Experimental IgA nephropathy

An animal model for IgA immune complex nephritis was developed. IgA immune complexes formed in vitro with an IgA anti-dinitrophenyl (DNP) derived from MOPC-315 plasmacytoma, and dinitrophenylated bovine serum albumin (DNP-BSA) produced mild focal glomerulonephritis in mice. Similar, but more severe pathological changes were produced with complexes formed in vivo either in normal mice or MOPC-315 tumor-bearing mice. In contrast to the focal nature of the PAS-positive glomerular lesions observed by light microscopy, immunofluorescent examination revealed IgA deposits in all glomeruli. This discrepancy between immunofluorescent and histopathologic findings as well as the distribution of the immune complexes within the affected glomeruli, are some of the features which bear resemblance between this experimental model and human IgA nephropathy. Fixation of complements by DNP-BSA-IgA immune complexes, formed in vitro or in vivo, was shown to occur in the glomeruli of mice with IgA immune complex nephropathy. The pattern of C3 glomerular deposits was similar to that of IgA. However, complement proved to be nonessential for complex deposition. This conclusion is based on the observation that decomplemented mice, although showing no deposition of C3 in their glomerulus, developed glomerular immunohistological changes similar to those observed in experimental mice that were not decomplemented. Polymeric IgA was observed to be critical for renal deposition of complexes and induction of nephritic histological changes. In contrast, monomeric IgA immune complexes failed to produce glomerular deposits. This finding raises the possibility that secretory IgA, which is predominantly polymeric, may play a role in human IgA-associated glomerulonephritis.     

发病前急性感染对成人IgA肾病患者血清及肾组织免疫球蛋白、补体水平的影响

目的分析发病前急性感染对成人免疫球蛋白A（IgA）肾病患者血清及肾组织免疫球蛋白（Ig）、补体（C）水平的影响，为明确感染因素在IgA肾病发生和发展的作用提供依据。 方法选取2014年10月至2018年2月海口市人民医院风湿肾病科收治的60例发病前急性感染成人IgA肾病患者作为研究组，选取同期60例发病前未出现急性感染成人IgA肾病患者作为对照组，观察对比2组患者的一般资料、血清Ig、C水平及肾组织Ig、C沉积强度。 结果在研究组中，43例（71.67%）患者于发病前发生急性上呼吸道感染，11例（18.33%）患者于发病前发生急性肺部感染，6例（10%）于发病前发生急性消化道感染。研究组患者的24 h尿蛋白定量、血清IgA、IgG水平分别为（2.82±1.33）g/d、（2.87±1.06）g/L、（8.14±3.04）g/L，均明显高于对照组，差异有统计学意义（P＜0.05）。研究组患者肾组织的IgA、IgG、C3、C4、C1q沉积强度均高于对照组，差异均有统计学意义（P＜0.05）。 结论发病前具有急性感染史的IgA肾病患者的蛋白尿症状更加严重，血清Ig水平和肾组织Ig、C沉积强度更高，其预后情况可能更差，临床医生应对此类患者给予充分重视和及时有效的干预治疗。     

妊娠致肾脏损害特点临床和肾活检病理的研究

目的　为探讨妊娠致肾脏损害的临床特点及病理特征。方法　对 46例妊娠致肾脏损害住院患者进行了临床和肾活检病理的分析研究。结果　 46例终止妊娠 3个月后仍有蛋白尿 ,合并肾功能不全者 2 6例 ( 56 .52 % ) ,肾活检免疫病理示 Ig G32例 ,Ig A36例 ,Ig M2 8例及 C338例肾小球血管袢及系膜区沉积 ;病理表现系膜增生性肾炎 2 8例、膜增生性肾炎 1 0例、局灶节段性肾小球硬化 6例、膜性肾病 2例 ,46例中合并小球硬化者 2 8例 ;胎儿死亡 36例 ( 76 .6 0 % )。结论　妊娠激发了免疫反应导致肾脏病变是肾小球疾病发病机制之一 ,积极诊治该类患者是临床不可忽视的问题。     

