Subendothelial Deposits Research Articles

Renal ultrastructure in lamb nephrosis

Ultrastructural investigation of the kidneys of 18 lambs with clinical nephrosis revealed that groups of tubules showing various degrees of degeneration up to necrosis could exist alongside tubules showing proliferative or regenerative changes. Lesions were most common in proximal convoluted tubules, less common in distal tubules and absent from collecting ducts or straight tubules, though the latter were often distended with hyaline or flocculent casts. The basement membranes of necrotic tubules were intact, suggesting that the potential for regeneration was unimpaired. Nine lambs had lesions in the glomeruli, though the distribution was focal. Glomerular lesions occasionally were acute and degenerative but more usually were proliferative, with occlusion of capillaries due to endothelial swelling and mesangial encroachment. Basement membrane splitting or reduplication was a feature of some glomeruli, but neither subepithelial nor subendothelial dense deposits were seen. The changes were consistent with damage by an unknown nephrotoxic factor or factors.

Mechanism of long-term degeneration of arterialized vein grafts

This study examined long-term changes in the morphology and cellular kinetics of rabbit vein grafts transplanted into the carotid artery. Six grafts were studied 1 year after implantation. Although the circumference and thickness of the wall were not different than at 12 weeks, degenerative changes occurred. The endothelial lining of the graft appeared intact, but large segments of the graft surface no longer excluded Evans blue dye, suggesting increased permeability. Collections of red blood cells were noted within the intima. Several grafts had extensive subendothelial fibrin deposits, often associated with foam cells, and evidence of previous hemorrhage, but these changes did not stimulate significant smooth muscle cell proliferation. Increased permeability with entrance of proteins and erythrocytes into the intima may result from increased wall tension or from low shear rates at the wall. Similar changes may lead to atherosclerosis in human vein grafts at late times.

Coronary atherosclerosis in the pig. Induced plaque injury and platelet response.

The thrombogenic potential of atherosclerotic diet-induced coronary atherosclerotic plaques was investigated in normal swine and in bleeder swine with homozygous von Willebrand disease. Fourteen paired normal and bleeder swine were placed on a 1% cholesterol diet for 1 to 16 weeks. Serum cholesterol was elevated in all animals at sacrifice. Foam cell deposits developed in all major epicardial coronary arteries, and lesions progressed over time from small subendothelial foam cell deposits to fibrous cap lesions that contained foam cells, elastic fibers, collagen, degenerative material, and smooth muscle cells. Balloon catheter injury resulted in platelet deposition, largely in a monolayer or as small platelet clumps devoid of fibrin. Lipid debris was present in injured areas of the subendothelium but did not induce thrombus formation. When the injury involved the media, platelet-fibrin thrombi were formed. Lipid was not present in these thrombi. Morphometric analysis of platelet deposition on ballooned atherosclerotic vessels showed similar numbers of platelets in both phenotypes. However, the attached platelets in bleeder pigs showed significantly less spreading than did those in the normal animals. The results show that injury to intimal foam cell and mixed cellular lesions in coronary arteries of cholesterol-fed swine does not promote the development of platelet-fibrin thrombus formation. In contrast, when the injury extended to the media, mixed thrombi were formed.

Mediation of immune glomerular injury.

This paper reviews current concepts of glomerular immune injury of both inflammatory and noninflammatory types. In noninflammatory lesions induced by antibody alone or C5b-9, the glomerular epithelial cell appears to be the principal target of injury. Similar mechanisms are probably operative in human diseases such as minimal change nephrotic syndrome and membranous nephropathy. In inflammatory lesions, circulating effector cells including neutrophils, macrophages, platelets, and probably lymphocytes as well as resident glomerular mesangial cells may mediate tissue injury. Human equivalents of these inflammatory lesions include most diseases associated with mesangial and/or subendothelial immune deposits and/or mesangial cell proliferation. Neutrophil-mediated injury appears to be consequent to both proteinases and oxidants, particularly the myeloperoxidase-H2O2-halide system. Platelets may be critically involved in neutrophil mediated injury as well. Platelets also mediate mesangial cell proliferation, probably by a release of platelet growth factors and stimulation of mesangial cell platelet-derived growth factor and platelet-derived growth factor receptor expression. Immunologically induced mesangial cell proliferation is associated with increased production of nephritogenic proteinase in vivo.

