阿霉素诱发局灶节段性肾小球硬化肾病大鼠模型的建立

目的 建立临床表现和病理特点与人类肾小球疾病相似的阿霉素肾病大鼠模型.方法 将40只SD大鼠完全随机分为造模组(32只)和对照组(8只),造模组完全随机分为首次注射阿霉素后2周组、4周组、8周组、12周组,每组各8只.造模组大鼠尾静脉分2次注射阿霉素,第1次注射按6 mg/kg给药,第2次子1周(7 d)后按4 mg/kg给药;对照组按照造模组方法经大鼠尾静脉2次注射等量生理盐水.检测各组大鼠24h尿蛋白量、血清总蛋白、白蛋白、CH、TG、BUN、Cr的变;双抗体夹心酶联免疫吸附方法检测各组大鼠血清基质金属蛋白酶( MMP)2、MMP-9、转化生长因子(TGF) -β1;免疫组化方法检测各组大鼠纤维连接蛋白(FN)和层粘连蛋白(LN)的表达化;光镜、电镜观察2组大鼠肾脏病理变化.结果 造模组24h尿蛋白定量明显增加,8周末达高峰.造模组大鼠2周、4周、8周和12周组与对照组相比,血清总蛋白、白蛋白明显降低[(50.7±3.6)、(42.2±3.4)、(40.4±3.1)、(41.7±3.3)g/L比(62.8±2.8) g/L、(22.2±1.8)、(16.4±1.7)、(14.8±2.1)、(13.0±2.2)g/L比(29.0±1.3)g/L];TG、CH明显升高[(5.2±1.4)、(6.1±1.5)、(7.3±1.5)、(7.2±1.2)mmol/L比(0.6±0.3)mmol/L,(3.8±1.7)、(5.6±1.9)、(8.6±2.7)、(9.6±1.6) mmol/L比(1.3±0.1)mmol/L];MMP-2、MMP-9降低[(151.4±2.4)、(100.5±3.1)、(76.5±3.6)、(83.7±3.1)μg/L;(73.4±2.7)、(58.9±2.2)、(35.4±2.0)、(33.3±1.5) μg/L],血清TGF-β1含量升高;肾组织FN、LN的表达和分布范围均明显增加.造模12周在可见部分肾小球出现局灶节段性硬化.结论 采用阿霉素首次大剂量(6mg/kg)冲击诱导,1周后小剂量(4mg/kg)给药的方法,大鼠在12周末可见部分肾小球出现局灶节段性硬化.     

局灶性节段性肾小球硬化的中西医结合治疗

<正>局灶性节段性肾小球硬化(FSGS)是指病理学上所累及部分的肾小球中部分毛细血管袢小叶的非炎症性硬化性病变。兹将其中西医结合治疗简介如下。     

参麦注射液延缓局灶节段性肾小球硬化进展的实验研究

目的：观察参麦注射液延缓局灶节段性肾小球硬化（FSGS）进展的可能性。方法：18只Wistar大鼠均分为正常对照组（A组）、参麦治疗组（B组）和模型组（C组）。采用小剂量分次用阿霉素－间羟胺－高脂饲料法建立大鼠FSGS模型。B组予参麦注射液治疗。测定尿蛋白、血生化指标、肾脏组织血流量、光镜及电镜检查。结果：治疗组2周后胆固醇升高的幅度低于模型组，肾组织血流量明显增加，肾小球硬化指数及肾小球细胞外基质／肾小球面积均明显降低，毛细血管腔通畅，基底膜改变及足突融合均较模型组明显减轻。结论：参麦可以组织学上延缓FSGS的进展。     

原发性局灶节段性肾小球硬化预后相关因素的研究进展

近年来局灶节段性肾小球硬化（FSGS）发病率增加,且治疗困难,预后较差,是导致终末期肾疾病的主要原因之一。肾脏病学家试图探索某些指标来拟诊和预测预后,该文简述了原发性FSGS预后相关因素如蛋白尿程度、血肌酐水平、肾小管间质病变、病理类型、治疗方法、治疗反应、基因、足细胞及足细胞蛋白等的研究进展。     