妊娠致肾脏损害特点临床和肾活检疫理的研究

目的：为探讨妊娠致肾脏损害的临床特点及病理特征,方法：对46例妊娠致肾脏损害住院患进行了临床和肾活检病理的分析研究,结果：46例终止妊娠3个月后仍有蛋白尿,合并肾功能不全26例（56．52％）,肾活检免疫病理示IgG32例,IgA36例,IgM28例及C338例肾小球血管袢及系膜区沉积;病理表现系膜增生性肾炎28例,膜增生性肾炎10例,局灶节段性肾小球硬化6例,膜性肾病2例,46例中合并小球硬化28例,胎儿死亡36例（76．60％）,结论：妊娠激发了免疫反应导致肾脏病变是肾小球疾病发病机制之一,积极诊治类患是临床不可忽视的问题。     

Drug induced nephrotic syndrome

This review summarizes drug induced nephrotic syndrome. Major drugs which induce drug related nephrotoxicity are antibiotics, NSAID, radiocontrast media, anticancer drug and antirheumatic drug. Drug induced nephropathy can show various forms of renal diseases. The nephropathy consists of acute tubular necrosis, acute tubulointerstitial nephritis, pre-renal type renal failure, obstructive renal failure, chronic tubulointerstitial nephritis and glomerular damage. Major drugs which induce nephrotic syndrome and glomerular damage are gold, penicillamine, bucillamine and NSAID. In the nephrotic syndrome due to these drugs, the major type of renal disease is the membranous glomerulonephritis and the nephropathy resolves completely when the drug is withdrawn; renal function does not deteriorate, and corticosteroids are unnecessary.     

Infection and chronic kidney disease

Many pathogens are thought to be involved in the development and progression of chronic kidney disease (CKD). The mechanism of kidney damage due to infection includes direct invasion of pathogens and deposition of antigen-antibody complex by immunological reaction. As to renal dysfunction induced by bacterial infection, some cases of poststreptococcal glomerulonephritis present progressive decline of glomerular filtration rate (GFR). Methicillin resistant Staphylococcus aureus (MRSA)-related glomerulonephritis and infectious endocarditis are known to cause acute renal failure, which clinicians often find difficulty in the treatment. Chronic pyelonephritis by repetitive vesicoureteral reflux or nephrolithiasis also cannot be disregarded. Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the most recognized etiology of virus associated nephropathy, and the representative histological changes are membranous nephropathy and membranoproliferative glomerulonephritis, respectively. Furthermore, morbidity of human immunodeficiency virus (HIV) associated nephropathy is increasing, reflecting the prolonged survival of HIV-infected patients. Thorough preventive/therapeutic strategies should be taken against these infections for improving clinical outcome.     

Detection of activated platelets in urinary sediments by immunofluorescence using monoclonal antibody to human platelet GMP-140 in patients with IgA nephropathy

The presence of activated platelets in the urinary sediments was studied by indirect immunofluorescence using monoclonal antigranular membrane protein (GMP)-140 antibody. GMP-140 is generally expressed on the activated-platelets and -vascular endothelial cells. The purpose of the present study was to determine if the presence of activated platelets in the urinary sediments is correlated with glomerular injuries in patients with IgA nephropathy. Fourteen patients with IgA nephropathy and 11 patients with diffuse mesangial proliferative glomerulonephritis without glomerular IgA deposition (PGN) were examined. The number of activated platelets in the urinary sediments was markedly increased in patients in the advanced stage of IgA nephropathy. The ratio of activated platelets to total platelets in the urinary sediments was also increased in such patients. It appears that the detection of activated platelets in the urinary sediments is useful in determining the degree of histological changes in IgA nephropathy. © 1993 Wiley-Liss, Inc.     