Splenic Pathology in Thrombotic Thrombocytopenic Purpura

To determine splenic pathology in thrombotic thrombocytopenic purpura (TTP), 10 spleens and two accessory spleens were studied. The eight women and two men ranged from 20 to 66 years of age (mean age, 39 years). Three spleens were enlarged. Thrombi were noted in arteries and arterioles in nine specimens: no associated inflammation was seen. Periodic acid-Schiff-positive diastase-resistant hyaline subendothelial deposits (SEDs) were present in all cases. Some arterioles showed a transition between thrombi and SEDs. The presence of platelets or platelet-related material in SEDs and thrombi was documented by factor VIII staining. Hyperplasia of B cells and germinal centers was present in 67%, and periarteriolar concentric fibrosis ("onion-skinning") in 58%. Histiocytes showed prominent iron deposits in 92% and hemophagocytosis in 83% of cases. Extramedullary hematopoiesis was present in 42%. Blood lakes, infarcts, and endothelial hyperplasia were rarely noted; microaneurysms were not seen. Ten spleens from patients with idiopathic thrombocytopenic purpura and 10 age-matched control spleens rarely showed SEDs or hemosiderosis and did not show hemophagocytosis or thrombi. We conclude that subendothelial deposits may be related to platelet thrombi incorporated into vessel walls. Germinal centers and periarteriolar concentric fibrosis may indicate an immunologic role in TTP, as in systemic lupus erythematosus.

Development of Progressive Glomerulosclerosis in Experimental Chronic Serum Sickness

A rat model of chronic serum sickness was used to study the pathogenesis of progressive glomerulosclerosis complicating experimental immune-complex glomerulonephritis. Chronic serum sickness was induced by immunising rats with bovine serum albumin followed by intraperitoneal administration of the antigen. Early lesions consisted of mesangial deposits of rat immunoglobulins, followed later by transient subendothelial and persistent subepithelial immune aggregates. On the basis of the peak level of proteinuria around day 80, three groups of rats were distinguished: I physiological proteinuria; II 50-500 mg/24 h; and III greater than 500 mg/24 h. The animals were killed at day 220 and the presence of mesangial proliferation, epithelial proliferation, and synechiae, as well as focal glomerulosclerosis was scored. It appeared that all and only proteinuric animals developed progressive glomerulosclerosis, although all three groups of animals passed through a phase with mesangial and subendothelial immune deposits. A strong correlation was found between the degree of proteinuria and the proportion of glomeruli affected. We conclude that the combination of mesangial and subendothelial deposits on the one hand and subepithelial deposits associated with increased protein loss on the other constitute a conditio sine qua non for the development of progressive glomerulosclerosis in this model. The use of specific antibodies to investigate the composition of the sclerotic lesions showed the presence of laminin and type IV collagen, but not of types I and III collagen in sclerotic areas of glomeruli. This indicates that the development of progressive glomerulosclerosis in this model is due to an increased production of glomerular basement membrane components by presumably solely glomerular cells after the occurrence of immunological glomerular injury.