参麦、苯那普利综合治疗局灶节段性肾小球硬化的实验研究

目的：观察参麦注射液及苯那普利对大鼠局灶节段性肾小球硬化（FSGS）的治疗作用。方法：30只Wistar大鼠均分5组：（1）正常对照组（A组）；（2）参麦治疗组（B组）；（3）苯那普利治疗组（C组）；（4）综合治疗组（D组）；（5）模型组（E组）。采用小剂量分次阿霉素-间羟胺-高脂饲料法建立大鼠FSGS模型。B组、C组及D组于实验第29d分别予参麦注射液或苯那普利或参麦注射液 苯那普利治疗。测定24h尿蛋白、血生化指标、肾脏组织血流量、光镜及电镜检查。结果：（1）治疗后2周时各治疗组尿蛋白排泄量开始降低。实验12周时各治疗组胆固醇升高的幅度均低于模型组。（2）肾组织血流量测定：综合治疗组肾组织血流量明显增加。（3）光镜检查：肾小球硬化指数（SI）：综合治疗组明显降低。肾小球细胞外基质（ECM）/肾小球面积（GA）：各治疗组均明显减低。（4）电镜检查：综合治疗组毛细胞血管通畅，未见足突融合及炎症细胞浸润。结论：参麦、苯那普利综合治疗可起到多靶位协同治疗FSGS的良好疗效。     

来氟米特联合泼尼松治疗儿童局灶节段性肾小球硬化的疗效观察

目的:观察来氟米特联合泼尼松对儿童局灶节段性肾小球硬化的治疗效果。方法:36例儿童局灶节段性肾小球硬化患儿,其中激素依赖型19例和激素抵抗型17例,分别给予来氟米特1 mg/kg,每天1次口服治疗,连续3 d后改为0.2～0.4 mg/kg,每天1次继续口服,泼尼松采用中长程疗法,2 mg/(kg.d)治疗8周后逐渐减量至适当剂量维持或停用。结果:儿童局灶节段性肾小球硬化肾病综合征生化指标显示激素抵抗型治疗12个月后血白蛋白上升(P>0.05)和24 h尿蛋白下降(P<0.05),激素依赖型治疗12个月后血白蛋白和24 h尿蛋白明显改善(P均<0.01)。36例患儿治疗后部分缓解5例,完全缓解10例,总缓解率41.67%,依赖型缓解率(57.90%)高于抵抗型(23.53%)(χ2=4.36,P<0.05)。结论:来氟米特联合泼尼松对于儿童局灶节段性肾小球硬化具有一定疗效。     

贝那普利治疗局灶节段性肾小球硬化症的疗效

目的:观察单用贝那普利及贝那普利联用激素对局灶节段性肾小球硬化症的疗效。方法:109例尿蛋白>1．0 g·d~(-1),血肌酐<133μmol·L~(-1)的局灶节段性肾小球硬化症患者随机分成单用组和联用组,单用组应用贝那普利10-30 mg·d~(-1)治疗,联用组应用贝那普利10～30 mg·d~(-1) 泼尼松1 mg·kg~(-1)·d~(-1)治疗,观察24 h尿蛋白定量,血白蛋白、胆固醇、肌酐的变化。结果:两组均能明显减少蛋白尿,治疗1月后尿蛋白即有显著下降(P<0．01)。两组尿蛋白减少差值及血肌酐比较差异无统计学意义(P>0．05)。结论:ACEI联用激素并不比单用ACEI治疗有更好的疗效,而单用ACEI可能为有效的治疗手段,又可避免激素的副作用。     

局灶性节段性肾小球硬化症的治疗

局灶性节段性肾小球硬化（Focal Segmental Glomerulosclerosis，FSGS）是一病理形态学诊断名词，FSGS表现为肾小球硬化性病变仅累及部分（局灶）肾小球，或受累的肾小球只有部分袢（节段）发生病变。FSGS患者临床主要表现蛋白尿，常为肾综水平蛋白尿。尽管人们认识到FSGS这一病理类型已有半个世纪，但在其认识和诊断上仍存在一些误区。     

20例儿童局灶节段硬化性肾小球肾炎临床病理分析

探讨儿童局灶节段硬化性肾小球肾炎临床及病理特点。方法对２０例儿童ＦＳＧＳ患者的临床表现,病理改变以及对激素治疗的反应进行观察,并进一步分析三者间关系。结果儿童ＦＳＧＳ的发生率为５％。临床表现以浮肿及蛋白尿为主,肾病综合征占７０％高血压及肾功能不全分别占１０％、５％。     

Emerging therapeutic strategies for minimal change disease and focal and segmental glomerulosclerosis

ABSTRACT

Introduction: Minimal change disease (MCD) and Focal and segmental glomerulosclerosis (FSGS) are two of the major causes of nephrotic syndrome (NS) in children and adults. According to KDIGO (Kidney Disease: Improving Global Outcomes) guidelines, the treatment of adult primary MCD and FSGS should be based on immunosuppressants and antiproteinuric drugs. Recently, Rituximab, a humanized monoclonal antibody (mAb) has emerged as a potential treatment for steroid or calcineurin inhibitor-dependent patients; it has however demonstrated lower efficacy in those with nephrotic syndrome that is resistant to the above indicated drugs.

