Thickening Of Capillary Walls Research Articles

Perivascular siderophages in skeletal muscle from a patient with diabetic neuropathy

Hemosiderin deposition in skeletal muscle histiocytes is uncommon but has been occasionally noted in hemochromatosis, hemosiderosis and Waldenstrom's macroglobulinemia. The purpose of this report is to describe the light microscopic and ultrastructural characterization of this abnormality in a patient with diabetes mellitus. A 56-year-old diabetic male presented with paresthesias and intermittent diffuse lower extremity myalgias. Neurologic examination was remarkable only for diminished vibratory sense in the toes, diminished deep tendon reflexes, and ankle-level stocking distribution hypalgesia. There was no clinical evidence of hemochromatosis and laboratory studies ruled out Waldenstrom's macroglobulinemia. Muscle biopsy showed modest variability in myofiber diameter with a few scattered angular atrophic type II fibers. There were numerous collections of granular pigment-containing histiocytes in endomysial and perimysial perivascular areas and marked thickening of blood vessels walls. The histiocytic pigment was bright blue with the Prussian blue stain. No pigment was seen in the myofibers. Ultrastructural examination revealed numerous perivascular histiocytes filled with hemosiderin containing granules of variable size and density and marked thickening of capillary walls with striking reduplication of basement membranes. A modest number of subsarcolemmal paracrystalline mitochondrial inclusions were present. X-ray dispersion analysis of the histiocytic pigment material confirmed the presence of iron in the lysosomal granules.

Anti-DNA antibodies form immune deposits at distinct glomerular and vascular sites

To investigate the capacity of lupus autoAb to produce glomerular immune deposits (ID) and nephritis, 24 murine monoclonal (m) anti-DNA antibodies (Ab), derived from either MRL-lpr/lpr, SNF1 or NZB lupus-prone mice and selected based on properties shared with nephritogenic Ig, were administered i.p. (as hybridomas) and i.v. (as purified Ig) to normal mice; at least four mice/mAb were evaluated. Three general patterns of immune deposit formation (IDF) were observed: extracellular ID within glomeruli (+/- blood vessels, N = 8); intranuclear ID (N = 5); or minimal or no ID (N = 11). The four MRL m anti-DNA Ab that produced significant extracellular ID demonstrated different disease profiles including: (a) mesangial and subendothelial ID with anti-basement membrane staining, associated with proliferative glomerulonephritis, PMN infiltration, and proteinuria; (b) diffuse fine granular mesangial and extraglomerular vascular ID, associated with proliferative glomerulonephritis and proteinuria; (c) dense intramembranous ID and intraluminal ID, associated with capillary wall thickening, mesangial interposition and expansion, aneurysmal dilatation and intraluminal occlusion of glomerular capillary loops, and heavy proteinuria; and (d) mesangial and extraglomerular vascular ID, associated with mild segmental mesangial expansion, without proteinuria. These MRL mAb were derived from four different mice, and they had variable pIs and isotypes. They all cross reacted with multiple autoantigens (autoAg), however, their autoAg binding profiles were distinguishable. Among the SNF1 derived mAb, four produced histologically and clinically indistinguishable disease characterized by diffuse mesangial and capillary wall ID, associated with cellular proliferation/infiltration and proteinuria. Three of the four mAb were derived from the same mouse and were clonally related; they were: IgG2b with SWR allotype, relatively cationic, highly cross reactive with similar Ag binding patterns, idiotypically related and encoded by identical VH and nearly identical VL sequences. We conclude that both the capacity of lupus autoAb to form ID and the location of IDF are dependent on properties unique to individual Ig. The results also indicate that the Ag binding region of the autoAb is influential in this process, and they suggest that multiple Ab-Ag interactions contribute to IDF in individuals with lupus nephritis. Furthermore, these observations raise the possibility that the pathologic and clinical abnormalities resulting from these interactions are influenced by the location of IDF, and that the dominant interaction, in a given individual, may be highly influential in the phenotypic expression of nephritis.