Renal disorders in rheumatoid arthritis]

Glomerulonephritis has been believed to be a rare complication in rheumatoid arthritis (RA). However, recent studies have revealed a focal segmental increase in mesangial cells and matrix in RA patients with hematuria. In our series, proteinuria, hematuria or both abnormalities were recognized in 74 (22%) out of 336 RA cases. Among 119 patients examined by renal biopsy, mild mesangial proliferative glomerulonephritis (GN) was found in 25 patients, of which 22 demonstrated mesangial IgA deposits, by immunofluorescent microscopy. Membranous nephropathy was noticed in 26 cases. Three cases of membranous nephropathy had no history of gold or D-penicillamine treatment. Electron microscopy revealed diffuse thinning of the glomerular basement membrane in 12 cases. The average thickness of the glomerular basement membrane was significantly thinner in RA patients than in normal subjects. The immunological processes associated with rheumatoid factor do not seem to be related to the renal lesions in RA patients.     

雷公藤多甙对IgA肾病大鼠免疫调节的实验研究

目的 观察雷公藤多甙对实验性IgA肾病大鼠的免疫调节作用.方法 采用牛血清白蛋白和葡萄球菌肠毒素复合免疫法建立大鼠实验性IgA肾病模型，比较正常对照组、模型组、雷公藤多甙组大鼠的尿红细胞、24 h尿蛋白、肾功能，以及红细胞C3b受体花环结合率和肾组织病理改变.结果 雷公藤多甙组大鼠的尿红细胞、尿蛋白、血清肌酐、血尿素氮含量均低于模型组（ P〈0.05），红细胞C3b受体花环率高于模型组（ P〈0.05），肾小球系膜区IgA沉积较模型组少，肾功能改善好于模型组.结论 雷公藤多甙对实验性IgA肾病大鼠有较好的治疗作用，对出现的免疫失调有调节作用。     

Plasmapheresis for crescentic IgA nephropathy: a report of two cases and review of the literature

Idiopathic IgA nephropathy is widely regarded as a slowly progressive disease that not infrequently results in end-stage renal failure. Only a minority of patients present with either a rapidly progressive form of glomerulonephritis, or with end-stage renal failure. Anecdotal reports of improved renal function after treatment with plasmapheresis have been published, but the efficacy of this therapy remains controversial. We describe the course of two young males presenting with uremia, hypertension, nephrotic-range proteinuria, and crescentic glomerulonephritis on renal biopsy. Both patients underwent therapy with steroids, immunosuppressive agents, and plasmapheresis without an appreciable improvement in renal function. A review of the literature does not offer any conclusive data to support the role of plasmapheresis in the treatment of rapidly progressive glomerulonephritis due to IgA nephropathy and points out the need to define criteria that may identify subsets of patients with this disorder who may potentially benefit from plasma exchange therapy. J. Clin. Apheresis 14:185-187, 1999. Published 1999 Wiley-Liss, Inc.     

膜型IgA肾病

肾病是我国常见的肾小球疾病，病理类型很多，但膜型ＩｇＡ肾病极罕见。本文报告３例膜型ＩｇＡ肾病。病理特点是系膜增生的同时，肾小球毛细血管基底膜增厚，并有钉突形成。患者有大量蛋白尿。系膜区有大量ＩｇＡ沉积，毛细血管基底膜外侧有ＩｇＧ沉积。超微结构显示在系膜区及基底膜上皮细胞下均有电子致密物。本文通过免疫荧光和免疫电镜的研究认为，膜型ＩｇＡ肾病是膜型肾小球肾炎与系膜增生型ＩｇＡ肾病的相互重叠。     

Proto-oncogene, proliferating cell nuclear antigen, perforin and growth factor gene expression in peripheral blood mononuclear cells from patients with IgA nephropathy]

IgA nephropathy, which is widely recognized as one of the most common primary glomerulonephritides, is characterized by the constant presence of IgA in the glomerular mesangium. We investigated proto-oncogenes, proliferating cell nuclear antigen (PCNA), perforin, platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF) mRNA expression in peripheral blood mononuclear cells (PBMC) obtained from patients with IgA nephropathy, patients with other types of glomerulonephritis and healthy age-matched controls. The majority of patients with IgA nephropathy showed elevated c-myc, c-fos, c-jun, c-raf, PCNA, perforin, PDGF-B chain, and IGF-I and -II mRNA expression in PBMC, while no these mRNA expression was detected in PBMC obtained from patients with other types of glomerulonephritis or normal controls. A positive correlation was noted between mRNA levels and urinary protein excretion. mRNA expression also correlated with the histopathological findings in the renal tissue of patients with IgA nephropathy. These studies suggest that abnormal regulation of proto-oncogenes, PCNA, perforin, PDGF and IGF gene expression in PBMC may be associated with the progression of IgA nephropathy and may be useful as an indicator of disease activity.     

