Presence of immunoglobulin M antibodies around the glomerular capillaries and in the mesangium of normal and passive Heymann nephritis rats

Summary Diffuse distribution of small, faintly staining, beaded deposits of rat immunoglobulin M (IgM) around the glomerular capillary blood vessels, and a more intensely staining larger deposition in the mesangium, were observed on the kidney sections of normal rats. As glomerular-fixed nephritogenic antigens are known to be present on the epithelial aspect of the glomerular basement membrane (GBM), especially at the soles of foot processes and at the slit pores, it was assumed that the IgM antibodies were directed against these antigens. Investigation by immunofluorescent antibody double-staining techniques of rat kidney sections obtained from normal and rabbit anti-FX1A-injected rats stained for the nephritogenic antigen showed that a number of antigenic sites in the glomeruli and in the mesangium shared antibody hits by heterologous rabbit IgG and autologous rat IgM antibodies. Most sites in the glomeruli stained specifically for rat IgM or rabbit IgG, but preferentially for the latter. The intensely fluorescent mesangial deposits stained mainly for rat IgM, indicating that at these sites the antigenic material was virtually saturated, while areas at the entry to the mesangial space also stained for rabbit IgG, indicating that at these locations free nephritogenic epitopes were still available for reaction with the anti-FX1A antibody. Western blot analysis have shown that the rabbit anti-rat FX1A IgG and the rat anti-rat KF3 IgM antibodies are directed against the same renal tubular-derived antigen with a molecular weight of 70,000. These experimental findings collectively demonstrate that the heterologous IgG and autologous IgM antibodies are directed against the same nephritogenic antigen, which is found in the glomeruli, the mesangium and the proximal convoluted tubules. Thus, the IgM autoantibody has a possible physiological role but, in addition, there is evidence of active immunophagocytic events, manifested in a rapid and continuous entrapment and expulsion of macromolecules after their processing by the mesangial cells of normal and passive Heymann nephritis rats.     

Bovine serum albumin (BSA) nephritis in rats II. Histological findings and complement activation by immune complex in SHR rats

We introduced a mesangiopathic form of glomerulonephritis in spontaneously hypertensive (SHR) rats. Bovine serum albumin (BSA) was given i.v. to primed rats for 3 weeks and they were unilaterally nephrectomized (Nx). Then, they received rabbit anti-BSA- (Group A) or normal serum (Group B) for seven days, and half the rats were killed to obtain another kidney (Ex-1). The remainder were killed two weeks later and their kidneys were examined (Ex-2). In Nx kidneys, the glomerular lesions were characterized by leucocyte accumulation in the capillary lumina and by deposition of rat IgG, rat C3 and BSA both in the mesangial area and along the capillary walls. Glomeruli of Ex-1 kidneys manifested varying degrees of hypercellularity in the mesangium; a few leucocyte accumulations in the capillary lumina were noted and the immune deposits had decreased in the mesangium but not on the capillary walls. In Ex-2 kidneys, mesangial hypercellularity was conspicuous. There were no remarkable histological differences between Group A and B rats; in Ex-1 and Ex-2 kidneys of Group A, rabbit IgG was closely associated with rat IgG or C3. Serological evaluation revealed that the amount of circulating rat anti-BSA antibody was relatively small and that C3 was consumed by newly formed circulating immune complexes during BSA administration. Polymorphonuclear leucocyte (PMN) binding assay revealed that complement fixation to the immune deposits occurred in vitro and that this activity was highest in tissue from Nx kidneys.     

Bovine serum albumin (BSA) nephritis in rats II. Histological findings and complement activation by immune complex in SHR rats.

