Promising roles and current limitations of bortezomib-based desensitization for kidney transplantation
Article information
Many transplant candidates show the presence of preformed antibodies against human leukocyte antigens (HLA), known as HLA sensitization, which poses a major immunological barrier to successful transplantation. Approximately 30%–40% of patients on the kidney transplant waiting list are sensitized to HLA, and among them, about 10%–15% have a calculated panel reactive antibody (cPRA) level >95%, making it extremely difficult to find a compatible donor [1]. In Korea, 15.4% of kidney transplant candidates show positive T-cell crossmatch responses. Of the 15.4% candidates, 64.5% showed complement-dependent cytotoxicity crossmatch (CDCX)-positive/flow cytometric crossmatch (FXM)-positive responses and 35.5% showed CDCX-negative/FXM-positive responses. These anti-HLA donor-specific antibodies (DSA) greatly increase the risk of antibody-mediated rejection (ABMR) and graft loss when transplantation is attempted without intervention. Therefore, desensitization therapies aimed at reducing or eliminating DSAs before kidney transplantation (KT) are crucial to enable transplantation in highly sensitized patients.
Standard desensitization protocols typically combine plasmapheresis (PP) with low- or high-dose intravenous immunoglobulin (IVIG) and anti-CD20 B-cell-depleting therapy (rituximab [RTX]) to remove circulating antibodies and suppress new antibody production. This approach has allowed many HLA-incompatible transplants and has improved patient survival in those who received a kidney versus those who remained on dialysis. However, conventional desensitization is often insufficient in patients with very high antibody levels or CDCX-positive responses. RTX selectively depletes CD20-expressing B cells, while IVIG neutralizes circulating DSAs and modulates immune responses through Fc receptor blockade and anti-idiotypic effects; however, it does not directly target long-lived plasma cells (LLPCs) responsible for sustained DSA production [2]. Consequently, patients with extremely strong DSA may remain at an unacceptably high risk of hyperacute or severe rejection despite standard desensitization.
Bortezomib, a 26S proteasome inhibitor originally used to treat multiple myeloma, offers a novel strategy to target plasma cells. In recent years, several groups have reported encouraging results using bortezomib-based desensitization (BOZ-DSZ) in highly sensitized patients [2–4]. This concept was first evaluated by Diwan et al. [2] in 2011, who administered bortezomib as a preconditioning agent to highly sensitized kidney transplant candidates. In this pilot study, bortezomib effectively depleted bone marrow plasma cells responsible for DSA production. Although short-term reductions in serum antibody titers were limited, the intervention enhanced the efficacy of subsequent PP, thereby providing proof-of-concept that targeting plasma cells could improve desensitization outcomes. Similarly, a prospective trial by Woodle et al. [3] in 2015 evaluated BOZ-DSZ and found that approximately 43% of the treated patients underwent transplantation, with a relatively low incidence of acute rejection among those who received a graft. In a 2016 study by Jeong et al. [4], a desensitization regimen combining bortezomib with high-dose IVIG was associated with an increased rate of deceased donor KT (DDKT) compared with controls.
In this issue of Kidney Research and Clinical Practice, Park et al. [5] reported a study examining the BOZ-DSZ protocol in a cohort of highly sensitized candidates awaiting either living donor KT (LDKT) or DDKT. A notable strength of this study is the inclusion of both LDKT and DDKT candidates in a clinically applicable desensitization protocol. These findings suggest that bortezomib can be incorporated into existing desensitization frameworks with relative ease, serving as an adjunct in patients refractory to standard therapy for LDKT, and as an initial desensitization protocol in DDKT candidates, without the logistical constraints of scheduling PP. Notably, bortezomib was used at limited protocolized doses (four doses in both LDKT and DDKT), minimizing toxicity while retaining efficacy. No significant hematological adverse effects or bleeding events were reported, and infectious complications were manageable. This study confirmed the feasibility of a bortezomib-based protocol in routine clinical practice and supported its integration into desensitization strategies for high-risk patients.
These findings align with and expand on a large-scale study by Woodle et al. [3]. In this multi-phase trial, 44 patients were treated across five protocol phases, which varied in the intensity of bortezomib dosing (1–2 cycles of 6–8 doses) and timing relative to PP and RTX. Significant reductions in immunodominant HLA antibody levels were observed in 86% of patients and importantly, these reductions were sustained for up to 10 months in the responders. Ultimately, 19 of the 44 patients (43.2%) underwent transplantation: 10 with deceased donors and nine with living donor grafts. When compared to these findings, Park et al.’s LDKT cohort [5] employed a less intensive bortezomib regimen (one cycle of four doses) combined with low-dose IVIG. This approach resulted in a higher rate of transplantation and effective DSA reduction. Specifically, 13 of 14 patients (92.9%) underwent LDKT, with 10 patients (71.4%) achieving a post-desensitization mean fluorescence intensity (MFI) of DSA below 5,000 and 80% (8 of 10) converting to negative T-cell CDCX. However, Park et al. [5] reported a relatively high incidence of biopsy-proven acute rejection (BPAR) within the first year (53.8%), and DSA remained detectable at the time of biopsy in six of the seven BPAR cases, raising concerns regarding the durability of immunological suppression achieved with the current BOZ-DSZ protocol. These findings highlight the need for further studies to evaluate whether repeated cycles of bortezomib enhance the long-term efficacy of desensitization by sustaining DSA suppression and reducing early alloimmune injury.