Non-H-2 genes alter the H-2 determined susceptibilities in immune complex nephritis

These experiments examined the effects of genes outside of the H-2 region on disease susceptibility and pathogenesis. Four strains of mice with the susceptible H-2 type, H-2d, but different non-H-2 genes were studied. B10, D2, Balb/c, NZB, and DBA/2J mice were injected with 4 mg of apoferritin i.p. q.d. for 28 days. B10, D2 and Balb/c mice developed proliferative and crescentic glomerulonephritis. NZB mice developed proliferative and crescentic glomerulonephritis with wire loop lesions suggestive of lupus. DBA/2J mice developed only minimal mesangial proliferation without crescents or necrosis. Electron microscopy showed subepithelial and mesangial deposits in B10, D2, moderate subepithelial and mesangial deposits in Balb/c, and marked mesangial, subendothelial and subepithelial deposits in NZB. Immunofluorescence demonstrated the presence of IgG, IgM, C3 and apoferritin in these deposits. The DBA/2J mice had only minimal mesangial deposits by immunofluorescence and electron microscopy. These experiments demonstrate that non-H-2 genes alter the H-2d determined disease susceptibility seen in H-2 congenic mice. NZB genes can alter the disease so that lupus-like lesions develop and DBA/2J genes can substantially ameliorate the disease.

Ultrastructural changes in IgA nephropathy in relation to histologic and clinical data

In order to evaluate the ultrastructural changes in IgA nephropathy (IgAN) and their relationship with light microscopic and clinical features, renal biopsy material from 239 Korean patients with IgAN was studied by light, electron and immunofluorescence microscopy. Forty-one were children and 198 were adults. Modified classification of Meadow et al (1972) for Henoch-Schönlein nephritis was used for the histologic grading of glomerular lesions. Forty-three adults (18%) exhibited histologic grades IV and V lesions in association with more severe clinical findings, when compared to the remaining 196 patients with histologic grades I to III. A significant difference was noted between children and adults in the severity of the glomerular lesions (P less than 0.01). Mesangial deposits were observed in all (100%), subendothelial deposits in 37%, subepithelial deposits in 18%, abnormalities in glomerular basement membrane (GBM) in 20%, mesangiolysis in 44%, and mesangial interposition in 25%. The frequency of GBM abnormalities and subepithelial deposits in children was significantly higher than that seen in adults (P less than 0.01). The abnormalities of GBM were not related to more severe clinical manifestations when our analysis was restricted to grade III histologic lesions. All of the above ultrastructural changes except for mesangial deposits were associated with more severe histologic grading in adults (P less than 0.025 or P less than 0.01). Yet a correlation between these ultrastructural changes and histologic grading could not be studied in children due to confinement of their histology within a more benign group. These results suggest that the five ultrastructural parameters described here appear to bear important prognostic value in adults with IgAN.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphologic changes in the renal glomerulus and the juxtaglomerular apparatus in human preeclampsia.

The renal biopsies of ten women with preeclampsia without other underlying renal disease were examined in detail using light and electron microscopy and immunofluorescence. Characteristic preeclamptic glomerular lesions with endocapillary cell swelling, subendothelial and mesangial deposits, and mesangial interposition were detected in each patient. Juxtaglomerular regions were not prominent and were poorly granulated on light microscopy; ultrastructurally, they showed myoepithelioid cells with sparse renin granulation and considerable heterogeneity of granule size and density in association with relatively meagre granular endoplasmic reticulum and Golgi profiles. These morphologic findings suggest that, in patients with clinical and renal biopsy evidence of preeclampsia, there is no significant stimulation of the renin-angiotensin system.

Morphometric analysis of pre-eclampsia in women biopsied in pregnancy and post-partum

The importance of endothelial cell swelling and subepithelial deposits in producing capillary wall thickening in women with pre-eclampsia is controversial. In this study renal biopsy tissue from 16 women with a diagnosis of pre-eclampsia was analyzed morphometrically. Women biopsied during pregnancy (N = 6) showed substantial, electron-dense subendothelial deposits in capillary loops, but these were rare or absent in women (N = 10) biopsied post-partum (P less than 0.01). Endothelial cell swelling was present in both groups of patients to an equal degree. Mesangial cell interposition occurred but was not the dominant feature, and was similar in both pregnancy and post-partum biopsies. The median percentage per patient occupied by basement membrane was similar for both groups. Subendothelial deposits appear to resolve early in the post-partum period.

