一项比较贝伐单抗与他克莫司在新诊断肾移植后的随机对照临床试验。
A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation.
机构信息
1 Division of Nephrology and Kidney Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 2 Department of Pathology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 3 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. 4 Department of Biostatistics, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
出版信息
Transplantation. 2017 Oct;101(10):2571-2581. doi: 10.1097/TP.0000000000001755.
BACKGROUND
Belatacept, an inhibitor of the CD28-CD80/86 costimulatory pathway, allows for calcineurin-inhibitor free immunosuppressive therapy in kidney transplantation but is associated with a higher acute rejection risk than ciclosporin. Thus far, no biomarker for belatacept-resistant rejection has been validated. In this randomized-controlled trial, acute rejection rate was compared between belatacept- and tacrolimus-treated patients and immunological biomarkers for acute rejection were investigated.
METHODS
Forty kidney transplant recipients were 1:1 randomized to belatacept or tacrolimus combined with basiliximab, mycophenolate mofetil, and prednisolone. The 1-year incidence of biopsy-proven acute rejection was monitored. Potential biomarkers, namely, CD8CD28, CD4CD57PD1, and CD8CD28 end-stage terminally differentiated memory T cells were measured pretransplantation and posttransplantation and correlated to rejection. Pharmacodynamic monitoring of belatacept was performed by measuring free CD86 on monocytes.
RESULTS
The rejection incidence was higher in belatacept-treated than tacrolimus-treated patients: 55% versus 10% (P = 0.006). All 3 graft losses, due to rejection, occurred in the belatacept group. Although 4 of 5 belatacept-treated patients with greater than 35 cells CD8CD28 end-stage terminally differentiated memory T cells/μL rejected, median pretransplant values of the biomarkers did not differ between belatacept-treated rejectors and nonrejectors. In univariable Cox regressions, the studied cell subsets were not associated with rejection-risk. CD86 molecules on circulating monocytes in belatacept-treated patients were saturated at all timepoints.
CONCLUSIONS
Belatacept-based immunosuppressive therapy resulted in higher and more severe acute rejection compared with tacrolimus-based therapy. This trial did not identify cellular biomarkers predictive of rejection. In addition, the CD28-CD80/86 costimulatory pathway appeared to be sufficiently blocked by belatacept and did not predict rejection.
背景
贝他西普是一种 CD28-CD80/86 共刺激通路抑制剂，可在肾移植中实现无钙调神经磷酸酶抑制剂免疫抑制治疗，但与环孢素相比，它与更高的急性排斥风险相关。到目前为止，还没有经过验证的贝他西普耐药排斥反应的生物标志物。在这项随机对照试验中，比较了贝他西普和他克莫司治疗患者的急性排斥率，并研究了急性排斥的免疫生物标志物。
方法
40 例肾移植受者按 1:1 随机分为贝他西普或他克莫司联合巴利昔单抗、霉酚酸酯和泼尼松龙治疗组。监测活检证实的急性排斥发生率。在移植前和移植后测量潜在的生物标志物，即 CD8CD28、CD4CD57PD1 和 CD8CD28 终末分化记忆 T 细胞，并与排斥反应相关。通过测量单核细胞上的游离 CD86 来监测贝他西普的药效动力学。
结果
贝他西普治疗组的排斥发生率高于他克莫司治疗组：55%比 10%（P=0.006）。所有 3 例因排斥而导致的移植物丢失均发生在贝他西普组。尽管 5 例贝他西普治疗的患者中有 4 例大于 35 个 CD8CD28 终末分化记忆 T 细胞/μL 发生排斥反应，但在贝他西普治疗的排斥反应者和非排斥反应者之间，生物标志物的中位数移植前值没有差异。在单变量 Cox 回归中，所研究的细胞亚群与排斥风险无关。在所有时间点，贝他西普治疗患者循环单核细胞上的 CD86 分子均处于饱和状态。
结论
与他克莫司为基础的治疗相比，贝他西普为基础的免疫抑制治疗导致更高和更严重的急性排斥反应。本试验未发现预测排斥反应的细胞生物标志物。此外，CD28-CD80/86 共刺激通路似乎被贝他西普充分阻断，并且不能预测排斥反应。
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