Sirolimus Therapy in Idiopathic and Lupus Membranous Nephropathy

这是一项2期试验，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。年龄大于13岁的患者被邀请参加，如果他们有持续性肾病范围蛋白尿，尽管使用了血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂的标准治疗。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症并发症的风险增加。目标血压低于国家高血压预防、检测、评估和治疗联合委员会(NHLBI，NIH)第六次报告建议的125/75。13岁以下的儿童被排除在外，因为在这项研究开始时，西罗莫司还没有在这个年龄段获得FDA的批准，并且因为在这个年龄段没有完整的药代动力学资料。此外，晚期肾功能不全患者(估计肾小球滤过率低于30毫升/分钟/1.73平方米)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(可能是不可逆转的)异常之前最有可能受益。排除活动性感染、高血压失控、慢性肝病、细胞减少症和在过去5年内被诊断为癌症或复发(不包括皮肤基底细胞癌)的患者。孕妇、哺乳母亲和没有实行节育措施的个人(男性和女性)被排除在外，因为西罗莫司在怀孕和婴儿期间的安全性尚未确定。患者在开始服用西罗莫司之前的两个月内不能服用免疫抑制剂或任何类型的实验性药物，但有两个例外。首先，在服用西罗莫司前的两个月内，狼疮膜性肾病患者被允许接受中等剂量的皮质类固醇治疗(不超过相当于泼尼松10毫克/天)，以控制系统性红斑狼疮的肾外表现。其次，肾病综合征恶化的患者被允许在较短的时间内停用其他免疫抑制剂后开始使用西罗莫司。西罗莫司负荷量为2 mg，每4h 1次，共3次，总剂量为6 mg，首日剂量大于或等于40 kg。西罗莫司的初始维持量为每天一次，每次2毫克。初始剂量和维持剂量针对较小的个体进行了修改。在治疗的前6个月，西罗莫司的剂量被调整到5-15 ng/ml的目标水平。如果在前6个月末仍未达到完全缓解，则在后6个月期间将目标水平提高到10-20 ng/ml。如果观察到某些毒副作用，则保留和/或减少西罗莫司的剂量。在整个研究过程中，密切监测肾功能、蛋白尿程度和副作用。有12名患者进入了这项研究，所有患者都已完成治疗或因副作用和疗效不足而退出西罗莫司治疗。只有两名患者获得了部分缓解。因此，我们不再招募或登记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.