【作者】 李秋红；

【导师】 唐琳；

【作者基本信息】 郑州大学 ， 内科学（肾脏病学）（专业学位）， 2017， 硕士

【摘要】 背景与目的特发性膜性肾病(idiopathic membranous nephropathy,IMN)在成人肾病综合征中是最常见的病理类型之一,大约占成人原发性肾病综合征的20%-40%。典型的病理表现为肾小球基底膜上皮细胞下免疫复合物沉积,基底膜弥漫增厚伴钉突形成。其发病机制尚未完全阐明,目前多数学者认为与免疫系统的异常激活有关,但也有研究者认为足细胞在IMN的蛋白尿和肾功能丧失进程中起重要作用。IMN患者临床自然病程差异悬殊,约1/3患者可以自发缓解,1/3患者可表现为持续性蛋白尿,而另外约1/3患者可能发展为终末期肾脏病(end-stage renal disease,ESRD)。因IMN预后差异大、对药物治疗敏感性不一、停药后复发率高,其治疗一直存在很大争议,至今无公认的最佳治疗。Reich H et.al认为蛋白尿>3.5g/d伴肾功能损伤或蛋白尿>8g/d属于高危组患者,该组患者应该接受免疫抑制治疗。糖皮质激素联合环磷酰胺(cyclophosphamide,CTX)方案是目前获得随机对照试验证据最多的IMN治疗方案,也是改善全球肾脏病预后组织(Kidney Disease Improving Global Outcomes,KDIGO)推荐的首选疗法,但由于环磷酰胺严重的副作用如性腺抑制、淋巴瘤和膀胱癌及经12个月的治疗后高复发率限制了其应用。因此选择疗效好、毒性低的免疫抑制剂一直是临床亟待解决的问题,KDIGO指南推荐神经钙调蛋白抑制剂(CNIs,环孢素A或他克莫司)作为IMN初始治疗的替换方案。目前国内的研究主要集中于比较不同种类免疫抑制剂治疗IMN的疗效与安全性。而缺乏同属神经钙调蛋白抑制剂的他克莫司(tacrolimus,TAC)与环孢素A(cyclosporine Cs A)治疗成人IMN的疗效和安全性比较的随机对照研究。因此,本研究纳入了31例IMN患者进行TAC与Cs A联合糖皮质激素治疗IMN的疗效与安全性的随机对照比较。方法选择2015年9月-2016年3月在郑州大学第一附属医院临床表现为肾病综合征和肾脏病理确诊为IMN患者31例,按免疫抑制剂方案随机分为TAC组(n=16)与Cs A组(n=15)。TAC组给予他克莫司胶囊的起始剂量为0.05-0.1mg/kg/d,Cs A组给予环孢素的起始剂量为3-5mg/kg/d,两组均每日量分2次口服,每12小时服药1次。1周后进行首次血液药物浓度检查,TAC的血液药物浓度控制在5-10ng/ml,Cs A的血液药物浓度控制在100-200ng/ml。若患者能够缓解,低水平的血液药物浓度也可以接受。两组患者起始均给予泼尼松0.5mg/kg/d(最大剂量60mg/d),并逐渐减量。观察两组患者血常规、肝肾功能、24小时尿蛋白定量、血浆白蛋白、总胆固醇、甘油三酯、血糖、他克莫司的血液药物浓度、环孢素的血液药物浓度,同时观察记录患者随访期间的不良反应。两组患者均随访6个月。结果经过6个月的随访,TAC组与Cs A组缓解率分别为87.5%、73.3%(P=0.318),完全缓解率分别为43.8%、33.3%(P=0.552),TAC组与Cs A组的平均缓解时间分别为2.4±1.3月、3.5±1.6月(P=0.045)。TAC组高尿酸血症、新发高血糖、四肢震颤的发生率高于Cs A组,多毛症、牙龈增生的发生率低于Cs A组,停药或给药后这些不良反应均可控制。结论TAC联合糖皮质激素与Cs A联合糖皮质激素治疗IMN的缓解率相近,且TAC和Cs A的不良反应各有侧重,临床上可依据患者的具体情况个体化给药。更多还原

