Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Transplantation. 2010 Dec 27;90(12):1486-92. doi: 10.1097/TP.0b013e3181fdd9b0.
We report our initial experience in using the proteasome inhibitor, bortezomib, to treat established antibody-mediated rejection (AMR) in 20 patients.
There were 16 kidney-only and 4 kidney-combined organ recipients with de novo donor-specific antibody (DSA) and histologic evidence of AMR with peritubular capillaries C4d deposition. AMR was diagnosed 19.8 months (range 1-71 months) posttransplant. Patients received intravenous corticosteroids followed by a 2-week cycle on days 1-4-8-11 of plasmapheresis and 1.3 mg/m² bortezomib; then 0.5 mg/kg intravenous immunoglobulin four times.
De novo class I DSA was detected in 11 (55%) and class II DSA in 18 (90%) recipients. The absolute mean difference between peak-nadir dominant DSA was 68,171 molecules of equivalent soluble fluorochrome (P<0.0001), representing 55%±22%. Only two patients (10%) had undetectable DSA after treatment. Patient survival is 100%, and graft survival is 85% with a mean follow-up of 9.8 months (range 2-20 months). The treatment was generally well tolerated but caused fatigue, gastrointestinal complaints, fluid retention, and thrombocytopenia in a number of patients. The last follow-up estimated glomerular filtration rate was 41.9±16.8 mL/min (range 20.6-72.2 mL/min). However, only 25% returned to their baseline renal function before AMR, and many have proteinuria with urine protein/creatinine more than 0.5 in 41% and more than 1.0 in 18%.
The bortezomib-containing regimen demonstrated activity in AMR but seems to be most effective before the onset of significant renal dysfunction (serum creatinine <3 mg/dL) or proteinuria (<1 g/day). The best use of bortezomib to treat AMR should be evaluated in controlled trials using dosing strategies that include longer courses or retreatment schedules.
我们报告了使用蛋白酶体抑制剂硼替佐米治疗 20 例已确诊的抗体介导排斥反应（AMR）的初步经验。
16 例为单纯肾脏移植，4 例为肾脏联合器官移植，供者特异性抗体（DSA）和组织学证据均显示 AMR，伴小管周毛细血管 C4d 沉积。AMR 在移植后 19.8 个月（1-71 个月）时诊断。患者接受静脉皮质激素治疗，随后进行为期 2 周的血浆置换，在第 1-4-8-11 天进行，硼替佐米 1.3mg/m²；然后静脉注射免疫球蛋白 0.5mg/kg，4 次。
11 例（55%）患者检测到新出现的 I 类 DSA，18 例（90%）患者检测到 II 类 DSA。峰值-谷值主导性 DSA 的绝对平均差异为 68171 个等效可溶性荧光分子（P<0.0001），占 55%±22%。治疗后仅有 2 例（10%）患者的 DSA 不可检测。患者存活率为 100%，移植物存活率为 85%，平均随访时间为 9.8 个月（2-20 个月）。该治疗方法总体上耐受性良好，但在许多患者中引起疲劳、胃肠道不适、液体潴留和血小板减少。最后一次随访估算的肾小球滤过率为 41.9±16.8mL/min（范围 20.6-72.2mL/min）。然而，仅有 25%的患者在 AMR 前恢复到基线肾功能，许多患者仍有蛋白尿，尿蛋白/肌酐比>0.5 的占 41%，>1.0 的占 18%。
硼替佐米治疗方案在 AMR 中显示出一定的疗效，但在明显肾功能不全（血清肌酐<3mg/dL）或蛋白尿（<1g/天）发生之前似乎效果最佳。在对照试验中，应评估硼替佐米治疗 AMR 的最佳用途，包括更长的疗程或再治疗方案。
