Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK.
Lancet. 2013 Mar 2;381(9868):744-51. doi: 10.1016/S0140-6736(12)61566-9. Epub 2013 Jan 9.
Membranous nephropathy leads to end-stage renal disease in more than 20% of patients. Although immunosuppressive therapy benefits some patients, trial evidence for the subset of patients with declining renal function is not available. We aimed to assess whether immunosuppression preserves renal function in patients with idiopathic membranous nephropathy with declining renal function.
This randomised controlled trial was undertaken in 37 renal units across the UK. We recruited patients (18-75 years) with biopsy-proven idiopathic membranous nephropathy, a plasma creatinine concentration of less than 300 μmol/L, and at least a 20% decline in excretory renal function measured in the 2 years before study entry, based on at least three measurements over a period of 3 months or longer. Patients were randomly assigned (1:1:1) by a random number table to receive supportive treatment only, supportive treatment plus 6 months of alternating cycles of prednisolone and chlorambucil, or supportive treatment plus 12 months of ciclosporin. The primary outcome was a further 20% decline in renal function from baseline, analysed by intention to treat. The trial is registered as an International Standard Randomised Controlled Trial, number 99959692.
We randomly assigned 108 patients, 33 of whom received prednisolone and chlorambucil, 37 ciclosporin, and 38 supportive therapy alone. Two patients (one who received ciclosporin and one who received supportive therapy) were ineligible, so were not included in the intention-to-treat analysis, and 45 patients deviated from protocol before study end, mostly as a result of minor dose adjustments. Follow up was until primary endpoint or for minimum of 3 years if primary endpoint was not reached. Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0·44 [95% CI 0·24-0·78]; p=0·0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1·17 [0·70-1·95]; p=0·54), but did differ significantly across all three groups (p=0·003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p=0·048).
For the subset of patients with idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months' therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence. Ciclosporin should be avoided in this subset.
Medical Research Council, Novartis, Renal Association, Kidney Research UK.
膜性肾病导致 20%以上的患者发展为终末期肾病。虽然免疫抑制疗法对一些患者有益，但对于肾功能下降的患者亚组，试验证据尚不可用。我们旨在评估免疫抑制是否能维持肾功能下降的特发性膜性肾病患者的肾功能。
这项随机对照试验在英国的 37 个肾脏单位进行。我们招募了活检证实的特发性膜性肾病患者（18-75 岁），血浆肌酐浓度低于 300μmol/L，并且在研究入组前的 2 年内，基于至少三次在 3 个月或更长时间内的测量，排泄性肾功能至少下降了 20%。患者通过随机数字表以 1:1:1 的比例随机分配接受仅支持治疗、支持治疗加 6 个月的泼尼松和苯丁酸氮芥交替周期治疗，或支持治疗加 12 个月的环孢素治疗。主要终点是根据意向治疗分析从基线进一步下降 20%的肾功能。该试验在国际标准随机对照试验注册处注册，编号为 99959692。
我们随机分配了 108 名患者，其中 33 名接受泼尼松和苯丁酸氮芥治疗，37 名接受环孢素治疗，38 名接受单纯支持治疗。有 2 名患者（1 名接受环孢素治疗，1 名接受支持治疗）不符合条件，因此未纳入意向治疗分析，45 名患者在研究结束前偏离了方案，主要是由于剂量的轻微调整。随访时间直到主要终点或如果未达到主要终点，则至少随访 3 年。泼尼松和苯丁酸氮芥组肾功能进一步下降 20%的风险明显低于支持治疗组（33 名患者中有 19 名[58%]达到终点，37 名患者中有 31 名[84%]，风险比[HR]0.44[95%CI0.24-0.78]；p=0.0042）；环孢素组（36 名中有 29 名[81%]）和单纯支持治疗组之间风险没有差异（HR1.17[0.70-1.95]；p=0.54），但在所有三组之间差异显著（p=0.003）。所有三组的严重不良事件都很常见，但泼尼松和苯丁酸氮芥组高于单纯支持治疗组（56 例 vs 24 例；p=0.048）。
对于特发性膜性肾病和排泄性肾功能恶化的患者亚组，泼尼松和苯丁酸氮芥 6 个月的治疗是我们的证据最支持的治疗方法。环孢素应避免在该亚组中使用。
医学研究委员会、诺华、肾脏协会、英国肾脏研究基金会。
