OPTIMAL IMMUNOSUPPRESSION IN RENAL TRANSPLANTATION

肾移植中的最佳免疫抑制

• 批准号: 6415300
• 负责人: STEPHEN R SMITH
• 金额: $ 29.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6415300
• 关键词: azathioprine; biopsy; clinical research; clinical trials; combination chemotherapy; cyclosporines; human subject; human therapy evaluation; immunosuppression; immunosuppressive; kidney transplantation; prednisone

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.

目的：在美国，环孢素（CsA）、泼尼松和硫唑嘌呤三联免疫抑制剂治疗一直是肾移植初始维持免疫抑制的主要药物。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晚期仅使用两种免疫抑制剂效果良好，然而，没有关于停用免疫抑制剂的对照比较试验。主要假设是，在移植后12个月或更长时间内，稳定的肾移植受者停用环孢素导致肾功能下降较慢，间质纤维化程度低于停用麦考酚酯或泼尼松。研究方法：这是一项开放标签、随机、对照、治疗比较试验，仅限于免疫抑制剂减少后急性排斥反应风险较低的患者。尸体和活体肾移植受者> 18岁，在移植后前三个月内最多发生一次急性排斥反应，并且没有后续事件，并且在入组前9个月肾功能稳定，将符合条件。将排除蛋白排泄量超过500 mg/24小时的患者，以及无法继续使用三种药物之一的患者。所有患者在移植后第一年内均接受标准维持免疫抑制治疗。12个月时，患者将接受MMF（1 g bid）、Neoral或Sandimmune（CsA）和泼尼松。患者将被随机分配至3组。入组将在肾移植后12-36个月进行，随访2年以评价肾功能，对于同意在基线和退出后5年接受同种异体移植物活检的患者，随访5年。3年内在4个中心入组的258例样本量将允许检测3组之间的差异2 ml/min/yr。分配至组I的患者将在12周内停用CsA，在停用CsA时短暂增加泼尼松剂量。分配至第II组的患者将在12周内接受泼尼松停药，在泼尼松停药后3个月内，CsA水平维持在通常目标范围的高端。分配至第III组的患者将在12周内停用MMF。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海醇清除率的GFR测量。在随机化之前，还将要求患者参加研究的活检部分。选择参加活检研究的患者将在随机化后和免疫抑制剂停药前立即接受方案活检。在免疫抑制剂减少之前，活检时发生急性排斥反应的患者将从研究中剔除，并且不会在最终分析中考虑。如果在任何时候，患者（在过去6个月内尚未进行充分活检）可能会恢复长期维持透析治疗，则将进行第二次方案活检。否则，移植后6年，功能正常的同种异体移植物患者将被要求接受第二方案活检。所有方案活检将由肾脏病理学家使用Banff标准进行盲态评分。此外，将对所有活检进行详细的形态测定分析。主要终点是通过移植后18至36个月之间进行的连续GFR测定（最小值为2）的斜率测量的GFR下降率。对于在移植后第18个月之前恢复透析的患者，斜率将基于基线和最终GFR测定。结果：迄今为止，10例患者已在当地入组，所有中心共入组约50例患者。中期分析尚未完成。重要性：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。