We introduced a mesangiopathic form of glomerulonephritis in spontaneously hypertensive (SHR) rats. Bovine serum albumin (BSA) was given i.v. to primed rats for 3 weeks and they were unilaterally nephrectomized (Nx). Then, they received rabbit anti-BSA- (Group A) or normal serum (Group B) for seven days, and half the rats were killed to obtain another kidney (Ex-1). The remainder were killed two weeks later and their kidneys were examined (Ex-2). In Nx kidneys, the glomerular lesions were characterized by leucocyte accumulation in the capillary lumina and by deposition of rat IgG, rat C3 and BSA both in the mesangial area and along the capillary walls. Glomeruli of Ex-1 kidneys manifested varying degrees of hypercellularity in the mesangium; a few leucocyte accumulations in the capillary lumina were noted and the immune deposits had decreased in the mesangium but not on the capillary walls. In Ex-2 kidneys, mesangial hypercellularity was conspicuous. There were no remarkable histological differences between Group A and B rats; in Ex-1 and Ex-2 kidneys of Group A, rabbit IgG was closely associated with rat IgG or C3. Serological evaluation revealed that the amount of circulating rat anti-BSA antibody was relatively small and that C3 was consumed by newly formed circulating immune complexes during BSA administration. Polymorphonuclear leucocyte (PMN) binding assay revealed that complement fixation to the immune deposits occurred in vitro and that this activity was highest in tissue from Nx kidneys.     

Glomerular lesions induced in the rabbit by physicochemically altered homologous IgG.

Immunization of rabbits with physicochemically altered homologous or even autologous IgG induces formation of antibodies combining with IgG of rabbit and of foreign species. Cardiac but not renal lesions were reported in such animals. This study examined the nephritogenic potential of the immune response to cationized or heat-aggregated homologous IgG of b9 or b4 allotype in rabbits of the b4 allotype. Rabbits injected with either b9 or b4 cationized IgG produced antibodies reactive with rabbit and human IgG and with histones; they also developed abnormal glomerular deposits of IgG b4 and C3 corresponding to alterations of the glomerular basement membranes (GBM). Rabbits injected with either b9 or b4 aggregated IgG developed antibodies reactive with rabbit and human IgG and abnormal glomerular deposits of IgG b4 and C3 in the GBM and in the mesangium with subendothelial and mesangial electron-dense deposits. Some rabbits in both groups had proliferative and exudative glomerulonephritis and proteinuria. The results showed that immunization of rabbits with physicochemically altered homologous IgG induces an immune response to rabbit and human IgG and to histones as well as glomerular deposits of autologous IgG and C3 and other glomerular lesions.     

Mesangial glomerulonephropathy with deposition of IgG, IgM, and C3 induced by mercuric chloride: a new model.

A mesangial glomerulonephropathy, characterized by the deposition of rat IgG, IgM, and C3 in the glomerular mesangium, was produced in Wistar rats by a prolonged administration of mercuric chloride (HgCl2). The HgCl2 was dissolved in sterile distilled water (0.2 mg. per ml.), and a group of 15 male Wistar rats was given injections subcutaneously three times a week on alternate days at a dosage of 0.15 mg. per 100 gm. of body weight for 27 weeks. A control group of nine rats was given injections of distilled water only. Mesangial glomerulonephropathy developed in 12 of 15 rats injected with HgCl2 and was characterized by the following: (1) coarse granular and nodular deposition of rat IgG, IgM, and C3 in the mesangium of all glomeruli, (2) absence of staining for rat albumin, IgA, and fibrin, (3) presence of electron-dense deposits in the mesangium, (4) focal and segmental proliferation of the mesangial matrix, (5) interstitial inflammation, (6) tubular atrophy, and (7) deposition of periodic acid-Schiff-positive material in the medulla adjacent to the thin limbs of the loops of Henle. Glycosuria and a slight increase in proteinuria were observed transiently in some rats. The blood urea nitrogen levels were normal in all rats. Eluates from the kidneys with heavy mesangial deposits contained rat IgG. However, the eluted antibody failed to react with normal rat kidney tissue components. None of the above findings were present in the control rats. The study provides a model of a mesangial nephropathy that seems to be immunologically induced; however, the mechanism for the formation and deposition of the immune deposits containing rat IgG, IgM, and C3, and the nature of the antigen(s) have not been elucidated.     

