环孢素治疗激素耐药型肾病综合征的研究进展

儿童激素耐药型肾病综合征(SRNS)的治疗相对棘手,目前治疗上常用的免疫抑制剂有环孢素(CsA)、环磷酰胺、他克莫司等。CsA的药物代谢动力学不稳定,需定期监测其血药水平。CsA对SRNS儿童的诱导缓解率优于安慰剂及环磷酰胺,与他克莫司相当。SRNS儿童在CsA停药后易出现复发,其复发率为45%～64%。为增强CsA的疗效、减少其肾毒性,推荐应用小剂量、长疗程CsA治疗儿童SRNS的方案。     

环孢霉素A相关肾毒性标志物的研究进展

环孢霉素A(cyclosporine A,CsA)是治疗激素依赖型和激素耐药型肾病综合征常用药物之一,但是在CsA治疗肾病综合征的同时往往会发生肾脏毒性,从而限制了CsA的使用.CsA可导致急慢性肾脏病,缺血的肾组织发生炎症以及纤维化.目前临床上通过尿系列微量蛋白、血肌酐等对CsA肾毒性进行监测,但尚不能早期发现肾脏损害.寻找一种无创且敏感性高的标志物来检测CsA的肾毒性是目前研究的热点.该文就目前已知的急性肾损伤标记物在监测CsA肾毒性方面的研究进展进行综述.     

儿童肾病综合征并发急性肾损伤的早期识别和治疗

肾病综合征(NS)是儿童时期最常见的原发性肾脏疾病之一,急性肾损伤(AKI)是NS的常见并发症,通常继发于低血容量、肾毒性药物暴露和感染等。近年来儿童NS并发AKI发病率有所上升,早期识别、正确诊断及治疗对改善预后至关重要。本文对儿童NS并发AKI的流行病学、病因、发病机制、诊断及治疗的新进展进行阐述。     

环孢素A治疗儿童难治性肾病综合征随机对照试验的系统评价

目的 评价环孢素A(CsA)治疗儿童难治性肾病综合征(RNS)的疗效和安全性.方法 按系统评价的要求全面检索了 Cochrane图书馆、PubMed、EMBASE、中国生物医学文献光盘数据库(CBMdisk)、中国期刊全文数据库(CNKI)和中国维普数据库(VIP),对符合纳入标准的文献按临床类型及干预措施分亚组进行Meta分析.结果 共纳入9篇文献(n=293),6篇4～7分,3篇1-3分.(1)在激素(GC)效应组中,CsA联合GC的近期疗效优于单用GC[OR值0.14,95%CI(0.03,0.71)],但与环磷酰胺、麦考酚酸酯的差异无统计学意义,比苯丁酸氮芥疗效差且易复发[OR值和95%CI分别为6.93(1.53,31.38)、0.06(0.01,0.58)],维持治疗期间保持CsA血药浓度在60～80 μg/L能降低远期复发率[OR值6.43,95%CI(1.21,34.19)],两组终末期肾病(ESRD)的发生率和病死率均为0.(2)在激素耐药组中,CsA的近期疗效优于安慰剂或支持治疗及环磷酰胺[OR值和95%CI分别为0.15(0.02,0.96)、0.41(0.03,5.00)],但复发率、ESRD的发生率和病死率的差异均无统计学意义.(3)CsA的安全性:CsA组的肾毒性、多毛和牙龈增生的发生率均高于对照组[OR值和95%CI分别为0.19(0.05,0.79)、0.06(0.02,0.19)、0.05(0.02,0.18)],但两组间高血压和肝毒性发生率的差异无统计学意义.结论 已有证据提示CsA能提高儿童RNS的近期疗效,但不能提高其远期和终点疗效,是治疗儿童RNS较理想的二线药物,其安全性较好,从总体趋势上看,CsA对儿童激素效应Ns的疗效优于激素耐药NS.此外,在维持治疗期间,保持CsA的血药浓度在60～80 ug/L能减少远期的复发率.     

