The cytotoxic T-lymphocyte-associated protein 4-(CTLA-4)−immunoglobulin G1-fragment crystallizable region fusion protein belatacept is considered to be a less nephrotoxic alternative to calcineurin inhibitor (CNI)–based immunosuppression in renal transplantation. Belatacept blocks the costimulatory pathway between the CD80/CD86 molecules on antigen-presenting cells and the CD28 molecule on T cells. It is administered by intravenous infusion every 4 weeks under medical supervision in the maintenance phase and herewith has the additional potential of improving outcome in patients with adherence problems to immunosuppressive medication. Belatacept has been shown to have an acceptable safety profile in de novo renal transplantations with slightly higher rates of acute rejection episodes than those observed with CNI-based therapy.1 Data on conversion in the posttransplant phase from an initially CNI-based immunosuppressive regimen to belatacept are, however, scarce and limited mainly to patients with low immunologic risk.2 The study by Ulloa et al3 in the current issue of Transplantation could fill this gap.
The authors analyzed 29 kidney transplant recipients who had donor-specific human leukocyte antigen (HLA) antibodies (DSA) at some time before conversion and were converted from CNI to belatacept based on biopsy findings indicative of CNI toxicity, chronic vascular lesions, or interstitial fibrosis/tubular atrophy on a median of 444 days after transplantation. Among the 16 patients with DSA at the time of belatacept conversion, 10 lost their DSA, 4 had a slight decrease, and 2 had a moderate increase in DSA reactivity. In 2 patients, new DSA specificities were observed at the last follow-up that were not detectable at conversion but were already present before transplantation. Therefore, these DSAs were not categorized as de novo. One patient died, and another one was diagnosed with a mixed-type antibody-mediated rejection in the absence of detectable DSA. Three patients were withdrawn from belatacept therapy because of antibody-mediated rejection, personal reasons, or cutaneous Kaposi sarcoma. No graft loss or severe infection episodes were noted in the 29 patients. Serum creatinine improved from 212 mmol/L at conversion to 161 mmol/L 12 months after conversion.
The study by Ulloa et al3 confirms and extends previous observations made by Gupta et al4 and Meneghini et al5 and shows for the first time in a larger cohort of 29 patients with DSA that conversion from CNI to belatacept does not increase the risk of de novo DSA development. Gupta et al4 had studied 6 sensitized patients, including 1 patient with DSA, who were converted from tacrolimus to belatacept at a median of 4 months posttransplant. All patients showed an improvement of renal function, and none of them developed de novo DSA or rejection episodes. One patient had class II DSA at the time of conversion with a maximum mean fluorescence intensity (MFI) of 6700, which had decreased to 4844 MFI at the last follow-up at 12 months without histologic evidence of rejection. Meneghini et al5 had reported on a single highly sensitized patient who was converted from tacrolimus to belatacept for a seriously debilitating psoriatic arthritis 3 years after kidney transplantation. Four years after conversion, this patient still maintained good kidney function without proteinuria and de novo DSA.5
However, the study by Ulloa et al3 has also limitations. It was conducted in a still small collective with a rather low sensitization grade; namely, only one patient had DSA reactivity above 3000 MFI at belatacept switch. Therefore, it remains unclear whether these results can be transferred to patient cohorts with a high degree of sensitization and stronger DSA reactivity. Furthermore, upon conversion to belatacept, the patients received an increased dose of mycophenolic acid which may also have influenced the results. Unfortunately, details of the exact mycophenolic acid dose are not provided in the study.
Despite these limitations, the findings by Ulloa et al3 are in agreement with the findings of the larger Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) and Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-Extended criteria donors (BENEFIT-EXT) studies, in which significantly fewer de novo DSAs were detectable 7 years after kidney transplantation in more as well as less intense belatacept groups than in cyclosporine-treated patients.6 In the BENEFIT study, the mean estimated glomerular filtration rate differed between the cyclosporine and less intense belatacept group by an impressive 27.2 mL/min in favor of patients treated with a less intense belatacept regimen.1 However, compared with cyclosporine-treated patients, patients in the less intense belatacept group experienced more severe T-cell–mediated rejections in the early phase after transplantation.7 This dissociation between an increased frequency of T-cell–mediated rejections in the early phase on the one hand and a lower frequency of de novo DSA formation in the long run on the other hand was particularly surprising. Meanwhile, it is assumed that belatacept is capable of suppressing de novo DSA responses in a T-cell–independent manner, directly by binding to the CD80 molecule on antibody-producing plasma cells or via reduction in secondary lymphoid organs of the follicular T helper subset which is responsible for the differentiation of B cells into plasma cells.8 de Graav et al,9 on the other hand, showed in vitro evidence that belatacept is less potent than tacrolimus in inhibiting follicular T-helper cell–dependent plasmablast formation. Therefore, the last words on the action of belatacept have not been spoken. More experience with this agent and large studies including presensitized patients will show whether it is a safe alternative to CNIs.
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3. Ulloa CE, Anglicheau D, Snanoudj R, et al. Conversion from calcineurin inhibitors to belatacept in HLA-sensitized kidney-transplant recipients with low-level donor specific antibodies.Transplantation20191032150–2156
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9. de Graav GN, Hesselink DA, Dieterich M, et al. Belatacept does not inhibit follicular T cell-dependent B-cell differentiation in kidney transplantation.Front Immunol20178641