系膜区IgG沉积为主的原发性系膜增生性肾小球肾炎的临床病理特征

肾小球系膜区免疫球蛋白沉积是原发性系膜增生性肾小球肾炎(MsPGN)常见的病理形态学特征,而最常见的是系膜区IgA为主的免疫复合物沉积引起的IgA肾病(IgAN).近年来提出了一种以系膜区IgM为主的免疫复合物沉积引起的IgM肾病.IgG作为一种最常见的血清免疫球蛋白,其常在多种肾小球肾炎中沉积,例如膜性肾病、系膜毛细血管性肾小球肾炎和急性感染性肾小球肾炎等.     

甘肃河西地区原发性IgA肾病的临床与病理分析

IgA肾病是一组以肾小球系膜区IgA沉积、同时伴系膜细胞增生和系膜基质增多为主要病理改变的原发性肾小球肾炎,我国IgA肾病占原发肾小球疾病的400～47％,且近10年有明显上升的趋势。甘肃河西走廊是一个多民族的西部落后地区,有关IgA肾病病理方面的研究资料严重缺乏。本文收集该地区111例原发性IgA肾病患者的临床病理资料,对其临床与病理相关性进行分析。     

杨霓芝教授治疗系膜增生性肾小球肾炎的临证经验

系膜增生性肾小球肾炎（mesangial proliferative glomerulonephritis,MsPGN）是一种以弥漫性肾小球系膜细胞增生及不同程度系膜基质增多为主要病理特征的原发性肾小球疾病。据其免疫病理可将其分为IgA肾病（以IgA沉积为主）及非IgA肾病两大类。     

我国IgA肾病临床与病理联系研究近况

IgA肾病是指一组以肾小球系膜区IgA沉积、同时伴系膜细胞增生和系膜基质增多为主要病理改变的原发性肾小球肾炎[1],是目前导致终末期肾病（ESRD）的主要病因之一[2]。我国IgA肾病占原发肾小球疾病的40%～47.2%,且近10年有明显上升的趋势[3]。肾脏免疫病理是诊断IgA肾病的金标准,     

陶筱娟治疗IgA肾病的经验

IgA肾病是以肾小球系膜区IgA免疫复合物沉积为特征的一类肾小球肾炎 ,是我国常见的肾小球疾病之一 ,约占原发性肾小球疾病的 1/ 3,是终末期肾衰竭的最主要原因之一[1] ,以反复发作的肾小球性血尿为主要临床表现 ,属中医“血证”、“尿血”范畴。本病的肾脏组织病理特点以系膜细胞和基质增生为主 ,国际上主要是应用细胞分子生物学新技术 ,对肾小球系膜增生相关的多种细胞因子水平等方面进行研究 ,而治疗性研究进展缓慢 ,迄今为止尚无特效治疗药物。浙江中医学院附属杭州市红十字会医院教授、杭州市名老中医陶筱娟教授在多年的临床实践中立…     

IgA肾病的病因与发病机制

IgA肾病(IgA Nephropathy，IgAN)是一组以IgA或IgA为主的免疫复合物在肾小球系膜区沉积为特征，临床和肾组织病理表现多样，且不伴系统性损害的原发性肾小球疾病。     

IgA肾病发病的免疫化学基础——IgA的免疫生物学

系膜IgA肾病(IgAN)是临床上最常见的原发性肾小球疾病之一,阐明其发病机理是近20年来重点研究的课题。IgAN的主要病理特征为肾小球系膜区IgA的沉积,IgAN患者的肾活检标本中免疫复合物(IC)洗脱物用蔗糖密度梯度离心和与分泌片结合能力测定等方法证实,沉积在肾小球的IgA为多聚IgA(PIgA)。体内或体外实验均证实单体IgA(mIgA)不会沉积在肾小球引起肾炎,动物实验也证实     

邓跃毅教授治疗IgA肾病临床经验

<正>IgA肾病(IgA Nephropathy)是一种常见的原发性肾小球疾病,其特征是肾活检免疫病理显示在肾小球系膜区以IgA为主的免疫复合物沉积,以肾小球系膜增生为基本组织学改变。其临床表现多种多样,主要表现为血尿,可伴有不同程度的蛋白尿、高血压和肾功能受损,是导致终末期肾脏病的常见的原发性肾小球疾病之一。IgA肾病在全世界分布广泛,在亚洲和太平洋地区是最常见的原发性肾小球疾病,占肾活检     

