Visualization of binding and uptake of oxidized low density lipoproteins by cultured mesangial cells.

BACKGROUND: It is hypothesized that oxidative modification of low density lipoprotein (LDL) in glomeruli may play an important role in the progression of initial glomerular injury to glomerulosclerosis. Recent biochemical studies have shown that cultured rat mesangial cells (RMC) express the scavenger receptors for oxidized LDL (Ox-LDL) suggesting that mesangial cells participate in the development of glomerulosclerosis through intracellular lipid loading. Yet it is not clear whether cultured human mesangial cells (HMC) also have receptors to take up Ox-LDL for foam cell formation. EXPERIMENTAL DESIGN: Colloidal gold or [125I]-labeled LDL was oxidized with copper ions. Binding experiments were performed by incubating the cultured human and rat mesangial cells at 4 degrees C with colloidal gold or [125I]-labeled Ox-LDL conjugates. The specificity of the [125I]-Ox-LDL binding was tested by competition experiments. Uptake and degradation studies were conducted by incubating the cells with labeled Ox-LDL at 37 degrees C. RESULTS: When the cells were incubated with Ox-LDL-gold particles for 2 hours at 4 degrees C, gold particles associated with noncoated plasma membrane or coated pits were only found in RMC, but not in HMC. The binding of Ox-LDL-gold to RMC was prevented by an excess of unlabeled Ox-LDL, polyinosinic acid or fucoidin. When the cells were incubated with increasing concentrations of [125I]-Ox-LDL, the specific binding of [125I]-Ox-LDL increased in both cells. The specific binding of [125I]-Ox-LDL (10 micrograms/ml) was 23% of the total binding for HMC and 47% for RMC, respectively. After incubation for 4 hours at 37 degrees C with Ox-LDL-gold conjugates only RMC, in particular, phagocytic mesangial cells exhibited extensive internalization of gold particles developing into foam cells. CONCLUSIONS: The results indicate that HMC have a small number of specific receptors for Ox-LDL and therefore a scavenger receptor-mediated pathway for Ox-LDL was not visualized. In contrast, RMC, particularly phagocytic cells, express a large number of specific receptors for Ox-LDL generating foam cells.

Nature of progressive glomerulosclerosis in human membranous nephropathy.

In membranous nephropathy (MN) the mechanism of progression is not well defined. We studied the lesions of focal segmental glomerulosclerosis (FSGS) in 95 patients with idiopathic MN in relation to other morphologic and clinical data. Forty-one patients (43%) showed FSGS, frequently accompanied by synechiae and hyalinosis. The patients with FSGS had a significantly greater degree of mesangial expansion, glomerular basement membrane (GBM) thickening, interstitial fibrosis, and arteriolosclerosis, as well as an increased level of serum creatinine, when compared to the patients without. Relative interstitial volume, in particular, significantly correlated to the serum creatinine level, thickness of GBM and % of glomeruli with FSGS. Glomerular size was not different in patients with or without FSGS. When clinical and morphological data of these patients were analyzed according to a staging technique of Ehrenreich and Churg [1968], the occurrence of FSGS was more frequently present in advanced stage. Intraglomerular fat deposition was only noted in advanced stage. No other morphologic or clinical parameters were related to the staging. Thickness of GBM or index of electron density of deposits, though well related to the morphological staging, did not show any relationship to clinical or laboratory data. Sixty-four patients were followed for more than a year (mean 3 years). Patients with FSGS had more frequent progression compared with those without. Patients with advanced stage and FSGS did not do worse than patients with stage I-II+II and FSGS. From these observations, we believe that the mesangial expansion, advanced GBM thickening, interstitial fibrosis and arteriolosclerosis are important morphological parameters, which may play a role in the genesis of FSGS or progression in MN. In addition, the occurrence of FSGS, but not the morphological staging, can predict the course of individual patients in MN.

Intraglomerular lipid deposition in routine biopsies.

