Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.

Desensitization in kidney transplantation: review and future perspectives.

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti-HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high-dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high-dose IVIg+rituximab in non-randomized trials. Overall experience in multiple centers, however, has shown high antibody-mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low-dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low-dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell-targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non-deletional strategies with IVIg.

Early and late acute antibody-mediated rejection differ immunologically and in response to proteasome inhibition.

BACKGROUND: The efficacy of plasma cell targeted therapies for antibody-mediated rejection (AMR) has not been defined in detail. The purpose of this study was to compare early and late acute AMR in terms of immunologic characteristics and responses with proteasome inhibitor (PI) therapy. METHODS: Renal transplant recipients with acute AMR were treated with PI-based regimens. Early acute AMR was defined as occurring within 6 months posttransplant. Immunodominant donor-specific antibody (iDSA) was defined as the DSA with the highest level. RESULTS: Results are expressed as early or late acute AMR. Thirty AMR episodes (13 early, 17 late) were treated in 12 and 16 patients. Early but not late AMR was associated with presensitization. Late AMR iDSA levels were higher, and specificities were primarily class II (DQ being most frequent). Early AMR patients demonstrated greater reduction in iDSA at 7, 14, and 30 days and at the posttreatment nadir (81.5%+21.2% vs. 51.4%+27.6%; P<0.01). Early AMR patients were more likely to demonstrate histologic resolution/improvement (87.5% vs. 53.8%; P=0.13). Both groups demonstrated significant improvement in renal function. CONCLUSIONS: Early and late AMR exhibit distinct immunologic characteristics and respond differently to PI therapy.