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对特发性和红斑狼疮膜性肾病患者的安全性和有效性。如果患者（年龄大于13岁）在接受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后仍患有持续性肾病性蛋白尿，则邀请他们参加研究。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，这是国家预防、检测、评估和治疗高血压联合委员会第六次报告（NHLBI， NIH）所建议的。13岁以下的儿童被排除在外，因为在这项研究开始时，西罗莫司尚未被FDA批准用于该年龄组，并且因为该年龄组没有完整的药代动力学资料。此外，晚期肾功能不全患者（估计肾小球滤过率小于30 mL/min/1.73 m2）被排除在外，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（可能不可逆的）异常之前是有益的。排除了活动性感染、未控制的高血压、慢性肝病、细胞减少症和过去5年内癌症诊断或复发的患者（不包括皮肤基底细胞癌）。孕妇、哺乳母亲和未实行节育的个人（男性和女性）被排除在外，因为孕期和婴儿期西罗莫司的安全性尚未确定。在开始使用西罗莫司之前的两个月内，患者不能服用免疫抑制剂或任何类型的实验性药物，只有两种情况例外。首先，允许狼疮膜性肾病患者在开始西罗莫司治疗前的两个月期间接受适度剂量的皮质类固醇（不超过相当于强的松10mg /天）来控制SLE的肾外表现。其次，肾病综合征恶化的患者在停止使用其他免疫抑制剂一段较短的间隔后允许开始使用西罗莫司。对于大于或等于40 kg的成人和儿童，西罗莫司第一天的负荷剂量为每4小时2 mg，共3次（总剂量为6 mg）。西罗莫司的初始维持剂量为2mg，每日一次。初始剂量和维持剂量对较小的个体进行了修改。在治疗期的前6个月，西罗莫司的剂量调整为达到5 - 15ng /mL的目标水平。如果在第一个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提高到10 - 20 ng/mL。如果观察到某些毒副作用，则保持和/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。12例患者进入本研究，所有患者均已完成西罗莫司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.