Progressive cytomegalovirus glomerulonephritis - An experimental model.

Although acute infection with murine cytomegalovirus (MCMV) resulted in a transient focal glomerulonephritis characterized by mesangial inclusions, infection of HA/ICR mice given antilymphocyte globulin (ALG) led to progressive glomerulonephritis and renal failure. ALG alone without virus failed to produce progressive renal disease. Mice given both MCMV and ALG developed severe proteinuria and azotemia with glomerular crescents by 30 days. By immunofluorescence, viral antigen was limited to mesangial zones and glomerular axial poles. Granular deposits of rabbit IgG from ALG, mouse IgG, and C3 along the peripheral glomerular capillary walls were first observed 12 days after infection. By electron microscopy, virus was found only in glomerular mesangial cells that resembled macrophages. Intramembranous and subepithelial deposits in peripheral capillary walls were associated with accumulations of polymorphonuclear leukocytes dissecting into glomerular basement membranes. These observations best fit a multiphasic mechanism of glomerular injury initiated by persistent virus in the mesangium, followed by deposits of rabbit IgG from ALG, mouse IgG, and C in the peripheral capillary walls, resulting in an amplified immune-complex-mediated injury. Because other viruses localize within the glomerular mesangium, viruses should be considered potential causes of mesangial injury and progressive glomerulonephritis.     

Detection of autoantibodies and glomerular injury in rabbits immunized with denatured human fibronectin monomer

Seven rabbits were studied after immunization with human plasma fibronectin which had been purified by preparative sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis run after reduction. Light- and electron-microscopic examination of kidneys revealed proliferative mesangial and capillary alterations in all of the rabbits immunized with fibronectin, but not in the rabbits immunized with fibrinogen or saline. In addition, one of the rabbits (Rabbit 4) also demonstrated dense deposits in a unique distribution within the glomerular basement membrane. Granular staining for rabbit IgG was present in the mesangium and along the basement membranes of the capillary loops of glomeruli from Rabbit 4 as detected by immunohistochemical methods. Sera from all of the rabbits immunized with human fibronectin contained IgG antibodies that reacted with rabbit fibronectin when tested by the Western blotting method. Preimmune sera and sera from rabbits immunized with fibrinogen or saline recognized neither human nor rabbit fibronectin. Although antibodies from several of the rabbits reacted with the 27,000-dalton, aminoterminal fragments of human fibronectin by the Western blotting method, only antibodies from Rabbit 4 recognized the 27,000-dalton fragment of rabbit fibronectin. These studies indicate that antibodies which recognize fibronectin of the host species and which are involved in the pathogenesis of glomerular injury can be induced by immunization with denatured heterologous fibronectin monomer.     

Uptake and disposal of BSA-coated latex particles by the rat mesangium: reaction with subsequently administered heterologous antiserum

Mesangial uptake and disposal of antigen-coated latex particles and the ability of subsequently injected antibody to maintain complexed antigen in the rat mesangium has been investigated. Carboxylate-modified latex particles, coated with bovine albumin (BSA) were injected i.v. to 36 Wistar rats. Twenty-two rats (group 1) were not treated further. Fourteen rats (group 2) received rabbit anti-BSA antiserum i.v. and i.p. 24 h later. Control groups were injected with uncoated, unmodified latex particles or soluble BSA with and without subsequent antibody administration. Latex was present in the mesangial matrix of rats in group 1 at 1 h in association with a diffuse mesangial distribution of BSA. At 24 h, BSA staining was markedly reduced and extracellular latex was no longer observed. Intracellular latex aggregates were present in experimental and control groups at 24 h-14 days in cytoplasmic vacuoles of hypertrophic mesangium which showed minor infiltration by macrophage-like cells. Progressive removal of latex aggregates coincided with declining mesangial reactivity. Rapid disappearance of antigen apparently results from local degradation of tracer in the mesangium. Antibody administration preserves BSA in the mesangium due to immune complex formation and is associated with retention of ingested latex by mesangial cells. However, efficient disposal of glomerular immune deposits by the mesangium appears to minimize infiltration by monocytes and prevents aggravation of glomerular inflammation.     

