Subendothelial Deposits Research Articles

An approach to immunomicroscopy of renal disease with immunoperoxidase and periodic acid-Schiff counterstain (IMPAS stain).

A series of 127 renal specimens reflecting a wide spectrum of renal pathology was evaluated with a direct immunoperoxidase technic in which frozen tissue was first reacted with anti-Ig(G,A,M) and anti-C3-peroxidase conjugates and subsequently counterstained with periodic acid-Schiff-hematoxylin (IMPAS). This technic permitted simultaneous evaluation of light-microscopic changes and yielded a permanent immunomicroscopic record. Frequently, a distinction could be made between epimembranous, intramembranous and subendothelial deposits, which was not possible using immunofluorescence. The findings were correlated with histologic, immunofluorescent and electron-microscopic results. General patterns of immune complex and autoantibody deposition were similar in 124 cases. In one case, there was poor correlation between results obtained by immunoperoxidase and immunofluorescence. In two other cases, deposits detected by electron microscopy were not identified by either immunoperoxidase or immunofluorescence. The IMPAS stain, combining immunomicroscopy with conventional light microscopy, may be a useful approach to the laboratory diagnosis of renal disease.

Distant evolution of kidney arteriolar lesions and hypertension after pregnancy toxemia.

60 patients were studied 3 months to 4 years after pregnancy. All had high pressure, gross proteinuria, and edema. In many cases, typical glomerular lesions and proteinuria disappeared rapidly. When arteriolar lesions are of grade I or II, they progressively disappear or remain unchanged and blood pressure returns to normal values. When arteriolar lesions are of grade III (endotheliitis, hyperplasia and edema of the media and subendothelial deposits), blood pressure remains at a high level or increases, without changes during the time of observation of the arteriolar lesion or of renal function.

Electron microscopic and immunohistochemical analysis of glomerular deposits in patients with bronchogenic carcinoma.

Kidneys of 27 consecutive autopsied patients with bronchogenic carcinoma without clinical renal disease were studied by electron microscopy and immunohistochemistry for the presence of glomerular deposits. Two patients had subepithelial electron-dense deposits compatible with immune complexes but failed to stain histochemically for immunoglobulin; most cases (19 of 27), including the two with complexes, demonstrated subendothelial deposition of fibrin. No tissue samples had histochemically detectable immunoglobulin. From this study it is suggested that renal immune complexes in lung cancer are rare.

Difficulties in the Use of D‐Penicillamine in the Treatment of Rheumatoid Arthritis

The difficulties encountered in administering D-penicillamine to 40 patients with rheumatoid arthritis (RA) over a six to 24 month period are recorded. Side-effects were frequent. Proteinuria occurred in 13 patients (33%) mainly in the fourth to the sixth month. Renal biopsies were performed in six patients and all showed light microscopy abnormalities. Electron microscopy performed in five patients revealed subepithelial deposits in all and in addition some had mesangial and subendothelial deposits. Seven patients (17.5%) developed eight episodes of thrombocytopaenia which was quickly reversed on cessation of treatment or reduction in dosage. On the positive side, there was significant improvement in most parameters of disease activity at six, 12 and 18 months compared to the pretreatment levels, but the results at two years were less impressive. Reduction in steroid dosage was considerable and was greater than half the mean pretreatment dose after two years but the absence of a control group makes the full significance of these uncertain. Patients on high and low dosage regimens were compared over a 12 month period of treatment. Although the differences were not statistically significant, withdrawals and side-effects were less frequent in the low dose group.

EXTRACORPOREAL IMMUNOADSORPTION: INITIAL EXPERIENCE IN HUMAN SYSTEMIC LUPUS ERYTHEMATOSUS

Extracorporeal immunoadsorption and filtration was used in treatment of a 29-year-old woman with severe lupus nephritis. For the previous 35 days single-stranded DNA (ssDNA) antibody and immune-complex levels had been continuously raised with only partial improvement on prednisone therapy. Levels of immune complexes and ssDNA antibodies were substantially reduced by extracorporeal plasma filtration and adsorption with DNA collodion charcoal. There were no major clinical complications. After perfusion, the reduction of ssDNA binding and immune complexes in serum was sustained, serum C'3 became normal, and serum creatinine and proteinuria improved. 28 days after perfusion, subendothelial glomerular deposits were much reduced compared with those in a pre-perfusion biopsy specimen. Selective immunoadsorption is a promising new approach to persistent lupus nephritis refractory to drug therapy alone.