The clinico-pathologic features of hepatitis B virus-associated glomerulonephritis

The frequency of hepatitis B surface antigen (HBsAg) was studied in the sera of 311 patients with various forms of primary glomerulonephritis and 43 patients with lupus nephritis. HBs antigenaemia was detected in 69 of the 311 patients (22 per cent) with primary glomerulonephritis and this prevalence of HBsAg carrier was significantly higher than that in the general population (p less than 0.001). These patients had no clinical or biochemical findings to suggest acute or chronic liver disease. A higher HBs antigenaemia carrier rate was not observed in patients with lupus nephritis. Three glomerulopathological entities, membranous nephropathy, IgA nephropathy, and mesangial proliferative glomerulonephritis, were found to be associated with a higher prevalence of HBs antigenaemia compared with the general population (p less than 0.001). Glomerular deposits of HBsAg and/or hepatitis core antigen (HBcAg) were detected in 41, 61, and 60 per cent of renal biopsy specimens from patients with membranous nephropathy, IgA nephropathy, and mesangial proliferative glomerulonephritis associated with persistent HBs antigenaemia respectively. During the mean study period of 40 months (range 12-180), 14 per cent of these patients with hepatitis-associated glomerulonephritis developed progressive renal failure, although none required maintenance dialysis. Our study suggests that hepatitis B virus antigenaemia may play a significant role in the development of specific forms of glomerulonephritis and that these hepatitis B virus-associated glomerulonephritides can run an indolent but relentless progressive clinical course.     

Measurement of serum IgA and C3 may predict the diagnosis of patients with IgA nephropathy prior to renal biopsy

The levels of serum IgA and C3 in patients with IgA nephropathy were determined using international standard serum (IFCC/CRM470) in a multicenter trial in Japan. The ratio of serum IgA to C3 (serum IgA/C3 ratio) without any information from renal biopsy was used for the diagnosis of IgA nephropathy. Three hundred and six patients with IgA nephropathy and other glomerular diseases, and 418 healthy adults were examined. The new diagnostic standardized criterion in patients with IgA nephropathy, obtained by nephelometric immune assay based on the international reference preparation CRM470, was 315 mg/dl. The serum IgA/C3 ratio was a more useful marker for distinguishing IgA nephropathy from non-IgA nephropathy together with serum IgA levels. This suggests that the measurement of serum IgA and C3 may predict the diagnosis of patients with IgA nephropathy prior to renal biopsy.     

328例肾脏疾病患者的肾脏病理分析

目的：了解近年经皮肾活检肾脏疾病患者的病理类型分布及其与临床症状的关系。方法：回顾分析2004年6月～2005年6月间因肾脏疾病住院行肾活检的患者的临床病理特点。结果：328例肾脏疾病中，原发性肾小球疾病257例（78．4％）、小管间质疾病16例（4．9％）、继发性肾脏病55例（16．8％）。原发性肾小球疾病中IgA肾病137例，占53．3％；继发性肾小球肾炎中狼疮肾炎、紫癜性肾炎和高血压肾损害较多，分别占32．7％、27．3％和18．2%；小管间质疾病以急性间质性肾炎为多，占68．8％。IgA肾病主要表现为蛋白尿并血尿；膜性肾病、高血压肾病主要表现为单纯性蛋白尿。单纯血尿主要病理类型是IgA肾病；单纯蛋白尿主要病理类型是IgA肾病和轻微病变。蛋白尿并血尿主要病理类型是IgA肾病、轻微病变和狼疮性肾炎；大量蛋白尿主要病理类型是轻微病变、IgA肾病和膜性肾病。结论：本组资料显示原发性肾小球疾病仍为我国最常见的肾脏疾病，其中以IgA肾病最常见；小管间质疾病发病率有增高，继发性肾脏病以狼疮肾炎最常见，其它特殊肾脏病有增加。     