Nature and extent of glomerular injury induced by cyclosporine in heart transplant patients

We sought to clarify whether low-dose cyclosporine (5.0 +/- 2.2 mg/kg/day) given for more than two years to prevent cardiac graft rejection induced glomerular injury and to quantify the extent of the lesions. After renal hemodynamic studies, renal biopsy specimens were obtained from 10 patients on cyclosporine and analyzed by a novel morphometric technique consisting of a tridimensional reconstruction of the glomerular tuft. Autopsy kidney specimens from three patients with no clinical history of renal disease, and from four patients who died with dilatative cardiomyopathy served as controls. The glomerular filtration rate and renal plasma flow were significantly depressed below normal values in transplant recipients given cyclosporine, averaging 35 +/- 8 and 325 +/- 94 ml/min/1.73 m2, respectively. Conventional light microscopy of specimens from controls and from patients who died with dilatative cardiomyopathy did not reveal renal structural abnormalities. By contrast kidney specimens from cyclosporine-treated patients had obliterative arteriolopathy and ischemic-type changes, with thickening and wrinkling of glomerular capillary wall. Morphometrical analysis of 28 control glomeruli and 40 glomeruli from patients with dilatative cardiomyopathy showed glomerular capillary tuft volumes (VCT) ranging between 1.2 and 2.3 microns 3 x 10(-6), whereas of 102 glomeruli from cyclosporine-treated patients 42.1% had VCT lower than 1.2 microns 3 x 10(-6) and 24.4% VCT higher than 2.3 microns 3 x 10(-6).(ABSTRACT TRUNCATED AT 250 WORDS)

Nonamyloidotic fibrillary glomerulopathy

A 29-year-old man had oedema, proteinuria in nephrotic range, haematuria and cardiac arrhythmia (second grade atrioventricular block). The pathologic findings of kidney biopsy showed in light microscopy diffuse mesangial matrix increase with mild mesangial proliferation and variable thickening of the glomerular capillary walls. IgG, c3 and c1q were intensely fluorescent and exhibited a diffuse granular pattern in mesangial areas and along the capillary walls. Both kappa and lambda chains were weakly positive in the same pattern. Ultrastructurally, microfibrils of about 20 nm in width were seen to be deposited in mesangial areas and along the glomerular basement membranes. Congo red stain and metachromasia were negative. Neither cryoglobulinaemia nor paraproteinaemia including light chains were found. The aetiology of nonamyloidotic fibrillary glomerulopathy is unknown and no clear-cut clinical or pathologic pattern has emerged. It may represent more than one disease process with a common morphologic expression.

Cytokines and endothelial cell biology

Ce travail resume les etudes qui ont permi la caracterisation de l'action specifique des cytokines sur les cellules endotheliales. Les cytokines agissent aussi sur l'endothelium dans des cas pathologiques cites dans cet expose

マウス加速型ｎｅｐｈｒｏｔｏｘｉｃ ｓｅｒｕｍ腎炎の形態学的検討

A glomerulonephritis was induced in mice by injection of subnephrotoxic dose of nephrotoxic serum (NTS) after preimmunization with rabbit IgG. In order to characterize this glomerulonephritis, light, electron and immunofluorescence microscopic studies were carried out 15 days after NTS injection, the time when increases in urinary protein and serum cholesterol and a decrease in serum albumin were apparent.Characteristic changes were widespread thickening of capillary walls and narrowing of the capillary lumen owing to widening of mesangial areas. In those capillary walls, the mesangial interposition into subendothelial areas was often noted ultrastructurally and double track was confirmed on sections stained with PAM. Linear deposition of mouse IgG was detected in capillary walls by immunofluorescence. In severely affected glomeruli, PAS-positive hyaline nodular lesion was observed light microscopically and massive mesangial deposits ultrastructurally.Visceral epithelial cells demonstrated fusion of the foot processes, microvilli formation, occasional proliferation and enlargement. Parietal epithelial cells proliferated, forming cellular or fibrocellular crescent.Based on these characteristics, it appears this nephritic model shares a common pathology with human membranoproliferative glomerulonephritis type 1 and crescentic glomerulonephritis and can be considered an appropriate model for producing severe nephritis for short periods.