Studies have suggested that lipids participate in the pathogenesis of chronic progressive glomerulosclerosis. To examine the frequency of intraglomerular lipid deposition in routine biopsies, renal biopsy material from 631 consecutive patients with glomerular lesions was studied by light, electron, and immunofluorescence microscopy. Fifty-three patients (8.4%) revealed ultrastructurally detectable lipid deposits in nonsclerotic glomeruli. Seven had minimal lesion, 13 focal-segmental glomerulonephritis, two membranous nephropathy, nine membranoproliferative glomerulosclerosis, 11 IgA nephropathy, and 11 other diseases. Ultrastructurally, the lesion affected small segments of glomeruli, with clusters of lipids which exhibited a heterogenous pattern. A subendothelial accumulation of lipids was observed in 60%, storage of lipids on mesangial matrix in 68%, and intramembranous deposition in 21%. Intracellular accumulation of fat was noted in 23%. Indirect immunofluorescence testing for apolipoprotein B (apo B) and oil red O (ORO) staining were performed in 94 cases. Positive results for apo B and ORO staining in nonsclerotic glomeruli were obtained in 24 patients (26%) and 16 cases (17%), respectively. The distribution of lipids seen in these patients was either in diffuse or focal segmental patterns. The clinical data of 40 patients with glomerular lipid deposition were compared with 80 controls from the residual group of patients matched for age, sex, and disease. Serum creatinine and cholesterol levels, and daily excretion of urinary protein were not significantly different between the two groups. These results suggest that an abnormal accumulation of lipids, mainly of apo B containing lipoprotein, in nonsclerotic glomeruli from routine biopsies is not as rare as previously thought. In addition, factors other than hypercholesterolemia seem to be operative for the glomerular lipid deposition observed in our patients.

Abnormalities of glomerular basement membrane in acute postinfectious glomerulonephritis.

The segmental abnormalities of glomerular basement membrane (GBM) were studied by electron microscopy in 69 renal biopsies with acute postinfectious glomerulonephritis (APGN) and correlated with the general morphologic features and clinical findings. Thirty-six were children and 33 were adults. Biopsies were grouped into three stages by light microscopy: exudative stage (25 patients), exudative-proliferative stage (26) and proliferative stage (18). Subepithelial deposits or "humps" were present in 59 patients (86%). The frequency of humps was significantly lower at the proliferative stage than that noted in the earlier biopsies (p less than 0.01). Intramembranous, subendothelial and mesangial deposits were shown in 83% to 88% of the patients. The overall frequency of GBM abnormalities was 45%, showing significantly higher frequency in children than in adults (p less than 0.01). Dissolving subepithelial deposits were often present in the foci with GBM abnormalities. The GBM lesions were not related to more severe clinical manifestations or outcomes, but tended to occur more frequently in later biopsies (p less than 0.01). These results suggest that abnormalities of GBM in APGN are more often present than formerly assumed, especially in children, and could be a normal response to subepithelial deposits. The occurrence of these lesions in other types of immune-related glomerulonephritis may be considered along the same lines.

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)

Hepatitis B e antigen-associated membranous nephropathy.

A case of hepatitis B virus (HBV)-associated membranous nephropathy (MN) is presented in an 18-year-old Korean male, whose renal disease had begun 9 years previously. He was positive for hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and antibody to hepatitis B core antigen (anti-HBc) in the serum. By immunofluorescence, HBeAg staining was noted in glomerular deposits in association with IgG, C3 and Clq, while neither HBsAg nor HBcAg was found in the glomerular deposits. The presence of glomerular HBeAg staining by FITC-monoclonal anti-HBe F(ab')2 fragments has been reported before, but never in non-Japanese patients. The demonstration of HBeAg in both the glomerular deposits and serum in this case supports the causal relationship of HBeAg and HBV-associated MN.

A renal biopsy study of hepatitis B virus-associated nephropathy in Korea.

