Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants
Complete Immunosuppression Withdrawal and Subsequent Allograft Function Among Pediatric Recipients of Parental Living Donor Liver Transplants
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DOI：
10.1001/jama.2011.2014
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发表时间：
2012-01-18
影响因子：
120.7
通讯作者：
Tchao, Nadia K.
中科院分区：
文献类型：
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作者：
Feng, Sandy;Ekong, Udeme D.;Tchao, Nadia K.
肝移植虽然可以挽救生命，但却给儿童带来了终身免疫抑制的负担，并有很大的发病率和死亡率的可能性。目的探讨儿童活体肝移植受者免疫抑制停药的可行性。设计、环境和患者：前瞻性、多中心、开放标签、单组试点试验，对20名稳定的接受父母活体供肝移植的儿童（11名男性，占55%）进行了研究，这些儿童接受的是病毒性肝炎或自身免疫性疾病以外的疾病，并进行了免疫抑制退出。移植时的中位年龄为6.9个月（四分位数范围[IQR]， 5.5-9.1个月），入组时的中位年龄为8岁6个月（IQR， 6岁5个月至10岁9个月）。其他入境要求包括：服用单一免疫抑制药物时同种异体移植物功能稳定，肝活检无急性或慢性排斥反应或明显纤维化的证据。在2006年6月5日至2009年11月18日期间，3个移植中心中的1个实施了至少36周的渐进免疫抑制撤除。患者的中位随访时间为32.9个月（IQR, 1.0-49.9个月）。主要终点是手术耐受患者的比例，定义为停止免疫抑制治疗至少1年且移植物功能正常的患者。次要临床终点包括手术耐受的持久性，以及排斥反应的发生率、时间、严重程度和可逆性。结果在20例儿童患者中，12例（60%;95% CI, 36.1%-80.9%）达到了主要终点，在停止免疫抑制治疗后维持同种异体移植功能正常的中位时间为35.7个月（IQR, 28.1-39.7个月）。完成停药后2年多的随访活检显示与基线活检相比无显著变化。8例患者未达到主要终点，继发于违反排除标准（n=1）、急性排斥反应（n=2）或不确定排斥反应（n=5）。7例患者增加或重新开始免疫抑制治疗；所有患者均恢复到同种异体移植物的基线功能。有手术耐受的患者与无手术耐受的患者相比，移植后开始免疫抑制停药（中位数分别为100.6个月[IQR， 71.8-123.5]和73.0个月[IQR， 57.6-74.9]， P= 0.03），门静脉炎症较少（91.7% [95% CI, 61.5%-99.8%]对42.9% [95% CI, 9.9%-81.6%]，无炎症，P= 0.04），筛查肝活检的C4d总评分较低（中位数为6.1 [IQR, 5.1-9.3]对12.5 [IQR, 9.3-16.8]， P= 0.03）。在这项初步研究中，60%的儿童父母活体肝移植受者在移植功能正常和同种异体移植组织学稳定的情况下，至少1年没有使用免疫抑制治疗。《美国医学协会杂志》上。2012年;307 (3): 283 - 293
Context Although life-saving, liver transplantation burdens children with lifelong immunosuppression and substantial potential for morbidity and mortality.Objective To establish the feasibility of immunosuppression withdrawal in pediatric living donor liver transplant recipients.Design, Setting, and Patients Prospective, multicenter, open-label, single-group pilot trial conducted in 20 stable pediatric recipients (11 male; 55%) of parental living donor liver transplants for diseases other than viral hepatitis or an autoimmune disease who underwent immunosuppression withdrawal. Their median age was 6.9 months (interquartile range [IQR], 5.5-9.1 months) at transplant and 8 years 6 months (IQR, 6 years 5 months to 10 years 9 months) at study enrollment. Additional entry requirements included stable allograft function while taking a single immunosuppressive drug and no evidence of acute or chronic rejection or significant fibrosis on liver biopsy. Gradual immunosuppression withdrawal over a minimum of 36 weeks was instituted at 1 of 3 transplant centers between June 5, 2006, and November 18, 2009. Recipients were followed up for a median of 32.9 months (IQR, 1.0-49.9 months).Main Outcome Measures The primary end point was the proportion of operationally tolerant patients, defined as patients who remained off immunosuppression therapy for at least 1 year with normal graft function. Secondary clinical end points included the durability of operational tolerance, and the incidence, timing, severity, and reversibility of rejection.Results Of 20 pediatric patients, 12 (60%; 95% CI, 36.1%-80.9%) met the primary end point, maintaining normal allograft function for a median of 35.7 months (IQR, 28.1-39.7 months) after discontinuing immunosuppression therapy. Follow-up biopsies obtained more than 2 years after completing withdrawal showed no significant change compared with baseline biopsies. Eight patients did not meet the primary end point secondary to an exclusion criteria violation (n=1), acute rejection (n=2), or indeterminate rejection (n=5). Seven patients were treated with increased or reinitiation of immunosuppression therapy; all returned to baseline allograft function. Patients with operational tolerance compared with patients without operational tolerance initiated immunosuppression withdrawal later after transplantation (median of 100.6 months [IQR, 71.8-123.5] vs 73.0 months [IQR, 57.6-74.9], respectively; P=.03), had less portal inflammation (91.7% [95% CI, 61.5%-99.8%] vs 42.9% [95% CI, 9.9%-81.6%] with no inflammation; P=.04), and had lower total C4d scores on the screening liver biopsy (median of 6.1 [IQR, 5.1-9.3] vs 12.5 [IQR, 9.3-16.8]; P=.03).Conclusion In this pilot study, 60% of pediatric recipients of parental living donor liver transplants remained off immunosuppression therapy for at least 1 year with normal graft function and stable allograft histology. JAMA. 2012;307(3):283-293