Lupus Nephritis: Electron-dense and Immune-fluorescent Deposits and Their Correlation with Proteinuria and Renal Function

Thirteen patients who had systemic lupus erythematosus were studied for the purpose of correlating the findings of light and electron microscopy and immunofluorescent studies with renal function and the presence of proteinuria. Subendothelial deposits of electron-dense material were found in all biopsy specimens, whereas mesangial and subepithelial deposits were not always present. IgG and beta 1c were constant findings in the glomerular membrane. The seven patients who were found to have extensive subendothelial deposits had moderate to massive proteinuria, and four of these patients had decreases in renal function. Most of the patients who had smaller subendothelial deposits had slight or insignificant proteinuria. Massive subendothelial deposits were mainly found in specimens showing histologic evidence of active lesions. Correlation was also found between proteinuria and the overall amount of deposits and their distribution. The prognosis was dependent on the severity of subendothelial deposits, the overall amount of deposits, and the morphologic form of lupus nephropathy.

Simultaneous immunologic studies of skin and kidney in systemic lupus erythematosus clinicopathologic correlations.

Thirty-two biopsies of kidneys and of normal skin were performed simultaneously on patients with systemic lupus erythematosus (SLE) to determine whether the deposition of immune reactants in skin was correlated with the severity of renal injury or with several serologic measures of systemic disease activity. Immunofluorescent deposits at the dermal-epidermal junction (lupus band test) did not correlate with any clinical or histologic measures of glomerulonephritis or with serologic abnormalities. Immune deposits in dermal venules were found in 56% of the skin biopsies and were correlated with hypocomplementemia and higher levels of immune complexes in serum, and possibly with glomerular subendothelial electron dense deposits. Azathioprine therapy was correlated with absence of both sub-epidermal and vascular immune deposits. Immuno-fluorescent findings on serial skin biopsies on 13 patients were highly inconsistent. It is concluded that the lupus band test is clinically useful only as a diagnostic aid but not helpful in assessing renal or serologic activity of lupus, and that dermal vascular deposits of immunoglobulin or complement are more frequent than previoulsy recognized and correlate with measures of circulating immune complexes.

The immune complex pathogenesis of glomerulonephritis and pulmonary vasculitis in Behçet's disease

A kidney and lung biopsy were performed on a patient with active Behçet's disease with renal and pulmonary involvement. Histologic, immunohistochemical and electron microscopic studies of the kidney biopsy specimen revealed a focal segmental necrotizing glomerulonephritis characterized by the presence of numerous subendothelial and occasional intramembranous deposits containing immunoglobulin G (IgG), the third component of complement (C3), the fourth component of complement (C4) and fibrin(ogen). Histologic and immunohistochemical studies of the lung biopsy specimen showed an acute venulitis and septal capillaritis associated with the presence of identical deposits within the walls of affected vessels. Circulating immune complexes were detected in the patient's serum by Raji cell assay. The findings indicate that the glomerulonephritis and pulmonary vasculitis occasionally occurring in Behçet's disease are due to the deposition of circulating antigen-antibody complexes. In addition, they strongly suggest that the majority of the major and minor manifestations of the disease, such as uveitis, cutaneous vasculitis, synovitis and meningoencephalitis, are a result of vascular immune complex deposition.

Autoimmune hematologic diseases associated with infraclinical systemic lupus erythematosus in four patients: A human equivalent of the NZB mice

In four patients with a diagnosis of autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura antinuclear antibodies and circulating immune complexes (Clq-BA test) have developed at some time in their history. Renal biopsy material was assayed with different methods. Immunofluorescence studies revealed granular deposits of immunoglobulin G (IgG), immunoglobulin M (IgM) and third component of complement (C3). Upon optic microscopy, three patients had mild mesangial proliferation, one a focal glomerulonephritis. Upon electron microscopy, all patients exhibited mesangial and/or subendothelial deposits. The patients have been followed for 18 to 37 years since the beginning of their disease. There has been no clinical evidence of systemic lupus erythematosus (SLE), although they present in their glomeruli immunologic and anatomic features compatible with this disease. These patients seem to be a human equivalent of the black NZB mouse which presents immunohematologic disorders and some biologic markers of SLE without having a full clinical picture of SLE.