IgA肾病气阴两虚证微观辨证研究

目的：探讨IgA肾病患者气阴两虚证与肾组织病理指标之间的相关性，为IgA肾病气阴两虚证的微观辨证提供依据，并对其他证型的深入研究提供借鉴。方法：对161例确诊为IgA肾病患者进行分组，其中气阴两虚证86例，非气阴两虚证75例，观察两组肾组织病理指标的变化。结果：86例气阴两虚证患者的病理分级多见Lee分型Ⅱ～Ⅳ级；气阴两虚证组肾小球系膜区免疫复合物沉积数目及程度均弱于非气阴两虚证组（P〈0.05）；气阴两虚证组患者的肾小球指数、系膜细胞增生、系膜基质增生、肾小管萎缩积分显著高于非气阴两虚证组（P〈0．05）；间质浸润、间质纤维化积分显著低于非气阴两虚讧组（P〈0．05）。结论：肾组织的病理分级、肾小球系膜区免疫复合物沉积数目及程度、肾小球指数、系膜细胞增生、系膜基质增生、肾小管萎缩、间质浸润、间质纤维化积分可作为IgA肾病气阴两虚证的微观辨证参考依据。     

IgA1 O-糖基化异常在IgA肾病发病进展中的作用及中医药干预

IgA肾病（IgA nephropathy,IgAN）是一组以IgA或IgA为主的免疫复合物在肾小球系膜区沉积为特征、临床和病理表现多样化,且不伴有系统性损害的最常见原发性肾小球疾病。IgA肾病约占我国原发性肾小球疾病的30％-40％,是亚洲乃至世界范围内最常见的肾脏疾病。     

IgA肾病患者IgA1糖基化异常及其致病机制

IgA肾病(IgAN)是导致终末期肾病最常见的原发性肾小球疾病。其病理特点为IgA1在肾小球系膜区沉积,IgA1分子的异常糖基化是导致IgAN发病的关键因素。多种与IgAN相关的基因位点已经被发现。这些基因编码的细胞因子参与了IgA1糖基化异常的发病机制。此外糖基化酶缺乏、分子伴侣甲基化异常都可能导致IgA1异常糖基化。异常糖基化的IgA1可通过自我聚集或形成免疫复合物沉积于系膜区,进而刺激系膜细胞增殖、分泌系膜基质、细胞因子、趋化因子、生长因子等,导致肾小球损伤。对IgA1异常糖基化的深入研究有助于了解IgA肾病的发病机制并提供新的诊断与治疗措施。     

Future directions in the treatment of IgA nephropathy

Summary: In IgA nephropathy (IgAN), there is a defect of clearance of immune complexes. Some of these patients are genetically predisposed to the development of the nephritis. Poorly solubilized polymeric IgA immune complexes are then deposited in the mesangium. Recent data indirectly suggest IgA-immune complexes from patients with IgAN are different from those of healthy subjects and they can exert pathophysiologic effect on target cells. Mesangial reactivity to the immune complexes triggers off release of cytokines, with decreased prostaglandin E2 synthesis and increase in thromboxane A2 production promoting mesangial cell proliferation. Angiotensin II (ATII)-induced mesangial cell contraction with efferent arteriolar vasodilatation initiates glomerular injury and may eventually lead to glomerulosclerosis due to increased synthesis of transforming growth factor-β (TGF-β) and platelet-derived growth factor PDGF). This paper highlights the possible therapeutic strategies in the future based on the recently reported pathogenetic findings in IgAN. These strategies include: (i) decreasing the synthesis of IgA-immune complexes; (ii) limiting the mesangial uptake of IgA-immune complexes; (iii) antagonizing the effect of PDGF and TGF-β to reduce mesangial proliferation and glomerulosclerosis; and (iv) reducing the noxious glomerular injury due to infiltrating neutrophils. The effective treatment of IgAN requires a further clarification of the pathogenesis of the nephropathy. Future therapeutic attempts to slow down the rate of renal deterioration in IgAN rest on the better understanding of the mechanisms mediating inflammatory injury in the kidney.     

