An overlapping syndrome of IgA nephropathy and membranous nephropathy?

This is the first report of primary glomerular disease with both mesangial IgA and subepithelial IgG deposits in the glomeruli at the same time. This nephropathy, discovered in 3 patients, is either a new disease entity or an overlapping of IgA nephropathy and membranous nephropathy. Follow-up studies may clarify the pathogenesis of IgA nephropathy and/or membranous nephropathy. In 1 patient the clinical findings resembled those of IgA nephropathy, and in the other 2 they were those of membranous nephropathy. Light microscopy showed generalized diffuse increases in mesangial cells and matrix, and there was slight capillary wall thickening. In the glomeruli, immunofluorescence microscopy demonstrated both granular deposits of IgA in the mesangium and granular deposits of IgG along the capillary loops. On electron microscopy, electron-dense deposits were identified not only in the mesangium but also on the epithelial side of the glomerular basement membrane. These findings were confirmed by the immunoperoxidase technique in electron-microscopic studies of these antibody classes. These glomeruli contained both the dense reaction products of IgA deposits in the paramesangium and mesangial matrix and the dense reaction products of IgG deposits on the epithelial side of the basement membrane.     

Epstein-Barr virus detection in kidney biopsy specimens correlates with glomerular mesangial injury

To determine the relationship between the detection of Epstein-Barr virus (EBV)-specific DNA and glomerular injury, 33 renal needle-biopsy specimens that had been formalin-fixed and paraffin-embedded were analyzed using polymerase chain reaction (PCR) with subsequent nonradioactive Southern blot technique. Light microscopic examination and immunofluorescence were also performed. In 30 of 33 renal biopsy specimens, the beta globin gene could be successfully amplified as integrity controls. These 30 patients consisted of 12 patients with immunoglobulin A nephropathy (IgAN), 10 patients with minor glomerular abnormalities, 6 patients with membranous nephropathy, and 2 patients with focal/segmental lesions. EBV was detected in 7 of 12 patients with IgAN (58%), 3 of 6 patients with membranous nephropathy (50%), 0 of 10 patients with minor glomerular abnormalities (0%), and 2 of 2 patients with focal/segmental lesions. EBV detection was not disease specific. The EBV detection ratio of the group with glomerular mesangial lesions (64%; 9 of 14 patients) was significantly greater than those without (19%; 3 of 16 patients; P < 0.012, chi-square test). The EBV detection ratio of the group with glomerular lesions (60%; 12 of 20 patients) was significantly greater than those without (0%; 0 of 10 patients; P < 0.0016, Fisher's exact test), and the EBV detection ratio of the group with fibrinogen deposits observed in immunofluorescence (73%; 11 of 15 patients) was significantly greater than those without (7%; 1 of 15 patients; P < 0.0002, chi-square test). The EBV detection ratio of the group with immunoglobulin deposits (57%; 12 of 21 patients) was also significantly greater than those without (0%; 0 of 9 patients; P < 0.0040, Fisher's exact test). These data suggest that EBV can damage the glomerular mesangium beyond disease units and be mediated by immunoglobulin in patients with various chronic glomerulonephritides.     

Glomerulonephritis associated with hepatitis B surface antigenemia. Report of a case with features of both membranous and IgA nephropathy

A 40-year-old man with hepatitis B surface (HBs) antigenemia developed the nephrotic syndrome. Renal biopsy revealed a glomerulonephritis with features of both membranous glomerulonephropathy and IgA nephropathy. Histologically some glomeruli showed mesangial expansion and hypercellularity only, while others contained sclerotic segments. Direct immunofluorescence demonstrated granular IgG-bearing deposits along the peripheral glomerular capillaries and IgA-containing ones in the mesangium. HBs antigen was detected by indirect immunofluorescence both along the glomerular capillary walls and within the mesangium. Granular epimembranous and mesangial deposits were observed by electron microscopy. A few mesangial deposits consisted of spherical particles, 35-100 nm in diameter. Although 3 cases of mixed membranous and IgA nephropathy have been previously reported, this appears to be the first one to be associated with HBs antigenemia.     

