Wistar rats rendered cirrhotic with carbon tetrachloride excreted significant proteinuria and hematuria. Serum levels of IgA and IgG were significantly elevated in cirrhotic animals. They showed mild mesangial proliferation and immunofluorescent studies revealed deposits of IgA and IgG predominantly in mesangial areas and along capillary walls. These findings were very similar to those seen in patients with hepatic cirrhosis or IgA nephropathy. The deposits of IgA were also found in hepatic tissue from cirrhotic animals. The intensity and distribution of glomerular IgA deposits were not diminished after treatment with acid buffer. These results suggest that glomerular IgA are IgA polymers and decreased hepatic clearance of hepatic IgA polymers may be responsible for the glomerular deposition of IgA.
We examined the effect of the anticomplementary agent K-76 monocarboxylic acid (K-76COOH), which is known to inhibit C5 activity, on immune complex glomerulonephritis in rats. Bovine serum albumin (BSA) nephritis was induced in rats by subcutaneous immunization and daily intravenous administration of BSA. K-76COOH (30 mg/kg) was administered intraperitoneally twice daily for 4 weeks. It was shown that K-76COOH would significantly reduce the development of proteinuria in the early stage of BSA nephritis, but it failed to suppress proteinuria in the late stage. There was no significant difference in glomerular changes between treated animals and non-treated controls. These findings suggest that C5, and the terminal complement components may play a significant role in protein excretion in the early stage of immune complex glomerulonephritis.
We investigated the natural killer (NK) cell activity of peripheral blood mononuclear cells (PBMC) and the suppressive factor of NK cell activity in patients on maintenance hemodialysis (HD). NK cell activity was significantly lower in patients on HD than in healthy controls (20.2 ± 16.5 vs. 31.0 ± 13.2%, p < 0.01). There was no difference in NK cell activity between patients treated with cuprophane and high-permeability membrane. NK cells from patients on HD showed a poor response to interleukin-2, and uremic sera significantly suppressed NK cell activity of normal PBMC. Although urea, creatinine, methylguanidine or guanidinosuccinic acid alone did not suppress the NK cell activity of normal PBMC, the guanidino compound did so significantly. It is suggested that defective NK cell activity in uremic patients explains in part their susceptibility to malignancy and infection. The immunosuppressive effect may be exhibited by synergism or mosaic of uremic toxins.
The incidence and pathogenetic role of hepatitis B surface antigen (HBsAg) were evaluated in patients with IgA nephropathy. Among 130 consecutive patients with IgA nephropathy, HBs antigenemia was detected in 4 patients (3.1%). Serum antibody to hepatitis B core antigen was positive in these 4 patients indicating that they were persistent carriers of hepatitis B virus. Serum hepatitis B e antigen (HBeAg) was detected in 1 patient, and antibody to HBeAg was positive in the other 3 patients. The incidence of HBs antigenemia was not significantly higher than the 2.0% of the general population. An immunofluorescent study in the renal tissues from the 4 IgA-nephritic patients with HBs antigenemia did not demonstrate HBsAg or HBeAg in the glomeruli. These findings suggest that HBsAg appears to play no role in the pathogenesis of IgA nephropathy.
Glomerulosclerosis is a common feature of progressive glomerular injury. We investigated whether experimental glomerulosclerosis could be induced by repeated immunologic injury to mesangial cells. Chronic mesangial proliferative glomerulonephritis (GN) was induced by repeated injections of polyclonal antibody directed against the Thy 1 antigen present on the mesangial cell membrane. An intravenous injection of anti-Thy 1 serum (ATS) was given weekly to 18 male Wistar rats, which were sacrificed at weeks 2, 4 and 6 after induction of GN. Blood urea nitrogen and serum creatinine were significantly elevated in rats with anti-Thy 1 nephritis at weeks 4 and 6 compared to normal rats. Progressive expansion of the mesangial matrix with diffuse sclerosis was observed at weeks 4 and 6 by silver methenamine staining. Ultrastructurally there was a prominent rough endoplasmic reticulum in the mesangial cells and collagenous fibrils in an expanded mesangial matrix. Immunohistochemical staining revealed a marked increase in type IV collagen and laminin in the mesangium at weeks 4 and 6. Thus, repeated immunologic injury restricted to the mesangium may result in the accumulation of extracellular matrix and the development of glomerulosclerosis. These studies emphasize the importance of the mesangial cell in progressive glomerular injury.
We evaluated the effect of the novel immunosuppressive agent, FK506, which is known to inhibit T cell immunity, on the development of lupus nephritis in MRL/MpJ-lpr/lpr (MRL/l) mice. FK506 was administered subcutaneously (1 mg/kg body weight) from 12 to 20 weeks of age in 13 MRL/l mice with spontaneous lupus nephritis. Nine animals receiving no treatment were used as the control. FK506 significantly reduced the development of proteinuria, lowered the level of BUN, and suppressed the elevation of serum anti-dsDNA antibodies. Histopathological study showed that FK506 significantly inhibited the progression of glomerular hypercellularity and crescent formation. Glomerular deposition of C3 was significantly reduced in the FK506-treated mice compared to the nontreated controls. These findings suggest that FK506 may protect against progression of lupus nephritis in MRL/1 mice, an animal model of systemic lupus erythematosus.
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