It would also be instructive to compare tolerability across studies. The known toxicity of bortezomib includes peripheral neuropathy and cytopenia. However, these side effects have been relatively manageable in transplantation trials. Woodle et al. [3] reported mild, mostly reversible neuropathy in a minority of patients and identified thrombocytopenia as the most common hematological side effect. Jeong et al. [4] also noted that the regimen was generally well tolerated with no unexpected safety concerns. Park et al. [5] did not provide detailed information on systemic adverse effects such as cytopenia or neuropathy, but they specifically reported no bleeding complications despite prior PP and bortezomib administration.
Although Park et al. [5] presented encouraging results, several important issues should be addressed in future studies. First, it was conducted retrospectively at a single center with a small sample size and lacked a contemporaneous control group of patients who either remained untreated or underwent conventional desensitization. A prospective, randomized controlled trial would be necessary to accurately quantify the additional effects of BOZ-DSZ. Second, the investigators did not perform functional assays of antibody pathogenicity, such as complement-binding tests, leaving the question of whether the detected DSAs could activate complement and thus cause injury unanswered. Additionally, the immune monitoring in this study was limited, so cellular analysis of plasma cell depletion and compensation by germinal center B cells is lacking, and the effect duration remains unclear. This is especially problematic in the DDKT setting, where unpredictable organ availability means that the desensitization effect may wane and alloantibody levels could rebound if transplantation is delayed. Furthermore, infectious complications were relatively frequent with the BOZ-DSZ regimen, with approximately 75% of transplant patients experiencing infections such as cytomegalovirus viremia, BK polyomavirus, or urinary tract infections. These findings suggest a need for further studies to evaluate more intensive or tailored strategies for infection prophylaxis in this setting. Finally, the BOZ-DSZ protocol showed limited efficacy against class II HLA antibodies, suggesting that this desensitization approach may not fully eliminate certain high-risk DSAs.
In addition to bortezomib, other plasma cell-targeting agents are being explored for use in desensitization protocols (Table 1). Carfilzomib, a second-generation irreversible proteasome inhibitor, selectively depletes plasma cells and is less neurotoxic than bortezomib. Early-phase trials combining carfilzomib with PP demonstrated a 72.8% reduction in the median maximum MFI of anti-HLA antibodies; however, DSAs often rebound to baseline levels within 3 to 4 months, suggesting that additional therapies are necessary to sustain the desensitization effect [6]. Another promising approach involves the use of anti-CD38 monoclonal antibodies such as daratumumab, which selectively target LLPCs that are typically resistant to conventional therapies. In highly sensitized patients awaiting KT (cPRA >95%), daratumumab has been shown to reduce anti-HLA antibody levels at 3 months; however, these levels returned to baseline by 6 months, suggesting humoral compensation [7]. To address this limitation, a combination of daratumumab and belatacept is currently being investigated in sensitized transplant candidates (NCT05145296). Similarly, combining bortezomib with belatacept has shown the potential to reverse ABMR and reduce DSA levels in patients unresponsive to conventional treatments (steroids, PP, and IVIG) [8]. Although not proteasome inhibitors, eculizumab (a complement C5 inhibitor) and imlifidase (an immunoglobulin G-degrading enzyme) are also emerging as new promising desensitization agents [9,10].
Various desensitization regimens
Park et al. [5] provided valuable evidence supporting the use of BOZ-DSZ in highly sensitized kidney transplant candidates. While their findings are promising, they also highlight the critical need for further research to optimize desensitization strategies. Large-scale prospective or randomized controlled trials are warranted to establish the efficacy, safety, and long-term benefits of BOZ-DSZ. Particular attention should be paid to strategies that maintain desensitization effects during an uncertain waiting period for DDKT. Tailoring desensitization based on antibody characteristics, including complement-binding capacity and HLA class specificity, may also enhance therapeutic precision. Ultimately, the development of durable and flexible desensitization protocols is essential to improve the transplantation opportunity and posttransplant outcomes in this high-risk population.
Notes
Conflicts of interest
All authors have no conflicts of interest to declare.
Data sharing statement
The data presented in this study are available from the corresponding author upon reasonable request.