Membranous glomerulopathy with Bowman's capsular and tubular basement membrane deposits

Bowman's capsular and tubular basement membrane (TBM) deposits are an extremely unusual finding in non-lupus membranous glomerulopathy (MGN). We report three atypical cases of MGN with abundant Bowman's capsular and TBM deposits. In two cases, MGN was idiopathic; in the third case, MGN occurred in the renal allograft in the setting of HCV seropositivity. In addition to the usual glomerular capillary wall deposits, immunofluorescence and electron microscopy revealed extensive immune deposits within Bowman's capsule and TBMs, predominantly at the base of parietal and tubular epithelial cells. These cases suggest a potential pathomechanism of autoantibody to secreted epithelial antigens shared by visceral, parietal, and tubular epithelial cells. In all three cases, indirect immunofluorescence was unable to detect autoantibody to normal renal epithelial or matrix constituents. Furthermore, ELISA was unable to demonstrate circulating antibody to major extracellular matrix components. The implications of these findings for the pathogenesis of MGN are explored.     

Development of kidney tubular basement membranes

Although some progress has been made in recent years, there are truly large gaps in our basic knowledge on how the TBM is assembled during development. Some of the new evidence presented here indicates that both the tubular epithelium and interstitial fibroblasts participate in TBM protein biosynthesis during nephrogenesis. In addition, newly assembled segments of TBM are spliced or inserted into existing TBM during tubule expansion and elongation. A similar splicing mechanism has been described previously in the GBM, endocrine organs, and intestinal villi, and this mechanism therefore probably represents a fundamental process of basement membrane formation. A major unresolved question at present, however, is how this mechanism operates at the molecular level. Does the newly formed basement membrane contain identical components as that already present? Since an enzymatic process is likely occurring in the insertion of new matrix into old, which enzymes are involved? What is the cellular origin of these enzymes and which matrix component(s) is their substrate? Even more fundamental yet unanswered questions have to do with the mechanisms of epithelial induction, basement membrane gene activation, and tubular morphogenesis. Once the basement membrane is fully formed at the completion of nephrogenesis, what controls basement membrane turnover and how does this operate? Clearly, much additional research is necessary to address these questions. This work is needed, however, before we can fully understand the important roles basement membranes play in normal development as well as in disease.     

New familial nephropathy involving glomerular and tubular basement membranes

We describe two siblings, an 8-year-old boy and a 9-year-old girl, with severe mental retardation, dwarfism, optic atrophy and nephropathy. Laboratory examination showed ₂-microglobulinuria, decreased creatinine clearance, hypercholesterolaemia and elevated serum levels of muscle enzymes. Renal biopsy from one of the patients demonstrated characteristic ultrastructural changes involving both the glomerular and tubular basement membrane. This group of symptoms and laboratory findings is quite distinct and differs from those of other reported familial nephropathy syndromes. We conclude that this disorder may represent a new syndrome of autosomal recessive inheritance.     

High-resolution ultrastructural comparison of renal glomerular and tubular basement membranes

BACKGROUND/AIMS: Glomerular basement membranes (GBM) and tubular basement membranes (TBM) consist of a fine meshwork composed mainly of type IV collagen. Each segment of tubules has specialized physiologic functions, and thus we investigated the ultrastructure of various basement membranes in rat kidneys. METHODS: Since purifying basement membranes from different tubule segments is technically challenging, we employed tissue negative staining rather than conventional negative staining to compare the ultrastructures of proximal and distal TBM and GBM in normal rats. We also assessed the distribution of extracellular matrix components including type IV collagen, laminin, heparan sulfate proteoglycan, and fibronectin in the basement membranes by immunohistochemistry. RESULTS: TBM and GBM of normal rats showed a fine meshwork structure consisting of fibrils forming small round to oval pores. Short- and long-pore diameters in proximal tubules were 3.3 +/- 0.5 and 3.9 +/- 0.6 nm, respectively, and in distal tubules 3.5 +/- 0.7 and 4.3 +/- 0.8 nm, respectively. For GBM the respective diameters were 2.5 +/- 0.5 and 3.0 +/- 0.5 nm. Immunohistochemical analysis showed no significant difference in distribution of extracellular matrix components between proximal and distal TBM. However, immunofluorescence scores of alpha1 chain of type IV collagen, fibronectin, and laminin were higher in the TBM than in the GBM. On the other hand, heparan sulfate proteoglycan was higher in the GBM. CONCLUSION: Ultrastructural differences in renal basement membranes may be related to differences in physiologic function in each segment. Copyright Copyright 1999 S. Karger AG, Basel     

