肾小球IgG4沉积与原发性膜性肾病临床及病理的关系

目的分析原发性膜性肾病肾小球免疫荧光IgG4亚型分布特点,探讨IgG4阳性强度与肾脏病理、临床表现及预后的关系。方法回顾分析2015年9月至2017年4月本院行原位肾活检、免疫荧光显示毛细血管袢上有IgG沉积且至少一个IgG亚型阳性强度1+及以上的原发性膜性肾病病例,分析肾小球IgG4亚型分布特点,探讨IgG4阳性强度与临床表现、病理指标及临床缓解的关系。结果共纳入250例患者,其中男性157例(62.8%),女性93例(37.2%),年龄(54.4±14.6)岁;IgG4阴性组40例,IgG4阳性组210例;IgG4阳性组根据IgG4阳性程度又分为弱阳性组(1+,114例)、中度阳性组(2+,62例)、强阳性组(3+、4+,34例)。IgG4阳性组24 h尿蛋白量、肾组织磷脂酶A2受体染色强阳性比例均高于IgG4阴性组(均P<0.05);IgG4强阳性组血白蛋白水平低于IgG4弱阳性组(P<0.05),且随着IgG4的阳性程度增高,IgG1的阳性强度也增高,IgG4强阳性组IgG1强阳性比例明显高于IgG4弱阳性组(P<0.05);各组肾小球硬化比例、肾小管萎缩程度、IgG2、IgG3及其余免疫荧光指标组间比较差异均无统计学意义。中位随访180(122,209)d,32例患者失访,余218例患者中,45例(20.6%)完全缓解,104例(47.7%)部分缓解,69例(31.7%)未缓解。以未缓解定义为结局事件,多因素Cox回归分析显示,肾组织IgG4高阳性强度(HR=1.371,95%CI 1.068~1.759,P=0.013)、男性(HR=1.818,95%CI 1.028~3.214,P=0.040)、初始24 h尿蛋白量大(HR=1.108,95%CI 1.003~1.225,P=0.043)是疾病缓解的独立危险因素。结论肾小球IgG4阳性与否及阳性程度与原发性膜性肾病的疾病严重程度相关,肾小球IgG4阳性程度可能成为原发性膜性肾病治疗反应的指标之一。     

IgA nephropathy in children: significance of glomerular basement membrane deposition of IgA

Seventeen children with IgA nephropathy were grouped according to the absence (group I, n = 10) or presence (group II, n = 7) of glomerular basement membrane (GBM) deposition of IgA to determine whether GBM deposition of IgA correlated with laboratory or pathologic data at diagnosis or clinical status at follow-up. Children in group II had significantly (p less than 0.01) more proteinuria at diagnosis than children in group I. The percentage of glomeruli demonstrating crescent formation was significantly (p less than 0.05) higher in group II biopsies. Chronic changes of fibrous crescents, segmental sclerosis, global obsolescence, tubular atrophy, and interstitial fibrosis were also significantly (p less than 0.001) more common in group II biopsies. After a mean follow-up period of 2 years, all children in group II have persistent proteinuria of more than 1 g/24 h, and 3 of 5 have renal insufficiency (2 require dialysis). In contrast, 2 of 9 group I children have proteinuria exceeding 1 g/24 h, and only 1 has renal insufficiency. We conclude that, as compared to children with IgA localized to the mesangium, children with IgA nephropathy and GBM deposition of IgA have a higher urinary protein excretion at the time of diagnosis, more severe histologic alterations including a greater percentage of glomeruli demonstrating crescent formation, more chronic changes of segmental or global sclerosis, tubular atrophy, and interstitial fibrosis. Such children usually have persistent proteinuria and are more likely to develop progressive renal disease.     

Clinicopathological significance of monoclonal IgA deposition in patients with IgA nephropathy

Background

Clinicopathological significance of monoclonal IgA deposition and its relation to bone marrow abnormalities in IgA nephropathy (IgAN) remains unclear.

Methods

We retrospectively investigated the prevalence and clinicopathological significance of monoclonal IgA deposition in 65 patients with IgAN. Serum-free light chain ratio, and urinary Bence Jones protein were also measured.

