Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, Soulillou J P
Institut de Transplantation et de Recherche en Transplantation and Institut National de la Santé et de la Recherche Médicale U437, CHU Hotel Dieu, Nantes, France.
Lancet. 1998 Feb 28;351(9103):623-8. doi: 10.1016/S0140-6736(97)08496-1.
Long-term administration of cyclosporin carries a risk of renal toxicity, and immunosuppressants are associated with an increased rate of malignant disorders. We undertook an open randomised study of the risks and benefits of two long-term maintenance regimens of cyclosporin in kidney-allograft recipients. The primary endpoint was graft function; secondary endpoints were survival and occurrence of cancer and rejection.
231 recipients of a first allograft with at most one previous rejection episode were randomised 1 year after transplantation. Most were receiving cyclosporin and azathioprine. One group received cyclosporin doses adjusted to yield trough blood concentrations of 75-125 ng/mL (low-dose group); the second received doses that yielded trough concentrations of 150-250 ng/mL (normal-dose group). Analysis was by intention to treat.
At 66 months' follow-up, the low-dose and normal-dose groups were similar in mean serum creatinine (182 [SD 160] vs 184 [157] micromol/L; p=0.9) and mean creatinine clearance (47.5 [25.1] vs 45.3 (22.5] mL/min; p=0.6). Nine of 116 patients in the low-dose group and one of 115 in the normal-dose group had symptoms of rejection (p<0.02). There was no difference between the low-dose and normal-dose groups in survival (95 vs 92%; p=0.7) or graft survival (89 vs 82%; p=0.17) at 6 years. 60 patients developed cancers, 37 in the normal-dose group and 23 in the low-dose group (p<0.034); 66% were skin cancers (26 vs 17; p<0.05).
We found no evidence that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival. The low-dose regimen was associated with fewer malignant disorders but more frequent rejection. The design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.
长期使用环孢素存在肾毒性风险，免疫抑制剂与恶性疾病发生率增加有关。我们对肾移植受者中环孢素两种长期维持方案的风险和益处进行了一项开放性随机研究。主要终点是移植肾功能；次要终点是生存率、癌症发生率和排斥反应。
231例首次接受移植且既往最多有一次排斥反应的受者在移植1年后进行随机分组。大多数患者正在接受环孢素和硫唑嘌呤治疗。一组接受调整剂量的环孢素，以使谷血浓度达到75 - 125 ng/mL（低剂量组）；另一组接受使谷浓度达到150 - 250 ng/mL的剂量（正常剂量组）。分析采用意向性治疗。
在66个月的随访中，低剂量组和正常剂量组的平均血清肌酐水平相似（分别为182[标准差160]和184[157]μmol/L；p = 0.9），平均肌酐清除率也相似（分别为47.5[25.1]和45.3[22.5]mL/分钟；p = 0.6）。低剂量组116例患者中有9例出现排斥反应症状，正常剂量组115例中有1例出现排斥反应症状（p<0.02）。6年时，低剂量组和正常剂量组的生存率（分别为95%和92%；p = 0.7）或移植肾生存率（分别为89%和82%；p = 0.17）无差异。60例患者发生癌症，正常剂量组37例，低剂量组23例（p<0.034）；66%为皮肤癌（分别为26例和17例；p<0.05）。
我们没有发现证据表明将环孢素谷血浓度减半会显著改变移植肾功能或移植肾生存率。低剂量方案与较少的恶性疾病相关，但排斥反应更频繁。基于强效免疫抑制剂组合的移植受者长期维持方案的设计应考虑到这些潜在风险。