Immunoelectron microscopic localization of fibronectin and complement to 'dense bodies' in Bowman's capsule and the glomerular basement membrane in membranous nephropathy

This study describes dense bodies seen in Bowman's capsule and the glomerular basement membrane in biopsies of membranous glomerulonephritis. Within these bodies, silver-enhanced immunogold labelling demonstrated the presence of fibronectin and the complement component C3b. These results suggests that dense bodies may play a role in opsonization and the immune process in membranous glomerulonephritis.     

Role of antibodies directed against tubular basement membranes in human renal transplantation

Direct immunofluorescence studies of graft biopsies from 662 renal transplant recipients demonstrated linear IgG deposition along tubular basement membranes (TBM) in 18 cases. In ten of them, circulating anti-TBM antibodies, whose detectable levels varied from 1/4 to 1/100, were demonstrated by indirect immunofluorescence on normal human kidneys. These antibodies reacted with every human kidney tested and in two cases, it could be demonstrated that they recognized the TBM of the patient's own end-stage kidney. Hence, they reacted as autoantibodies. Circulating anti-TBM antibodies were detected within the first 6 months after transplantation, remained present for an average of 3 months, and never recurred once they had disappeared. Serial biopsies demonstrated the loss of IgG linear fixation on TBM. Neither tubular nor interstitial injury was significantly associated with the presence of anti-TBM antibodies, and the transplant survival was not different in these patients who developed anti-TBM antibodies compared to our entire population of transplant biopsies.     

Sulfated glycosaminoglycan content of glomerular and tubular basement membranes of individuals of different ages

The glycosaminoglycan content of glomerular and tubular basement membranes in individuals ranging from preterm neonates to 90-years-old people was determined with a spectrophotometric assay after papain digestion. A decrease of glycosaminoglycans until the age of 2.5 years was observed only in glomerular basement membrane. Tubular basement membranes did not show significant changes with age. Glomerular basement membranes of neonates had a higher glycosaminoglycan content than tubular basement membranes.     

Autoantibody specific for the glomerular mesangium and Bowman's capsule in man.

Investigation of serum from a nominally healthy subject revealed an unusual autoantibody with specificity for the glomerular mesangium and Bowman's capsule. Immunofluorescence studies on rodent kidney sections revealed typical mesangial fluorescence and intense linear staining of Bowman's capsule. The antibody was organ, but not species, specific and did not correspond to any previously described antibody with anti-mesangial activity (e.g. anti-actomyosin or anti-fibronectin). Intravenous injection in mice resulted in heavy mesangial deposition of antibody within one hour, the antibody disappeared within 2--4 weeks, and no urinary abnormalities were seen. Retrospective analysis of clinical data revealed a history of chronic hepatitis and possible drug abuse, but no evidence for impaired renal function at any timepoint. To our knowledge this is the first report of specific anti-mesangial antibody in man, the pathogenetic relevance remains unclear.     