Pathological studies on nephrotoxic serum nephritis accelerated with rabbit ?-globulin in mice

In order to characterize nephrotoxic serum nephritis accelerated with rabbit gamma-globulin in mice, histopathological studies were carried out 15 days after NTS injection, the time when increases in urinary protein and serum cholesterol and a decrease in serum albumin were apparent. Characteristic changes were widespread thickening of glomerular capillary walls and widening of mesangial areas, owing to deposits of mesangial matrixlike substances. The mesangial interposition into subendothelial areas and the resultant narrowing of the capillary lumen were shown ultrastructurally. In severely affected glomeruli, a hyaline nodular lesion was observed. Visceral epithelial cells demonstrated fusion of the foot processes, microvilli formation, occasional proliferation, and enlargement. Parietal epithelial cells proliferated, forming a cellular crescent. Based on these characteristics, it appears this nephritic model shares a common pathology with human membranoproliferative glomerulonephritis type 1 and crescentic glomerulonephritis and can be considered an appropriate model for producing severe nephritis for short periods.

The histopathology of the hemolytic uremic syndrome associated with verocytotoxin-producing Escherichia coli infections

Verocytotoxin-producing Escherichia coli (VTEC) infection was present in three cases of hemolytic uremic syndrome (HUS), two fatal and one non-fatal, in which detailed histopathologic investigations were conducted. Two patients had a prodrome of bloody diarrhea, one of whom required a hemicolectomy for severe bleeding. The renal histopathology was characterized primarily by glomerular thrombotic microangiopathy (TMA) with greater than 95% of glomeruli showing changes of capillary wall thickening, endothelial cell swelling, and narrowing or thrombosis of the capillary lumen. Preglomerular arterioles were frequently thrombosed, and abnormalities of the medium-sized vessels, including endothelial cell damage and thrombosis, were also commonly observed. Gastrointestinal involvement was prominent in all three cases. The colon was most severely involved, with marked mucosal and submucosal edema and hemorrhage, in the absence of significant inflammation or widespread ulceration. Microvascular angiopathy was present in all cases, with changes ranging from endothelial cell damage to overt thrombosis. Similar pathology was seen throughout the small bowel, including the presence of TMA. In one patient, typical morphologic changes of pseudomembranous enterocolitis were found in the absence of infection with Clostridium difficile. The nature of vascular involvement in the kidneys and intestinal tract supports the hypothesis that HUS is mediated by systemic toxemia, and that endothelial cells are the primary target cells for the action of verocytotoxin.

Experimental gold nephropathy in guinea pigs: Detection of autoantibodies to renal tubular antigens

Renal tubular dysfunction was induced in Hartley guinea pigs by injection of sodium aurothiomalate (gold) as manifested by excretion of tubular basement membrane (TBM) antigen and renal tubular epithelial (RTE) antigen in urine and tubular proteinuria. Following the tubular dysfunction, autoimmune tubulointerstitial nephritis (TIN) and/or immune complex nephropathy (ICN) developed in a large proportion of animals. TIN was associated with anti-TBM antibodies, and the histological features were characterized by tubular lesions with interstitial mononuclear cell infiltration, destruction of tubules, and interstitial fibrosis. In ICN, the glomerular lesions consisted of partial thickening of capillary walls and mesangial cellularity, and granular immune deposits were seen in the mesangial area and on capillary walls. Furthermore, electron-dense deposits were demonstrated in the mesangial area and in the glomerular basement membrane (GBM) by electron microscopy. Anti-RTE antibodies were detected in the sera and eluates from the kidney of animals with ICN. RTE antigens were also detected in the glomerular deposits by indirect immunofluorescence using anti-guinea pig RTE antibody. These results suggest that TBM and RTE antigens released from renal tubules damaged by a direct toxic action of gold may lead to antibody formation against these antigens and induce TIN and/or ICN.

Fibronectin and deposits of fibrinolytic components in glomerular capillary walls.

