Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy

这是一项2期临床试验，旨在评估一种新的免疫抑制药物西罗莫司在特发性和狼疮膜性肾病患者中的安全性和有效性。 如果患者（13岁以上）接受血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂标准治疗后仍有持续性肾病范围蛋白尿，则邀请其参加研究。 持续性肾病范围蛋白尿患者发生肾功能恶化以及心血管和血栓栓塞并发症的风险增加。 目标血压低于125/75，如国家高血压预防、检测、评估和治疗联合委员会（NHLBI，NIH）第六次报告所建议的。 13岁以下的儿童被排除在外，因为在本研究开始时，西罗莫司尚未获得FDA批准用于该年龄组，并且因为该年龄组的完整药代动力学特征不可用。 此外，排除了晚期肾功能不全患者（估计肾小球滤过率低于30 mL/min/1.73 m2），因为我们预计西罗莫司最有可能在进行性肾小球硬化和间质纤维化成为主要（可能不可逆）异常之前获益。 排除了活动性感染、未控制的高血压、慢性肝病、血细胞减少和癌症诊断或前5年内复发（不包括皮肤基底细胞癌）的患者。 由于尚未确定西罗莫司在妊娠期和婴儿期的安全性，因此排除了孕妇、哺乳期母亲和未采取避孕措施的个体（男性和女性）。 在开始西罗莫司治疗前的两个月内，患者不能服用任何类型的免疫抑制剂或实验性药物，但有两个例外。 首先，允许狼疮膜性肾病患者在开始西罗莫司治疗前2个月内接受中等剂量的皮质类固醇（不超过泼尼松10 mg/天的当量），以控制SLE的肾外表现。第二，肾病综合征恶化的患者允许在较短的停用其他免疫抑制剂的时间间隔后开始西罗莫司治疗。 对于成人和体重≥ 40 kg的儿童，西罗莫司的负荷剂量为2 mg，每4小时一次，共3次（总剂量为6 mg），第一天给药。 这些个体的西罗莫司初始维持剂量为2 mg每日一次。 针对较小的个体修改了初始剂量和维持剂量。 在治疗期的前6个月内，调整西罗莫司的剂量以达到5 - 15 ng/mL的目标水平。 如果在前6个月结束时未达到完全缓解，则在第二个6个月期间将目标水平增加至10 - 20 ng/mL。 如果观察到某些毒副作用，则暂停和/或降低西罗莫司剂量。 在整个研究过程中密切监测肾功能、蛋白尿程度和副作用。 12例患者进入本研究，所有患者均已完成治疗或因副作用和缺乏疗效而退出西罗莫司治疗。 只有两名患者获得了部分缓解。 因此，我们不再招募或入组受试者进入本研究。 研究和数据分析正在进行中。

This is a phase 2 trial to evaluate the safety and effectiveness of a new immunosuppressive drug, sirolimus, in patients with idiopathic and lupus membranous nephropathy. Patients (older than 13 years) were invited to participate if they had persistent nephrotic range proteinuria despite standard treatment with an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker. Patients with persistent nephrotic range proteinuria are at increased risk for renal function deterioration as well as cardiovascular and thromboembolic complications. The target blood pressure was less than 125/75, as recommended by the Sixth Report Joint National Commission on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (NHLBI, NIH). Children less than 13 years were excluded because at the time this study was initiated, sirolimus had not been approved by the FDA in this age group and because a complete pharmacokinetics profile was not available in this age group. Furthermore, patients with advanced renal insufficiency (estimated glomerular filtration rate less than 30 mL/min/1.73 m2) were excluded because we anticipated that sirolimus would most likely be beneficial before progressive glomerular sclerosis and interstitial fibrosis had become the dominant (and probably irreversible) abnormalities. Patients with active infections, uncontrolled hypertension, chronic liver disease, cytopenias and a cancer diagnosis or recurrence within the preceding 5 years (excluding basal cell carcinoma of the skin) were excluded. Pregnant women, nursing mothers and individuals (men and women) not practicing birth control were excluded because the safety of sirolimus during pregnancy and infancy had not been determined. Patients could not take immunosuppressive agents or experimental medications of any type during the two-month period prior to initiating sirolimus, with two exceptions. First, patients with lupus membranous nephropathy were permitted to have received modest doses of corticosteroids (no more than the equivalent of prednisone 10 mg/day) for control of extra-renal manifestations of SLE during the two-month period prior to starting sirolimus. Second, patients with worsening nephrotic syndrome were allowed to start sirolimus after a shorter interval off other immunosuppressive agents. The loading dose of sirolimus was 2 mg every 4 hours for 3 doses (total dose of 6 mg) on the first day for adults and children greater than or equal to 40 kg. The initial maintenance dose of sirolimus for these individuals was 2 mg once daily. The initial and maintenance doses were modified for smaller individuals. The dose of sirolimus was adjusted to achieve a target level of 5 - 15 ng/mL during the first 6 months of the treatment period. The target level was increased to 10 - 20 ng/mL during the second 6 months if a complete remission had not been achieved by the end of the first 6 months. The sirolimus dose was held and/or reduced if certain toxic side effects were observed. Renal function, the degree of proteinuria and side effects were monitored closely throughout the study. Twelve patients have entered this study, and all patients have completed treatment or were withdrawn from sirolimus treatment because of side-effects and lack of efficacy. Only two patients have achieved a partial remission. Consequently, we are no longer recruiting or enrolling subjects into this study. Study and data analyses are ongoing.