Efficacy of mizoribine followed by low-dose prednisone in patients with idiopathic membranous nephropathy and nephrotic-range proteinuria

Abstract

Background: Idiopathic membranous nephropathy (IMN) patients with persistent high-grade proteinuria are at the highest risk for developing end-stage renal failure. We previously reported the effects of treatment with mizoribine followed by low-dose prednisone treatment in 4 IMN patients. The purpose of the present study was to further assess the effects of this combined treatment in a larger study group. Method: Thirteen patients with IMN and nephrotic-range proteinuria received combined treatment. Mizoribine was initiated at a dose of 150?mg/day, and 2–3 months later, 20?mg/day prednisone was added to the mizoribine regimen. The dosage of prednisone and/or mizoribine was tapered according to the urinary protein-to-creatinine ratio (P/C). We evaluated patient responses for up to 12 months after the initiation of combination therapy. Results: Before treatment, patient urinary P/C ranged from 3.7 to 15.9?g/g. Although these values did not decrease during mizoribine monotherapy, all patients showed dramatic P/C decreases over the course of combination therapy. At 3, 6, and 12 months after combination therapy, 15%, 31%, and 62% of patients attained complete remission, respectively, and all patients were in partial or complete remission 6 months after combination therapy. No notable side effects were observed. Conclusion: The addition of prednisone after mizoribine monotherapy can be beneficial for all IMN patients with nephrotic-range proteinuria syndrome. The risks associated with immunotherapy can be decreased by initially prescribing mizoribine alone, which might act as a base for establishing therapy, followed by low-dose prednisone treatment.     

C1q的沉积对V型狼疮性肾炎和原发性膜性肾病的鉴别诊断意义

目的:研究C1q在V型狼疮性肾炎、原发性膜性肾病及病理组织学为不典型膜性肾病肾活检标本中的沉积,分析其不同及意义。方法:对V型狼疮性肾炎、原发性膜性肾病和不典型膜性肾病的患者的肾活检组织进行C1q免疫组化染色,并收集临床和血清学指标,进行统计学分析。结果:V型狼疮性肾炎会出现C1q的沉积,原发性膜性肾病不会出现C1q的沉积,一些病理组织学表现不典型的膜性肾病,会出现C1q的沉积,后者阳性率与狼疮性肾炎接近,与膜性肾病相比,差异有统计学意义。结论:C1q阳性且病理组织学为不典型膜性肾病的患者,极有可能是早期的V型LN。     

方格星虫提取物对膜性肾病模型的治疗作用及机制初探

目的:初步探讨方格星虫粗提物(SNP)对膜性肾病(MN)的治疗作用及其可能机制。方法:50只SD大鼠随机分为模型组和对照组,模型组大鼠腹腔一次注入抗FxlA血清建立被动性Heymann肾炎模型,模型建立1周后依24 h尿蛋白排泄量(24 h UPE)随机将Heymann肾炎大鼠分为SNP治疗组和未治疗组,治疗组用SNP灌胃治疗。考马斯亮蓝法每周测定24 h UPE。治疗4周结束后处死大鼠取双肾,光镜、电镜观察肾脏病理改变,RT-PCR法检测肾组织nephrin mRNA和podocin mRNA的表达量。结果:SNP治疗4周后大鼠24 h UPE较未治疗组降低(P<0.05);模型组大鼠肾小球基底膜增厚,上皮下电子致密物沉积,足细胞足突融合等病理改变,SNP治疗组大鼠上述病变较未治疗组减轻,经测定,足细胞足突融合率较未治疗组显著降低(P<0.01);SNP治疗组nephrin mRNA和podocin mRNA表达量较未治疗组升高(P<0.05)。结论:SNP可通过上调膜性肾病大鼠足细胞nephrin和podocin基因表达水平,一定程度上减轻足细胞足突融合,进而减少尿蛋白滤过,可能对人类膜性肾病具有辅助治疗作用。     

Involvement of prohibitin 1 and prohibitin 2 upregulation in cBSA-induced podocyte cytotoxicity

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, when not effectively treated. The aim of this study was to discover new targets for the diagnosis and treatment of MN. A reliable mouse model of MN was used by the administration of cationic bovine serum albumin (cBSA). Mice with MN exhibited proteinuria, histopathological changes, and accumulation of immune complexes in the glomerular basement membrane. Label-free proteomics analysis was performed to identify changes in protein expression, and the overexpressed proteins were evaluated. There were 273 proteins that showed significantly different expression in mice with MN, as compared to the controls. String analysis showed that functions related to cellular catabolic processes were downregulated in MN. Among the differentially expressed proteins, prohibitin 1 (PHB1) and prohibitin 2 (PHB2) were upregulated in the kidneys of mice with MN, as demonstrated by immunohistochemistry (IHC), and this upregulation was observed in both the tubular cells and glomeruli. Both shRNA-mediated knockdown of PHB1 or PHB2 inhibited tumor suppressor p53 expression and significantly promoted podocyte proliferation. In addition, both PHB1 and PHB2 were responsible for cBSA-induced cytotoxicity. Microarray analysis further revealed that the upregulation of PHB1 and PHB2 may be due to a blockage of proteasome activity. These data demonstrate that the upregulation of PHB2 is involved in cBSA-mediated podocyte cytotoxicity, which may lead to MN development.     

