Kiyoshi Izumino

Depressed natural killer cell activity in uremia: evidence for immunosuppressive factor in uremic sera

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 less than 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.

Effect of Probucol on Hyperlipidemia in Patients with Nephrotic Syndrome

We have evaluated the effect of the antihyperlipidemic agent probucol on hyperlipidemia in patients with nephrotic syndrome. Twelve patients with long-standing nephrotic syndrome received 500 mg of probucol daily for 12 weeks. Serum total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol were significantly lowered with probucol treatment. There were no differences in urine protein, serum total protein, serum albumin and renal function before and after probucol treatment. No drug-related side effects were observed during our study. These results indicated that probucol was effective against hyperlipidemia and free from side effects in patients with persistent nephrotic syndrome. The use of probucol is therefore suggested to be advisable when antihyperlipidemic treatment is required in some subgroups of nephrotic syndrome.

Effect of a Novel Immunosuppressant, FK506, on Spontaneous Lupus Nephritis in MRL/MpJ-lpr/lpr Mice

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/l mice, an animal model of systemic lupus erythematosus.

Membranoproliferative Glomerulonephritis Associated with Chronic Hepatitis B in Adults: Pathogenetic Role of HBsAg

Two adult cases of membranoproliferative glomerulonephritis (MPGN) associated with chronic hepatitis B were reported. Serum HBsAg, HBeAg and anti-HBc were positive. Glomerular changes were essentially the same in both patients and consistent with MPGN type III. Immunofluorescence microscopy revealed diffuse granular and lumpy deposits of IgG, IgA, IgM, C1q and C3 along glomerular capillary walls and in mesangial areas. Granular deposition of HBsAg was observed along capillary walls and in mesangial areas, and the staining patterns were similar to those of immunoglobulins and complements in both patients. Glomerular deposition of HBeAg, however, was negative in one case, and only slight and segmental in the other case. These findings suggest that HBsAg rather than HBeAg may play a role in the pathogenesis of MPGN associated with hepatitis B virus infection in adults.

Effect of the Antiplatelet Agents Ticlopidine and Dipyridamole on Experimental Immune Complex Glomerulonephritis in Rats

The effect of the antiplatelet agents ticlopidine and dipyridamole on immune complex glomerulonephritis in rats was evaluated. Bovine serum albumin (BSA) nephritis was induced in rats with subcutaneous immunization and intravenous dosage of BSA. Ticlopidine and dipyridamole were administered for 4 weeks before and for 7 days after onset of proteinuria. It was shown that both ticlopidine and dipyridamole could reduce the development of proteinuria when administered before the onset of proteinuria. Ticlopidine also reduced the amount of urinary protein after onset of proteinuria, and may thus be more effective against urinary protein excretion. When the antiplatelet agents were administered before onset of glomerulonephritis, blood urea nitrogen and serum creatinine levels were significantly lower, and glomerular hypercellularity and mesangial widening were milder in animals treated with ticlopidine than in controls. Glomerular deposition of BSA was less intense in treated animals than in nontreated controls. Thus, ticlopidine as well as dipyridamole was found to inhibit the development of proteinuria and glomerular alteration. It is suggested that ticlopidine could be more effective than dipyridamole against the development of immune complex glomerulonephritis in rats.

GLOMERULAR DEPOSITION OF IgA IN EXPERIMENTAL HEPATIC CIRRHOSIS

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 immunofiuorescent 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. ACTA PATHOL. JPN. 35: 561–567, 1985.

Effect of the Immunosuppressive Agent, Ciclosporin, on Experimental Immune Complex Glomerulonephritis in Rats

Effect of the immunosuppressive agent, ciclosporin (CS), on bovine serum albumin (BSA) nephritis in rats was evaluated. Eight weeks after immunization, 19 male Wistar rats received a daily intravenous dose of BSA (2 mg). Two weeks later, 11 rats received BSA and an oral dose of CS (10 mg/kg), and 8 rats received only BSA for 2 weeks. Urinary protein was measured weekly and serum anti-BSA antibody was measured by passive hemagglutination biweekly. The animals were killed at the 12th experimental week and blood samples and kidney specimens were obtained. BUN and serum creatinine were measured at the time of sacrifice. Kidney specimens were processed for light and immunofluorescent microscopic examination. Urinary protein excretion was significantly less in CS-treated rats than in nontreated controls at the 2nd week after treatment (5.3 +/- 1.3 vs. 25.6 +/- 10.3 mg/day, p less than 0.05). Anti-BSA antibody titers were lower in treated rats than in controls at the 2nd week after the treatment. There were no significant differences in the levels of BUN and serum creatinine between two groups. Glomerular hypercellularity and mesangial widening were milder in treated rats than in controls, and glomerular deposition of BSA was less intense in treated rats than in controls. These results suggest that CS suppressed the antibody production and the development of glomerular changes in rats with immune complex glomerulonephritis.

IgA Nephropathy and Hepatitis B Virus

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.

Effect of the Antiplatelet Agents Ticlopidine and Dipyridamole on Nephrotoxic Serum Nephritis in Rats

The effect of the antiplatelet agents, ticlopidine and dipyridamole, on nephrotoxic serum nephritis (NTN) was evaluated in rats. An accelerated form of NTN was induced with preimmunization of rabbit IgG 7 days before injection of rabbit antirat nephrotoxic serum. Twelve animals received a peroral dose of 20 mg of ticlopidine daily, and 12 animals received a peroral dose of 10 mg of dipyridamole twice daily for 7 days. It was shown that both ticlopidine and dipyridamole were able to significantly reduce urinary protein excretion. There was, however, no significant difference in glomerular changes between treated animals and nontreated controls. Ticlopidine and dipyridamole were found to suppress the development of proteinuria in accelerated NTN. Although the antiaggregative action of dipyridamole was relatively weak in vivo, dipyridamole was found to be rather effective on protein excretion in the present study. These results support the significant role of platelets in the development of proteinuria in glomerulonephritis, and it is suggested that dipyridamole may have an antiproteinuric effect other than inhibition of platelet aggregation.

Effects of the platelet-activating factor antagonists CV-6209 and CV-3988 on nephrotoxic serum nephritis in the rat

Platelet-activating factor (PAF) is known as an important mediator in the pathogenesis of glomerular injury. In the present study, we evaluated the effect of the specific PAF antagonists CV-6209 and CV-3988 on accelerated nephrotoxic serum nephritis (NTN) in the rat. The amount of urinary protein excretion was significantly less in the rats treated with CV-6209 or CV-3988 on the 5th and 7th day of treatment than in the nontreated controls. The results of light- and immunofluorescence-microscopic examination did not demonstrate any favorable effect on glomerular changes by these PAF antagonists. However, CV-6209 protected against the loss of glomerular anionic charges in rats with NTN. Thus, it is suggested that PAF is a potent mediator of protein excretion, and that the loss of glomerular anionic charges is an important mechanism for the mediation of PAF in glomerulonephritis.