Preparative polyacrylamide gel electrophoresis in the isolation of the nephritogenic proteins of passive Heymann nephritis

To study kidney antigens involved in the formation of glomerular subepithelial immune deposits in passive Heymann nephritis polypeptides of 500, 130 and 105 kDa were isolated from rat kidney brush border (BB) membrane fraction using preparative polyacrylamide gel electrophoresis. Polyclonal antibodies raised against these proteins were specific for their respective antigens in immunoblotting. All three antisera bound to proximal tubular BB of kidney and to apical surfaces of several other epithelia as shown by indirect immunofluorescence on frozen sections of normal rat tissues. The anti-500 kDa and anti-105 kDa, but not the anti-130 kDa, antibodies also stained glomeruli and the anti-105 kDa antibodies also endothelial cells. After injection into rats the anti-500 kDa IgG bound to kidney glomeruli forming diffuse, granular deposits of rabbit IgG along the glomerular capillary walls, as shown by direct immunofluorescence. In electron microscopy the immune deposits were subepithelial and electron dense. The deposits remained in glomeruli for at least 60 days and increased with time. Deposits of C3 were not detected and proteinuria did not develop. The anti-130 kDa and the anti-105 kDa IgGs did not form glomerular deposits after in vivo injections. The results suggest that the 500 kDa and the 105 kDa proteins or related antigens are present in glomeruli and the 500 kDa protein is located on the epithelial side of the glomerular basement membrane. Circulating antibodies can bind to the 500 kDa protein forming immune complexes which rearrange and form electron dense deposits. The results further demonstrate that preparative gel electrophoresis is a useful technique for the isolation of kidney proteins of immunopathologic interest.     

IgA-associated renal diseases: Antibodies to environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli

Levels of IgA1, IgA2, IgM, and IgG antibodies specific for 10 ubiquitous food and bacterial antigens were examined by radioimmunoassay in the sera of 29 patients with IgA-associated renal diseases and 22 normal individuals. No significant differences were observed between patient and normal groups in the levels of IgA1 antibodies, and IgA2 antibodies were detected in only a few individuals in either group. Minor differences in IgM or IgG antibodies were seen against some antigens. Significant positive correlations between IgA1 and IgG and between IgA1 and IgM antibodies to casein were found in the patient group. Analysis of the molecular form of serum IgA1 antibodies revealed that although the pattern of polymeric and monomeric forms varied between individuals and between antibody specificities, there was no preponderance of one form in either patient or normal groups. Examination of kidney biopsies from 50 patients with IgA-associated renal diseases revealed that IgA1 represented the predominant subclass deposited in the glomerular mesangium; glomeruli from three patients contained both IgA1 and IgA2. Seventy-eight percent of the patients also had deposits of IgM, although IgA and IgM deposits did not always coincide. When IgG was present in glomeruli (45% of patients), the IgG1 subclass predominated. J chain was detectable in glomeruli of only four patients. C3 was detected in glomeruli of 95% of the patients, although the distribution of C3 did not always coincide with that of IgA. Indirect immunofluorescence staining with rabbit antisera to various environmental antigens showed that milk protein antigens could be deposited in association with IgA in the glomerular mesangium.     