Glomerulopatía por invaginación podocítica; reporte del primer caso en Latinoamérica y revisión de la literatura

BackgroundPodocyte infolding glomerulopathy (PIG) is a condition of uncertain origin, frequently associated with autoimmune diseases. Its specific treatment and clinical course are unknown.It is characterised by thickening of the capillary walls due to the presence of non-argyrophilic intramembranous bubbles similar to those found in membranous glomerulopathy, but without electron-dense deposits of immune complexes in the ultrastructure, where translucent microspheres generated by invagination of the podocyte cytoplasm into the basement membranes are observed.ObjectivesGenerally reported in young females patients. To date, few cases in Asian patients have been reported. Our case is the first to be reported in a Latin American Caucasian patient.MethodsA 38-year-old woman with SLE. In 2014 she presented with nephrotic syndrome empirically treated with corticosteroids (CO) and intravenous cyclophosphamide with good response. She had a relapse in April 2015 with normal renal function and no extrarenal lupus activity, so she was referred to our hospital to be biopsied.ResultsThe biopsy reported focal segmental glomerular sclerosis without deposits of immune complexes in the immunofluorescence. However, methenamine silver staining revealed clear spaces in the capillary walls accompanied by marked podocyte alterations. On electron microscope study, numerous aggregates of microvesicular and cylindrical ultrastructures bound to the membranes were observed, without evidence of dense deposits, and diffuse effacement of pedicel foot processes, confirming the suspected diagnosis.ConclusionsThis is the first reported case of what can be considered a new pathological glomerular entity in a Latin American Caucasian patient, whose clinical course and therapy are still unknown.     

鞍隔孔区解剖学研究及其临床意义

目的 通过鞍隔孔区结构的解剖学研究,分析经蝶入路脑脊液漏的发生机制,以及空蝶鞍(ES)的形成原因. 方法 对8例胎儿标本进行组织学连续切片后,做HE和Masson染色,并在显微镜下对鞍隔孔附近结构进行观察;另取10例成人尸头标本,模拟经蝶入路手术,并在手术显微镜下观察鞍隔孔区解剖结构. 结果 鞍上蛛网膜在垂体柄上端和其表面的软脑膜紧密结合,并转折进入鞍内;同时在垂体上表面处,鞍隔从四周紧密包绕并和表面的软脑膜紧密结合,而难以从组织学切片上分辨二者的界限:鞍上蛛网膜池由于蛛网膜、软脑膜和鞍隔的束缚而终止于鞍隔孔上部. 结论 鞍隔、软脑膜和鞍上蛛网膜三者之间存在着严密的解剖学关系,其也是防止脑脊液漏和ES发生的关键因素.这三者的先天性缺损、生理性或者病理性破坏,尤其是在经蝶入路中对垂体腺瘤的过分牵拉,导致鞍上蛛网膜和软脑膜分离或者破裂,可能是造成术中脑脊液漏发生的重要原因;另外鞍隔、软脑膜和垂体上表面之间的分离也可能是造成ES的关键因素.     

来氟米特联合糖皮质激素治疗类风湿性关节炎相关肾损害43例临床分析

目的研究来氟米特（LEF）治疗风湿性关节炎相关肾损害的疗效和安全性。方法排除药物等继发因素,经临床及肾活检确诊与类风湿性关节炎本身相关的肾损害患者43例,随机分为实验组24例（来氟米特＋糖皮质激素）和对照组19例（糖皮质激素）。观察治疗12周后两组相关生化指标、疗效和不良反应,并进行评价。结果治疗12周后实验组、对照组疗效比较：实验组完全缓解8例（33.33%）,显效4例（16.67%）,有效5例（20.83%）,无效7例（29.17%）,总有效17例（70.83%）;对照组完全缓解2例（10.53%）,显效4例（21.05%）,有效3例（15.79%）,无效10例（52.63%）,总有效9例（47.37%）。实验组与对照组比较,总有效率有显著性差异（P〈0.05）。结论来氟米特联合糖皮质激素治疗类风湿性关节炎相关肾损害近期降尿蛋白疗效显著,肾功能稳定,具有较好的耐受性及安全性。     

