环孢素A在不同病理类型慢性肾小球疾病治疗中的应用进展

慢性肾小球疾病可分为原发性和继发性,原发性肾小球疾病中常见的病理类型包括以下5种：膜性肾病（membranous nephropathy,MN）、微小病变型肾病（minimal change glomerulonephropathy,MCD）、系膜增殖性肾小球肾炎（mesangial proliferative glomerulonephritis,MsPGN,包括IgA系膜增殖性肾小球肾炎和非IgA系膜增殖性肾小球肾炎）、局灶节段性肾小球硬化（focal segmental glomerular sclerosis,FSGS）和膜增殖性肾小球肾炎（membranoproliferative glomerulonephritis,MPGN）,常见的继发性肾小球疾病的病理类型有狼疮肾炎、过敏性紫癜性肾炎、乙型肝炎病毒相关性肾炎等.     

不同病理类型肾病综合征患儿环孢素亲合素mRNA表达的观察

目的探讨环孢素亲合素(CyP)在儿童难治性肾病中基因表达及临床意义.方法采用逆转录聚合酶链反应(RT-PCR)测定33例难治性肾病患儿血白细胞中CyPmRNA的表达,并以正常儿童作对照.结果CyP碱基对为408bp与β-actin条带(234bp)可清晰区分.系膜增殖性肾小球肾炎(0.289±0.017)、局灶节段性肾小球硬化(0.287±0.006)患儿的血白细胞中CyPmRNA的水平高于微小病变型肾病(0.271±0.007)和膜增殖性肾小球肾炎(0.267±0.008);激素依赖、激素耐药、频繁复发患儿之间CyPmRNA表达无差异.肾病组急性期(0.281±0.016)CyPmRNA水平高于恢复期(0.267±0.100)与对照组(0.258±0.011).结论监测难治性肾病CyPmRNA的表达可能对环孢素的治疗有指导意义.     

环孢素在特发性肾病综合征中的应用

环孢素(Cyclosporin、CS)是一种T淋巴细胞功能的特异调节剂,已被广泛地应用于器官移植领域,使器官移植的成功率大大提高。最近,有些学者将CS试用于难治性的特发性肾病患者的治疗,虽然目前治疗的病例数量还不多,结果亦不尽一致;但是初步疗效是明显的,有希望成为治疗难治性肾病的重要药物。为了全面评价CS的疗效,权衡其利弊及正确使用此药,故将近几年来CS在特发性肾病综合征中的应用情况作一介绍。     

环孢素A治疗肾病综合征的进展

环孢素A(CyA)的免疫抑制作用大多是通过抑制活性T细胞产生IL-2和其他淋巴因子而产生的,从而影响抗体产生和抑制炎症反应。CyA治疗儿童激素依赖型肾病综合征(NS)疗效较好,而对激素无效型NS效果差,且发生肾毒性的危险性高,发现肾毒性最可靠的方法是肾活检。CyA治疗成人特发性NS:微小病变型是CyA治疗的最佳适应症;而对局灶节段型肾小球硬化型则应用时必须注意肾功能及肾活检病理的间质损害;膜性肾病短期CyA治疗效果好,但复发率高;IgA肾病,CyA控制蛋白尿的长期效果较好,而肾毒性或高血压发生的可能性高。总之,CyA用于治疗Ns若成人开始剂量不超过5mg/kg/日,儿童不超过6mg/kg/日,同时监测肾功能变化等,则CyA应用是安全的。     

环孢素A治疗儿童特发性肾病综合征

儿童特发性肾病综合征约90%对激素是敏感的,但当减量或停药后有半数以上病人会复发,且这些病人常是激素依赖或副作用导致应用其它药物如烷化剂,而这些药物也有副作用。10%的病人对激素治疗是无效的,其中50%以上会发展到终末期肾衰,且激素无效的病人应用烷化剂疗效也不肯定,为此作者应用环孢素A治疗儿童肾病综合征,观察其疗效,并通过重复肾活检来评价其副作用和肾毒性。     

环孢素A结合中医药治疗难治性肾病综合征

由于单用环孢素Ａ(ＣｓＡ)治疗难治性肾病综合征复发率高 ,并易有慢性肾毒性。我们在临床上结合中医药协同治疗 6例 ,设对照 3例共 9例 ,进行前瞻性临床研究。材料与方法1.9例均频繁复发 ,6个月内复发 2次以上 ,12个月以内复发 3次以上 ,曾应用强的松 1ｍｇ·ｋｇ-1·ｄ-1及环磷酰胺(ＣＴＸ)总量 6～ 8克以上仍无效或激素减量又复发。2 .6例中西医结合组 ,男 3例 ,女 3例 ,平均 36岁。 3例ＣｓＡ加激素作对照组 ,男 1例 ,女 2例 ,平均 38岁。 9例均服ＣｓＡ 5ｍｇ·ｋｇ-1·ｄ-1。 6例辨证论治为基础 ,加防己 10克 ,黄芪 40克 ,人参 10克 ,…     