The pathogenic role of the hepatitis B virus (HBV) infection for glomerulonephritis (GN) is not clear. The frequency of HBsAg has been studied in sera of 732 consecutive patients who have glomerular diseases by using radioimmunoassay. The frequency of HBs antigenemia was 11.9%, which was not different from that in the general population of South Korea. Of the 87 HBsAg seropositive patients with GN, 29 cases with membranoproliferative GN (MPGN) and eighteen with membranous nephropathy (MN) were diagnosed as having HBV-associated nephropathy. Eighty-seven and one-half percent of the adults with MPGN and 80% of the children with MN were HBsAg carries. The morphologic findings and laboratory data in cases with HBV-associated MPGN and MN did not differ significantly from those observed in patients with MPGN and MN without circulating HBsAg. Yet mesangial deposits were more frequently noted in patients with HBV-associated MN when compared to others with idiopathic MN. Glomerular deposits of HBsAg were not detected using indirect immunofluorescence technique. Even though HBsAg was not demonstrable within the glomeruli, HBV infection seems to play an important role in the pathogenesis of MPGN in Korean adults and MN in children.

Acute renal failure associated with hematuria in IgA nephropathy.

Severe acute deterioration of renal function, which occurred during the episode of massive gross hematuria, is described in two patients with IgA nephropathy (IgAN). The renal failure abated gradually after dialytic support. Renal pathology in each case revealed focal proliferative glomerulonephritis with less than 14% of the glomeruli affected by crescents or sclerosis. In contrast to the mild glomerular lesions, acute tubular cell injury in relation to phagocytosis of erythrocytes or pigments and/or tubular obstruction was prominent. We think our observations support the previous reports that tubular lesions in relation to heavy glomerular bleeding may be a cause of severe acute renal failure in patients with IgAN.

IgA nephropathy in Korea: a morphological and clinical study.

IgA nephropathy (IgA N) is the most common type of primary glomerulonephritis (27.5%) in South Korea and leads to renal failure in a significant number of cases. To evaluate the possible prognosticators of this disease, renal biopsy material from 142 Korean patients with IgA N was studied by light-, electron- and immunofluorescent microscopy, and a clinicopathologic correlation was made. Modified classification of Meadow et al. [1972] for Henoch-Schoenlein nephritis was adopted for the histologic grading of glomerular lesions. Twenty-three biopsies (16.2%) exhibited histologic grades IV and V lesions in association with high levels of proteinuria, serum creatinine and blood pressure and a low frequency of gross hematuria when compared to the remaining 119 biopsies with histologic grades I to III lesions. Ninety-one patients were followed for one to 6.5 years (mean, 3.4 years). Seventeen patients (18.7%) had chronic renal insufficiency, of whom eleven eventually showed endstage renal failure. More than 70% of the patients with histologic grades IV and V exhibited progressive renal disease, whereas patients with grades I to III lesions had a benign course (p less than 0.0005). These results suggest that histologic grading may be the best index to predict the present state or the subsequent progression of the lesion in IgA N.

Henoch-Schoenlein nephritis in adults: a clinical and morphological study.

Renal prognosis is not clear in adults with Henoch-Schoenlein nephritis (HSN). Renal biopsy material from seventeen adult patients with HSN was studied by light-, electron-, and immunofluorescent microscopy, and a clinicopathologic correlation was made. The outstanding glomerular lesion was a mesangial IgA deposition, apart from the proliferative glomerulonephritis associated with segmental lesions or crescents. At the time of biopsy five patients (29%) presented with renal insufficiency complicated by nephrotic syndrome and/or hypertension. After a mean follow-up period of 3.2 years, ten patients showed complete recovery, two had minor urinary abnormalities, and five exhibited moderate proteinuria with or without hematuria. No patients had died nor developed chronic renal failure. Our data indicate that the outcome of HSN in adults is favorable similar to that in children. No initial clinical nor pathological features could be associated with a poor prognosis in this study. Further follow-up is needed in view of the unpredictable nature of this disease.