OPTIMAL IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION

目的：环孢素（CsA）、强的松和硫唑嘌呤的三联免疫抑制剂治疗一直是美国肾移植初始维持免疫抑制的主要方法。这些药物具有不同的作用机制和不同的毒性。许多患者在肾移植后仅使用两种免疫抑制剂治疗效果良好，然而，目前尚无免疫抑制剂停用的对照比较试验。主要假设是，在移植后12个月或更长时间，稳定的同种异体肾移植受者停用环孢素比停用麦考酚酸或泼尼松导致肾功能下降更慢，间质纤维化更少。方法：这是一项开放标签，随机，对照，治疗性比较试验，仅限于免疫抑制降低后急性排斥反应低风险的患者。18岁的尸体和活体肾移植受者，在移植后的前三个月内最多有一次急性排斥反应，并且在入组前9个月肾功能稳定，将符合条件。蛋白质排泄量超过500mg /24小时的患者将被排除在外，无法继续使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的第一年接受标准维持性免疫抑制治疗。在12个月时，患者将接受MMF （1g bid）、Neoral或Sandimmune （CsA）和强的松。患者将被随机分为3组。入组将在肾移植后12-36个月进行，随访2年用于肾功能评估，5年用于同意在基线和停药后5年接受同种异体移植活检的患者。在4个研究中心进行为期3年的258个样本量研究，可以发现三组之间的差异为2ml /min/yr。被分配到I组的患者将在12周内停用CsA，在停用CsA时，强的松剂量会短暂增加。被分配到II组的患者将在12周内进行泼尼松停药，在泼尼松停药后3个月，CsA水平维持在通常目标范围的高端。分配到第三组的患者将在12周内进行MMF停药。在移植后12、18、24、30和36个月，患者将进行体格检查、标准实验室检查和使用碘己醇清除率测量GFR。在随机化之前，患者还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立即进行方案活检，并在停止免疫抑制之前进行。在免疫抑制减少之前，活检出现急性排斥反应的患者将被从研究中剔除，并且在最终分析中不被考虑。如果在任何时候，患者（在过去6个月内没有进行足够的活检）可能会回到慢性维持性透析治疗，则需要进行第二次方案活检。否则，移植后6年具有功能的同种异体移植物患者将被要求进行第二次方案活检。所有方案活检将由肾脏病理学家使用班夫标准进行盲目评分。此外，将对所有活检进行详细的形态计量学分析。主要终点是移植后18至36个月间通过连续GFR测定（最小2）的斜率测量的GFR下降率。对于移植后18个月前再次透析的患者，斜率将基于基线和最终GFR测定。结果：到目前为止，已有10名患者在当地入组，所有中心共入组约50名患者。一项临时分析尚未完成。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，并希望能够更好地限制给予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.