A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology

Introduction
The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand.
Aim
To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology–surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology.
Methods
Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months
Results
CNI withdrawal (on-treatment analysis) associated with better graft function (p <0.001) and lower chronic histopathology composite scores in protocol biopsies at 12 (p = 0.003) and 24 (p = 0.013) months, without affecting patient (p = 0.81) or graft (p = 0.93) survival, or rejection rate (p = 0.17).
Conclusion
CNI (tacrolimus) withdrawal at six months may provide a strategy for decreased nephrotoxicity and improved long-term function in steroid-free low immunological risk renal transplant patients.
Trial Registration
ClinicalTrials.gov NCT00556933

引言
影响肾同种异体移植（renal allograft）存活的两大最主要阻碍因素为排斥反应，以及用于预防排斥反应的免疫抑制剂所直接引发的肾毒性。钙调磷酸酶抑制剂（Calcineurin Inhibitors, CNI）是多数免疫抑制治疗方案的支柱药物，其肾毒性尤为显著。在低毒性抗排斥药物获批上市前，优化现有免疫抑制剂的临床应用方案是当前唯一可行的应对策略。

研究目的
旨在明确强化兔抗胸腺细胞球蛋白（rabbit anti-thymocyte globulin, rATG）诱导治疗联合钙调磷酸酶抑制剂（CNI）撤药，单独或联合应用是否可改善移植物功能，并降低移植物慢性组织病理学改变——该改变可作为移植物乃至患者生存预后的替代评估指标。如既往研究报道所示，单次大剂量rATG（24小时内给药）具有良好的耐受性，且与更佳的肾功能、更少的感染事件以及更长的患者生存期相关。本研究旨在进一步验证完全停用CNI是否可改善肾功能并减轻移植物病理损伤。

研究方法
2004年4月20日至2009年4月14日，我们开展了一项前瞻性、随机、非盲肾移植临床试验，对比两种rATG给药方案：单次剂量组（6mg/kg）与分次剂量组（隔日1.5mg/kg，共给药4次），计划入组180例患者。后续维持免疫抑制治疗采用他克莫司（tacrolimus，一种CNI类药物）联合西罗莫司（sirolimus，一种哺乳动物雷帕霉素靶蛋白抑制剂（mammalian target of rapamycin inhibitor））。本文报告了入组满6个月后，将患者的维持方案转换为最小剂量他克莫司/西罗莫司，或吗替麦考酚酯（mycophenolate mofetil）/西罗莫司后的结局。主要研究终点为12个月与24个月时方案规定的肾活检所评估的移植物功能与慢性组织病理学改变。

研究结果
治疗依从性分析显示，停用CNI可改善移植物功能（p<0.001），并在12个月（p=0.003）与24个月（p=0.013）时降低方案活检中的慢性组织病理学综合评分，且未对患者生存率（p=0.81）、移植物存活率（p=0.93）或排斥反应发生率（p=0.17）产生显著影响。

研究结论
对于无激素、低免疫风险的肾移植患者，于术后6个月停用钙调磷酸酶抑制剂（他克莫司）或可作为一种减轻肾毒性、改善长期移植物功能的治疗策略。

临床试验注册
ClinicalTrials.gov NCT00556933