Massive eosinophilic infiltration in a patient with the nephrotic syndrome and drug-induced interstitial nephritis.

The pathologic feature of acute interstitial nephritis is the infiltration of mononuclear cells, predominantly lymphocytes and monocytes, into the interstitium. We present an unusual case of a 49-year-old man with drug-induced acute interstitial nephritis whose renal biopsy specimen showed a massive infiltration of eosinophils into the interstitium and eosinophils infiltrating into the glomerulus through a gap in Bowman's capsule and the juxtaglomerular zone. The patient initially was referred to us with a recurrence of the nephrotic syndrome. Deterioration of renal function and an increase in proteinuria was noted at that time. Triazolam, a sleep inducer, was the suspected cause of the acute interstitial nephritis. Renal biopsy revealed sclerotic glomeruli containing eosinophils among massive infiltrated eosinophils and a loss of endothelial cells and mesangial cells in contrast to a preservation of epithelial cells. Infiltrating eosinophils were directly attached to the glomerular basement membrane, and free granules from the eosinophils were observed in the capillary lumen. In addition to chronic sclerotic change, eosinophils may have further damaged the glomerular capillary wall, leading to an increased severity of proteinuria in this case.

Minimal-change nephrotic syndrome associated with systemic lupus erythematosus.

A case of systemic lupus erythematosus (SLE) associated with minimal-change nephrotic syndrome (MCNS) is described. A 41-year-old woman with SLE presented with symptoms of nephrotic syndrome. Renal biopsy revealed minor glomerular abnormalities without the deposition of immune complexes. The initial heavy proteinuria promptly decreased after the prednisolone dosage was increased and disappeared 4 weeks later. The patient had a relapse of nephrotic syndrome without exacerbation of immunoserological reactions when the prednisolone dose was subsequently decreased. Remission was achieved 5 days after methylprednisolone pulse therapy. T cell dysfunction, which is present both in SLE and MCNS, might have triggered MCNS during the course of SLE.

Immunoreactivity of the JK-132 monoclonal antibody directed against basement membrane collagen in normal and diabetic glomeruli.

The possible involvement of basement membrane-associated collagen (recognized by the monoclonal antibody JK-132) in the evolution of diabetic nephropathy was studied in kidney specimens from seven patients with noninsulin-dependent diabetes mellitus, and its distribution was compared with those of antibodies against alpha 1 to alpha 4 chains of type IV collagen. JK-132, a monoclonal antibody against basement membrane-associated collagen, reacted immunohistochemically exclusively with the mesangial matrix of the glomerular capillary. In contrast, antibodies to the alpha 1 and alpha 2 chains (IV) reacted strongly with mesangial matrix, and less strongly with the glomerular basement membrane (GBM). Antibodies to the alpha 3 and alpha 4 chains (IV) reacted mainly with GBM. In diabetes, JK-132 reacted most extensively with the expanded mesangial matrix, its staining intensity increasing with progression of the diabetic glomerulosclerosis. Antibodies to the alpha 1 and alpha 2 chains (IV) reacted prominently with the expanded mesangial matrix but less strongly with the GBM. Antibodies to the alpha 3 and alpha 4 chains reacted intensely with the thickened GBM. These results suggest that basement membrane-associated collagen differs from alpha 1 to alpha 4 chains of type IV collagen and that basement membrane-associated collagen is a good marker of mesangial expansion in diabetic nephropathy.

Ultrastructural localization of the three major basement membrane components--type IV collagen, heparan sulfate proteoglycan and laminin--in human membranous glomerulonephritis.

Membranous glomerulonephritis (MN) is characterized by the presence of subepithelial immune complexes and thickening of the glomerular basement membrane (GBM). Immune complexes are recognized as subepithelial electron-dense deposits (EDDs) by electron microscopy. We used immunogold electron microscopy to detect the GBM components--type IV collagen, heparan sulfate proteoglycan (HS-PG) and laminin--in thickened GBM, and studied the relationship between immune complexes and these GBM components. We demonstrate that the three major basement membrane components are distributed throughout the newly synthesized GBM. These findings suggest that type IV collagen, HS-PG, and laminin together comprise the spike-like structures and the newly synthesized GBM-like matrix in the thickened GBM of idiopathic MN and membranous lupus nephritis. The newly constructed matrix in the GBM appears to be composed of nearly normal GBM. In type IV collagen, the alpha 1-chain was rarely present on the newly synthesized basement membrane in the lamina rara externa, while alpha 3-chain was present on the subepithelial newly synthesized basement membrane. HS-PG was found within EDDs in membranous lupus nephritis. This suggests that anti-DNA antibody may cross-react with the HS-PG component of the GBM and thus form a subepithelial immune complex.

