Mycophenolate mofetil and cyclosporine in the treatment of steroid-dependent nephrotic syndrome with frequent relapses

We describe the case of an 8-year-old patient, with steroid-dependent minimal lesion nephrotic syndrome, with frequent relapses despite treatment with cyclosporine. After the switch to mycophenolate mofetil the patient had new relapses, and there was difficulty in controlling the disease. The reintroduction of cyclosporine combined with mycophenolate mofetil obtained an optimal response, with a longer relapse-free time. Due to their kinetic variability, the blood levels of both drugs were closely monitored during follow-up.     

频复发/激素依赖肾病综合征儿童利妥昔单抗治疗1年以上随访情况的系统评价/Meta分析

背景：权威指南和共识均推荐将利妥昔单抗（RTX）应用于儿童激素敏感型肾病综合征（SSNS）中频复发/激素依赖肾病综合征（FRNS/SDNS）的治疗,但仍存在临床适应证不统一、治疗和随访方案多样等问题。目的：了解RTX首疗程治疗缓解期FRNS/SDNS随访1年以上复发和激素使用情况结局。设计：系统评价/Meta分析。方法：检索PubMed、Embase、Cochrane、Scopus和中国生物医学文献服务系统数据库,从建库至2022年6月26日,以SSNS、FRNS、SDNS和 RTX构建中英文数据库检索式。同一篇文献初筛、全文筛选和证据提取均由2人完成,有争议和不确定的文献由第3人复核审查。纳入至少1组干预措施使用RTX治疗1~22岁SSNS患儿的研究。主要结局指标:RTX干预后随访≥1年的复发率、首次复发时间,激素累积剂量和停用比例。结果:符合本文临床结局的文献26篇（RCT 8篇、非随机对照试验 1篇、队列研究8篇、病例系列报告9篇）,中文文献1篇,英文文献25篇。基于FRNS/SDNS病例的随访≥1年复发率的9项研究的Meta分析显示,RTX较对照组复发率下降了78%(OR=0.22,95%CI:0.09~0.53),在FRNS/SDNS+（RTX干预前已使用其他免疫抑制剂）亚组病例中,RTX较对照组复发率下降了67%(OR=0.33,95%CI:0.12~0.94),在FRNS/SDNS-（RTX干预前未使用其他免疫抑制剂）亚组病例中,RTX-（不联用其他并免疫抑制剂）较对照组复发率下降了85%(OR=0.15,95%CI:0.03~0.68)。基于20项研究的Meta分析显示,RTX复发率42% (95%CI:32%~53%)。基于FRNS/SDNS+随访≥1年首次复发时间的9项研究的Meta分析显示,首次复发时间9.89（95%CI: 7.14~12.65)月。基于FRNS/SDNS-开始干预至随访≥1年中位首次复发时间的3项研究的 Meta分析显示,RTX（1~2剂）较对照组中位首次复发时间长20 d,中位生存比（MSR）为0.69(95%CI:0.52~0.87）。基于FRNS/SDNS的12个月激素累积剂量减少结局的4项研究的Meta分析显示,RTX较对照组年激素累积剂量减少明显,差异有统计学意义(SMD=-1.12,95%CI:-1.49~-0.74)。基于FRNS/SDNS的随访3个月激素停用率的2项研究的Meta分析显示,RTX是对照组（CNI或CTX）随访3个月激素停用率的14.6倍 (OR=14.62,95%CI:5.43~39.39)。基于FRNS/SDNS+的RTX治疗6个月停用激素率的3项研究的Meta分析显示,停用激素率68%（95%CI:56%~79%）。结论:与对照组相比,RTX从随访1年的首次复发时间中获益有限,可从激素减量中获益但不能从停用激素率中获益。RTX治疗FRNS/SDNS随访12个月较安慰剂治疗或空白对照至少可降低88%的复发率,FRNS/SDNS接受RTX治疗随访1年复发率43%。RTX治疗FRNS/SDNS+可获得10个月的无复发生存时间。     

