Bortezomib in late humoral kidney transplant rejection

Despite major advances in transplant medicine, improvements in long-term kidney transplant survival have not been commensurate with those observed shortly after transplantation. It has become evident that alloantibody formation against donor human leukocyte antigens (HLA) is a leading cause of late allograft dysfunction and loss. Late antibody-mediated rejection (AMR) is now well known to constitute a separate rejection entity. However, for this rejection type, appropriate targeted treatment has not yet been defined. One promising strategy could be the targeting of alloantibody-producing plasma cells. There is now accumulating evidence that the proteasome inhibitor bortezomib, a compound approved for multiple myeloma, may also substantially affect the function and integrity of non-malignant alloantibody-secreting plasma cells. The impact of this agent on the course of late AMR processes, however, has not yet been systematically investigated. In the planned non-commercial phase IIa, proof of concept, study we will examine the effect of bortezomib on late AMR after kidney transplantation. We plan an initial cross- sectional HLA antibody screening (bead array technology) of 1000 kidney transplant recipients [functioning graft at =180 days; glomerular filtration rate (GFR) >20 ml/min/1.73 m 2 ] to identify patients with detectable donor-specific antibodies (DSA). DSA-positive recipients will be subjected to kidney allograft biopsy to detect morphological features consistent with AMR. Forty-four patients with late AMR will be included in a randomized double-blind placebo-controlled parallel-group intervention trial (stratified 1:1 randomization). Patients in the active group will receive two cycles of bortezomib (4 x 1.3 mg/m 2 over two weeks; three-month interval between cycles) under anti- viral prophylaxis (control group: placebo) and careful monitoring of potential adverse events. The primary end point will be the course of estimated GFR over 24 months after randomization (intention-to-treat analysis). The sample size was calculated according to the assumption of a 5 ml/min/1.73 m 2 difference in GFR slope (per year) between the two groups (alpha: 0.05; power: 0.8). Secondary endpoints are the course of DSA levels and protein excretion, measured GFR after 24 months, transplant and patient survival, and the development of acute and chronic morphological lesions in 24-month protocol biopsies. Our study will clarify the impact of an innovative anti-humoral strategy on the deleterious effects of late AMR processes. The establishment of a therapeutic strategy capable to successfully prevent graft injury and improve transplant outcomes will have a major impact on clinical practice.

Transplantation is regarded as the renal replacement therapy of choice for patients with kidney failure. Despite enormous advances in transplant medicine, long-term survival of organ allografts is still limited, mainly due to chronic rejection. There are still no evidence-based treatment options for established late antibody-mediated rejection (ABMR), and the results of uncontrolled observational studies are controversially discussed. In this prospective, double-blind, randomized, placebo-controlled trial, we investigated whether the proteasome inhibitor bortezomib, which may directly target alloantibody-producing plasma cells, is able to influence the course of established late ABMR. In a systematic cross-sectional screening of 741 long-term kidney transplant recipients we were able to identify 111 recipients who have formed donor-specific antibodies against the transplanted organ. Forty-four of these recipients were randomized to receive either two cycles of bortezomib or placebo. A major result of the interventional trial was that bortezomib failed to improve the course of kidney function over the two-year observation period (surrogate of long-term survival; primary endpoint). There was also no difference between groups with respect to patient and graft survival or the natural course of rejection phenotypes. Bortezomib treatment led to more gastrointestinal adverse events and was associated with (commonly mild) thrombo- and leukocytopenia. The results of this study demonstrate that proteasome inhibition to treat late ABMR does not improve transplant outcomes. Our results underscore the need of systematic prospective trials to clarify the true efficiency of innovative treatment strategies in this specific context. Our screening results and the detailed characterization of the natural course of late ABMR may provide a valuable foundation for the design of future interventional trials.