Vieira Carlos A, Agarwal Avinash, Book Benita K, Sidner Richard A, Bearden Christopher M, Gebel Howard M, Roggero Anthony L, Fineberg Naomi S, Taber Timothy, Kraus Michael A, Pescovitz Mark D
Department of Surgery, Indiana University, Indianapolis, IN, USA.
Transplantation. 2004 Feb 27;77(4):542-8. doi: 10.1097/01.tp.0000112934.12622.2b.
Preformed HLA 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.
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. Peripheral lymphocyte cell surface markers and HLA Ab levels (%PRA and titers) were tested using flow cytometry.
There were four significant adverse events: a suspected histoplasmosis infection; two Tenchkoff dialysis catheter infections; and fever (38.7 degrees C) 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.
RTX can be safely administered and may be an effective agent to reduce high-titer anti-HLA Abs in subjects awaiting kidney transplantation.
预先形成的HLA抗体（Ab），以群体反应性抗体（PRA）报告，会延长肾移植患者的等待时间。我们推测利妥昔单抗（RTX）可通过B细胞耗竭降低PRA。这项初步研究报告了RTX在终末期肾衰竭患者中的安全性、药代动力学和药效学。
该研究是一项由研究者发起的针对慢性透析患者（PRA>50%）的RTX单剂量、剂量递增的I期试验。它获得了机构审查委员会和食品药品监督管理局的批准。9名受试者分别接受50、150或375mg/m的单剂量RTX治疗（每组3人）。使用流式细胞术检测外周淋巴细胞表面标志物和HLA Ab水平（%PRA和滴度）。
有4起严重不良事件：1例疑似组织胞浆菌感染；2例Tenchkoff透析导管感染；以及输注期间发热（38.7℃）。RTX治疗后2天，CD19细胞耗竭（RTX治疗前181±137 vs. RTX治疗后12±5.6，P = 0.006）。9名受试者中有2名（22%）的PRA无明显变化。在其他7名患者中，1名患者的PRA从87%降至51%，同时荧光强度降低；5名患者的直方图结构发生变化，提示抗体特异性丧失；1名患者在治疗后6个月时PRA滴度从1:64降至1:16，降低了四倍。此外，7名患者中有1名将供体特异性交叉配型转为阴性，并成功接受了活体供肾移植。
RTX可以安全给药，可能是降低等待肾移植患者高滴度抗HLA Abs的有效药物。