泼尼松联合霉酚酸酯与环孢霉素A治疗儿童激素耐药型肾病综合征的疗效比较

目的 比较泼尼松联合霉酚酸酯(MMF)与环孢霉素A(CsA)治疗儿童激素耐药型肾病综合征(SRNS)的疗效。方法 收集2004年1月至2013年12月住院并采用泼尼松联合MMF或CsA治疗的164例SRNS患儿的临床资料,回顾性分析泼尼松联合MMF(简称MMF组;n=112)与泼尼松联合CsA(简称CsA组;n=52)治疗儿童SRNS的临床疗效。结果 CsA组治疗后1个月的缓解率为67.3%(35/52),高于MMF组(42.9%,48/112)(PPPP结论 泼尼松联合MMF或CsA治疗儿童SRNS疗效均较好且安全,治疗3个月内CsA优于MMF。     

Autoimmune thyroiditis in a child with steroid-dependent nephrotic syndrome

Autoimmune thyroiditis is rarely described in association with nephrotic syndrome. Herein we report a girl who developed autoimmune thyroiditis insidiously during the course of minimal change nephrotic syndrome. She was streroid-sensitive, but developed severe steroid dependency and did not respond to cyclophosphamide therapy. She went into stable remission with levamisole. Five months after introduction of levamisole a mild goiter was found on systematic examination at school. The diagnosis of autoimmune thyroiditis was established with typical ultrasound appearance of the thyroid gland along with significant titers of antithyroid antibodies. It is very unlikely that levamisole was responsible for thyroiditis because experimental animal administration of high doses of levamisole inhibited lymphocyte infiltration of the thyroid. Since levamisole has had a beneficial effect on the nephrotic syndrome in our patient we decided to continue the treatment. She has been receiving levamisole for 3 years, and no adverse effects have been observed during the treatment period.     

霉酚酸酯与间断性环磷酰胺静脉冲击疗法治疗弥漫增生型狼疮性肾炎的Meta分析

目的 评价霉酚酸酯(MMF)与间断性环磷酰胺(CTX)静脉冲击疗法治疗弥漫增生型狼疮性肾炎(DPLN)的有效性和安全性.方法 检索PubMed、MEDLINE和中国期刊网等数据库,收集MMF与间断性CTX静脉冲击疗法治疗DPLN的随机对照试验14篇.使用RevMan 5.0软件分析评价临床总缓解率、复发率、病死率、疱疹的情况.结果 患者临床总缓解率,MMF较间断性CTX静脉冲击疗法高(P＜0.05).而复发率、病死率、疱疹情况,差异无统计学意义(P＞0.05).结论 MMF治疗DPLN的有效性和安全性较间断性CTX静脉冲击疗法为优.     

吗替麦考酚酯治疗儿童难治性肾病综合征

目的：观察吗替麦考酚酯（MMF）分散片联合泼尼松治疗难治性肾病综合征（RNS）的疗效性及安全性。方法：采用前瞻性多中心对照方法，10个中心共142例患者入选。治疗组87例，对照组55例。治疗组以MMF分散片（每日30～40 mg/kg）联合泼尼松（每日0.5～1 mg/kg）治疗，服MMF 6个月后，如无效应者停药，有效者减量维持治疗6个月，维持剂量每日10～20 mg/kg；对照组以环磷酰胺（CTX）冲击，每2周连用2 d，每日10 mg/kg 联合泼尼松治疗，疗程3个月，随后第4，7，10个月的第1天分别给予CTX 500 mg/m2，静脉点滴1次。泼尼松服用2～3个月开始减量。定期检测尿蛋白、肝肾功能及药物副作用。观察随访期共1年。结果：MMF治疗组87例中58例获完全效应，16例部分效应，9例表现为早期效应，4例治疗失败，治疗总有效率95.4％，尿蛋白转阴67例（77％）；CTX组55例中35例获完全效应，9例部分效应，1例早期效应，10例治疗失败，治疗总有效率81.8％，尿蛋白转阴36例（65.4％）。两组尿蛋白转阴率统计学差异无显著性，有效率MMF治疗组较CTX组高，而且有统计学意义(P<0.01)。尿蛋白转阴天数、低蛋白血症恢复天数、尿量恢复时间、高脂血症、水肿消退时间等方面MMF明显优于CTX。MMF治疗组用药期间主要副作用有一过性转氨酶升高3例次、感染32例次、消化道症状11例次、月经紊乱、肌肉颤动各1例次；对照组发生转氨酶升高9例次、感染30例次、消化道症状15例次、血红蛋白降低4例次、白细胞降低2例次、脱发7例次。结论：结果表明，推荐MMF每日20～35 mg/kg联合泼尼松0.5～1 mg/kg治疗难治性肾病综合征，尿蛋白转阴率不劣于CTX，而且起效时间较CTX短，药物副作用少。     