Gingival biopsy in thrombotic thrombocytopenic purpura.

Gingival biopsy has been advocated as a readily available, safe, rapid histologic confirmation of the clinical diagnosis of thrombotic thrombocytopenic purpura. Eighteen gingival biopsies from 16 patients with proven thrombotic thrombocytopenic purpura were reviewed. Seven (39%) showed characteristic histologic changes: [1] subendothelial hyalinelike deposits; [2] intraluminal deposits; [3] lack of inflammatory change in vessels and stroma. To assess specificity, gingival sections from 154 patients with oral pathology only and from 50 unselected autopsies were reviewed: 10% to 20% of biopsies from patients with oral pathology only (primarily inflammation) and three of 50 autopsy specimens showed occasional intraluminal deposits but no subendothelial deposits. In addition, other histologic features permitted them to be distinguished from thrombotic thrombocytopenic purpura. We conclude that gingival biopsy in thrombotic thrombocytopenic purpura, although helful in confirming the diagnosis, is less often positive than has been suggested. Biopsy of grossly inflamed gingiva should be avoided.

Immunopathology of membranoproliferative glomerulonephritis with subendothelial deposits (Type I MPGN)

Immunofluorescence microscopy (IF) studies were carried out in 36 patients with Type I MPGN and showed the constant presence of deposits containing C3. Based on the presence or the absence of immunoglobulins (Ig), two main patterns were observed. Complement profiles (30 patients) and C3NeF activity (20 patients) were studied in the two groups defined by IF. Our findings indicate an activation of the complement system through the classical pathway even in the group characterized by the absence of Ig. Such an activation suggests the role of immune complexes in the pathogenesis of the disease. Because of the presence of C3NeF activity in occasional patients, a superimposed activation through the alternative pathway is not unlikely. In two additional patients, one with predominant IgA within the deposits and one with C2-deficiency, the complement system is probably activated through the alternative pathway.

1080 SILENT LUPUS NEPHRITIS (LN) IN CHILDREN

Silent LN has been reported in adults (Med. 56:493, 1977). In order to determine its occurrence in children with SLE, 10 who were diagnosed during the past 18 months underwent renal biopsy at the time of diagnosis. Six of 10 had no evidence of renal disease by urinalysis, creatinine clearance, or 24-hour protein excretion, and they are the basis of this report. The mean age was 12 years. The mean duration from onset of symptoms to biopsy was 4 months. Four of 6 had low C3, 5 of 6 had elevated DNA binding, and 3 of 6 received prednisone prior to biopsy. All biopsies had > 10 glomeruli. All had histologic changes on light microscopy: 5 had mesangial proliferation and one had diffuse proliferative LN. On fluorescent microscopy, 4 of 5 had IgG and 5 of 5 had C3 along capillary loops; 3 of 5 had IgG and 3 of 5 had C3 in the measngium. On electron microscopy, 4 of 6 had mesangial deposits, one had subepithelial and 2 had subendothelial deposits. Mean follow-up was 7 months. Renal function has been preserved in all, but 2 have developed overt nephritis. Analyses of clinical and laboratory data do not distinguish these 6 children from the other 4 presenting with overt nephritis. Conclusions: 1) Silent LN occurs in childhood as well as in adult SLE. 2) The commonest histologic appearance is diffuse mesangial proliferation with a varying pattern of immune deposits. 3) Findings from early biopsy may be important in planning management and assessing prognosis.

Aggravating factor in lupus nephritis; electron microscopic observation.