Immune-complex nephritis in the rabbit produced by injections of rat renal tubular fraction 3 antigen

Rabbits used for the production of anti-rat kidney tubular fraction 3 antibody developed a form of immune-complex glomerulonephritis which was characterized by the deposition of immune complexes in the glomerular basement membrane and in the mesangium. The deposits were composed of the injected rat kidney antigen and rabbit antibody to the injected antigen. Eluted gamma-globulin obtained from the diseased rabbit kidneys reacted only with the brush-border region of the proximal convoluted tubules of normal rat kidney sections but not with normal rabbit kidney sections, in an indirect fluorescent antibody test. The developing kidney disease does not appear to have an autoimmune component.     

Immune-complex nephritis in the rabbit produced by injections of rat renal tubular fraction 3 antigen.

Rabbits used for the production of anti-rat kidney tubular fraction 3 antibody developed a form of immune-complex glomerulonephritis which was characterized by the deposition of immune complexes in the glomerular basement membrane and in the mesangium. The deposits were composed of the injected rat kidney antigen and rabbit antibody to the injected antigen. Eluted gamma-globulin obtained from the diseased rabbit kidneys reacted only with the brush-border region of the proximal convoluted tubules of normal rat kidney sections but not with normal rabbit kidney sections, in an indirect fluorescent antibody test. The developing kidney disease does not appear to have an autoimmune component.     

Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat

The present report describes the natural history of an experimental acute glomerulonephritis with massive proteinuria induced by a single intravenous injection of a (mouse) monoclonal anti-rat Thy 1.1 antibody into the rat. The disease is characterized by direct although transient binding of this monoclonal antibody to glomerular basement membrane and mesangium after injection as demonstrated by immunofluorescence microscopy. Immediate activation of complement occurs as shown by glomerular deposition of C3 and C9. Concomitant activation of the coagulation cascade is reflected by the presence of fibrinogen deposits in the affected glomeruli. One hour after injection mesangial alterations are prominent including condensation of mesangial cell chromatin, and lysis of mesangial cells as shown by light- and electron- microscopy, leading to the formation of aneurysms in the capillary tuft. Commencing on day 4 mesangial cell proliferation can be observed, accompanied by glomerular crescent formation at day 14, which decreases gradually 3 weeks after antibody administration, whereas mesangial hypercellularity can be observed up week 10 after intravenous injection of the antibody. The disease is clinically characterized by a massive transient proteinuria starting immediately after antibody injection, reaching mean values of 300 mg/24 hours at days 2 to 4, gradually decreasing to normal levels after 3 weeks. It is concluded that in this unique model of glomerulonephritis induced by a monoclonal antibody, recognition of Thy 1.1 epitopes as well as activation of complement including the C5-C9 membrane attack complex may play a major role in the pathogenesis of this experimental disease.     

Anti-DNA antibody derived from a systemic lupus erythematosus (SLE) patient forms histone–DNA–anti-DNA complexes that bind to rat glomeruli in vivo

Histone can mediate the binding of both free DNA and DNA complexed to anti-DNA antibody to the glomerular capillary wall. We tested whether preformed histone–DNA–anti-DNA immune complexes (IC) could bind to the glomerular capillary wall. The immune complex, generated with anti-DNA antibody derived from an SLE patient and excess of ¹²⁵I-DNA followed by digestion with DNase, was mixed with histones. The complex containing 4 μg DNA was injected via the aorta into the left kidney of rats. At 15 min, 1.3% of the histone–DNA–anti-DNA antibody complex bound (measured as ¹²⁵I-DNA), when histone was omitted less than 0.1% of the DNA–anti-DNA antibody complex bound. By immunofluorescence human immunoglobulins and histones, representing the IC, could be observed in a capillary pattern; but no complement deposition was detected. Electron microscopy revealed discrete, electron dense deposits in a subendothelial, subepithelial and mesangial localization at 15 min. These results provide direct evidence that antibodies from serum of SLE patients can form soluble histone–DNA–anti-DNA immune complexes that bind to the glomerular capillary wall in vivo     

Studies with antibodies to cultured rat glomerular epithelial cells. Subepithelial immune deposit formation after in vivo injection