霉酚酸酯治疗二岁以下婴幼儿激素抵抗型肾病综合征临床研究

婴幼儿肾病综合征是儿童肾病综合征的特殊类型,大部分患儿临床表现为肾炎型肾病综合征,病理表现为非微小病变型肾病,50%～80%的患儿为难治性肾病(RNS)[1-3],且近年来有增多趋势.本研究对16例2岁以下的激素抵抗型肾病综合征联合使用霉酚酸酯(mycophenolate mofetil,MMF)治疗,探讨其疗效和安全性.     

Mycophenolate mofetil therapy for children with intractable nephrotic syndrome

BACKGROUND: Cyclosporin A (CyA) can suppress relapses and reduce proteinuria in frequent-relapse nephrotic syndrome (FRNS) and steroid-resistant nephrotic syndrome (SRNS). However, some patients remain resistant to CyA therapy. The purpose of the present paper was to evaluate mycophenolate mofetil (MMF) treatment in pediatric patients with CyA-resistant intractable nephrotic syndrome. METHODS: MMF therapy was given to 11 patients with FRNS who had relapse despite CyA therapy, and one patient with SRNS who had been receiving combined therapy using steroid and CyA until immediately before the start of MMF. MMF was administered at a daily dose of 750-1000 mg/m(2) in two divided doses. RESULTS: Ten of the 11 patients with FRNS were able to maintain remission. Among them, seven patients remained relapse free for 1 year, and two patients had a decrease in the frequency of relapse after initiation of MMF therapy. One patient, however, had repeated cycles of remission and relapse, and was considered resistant to MMF therapy. The total prednisolone dose during the period from month 6 to month 12 after the start of MMF therapy was significantly lower than that during the 6 month period before the start of MMF therapy. The patient with SRNS, who had not achieved remission despite CyA administration, had complete remission on MMF. No serious adverse effects were seen in any of the present patients. CONCLUSION: MMF could be useful in CyA-treatment-refractory FRNS and CyA-resistant SRNS.     

霉酚酸酯与环磷酰胺治疗肾病综合征型紫癜性肾炎疗效比较

目的 比较霉酚酸酯（MMF）与环磷酰胺（CTX）静脉冲击治疗以肾病综合征为临床表现的紫癜性肾炎（HSPN）的疗效。方法 将37例临床表现为肾病综合征的HSPN患儿分为两组：一组用激素联合MMF治疗,另一组行激素联合CTX冲击治疗。结果 治疗6、9和12个月临床完全缓解率MMF组与CTX组分别为36．8％和27．8％、63．2％和44．4％、68.4％和44．4％（P〉0．05）;临床部分缓解率MMF组与CTX组分别为36．8％和38．9％、31．6％和44．4％、26-3％和33．3％（P〉0．05）;总缓解率（完全＋部分缓解）MMF组与CTX组分别为73．7％和66．7％、94．7％和88．9％、94．7％和77．8％（P〉0．05）,两组在临床缓解率上差异无统计学意义。治疗6、12个月时尿蛋白缓解率MMF组高于CTX组,分别为73．7％与33-3％（P〈0．05）、和84．2．与50．O％（P〈0．05）。治疗6个月时血尿缓解率MMF组高于clx组,为47．4％与16．7％（P〈0．05）,12个月时两组血尿缓解率相近（73．7％与66．7％,P〉o．05）。MMF组出现不良反应4例,轻度胃肠道反应2例和呼吸道感染2例;CTX组不良反应7例,表现为严重胃肠道反应3例,支气管肺炎、白细胞下降、肝功能损害、脱发各1例。结论 与CTX结合小剂量激素治疗相比较,MMF结合小剂量激素治疗以肾病综合征为临床表现的HSPN有相近的临床缓解率,而在缓解蛋白尿和血尿方面,MMF较CTX更为有效。MMF不良反应亦明显少于CTX。     