Effects of a specific thromboxane synthetase inhibitor on development of experimental Dirofilaria immitis immune complex glomerulonephritis in the dog.

Twelve Beagle dogs were immunized with aqueous-soluble Dirofilaria immitis antigens, and subsequent to at least fivefold increases in serum antibody titer, 6 mg of homologous antigen was infused into the left renal artery. Six dogs were treated once daily starting the day of infusion with 0.75 mg/kg of 1-benzylimidazole (1-BIM) in saline. Six control dogs were given saline only. Light, immunofluorescent, and transmission electron microscopic examinations of renal tissue from control dogs, 10 days after antigen infusion, showed a mesangioproliferative glomerulonephritis in the left kidney with polymorphonuclear leukocyte (PMNL) infiltration and fibrin deposition. Immunoglobulin (Ig) G, M, C3, and Dirofilaria antigen deposits were observed in a segmental granular pattern. Mesangial, subendothelial, and intramembranous electron dense deposits were observed, and anti-Dirofilaria antibodies were demonstrated in kidney eluates from each dog. Administration of 1-BIM had no significant effect on IgG, IgM, C3, or antigen deposits, electron dense deposits, or concentration of antibody in kidney eluates. However, 1-BIM-treated dogs had less glomerular cell proliferation, periodic acid-Schiff (PAS) positive glomerular staining, PMNL infiltration, and fibrin deposition. These data suggest that thromboxane is an important mediator in the development of immune complex glomerulonephritis, and that in certain circumstances, inhibition of thromboxane synthesis may be an effective therapy for immune complex glomerulonephritis in the dog.

Platelets mediate neutrophil-dependent immune complex nephritis in the rat.

Neutrophils and platelets are frequently present in glomeruli in immune glomerulonephritis (GN). No role for the platelet in acute neutrophil-mediated renal injury has been defined. We investigated a neutrophil-mediated model of subendothelial immune complex GN in the rat. Rats were platelet-depleted (mean platelet less than 10,000/microliter) with goat anti-platelet IgG before induction of GN by the renal artery perfusion of concanavalin A followed by anti-concanavalin A IgG. Platelet-depletion resulted in a significant reduction in albuminuria (7 +/- 2 vs. 55 +/- 10 mg/24 h) and fractional albumin excretion (0.045 +/- 0.01 vs. 0.410 +/- 0.09) compared with controls. The decrease in albuminuria was not due to differences in blood or glomerular neutrophil counts, complement, renal function, or glomerular antibody binding. Platelet-depleted rats had equivalent subendothelial deposits and glomerular endothelial cell injury but had minimal platelet infiltrates and fibrin deposition compared with controls. These studies demonstrate a role for platelets in mediating acute neutrophil-induced glomerular injury and proteinuria in this model of GN.

Biosynthesis of chondroitin sulfate proteoglycan by P388D1 macrophage-like cell line.

Macrophages are in large part responsible for the subendothelial deposition of lipid within the artery wall during the early stages of atherogenesis. Proteoglycans secreted by these cells may play a role in this pathological process either by trapping lipoproteins in the extracellular matrix or by enhancing the formation of lipid-laden foam cells. The synthesis and secretion of proteoglycan was studied in the P388D1 macrophage-like cell line cultured in the presence of 35S-sulfate. The radiolabeled proteoglycan had a Kd of 0.69 on Sepharose CL-2B corresponding to an Mr of 2.8 x 10(5). It consisted of approximately 13 chondroitin sulfate chains of Mr 20,000 attached to a core protein with an Mr of 18,000. The chondroitin sulfate chains contained both N-acetylgalactosamine 6-sulfate and N-acetylgalactosamine 4-sulfate residues. No disulfated N-acetylgalactosamine residues were present. The P388D1 proteoglycan bound specifically to immobilized human low density lipoprotein. These results suggest that, in the focal regions of the arterial wall in which macrophages are found during the development of fatty streaks, proteoglycans secreted by these cells may affect the transport and cellular metabolism of plasma-derived lipids.