Unusual glomerulopathy with aggregated subepithelial microspheric particles resembling membranous nephropathy: a variant of glomerulopathy associated with podocytic infolding?

A 69-year-old woman presented with unusual electron microscopic findings. The patient was admitted to ascertain the cause of her persistent proteinuria, and kidney biopsy was performed. While light microscopic findings and immunofluorescence study suggested membranous nephropathy, electron microscopic study showed microspheric particles aggregated in the subepithelial space where electron-dense deposits should have existed. While the microspheric particles could have been unusual and rough deposits, detailed study suggested that the particles could be parts of glomerular podocytes, for example foot processes. This unusual finding was considered as being in a unique clinical course of membranous nephropathy, but a variant of glomerulopathy associated with podocytic infolding, proposed by Joh et al. (J Nephrol 49:61–67, 2007), could not be excluded.     

Insulin deposits in membranous nephropathy associated with diabetes mellitus.

Seven diabetic patients with membranous nephropathy were immunohistologically studied in order to clarify the role of extrinsic insulin in membranous nephropathy. In three cases (group A), granular deposits of insulin were detected along the glomerular capillary wall with indirect immunoperoxidase technique using anti-porcine insulin antibody, where IgG and C3 were deposited in the identical pattern. The other four cases (group B), 8 of idiopathic membranous nephropathy, and 5 of diabetic glomerulosclerosis showed no insulin deposit in the glomerulus. Clinically, proteinuria was heavier in group A (mean +/- SE; 32.0 +/- 5.4 g/day) than in group B (5.5 +/- 0.5). Nephrotic syndrome developed after the beginning of the therapy with porcine insulin, and in two of them, proteinuria was ameliorated after porcine insulin was replaced by human insulin. Since porcine insulin is a heterologous peptide for human beings and has antigenicity when injected into patients, immune complex composed of insulin and anti-insulin antibody may cause membranous nephropathy in some diabetic patients treated with this animal insulin.     

Study on the swine glomerulopathy resembling human IgA nephropathy

Naturally occurring swine glomerulopathy was investigated and its glomerular tissue injury was compared with that of human IgA nephropathy. Mild proteinuria (30%) and microhematuria (17%) was found in 30 six-month-old swine. Serum creatinine level was 1.8 +/- 0.4 (mean +/- SD) mg/dl. Light microscopy (LM) disclosed diffuse or focal glomerulopathy with mesangial enlargement and hemispherical deposits in six-month-old swine. Electron microscopy revealed dense deposits in the mesangial, para-mesangial and sub-endothelium areas. On immunofluorescence+ (IF) staining findings, granular deposits of IgA (97%), IgG (97%), IgM (80%), C3 (100%), and mycoplasma hyorhinis (MH) antigen (90%) were found in the mesangial areas and along the capillary walls. One three-month-old pig and one five-year-old Goettingen mini pig were also found to have granular deposits of immunoglobulin and MH antigen in the glomerulus. In contrast, no glomerular lesion was found in all 4 new-born pigs and 4 fetal pigs by LM and IF study. In six-month-old swine anti-nuclear factor and anti-DNA antibody were negative, and no pathological lesion was found in the liver by LM. And IgA and MH antigen containing circling immune complexes were positive in sera by Raji cell assay, and moreover IgA and MH antigen was found co-depositing by the double stain techniques. These findings suggest that swine glomerulopathy is similar in appearance to human IgA nephropathy and MH antigen may contribute to the development of this nephropathy.     