The distribution of fibronectin (FN) and the depositions of fibrinolytic components in human renal glomeruli with a variety of pathologic disorders were examined on biopsy specimens by immunofluorescence and immunoenzymatic methods. In a majority of the cases with thickening of capillary walls and/or with fibrin deposits in the capillary walls, staining for FN along the walls of the capillary loops (capillary pattern) was noted in addition to the staining in the mesangial area. In the capillary pattern with fibrin deposition, deposits of alpha 2-plasmin inhibitor and plasminogen, which are major components of the fibrinolytic system, were also seen along the capillary walls with a high frequency of occurrence. Plasminogen deposits, however, were found only in the glomeruli with deposits of alpha 2-plasmin inhibitor. There was no direct relationship between the degree of proteinuria and the appearance of the capillary pattern of FN or the deposition of the fibrinolytic components. These findings suggest that the appearance of FN in the walls of the capillary loops has some causal relationship with the local activation of blood coagulation factors which is frequently followed by activation of the fibrinolytic enzyme system.

Renal lesions in the obliterative cardiomyopathies: endomyocardial fibrosis and Loffler's endocarditis.

Electron and, or light microscopic examination of paraffin embedded renal tissue obtained from necropsies on eleven patients with obliterative cardiomyopathy showed a variety of abnormalities. Glomerular lesions present in patients with endomyocardial fibrosis included capillary wall thickening, basement membrane duplication, mesangial expansion and interposition, intraluminal fibrin and dense subendothelial deposits. These changes, some of which have been reported earlier in patients with Loffler's endocarditis, probably result from deposition and organisation of immune complexes.

Thickening of glomerular capillary walls: a guide to differential diagnosis by electron microscopy.

Thickening of capillary walls is a feature of many glomerular diseases. Widening of the wall may be produced by deposits and other changes affecting either subepithelial and subendothelial regions or the glomerular basement membrane itself. Careful light microscopic examination using special stains can distinguish some patterns of capillary wall thickening, but electron microscopy is needed to demonstrate most lesions clearly. In this brief review, a guide to the major causes for capillary wall thickening is discussed, using a simple classification, and some of the patterns are illustrated. Precise delineation of the capillary wall changes in glomerular diseases is important to insure accurate classification and a clear understanding of pathogenetic mechanisms.

Age-related immunohistopathological changes of murine lupus nephritis in NZB/NZW F1 mice using serial renal biopsy.

Serial renal biopsies were performed to examine the age-related morphological changes of murine lupus nephritis in NZW / NZB (NZB / W) F1mice. Renal biopsies were performed at 3, 5, 7 and 9 months of age in the same mouse. The earliest histological change was slight mesangial thickening. Mesangial hypercellularity was seen in one-third of all the cases at 7 months. With age, the incidence of mesangial thickening was progressively increased, and capillary wall thickening appeared simultaneously. The incidence of interstitial cell infiltration was found in 100% at 11 months. Significant correlations among the capillary wall thickening, crescent formation and proteinuria were observed. In an immunofluorescent study, a significant correlation between immunofluorescent deposition in the capillary wall and proteinuria was observed. The pattern of immunoglobulin deposition changed from mesangial type to capillary type with age. However, the pattern of gp 70 (retroviral antigen) deposition in glomeruli varied considerably, and in some mice the gp 70 deposition decreased with age. Furthermore, a significant correlation between the titer of circulating gp 70 immune complex (IC) and gp 70 deposits in glomeruli was found. These results suggest that the age-related morpholigical changes are due to multifarious characters of IC and due to numerous immunological disorders.

Crescentic type nephritis induced by anti-glomerular basement membrane (GBM) serum in rats.

An experimental model of crescentic type nephritis was established by immunizing rats that had been given at i.v. nephritogenic dose (0.4 ml/animal) of rabbit anti-rat glomerular basement membrane (GBM) serum [anti-GBM serum] with 5 mg of rabbit gamma-globulin in Freund's complete adjuvant, and the process of nephritis was investigated by means of biochemical, histopathological and immunopathological analyses. Rats treated with anti-GBM serum and then with rabbit gamma-globulin (group II) showed significantly high levels or a tendency for high levels of urinary protein content, N-acetyl-beta-glucosaminidase activity and plasmin-like activity from the 20th day to the 40th day observations after the induction of nephritis, when compared to rats given anti-GBM serum alone (group I). On the 40th day, plasma urea nitrogen, cholesterol and fibrinogen levels were significantly higher in group II than in group I. Glomerular histopathological examination on the 40th day revealed that the incidence and the degree of severity of crescent formation, adhesion of capillary walls to Bowman's capsule and fibrinoid degeneration were remarkably greater in group II than in group I. However, no significant difference was seen between both groups on the thickening of capillary walls and mesangial proliferation. Linear deposits of rabbit IgG and rat IgG along the capillary walls as well as fibrinogen-reactive material deposits in Bowman's capsular spaces were observed by the immunofluorescence technique in both groups. The deposition of fibrinogen-reactive materials was considerably greater in group II than in group I. Moreover, the deposition of rat IgG was slightly greater in group II. These results suggest that the nephritis of group II closely resembles rapidly progessive glomerulonephritis in humans and thus seems to be an adequate experimental model for screening beneficial drugs on this type of nephritis.