Characteristics of Glomerular Lesions in Hepatitis B Virus Infection

In an attempt to clarify a participation of hepatitis B virus (HBV) in the development of hepatic glomerulopathy in adults, kidney specimens obtained from 151 patients with liver diseases were studied. Although mesangial proliferation was more severe in patients with chronic hepatitis or liver cirrhosis than in those with acute hepatitis, no significant difference was observed between 82 serum hepatitis B surface antigen (HBsAg)-positive (HBV-related group) and 69 negative patients (HBV-nonrelated group). However, double contours of the glomerular capillary walls were observed more often in the former group (18/82, P less than .01), especially in the HBeAg-positive subgroup (8/24, P less than .001), than in the latter (3/69). In addition, glomerular capillary spike formation or a bubblelike appearance was observed in seven patients of the former group. Of these, all five patients examined were HBeAg-positive in their serum. By electron microscopic studies, subendothelial dense deposits and mesangial interpositions were observed more frequently in the HBV-related group, and subepithelial deposits were found only in the HBeAg-positive subgroup. The immunofluorescence study revealed IgA-dominant mesangial deposition in both HBV-related and nonrelated groups. As for the capillary wall deposits, however, IgG was dominant in 13 of the HBV-related group, but only one of the nonrelated group (P less than .01). Furthermore, one patient in the HBV-related group showed capillary wall-dominant HBeAg combined with IgG deposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical choroidal thrombosis, hypertension, and diabetes mellitus: an electron microscopic study.

Changes in the choroidal artery were examined at autopsy in 16 Japanese patients with hypertension and insulin-dependent diabetes mellitus. These changes could be divided into 1) arteriosclerotic ones consisting of intimal thickening due to migration of smooth muscle cells, 2) hyaline deposits in the subendothelium, 3) extensive degeneration (moth-eaten atrophy and necrosis) of medial smooth muscle cells, and 4) changes resulting from fibrinoplatelet thrombi and their organization (recanalization and obstruction). The intimal thickening and medial damage correlated with aging, were accelerated by hypertension, and were remarkable in arterioles less than 60 micron in diameter. Diabetes mellitus apparently did not enhance these vascular changes. Thrombotic occlusion or narrowing of the choroidal artery was frequently observed in the arterioles of patients with hypertension and diabetes mellitus who had chronic azotemia or renal insufficiency. Subendothelial hyaline deposits were increased in patients with diabetes. The narrowing or obstructive changes in the choroidal artery were extensive in the intraocular blood vessels. These changes may be secondary and induce damage to other intraocular blood vessels and tissues, including the retina.

12 Renal pathology in pre-eclampsia

Pre-eclampsia affects the kidney both functionally and morphologically. Renal haemodynamics decrease and urinary protein excretion increases, in part due to lesions affecting the glomerulus, where a combination of changes produces a characteristic appearance and permits differentiation of pre-eclamptic nephropathy from other glomerular alterations associated with hypertension in pregnancy. In pre-eclampsia the glomerulus is diffusely enlarged and bloodless, due not to proliferation, but to hypertrophy of the intracapillary cells. These alterations, best described ultrastructurally, include hypertrophy of the cytoplasmic organelles in endothelial and occasionally mesangial cells, particularly the lysosomes, which undergo marked enlargement and vacuolization (due to accumulation of free neutral lipids). These reactive changes have been termed 'glomerular capillary endotheliosis'. Other lesions, observed occasionally, include subendothelial and mesangial electron-dense deposits, as well as interposition of mesangial cell cytoplasm or mesangial matrix along an otherwise normal basement membrane. Some investigators have described immunohistologic findings (presence of IgM, IgG and fibrin) which they believe specific for pre-eclampsia, and others have claimed the disease may cause focal segmental glomerulosclerosis (FSGS). We believe the immunohistologic findings are non-specific and insudative, and that FSGS when present predates the pre-eclamptic complication. Finally, the renal lesions appear fully reversible and the disease has no remote cardiorenal effects on its patients.