Ultrastructural localization of three major basement membrane components--type IV collagen, heparan sulfate proteoglycan and laminin in the normal human GBM.

Human glomerular basement membrane (GBM) is known to contain type IV collagen, heparan sulfate proteoglycan (HS-PG) and laminin in the extracellular matrix. In this study, ultrastructural distribution of these antigens was investigated in normal human glomeruli using the immunogold technique. Type IV collagen was present throughout the GBM, mainly on the lamina densa, and all over the mesangial region. HS-PG was present on the laminae rarae, predominantly on the lamina rara externa, and periphery of the mesangial region. Laminin was present throughout the GBM and peripheral region of the mesangial matrix. Our study demonstrated the preferential localization of each component in the GBM.

Ultrastructural changes of extracellular matrices in diabetic nephropathy revealed by high resolution scanning and immunoelectron microscopy.

BACKGROUND: Diabetic nephropathy is invariably associated with proteinuria. EXPERIMENTAL DESIGN: To delineate the mechanism(s) of proteinuria in diabetic nephropathy, ultrastructural changes of the glomerular basement membranes (GBMs) were studied by high resolution scanning and immunoelectron microscopy. Acellular glomeruli from diabetic and age-matched control human subjects were prepared by detergent method and subjected to conductive staining, the technique in which the tissues are impregnated with metals rather than surface-coated with metallic alloys for visualization by electron microscopy. Subsequent to conductive staining, the tissues were examined by in-lens field emission scanning electron microscopy. RESULTS: Thirty glomeruli, each from the control and diabetic groups, were examined by scanning microscopy. In diabetic GBMs, a loose meshwork structure consisting of numerous pores of approximately 8 nm in diameter and distinct strands was observed. In contrast, meshwork structure was not readily discernible in controls and a few pores were observed. Five glomerular capillary loops, each from control and diabetic groups, were examined by immunoelectron microscopy. In controls, heparan sulfate-proteoglycan was localized in the lamina rara interna and externa, and type-IV collagen was distributed throughout the whole width of the GBM. In diabetic GBMs, a relative loss of staining of heparan sulfate-proteoglycan, both in the lamina rara interna and externa of the GBM, was observed. Type IV collagen was distributed in all layers of the thickened GBM, and the absolute number of the immunogold particles was increased. However, immunogold particle density of type IV collagen per unit area was decreased as compared with the control. CONCLUSIONS: These ultrastructural and immunoelectron microscopic changes in the GBM may explain the loss of charge as well as size selectivities of the glomerulus, as observed in diabetic nephropathy associated with proteinuria.

A case of nephrotic syndrome and renal dysfunction in a pregnant woman with diabetes mellitus.

A 29-year-old diabetic woman who developed severe anaemia, nephrotic syndrome, and hypertension before the 28th week of gestation, had residual evidence of toxaemia and renal dysfunction more than 1 month following delivery. The histopathological findings of renal biopsy specimens were considered most consistent with toxaemia of pregnancy complicated by diabetic glomerulosclerosis. We consider that rapid acceleration of renal dysfunction may have been induced by: (1) poor control of diabetes before pregnancy; (2) glomerular hyperfiltration of the remnant nephrons throughout pregnancy; (3) hypercoagulopathy associated with pregnancy; (4) appearance of hypertension following these three conditions.

Heparan sulfate proteoglycans are lost in patients with diabetic nephropathy.

The pathogenesis of diabetic nephropathy relative to the changes in the glomerular extracellular matrices was investigated. Renal tissues from 10 diabetic patients were immunostained with antibodies directed against heparan sulfate proteoglycans (HS-PGs), laminin, type IV collagen and fibronectin. Seven patients were nephrotic and had advanced glomerulosclerosis with nodular lesion, while the other 3 had no renal manifestations or minor glomerular tissue alterations. Controls included kidneys removed from patients with renal tumors and specimens obtained by renal biopsy from patients with IgA nephropathy. Relationships among proteinuria, intensity of fluorescence and glomerular changes were studied. In diabetes 3 patients with minor glomerular lesions were found to have no changes in various components of extracellular matrices. A marked reduction in the intensity of staining with anti-HS-PG antibodies was observed in renal specimens from patients with nodular glomerulosclerosis and proteinuria, while a mild decrease in the intensity of fluorescence was observed in tissues stained with antilaminin antibodies. An increase compared to normal control sample findings in type IV collagen and fibronectin was observed in the mesangium of sclerosing glomeruli. No loss of HS-PG was observed in patients with IgA nephropathy. These results indicate that glomerular extracellular matrix HS-PG is lost in association with diabetic nephropathy; this loss results in alteration of the charge-selective properties of glomerular capillaries. This alteration may, in part, be the cause of the proteinuria associated with diabetic nephropathy.