47 renal biopsies from 36 patients with SLE were examined in detail to compare with clinical courses and ultrastructural findings. Of 36 patients, 8 cases were free from renal involvement. The severity of electron dense deposits in glomeruli with lupus nephritis were generally well correlated with each clinical feature obtained. Moreover, mesangiocapillary cell proliferation was considered to be the main morphological promoting factor in poor prognosis of the lupus nephritis. Prominent circumferential subendothelial dense deposits were suggested to enhance to enhance the proliferation of mesangial cells, mostly with a mode of circumferential interposition. In each deposit with lapse of time and/or treatments, subepithelial deposits were gradually degraded to granular material but not lucent, though most subendothelial deposits rapidly disappeared without any remnant structure or with only a few flocculent materials. Mesangial deposits were mostly stabilized and rarely turned membranous.

Clinicopathological concepts and the treatment of glomerular disease

While a morphological classification of glomerular disease is the only practical approach at the present time, it is essential in its use to recognize that whereas each biopsy can be fitted into a specific category, serial biopsies in the same patient may change from one category to another. The purpose of a renal biopsy is both in establishing the prognosis and as a guide to treatment. Discussion of recent advances in the understanding of the morphology of glomerular disease and the related clinical management will be confined in five types of lesions. Focal and segmental proliferative glomerulonephritis, focal and segmental hyalinosis and/or sclerosis, mesangiocapillary glomerulonephritis, diffuse endocapillary and extracapillary glomerulonephritis and lupus nephritis. Focal and segmental proliferative glomerulonephritis may or may not be associated with the syndrome of recurrent macroscopic haematuria and may or may not show associated mesangial IgA. Children frequently show minimal changes on light microscopy, whereas adults usually show focal and segmental proliferative lesions with or without crescents. Between active phases only focal and segmental sclerosis may be seen. Progression to renal failure may be observed in an adult whereas children usually have an excellent long-term outcome. The glomerular lesion of focal and segmental hyalinosis may also occur as a secondary phenomenon in various forms of scarring or sclerosis in the glomerulus. The primary form is usually accompanied by the nephrotic syndrome. About 70% of patients develop renal failure over 10 years thus the prognosis is poor. Mesangiocapillary glomerulonephritis has become much more clearly defined. Two distinct morphological types occur, one associated with dense deposits and the other with sub-endothelial deposits. In both the prognosis is poor. The greatest advance in treatment in recent years has been made in that of diffuse crescentic glomerulonephritis which has a very poor prognosis untreated. Dramatic results have been obtained using plasmapheresis. Lupus nephritis will be discussed as an example of a specific disease entity in which many different morphological varieties are seen.

α1-Antitrypsin and Membranoproliferative Glomerulonephritis

Although associations of apparently disparate diseases are worthy of reporting, the possibility of chance associations warrants examination. The report of Moroz et al. (Pediatrics 57:232, February 1976) of an association between α1-antitrypsin (α1AT) deficiency and membranoproliferative glomerulonephritis (MPGN) is such a situation. Levels of α1AT were measured by radial immunodiffusion in eight patients with MPGN. Seven patients, including two with partial lipodystrophy, are persistently hypocomplementemic. Five have "dense deposit disease," two have subendothelial deposits with mesangial interposition, and one has not had electron microscopy study.

Mesangial proliterative glomerulonephritis with irregular intramembranous deposits: Another variant of hypocomplementemic nephritis

Two patients with a persistent mesangial proliferative glomerulonephritis and reduced serum C3 levels have been followed for six and 10 years. Both have had a mild course with normal renal function and spontaneous morphologic improvement. Levels of the fourth component (C4) and second component (C2) of complement, and properdin factor B have been normal; the third component (C3) of complement nephritic factor has not been detected. Ultrastructurally, irregular intramembranous electron-dense deposits are present, primarily within the lamina densa. These deposits are separated by varying lengths of normal-appearing glomerular basement membrane. Intramembranous and subendothelial electron-lucent areas, containing vesicles, are also seen. Subendothelial deposits, mesangial interposition, splitting of the glomerular basement membrane and ribbon-like intramembranous deposits are not found. The disease in these patients was clinically indistinguishable at onset from membranoproliferative glomerulonephritis (MPGN). The possibility of a variant with mild clinical course, no progression and spontaneous morphologic improvement is important in planning and assessing treatment programs in this disease group.