Hepatitis B e antigen-associated membranous nephropathy

A case of hepatitis B virus (HBV)-associated membranous nephropathy (MN) is presented in an 18-year-old Korean male, whose renal disease had begun 9 years previously. He was positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and antibody to hepatitis B core antigen (anti-HBc) in the serum. By immunofluorescence, HBeAg staining was noted in glomerular deposits in association with IgG, C3 and Clq, while neither HBsAg nor HBcAg was found in the glomerular deposits. The presence of glomerular HBeAg staining by FITC-monoclonal anti-HBe F(ab')2 fragments has been reported before, but never in non-Japanese patients. The demonstration of HBeAg in both the glomerular deposits and serum in this case supports the causal relationship of HBeAg and HBV-associated MN.     

Gouty kidney associated with membranous nephropathy: participation of renal tubular epithelial antigen

Histological studies were performed on 3 patients with gout and proteinuria measured at 1.0 g a day or more. Light microscopy revealed diffuse thickening of the glomerular capillary walls accompanied by spike formation and bubble-like appearance as well as tophaceous granuloma in the interstitium, tubular atrophy and benign nephrosclerosis. Immunofluorescence technique showed fine granular deposits of IgG and C3 along the glomerular capillary walls together with the renal tubular epithelial antigen (RTE) in 1 patient. Subepithelial dense deposits were also observed by electron microscopy. These findings suggest that the association of membranous nephropathy should be considered in patients with gout having moderate to severe proteinuria and that RTE may be involved in the pathogenesis of subepithelial deposits in gouty membranous nephropathy.     

A case presenting with rapid renal damage caused by immunoglobulin D lambda-type multiple myeloma accompanied by granular lymphocyte proliferative disorder

A 69-year-old man was referred to our hospital for severe anemia. The atypical lymphocyte count, including granular lymphocytes, was 2,750/μL. Lymphocyte surface marker analysis showed CD3+, CD5+, CD16+, and CD56+ cells. Mixed T cell- and natural killer cell-type granular lymphocyte proliferative disorder (GLPD) was diagnosed. Because his serum creatinine levels deteriorated rapidly over the next 3 months, from 0.96 to 3.27 mg/dL, he was admitted to our hospital. The serum levels of immunoglobulins (Ig) other than IgD had decreased, and monoclonal protein was detected in the gamma-globulin region. Immunoelectrophoresis revealed IgD and lambda (λ) proteins in the serum and λ-type Bence-Jones protein in the urine. Renal biopsy examination revealed widespread tubular atrophy and interstitial fibrosis, and cast formation with λ protein deposits in tubular lumens, indicating cast nephropathy. These results indicated that the rapid renal damage was caused by IgD λ-type multiple myeloma accompanied by GLPD. The clinical course of GLPD is not usually aggressive and the findings of physical examinations are not significant. GLPD is usually associated with cytopenia (neutropenia or anemia), viral infections, collagen diseases, neoplasms such as malignant lymphoma, or chronic infections. To date, there are only 2 case reports of GLPD accompanied by multiple myeloma but without renal function or renal histological findings. When the clinical course of GLPD is aggressive and is accompanied with rapid renal damage, multiple myeloma should be considered as a complication.     

A case of anti-GBM nephritis (crescentic glomerulonephritis) associated with membranous nephropathy]

We report a case of endstage renal disease due to simultaneous occurrence of membranous nephropathy and crescentic glomerulonephritis associated with anti-GBM antibodies. The patient was a 60-year-old male and was hospitalized for prolonged anorexia and general malaise. On admission, his body temperature was 38.5 degrees C. Urinalysis revealed 3+ proteinuria and the sediment contained abundant erythrocytes. The urea nitrogen was 142.4 mg/dl, the creatinine 19.5 mg/dl, the potassium 6.47 mEq/dl and CRP 10.1 mg/dl. Anti-GBM antibodies were 1000EU/ml. Immediately after initiating hemodialysis, pulse steroid therapy, plasma exchange and continuous heparinization were performed. However, renal function had been impaired and maintenance hemodialysis was required. Histological examination of the renal specimen revealed marked epithelial crescent formation, whereas thickening of basement membrane and mesangial proliferation were not observed. By immunofluorescent staining, both bright linear and fine granular fixation of IgG and fine granular fixations of C3 along the glomerular capillary walls were observed. Electron microscopy showed subepithelial electron lucent deposits and thickening of the glomerular basement membrane, diagnostic of the advanced membranous nephropathy (stage IV).     