【Abstract】 Background and aim Idiopathic membranous nephropathy(IMN)is one of the most common pathological types of nephrotic syndrome in adults accounting for 20% to 40% of primary nephrotic syndrome in adult patients.The fundamental pathological mechanism of IMN is that immune complex deposits under glomerular basement membrane(GBM)and the GBM diffusely thicken with spikes.Its pathogenesis is still unclear,most scholars think that abnormal activation of the immune system is essential for the occurrence and development of IMN at present,but IMN is also regarded as a podocytopathy and podocytes play an important role in the process of proteinuria and renal function loss.The clinical natural course of IMN is variable and not easy to predict.Generally,about one third of patients achieve spontaneous remission,in another third,proteinuria persists for years,while the final third of patients are likely to develop end-stage renal disease(ESRD).Due to the large difference of prognosis,different susceptibility to therapy and great relapse rate after drug withdrawal,the treatment has been controversial.Reich H et.al recommended that immunosuppressive therapy should be given to the patients whose urinary protein excretion exceeds 3.5 g/d with renal function injury or proteinuria exceeds 8 g/d.The best proven therapy for patients with IMN is the combined of cyclophosphamide(CYC)and corticosteroids,which is also the preferred therapeutic regimen recommended by Kidney Disease Improving Global Outcomes(KDIGO).However,the potential side effects(such as gonadal dysfunction,lymphoma and bladder cancer)associated with the use of CYC and high recurrence rate after 12 months of treatment have left many physicians reluctant to use this regimen.So choosing an effective and low toxic immumosuppressant has always been a clinical problem to be solved.KDIGO guidelines recommend calcineurin inhibitors(CNIs,Cs A and TAC)as the replacement strategies of initial treatment for IMN patients.In precious studies,investigators performed trials to compare the effectiveness between different kinds of immunosuppresants in the treatment of IMN.However,there is a lack of randomized controlled study comparing the efficacy and safety between different kinds of CINs(TAC,Cs A)in treating adult patients with IMN.Therefore,we admitted 31 patients with IMN to compare the efficacy and safety between TAC and Cs A combined with corticosteroids in this randomized research.Methods 31 patients who were clinically diagnosed nephrotic syndrome and confirmed as IMN by renal biopsy in the first affiliated hospital of Zhengzhou university from Sep 2015 to Mar 2016 were recruited to our study.They were randomly administered TAC(n=16)or Cs A(n=15)combined with corticosteroids.Patients randomized to the TAC group were administered at 0.05-0.1 mg/kg/d and was divided into 2 equal doses at 12-hour intervals.The drug concentration was first checked after 1 week.We adjusted the dosage according to the whole blood concentration,with a target of 5-10 ng/m L.For the Cs A group,patients received Cs A at 3-5 mg/kg/d divided into two doses at intervals of 12 hours initially.The dose was adjusted to achieve a blood trough concentration of 100-200 ng/m L.Lower blood trough concentration levels of TAC or Cs A were accepted if patients were in remission.Both groups received oral prednisone at a dose of 0.5 mg/kg/d.Then we further tapered the dosage slowly down to a dosage of 10 mg/d and maintained that dosage throughout the remainder of the 6-month therapy period.Laboratory evaluation including serum levels of creatinine,alanine aminotransferase,24-hour urinary protein,albumin,total cholesterol,triglycerides,glucose,as well as complete blood counts was measured at baseline and at monthly intervals for 6 months.Physical examination and screening for side effects were also performed at each visit.The patients were followed for 6 months.Results After 6 months of therapy,the percentages of remission(either CR or PR)in the TAC group vs.Cs A group were 87.5% vs.73.3%(P =0.318),respectively.While,the percentages of complete remission(CR)in the TAC group vs.Cs A group were43.8% vs.33.3%(P =0.552).In addition,mean time to PR was 2.4±1.3months in the TAC group vs.3.5±1.6 months in the Cs A group(P=0.045).Hyperuricemia,hyperglycemia and hand tremor tended to be more common in the TAC group than in the Cs A group.However,common adverse effects in the Cs A group included hypertrichosis and gingival hyperplasia.All of those side effects were under control after drug withdrawal.Conclusion TAC or Cs A combined with corticosteroids was both useful for adults with IMN.But TAC was not inferior than Cs A in efficacy.Otherwise,TAC and Cs A had different side effects,so CNIs should be used individualizedly in patients with IMN.更多还原