CRESCENTIC TYPE NEPHRITIS INDUCED BY ANTI-GLOMERULAR BASEMENT MEMBRANE (GBM) SERUM IN RATS

An experimental model of crescentic type nephritis was established by immunizing rats that had been given at i.v. nephritogenic dose (0.4 ml/animal) of rabbit anti-rat glomerular basement membrane (GBM) serum [anti-GBM serum] with 5 mg of rabbit γ-globulin in Freund’s complete adjuvant, and the process of nephritis was investigated by means of biochemical, histopathological and immunopathological analyses. Rats treated with anti-GBM serum and then with rabbit γ-globulin (group II) showed significantly high levels or a tendency for high levels of urinary protein content, N-acetyl-β-glucosaminidase activity and plasmin-like activity from the 20th day to the 40th day observations after the induction of nephritis, when compared to rats given anti-GBM serum alone (group I). On the 40th day, plasma urea nitrogen, cholesterol and fibrinogen evels were significantly higher in group II than in group I. Glomerular histopathological examination on the 40th day revealed that the incidence and the degree of severity of crescent formation, adhesion of capillary walls to Bowman’s capsule and fibrinoid degeneration were remarkably greater in group ll than in group I. However, no significant difference was seen between both groups on the thickening of capillary walls and mesangial proliferation. Linear deposits of rabbit IgG and rat IgG along the capillary walls as well as fibrinogen-reactive material deposits in Bowman’s capsular spaces were observed by the immunofluorescence technique in both groups. The deposition of fibrinogen-reactive materials was considerably greater in group II than in group I. Moreover, the deposition of rat IgG was slightly greater in group II. These results suggest that the nephritis of group II closely resembles rapidly progessive glomerulonephritis in humans and thus seems to be an adequate experimental model for screening beneficial drugs on this type of nephritis.

STUDIES ON ANTINEPHRITIC EFFECT OF MIZORIBINE (P-INN,BREDININ®), A NEW IMMUNOSUPPRESSIVE AGENT, AND AZATHIOPRINE (1) EFFECT ON THE NEPHROTIC TYPE OF ANTI-GBM NEPHRITIS IN RATS

The present study was made to investigate the antinephritic effect of mizoribine in comparison to that of azathioprine by using the nephrotic type of anti-rat glomerular basement membrane rabbit serum (anti-GBM serum)-induced nephritis in rats. The nephrotic type nephritis was induced in rats by two i.v. injections of anti-GBM serum at a 10 day interval. Both drugs were given orally, daily from the 2nd day following the first injection of anti-GBM serum to the 21st day. Mizoribine in doses of 5 and 7.5 mg/kg/day significantly inhibited urinary protein excretion by 30-40% on the 22nd day. Mizoribine at both doses showed an inhibitory tendency on urinary alkaline phosphatase (ALP) excretion on the 9th and 16th days. On the 22nd day, this drug at a dose of 7.5 mg/kg/day inhibited plasma cholesterol (CL) content by 59.6% and wet weight of kidneys by approx. 50%, but no significant difference was seen between the drug-treated and control groups. When renal tissues on the 22nd day were observed under light microscopy, mizoribine at both doses remarkably prevented glomerular changes such as mesangial proliferation and thickening of capillary walls and significantly inhibited the index of glomerular lesions (IGL) by over 60%. On the other hand, azathioprine at a dose of 20 mg/kg/day was as effective as mizoribine at 5 mg/kg/day in inhibiting urinary protein and ALP excretions, plasma CL content and kidney weight.However, azathioprine showed little effect on the IGL. From these results, mizoribine at the dose level of 1/4 to 1/3 of azathioprine showed a more potent effect than azathioprine in this model. Therefore, mizoribine is also expected to have a beneficial effect on nephrotic type nephritis in clinical fields.