An unusual variant of membranous nephropathy with abundant crescent formation and recurrence in the transplanted kidney.

A patient with what initially appeared to be a typical membranous nephropathy had a progressive course to renal failure, nephrectomy, and transplantation. The nephrectomy specimen revealed abundant glomerular crescents and capsular synechiae. Post-transplantation the patient again developed a membranous nephropathy with florid crescents. Radioimmunoassay and indirect immunofluorescence tests failed to reveal anti-glomerular basement membrane antibody in the serum or kidney. It appears that there is a form of membranous nephropathy with crescent formation, unrelated to anti-GBM antibody, which has the capacity to recur after transplantation.     

Myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyarteritis (MPA) associated with Hashimoto's thyroiditis and increased serum rheumatoid factor

An autopsy case of microscopic polyarteritis (MPA) associated with Hashimoto's thyroiditis that showed glomerular immunoglobulin and complement depositions and high titers of rheumatoid factor and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) is reported. A 72-year-old woman was admitted to our hospital because of renal failure that had deteriorated from a serum creatinine value of 175.8 to 1874.1 μmol/l in 4 weeks. Laboratory studies on admission revealed proteinuria, numerous red blood cells, granular casts and red blood casts in the urine, increased serum blood urea nitrogen (47.8 mmol/l), anemia (hemoglobin, 60 g/l), and thrombocytopenia (platelets, 71 × 10⁹/l). Emergency hemodialysis was started; however, the patient died on the fifth hospital day because of ventricular tachycardia, and an autopsy was performed. At autopsy, the patient was found to have had increased serum levels of immune complexes, rheumatoid factor, IgG rheumatoid factor, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), anti-thyroglobulin antibody, and anti-thyroid peroxidase antibody, and decreased serum complement levels. Microscopic examination revealed crescentic glomerulonephritis in almost all glomeruli, and positive granular deposits of IgG, IgA, IgM, C1q, C3, and C4 in the mesangium and along the capillary walls. Typical fibrinoid necrosis was found in the small arteries of the stomach, colon, small intestine, and bladder. Finally, Hashimoto's thyroiditis was noted. To our knowledge, this is the first case of MPO-ANCA-positive MPA associated with Hashimoto's thyroiditis and increased serum rheumatoid factor levels. Received: February 9, 2000 / Accepted: July 4, 2000     

Pathogenetic and therapeutic approaches to IgA nephropathy using a spontaneous animal model,the ddY mouse

IgA nephropathy is the most common primary chronic glomerulonephritis in the world and was first described by Berger et al. (J Urol Nephrol 74:694–695;1968). Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. In advanced patients, global glomerular sclerosis, crescent formation and tubulo-interstitial fibrosis are marked in light microscopy. IgA nephropathy is generally considered to be an immune-complex mediated glomerulonephritis. Although more than 40 years have passed since this disease was firstly described, the pathogenesis/initiation factors of IgA nephropathy are still obscure. The objective of this review is to explain the pathogenesis and treatment based on our previous data of ddY mouse, a spontaneous animal model for IgA nephropathy.     

Abnormal distribution of mesangium-specific laminin in glomeruli of patients with idiopathic membranous nephropathy

Using a monoclonal antibody, the distribution of the mesangium-specific laminin that binds only to the mesangium in normal kidney, was studied immunohistochemically in renal tissues obtained from patients with different glomerulonephritides including idiopathic membranous nephropathy. In minimal change nephrotic syndrome and IgA nephropathy, the mesangium-specific laminin staining was restricted to the mesangium, as is observed in the normal kidney. However, in patients with idiopathic membranous nephropathy, the monoclonal antibody against the mesangium-specific laminin reacted with the glomerular peripheral capillary walls including subepithelial protrusions or 'spikes', as well as with the mesangium. These results suggest that the quality of laminin produced in response to the challenge of immune deposits in the peripheral capillary walls may be different from that in the rest of the glomerular basement membrane in idiopathic membranous nephropathy.     