To investigate the role of glomerular epithelial cell (GEC) membrane proteins in the in situ formation of subepithelial immune deposits, the authors raised a rabbit antiserum against GEC that had been grown in culture (anti-GEC). By indirect immunofluorescence (IF) on normal rat kidney, anti-GEC stained proximal tubular brush border (BB). After intravenous injection into animals, granular glomerular capillary wall staining for IgG was present by IE and subepithelial immune deposits were identified by standard transmission and immunoelectron microscopy. Using the latter technique, injected anti-GEC IgG was identified beneath slit diaphragms and in endocytic-coated pits and intracellular vesicles of podocytes. Anti-GEC immunoprecipitated gp330 and two other proteins from radiolabeled BB. These proteins also were identified by sheep anti-rat Fx1A, the antiserum responsible for passive Heymann nephritis. Anti-GEC and anti-Fx1A also immunoprecipitated five identical proteins from surface-labeled GEC. Biosynthetically-labeled but not surface-labeled GEC contained immunoprecipitable gp330. Thus, injection into rats of antibodies raised against cultured GEC can produce subepithelial immune deposits, a disease process classically induced by antibodies to BB or its purified components. In addition to gp330, GEC and BB share other antigenic determinants that may contribute to the formation of these immune deposits.     

Immune complex glomerulonephritis in mice infected with Escherichia coli.

C57Bl/6 mice were injected intraperitoneally with 10(8) to 2 x 10(8) living K 38 Escherichia coli (E. coli) and serological changes and kidney involvement were studied. E. coli were found in the blood 45 min to 24 hr after injection. In serum, large amounts of deoxyribonucleic acid (DNA) were present 24 hr after E. coli injection, and thereafter disappeared. Seven days after infection, antibodies directed against E. coli, anti-DNA antibodies and C1q-binding substances were found in serum and the kinetics of the variations of these parameters were studied until day 35. Kidney lesions were evaluated immunochemically and by optical and electron microscopy. In the glomeruli, heavy granular deposits of IgG and IgM were constantly found in mesangium and along capillary walls. In most kidneys slight granular deposits of IgG and IgM were also found in the tubules. Histological studies revealed in the glomeruli mild endocapillary cell proliferation, focal thickening of glomerular basement membrane and dense deposits in mesangial and subendothelial areas and inside the glomerular basement membrane; in the tubules dense deposits were focally observed inside the tubular basement membrane.     

An allograft kidney showing both features of IgA nephropathy and membranous glomerulonephritis--a case report.

We report a case of glomerular disease with both mesangial IgA and subepithelial IgG deposits in the allograft kidney. The patient was a 36 year-old man who had received a renal allograft 1 year previously. Fifteen days before admission, he discovered a microscopic hematuria without clinical evidences of allograft rejection. Light microscopy showed diffuse increase of mesangial matrix without mesangial cell proliferation. Capillary walls were diffusely and mildly thickened. Immunofluorescence microscopy demonstrated both granular deposits of IgA in the mesangium and IgG along the capillary walls. On electron microscopy, electron-dense deposits were identified not only in the mesangium but also on the epithelial side of the glomerular basement membrane.     

Nephritogenicity of anti-proteoglycan antibodies in experimental murine lupus nephritis.