长疗程环孢素A治疗儿童激素耐药型肾病综合征的疗效和预后

目的 观察激素耐药的儿童肾病综合征(SRNS)应用环孢素A(CsA)长疗程治疗的疗效并分析影响疗效的相关因素.方法 回顾性分析疗程2年的CsA治疗SRNS病例20例,男:女为3:1;平均年龄5.5岁,肾病病理类型微小病变(MCNS)15例,局灶节段肾小球硬化(FSGS)4例,系膜增生性肾炎(MsPGN)1例.结果 (1)完全缓解13例(65%),部分缓解4例(20%),CsA无效3例(15%),总有效率85%.平均随访时间40.5个月,复发率45%.(2)CsA治疗微小病变肾病的有效率为93%,非微小病变为60%,但两者差异无统计学意义.(3)毒副作用:多毛、齿龈增生和高血压的发生率分别为75%、25%和10%,2例出现可逆性的肾损伤,4例出现尿NAG/Cr增高,神经系统症状2例.3例重复肾活检未发现CsA相关的肾小管间质纤维化病变.结论 对儿童激素耐药型肾病综合征CsA长疗程治疗有良好的疗效.小剂量CsA长期治疗未发现药物相关的肾小管间质纤维化和肾功能损伤.CsA长期治疗的安全性和预后有待进一步研究.     

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。     

儿童免疫相关性疾病临床实用热点问题专家建议系列之三——环孢素在中国儿童免疫相关疾病中的应用建议

正环孢素又名环孢素A(cyclosporin A,CsA),是从土壤真菌中分离出来的一种强效的T细胞特异性免疫抑制剂,自20世纪80年代来被广泛用于预防器官移植后的排斥反应,成为当前主要的免疫抑制剂之一。随着对其免疫抑制作用的认识不断深入,近年来CsA亦被广泛用于治疗儿童免疫相关性疾病并取得较好疗效,但在临床应用中也出现了包括适应证、药物不良反应、药物浓度高低等问题。为规范CsA在儿童免疫相关性疾病中的应用,亚太医学生物免疫学会儿童过敏免疫风湿     

肾病综合征患儿的脂代谢紊乱

肾病综合征(NS)是小儿泌尿系统常见疾病之一,高脂血症作为NS的4大临床症状之一,常表现为总胆固醇、低密度脂蛋白、三酰甘油、脂蛋白a水平的升高以及高密度脂蛋白水平的降低,脂代谢紊乱可导致动脉粥样硬化,且具有一定的肾毒性,对儿童NS病情的进展和预后具有重要的意义.因此临床工作者对NS患儿脂代谢紊乱进行早期诊断和调脂治疗至关重要.现参阅国内外最新的研究进展,对小儿NS脂代谢紊乱的诊断参考指标及早期干预治疗作如下阐述,以便于临床医师参考应用.     

环胞霉素A治疗重型再生障碍性贫血

自从开展应用环胞霉素A(CSA)治疗再障以后,许多实验及临床资料均已证实该药确有疗效。更为有意义的是,CSA 已为部分经临床应用各种药物和 ATG等免疫抑制剂无效的难治性再障而又无条件作 BMT 治疗者,开辟了新的治疗途径。因此CsA不失为一种颇有发展前途的治疗再障的有效药物,值得临床参考应用。但是,仍有待于继续研究与观察,以进一步明确再障的免疫紊乱机理和应用 CSA 的适应症,并寻求更为合理的的用药剂量、疗程和如何防治肾、肝毒性反应与其它副作用的方法,以及如何采用更为理想的联合治疗方案以进一步提高疗效。     

环孢霉素加强的松治疗肾病综合征

环孢霉素已用于治疗成人和儿童肾病综合征(NS)。由于患者的肾组织损伤,对类固醇激素(激素)的敏感性和环孢霉素的剂量不同,治疗效果也各异。该文旨在研究早期应用环孢霉素治疗 NS 能否诱导持续的缓解。方法 28例 NS 患儿符合如下标准:(1)NS     

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome.

BACKGROUND: Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients. AIMS AND METHODS: In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50-150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed. RESULTS: Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6-144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN. CONCLUSION: An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.     

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Background

Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients.

Aims and Methods

In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50–150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed.

Results

Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6–144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN.

Conclusion

An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.     

Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab

The efficacy of rituximab (RTX) as the sole therapy for preventing relapses of nephrotic syndrome (NS) is transient in most patients; therefore, the optimal therapy required for maintaining a successful response to a biological agent remains a challenge. We conducted a prospective study to compare the efficacy of cyclosporine (CsA) with that of mycophenolate mofetil (MMF) as maintenance therapy after a single infusion of RTX. Of 29 patients with persistent steroid-dependent NS despite the use of CsA and/or MMF, 13 without chronic nephrotoxicity continued CsA therapy, maintaining a 2-h post-dose CsA level of 400–500 ng/ml (CsA group). The remaining 16 were treated with MMF, maintaining a pre-dose level of 2–5 μg/ml of mycophenolic acid (MMF group). The median duration of CsA and MMF treatment was 18 and 19 months, respectively. Despite the mean number of relapses before RTX treatment being significantly lower in the MMF group than in the CsA group (2.3/year vs. 4.6/year, p?<?0.01), treatment failure occurred more frequently in the MMF group (7/16) than in the CsA group (2/13). The rate of sustained remission was also significantly higher in the CsA group than in the MMF group (p?<?0.05). Conclusion: In patients with severe steroid-dependent NS, CsA appears to be more effective than MMF for maintaining remission after a single infusion of RTX.     