Preeclamptic nephropathy associated with membranous nephropathy

We report a patient who had nephropathy of toxemia of pregnancy associated with membranous glomerulonephritis, which deteriorated 3 months after delivery. Electron microscopy revealed electron-dense deposits on the subepithelial surface of the glomerular basement membrane and finely granular/fibrillar materials in the subendothelial space. As a result of treatment with prednisolone and anticoagulants, marked alleviation of both proteinuria and edema was achieved. We therefore consider that the change from subclinical to clinical membranous nephropathy could be attributed to pregnancy. Received: February 22, 2001 / Accepted: July 12, 2001     

Mechanisms of immune-deposit formation and the mediation of immune renal injury

The passive trapping of preformed immune complexes is responsible for some forms of glomerulonephritis that are associated with mesangial or subendothelial deposits. The biochemical characteristics of circulating antigens play important roles in determining the biologic activity of immune complexes in these cases. Examples of circulating immune complex diseases include the classic acute and chronic serum sickness models in rabbits, and human lupus nephritis. Immune deposits also form “in situ”. In situ immune deposit formation may occur at subepithelial, subendothelial, and mesangial sites. In situ immune-complex formation has been most frequently studied in the Heymann nephritis models of membranous nephropathy with subepithelial immune deposits. While the autoantigenic target in Heymann nephritis has been identified as megalin, the pathogenic antigenic target in human membranous nephropathy had been unknown until the recent identification of neutral endopeptidase as one target. It is likely that there is no universal antigen in human membranous nephropathy. Immune complexes can damage glomerular structures by attracting circulating inflammatory cells or activating resident glomerular cells to release vasoactive substances, cytokines, and activators of coagulation. However, the principal mediator of immune complex-mediated glomerular injury is the complement system, especially C5b-9 membrane attack complex formation. C5b-9 inserts in sublytic quantities into the membranes of glomerular cells, where it produces cell activation, converting normal cells into resident inflammatory effector cells that cause injury. Excessive activation of the complement system is normally prevented by a series of circulating and cell-bound complement regulatory proteins. Genetic deficiencies or mutations of these proteins can lead to the spontaneous development of glomerular disease. The identification of specific antigens in human disease may lead to the development of fundamental therapies. Particularly promising future therapeutic approaches include selective immunosuppression and interference in complement activation and C5b-9-mediated cell injury.     

Prolonged membranous lupus nephritis with change of anti-ssDNA antibody titer and repeated renal relapse

We report a case of a 44-year-old woman with nephrotic syndrome who underwent renal biopsy three times. On each occasion, light microscopy showed membranous nephropathy with mild to moderate thickening of the glomerular capillary walls. Immunofluorescence microscopy showed predominant deposition of immunoglobulin (Ig) G, IgG1, IgG2, IgG3, and IgG4; C3; and C1q along the glomerular capillary walls and deposition of IgM and IgA in some parts of the walls. Electron microscopy revealed the accumulation of electron-dense deposits in the mesangium and the subepithelial area of the glomerular basement membrane. Virus-like particles were detected in the subendothelial cells in all three biopsy specimens. A definitive diagnosis of systemic lupus erythematosus (SLE) was made at the time of the second admission, when she was 31 years old. A diagnosis of membranous lupus nephritis was then made on the basis of the pathological and clinical findings. A change in anti-single-stranded (ss)DNA antibody titers was of particular interest in this patient. Occasional small increases in anti-double-stranded (ds)DNA antibody were found, but increased anti-ssDNA antibody titers occurred before there was any elevation of urinary protein during renal relapse, and a sustained increase in the titers was shown subsequently. Hypocomplementemia occurred in parallel with the increase of anti-ssDNA antibody. Immunosuppressive therapy with steroid promptly eliminated anti-dsDNA antibody, but anti-ssDNA antibody remained positive. The patient had normocomplementemia and proteinuria was absent. Later, anti-ssDNA antibody decreased. Renal function has remained in the normal range for 20 years.     