BACKGROUND: Cross-reactivity between anti-DNA antibodies and heparan sulfate (HS)/heparan sulfate-proteoglycan (HS-PG) of glomerular basement membrane has been previously reported. Conceivably, this determines the final outcome of glomerular injury in lupus nephritis. EXPERIMENTAL DESIGN: We investigated the status of glomerular injury in NZB/NZW F1 mice after the administration of rabbit anti-HS-PG antibody (experiment group). The controls received normal rabbit IgG only. RESULTS: All experimental animals became proteinuric 2 weeks after the administration of anti-HS-PG. The animals of the older age group (16 weeks) had significant hematuria as well. Their glomeruli exhibited hypercellularity with a heavy influx of polymorphonuclear leukocytes and monocytes into their capillaries, and some of them exhibited crescentic changes. Electron-dense deposits were present in subepithelial, subendothelial, and mesangial regions of the glomeruli. The control group had normocellular glomeruli with a few mesangial deposits. Mouse IgG and C3 displayed a granular pattern of immunofluorescence in the experimental group. Anti-rabbit IgG titers in the serum were higher in the control group, which lower in the renal glomerular eluates. No significant differences were observed in the concentrations of anti-dsDNA and -ssDNA either in the sera or in the eluates. There was also no difference between the control and experimental group in terms of antibody synthesis by the splenic lymphocytes and their proliferation subsequent to antigenic challenge. CONCLUSIONS: Data suggest that administration of anti-HS-PG accentuates the glomerular injury during the natural course of lupus nephritis in (NZB/NZW F1 mice; seemingly these two antibodies (anti-HS-PG and -DNA) do not competitively inhibit the binding of the other to the same anionic sites of glomerular basement membrane enriched with heparan sulfate in vivo.     

Protein aggregates in extracorporally perfused rabbit kidneys

Eighteen rabbit kidneys were perfused ex vivo for 1 h with allogeneic blood, and in 16 a solution of xenogeneic aggregate-free, aggregated or antibody-complexed protein was added to the perfusate 5 min after the start (human immunoglobulins or serum albumin, partly cationized, were used). The kidneys were examined by light and electron microscopy and the human and rabbit immunoglobulin (or albumin) precipitates were detected by direct immunofluorescence and ultrastructural immunohistochemistry. In 13 kidneys the perfusion produced small segmental glomerular endocapillary aggregates of platelets, leukocytes, and granular precipitates reactive with both anti-rabbit and anti-human antibodies. No typical deposits were seen in mesangium or in periphery of glomerular capillaries but rabbit Ig penetrated to the inter- and subepithelial spaces of proximal convoluted tubules. Three kidneys perfused by cationized aggregated human Ig (or by cationized albumin-antialbumin complexes) exhibited a destructive lesion with rapid breakdown of blood flow and massive global endocapillary plugs of similar ultrastructure but with focal endothelial sloughing. Pericapillary granular precipitates of human and rabbit Ig were seen in these kidneys. When the blood with cationized Ig aggregates was used for perfusion of two further kidneys extensive endocapillary aggregates with endothelial damage reappeared but the extracapillary penetration and precipitation were lacking and the blood flow largely improved. Membrane polyanion of podocytes stained by colloidal iron was preserved even in close proximity of cationized complex precipitates. Thus, in the ex-vivo perfusion model the preformed neutral aggregates did not penetrate through the glomerular capillary wall and were not phagocytized by mesangial cells. The cationized aggregates induced rapid circulatory failure with massive platelet clumping and granular pericapillary "humps" ultrastructurally different from the deposits of human and experimental immune complex glomerulonephritis.     

Immune complex glomerulonephritis mediated by thyroid antigens.

Hypothyroidism, microscopic hematuria, and proteinuria developed in an 11-year-old girl. A renal biopsy specimen showed increased mesangial cells and matrix with focal glomerular basement membrane thickening. Three years later, a pronounced increase in proteinuria was detected. Elevated levels of antibody to thyroid microsomal antigen and thyroglobulin were found in the serum. A renal biopsy specimen showed a pronounced increase in mesangial cells and matrix with generalized glomerular basement membrane thickening. Electron microscopic studies demonstrated granular deposits in the capillary walls and mesangium. Immunofluorescent studies revealed granular deposits of IgG, IgM, and C3, primarily on the glomerular basement membrane. By indirect immunofluorescence, granular glomerular basement membrane and mesangial staining were detected with antibody specific for thyroglobulin and thyroid microsomal antigen. These observations suggest development of immune complex glomerulonephritis mediated by thyroid antigens.