Differential Treatment Effects for Renal Transplant Recipients With DSA-Positive or DSA-Negative Antibody-Mediated Rejection

Abstract

BackgroundAntibody-mediated rejection (ABMR) is the main cause of renal allograft loss. The most common treatment strategy is based on plasmapheresis plus the subsequent administration of intravenous immunoglobulin (IVIG). Unfortunately, no approved long-term therapy is available for ABMR. The current study was designed to analyze the effect of various ABMR treatment approaches on allograft survival and to compare treatment effects in the presence or absence of donor-specific antibodies (DSAs).MethodsThis single-center study retrospectively analyzed 102 renal allograft recipients who had biopsy-proven ABMR after transplant. DSA was detectable in 61 of the 102 patients. Initial standard treatment of ABMR consisted of plasmapheresis (PS) or immunoadsorption (IA), followed by a single course of IVIG. In case of nonresponse or recurrence, additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab, were administered. In a second step, persistent ABMR was treated with increased maintenance immunosuppression, long-term therapy with IVIG (more than 1 year), or both.ResultsOverall graft survival among transplant patients with ABMR was <50% after 3 years of follow-up. Compared to the use of PS/IA and IVIG alone, the use of additional immunosuppressive medications had no beneficial effect on allograft survival (p = 0.83). Remarkably, allografts survival rates were comparable between patients treated with the combination of PS/IA and IVIG and those treated with a single administration of IVIG (p = 0.18). Renal transplant patients with ABMR but without DSAs benefited more from increased maintenance immunosuppression than did DSA-positive patients with ABMR (p = 0.01). Recipients with DSA-positive ABMR exhibited significantly better allograft survival after long-term application of IVIG for more than 1 year than did recipients with DSA-negative ABMR (p = 0.02).ConclusionsThe results of our single-center cohort study involving kidney transplant recipients with ABMR suggest that long-term application of IVIG is more favorable for DSA-positive recipients, whereas intensification of maintenance immunosuppression is more effective for recipients with DSA-negative ABMR.

The role of anticomplement therapy in the management of the kidney allograft

“…[48][49][50][51][52][53][54][55][56][57] Another single-center retrospective study involving 102 kidney transplant recipients with biopsy-proven AMR who were treated initially with plasmapheresis or immunoadsorption, followed by a single course of IVIG, and in the case of nonresponse or recurrence, with added additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab. 58 However, only three patients received eculizumab, so, from the point of view of eculizumab, it amounted to a case series. 58 Although anticomplement therapy is a potential therapeutic option for treatment-resistant acute AMR episodes based on the underlying pathophysiology, the clinical evidence advocating for such therapeutic approach is yet limited and insufficient.…”

“…58 However, only three patients received eculizumab, so, from the point of view of eculizumab, it amounted to a case series. 58 Although anticomplement therapy is a potential therapeutic option for treatment-resistant acute AMR episodes based on the underlying pathophysiology, the clinical evidence advocating for such therapeutic approach is yet limited and insufficient.…”

“…Another single‐center retrospective study involving 102 kidney transplant recipients with biopsy‐proven AMR who were treated initially with plasmapheresis or immunoadsorption, followed by a single course of IVIG, and in the case of nonresponse or recurrence, with added additional immunosuppressive medications, such as rituximab, bortezomib, thymoglobulin, or eculizumab 58 . However, only three patients received eculizumab, so, from the point of view of eculizumab, it amounted to a case series 58 .…”

Successful AAV8 readministration: Suppression of capsid‐specific neutralizing antibodies by a combination treatment of bortezomib and CD20 mAb in a mouse model of Pompe disease

“…[18][19][20] Bortezomib (Takeda Pharmaceutical Company, Tokyo, Japan) is a Food and Drug Administrationapproved 26S proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma, 21,22 which has also been widely used as an immune suppressive agent for patients with other conditions. [23][24][25][26][27][28][29] Bortezomib has broad effects on the immune system including the suppression of IgG antibody production, inhibition of Tcell proliferation, induction of T-cell apoptosis, preservation of natural regulatory T cells, and prevention of antigen presentation on MHC class I molecules to CD8 + T cells. 30 Bortezomib is particularly effective in targeting and depleting mature antibody-producing plasma cells with high rates of immunoglobulin synthesis through induction of apoptosis by the rapid accumulation of unfolded proteins.…”

“…More importantly, these agents have been very well tolerated in patients with Pompe disease with few safety concerns 18–20 . Bortezomib (Takeda Pharmaceutical Company, Tokyo, Japan) is a Food and Drug Administration‐approved 26S proteasome inhibitor for the treatment of multiple myeloma and mantle cell lymphoma, 21,22 which has also been widely used as an immune suppressive agent for patients with other conditions 23–29 . Bortezomib has broad effects on the immune system including the suppression of IgG antibody production, inhibition of T‐cell proliferation, induction of T‐cell apoptosis, preservation of natural regulatory T cells, and prevention of antigen presentation on MHC class I molecules to CD8 + T cells 30 .…”