[Effect of protease inhibitor on primary glomerulonephritis and the mechanism of the effect].

Effect of serine protease inhibitor Camostat Mesilate (Foipan) on primary glomerulonephritis and it's mechanism were evaluated. Forty-two patients having primary glomerulonephritis (13 cases of IgA nephropathy, 11 cases of membranous nephropathy and others), aged 18 to 81 years were selected for this study. At the start of our study, twenty-one patients had received other drugs (13 cases of dipyridamole and 13 cases of prednisolone). A control period of four weeks was established to confirm that the levels of proteinuria and renal functions were stable. Patients were orally administered with 600 mg of Camostat Mesilate per day for four weeks. Effect of Camostat Mesilate was judged by urinary protein excretion, hematuria, serum total protein, albumin, Ccr, creatinine and BUN. In order to reveal the mechanism of the effect laboratory data such as granulocyte elastase, CH50, C3, C4, fibrinogen, platelate factor 4, beta-thromboglobulin, thromboxane B2 and prostaglandin F1 alpha were evaluated before and after the treatment. Parameters were analyzed by using paired t-test. Mean (+/- SEM) urinary protein excretion reduced from 4.31 +/- 0.91 to 2.80 +/- 0.43 g/day (p less than 0.05), and score of hematuria decreased from 1.8 +/- 0.16 to 1.5 +/- 0.15. A significant decrease in urinary protein excretion was seen in membranous nephropathy and a significant decrease in hematuria was seen in IgA nephropathy. In combination therapy (dipyridamole, prednisolone) urinary protein excretion markedly decreased (p less than 0.05) and in Camostat Mesilate therapy score of hematuria markedly decreased (p less than 0.05). Camostat Mesilate had no effects on renal function assessed by Ccr, creatinine and BUN.(ABSTRACT TRUNCATED AT 250 WORDS)

Three-dimensional architecture of glomerular extracellular matrices in diabetic glomerulosclerosis.

The three-dimensional ultrastructural changes of the glomerular extracellular matrices in diabetic glomerulosclerosis were studied in acellular rat and human diabetic glomeruli by scanning electron microscopy. The mesangial matrix appeared as fenestrated septa with oval stomata between the glomerular capillaries in normal control specimens. In diabetic glomerulosclerosis, both in humans and rats, expansion of mesangial matrix and narrowing of the mesangial fenestrae were observed. A thin layer of the mesangial matrix extended into the peripheral glomerular basement membrane (GBM) subendothelially. Thickening of the GBM in diabetic nephropathy might be due to expansion of the mesangial matrix into the peripheral GBM.

Nondiabetic renal disease complicating diabetic nephropathy.

The clinicopathological and laboratory findings for 35 diabetic patients who had undergone renal biopsy from 1982 to 1990 were reviewed. Ten of these patients (28.6%) were found to have nondiabetic renal diseases. Five of those patients (14.3%) suffered from nondiabetic renal disease complicated by diabetic nephropathy. Nondiabetic renal diseases included IgA nephropathy, idiopathic membranous nephropathy, membranoproliferative glomerulonephritis (types I and III), minimal change disease, and toxemia of pregnancy. The diagnosis of nondiabetic renal diseases complicated by diabetes is important for the treatment of renal disease. Urinary abnormalities and/or deterioration in renal function inconsistent with the natural history of diabetic nephropathy were suggestive of the presence of nondiabetic renal disease.

Effect of proteinase inhibitor camostat mesilate on nephrotic syndrome with diabetic nephropathy.

The effect of serine protease inhibitor Camostat Mesilate on nephrotic syndrome with diabetic nephropathy was evaluated. Eight patients with nephrotic syndrome associated with diabetic nephropathy were orally administered 600 mg of Camostat Mesilate per day. Three patients showed a reduction of urinary protein excretion promptly at 4 weeks. Serum protein and degree of edema improved significantly at 4 weeks. Camostat Mesilate had no effect on renal function assessed by creatinine clearance. During the observation period there were no significant changes in blood pressure, level of blood sugar, or HbA1c. Camostat Mesilate would be beneficial for the treatment of diabetic nephropathy.

Changes in glomerular extracellular matrices components in diabetic nephropathy.