Results

Thirty-nine percent of patients were men, median age was 40 and median observation period was 31 months. Five patients (Group M) showed monoclonal IgA lambda deposition and one showed monoclonal IgA kappa deposition. Fifty-nine patients (Group P) showed polyclonal IgA deposition. There were no significant differences in the degree of proteinuria, hematuria and renal function between Group M and Group P. Total protein and albumin were significantly lower in Group M than in Group P. According to the Oxford classification, the percentage of patients with M1 was significantly higher in Group M than in Group P. One patient in Group P showed serum monoclonal IgG lambda. No patient showed abnormal serum-free light chain ratio. Seventy-five percent in Group M and 42 % in Group P were treated with steroid. Three patients in Group P progressed to end-stage renal disease (ESRD). The frequency of disappearance of proteinuria or hematuria and progression to ESRD was not different between the groups.

Conclusions

The prevalence of monoclonal IgA deposition was 9.2 %. Although some parameters differed between the groups, renal outcome were similar. Thus, IgAN with monoclonal IgA deposition seems not to be different entity from those with polyclonal IgA deposition.

     

The glomerular response to IgA deposition in IgA nephropathy

Compelling evidence points to a role for IgA receptors in the pathogenesis of IgA nephropathy. The soluble form of the type I IgA receptor (FcalphaRI or CD89) forms complexes with IgA that can be found in patients' serum and that initiate the disease in CD89 transgenic mice. A nonclassic IgA receptor, identified as the transferrin receptor (TfR), is highly expressed in patients' mesangium and colocalizes with IgA deposits. TfR preferentially binds polymeric IgA1 complexes, but not monomeric IgA1 or IgA2. The TfR-IgA1 interaction is dependent on carbohydrate moieties because hypoglycosylated IgA1 has superior binding to TfR than normally glycosylated IgA1. Polymeric IgA1 binding enhances mesangial cell TfR expression and results in cell proliferation and inflammatory and profibrogenic cytokine and chemokine production, suggesting a pivotal role in mesangial cell proliferation, matrix expansion, and recruitment of inflammatory cells. We propose that, as a second event, activation of the classic, FcRgamma-associated transmembrane FcalphaRI expressed on circulating myeloid leukocytes takes place. FcalphaRI/gamma2 cross-linking in human FcalphaRI transgenic animals promotes disease progression by enhancing leukocyte chemotaxis and cytokine production, and IgA immune complexes from IgA nephropathy patients induce FcalphaRI-dependent cell activation. This review therefore details the functional consequences of IgA/receptor interactions and discusses proposed mechanisms to explain the development and chronicity of the disease.     

IgA nephropathy: immune mechanisms beyond IgA mesangial deposition

IgA nephropathy is attributable to mesangial IgA immune complex deposition. The pathogenic potential of frequently colocalized IgG deposits may depend on polarized T-helper cytokines that modulate Fcgamma receptors of infiltrating macrophages, leading to either activation or inhibition that determines glomerular injury.     

Soluble fibrin formation in the mesangial area of IgA nephropathy

Background Fibrin monomer and its derivatives in blood are found in an early stage of thrombosis. When they are produced in blood, they form complexes with fibrinogen, and they exist as soluble complexes named soluble fibrin (SF). As final insoluble products, cross-linked fibrin (XFb) is often observed in mesangial areas in active types of human glomerulonephritis. To clarify the mechanisms of mesangial SF production and its relationship to XFb deposition in IgA nephropathy (IgAN), an immunohistochemical study was conducted. Methods Nineteen patients with IgAN were studied. XFb was detected in renal biopsy specimens using anti-d-dimer antibody combined with plasmin exposure. SF was detected with a monoclonal antibody (IF-43), and factor V was detected with a specific rabbit antibody. The relationships of SF staining to the disease activity index, XFb deposition, and factor V staining was evaluated. Results XFb, factor V, and SF were observed in the mesangium in 14, 11, and 8, respectively, of a total of 19 specimens. SF had frequent staining in the proliferating areas, showing a significant relationship to XFb or factor V (P < 0.05). Furthermore, XFb, factor V, and SF depositions were markedly correlated with disease activity (P < 0.001 in each case). Conclusions These findings suggest that SF is formed in the mesangial area in active IgA nephropathy accompanied by mesangial proliferation, in particular, in its early stage.     