Morphometric study of glomerular basement membrane and proximal tubular basement membrane in adult thin basement membrane disease

Background. Thin basement membrane disease (TBMD) is a benign hereditary glomerulopathy with a diffuse attenuation of glomerular basement membrane (GBM). Whether the development of renal basement membranes other than GBM is normal in TBMD has not yet been resolved. Methods. We performed a morphometric study to measure the thickness of GBM and proximal tubular basement membrane (P-TBM) in 44 adult patients with TBMD and in 10 adult diseased controls confirmed to have minor glomerular abnormalities. Results. There was a significant difference between the patients with TBMD and the diseased controls in the thickness of the GBM; however, there was no significant difference between the two groups in the thickness of the P-TBM. In the patients with TBMD, the thickness of the GBM was unchanged with age, but the thickness of the P-TBM increased with age, as did that in the diseased controls. Conclusion. Our morphometric study clarified that the development of P-TBM was normal in the patients with TBMD. Received: October 7, 1998 / Accepted: May 27, 1999     

Renal interstitial cell infiltration in rats induced by immune reactions around proximal tubular basement membrane

Background. Since it has been shown that the severity of tubulointerstitial nephritis (TIN) and, in particular, the degree of monocyte infiltration, correlate both with the degree of renal impairment at biopsy and with the risk of disease progression, attention has been focused on the development of experimental models of TIN. Methods. We induced TIN by injecting rats with a monoclonal antibody, R3b1 (which binds around the proximal tubular basement membrane (TBM) but not to glomeruli), and also by enhancing the host immune reactions to R3b1 bound around the TBM. Results. R3b1 was demonstrated to bind around the proximal TBM but not to glomeruli in vitro and also in vivo. The binding of R3b1 around the proximal TBM induced mild focal ED-1-positive cell infiltration in the interstitium. Enhanced host immune reaction to bound R3b1 resulted in a transient increase in the number of focally infiltrated ED-1-positive cells in the interstitium, although it shortened the period during which R3b1 was demonstrable around the TBM. There were no significant increases in immunostaining for vimentin and osteopontin, or collagen types I and IV, suggesting that, immunohistochemically, there was no tubular cell damage and no interstitial fibrosis, respectively. Light microscopy revealed focal interstitial cell infiltration, supporting the results obtained by immunofluorescence as ED-1-positive cell infiltration. Tubular cell atrophy, enlargement, and interstitial fibrosis were not observed. Conclusions. The enhancement of host immune reaction to mouse immunoglobulins, i.e., to monoclonal antibody R3b1 bound around the proximal TBM induced by two immunizations, resulted in an increased degree of focal ED-1-positive cell infiltration in the interstitium, but no demonstrable tubular cell injury or interstitial fibrosis. R3b1 did not induce progressive tubulointerstitial injury, even in rats preimmunized and booster-immunized with mouse IgG. Received: July 6, 1998 / Accepted: April 28, 2000     

Podocyte bridges between the tuft and Bowman's capsule: an early event in experimental crescentic glomerulonephritis

Although experimental crescentic glomerulonephritis starts with an endocapillary inflammation, the crescents themselves seem to originate from the proliferation of parietal epithelial cells (PEC). In this study, an attempt was made to disclose a link between the two processes by a morphologic analysis of early stages of the disease. Mice were immunized with rabbit IgG in complete Freund's adjuvant on day -6. At day 0, they received an intravenous injection of a rabbit antiglomerular basement membrane serum. On days 3, 6, and 10, the kidneys were fixed by vascular perfusion for examination by light and electron microscopy. On day 3, morphologic alterations affected mainly the endocapillary compartment; most podocytes appeared to be intact. On day 6, alterations of podocytes were widespread, including foot process effacement and prominent microvillous transformation, and some crescents were found. On day 10, crescents were found in 40% of glomeruli. The most surprising finding was podocytes that adhered to both the glomerular basement membrane and the parietal basement membrane, thus forming bridges between the tuft and Bowman's capsule. Those podocyte bridges were sparse on day 3 but were regularly encountered on days 6 and 10 in glomeruli without crescents and also as a component of crescents. They were interposed between PEC and later between the cells of a crescent without formation of junctional connection with these cells. It is proposed that the spreading of podocytes on the parietal basement membrane represents a lesion of the parietal epithelium and that this process initiates the proliferation of PEC to form a crescent.