环孢霉素A与他克莫司治疗儿童难治性肾病综合征疗效及安全性对照研究

目的 评估环孢霉素A与他克莫司治疗儿童难治性肾病综合征的疗效及安全性。方法 回顾性分析2012年6月至2018年6月在上海市儿童医院接受环孢霉素A与他克莫司治疗的118例难治性肾病综合征患儿信息，包含患儿一般情况、实验室检查、肾组织病理、治疗后转归及不良反应等，并进行统计分析。采用Kaplan-Meier生存分析绘制生存曲线，行相关比较分析。结果 一般临床资料：纳入环孢霉素A治疗病例总计66例，其中18例为激素耐药型肾病综合征，45例为激素依赖型肾病综合征，3例为频反复型肾病综合征，其中56例行肾穿刺活检。52例他克莫司组中12例为激素耐药型肾病综合征，40例为激素依赖型肾病综合征，其中47例行肾穿刺活检；疗效及安全性分析：环孢霉素A与他克莫司对难治性肾病综合征维持远期完全缓解无组间差异。但治疗第6个月，难治性肾病综合征他克莫司组完全缓解率（86.5%）明显高于环孢霉素A组（68.2%），差异有统计学意义（P<0.05），其中以激素依赖型/频反复型肾病综合征疗效差异有统计学意义（P<0.05），激素耐药型肾病综合征组间疗效无统计学差异。此外，在微小病变组及非微小病变组内，环孢霉素A与他克莫司无疗效差异；副反应方面，他克莫司组多毛症发生率、牙龈增生发生率均明显低于环孢霉素A组，且有显著性差异（P<0.01），但在使用他克莫司第16个月及18个月后出现2例急性胰腺炎患儿。环孢霉素A组急性肾损伤（5/66）及慢性肾毒性改变（2/66）发生率高于他克莫司组。结论 环孢霉素A与他克莫司对难治性肾病综合征远期疗效无差异。对于激素依赖型/频反复型肾病综合征患儿，他克莫司短期疗效较环孢霉素A更好，但需警惕急性胰腺炎发生。对环孢霉素A累计治疗时间超过30个月患儿需高度警惕钙调神经磷酸酶抑制剂肾毒性发生。     

Pseudotumor cerebri after allogeneic bone marrow transplant associated with cyclosporine a use for graft-versus-host disease prophylaxis

Pseudotumor cerebri (PTC) is a syndrome of increased intracranial pressure for which several risk factors have been described. We report 2 patients who developed PTC after cyclosporine A (CsA) therapy for graft-versus-host disease (GvHD) prevention after bone marrow transplant. Both patients were obese which may have also contributed to the PTC. Cessation of CsA and combinations of mycophenolate mofetil or tacrolimus and systemic steroids and/or acetazoleamide were effective in managing the symptoms, improving the ocular complications and keeping GvHD asymptomatic. These cases suggest that induction of PTC by CsA used for GvHD prophylaxis in patients undergoing bone marrow transplant is not rare. Physicians who are following patients on CsA need to be alert to the possibility of PTC. Prompt diagnosis followed by thorough evaluation and treatment are crucial for preventing visual loss and improving associated symptoms.     

Trends in immunosuppressive therapy: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS)

The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) data registry has now compiled data for 11 years, and includes data on 6038 renal transplants in 5516 patients. With the availability of new data and immunosuppressive medications, trends in their usage continue to change. NAPRTCS data have previously demonstrated that increased doses of cyclosporin A (CsA) are associated with improved allograft outcomes, and there has been a steady increase in the dose of CsA given post-transplantation. Transplants that occurred in 1987, 1989, 1991, and 1993 received a mean one-year post-transplant dose of 6.5, 7.0, 7.7, and 8.2 mg/kg/d, respectively. In the 1995 cohort, the dose decreased to 7.4 mg/kg/d. Since the introduction of Neoral, its use has steadily increased. Of the 1997 cohort, 81% report Neoral as the formulation of CsA used. The dose of CsA given, however, has not changed. At day 30 post-transplant, the dose was 7.0 mg/kg/d for Sandimmune and 7.4 mg/kg/d for Neoral. Finally, the outcome in black transplant patients is inferior to that of nonblack. Evaluation of CsA blood levels revealed that at 1 year post-transplant, black patients consistently have CsA levels higher than nonblacks, and a lower percentage of black patients have a CsA level < 100 ng/mL. The percentage of patients using triple therapy (prednisone, azathioprine, and CsA) remained stable from 1987 to 1993 at 80-85%. However, in 1996 only 30% of patients were receiving triple therapy. This is probably due to the introduction of mycophenolate mofetil (MMF). Comparing the 1996-97 cohorts, there has been no significant change in the percentage of patients receiving prednisone (96.2% vs. 95.4%) or CsA (83.1% vs. 79.6%). However, during this time, the use of azathioprine has decreased from 50.0% to 35.8%, the use of tacrolimus has increased from 2.5% to 10.8%, and the use of MMF has increased from 6.5% to 35.8%.     