P选择素在原发性肾病综合征患者肾组织不同病理类型中的表达及其意义

目的：为探讨粘附分子P选择素（CD62P）在原发性肾病综合征（NS）患中的致病作用及其与肾组织各种病理类型的关系。方法：肾穿刺活检法取NS患肾组织,以直接免疫荧光标记单克隆抗体,周围血以流式细胞仪的方法,进行了CD62P表达的研究。结果：（1）98例NS患显示CD62P表达85例（86．7％）,病理类型的表达以MPGN,MsPGN显,MN,FSGS次之,MCD最弱;（2）同组患周围血CD62P表达量较正常组明显增高（P＜0．01）;（3）CD62P在肾组织的表达与周围血表达水平密切相关,且与肾脏各种病理类型的病变部位一致。结论：CD62P在NS患不同病理类型中的表达,提示其在NS发病机制中具有重要作用。     

环孢霉素A治疗成人原发性肾病综合征的系统评价

目前治疗原发性肾病综合征的一线药物主要为糖皮质激素,但对于那些频繁复发、激素依赖、激素抵抗的患者,常加用免疫抑制剂联合治疗。自1985年环孢霉素A首次应用于治疗肾病综合征以来,已广泛应用于临床自身免疫性疾病的治疗中,并且取得了较好的效果。近年来随着其不良反应,如肾脏损害、高血钾、高血压、神经系统毒性、胃肠系统毒性、多毛症等报道的不断增多,人们对环孢霉素A的临床应用存在广泛争议。在此情况下,有必要对这些研究进行系统评价,以了解环孢霉素A治疗原发性肾病综合征的疗效和安全性。     

Convulsion during cyclosporin A therapy for nephrotic syndrome

A 10-year-old boy with nephrotic syndrome developed convulsions 6 weeks after the start of cyclosporin A (CyA) therapy. Generalized tonic-clonic convulsion occurred during relapse of nephrotic syndrome after influenza A infection. T2-weighted magnetic resonance imaging (MRI) showed high signal intensities in bilateral parieto-occipital lobes. He recovered from the convulsions and the MRI findings returned to normal early without neurological sequelae. CyA was discontinued for 1 week and then restarted. He has had no further convulsions or recurrence of nephrotic syndrome since that time. He had no evidence of high blood level of CyA, hypertension, electrolyte abnormalities, or renal or hepatic dysfunction. He was diagnosed with CyA-related reversible posterior leukoencephalopathy syndrome based on the rapid recovery of clinical symptoms and the characteristic MRI finding. Influenza A infection may have damaged the blood-brain barrier, paving the way for central nervous system toxicity. Received: December 3, 1998 / Accepted: June 7, 1999     

Secondary resistance to cyclosporin A in children with nephrotic syndrome

We investigated the phenomenon of secondary resistance to cyclosporin (CsA) in children with steroid dependent (SD) or steroid resistant (SR) nephrotic syndrome. Secondary resistance was defined as an initial response to CsA with relapse on withdrawal of therapy and absent or diminished response on reinstitution of the drug. Thirty-two children with nephrotic syndrome who were treated with CsA were included in the study. Twenty-two of the children (15 of 15 SD and 7 of 17 SR) responded while ten demonstrated primary CsA resistance. Of these 22 responders, 20 relapsed when therapy was tapered or discontinued. Cyclosporin was reinstituted in 19. Ten responded, demonstrating CsA dependence, and nine exhibited secondary CsA resistance. Focal segmental glomerular sclerosis (FSGS) was present in one patient with CsA dependence on the initial biopsy and in two of six on a subsequent biopsy. In comparison, seven of nine patients with secondary CsA resistance and ten of ten with primary CsA resistance had FSGS on the initial or subsequent biopsy ( P=0.03). C4 and/or C1q were present on the initial biopsy in one patient with CsA dependence as compared to six of nine with secondary CsA resistance ( P=0.02). Four patients with secondary CsA resistance had an accelerated progression to end-stage renal disease (ESRD). We conclude that the presence of FSGS, or of C4 and/or C1q, appears to increase the risk of secondary CsA resistance and some of these children rapidly progress to ESRD.     

Long-term cyclosporin A treatment of minimal-change nephrotic syndrome of childhood

We evaluated the efficacy of long-term cyclosporin A (CyA) treatment in the maintenance of remission in 40 children with steroid-dependent minimal-change nephrotic syndrome (MCNS). CyA was given in an initial dose of 5 mg/kg per day, adjusted to maintain a trough whole blood level of 50–150 ng/ml. All the 40 children received CyA for 1 year. In 18 patients, CyA was continued for a further period of at least a year without interruption; 9 patients had a second course of CyA therapy after an interval of at least 1 month. Of the 40 children 29 (72%) had one or more relapses during treatment with CyA, with 16 (40%) relapsing during the 1st year. During the second period of CyA, 10 (56%) of the 18 children treated continuously relapsed, whereas all the 9 children who had an interrupted course of therapy relapsed. CyA was discontinued at one time in 27 patients, all of whom subsequently relapsed, with a median time to relapse of 26 days. Long-term prednisolone in addition to CyA was required to maintain remission in 16 (40%) of the whole group. The results suggest that the long-term use of CyA is able to maintain remission of MCNS, although 40% of the patients also required low-dose alternate-day steroids; patients appeared to fare worse if the CyA course was interrupted; no patient experienced a long-term remission after CyA was stopped.     