86例膜性肾病回顾性分析及对CD4^＋CD^25＋调节性T细胞的初步研究

目的：回顾性总结、分析86例膜性肾病患者的临床表现、实验室检查及肾活检病理的特点及相互联系,认识膜性肾病的发病和流行病学特点。通过对特发性膜性肾病（idiopathic membranous nephropathy,IMN）患者和正常人外周血CD4＋CD2＋5调节性T细胞（Treg细胞）数量的检测,了解Treg在IMN患者外周血的变化规律,探讨其在IMN发病中的作用。方法：2004年3月～2008年12月间病理确诊为膜性肾病患者86例,分析患者一般资料、病理类型和临床特征。选择2007年～2008年IMN患者10例,随机选取与IMN患者年龄相匹配的健康志愿者10例,检测所有对象外周血Treg细胞数量。结果：（1）86例膜性肾病患者,其中IMN68例,占80%,4例患者随访后确诊为恶性肿瘤;继发性膜性肾病18例（其中乙肝病毒相关性肾炎5例,狼疮性肾炎4例,移植肾肾小球肾炎1例）,占20%。（2）IMN免疫荧光以IgG沉积为主,乙肝病毒相关性肾炎C1q沉积较IMN多（P〈0.05）,并均存在HBsAg沉积,与IMN相比狼疮性肾炎C1q沉积明显增多,C4也多于IMN（P〈0.05）。（3）病理分期分布特点：Ⅱ期膜性肾病多见。（4）IMN患者治疗前外周血Treg细胞占CD4＋淋巴细胞的百分比为（7.46±0.94）%,正常对照组为（6.54±1.0）%。结论：（1）根据病因分为IMN及继发性膜性肾病两种,男性发病率大于女性,中老年多发,继发性膜性肾病的年龄及性别分布根据病因的不同而有所不同,临床表现均以肾病综合征表现为主;IMN发病率明显大于继发性膜性肾病。（2）免疫荧光检查：IMN以IgG及C3沉积为主,乙肝病毒相关性肾炎均存在乙肝表面抗原,狼疮性肾炎与乙肝病毒相关性肾炎的C1q沉积较特发性膜性肾病明显增多（P〈0.05）。（3）IMN患者外周血Treg细胞数量较正常人增多。     

两种膜分离器对血浆置换后血细胞数及血生化影响的比较

目的：比较两种不同材料制备的膜型血浆分离器PS-06与Evacure-4A在人工肝血浆置换治疗后对患者血细胞数、肾功能、血电解质及血氨的影响．方法：在内科综合治疗基础上联合人工肝血浆置换治疗患者112例,应用KM-8800型血浆置换装置(Kuraray)和PS-06、Evacure-4A两种膜型血浆分离器,其中应用PS-06膜型血浆分离器(A组)54例,应用Evacure-4A膜型血浆分离器(B组)58例,检测治疗前后的血常规、肾功能、血电解质及血氨．结果：患者术后各项指标的增减百分率比较,其中血小板(PLT)、血红蛋白(Hb)、血氨(NH_3)下降率(治疗后/治疗前)A组与B组间有显著性差异(PLT：92．2%±14．8% vs 99．8%±22．4%,P＜0．05；Hb：88．1%±9．7% vs 94．8%±3．8%,P＜0．01；NH_3：81．2%±22．7% vs 66．6%±13．7%,P＜0．01),其他各项指标增减百分率无统计学意义(P＞0．05)．结论：人工肝血浆置换治疗中Evacure-4A膜型血浆分离器对血小板无明显影响,对血红蛋白影响较小,并能更有效地清除患者体内尿素氮、肌酐及血氨等毒性代谢产物,明显优于PS-06膜型血浆分离器．     

Collagen types in various layers of the human aorta and their changes with the atherosclerotic process

The types of collagen components extracted from human aortas by repeated pepsin digestion were investigated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), after differential salt precipitation, cyanogen bromide (CNBr) cleavage and β-mercaptoethanol reduction. For further extraction of collagen components, repeated pepsin digestion was carried out, and two extracts, the former and latter, were obtained. The greatest increase was seen in type V collagen followed by type III in the former extract. Type I collagen was continually extracted, so the proportion of type I to other types became greater with the number of extractions. SDS-PAGE of the residue treated with CNBr revealed that it contained the greatest amount of type I, followed by the latter extract. Type I collagen comprised approximately two-thirds of the total collagen. It was the most predominant in the intima and adventitia but was also obviously abundant in the media. The proportion of type III collagen to total collagen fell slightly with f advancing atherosclerosis, since the amounts of types I and V showed some increase. A band of the 3(V) chain of type V collagen in the intima was occasionally detected between the bands of the al(V) and 2(V) chains. Basement membrane collagen, type IV, which was extracted predominantly from the intima and subintima, showed a heterogenous distribution as to molecular size, ranging from 50 Kd to 140 Kd. The l(IV) and 2(IV) collagens were found at positions corresponding to 100 Kd and 80 Kd, respectively. The d content of collagen type IV also increased with the proliferative fibrotic process. Type VI collagen was found in the intima and subintima of the human aorta at a position corresponding to an approximate molecular weight of 150 Kd, and it was reduced to fragments of 40 Kd, 45 Kd and 52 Kd.