Pathogenetic significance of aberrant glycosylation of IgA1 in IgA nephropathy

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium. Among abnormalities of the IgA immune system reported so far in IgAN, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, in tonsillar lymphocytes, and in eluate from mesangial deposits, and characterized by decreased O-linked N-acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars. IgA1 with incomplete galactosylation has a tendency to accumulate in glomerular mesangium by self-aggregation or immune complex formation. Glomerular mesangial cells exposed to immune complexes of these IgA1 can proliferate and secrete cytokines, chemokines, growth factors, and extracellular matrix components promoting inflammatory reactions in the glomeruli. Although genes encoding enzymes involved in the O-glycosylation process, such as C1GALT1, have been reported to be responsible for susceptibility to IgAN, recent evidence suggests that the abnormality is restricted to a small fraction of B cell populations and arises from dysregulated IgA1 production and secretion in mucosal immune system. This review will focus on and discuss the role of incompleteness of IgA1 O-galactosylation in the pathogenesis of IgAN and propose a possible mechanism in which abnormal IgA1 occurs in IgAN. Presented at the 37th Eastern Regional Meeting of the Japanese Society of Nephrology.     

Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy

Although there are many papers about IgA nephropathy (IgAN) and tonsils, respectively, reviews about the relationship between tonsils, tonsillitis, tonsillectomy, and IgAN are limited. In this review, we introduced the structure, development, and function of tonsils, difference of tonsils with and without IgAN, consistency of both tonsillar IgA and glomerular IgA, the effect of tonsil stimulation, tonsil infection, and tonsillectomy on IgAN showed some evidences in which tonsils were closely related to IgAN and polymeric IgA1 deposited in glomerular mesangium were at least in part of tonsillar origin. Tonsillectomy can improve the urinary findings, keep stable renal function, improve mesangial proliferation and IgA deposit, have a favorable effect on long-tern renal survival in some IgAN patients, and do not cause significant immune deficiency and do not increase incidence of the upper respiratory tract infections, and can be used as a potentially effective treatment. The indications of tonsillectomy in patients with IgAN include mainly the deterioration of urinary findings after tonsillar infection, mild or moderate renal damage. However, tonsillectomy may not be enough and may not change the prognosis in IgAN patients with marked renal damage.     

Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis in the world, is characterized by IgA immune complex-mediated mesangial cell proliferation. The transferrin receptor (TfR) was identified previously as an IgA1 receptor, and it was found that, in biopsies of patients with IgAN, TfR is overexpressed and co-localizes with IgA1 mesangial deposits. Here, it is shown that purified polymeric IgA1 (pIgA1) is a major inducer of TfR expression (three- to four-fold increase) in quiescent human mesangial cells (HMC). IgA-induced but not cytokine-induced HMC proliferation is dependent on TfR engagement as it is inhibited by both TfR1 and TfR2 ectodomains as well as by the anti-TfR mAb A24. It is dependent on the continued presence of IgA1 rather than on soluble factors released during IgA1-mediated activation. In addition, pIgA1-induced IL-6 and TGF-beta production from HMC was specifically inhibited by mAb A24, confirming that pIgA1 triggers a TfR-dependent HMC activation. Finally, upregulation of TfR expression induced by sera from patients with IgAN but not from healthy individuals was dependent on IgA. It is proposed that deposited pIgA1 or IgA1 immune complexes could initiate a process of auto-amplification involving hyperexpression of TfR, allowing increased IgA1 mesangial deposition. Altogether, these data unveil a functional cooperation between pIgA1 and TfR for IgA1 deposition and HMC proliferation and activation, features that are commonly implicated in the chronicity of mesangial injuries observed in IgAN and that could explain the recurrence of IgA1 deposits in the mesangium after renal transplantation.     

Mechanisms of tubulointerstitial injury in IgA nephropathy

BACKGROUND: IgA nephropathy (IgAN) runs a highly variable clinical course, with frequent involvement of tubulointerstitial damage. A subgroup of IgAN with severe tubulointerstitial damage is often associated with the most rapid progression to end-stage renal failure. In IgAN, mesangial sclerosis and tubulointerstitial damage were found to be correlated with the increase in pore size of the glomerular barrier. METHODS: The direct toxicity of proximal tubular epithelial cells (PTEC) by IgA in IgAN is still unresolved. Activation of PTEC by mediators released from infiltrating cells or resident kidney cells that induce tubular inflammation is the common final pathway in most chronic renal diseases. We hypothesize that mediators released from human mesangial cells (HMC) triggered by IgA deposition may lead to PTEC activation. RESULTS: We found that IgA binding to PTEC was less than one tenth that of HMC. The binding was nonspecific and exhibited no increased cell proliferation or enhanced synthesis of cytokines or adhesion molecules. However, when PTEC were cultured with IgA-HMC spent medium prepared from IgAN patients, there was enhanced proliferation of PTEC and increased synthesis of cytokines and adhesion molecules. CONCLUSION: These findings implicate a glomerulotubular cross-talk with mediators released from the mesangium, contributing to the pathogenesis of tubulointerstitial damage in IgAN. There are preliminary data to suggest that the expression of angiotensin II subtype-1 receptor and angiotensin II subtype-2 receptor in PTEC differs from that of HMC. These novel findings may provide clinicians new therapeutic approach for selective blockade of the tubulointerstitial injury in IgAN.     

Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), characterized by predominant or exclusive deposition of IgA1 in glomerular mesangium, is the most common primary glomerulonephritis worldwide. At present, the treatment is always limited due to the incomplete understanding of the pathogenesis of IgAN. Mesangial deposited IgA1 is the common final pathway leading to glomerulonephritis and renal injury. IgA1 protease, a proteolytic enzyme with strict substrate specificity for human IgA1, may be an effective therapeutic candidate for IgAN by removing the mesangial deposited IgA1.     

Tonsillectomy and IgA nephritis

IgA nephritis (IgAN) is an autoimmune disease characterized by deposits of IgA in the glomerular mesangium. Clinically, the disease may be punctuated by episodes of macroscopic haematuria often associated with pharingotonsillitis or may be oligosyntomatic with microscopic haematuria and mild proteinuria. The natural course of IgAN may be indolent and benign; however, some 30-50% of patients may progress to end-stage renal disease when follow-up is extended to ≥20 years. In patients with IgAN, circulating IgA1 molecules have an aberrant structure of O-glycans in the hinge region, which is characterized by abbreviated glycans composed of N-acetylgalactosamine, with or without sialic acid. These aberrant IgA1 trigger the production of autoantibodies, with formation of immune complexes that deposit in the mesangium causing inflammation and production of extracellular matrix. A number of experimental and clinical data outlined a possible pathogenetic role of tonsillitis. As a consequence, tonsillectomy has been frequently performed in Japan. Observational studies, made in patients with normal renal function and mild proteinuria, reported that tonsillectomy could reduce the episodes of macrohaematuria as well as the entity of microhaematuria and proteinuria. However, the available studies had short-term follow-up and could not asses the role of tonsillectomy in protecting from renal function deterioration. In a longitudinal retrospective study, Isseki et al. compared the outcome of tonsillectomized patients with IgAN with that of IgAN patients who did not receive tonsillectomy. Tonsillectomized patients had a higher number of remissions and a better slope of glomerular filtration rate in comparison with controls. These data are interesting and suggest that tonsillectomy may prevent renal dysfunction in patients with IgAN and normal renal function. However, the retrospective nature of the study and the presence of some confounding factors require further investigations to confirm these promising data.     

CagA promotes proliferation and secretion of extracellular matrix by inhibiting signaling pathway of apoptosis in rat glomerular mesangial cells

Cytotoxin-associated antigen A (CagA), a major virulence factor of Helicobacter pylori (Hp), is associated with the pathogenesis of peptic ulcer and gastric cancer. Recent researches demonstrated that Hp exists in palatine tonsil in all studied IgA nephropathy (IgAN) patients, most of which were CagA-positive, suggesting that CagA may be a causative pathogenic factor of IgAN. However, the underlying molecular mechanisms and signaling pathway are still largely unclear. In the present study, CCK8 assay, enzyme-linked immunosorbent assay, and immunohistochemistry were performed to investigate the effect of CagA on cell proliferation and extracellular matrix secretion in rat glomerular mesangial cells. RT-PCR and western blotting were used to reveal the potential signaling pathway. Rat glomerular mesangial cells were treated with recombinant CagA protein for 72 h, in a dose- and time-dependent manner. We found that CagA promoted cell proliferation and extracellular matrix secretion by inhibiting signaling pathway of apoptosis. Taken together, these findings suggested that CagA induced cellular injury in glomerular mesangium by proliferation and secretion of extracellular matrix, and may play an important role in pathogenesis of IgAN.     

Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.

BACKGROUND: In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN. METHODS: Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP-IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-beta 1 by cultured mesangial cells was also examined. RESULTS: IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-beta 1 production in a time- and dose-dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating cells with neutralizing antibody against MIF. CONCLUSIONS: Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1 expression in an experimental model of IgAN.