Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.
Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy.
PLoS Med. 2021 Jun 24;18(6):e1003668. doi: 10.1371/journal.pmed.1003668. eCollection 2021 Jun.
We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.
ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.
In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.
ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
我们比较了霉酚酸酯（MMF）和硫唑嘌呤（AZA）在接受无激素、低剂量环孢素（CsA）微乳剂维持免疫抑制的肾移植受者中对急性细胞排斥（ACR）和慢性移植肾肾病（CAN）的保护作用。
ATHENA 是一项由 6 家意大利移植中心进行的实用、前瞻性、多中心试验，比较了 233 名接受低剂量胸腺球蛋白和巴利昔单抗诱导的首次死亡供体肾移植的同意者的结局，并随机分为 MMF（750mg 每日 2 次，n=119）或 AZA（75-125mg/天，n=114）加用低剂量 CsA 微乳剂和 1 周激素维持治疗。在没有急性临床或亚临床排斥的患者中，逐渐减半 CsA 剂量。主要终点是活检证实的 CAN。分析是意向治疗。参与者于 2007 年 6 月至 2012 年 7 月入选，并随访至 2016 年 8 月。两组间供体和受者特征、供体/受者错配以及随访时 CsA 血药浓度相似。在中位（四分位间距（IQR））随访 47.7（44.2 至 48.9）个月期间，MMF 组 87 例活检患者中有 29 例（33.3%）和 AZA 组 88 例中有 31 例（35.2%）发生了 CAN（风险比（HR）[95%置信区间（CI）]：1.147（0.691 至 1.904，p=0.595）。MMF 组和 AZA 组分别有 20 例和 21 例患者出现临床[HR（95%CI）：0.58（0.34 至 1.02）；p=0.057）或活检证实的亚临床[HR（95%CI）：1.49（0.76 至 2.92）；p=0.249]ACR。联合事件[HR（95%CI）：0.85（0.56 至 1.29）；p=0.438）、患者和移植物存活率、延迟移植物功能（DGF）、3 年肾小球滤过率（GFR）[53.8（40.6 至 65.7）与 49.8（36.8 至 62.5）mL/min/1.73m2，p=0.50]和不良事件（AE）在两组间无显著差异。除 CAN 以外的慢性评分可预测长期移植物结局。研究的局限性包括样本量小和设计未设盲。
在接受低剂量 CsA 和无激素治疗的肾移植受者中，MMF 与 AZA 相比没有显著优势。这一发现表明，由于 AZA 成本较低，在联合使用最小化免疫抑制的情况下，AZA 可以安全替代 MMF。
ClinicalTrials.gov NCT00494741；EUDRACT 2006-005604-14。
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