Reversible Crescentic Glomerulonephritis Following an Acute Exacerbation of Chronic Relapsing Pancreatitis

A patient had recurrent episodes of acute glomerulonephritis following exacerbations of chronic relapsing pancreatitis. Light microscopy of the renal biopsy performed during the episode of acute glomerulonephritis showed fibroepithelial crescents involving 70% of the glomeruli. The patient recovered without specific therapy. The time interval involved and the presence of subendothelial deposits with mesangial deposition of C3 complement and IgM suggest immune complex injury.

The association of familial liver disease, subepidermal immunoproteins, and membranoproliferative glomerulonephritis

Herein we report a new familial form of hepatic disease. Each of the four patients had splenomegaly, hypersplenism, a small liver, biochemical evidence of hepatic excretory dysfunction and hepatocellular damage, kidneys without demonstrable cysts, and normal blood pressue. An evaluation of serum immunoproteins, autoantibodies, histocompatibility antigens, and mixed lymphocyte reactivity further defined the immunologic features of this syndrome. Extrahepatic manifestations included a papulosquamous dermatitis with deposition of immunoglobulins and complement in both normal and abnormal skin, a membranoproliferative glomerulonephritis with subendothelial deposits, arthritis, and pericardial, pleural, and synovial effusions.

THE SIGNIFICANCE OF ELECTRON DENSE DEPOSITS IN MILD LUPUS NEPHRITIS

The prognostic significance of mild proliferative lupus nephritis (focal or pure mesangial proliferation) has remained unclear because previous reports have failed to correlate changes on both light (LM) and electron (EM) microscopy with the clinical course. Twenty-one pts with SLE and a mild proliferative lesion on LM of the initial renal biopsy (RBx) were studied. In 11 cases either no electron dense deposits (6 pts) or deposits limited to the mesangial region alone (5 pts) were seen on EM. All 11 pts have had a good clinical outcome (mean followup 35 mo.) with normal BP and improved or normal renal function. Proteinuria increased in one pt to 0.6 Gm/d and in another pt to 5.0 Gm/d. A 2nd RBx in the latter pt revealed a membranous lesion with subepithelial deposits. In the remaining 10 pts abundant subendothelial electron dense deposits were present by EM on the initial RBx. Five of these pts have been stable or improved clinically (mean followup 30 mo.). However, the other 5 pts have all deteriorated clinically with increased proteinuria, reduced renal function, and significant HBP (mean followup 35 mo.). A second RBx in 4 of these pts revealed severe proliferative changes with persistence of subendothelial deposits. Three of these pts have died and one is on hemodialysis. These data indicate 1) progression and clinical deterioration was seen only in pts with persistent subendothelial deposits; and 2) the location of electron dense deposits by EM was of greater significance than the degree of proliferation by LM.

SEQUENTIAL HISTOLOGIC CHANGES IN UNTREATED MESANGIALCAPILLARY GLOMERULONEPHRITIS (MCGN)

Since recent data have suggested that hlstologic improvement in MCGN may be associated with longtenn steroid therapy, 4 patients with well documented MCGN who had not received steroids or immunosuppressive agents were studied. A second renal biopsy (bx) was performed 3, 3, 4, and 5 years after the initial diagnosis (1st bx). On the 1st bx, all patients had diffuse mesangial proliferation, lobulation, and splitting of the basement membrane: one patient hed subendothelial deposits, one patient had no deposits, and 2 patients had mesangial/subepithelial deposits. On the second bx, there were progressive changes only in the one patient with subendothelial deposits (i.e., increased proliferation and nodular sclerosis). In the other 3 patients, there were either no significant changes (one patient) or a decrease in the degree of mesangial hypercellularity/proliferation (2 patients). Interstitial fibrosis and mesangial sclerosis were seen on the 2nd bx in all 4 patients. These data suggest that renal histologic improvement (i.e., decreased cellularity/proliferation) may occur in patients with MCGN who are untreated. However, the presence of interstitial fibrosis and mesangial sclerosis suggests that some irreversible changes have occurred.