Area covered: Analysis of ongoing and already completed clinical trials, retrieved from clinicaltrials.gov, clinicaltrialsregister.eu and PubMed involving new therapies for nephrotic syndrome secondary to MCD and FSGS.

Expert opinion: The most promising drugs under investigation for MCD and FSGS are mAbs. We are hopeful that new therapeutic options to treat multi-drug resistant MCD and FSGS will emerge from currently ongoing studies. What appears certain is the difficulty in enrolling patients affected by orphan renal diseases and the selection of valid endpoints in clinical trials, such as kidney failure.     

Treatment of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease, but a lesion affecting the podocyte. Secondary FSGS may be due to a host of various factors, and patients are rarely nephrotic, requiring symptomatic treatment only. The best prognostic feature of nephrotic FSGS is its response to corticosteroids. Some forms are most likely of immunological origin, relapse in a renal transplant and justify immunosuppressive treatment. In a growing number of cases, genetic profiling of molecules that contribute to the podocyte slit diaphragm permselectivity to albumin has identified defects that do not represent indications for immunosuppression. In the other forms, corticosteroids and cyclosporin A (CsA) remain the mainstay of treatment, with better efficacy when CsA is associated with steroids. The renal tolerability of CsA is reasonably good when the dosage is low. CsA dependency is not constant. Alkylating agents are reluctantly indicated in steroid-sensitive forms, which are rare. They are mostly ineffective in steroid-resistant forms. Tacrolimus seems a promising therapy with low toxicity, but it is usual for dependency on the drug to occur. Sirolimus seems to be ineffective. Azathioprine is not considered indicated, despite rare reports with favourable results, which would deserve further controlled trials. Recent publications indicate that mycophenolate mofetil might usefully find a place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the elusive substance that causes the nephrotic syndrome and its relapse on a transplant has not led to practical treatment options.     

An update on the treatment options for focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is not a disease but a lesion initially affecting the podocyte. Various factors may induce ‘secondary’ FSGS, including defects in molecules that contribute to the podocyte slit diaphragm permselectivity to albumin. They do not represent indications for immunosuppression and require symptomatic treatment only, comprising angiotensin 2 and endothelin antagonists. Primary (idiopathic) FSGS is possibly but not certainly of immunologic origin, owing to an elusive glomerular permeability factor (GPF), explaining relapse on a renal transplant and justifying an immunosuppressive treatment. The best prognostic feature of primary nephrotic FSGS is its response to corticosteroids. Alkylating agents are mostly ineffective in steroid-resistant forms. An association of corticosteroids and cyclosporine A (CsA) remains the mainstay of treatment, with a good tolerability when CsA dosage is low. A definite advantage of tacrolimus on CsA has not yet been established. Sirolimus appears ineffective and potentially harmful. Azathioprine is not indicated. A number of mostly uncontrolled trials indicate that mycophenolate mofetil might find an adjunctive place in the treatment. Plasmapheresis is of no avail outside the special case of relapse in a transplanted kidney. Immunoabsorption of the GPF has not led to practical treatment options. Anecdotal reports on rituximab are as yet too few to determine whether this monoclonal anti-CD20 antibody will find a place in the treatment of primary FSGS.     

罗格列酮对阿霉素致肾小球硬化症大鼠的尿蛋白排泌量及肾小球蛋白(synaptopodin)表达的影响

目的 观察罗格列酮(胰岛素增敏药)对阿霉素致肾病大鼠的尿蛋白排泌量及肾小球蛋白表达的影响.方法 用罗格列酮治疗阿霉素诱导的局灶节段性肾小球硬化(FSGS)大鼠模型;用双缩脲法动态检测大鼠24 h尿蛋白量;分别用荧光实时定量PCR和免疫组织化学法检测大鼠肾组织synaptopodin mRNA和蛋白表达量.结果 罗格列酮能显著减缓FSGS大鼠尿蛋白排泄量的增加(P＜0.05);恢复大鼠肾组织蛋白表达量(P＜0.05),而不影响其mRNA表达量(P＞0.05);FSGS大鼠肾组织蛋白表达量与尿蛋白排泄量呈负相关(P＜0.01).结论 罗格列酮能减轻FSGS模型尿蛋白排泌量,其机制可能部分与维持足细胞足突肌动蛋白微丝骨架系统的稳定有关.     