Influence of mesangial proliferation on posturally induced change in glomerular filtration rate.

The effect of the change from supine to upright position on GFR (measured by creatinine clearance) was studied in nonazotemic patients with biopsy-proven primary glomerulonephritis. Compared to healthy subjects, the fall in GFR following the postural change was significantly larger in patients with mesangial proliferation (MP) and with both MP and thickening of glomerular capillary wall (GCW), while similar in those with thickening of GCW alone, suggesting that MP, but not thickening of GCW, augments posturally induced fall in GFR. The augmented fall in GFR in patients with MP was accompanied by larger fall in GFR per unit increase in plasma renin activity than in healthy subjects, and was eliminated by angiotensin-converting enzyme inhibition. We conclude that MP augments posturally induced fall in GFR through affecting glomerular reactivity to angiotensin II.

Concurrent Membranous Glomerulopathy and Diabetes Mellitus

To the Editor. —We read with interest the case reports and review of idiopathic membranous glomerulopathy in diabetic patients recently published in theArchives(1980;140:624-627). All of the cases discussed membranous glomerulopathy occurring many years after the onset of diabetes mellitus. Such a temporal disassociation could be taken as evidence for pathogenetically unrelated concurrence of two not uncommon diseases. We would like to report a case in which membranous glomerulopathy and insulin-resistant diabetes mellitus occurred almost simultaneously. This concurrent onset of two possibly immune-mediated diseases suggests common pathogenesis. Report of a Case. —A previously healthy 25-year-old man in whom nephrotic syndrome (10 g/24 hr proteinuria) with microscopic hematuria developed underwent a renal biopsy five months after onset. By light microscopy, there was diffuse global capillary wall thickening, with only mild focal segmental mesangial hypercellularity. Immunofluorescence microscopy disclosed diffuse global granular capillary loop deposition of IgG, 3+; IgM, 1 +; IgA, 1

Early Pathologic Features of Hereditary Nephritis: A Clinicopathologic Correlation

The histologic, immunofluoresence and electron microscopic features of renal biopsies from twelve patients having hereditary nephritis were examined and correlated with the clinical data. In ten patients with normal renal function, light microscopy showed similar but nonspecific glomerular abnormalities consisting of mild focal and segmental hypercellularity and thickening of capillary walls. Biopsies from two patients with azotemia had diffuse lesions of the glomeruli and associated interstitial fibrosis. There were no characteristic findings on immunofluorescence. Electron microscopy revealed alterations in thickness and density of the glomerular capillary basal lamina in all patients. However, lamellation of the basement membrane and the presence of electron dense granules were present only in the two patients with renal functional impairment. These findings support the view that hereditary nephritis is a form of glomerular disease in which ultrastructural changes in the basal lamina of glomerular capillaries are the earliest and most consistent lesions. However, the morphologic spectrum of these ultrastructural abnormalities is broader than previously recognized.

Experimental Orchitis Induced in Rats by Passive Transfer of an Antiserum to Seminiferous Tubule Basement Membrane

A multifocal damage of the testis was obtained when rats were injected intravenously or under the tunica albuginea of the testis with a rabbit antiseminiferous tubule basement membrane serum. The damage was characterized by foci of perivascular and peritubular infiltrates of mononuclear round cells, infolding, thickening, and rupture of the seminiferous tubular wall and different degrees of injury of the germinal epithelium such as, cell disorganization, cell sloughing, and atrophy. Delamination and thickening of seminiferous tubule basement membrane and vacuolization of the Sertoli cell cytoplasm was often observed by electron microscopy. A linear deposit of rabbit gamma-globulin was detected by immunohistochemical techniques along the basement membranes of the seminiferous tubules and vessels. Testicular damage was not detected in rats injected with normal rabbit serum, used as control. In the kidneys of rats injected intravenously with the immune serum, a deposit of rabbit gamma-globulin was detected along glomerular basement membrane. Focal areas of mononuclear cell infiltrates, hypercellularity of glomeruli and thickening of glomerular capillary walls and Bowman's capsule were also observed.