Clinical significance of polymeric and monomeric IgA complexes in patients with IgA nephropathy

IgA nephropathy is currently considered an immune complex (IC) disease. However, though several groups have demonstrated the presence of IgA-IC in the sera of patients by various techniques, a correlation with clinical activity of the nephropathy has not always been found. Since these assays detect (simultaneously) polymeric and monomeric IgA-IC, the pathogenicity of these two classes of complexes could not be established. In this work, we have studied in 66 patients with IgA nephropathy the existence and significance of such IC, by means of a technique described in our laboratory, based on the specific binding of secretory component for polymeric IgA. Furthermore, IgG-ICs were also determined by the standard Raji cell assay in ELISA. The prevalence of these complexes was as follows: Multimeric (polymeric and monomeric) IgA-ICs were detected in 55% of 66 patients studied, polymeric IgA-ICs in 30%, monomeric IgA-ICs in 39%, and IgG-ICs in 46%. The intermittency of all these complexes was clearly noted in sequential examinations. A significant correlation (P less than .025) with hematuria was only found with polymeric IgA-IC, but not with multimeric IgA-IC, monomeric IgA-IC, or IgG-IC. Polymeric IgA-ICs were more frequently observed at the initial phases of the disease. Analytical ultracentrifugation showed that polymeric IgA-IC was of larger size than monomeric IgA-IC. The major pathogenicity of polymeric IgA-IC is in agreement with the finding of this immunoglobulin at the mesangial level in patients and animals with IgA nephropathy.     

Participation of complement components in glomerular deposition in IgA nephropathy

To clarify the role of complement components in glomerular deposition in IgA nephropathy, clinicopathological and immunohistological studies were performed on 299 patients (171 males and 128 females; age, 9-71 years). Glomerular IgA deposition with IgG and/or IgM was observed more frequently in patients with Clq and/or C4 than in those with only C3 deposition (P less than 0.001). Patients with glomerular deposition of Clq and/or C4 showed more severe proteinuria (1 g/24 hr less than), a lower glomerular filtration rate (GFR), a higher incidence of duplication of capillary walls and more severe proliferation of mesangial cells and an increase in mesangial matrix (P less than 0.05), as compared to those without both Clq and C4. Patients with glomerular C3 deposition had significantly lower serum CH50 levels at the time of renal biopsy (P less than 0.02) and a significantly higher incidence of sclerotic lesions (P less than 0.05). Patients with C3 deposition in the mesangium and peripheral capillaries had significantly higher serum IgA levels (P less than 0.02), a significantly higher incidence of adhesion (P less than 0.01), duplication and endocapillary proliferation (P less than 0.05) and a more severe increase in mesangial cells (P less than 0.01) than those with C3 deposition only in the mesangium. The above findings demonstrate that analysis of the complement system in glomeruli is important for the evaluation of glomerular damage, clinical findings and prognosis.     

Ultrastructure of mesangial type III collagen deposition in a patient with IgA nephropathy

We report a case of IgA nephropathy with focal and segmental deposition of type III collagen in mesangium, confirmed by immunohistochemical and electron microscopic methods. Tissue negative staining showed that focal and segmental fibrotic lesions in the mesangial area consisted of disarrayed or curled striated collagen fibers and striated membranous structures. Diabetes mellitus, hypertension, and advanced glomerular sclerosis were absent in this case, and mesangial cells surrounding the type III collagen showed vacuolar degeneration revealed by electron microscopy. Production of type III collagen may be the marker for phenotypic change of mesangial cells in immune-mediated glomerular diseases.     

Chronicity index and mesangial IgG deposition are risk factors for hypertension and renal failure in early IgA nephropathy

To determine the natural history in early immunoglobulin A (IgA) nephropathy, we evaluated the long-term follow-up of 27 normotensive nonazotemic adult idiopathic IgA nephropathy patients with chronic hematuria who derived from a prospective regional epidemiological study of glomerulonephritis conducted between 1978 and 1984. As controls, 17 thin glomerular basement membrane (GBM) patients, 24 patients with normal renal tissue, and nine patients with miscellaneous nephropathies were followed up. Median follow-up was 11 years (range, 8 to 14 years). Renal biopsies, performed within 2 years after patient identification, were scored semiquantitatively in terms of activity and chronicity indices, using a modified National Institutes of Health (NIH) scoring system. During follow-up, two patients with IgA nephropathy went into histological remission, and 12 IgA nephropathy patients showed disease progression, of whom three developed renal failure. Initial proteinuria over 1 g/d was associated with a high activity score, extracapillary lesions, and late onset of uremia. Mesangial IgG deposition and a higher initial chronicity index were associated with development of hypertension during follow-up. In the multivariate analysis, a high initial chronicity index, erythrocyturia, and mesangial IgG deposition are independent determinants of progression of disease. We conclude that in patients with IgA nephropathy, identified early in the course of disease, erythrocyturia, a high chronicity index, and mesangial IgG deposition in the presence of normal renal function are risk factors for decreased renal survival. Disappearance of hematuria is associated with remission of IgA nephropathy immunopathologically and low activity and chronicity indices at initial biopsy.     

