Induction Therapy With Autologous Mesenchymal Stem Cells in Living-Related Kidney Transplants A Randomized Controlled Trial
Induction Therapy With Autologous Mesenchymal Stem Cells in Living-Related Kidney Transplants A Randomized Controlled Trial
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DOI：
10.1001/jama.2012.316
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发表时间：
2012-03-21
影响因子：
120.7
通讯作者：
Ricordi, Camillo
中科院分区：
文献类型：
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作者：
Tan, Jianming;Wu, Weizhen;Ricordi, Camillo
背景：基于抗体的诱导治疗加钙调神经磷酸酶抑制剂（CNI）可降低肾移植受者的急性排斥反应率;然而，机会性感染和CNI毒性作用仍然具有挑战性。据报道，间充质干细胞（MSCs）已成功治疗移植物抗宿主病（graft-vs-host disease.Objective），评估自体MSCs作为终末期肾病患者抗体诱导的替代品，这些患者接受来自活体亲属供者的ABO相容、交叉配型阴性肾移植。干预患者在肾再灌注时和两周后接种骨髓来源的自体MSC（1-2 × 10（6）/kg）。53例患者接受标准剂量，52例患者接受低剂量CNI（标准的80%）;对照组中的51名患者接受抗IL-2受体抗体加标准剂量CNIs。主要结果测量主要测量是1年急性排斥反应和肾功能的发生率（估计肾小球滤过率[eGFR]）;第二个指标是患者和移植物的存活率和不良事件的发生率。6个月后，53名患者中有4名在自体MSC加标准剂量CNI组中，（95% CI，0.4%-14.7%; P= 0.04），52例患者中有4例（7.7%）（95%CI，0.5%-14.9%; P= 0.046），相比之下，51例对照组中有11例（21.6%; 95%CI，10.5%-32.6%）发生活检证实的急性排斥反应。自体MSC组中没有患者发生糖皮质激素抵抗性排斥反应，而对照组中有4例患者（7.8%）在术后第一个月显示eGFR水平升高（95% CI，0.6%-15.1%;总体P= 0.02）。两个MSC组的肾功能恢复得更快，显示手术后第一个月的eGFR水平高于对照组。接受标准剂量CNI的患者平均差异为6.2 mL/min/1.73 m2（95% CI，0.4-11.9; P=.04），而接受低剂量CNI的患者平均差异为10.0 mL/min/1.73 m2（95% CI，3.8-16.2; P=.002）。此外，在1年随访期间，MSC治疗组的综合分析显示，与对照组相比，机会性感染的风险显著降低（风险比，0.42;结论在肾移植患者中，自体骨髓间充质干细胞的应用较抗IL-2受体抗体诱导治疗可降低急性排斥反应的发生率，降低机会性感染的风险，并在1年时更好地评估肾功能。
Context Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease.Objective To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor.Design, Setting, and Patients One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed.Intervention Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs.Main Outcome Measures The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events.Results Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P=.04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P=.046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control showing increased eGFR levels during the first month postsurgery group did (95% CI, 0.6%-15.1%; overall P=.02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02)Conclusion Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year.