A case of membranous glomerulonephritis in renal allograft

A 39-year-old man who had been diagnosed with immunoglobulin A (IgA) nephropathy underwent renal transplant from his father. The operation was performed under cyclosporine, prednisolone and mizoribine treatment. Renal function was stable following transplantation, but proteinuria ranged between 1 g/day and 3 g/day. Protocol biopsy 1 year after transplantation revealed membranous glomerulonephritis, with IgG and C3 deposits under immunofluorescence, and subepithelial deposits detected on electron microscopy. The patient was treated by limiting protein intake, controlling blood pressure and administering candesartan. Proteinuria decreased from 5.6 g/day to 1 g/day, but a graft biopsy was performed 2 years after transplantation because of a slightly increasing creatinine level. There was no sign of rejection, and IgG and C3 deposits observed under immunofluorescence had decreased. After the graft biopsy, the creatinine level was stable and proteinuria decreased to 0.7 g/day. In conclusion, de novo nephropathy such as membranous glomerulonephritis should also be considered a possible cause of proteinuria following renal transplantation.     

Clinicopathological study of originally non-lupus “full-house” nephropathy

Background: Glomerular “full-house” immunofluorescence staining commonly indicates lupus nephritis. However, some non-lupus nephropathy also can present with a “full-house” immunofluorescence pattern mimicking lupus nephritis. The goal of this study is to define the clinicopathological spectrum of originally non-lupus “full-house” nephropathy. Methods: Records of 24 patients with “full-house” nephropathy in the absence of clinical or serological evidence of systemic lupus erythematosus (SLE) at the time of renal biopsy were abstracted for demographics, clinical presentation, laboratory data, renal biopsy findings, and clinical follow-up. Results: The clinicopathological diagnoses included membranous glomerulonephritis (GN) (46%), IgA nephropathy (21%), membranoproliferative GN (12.5%), postinfectious GN (12.5%), C1q nephropathy (4%), and unclassified mesangial GN (4%). No one had endothelial tubuloreticular inclusions. One patient originally diagnosed as IgA nephropathy developed anti-DNA antibody and another one patient with membranous GN developed hypocomplementemia 8 months and 10 months after renal biopsy, respectively. The two patients also developed clinical symptoms of lupus subsequently. Conclusions: There was a broad spectrum of glomerular histological findings in non-lupus “full-house” nephropathy. The possibility of “full-house” nephropathy preceding the emergence of overt systemic lupus erythematosus remained to be elucidated.     

Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy.

BACKGROUND: Several studies have shown a predominant glomerular deposition of IgG4 in patients with idiopathic membranous nephropathy (MN), whereas significant depositions of other IgG subclasses have been shown in patients with lupus-associated MN and bucillamine-induced MN. METHODS: We examined the distribution patterns of glomerular IgG subclass deposits in 10 patients with malignancy-associated MN (M-MN) and in 15 patients with idiopathic MN by immunofluorescence (IF) microscopy. RESULTS: The glomerular IF intensities of IgG1 and IgG2 were significantly stronger in the malignancy group than in the idiopathic group (P<0.05). In contrast, there were no differences in glomerular IF intensities of IgG3 and IgG4 between the two groups. CONCLUSION: Our findings suggest that the distribution patterns of glomerular IgG subclass deposits are different in idiopathic MN and M-MN. The strong IF intensity of glomerular IgG1 and IgG2 in M-MN may provide a possible predictor for this condition.