*Purpose: Kidney transplant recipients with failed allografts suffer from high rates of humoral sensitization. Immunosuppression (IS) strategies are highly variable in these patients with many discontinuing IS, often resulting in HLA antibodies that complicate re-transplantation. Despite this risk, common practice has maintained that the risks of infection and metabolic toxicities of IS outweigh the potential benefit of antibody prevention. The advent of belatacept with its favorable toxicity profile and ability to prevent alloantibodies render it an appealing IS option to minimize sensitization and facilitate re-transplantation in kidney transplant recipients with failed allografts.

*Methods: We designed a single center, randomized controlled trial to evaluate the impact of belatacept on HLA antibody formation in patients with failed renal allografts. Kidney transplant recipients (>1-yr post-transplant, 18-70 yrs) with failing (GFR<20, PreD) or failed allografts (PostD) were randomized to receive belatacept (BELA) or IS discontinuation (ISD) and followed for 36 months. Group assignment was made according to a computer-generated randomization table. PreD subjects not yet on dialysis were converted to belatacept or maintained on their current IS, and once on dialysis continued on belatacept monotherapy or their IS discontinued. PostD subjects already on dialysis were converted to belatacept monotherapy or their IS discontinued. Outcomes measured were the development of donor-specific antibodies (DSA) and degree of sensitization as measured by flow-based panel reactive antibody (PRA) assessment, Luminex-based HLA single antigen bead specificity testing and calculated PRA (cPRA).

*Results: 13 patients were randomized to BELA (n=6, mean age, 55.2 [SD, ±9.8] yrs; median graft survival, 215.4 [range, 44.6-318.2] mos) or ISD (n=7, mean age, 46.9 [±14.2] yrs; median graft survival, 228.4 [58.8-280.1] mos). 4 BELA (mean HLA mismatches, 6.5 [±1.3]) subjects transitioned to belatacept monotherapy and 4 ISD (mean HLA mismatches, 6.75 [±1.3]) subjects discontinued IS for a mean follow up of 27.5 [±9.9] and 23.8 [±8.3] mos, respectively. While 75% (3/4) of BELA and 100% (4/4) of ISD subjects developed DSA, BELA subjects experienced less of an increase in Class I (median, 0 [0-38] vs. 38.5 [16-99] %) and Class II (median, 17 [0-73] vs. 93 [0-99] %) PRA compared to ISD subjects. BELA patients also developed fewer total HLA antibodies (median, 24,482 [0-71,089] vs. 280,607 [52,357-789,978] MFI) and lower cPRA (median, 35.4 [0-84.2] vs. 91.2 [66.1-98.7] %) than ISD subjects. One ISD and 2 BELA deaths occurred during transition to dialysis.

*Conclusions: Belatacept monotherapy reduced the burden of alloantibodies in kidney transplant recipients with failed allografts compared to IS discontinuation, potentially facilitating re-transplantation and better outcomes.

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