Contrasting response to cyclosporin in refractory nephrotic syndrome

We studied the effects of cyclosporin A (CsA), given for three months, in 14 patients with nephrotic syndrome refractory to treatment with prednisone and/or other immunosuppressants. CsA was given in a starting dose of 6 mg/kg and plasma through levels (RIA) were kept between 50 and 150 ng/ml. Diagnosis included: idiopathic membranous glomerulonephritis (n = 6), focal segmental glomerulosclerosis (n = 3), minimal change disease (n = 3) and membranoproliferative glomerulonephritis (n = 2). Three patients with non-immunologically mediated nephrotic syndrome due to Alport's syndrome were studied as well. Considering all patients and diagnostic groups together, proteinuria decreased from 9.0 +/- 4.3 to 4.7 +/- 3.8 g/24 h during CsA treatment (mean +/- SD; p less than 0.01). However, serum creatinine increased from 121.8 +/- 60.5 to 150.4 +/- 64.6 mol/l (p less than 0.01) and glomerular filtration rate as estimated by 24-hour creatinine clearance fell from 85.5 +/- 33.7 to 72.1 +/- 37.2 ml/min (p less than 0.05). When compared to other diagnostic groups, fractional excretion of protein, i.e. protein excretion corrected for changes in glomerular filtration rate, fell only in IMGN (ANOVA, p less than 0.05). We conclude that CsA reduced proteinuria in patients with refractory nephrotic syndrome. In the majority of these patients this reduction could be due to a renal hemodynamic, rather than an immunomodulatory effect of the drug. Only in IMGN the latter action of the drug may be of importance.     

Skeletal effects of low-dose cyclosporin A therapy in children with nephrotic syndrome

Background. High doses of cyclosporin A (CsA) produce high-turnover osteopenia in rats. The aim of this study was to determine whether low-dose CsA affects the skeleton in children with nephrotic syndrome. Methods. Biochemical parameters of mineral and skeletal homeostasis, and bone mineral density (BMD) in eight boys with steroid-dependent, frequently relapsing minimal change nephrotic syndrome who had received low-dose CsA (between 1.6 and 3.1 mg/kg per day) for 2 years were compared with measurements in the same patients before CsA therapy and who had received glucocorticoids for long periods, and with measurements in age-matched controls. Results. It was possible to discontinue glucocorticoid therapy within 4 months after the start of CsA therapy. There was a significant increase in the mean serum alka-line phosphatase concentration in CsA therapy patients compared with the same patients before CsA therapy and the controls. Serum osteocalcin and tartrate-resistant acid phosphatase, and urinary deoxypyridinoline concentrations in CsA therapy patients did not differ from those in the controls. BMD in CsA therapy patients was increased significantly compared with values in the same patients before CsA therapy. BMD in CsA therapy patients was lower than that in the controls, but remained within 80% of the overall mean BMD value. Conclusions. Two years of low-dose CsA therapy without glucocorticoids does not appear to induce high-turnover osteopenia in children with steroid-dependent nephrotic syndrome. Received: February 7, 2000 / Accepted: May 10, 2000     

D二聚体与原发性肾病综合征临床及病理的相关分析

目的 对血清D二聚体（D-Dimer,简称D-D）与原发性肾病综合征（primary nephrotic syndrome,PNS）临床及病理资料相关性进行分析,探讨血清D-D在PNS中的临床意义.方法 符合肾病综合征的诊断标准及本研究排除标准的肾病综合征患者为PNS组,健康体检者为对照组,收集一般临床指标和患者的病理资料,进行病例对照研究与临床及病理资料分析.结果 （1）120例PNS患者血清D-D水平较60例正常人的血清D-D水平明显升高,差异有统计学意义（P＜0.05）.（2）临床资料显示120例PNS患者中,血清D-D水平与C-反应蛋白（CRP）、24 h尿蛋白之间存在正相关（r=0.429,P=0.000;r=0.481,P=0.000）,但与白蛋白（Alb）、血尿素氮（BUN）、血肌酐（SCr）、血清三酰甘油（TG）、血清总胆固醇（CHOL）之间无相关性（P＞0.05）.（3）微小病变型肾病、系膜增生性肾小球肾炎、系膜毛细血管性肾小球肾炎、膜性肾病及局灶性节段性肾小球硬化5种病理类型间血清D-D水平相比有统计学意义（P＜0.05）,其中微小病变型肾病和膜性肾病患者的血清D-D水平均较其他3种病理类型患者的血清D-D水平明显升高,有统计学意义（P＜0.05）,而微小病变型肾病和膜性肾病患者间及其余3种病理类型患者间的血清D-D水平相比无统计学意义（P＞0.05）.结论 PNS存在高凝状态,血清D-D水平可间接提示蛋白尿严重程度,并且可能间接预测PNS病理的类型.