Amelioration of murine lupus nephritis by dimethylsulfoxide

Dimethylsulfoxide was given to NZB W F 1 female mice from age 10 weeks to see if proteinuria and glomerular injury could be reduced. Twenty mice were randomly assigned to saline or DMSO treatment groups and the following studies were done: urine protein determination, serum concentrations of creatinine, IgG, C3, and albumin; and ANA titers. Kidney tissue were studied by light, immunofluorescent and electron microscopy. DMSO-treated mice had significant reductions in protein excretion at 5 and 6.5 months of age; in urine protein/creatinine ratio at 6.5, 7, and; 7.5 months; in serum C 3 at 7.5 months; and in serum creatinine concentration. There were no significant differences among serum IgG, nor among the ANA titers. Histopathologic studies revealed nearly normal kidneys in 5 6 DMSO-treated mice whereas 4 8 controls had severe mixed membranous and membranoproliferative glomerulonephritis. Ultrastructural studies revealed mesangial, subendothelial, and subepithelial deposits and membranous transformation of the glomerular capillary wall. DMSO therefore appears capable of ameliorating glomerular injury in NZB W F 1 mice.

Immunopathogenetic Mechanisms in Renal Disease

This review deals with various immunopathogenetic mechanisms of renal diseases. Although immune-complex nephritis was long thought to be the result of deposition of circulating immune complexes, recent studies have revealed the importance of in situ formation. In experimental Heymann nephritis, an antigen (gp 330) has been localized on glomerular epithelial cells, and antibodies reactive with gp 330 have been eluted from glomeruli; deposits appear to result from shedding of complexes from the podocyte surface into the basement membrane. In human disease, it seems likely that mesangial and subendothelial deposits most often result from deposition of circulating immune complexes, whereas subepithelial deposits are formed mainly in situ. Cell-mediated immune mechanisms are capable of producing glomerular injury, as shown in experimental models. In humans, Wegener's granulomatosis and idiopathic crescentic glomerulonephritis may involve such mechanisms. In certain forms of experimental and human tubulointerstitial nephritis, cell-mediated immunity also seems to play an important role.

Juvenile renal disease in the Doberman Pinscher: Ultrastructural changes of the glomerular basement membrane

Ten cases of juvenile renal disease in Doberman Pinschers were examined by light microscopy and 8 of them additionally by electron microscopy. Two distinct basic ultrastructural lesions of the glomerular basement membrane (GBM) were observed. One is characterized by lamellation of the lamina densa with intramembranous focal areas of lucency containing electron-dense particles, the second by diffuse attenuation of the lamina densa with intramembranous and/or subendothelial deposition of matrix entrapping cross-banded fibres (collagen). Based on similar ultrastructural changes in other hereditary nephropathies in man and dogs, a metabolic or biochemical basis for the structural lesions is suspected.

Clq nepropathy: A case report of a newly described glomerularopathy

A distinctly new pathologic entity that causes steroid resistant nephrotic syndrome has been described by Jennette and Hipp. Clq nephropathy gets its name from the strong positivity of Clq localized by immunofluorescence. Reactions for C3, IgG and IgM are present, with a mild reaction for IgA occuring in some cases.The ultrastructural features of Clq glomerular nephropathy (Clq GN) and systemic lupus erythmatosis glomerular nephropathy (SLE GN) are strikingly similar in that they both demonstrate mesangial cell proliferative activity, mesangial dense deposits, and subendothelial or subepithelial dense deposits. One ultrastructural difference between Clq GN and SLE GN is the lack of endothelial tubuloreticular inclusions in Clq GN.The most interesting aspect of Clq GN is that although the glomerular changes resemble SLE GN by light microscopy and electron microscopy, these patients lack clinical or serological evidence for SLE. Specifically, serological tests for ANA, anti-DNA, and LE are all negative in Clq GN patients.