Cyclosporine therapy for steroid-resistant nephrotic syndrome. A controlled study

We have conducted a controlled trial on the efficacy of cyclosporine in eight patients with steroid-resistant nephrotic syndrome (four with idiopathic minimal lesion nephrotic syndrome and four with focal segmental glomerulosclerosis). Patients were randomly allocated to a cyclosporine (5 mg/kg/d) or a control group. After eight weeks of therapy and one month without cyclosporine therapy, patients in the control group were given cyclosporine for eight weeks and those in the cyclosporine group became controls. Before the initiation of treatment, there was no difference between the groups with regard to proteinuria and serum albumin levels. Proteinuria remained unchanged in the cyclosporine group, while there was a significant increase in proteinuria in the control group. There were no significant changes in serum albumin levels in either group during the trial. This study does not support the use of cyclosporine at the dose of 5 mg/kg/d in patients with steroid-resistant minimal lesion nephrotic syndrome or focal segmental glomerulosclerosis.     

Relapse of nephrotic syndrome following remission for 20 years

Relapse of the nephrotic syndrome in a patient who was in remission for 20 years is discussed. The initial renal biopsy performed 3 years after the onset of the nephrotic syndrome showed focal and segmental glomerulosclerosis (FSGS). The second renal biopsy performed 20 years later was compatible with a diagnosis of minimal change nephropathy (MCN).     

环磷酰胺与霉酚酸酯治疗狼疮性肾炎疗效比较的系统评价

目的 比较环磷酰胺的标准治疗与霉酚酸酯治疗狼疮性肾炎的有效性和安全性.方法 检索Cochrane图书馆、MEDLINE、EMBASE、中国生物医学文献光盘数据库、中国循证医学/Cochrane中心数据库相关的随机对照试验,并进行meta分析.结果 共纳入11个随机对照试验,meta分析显示霉酚酸酯治疗组的总有效率和完全缓解率高于环磷酰胺治疗组,两组复发率比较差异无统计学意义,环磷酰胺组的死亡率、感染率、闭经率均高于霉酚酸酯组,霉酚酸酯组的腹泻发生率高于环磷酰胺组.结论 在应用糖皮质激素的基础上,霉酚酸酯治疗狼疮性肾炎的疗效至少与环磷酰胺相当,药物的总体不良反应轻于环磷酰胺.     

Pediatric renal transplantation with mycophenolate mofetil immunosuppression in a single center from Mexico

An MMF-based immunosuppression has reduced the acute rejection rate in adults and in children in the early post-transplantation period. In the present study, pediatric renal transplantation patients on a CyA, MMF, and steroids regimen were prospectively evaluated. Patients with CyA, MMF, and steroid therapy without antibody induction were evaluated for surgical aspects, renal function, rejection, and survival, growth after transplantation, adverse events and medication discontinuation. Between February 2003 and May 2005, 21 kidney transplantation patients under 18 yr old were followed for at least 12 months. Within one year after transplantation, three patients developed four episodes of acute rejection (19%). Graft loss because of rejection occurred in one patient. One-year mean serum creatinine was 1.19 +/- 0.3 mg/dL. Mean calculated CrCl by Schwartz formula was 82.3 +/- 19.7 mL/min*1.73 m(2). Major adverse events included infections of the urinary tract and diarrhea, abdominal pain, and GI symptoms. No patients have discontinued the use of MMF. Good results in pediatric kidney transplantation can be achieved by using CyA/MMF/steroids. MMF is effective and relatively safe in reducing the incidence of acute rejection even without induction therapy 12 months after transplantation.     

