Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics
Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation: 1. Safety, pharmacodynamics, and pharmacokinetics
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DOI：
10.1097/01.tp.0000112934.12622.2b
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发表时间：
2004-02-27
期刊：
影响因子：
6.2
通讯作者：
Pescovitz, MD
中科院分区：
文献类型：
--
作者：
Vieira, CA;Agarwal, A;Pescovitz, MD
背景预先形成的HILA抗体（Ab），报告为群体反应性抗体（PRA），延长患者等待肾移植的时间。我们假设利妥昔单抗（RTX）可以通过B细胞耗竭减少PRA。这项初步研究报告了RTX在终末期肾功能衰竭患者中的安全性、药代动力学和药效学。该研究是一项在慢性透析患者（PRA > 50%）中进行的RTX单次给药、剂量递增I期试验。它得到了机构审查委员会和食品和药物管理局的批准。9名受试者接受单剂量RTX治疗（每组n = 3），剂量为50、150或375 mg/m2。采用流式细胞仪检测外周血淋巴细胞表面标志和HLA抗体水平（%PRA和滴度）。有4起严重的不良事件：疑似组织胞浆菌感染; 2起Tenchkoff透析导管感染;以及输注期间发热（38.7 ℃）。RTX治疗后2天，CD 19（+）细胞出现耗竭（RTX治疗前181 +/- 137 vs. RTX治疗后12 +/- 5.6，P = 0.006）。在2/9例（22%）受试者中，PRA无明显变化。在其他7名患者中，1名患者的PRA从87%降低至51%，同时荧光强度降低; 5名患者的直方图结构发生变化，表明抗体特异性丧失; 1名患者的PRA滴度在治疗后6个月时降低了4倍，从1：64降至1：16。此外，7例患者中有1例将供体特异性交叉配型转为阴性，并成功进行了活体供肾移植。RTX可以安全地施用，并且可能是减少等待肾移植的受试者中的高滴度抗HLA抗体的有效药剂。
Background. Preformed HILA antibodies (Ab), reported as panel-reactive antibody (PRA), prolong patient waiting time for kidney transplantation. We hypothesized that rituximab (RTX) could reduce PRA via B-cell depletion. This initial study reports the safety, pharmacokinetics, and pharmacodynamics of RTX in patients with end-stage renal failure.Methods. The study was an investigator-initiated single-dose, dose-escalation phase I trial of RTX in chronic dialysis patients (PRA > 50%). It was approved by the Institutional Review Board and the Food and Drug Administration. Nine subjects were treated with a single dose of RTX (n = 3 per group) at 50,150, or 375 mg/m(2). Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry.Results. There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7degreesC) during infusion. At 2 days after RTX therapy, there was depletion of CD19(+) cells (pre-RTX 181 +/- 137 vs. post-RTX 12 +/- 5.6, P = 0.006). In 2 (22%) of 9 subjects, there was no appreciable change in PRA. Among the other seven patients, one had a decrease in PRA from 87% to 51% with a concurrent decrease in fluorescence intensity; five patients had changes in histogram architecture suggesting loss of antibody specificity; and one patient had a fourfold decrease in PRA titer from 1:64 to 1:16 at 6 months after treatment. In addition, one of the seven patients converted a donor-specific crossmatch to negative and underwent a successful living donor kidney transplantation.Conclusions. RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.