need to reduce the preformed DSA and anti-ABO antibody levels before HLAi or ABOi LDKT and maintain them at low levels after LDKT. Anti-ABO antibodies cannot induce overt ABMR when they are maintained at low levels during the initial 3–4 weeks, especially after ABOi LDKT, and this phenomenon is called accommodation. It explains the better prognosis of ABOi KT than that of HLAi KT, and emphasizes the importance of controlling the DSA levels rather than anti- ABO antibodies during simultaneous HLAi and ABOi LDKT.

ABMR diagnosis is based on kidney biopsy and DSA test results. Diagnosis of biopsy-proven ABMR is based on the Banff criteria [1114]. Here, both DSA titer and spectrum increased, probably owing to the boosting effects exerted by alloantigen stimulation, while the kidney biopsy demonstrated microvascular inflammation and vasculitis along with C4d deposition, confirming the ABMR diagnosis.

Optimal regimens of ABMR prevention and treatment have not yet been established due to the lack of randomized controlled trials. However, the current care standard comprises of therapeutic plasmapheresis and IV-Ig with rituximab or bortezomib. Recently, complement inhibitors, including eculizumab, have also been introduced [1]. Despite desensitization in this case, our patient exhibited DSA levels higher than those before transplantation and developed severe, dialysis-dependent, early ABMR. Combination of 14 therapeutic plasmapheresis sessions, steroid pulse therapy, high-dose IV-Ig and bortezomib improved this severe ABMR. We used two doses of bortezomib in desensitization because our center had often experienced cases of side effects, such as gastrointestinal troubles, with three to four doses of bortezomib. Interestingly, the anti-ABO antibody levels in this patient had not substantially increased after transplantation and did not seem to contribute to ABMR. These results suggested that DSA is a more important risk factor than anti-ABO antibody for ABMR in simultaneous HLAi and ABOi LDKT, and timely treatment can rescue even dialysis-dependent, severe ABMR.

This extreme but rare case of early severe ABMR following simultaneous HLAi and ABOi LDKT emphasizes the focus on rebound DSA and risk of early ABMR, despite a successful initial posttransplant clinical course after desensitization. DSA rebound in this case could be attributed to the booster immune response of memory B-cells that were not completely depleted in the lymph nodes by rituximab treatment or the long-lived plasma cells in the bone marrow that were resistant to bortezomib or were replenished by humoral compensation [413]. Humoral compensation indicates that increased germinal center B-cells and follicular helper T-cells under B-cell activating factor (BAFF) can replenish plasma cells again after initial depletion [14]. Therefore, combination of bortezomib with BAFF inhibitors or belatacept that interferes with B-T interaction could be used to overcome humoral compensation for refractory DSA [15]. Due to this limitation of the current regimens, it is essential to monitor DSA and anti-ABO levels in HLAi or ABOi LDKT during the initial 3–4 weeks after desensitization.