Serum indoxyl sulfate as an early marker for detecting chronic cyclosporine nephrotoxicity

Background: Cyclosporine A (CsA) is an effective agent for frequently relapsing steroid‐dependent nephrotic syndrome (FR‐SDNS), but its use can also be complicated by renal toxicity. Because no biochemical markers from urine or blood samples have yet been established for detecting CsA‐induced renal injury to date, repeated renal biopsies are therefore required for all patients with long‐term CsA treatment. The purpose of the present study was therefore to detect early change of CsA nephropathy (CsAN) using blood samples. Methods: Several biochemical markers were analyzed in an attempt to examine the renal function in 24 patients with FR‐SDNS who had been treated with CsA. Those included serum cystatin C and indoxyl sulfate, as well as creatinine and β2‐microglobulin. Results: Renal biopsy findings indicated chronic CsAN in 13 of the 24 patients. Among those markers, only serum indoxyl sulfate was significantly elevated in patients with CsAN. Conclusions: It may be possible for measurement of serum indoxyl sulfate level to replace repeated renal biopsies in evaluation of chronic CsAN in pediatric patients with FR‐SDNS.     

Alterations of cyclosporin A metabolism induced by mycophenolate mofetil

Unexpectedly lower CsA 2-h levels were found in patients who received additional immunosuppression by MMF in our center. The aim of this study is to prove whether there are differences in CsA metabolization when MMF is added to treatment. In 33 children who received an immunosuppression of prednisolone and CsA as well as in 15 children who were treated with additional MMF, C2 and C0 were taken. In 11 children, full AUC of CsA were obtained. C2 levels differed significantly (p < 0.05) between patients treated with (617 +/- 230 ng/mL) and without MMF (750 +/- 271 ng/mL) but with similar CsA dosages. C2 correlated better with the AUC than CsA levels at other time points with r = 0.95. The equation AUC = 139 + 6.17 x C2 was calculated to match best in a C2-limited sampling strategy. This formula proved to be safer than equations that had been published before. According to our findings, we suspect that MMF alters the CsA metabolism. When MMF is used in pediatric transplant recipients, either target values of CsA have to be changed or patients may require higher doses of CsA.     

Effect of grapefruit juice on cyclosporin A pharmacokinetics in pediatric renal transplant patients

Cyclosporin A (CsA) is an important immunosuppressant that is prone to numerous drug interactions. Grapefruit juice has been investigated, as a possible adjunct to CsA dosing in adult renal transplant recipients, to decrease CsA metabolism and reduce dosages. This study investigated this combination in pediatric renal transplant patients. Six stable pediatric renal transplant patients were entered into an open-label, four-period cross-over study in which patients were given their current CsA dose as either an oral solution (CsA-Sol) or a microemulsion (CsA-ME). In addition, drugs were administered concurrently with water or grapefruit juice. Steady-state pharmacokinetic profiles were taken during each of the four periods. Following the concurrent administration of grapefruit juice, CsA whole-blood 12-h trough levels were significantly increased during CsA-Sol dosing. Furthermore, the CsA elimination rate constant was significantly reduced during the same period. After CsA-ME dosing, no differences in CsA pharmacokinetics were found between concurrent water or grapefruit ingestion. Grapefruit juice co-administration reduced the production of CsA metabolites, AM1 and AM9, during CsA-Sol dosing. No changes in CsA metabolite production were found when patients were given CsA-ME with grapefruit juice as compared with water. Hence, alterations in CsA absorption and elimination occur with concurrent grapefruit juice ingestion when stable pediatric renal transplant patients are taking the oral CsA solution, but not the microemulsion formulation. These changes may be mediated by alterations in intestinal or hepatic metabolism, or drug absorption. The effect of grapefruit juice on CsA absorption is not readily predictable in these patients.