Sequential measurement of mesangial matrix area occupying the glomerulus in children with IgA nephropathy

Background IgA nephropathy is the most common form of primary glomerulonephropathy in children it has a variable clinical course, from spontaneous remission to progression to renal death. It has been reported that predominant mesangial hypercellularity is characteristic of early lesions, and that it changes to a gradual matricial increase, with sclerosis, according to the disease progression. Methods A sequential measurement of the ratio of mesangial matrix area to glomerular area (M/G) was done in 5 children with moderately proteinuric IgA nephropathy, who underwent 3 consecutive, repeat renal biopsies. A prompt initiation of alternate-day prednisolone therapy (an initial dosage at 1 mg/kg, maximum 60 mg) after the first renal biopsy was done in 4 cases. The remaining patient received this therapy after the second renal biopsy. Results A sequential measurement of the M/G in the former cases did not show an increase between the biopsies, while measurement of the latter one showed a progressive increase. Moreover, the case that had an increase in the M/G showed renal impairment at the third biopsy. Conclusion Although a small number of cases were examined, a sequential measurement of the M/G in children with moderately proteinuric IgA nephropathy may be a valuable indicator for a more precise evaluation of clinical outcome in a clinical setting.     

Clinicopathological significance of light chain deposition in IgA nephropathy

Background

Clinicopathological significance of light chain deposition in IgA nephropathy and the relation of monotypic IgA deposition to bone marrow abnormalities are important issues to be clarified.

Methods

We retrospectively investigated light chain deposition in 526 patients with IgA nephropathy. We divided the patients into 5 groups according to the balance of intensity of both light chain deposition: lambda monotypic, lambda dominant, polytypic, kappa dominant and kappa monotypic. Clinicopathological parameters were compared among the groups. The relation of monotypic IgA deposition to hematological malignancy was also evaluated.

Results

The prevalence of monotypic IgA deposition was 6.3%, 33 patients (21 lambda and 12 kappa). Thirty-two (4.0%) and 10 patients (1.9%) were classified into lambda and kappa dominant groups, respectively. Polytypic IgA deposition was observed in 455 patients (85.7%). Age of onset, age at biopsy, urinary protein creatinine ratio, the percentage of global glomerulosclerosis, and the degree of IgA and C3 deposition were different among the groups. However, there was no gradual difference according to the groups. No patient with monotypic IgA deposition showed hematological abnormality at biopsy and during follow-up.

Conclusions

The prevalence of IgA monotypic deposition was extremely low. Clinicopathologically, we could not differentiate patients with monotypic IgA deposition from those with polytypic one and no hematological disorder was documented in patients with monotypic IgA deposition. Whether IgA nephropathy with monotypic IgA deposition and that with polytypic one is the same entity or not, and relation between monotypic IgA deposition and hematological malignancy should be clarified by further investigations.

     

Differential effects of FMLP-activated neutrophils from patients with IgA nephropathy enhanced endothelin 1 production of glomerular mesangial cells

BACKGROUND: Neutrophil infiltration in the glomeruli is common in patients with IgA nephropathy (IgAN). The pathogenetic roles of the infiltrated neutrophils and their relationship with glomerular mesangial cells, however, are not clear. METHODS: We examined the effects of coculture with N-formyl-methionyl-leucyl-phenylalanine (FMLP) activated neutrophils on the viability, endothelin 1 (ET-1) production, and ET-1 mRNA expression of rat glomerular mesangial cells. Neutrophils were isolated from 15 IgAN patients, from 13 patients with non-IgA mesangial proliferative glomerulonephritis (MsPGN), and from 10 normal controls. RESULTS: The ET-1 production by mesangial cells was significantly higher after stimulation with FMLP-activated neutrophils from IgAN patients than that of MsPGN patients and normal controls, and this effect was significantly abolished by pretreating mesangial cells with superoxide dismutase and partly abolished by catalase. The ET-I mRNA expression of mesangial cells showed a parallel increase with ET-1 protein. The trypan blue exclusion test showed significant mesangial cell death after stimulation with FMLP-activated neutrophils as compared with quiescent neutrophils, and the cell death was also prevented by superoxide dismutase but not catalase. The FMLP-activated neutrophils from IgAN patients produced more superoxide than those of MsPGN patients and normal controls. CONCLUSION: The FMLP-activated neutrophils from patients with IgAN have differential effects in enhancing the cell death and the ET-1 production of glomerular mesangial cells through the release of superoxide.     