The changes in glomerular extracellular matrices components in diabetic nephropathy were investigated. Indirect immunofluorescence staining, using polyclonal antibodies to heparan sulfate proteoglycan (HS-PG), laminin, type IV collagen, and fibronectin was carried out on renal specimens obtained by needle biopsy. Immunofluorescence intensity and distribution were observed. HS-PG and laminin decreased in the capillary walls; on the other hand, type IV collagen and fibronectin tended to increase in the mesangial area. HS-PG and laminin decreased in inverse proportion to sclerosis grades and proteinuria. These changes seemed to play an important role in progression of diabetic glomerulosclerosis.

Increased concentrations of the basement membrane component type IV collagen in sera and urine of diabetics.

We measured serum and urinary concentrations of type IV collagen by radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) in diabetics. Serum and urinary concentrations of type IV collagen measured by RIA and ELISA were increased compared to those of control subjects. In diabetics with macroproteinuria or with renal insufficiency, serum and urinary concentrations of type IV collagen were higher than in diabetics without nephropathy or with early renal damage as determined by the presence of microproteinuria. These results suggest that serum and urinary concentrations of type IV collagen are increased in patients with advanced diabetic nephropathy. These increases may indicate that alteration of basement membrane metabolism has occurred in diabetics.

[Effect of methylprednisolone pulse therapy in patients with lupus nephritis assessed by WHO morphologic classification].

To determine indications for treatment with high-dose intravenous methylprednisolone pulse therapy in lupus nephritis, we retrospectively assessed the response to pulse therapy over oral prednisolone administration in 120 biopsy proven lupus nephritis patients according to WHO morphologic classification. In the pulse group, 1 g of methylprednisolone was administered on three consecutive days and oral steroid therapy (40-30 mg) was started. In many occasions in treating class III and IV-b, repeated pulse therapy was performed. In control oral prednisolone group, middle-dose steroid therapy (50-30 mg) was started. In patients with minor glomerular abnormalities and mesangial lupus nephritis, rapid improvement of serological activities was observed in pulse group assessed by serum complement level, anti-DNA antibodies, and anti-nuclear antibodies. In patients with focal lupus nephritis, rapid rise in serum complement level and fall in proteinuria was observed in the pulse group. In patients with diffuse proliferative lupus nephritis with active necrotizing lesions, faster rise in serum complement level and proteinuria were observed in the pulse group. In patients with membranous lupus nephritis there was no significant difference between two groups. In comparison with the effect of pulse therapy among each morphologic class, the rise of serum complement level was slowest in class IV-b. Both group of IV-b and V manifested nephrotic syndrome and by pulse therapy the decrease in urinary protein was faster and more significant in class IV-b compared with class V. No significant adverse effect of methylprednisolone was observed during about 150 times of pulse therapy. Bacterial, viral infections such as herpes zoster and fungal infections were observed in pulse group as often as control group.

[Percutaneous renal biopsy using Biopty biopsy instrument and Biopty biopsy needle].

We assessed the clinical usefulness of Biopty biopsy instrument & Biopty biopsy needle in percutaneous renal biopsy (PRB) compared with Tru-cut disposable needle and Vim-Silvermann needle. Sixty cases, each consisting 20 cases, were performed PRB by 3 different needles. There was no significant differences between Biopt y-cut needle and Tru-cut needle in the length of renal biopsy tissue and number of glomeruli obtained. The frequency of clinical complications such as fever, flank pain and decrease in Ht greater than 2% was lower in Biopty needle group after PRB. The frequency of middle and large size of hematoma was also lower in Biopty needle group after PRB. We could also obtain specimen from transplanted kidney without complications except small hematoma. From three results, Biopty biopsy needle is a useful tool in performing PRB.

Effect of 15(R)-15-methyl PGE2 (arbaprostil) on duodenal bicarbonate secretion in rat.

The present study was designed to observe the effect of 15(R)-15-methyl PGE2 (arbaprostil) on duodenal bicarbonate secretion in male Wistar rats anesthetized with urethane. A proximal duodenal loop (1.5cm) was made and perfused with saline (pH4.5) in an air tight circle system. The pH and Pco2 of the perfusing fluid were measured continuously and the quantity of bicarbonate was calculated according to the Henderson-Hasselbalch equation. Vehicle or arbaprostil was injected intravenously as a bolus injection. The total output of bicarbonate in 30 min was as follows; control: 0.449 +/- 0.093 microEq (mean +/- SE); 1,10 and 100 mu/kg of arbaprostil: 0.752 +/- 0.218, 2.75 +/- 0.430 and 5.958 +/- 0.578 microEq respectively. Arbaprostil (10 and 100 micrograms/kg) increased the total output of bicarbonate significantly (p less than 0.001). The rate of secretion was also increased by arbaprostil.