Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy

这是一项 2 期试验，旨在评估新型免疫抑制药物西罗莫司对特发性狼疮膜性肾病患者的安全性和有效性。 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出现持续性肾病范围蛋白尿，则被邀请参加。 持续性肾病范围蛋白尿患者肾功能恶化以及心血管和血栓栓塞并发症的风险增加。 根据国家高血压预防、检测、评估和治疗联合委员会（NHLBI、NIH）第六次报告的建议，目标血压低于 125/75。 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，而且还没有该年龄组的完整药代动力学特征。 此外，晚期肾功能不全（估计肾小球滤过率低于 30 mL/min/1.73 m2）的患者被排除在外，因为我们预计西罗莫司在进行性肾小球硬化和间质纤维化成为主要（且可能不可逆转）异常之前最有可能有益。 患有活动性感染、未控制的高血压、慢性肝病、血细胞减少症以及过去 5 年内诊断出癌症或复发的患者（不包括皮肤基底细胞癌）被排除在外。 孕妇、哺乳期母亲和未实行节育的个人（男性和女性）被排除在外，因为西罗莫司在怀孕和婴儿期的安全性尚未确定。 患者在开始西罗莫司治疗前的两个月内不能服用免疫抑制剂或任何类型的实验药物，但有两种例外。 首先，狼疮膜性肾病患者在开始使用西罗莫司之前的两个月内被允许接受适度剂量的皮质类固醇（不超过相当于泼尼松 10 mg/天）以控制 SLE 的肾外表现。其次，肾病综合征恶化的患者在停用其他免疫抑制剂的较短时间间隔后被允许开始使用西罗莫司。 成人和体重大于或等于40 kg的儿童西罗莫司的负荷剂量为每4小时2 mg，第一天共3剂（总剂量6 mg）。 这些人的西罗莫司初始维持剂量为每日 2 毫克。 针对体型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 个月结束时尚未实现完全缓解，则在后 6 个月内将目标水平提高至 10 - 20 ng/mL。 如果观察到某些毒副作用，则维持和/或减少西罗莫司剂量。 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名患者进入了这项研究，所有患者均已完成治疗或因西罗莫司治疗的副作用和缺乏疗效而退出治疗。 只有两名患者获得部分缓解。 因此，我们不再招募或招募受试者参加这项研究。 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.