An open, randomized trial study on the therapeutic effect of recombinant alpha-interferon (IFN alpha) in 40 patients with hepatitis B virus membranous nephropathy (HBVMN) was conducted. All were pathologically proven to have HBVMN which showed no response to corticosteroid treatment represented by persistent heavy proteinuria. Both HBeAg and HBsAg were positive in all. Group 1 was composed of 20 patients who were treated with recombinant IFN alpha (5 subjects, body wt < 20 kg; 8 subjects, body weight > or = 20 kg) by subcutaneous (s.c.) injection three times a week for 12 months. In group 2 there were 20 patients who received supportive treatment only. At the end of the third month of treatment, all patients in Group 1 were free of proteinuria. In contrast, 10 patients (50%) in Group 2 had persistent heavy proteinuria and another 10 patients (50%) had light proteinuria with exacerbation during respiratory tract infection. At the end of the twelfth month, 8 patients (40%) in Group 2 still had persistent heavy proteinuria and 12 patients (60%) had light proteinuria with frequent relapses. Eight patients (40%) in Group 1 had HBeAg seroconversion between the fourth and sixth months and HBsAg seroconversion between the tenth and twelfth months. HBe seroconversion only [HBeAg (-)/HBsAg (+)] was found in four patients. Four patients had no change in HBV serological markers [HBeAg (+)/HBsAg (+)]. The remaining 4 patients had HBeAg (-)/HBeAb (+) HBsAg (-)/HBsAb (-) at the end of the twelfth month. In contrast, there was no seroconversion of HBeAg (+)/HBsAg (+) in Group 2 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
To evaluate the clinical features, immunological profiles and the prognosis of hepatitis B virus-associated membraneous nephropathy (HBVMN), 34 patients (25 boys and 9 girls) were studied from April 1981 to November 1987. With Fab fragments of monoclonal antibodies, hepatitis B e antigen (HBeAg) was detected in the glomerular deposits from 30 cases (88.2%) and in the sera from 32 cases (94.1%). These results suggest that HBeAg plays an important role in the development of HBVMN. In addition, clinical trials of 32 cases demonstrate a relatively poor response to the steroid therapy with persistent heavy proteinuria (32.4%) or a high frequent relapse rate (38.2%); only 1 case (3.1%) had early response. In 4 cases follow-up renal biopsy was performed, progressive sclerosis with interstitial fibrosis being noted in each instance. The stage of membraneous nephropathy examined under the light microscope, had progressed from stage I or II to stage III. One had impaired renal function. Therefore, HBVMN does not always take a benign course. In the immunological profiles, significant hypocomplementemia with low C3, C4 and properdin factor B levels were found during the initial 6 months after the onset of disease. Hepatitis B surface antigen (HBsAg) circulating immune complexes (CIC) were also significantly higher. However, the levels of HBsAg CIC did not correlate with the degree of proteinuria or hematuria. In patients with persistent HBsAg carriage, serum HBeAg status alone did not correlate with remission rate, and remission occurred usually before the HBeAg seroconversion to anti-HBe. These results suggest that factors other than HBeAg play important roles in HBVMN.
Previously we found that corticosteroid treatment in the hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) was not associated with a favorable outcome. To distinguish the differences of the HBV DNA in macrophage, T and B cells among HBVMN patients with or without corticosteroid treatment, serial studies at different time points were investigated. HBV DNA appeared as an "episomal" molecule as with 3.2 kb in macrophage, T and B cells. This molecule disappeared after 12 months among HBVMN patients without corticosteroid treatment. HBV DNA, by contrast, appeared as episomal form even three years later in T cells, with frequent proteinuria among HBVMN patients with corticosteroid treatment. This finding indicates that the use of corticosteroids leads to a potential risk of enhancing HBV viral replication in T cells. We studied 24 HBVMN patients who had previously received corticosteroid treatment and had persistent proteinuria, who were administered combination therapy with adenine arabinoside for two weeks and thymic extract (Thymostimulin) for six months to decrease urine protein loss and obtain seroconversion. These 24 patients had heavy (22 of 24, 91.6%) or mild (2 of 24, 8.4%) proteinuria prior to adenine arabinoside and thymostimulin treatment. All 24 patients demonstrated HBV DNA in mononuclear cells and simultaneously exhibited sera positive with HBsAg and HBeAg. In contrast, after treatment only one case (4.2%) had heavy and two cases (8.4%) mild proteinuria; HBV DNA was demonstrated in macrophage (4 of 24, 16.7%), T cells (9 of 24, 37.5%), and B cells (6 of 24, 25%) as well as serum (24 of 24, 100%) prior to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
To elucidate the questions of why not all patients with hepatitis B virus (HBV) infection develop HBV membranous nephropathy (HBVMN), we first measured serum HBe circulating immune complex (CIC) during the acute nephrotic phase of HBVMN and in HBV carriers. We found that the level of HBe CIC was low in the HBVMN patients and absent either in HBsAg+/ HBeAg+ patients without HBVMN or HBsAg+/HBeAg- asymptomatic carriers. Second, we needed to characterize the cellular immune response to HBV in patients with HBVMN. However, lack of a suitable autologous effector/ target cell system makes a precise study of HBVMN pathogenesis difficult. In the present study, we established a model system by using autologous HBcAg-expressing Epstein-Barr-virus-immortalized lymphoblastoid cell lines (LCL) as stimulator/target cells. Both proliferative response after stimulation with HBcAg and cytotoxic activity against autologous HBcAg-expressing LCL of the peripheral blood T cells obtained from the HBVMN patients and HBsAg carriers could be measured. Using autologous HBcAg-expressing LCL as stimulator/target cells for the study of HBcAg-specific cytotoxic T lymphocytes, we found that HBVMN patients had lower cytotoxic activity than did both HBV carriers and HBsAg-/HBsAb+, HBeAg-/HBeAb+ children. From the in vitro cytokine production study of peripheral blood T cells after stimulation with HBcAg, we found that T-helper-cell-1 -related IL-2 and IFN-γ productions were very low in HBVMN patients but T-helper-cell-2-related IL-10 production was higher in HBsAg+/HBeAg+ patients with HBVMN than in those without HBVMN. Based on these findings, we conclude that HBVMN children seem to have an inadequate cellular immune response to HBcAg.
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