Detection of anionic sites and immunoglobulin A deposits in the glomerular capillary walls from patients with IgA nephropathy

A study of anionic sites in the glomerular basement membrane (GBM) from patients with immunoglobulin A (IgA) nephropathy is described. The relationship between the deposition of IgA and the detection of glomerular extracellular components, i.e., noncollagenous (NC-1) domain of Type IV collagen, in the glomerular capillary walls was examined by double immunofluorescence. Renal biopsy specimens from patients with IgA nephropathy were immersed in polyethyleneimine (PEI) as a cationic probe and then examined by electron microscopy. Renal specimens were also incubated with mouse monoclonal anti-NC-1 domain of Type IV collagen and then stained with fluorescein isothiocyanate (FITC)-labelled goat antimouse Ig antiserum. After these reactions, sections were stained with rhodamine-labelled rabbit antihuman IgA antiserum. GBM subepithelial anionic sites marked by PEI were altered by the deposition of electron-dense deposits (EDD) in patients with IgA nephropathy and there was a significant correlation between the levels of proteinuria and the incidence of EDD in the GBM in such patients. Marked proteinuria was observed in patients who showed loss of anionic sites in the GBM by electron microscopy. By double immunofluorescence, IgA was shown to be focally deposited outside the NC-1 domain of Type IV collagen-detected regions in the same patients. The authors concluded that high levels of proteinuria might be due to alterations of the size barrier and/or anionic sites of GBM in the moderate stage of IgA nephropathy.     

IgA nephropathy in a patient with dominant dystrophic epidermolysis bullosa

Dystrophic epidermolysis bullosa (DEB) is a rare and severe hereditary dermatosis. On the other hand, IgA nephropathy is the most common form of glomerulonephritis in childhood and adults, and clinically characterized by microhematuria and proteinuria and histologically by deposition of immunoglobulin A in mesangial lesions. Several renal complications of recessive DEB including IgA nephropathy and amyloidosis have been reported. However, there have been no reports on dominant DEB associated with IgA nephropathy. We report here for the first time a 17-year-old girl with dominant DEB associated with IgA nephropathy. The patient has suffered from episodes of urinary, upper airway, and skin infections. At 17 years of age, proteinuria and hematuria were detected, with a high value of serum IgA. Renal biopsy was performed, and immunofluorescence microscopic examination revealed segmental deposits of IgA in mesangial lesions, with many glomeruli exhibiting diffuse segmental mesangial-proliferative glomerulonephritis. We diagnosed dominant DEB associated with IgA nephropathy on the basis of proteinuria, hematuria, and deposits of IgA in mesangial lesions on immunofluorescence microscopic examination, and diffuse segmental mesangial-proliferative glomerulonephritis. These findings suggest that repeated skin infections might have contributed to the pathogenesis of IgA nephropathy in this patient.     

Renal expression of intercellular adhesion molecule-1 in different forms of glomerulonephritis.

