Three-Year Outcomes in Kidney Transplant Recipients Switched From Calcineurin Inhibitor-Based Regimens to Belatacept as a Rescue Therapy.

Background: The long-term benefits of conversion from calcineurin inhibitors (CNIs) to belatacept in kidney transplant recipients (KTr) are poorly documented.Methods: A single-center retrospective work to study first-time CNI to belatacept conversion as a rescue therapy [eGFR <30 ml/min/1.73 m2, chronic histological lesions, or CNI-induced thrombotic microangiopathy (TMA)]. Patient and kidney allograft survivals, eGFR, severe adverse events, donor-specific antibodies (DSA), and histological data were recorded over 36 months after conversion. Results: We included N = 115 KTr. The leading cause for switching was chronic histological lesions with non-optimal eGFR (56.5%). Three years after conversion, patient, and death-censored kidney allograft survivals were 88% and 92%, respectively, eGFR increased significantly from 31.5 ± 17.5 to 36.7 ± 15.7 ml/min/1.73 m2 (p < 0.01), the rejection rate was 10.4%, OI incidence was 5.2 (2.9-7.6) per 100 person-years. Older age was associated with death, eGFR was not associated with death nor allograft loss. No patient developed dnDSA at M36 after conversion. CNI-induced TMA disappeared in all cases without eculizumab use. Microvascular inflammation and chronic lesions remained stable. Conclusion: Post-KT conversion from CNIs to belatacept, as rescue therapy, is safe and beneficial irrespective of the switch timing and could represent a good compromise facing organ shortage. Age and eGFR at conversion should be considered in the decision whether to switch.

Daratumumab in Sensitized Kidney Transplantation: Potentials and Limitations of Experimental and Clinical Use.

BACKGROUND: Donor-specific antibodies are associated with increased risk of antibody-mediated rejection and decreased allograft survival. Therefore, reducing the risk of these antibodies remains a clinical need in transplantation. Plasma cells are a logical target of therapy given their critical role in antibody production. METHODS: To target plasma cells, we treated sensitized rhesus macaques with daratumumab (anti-CD38 mAb). Before transplant, we sensitized eight macaques with two sequential skin grafts from MHC-mismatched donors; four of them were also desensitized with daratumumab and plerixafor (anti-CXCR4). We also treated two patients with daratumumab in the context of transplant. RESULTS: The animals treated with daratumumab had significantly reduced donor-specific antibody levels compared with untreated controls (57.9% versus 13% reduction; P<0.05) and prolonged renal graft survival (28.0 days versus 5.2 days; P<0.01). However, the reduction in donor-specific antibodies was not maintained because all recipients demonstrated rapid rebound of antibodies, with profound T cell-mediated rejection. In the two clinical patients, a combined heart and kidney transplant recipient with refractory antibody-mediated rejection and a highly sensitized heart transplant candidate, we also observed a significant decrease in class 1 and 2 donor-specific antibodies that led to clinical improvement of antibody-mediated rejection and to heart graft access. CONCLUSIONS: Targeting CD38 with daratumumab significantly reduced anti-HLA antibodies and anti-HLA donor-specific antibodies in a nonhuman primate model and in two transplant clinical cases before and after transplant. This supports investigation of daratumumab as a potential therapeutic strategy; however, further research is needed regarding its use for both antibody-mediated rejection and desensitization.

Belatacept-based immunosuppressive regimen in HIV-positive kidney transplant recipients.

BACKGROUND: Kidney allograft survival in human immunodeficiency virus (HIV)-positive patients is lower than that in the general population. Belatacept increases long-term patient and allograft survival rates when compared with calcineurin inhibitors (CNIs). Its use in HIV-positive recipients remains poorly documented. METHODS: We retrospectively report a French cohort of HIV-positive kidney allograft recipients who were switched from CNI to belatacept, between June 2012 and December 2018. Patient and allograft survival rates, HIV immunovirological and clinical outcomes, acute rejection, opportunistic infections (OIs) and HLA donor-specific antibodies (DSAs) were analysed at 3 and 12 months, and at the end of follow-up (last clinical visit attended after transplantation). Results were compared with HIV-positive recipients group treated with CNI. RESULTS: Twelve patients were switched to belatacept 10 (2-25) months after transplantation. One year after belatacept therapy, patient and allograft survival rates scored 92% for both, two (17%) HIV virological rebounds occurred due to antiretroviral therapy non-compliance, and CD4+ and CD8+ T-cell counts remained stable over time. Serious adverse events included two (17%) acute steroid-resistant T-cell-mediated rejections and three (25%) OIs. Kidney allograft function significantly increased over the 12 post-switch months (P = 0.009), and DSAs remained stable at 12 months after treatment. The control group showed similar results in terms of patient and kidney allograft survival rates, DSA characteristics and proteinuria. CONCLUSIONS: Switch from CNI to belatacept can be considered safe and may increase long-term kidney allograft survival in HIV-positive kidney allograft recipients. These results need to be confirmed in a larger cohort.