Investigational drugs in development for focal segmental glomerulosclerosis

Introduction: Focal segmental glomerulosclerosis is an important cause of end stage kidney disease and is a paradigm for the study of glomerular scarring. There are no FDA approved treatments for this condition. Current therapies, assessed based on reduction in proteinuria, are generally effective in a subset of patients which suggests that FSGS is a heterogeneous group of glomerular disorders or podocytopathies that converge on a common histopathological phenotype.

Areas covered: We searched for investigational drugs agents that target different pathophysiological pathways using the key words ‘FSGS’ and ‘podocyte’ in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Medline, the Web of Science and the Cochrane Central Register of Controlled Trials Library.

Expert opinion: Progress is being made in defining the mechanism of action of subtypes of FSGS. Current and investigational therapies for FSGS target these different pathways of injury. It is anticipated that advances in systems biology will further refine the classification of FSGS by subdividing the disease based on the primary mechanism of glomerular injury, identify biomarkers to discriminate between different subtypes, and enable appropriate selection of appropriate therapy for each individual in accordance with the goals of precision medicine.     

复方积雪草对局灶硬化性肾小球肾炎模型小鼠肾组织内细胞因子表达的调控作用

目的了解局灶硬化性肾小球肾炎(FGS)模型小鼠的细胞因子表达谱,以及复方积雪草对其细胞因子网络的表达调控作用.方法通过BALB/c小鼠尾静脉一次性注射阿霉素(11 mg*kg-1),诱导成FGS肾炎模型,以复方积雪草制剂灌胃治疗 4 wk,分别取1、4 wk 肾组织,提取其总RNA,通过反转录掺入荧光素CY3-dUTP/CY5-dUTP,转录产物与细胞因子基因芯片杂交,芯片扫描并进行图像分析.结果基因表达谱芯片检测表明复方积雪草可抑制PDGF-α、PDGF-β、PDGF受体、VEGF mRNA的表达;能抑制IL-9、IL-7R2、MIP等因子的mRNA的表达;经复方积雪草刺激后,肾组织中癌基因c-Myc,Jun表达被抑制.结论复方积雪草具有抗肾纤维化作用,其作用效应可能是多种细胞因子共同调控的结果.     

小鼠局灶性脑缺血再灌注模型的建立与评价

目的 建立小鼠局灶性脑缺血再灌注（I/R）模型并予以评价.方法 将昆明小鼠60只随机分为假手术组30只,I/R模型组30只.改良线栓法制备小鼠大脑中动脉阻塞/再灌注（MCAO/R）模型.通过神经行为学评分、氯化三苯基四氮唑（TTC）染色法测定脑梗死比（％）、干湿重法测定脑含水量（％）及HE染色观察脑组织病理改变评价模型可靠性.结果 模型存活率为83.33％,造模总成功率为76.67％.假手术组的小鼠神经行为学评分为0分,脑梗死比为0,脑含水量（77.29±0.45）％.I/R模型组的小鼠神经行为学评分为（2.42±0.63）分,脑梗死比为（23.03±3.42）％,脑含水量（83.18±1.65）％,均较假手术组明显增高（P＜0.01）;病理检查出现典型脑梗死病理改变.结论 改良线栓法成功建立简便、可靠的小鼠局灶性I/R模型.     

吡格列酮对阿霉素致肾小球硬化大鼠肾脏氧化应激的影响

目的 观察吡格列酮(胰岛素增敏剂)对阿霉素致肾小球硬化大鼠肾脏氧化应激的影响.方法 经单侧肾切除加上重复注射阿霉素诱导,建立肾小球硬化大鼠模型,Wistar大鼠32只随机分为假手术对照组,阿霉素致肾小球硬化模型组和吡格列酮治疗组,治疗组大鼠,于第1次尾静脉注射阿霉素后给予吡格列酮10 mg·kg-1·d-1灌胃治疗,共12周.治疗12周末,测定各组大鼠24 h尿蛋白排泄量、尿肌酐、血清肌酐及尿素氮;进行肾脏病理学检查,计算肾小球硬化指数(GSI);检测肾组织和尿中丙二醛(MDA)的含量及肾组织超氧化物歧化酶(SOD)与谷胱甘肽过氧化物酶(GSH-Px)的活性.结果 吡格列酮治疗组,24h尿蛋白排泄量、血清肌酐及尿素氮等与模型组比较均有不同程度的改善(P＜0.05),肾小球硬化程度也明显减轻(P＜0.05),治疗组肾组织和尿中的MDA含量明显低于模型组,SOD与GSH-Px活性明显高于模型组(P＜0.05).结论 吡格列酮能抑制阿霉素致肾小球硬化大鼠肾脏氧化应激反应,对该模型大鼠具有肾脏保护作用.