Development Of Membranous Glomerulonephritis Research Articles

The effect of cyclosporin A on the interstitial mononuclear cell infiltration and the induction of Heymann's nephritis

Heymann's nephritis was induced with brush-border (BB) antigen. Interstitial mononuclear cell infiltration was studied with cytological examinations of fine-needle aspiration biopsies (FNAB), and with immunoperoxidase stains of frozen sections with monoclonal antisera. The effect of cyclosporin A (CyA), 20 mg/kg when administered intraperitoneally for 8 days in association with both initial immunization, and with the booster 4 weeks later, on the interstitial leukocyte infiltration and on the development of membranous glomerulonephritis (MGN) and proteinuria were investigated. Another group of rats was immunized, but not given CyA. Experimental animals were killed in groups 3, 6 and 20 weeks after initial immunization. CyA inhibited significantly the initial interstitial lymphocyte and blast cell response at 3 weeks (FNAB), but did not inhibit the secondary response after the booster. The anti-BB titre reacted in a similar fashion. Immunoperoxidase stains indicated a clearly suppressed T suppressor/cytolytic (T s/c) cell response. Glomerular basement membrane (GBM) deposits of IgG developed more slowly and were more scarce in the CyA-treated rats, when compared with the untreated group. Only one out of 15 CyA treated rats developed C3 deposits in the GBM during the course of the study, and none developed proteinuria, when most untreated rats (10/17) had C3 deposits and were nephrotic at 20 weeks. Thus, CyA depressed the initial interstitial cellular response after immunization with BB antigen, and also inhibited the development of antibody response, C3 deposits and proteinuria of Heymann nephritis. These effects of CyA may be contributed to an inhibited amplification of the autoimmune response associated with interstitial damage and continuous release of autoantigen.

Interaction between gene polymorphisms of nitric oxide synthase and renin-angiotensin system in the progression of membranous glomerulonephritis.

The renin-angiotensin system (RAS) and nitric oxide synthase (NOS) play a key role in the progression of primary glomerulonephritis (GN). Although previous studies have examined genetic risk associated with single gene variations, experiments assessing risk conferred by multiple gene variations are still scanty. The effect of combination of variant alleles of four genes encoding for three components of the RAS [angiotensin converting enzyme insertion/deletion (ACE I/D), angiotensin II receptor 1 (AT1R 1166A/C), angiotensinogen (AGT M235T)] and for NOS (ecNOS4b/a) on the development and progression of membranous GN (MGN) were evaluated in a longitudinal study comparing 117 patients with serum creatinine (s-Cr) <1.5 mg/dl at renal biopsy and follow-up > or = 5 years (Kaplan-Meier and Cox multivariate analysis). The control group consisted of DNA from 171 organ donors. We found no relationship between single or combined variations of the four gene polymorphisms and development of MGN. Among single gene variations, there were no independent genetic risk factors for the progression of renal disease, after adjustment for age, sex, hypertension, proteinuria, s-Cr, chronicity and activity index. However, double variation coincidences such as the combination of the allele a of ecNOS4b/a and both the allele D of ACE I/D (chi(2) =4.80, P = 0.028; HR = 1.97, 95% CI 0.98-3.96) and the allele T of AGT (M235T) (chi(2) = 5.09, P = 0.024; HR = 2.84, 95% CI 1.39-5.82) exerted an additional effect that was higher than that of the single gene variations. This study is the first to demonstrate a role for an interaction between simultaneous variations of genes encoding for NOS and components of RAS in the progression of MGN. Interactions between various polymorphisms may explain conflicting results obtained in previous studies that examined single gene variations, since the effect of a single locus variation may be influenced by the simultaneous presence of other variant alleles in polygenic diseases such as primary GN. However, the small sample sizes and possible multiple interactions limited the interpretation of the current findings, which may represent true biological interaction or simply statistical interactions or spurious results due to the small sample sizes.