The fate of glomerular mesangial IgA deposition in the donated kidney after allograft transplantation

OBJECTIVE: To investigate the fate of the mesangial IgA deposits in the donor kidney after allograft transplantation. METHODOLOGY: Routine pre-transplant cadaveric donor kidney biopsy and repeated renal biopsies were performed at months 1, 3, and 6 after renal transplantation. The patients, 342 in number, were divided into IgA positive deposition kidney group (group A, n = 83) and non-IgA deposition kidney group (group B, n = 259). There were no significant differences between the two groups' sex, age, time of hemodialysis, warm ischemia time, cold ischemia time, complement-dependent cytotoxicity, level of panel-reactive assay, and the distribution of original disease. RESULTS: Recipients in group A received donor kidney with glomerular mesangial proliferation and marked diffuse granular IgA deposition. All of them showed edema, nephrotic range protienuria, microhematuria, hypoalbuminemia, hypertension, and delayed graft function. Borderline change was higher in group A than in group B, 37.3 and 16.2% (p < 0.001), respectively. Acute allograft rejection was higher in group A than in group B, 31.3 and 19.3% (p < 0.001), respectively. The glomerular mesangial IgA deposits gradually disappeared from the mesangial regions in grafts of acute rejection. Graft survival in both groups was not significant, being 93.8 and 95.6% in 1 yr, and 86.7 and 88.3% in 3 yr. CONCLUSION: Clinical features of the recipients which received from donor kidney with glomerular mesangial proliferation and marked diffuse granular IgA deposition: edema, proteinuria, microhematuria, hypoalbuminemia, hypertension, and delayed graft function. The presence of IgA deposits on donated kidney, by a possible increase of the immunogenicity of these kidneys, might be a cause of increased rejection. There were no significant differences between the two groups on long-term allograft survival.     

Abnormal glycosylation of serum IgG in patients with IgA nephropathy

Background We postulated that IgA nephropathy (IgAN) involved alterations of serum IgG. The present study was undertaken to elucidate changes in serum IgG oligosaccharide structure analysis and to assess the diagnostic usefulness of this analysis in IgAN. Methods The subjects were 28 children who were definitively diagnosed as having IgAN on the basis of renal biopsy and who had not received treatment for this disease; 27 healthy children; 15 untreated adults definitely diagnosed as having IgAN; 5 patients with other nephropathies; and 61 healthy adults. Oligosaccharide analyses of IgG were performed by reverse-phase high-performance liquid chromatography (HPLC) developed by Takahashi and colleagues. Results In both the children and the adults, the peak area ratio of isomers with two different galactosyl-N-acetylglucosamine (Gal-GlcNAc) binding sites was significantly lower in the presence of IgAN than in the healthy subjects (P < 0.05 in children and P < 0.001 in adults). The ratio of Gal-free oligosaccharides to Gal-positive oligosaccharides did not differ according to the presence or absence of IgAN in children or in adults. Conclusions The analysis of the oligosaccharide structure of serum IgG seems to be useful in diagnosing IgAN.     

Mannose-binding lectin gene polymorphism associated with the patterns of glomerular immune deposition in IgA nephropathy

OBJECTIVE: To elucidate the genetic background underlying the diversity of mesangial immune deposition in IgA nephropathy (IgAN), we investigated the distribution of mannose-binding lectin (MBL) gene codon 54 polymorphism and serum MBL levels in IgAN patients. METHODS: Seventy-seven IgAN patients with glomerular IgA and C3 deposits (Group A) and 70 with glomerular IgA, IgG, IgM, C3 and Clq deposits (Group AGM) were included in the present study. Control group consisted of 140 normal adults. MBL genotypes were investigated by polymerase chain reaction and restriction fragment length polymorphism. Serum MBL levels with different genotypes were also assayed in some subjects. RESULTS: The variant allele (GAC) was markedly associated with Group AGM (OR = 1.95, 95% C.I.: 1.06-3.58). In both Group A and Group AGM, more patients carrying the variant allele had episodes of upper respiratory or gastrointestinal infections prior to onset or exacerbation of IgAN than wild homozygotes (GGC/GGC). In addition, a significant difference in serum MBL level was also observed between wild homozygotes and heterozygotes (GGC/GAC) (GGC/GGC > GGC/GAC) (p<0.0001) in all groups, while there was no difference for subjects with the same genotypes among the three groups (p > 0.05). Serum MBL levels of the rare variant homozygotes approached zero. CONCLUSIONS: Our findings provide evidence that the host defense molecule, MBL, may be involved in the formation of the diversity of glomerular immune deposition in IgAN. Genetic deficiency of MBL may partially account for abundant immune deposits in some IgAN patients.