1. Expression of intercellular adhesion molecule-1 was investigated in five normal kidneys and 47 renal biopsies with the use of monoclonal antibody 7F7 and immunoperoxidase staining. 2. In the normal kidney, intercellular adhesion molecule-1 was expressed on endothelial cells of glomerular and peritubular capillaries, on Bowman's capsule, on some interstitial cells and weakly in the mesangium. 3. Increased glomerular staining was detected in early cases of rapidly progressing glomerulonephritis (5/8) and in some cases of non-IgA mesangioproliferative glomerulonephritis (5/9), IgA nephropathy (3/5), Henoch-Schoenlein purpura (2/2), lupus nephritis (5/6) and focal segmental glomerulosclerosis (1/3). A decrease in intercellular adhesion molecule-1 expression was noted in advanced rapidly progressive glomerulonephritis (3/8), two cases of membraneous nephropathy, one severe mesangioproliferative glomerulonephritis biopsy, the two membranoproliferative glomerulonephritis biopsies and in sclerotic loops in focal segmental glomerulosclerosis. 4. Expression de novo on tubular epithelial cells occurred in rapidly progressive glomerulonephritis, in membranoproliferative glomerulonephritis, and to a lesser extent in some cases of membraneous nephropathy, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, a severe case of mesangioproliferative glomerulonephritis and in the mixed essential cryoglobulinaemia case. In 63% of positive tubuli, intraluminal cells which expressed CD18, the common beta-chain of leucocyte-function-associated antigen-1, Mac-1 and p150,95, were present. 5. Intercellular adhesion molecule-1 was also found on the majority (59%) of infiltrating mononuclear cells in all forms of glomerulonephritis.     

Autoimmunity to glomerular antigens in Henoch-Schoenlein nephritis.

1. Henoch-Schoenlein nephritis and IgA nephropathy share clinical and immunological features, but the pathogenesis of neither condition is established. We have recently described IgG autoantibodies to glomerular components in active IgA nephropathy and have now sought evidence for a similar autoimmune component in Henoch-Schoenlein purpura. 2. Sera from 26 patients with Henoch-Schoenlein nephritis and six patients with Henoch-Schoenlein purpura without accompanying nephritis were studied and compared with sera from 20 patients with other forms of glomerulonephritis and 40 normal subjects. E.l.i.s.a.s were developed to detect IgA and IgG binding to the ligand from whole human glomeruli previously described, laminin, DNA, cardiolipin (diphosphatidylglycerol) and a panel of dietary constituents (BSA, alpha-caesin, beta-lactoglobulin, ovalbumin and wheat gliadin). 3. Sera from 16 of the 26 patients with Henoch-Schoenlein nephritis displayed increased IgG binding to the human glomerular extract compared with the normal control group (P < 0.001), whereas IgG binding was not significantly raised in the patients with Henoch-Schoenlein purpura without evidence of renal involvement. IgA binding was not raised compared with control subjects. Serum IgA and IgG binding to other potential autoantigens or antigens present on dietary constituents was not significantly different in patients with Henoch-Schoenlein nephritis or patients with Henoch-Schoenlein purpura without nephritis compared with control subjects. 4. Western blotting of the denatured and reduced glomerular extract revealed binding of IgG, from the sera of patients with active Henoch-Schoenlein nephritis, to glomerular components of M(r) 48,000 and 58,000, similar to the M(r) of the glomerular antigens identified in IgA nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Immunofluorescent Localization of Antihemophilic Factor Antigen and Fibrinogen in Human Renal Diseases

Tissue localization of antihemophilic factor (AHF, factor VIII) antigen and fibrinogen by immunofluorescent microscopy was determined in 146 specimens of normal and diseased kidneys. AHF antigen was present in the endothelial cells of glomeruli, peritubular capillaries, arteries, and veins of normal kidneys; a distribution similar to that in other tissues. In scleroderma and malignant hypertension, deposition of AHF antigen and fibrinogen was limited to the markedly thickened endothelial layers of arteries. More extensive intense deposition of both AHF antigen and fibrinogen in glomeruli and in arterial walls were present in hyperacute renal homograft rejection, hemolyticuremic syndrome, postpartum renal failure, and in some cases of acute homograft rejection. In contrast, deposition of fibrinogen was observed in glomerular epithelial cresents in severe proliferative glomerulonephritis, but AHF deposition was not present in these lesions. Glomerular deposition of fibrinogen without increased AHF standing was also detected in renal tissue from patients with anaphylactoid purpura nephritis and in recurrent macroscopic hematuria with focal glomerulonephritis. Increased staining of peritubular capillaries with anti-AHF was seen in diseased kidneys irrespective of etiology. Immunofluorescent localization of AHF, a participant in the intrinsic coagulation pathway, offers a new way by which to analyze the mechanisms responsible for fibrinogen deposition in disease.