OPTIMAL IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION

目的：环孢素(CsA)、泼尼松和硫唑嘌呤三联免疫抑制疗法在美国已成为肾移植早期维持免疫抑制的主要药物。许多患者在肾移植后晚期仅使用两种免疫抑制剂效果良好，然而，目前还没有关于停用免疫抑制剂的对照对照试验。基本假设是，稳定的同种异体肾移植受者在移植后12个月或更长时间停用环孢素A，与停用霉酚酸酯或强的松相比，肾功能下降较慢，间质纤维化较少。方法：这是一项开放标签、随机、对照、治疗对比试验，仅限于免疫抑制减少后急性排斥反应风险较低的患者。18岁的身体和活体肾移植受者在移植后前三个月内最多发生一次急性排斥反应，且在入院前9个月内肾功能稳定。每24小时蛋白质排泄量超过500毫克的患者将被排除在外，那些无法继续服用三种药物之一的患者也将被排除在外。所有患者将在移植后第一年接受标准维持免疫抑制治疗。12个月后，患者将接受MMF(1g，2次/d)、新诺拉或桑地蒙(CsA)和泼尼松的治疗。患者将随机分为3组。登记将在肾移植后12-36个月进行，肾功能评估的随访时间为2年，同意在基线和停药后5年接受同种异体移植活组织检查的患者为5年。三年内在四个中心登记的258个样本量将允许检测三组之间2ml/分钟/年的差异。被分配到I组的患者将经历超过12周的CsA停药，并在CsA停止时一过性增加泼尼松剂量。被分配到第二组的患者将经历12周以上的泼尼松停药，停用强的松后3个月内CsA水平保持在通常目标范围的高端。被分配到第三组的患者将在12周内停用MMF。在移植后12个月、18个月、24个月、30个月和36个月，患者将接受体检、标准实验室测试和使用碘海醇清除法进行GFR测量。在随机化之前，患者也将被要求参加研究的活检部分。选择参加活检研究的患者将在随机分组后和免疫抑制停药前立即接受常规活检。活检中出现急性排斥反应的患者将在任何免疫抑制减少之前被排除在研究之外，最终将不会被考虑。如果患者(在过去六个月内没有做过充分的活检)在任何时候都有可能重新接受慢性维持性透析治疗，将进行第二次常规活检。否则，移植后6年，同种异体移植物功能正常的患者将被要求接受第二次方案活组织检查。所有方案活检将由肾脏病理学家使用Banff标准进行盲法评分。此外，还将对所有活检组织进行详细的形态计量分析。主要终点是通过移植后18至36个月间连续测定GFR的斜率(最少2个)来衡量GFR的下降率。对于在移植后18个月前恢复透析的患者，斜率将基于基线和最终的GFR测定。结果：到目前为止，已有10名患者在当地登记，所有中心总共约有50名患者。中期分析尚未完成。意义：当整个研究完成后，我们将能够更好地指导肾移植受者的免疫抑制治疗，并有望更好地限制给这些患者的昂贵和潜在毒性药物的数量。

Purpose: Triple immunosuppressant therapy with cyclosporine (CsA), prednisone, and azathioprine has been the mainstay of initial maintenance immunosuppression for renal transplantation in the U.S. These drugs have different mechanisms of action and different toxicities. Many patients do well with only two immunosuppressant agents late after renal transplantation, however, there are no controlled comparative trials of the withdrawal of immunosuppressant agents. The primary hypothesis is that withdrawal of cyclosporine in stable renal allograft recipients 12 months or more after transplantation results in a slower decline in renal function and less interstitial fibrosis than withdrawal of either mycophenylate or prednisone. Methods: This is an open label, randomized, controlled, therapeutic comparison trial, limited to patients at low risk for acute rejection following a decrease in immunosuppression. Cadaveric and living renal transplant recipients > 18 yr old with at most one acute rejection episode within the first three months after transplant and no subsequent episodes, and stable renal function for 9 months prior to entry will be eligible. Patients with more than 500 mg of protein excretion/24 hr will be excluded as will those unable to continue one of the three drugs. All patients will have been treated with standard maintenance immunosuppression during the first year after transplantation. At 12 months patients will be receiving MMF (1 g bid), Neoral or Sandimmune (CsA), and prednisone. Patients will be randomly allocated to 3 groups. Enrollment will occur 12-36 months after renal transplantation and follow-up will be for 2 years for evaluation of renal function and 5 years for those patients who agree to undergo allograft biopsies at baseline and 5 years after withdrawal. A sample size of 258 enrolled at four centers over 3 years will allow the detection of a difference of 2 ml/min/yr between the three groups. Patients allocated to group I will undergo withdrawal of CsA over 12 weeks, with a transient increase in the prednisone dose at the time of CsA cessation. Patients allocated to group II will undergo prednisone withdrawal over 12 weeks, with CsA levels maintained in the high end of the usual target range for 3 months after withdrawal of prednisone. Patients allocated to group III will undergo MMF withdrawal over 12 weeks. At 12, 18, 24, 30 and 36 months after transplantation patients will have a physical exam, standard laboratory tests, and a GFR measurement using iohexol clearance. Prior to randomization, patients will also be asked to participate in the biopsy portion of the study. Patients who elect to participate in the biopsy study will undergo a protocol biopsy immediately after randomization and prior to immunosuppression withdrawal. Patients who have acute rejection on the biopsy will be dropped from the study before any reduction in immunosuppression, and will not be considered in the final analysis. If at any time it appears likely that a patient (who has not already had an adequate biopsy within the previous six months) may return to chronic, maintenance dialysis therapy, a second protocol biopsy will be obtained. Otherwise, 6 years after transplantation patients with functioning allografts will be asked to undergo a second protocol biopsy. All protocol biopsies will be scored blindly by a renal pathologist using the Banff criteria. In addition, a detailed morphometric analysis will be carried out on all biopsies. The primary endpoint is the rate of decline in GFR as measured by the slope of serial GFR determinations (minimum of 2) made between 18 and 36 months after transplantation. For patients who return to dialysis before the 18th month post-transplant, the slope will be based on the baseline and final GFR determinations. Results: To date 10 patients have been enrolled locally and approximately 50 total by all centers. An interim analysis has not yet been completed. Significance: When the entire study is completed, we will be able to better guide immunosuppressive therapy in renal transplant recipients and hopefully be better able to limit the amount of expensive and potentially toxic medication given to these patients.