Induction therapy for pediatric focal proliferative lupus nephritis: cyclophosphamide versus mycophenolate mofetil

PURPOSE OF THE STUDY: Although cyclophosphamide has been used with success in children, mycophenolate may be a better alternative with less toxicity. The objective of this study is to determine the efficacy of mycophenolate compared with cyclophosphamide as induction therapy in children with class III lupus nephritis. METHODS: We retrospectively studied pediatric patients with class III lupus nephritis from two pediatric centers from January 1991 to December 2005 who were treated either with monthly cyclophosphamide or mycophenolate mofetil for the first 6 months. Thirteen patients were studied, with seven patients in the cyclophosphamide group and six patients in the mycophenolate group. RESULTS: At 6 months, in the cyclophosphamide group, no patient had achieved complete remission, while 57% were in partial remission. In the mycophenolate group, 66% had achieved complete remission, 17% were in partial remission, and 17% were not in remission. DISCUSSION: In a small group of children with class III lupus nephritis, we observed a trend of more patients in the mycophenolate group achieving remission at 6 months. However, the long-term benefit of using mycophenolate as an induction agent is still unclear.     

环磷酰胺静脉冲击治疗儿童激素依赖性肾病综合征32例疗效分析

目的　了解大剂量环磷酰胺静脉冲击疗法 (CTX PT)治疗儿童激素依赖性肾病的近期疗效以及影响疗效的相关因素。方法　总结 1991年 9月至 2 0 0 0年 6月接受CTX PT治疗的激素依赖性肾病 3 2例 ,并就其疾病类型、临床观察指标等与疗效的关系进行了分析。结果　①用CTX PT治疗 2 3例有效 (有效率 71 9% )。②影响疗效的因素主要有疾病的临床、病理类型以及血清肌酐 (SCr)水平。单纯性肾病疗效明显好于肾炎性肾病(有效率分别为 85 0 %和 5 0 0 % ,P<0 0 5 ) ;病理表现为微小病变 (MCNS)者明显好于非MCNS ;SCr水平在治疗前较高者提示可能疗效也差。CTX PT疗效与性别、发病年龄、血清白蛋白、球蛋白、血胆固醇、免疫球蛋白、2 4h尿蛋白排泄量等无关 (P >0 0 5 )。③毒副作用 :11例 (3 4 4% )未见明显CTX毒副作用 ;2 1例 (65 6% )出现不同程度的副作用 ,主要为急性胃肠道反应占 40 6% (3d内缓解 ) ,其它副作用少见 ,而且这些毒副作用均为一过性并很快恢复正常。结论　CTX PT治疗儿童激素依赖性肾病有效率为 71 9% ,影响疗效的因素主要有疾病的临床、病理类型以及SCr水平等。     

Efficacy of levamisole in children with frequently relapsing and steroid-dependent nephrotic syndrome

Objectives

To assess the efficacy of levamisole in frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome.

Study Design

Retrospective analysis of hospital case records.

Setting

Pediatric nephrology department of a tertiary referral pediatric hospital.

Participants

62 children with frequently relapsing nephrotic syndrome and 35 children with steroid-dependent nephrotic syndrome.

Methods

Case records of children who were diagnosed as steroid-dependant or frequently-relapsing nephrotic syndrome from June 2004 to June 2011, were reviewed. Levamisole was given daily (2 mg/kg/d) along with tapering doses of alternate day steroids after remission on daily steroids.

Results

Levamisole was effective in 77.3% children with a better (80.6%) efficacy in frequently relapsing nephrotic syndrome. A total of 34 children completed 1 year follow-up post levamisole therapy. The cumulative mean (SD) steroid dose 1-year before therapy was 4109(1154) mg/m² and 1-year post therapy was 661 (11) mg/m² (P<0.001). The relapses were also less during the period of post-levamisole therapy.

Conclusion

Levamisole is an effective alternative therapy in frequently relapsing and steroid-dependent nephrotic syndrome.