Inhibition of the CD40-CD40ligand pathway prevents murine membranous glomerulonephritis

Several forms of glomerulonephritis are induced by antibodies against self or foreign antigens. Normal B lymphocyte antibody production requires T cell costimulatory signals provided in part by T cell surface expression of gp39/CD40ligand (CD40L) that engages the B cell receptor CD40 and induces B cell differentiation and immunoglobulin class switching. We assessed the effect of disrupting the CD40L-CD40 costimulatory pathway, using a CD40-Ig fusion protein, on the development of membranous glomerulonephritis (MGN) in the mouse. MGN is induced by mouse antibodies that recognize and bind to exogenously administered rabbit anti-mouse renal tubular brush border (RbAMBB) IgG immobilized in the glomerular capillary wall. MGN did not occur in nude mice, showing the need of the T cell function. C57Bl/10 mice immunized with RbAMBB and treated with CD40-Ig fusion protein displayed a delayed autologous response and absence of MGN lesions, while control fusion proteins failed to prevent the development of the disease. These observations provide evidence that disruption of the CD40-CD40L costimulatory pathway can prevent the development of MGN by suppressing T cell-dependent antibody production.

Membranous Glomerulonephritis in Renal Transplant

A patient with membranous glomerulonephritis (MGN) presented with recurrent disease after renal transplantation. The disease on the original and the transplanted kidney was characterized by diffuse subepithelial electron-dense deposits on the glomerular basement membranes. Including this case, 23 cases of MGN have been reported in renal transplants, of which 8 are 'recurrent' and 15 are 'de novo'. This incidence of 'de novo' MGN makes it the most common type of 'de novo' glomerulonephritis in renal transplants. Survey of clinical and morphological features of the cases of both the 'de novo' and the 'recurrent' disease failed to identify a specific cause of the MGN. Hypothetically, immunosuppression in transplanted patients may lower the antibody response to levels that favor the development of membranous glomerulonephritis.

THE ROLE OF HBe ANTIGEN IN THE PATHOGENESIS OF HB ASSOCIATED MEMBRANOUS GLOMERULONEPHRITIS

The purpose of the present study is to investigate the role of HBe antigen in the pathogenesis of membranous glomerulonephritis (MGN) in Japanese children. Of 364 children who underwent renal biopsy from 1976 through 1978 in our institution, 11(10 male, 1 female, ages 1 - 14 years) were found to be HBs antigen carriers and comprise the subject of the present study. All of them exhibited some abnormality on a routine urinalysis at one time during the course. Serum HB associated antigens were studied in all. A routine light, fluorescent and electron microscopic study was performed on 14 biopsied specimens from the 11children. In addition, direct immunofluorescence for HBsAg, HBeAg & HBcAg was done in the majority of the specimens. The results are summerized in the table. The 14 specimens were divided into 2 groups depending upon clinical manifestations at the time of renal biopsy (Group A: 9 specimens from 9 children with nephrotic syndrome or heavy proteinuria, Group B: 5 specimens from 4 children with minimal hematuria). All of the Group A specimens showed MGN stage II or III and the Group B showed either minimal changes or MGN stage IV. In all of the 5 Group A specimens studied HBeAg immune complex was present along the glomerular capillary wall, but not present in any of the 4 Group B specimens. However, HBsAg was demonstrable in only one of the 11 specimens tested. At the time of renal biopsy, circulating HBeAg was studied in 8 children (Group A: 4, Group B: 4). It is of interest that 2 of the 4 Group B children were found to have HBe antigenemia. The above data suggests there is a highly significant relationship between glomerular HBeAg immune complex and the development of MGN. We believe that most cases of HB associated nephropathy seen in the Japanese children are HBeAg mediated MGN.

Immunochemical properties of rabbit antibodies in membranous glomerulonephritis.

Four of 15 rabbits, injected with hen's egg albumin (EA) intramuscularly once a week for a period in excess of 12 weeks, developed membranous glomerulonephritis (MGN). It was demonstrated that the quantities and qualities of antibodies produced in the MGN rabbits were different than those of non‐membranous glomerulonephritis (non‐MGN) rabbits. MGN rabbits produced small to moderate amounts of total antibodies and precipitating antibodies as measured by antigen‐binding capacity (ABC‐33) of Farr's method and precipitation with radioactive antigen (P‐80), particularly after 12 weeks of immunization. The precipitating efficiencies of the antibodies in their sera declines remarkably and their avidity were lower than those of non‐MGN rabbits late in the course of immunization. MGN rabbits formed relatively small antigen‐antibody complexes after intravenous injection of antigen, which were slowly removed from their circulation. From these results, it was concluded that the properties of antibodies correlated closely with the development of MGN.