HBV-associated Membranous Nephropathy Research Articles

Anti-Phospholipase A2 Receptor Antibody in Membranous Nephropathy

The M-type phospholipase A2 receptor (PLA2R) is a target autoantigen in adult idiopathic membranous nephropathy (MN), but the prevalence of autoantibodies against PLA2R is unknown among Chinese patients with MN. Here, we measured anti-PLA2R antibody in the serum of 60 patients with idiopathic MN, 20 with lupus-associated MN, 16 with hepatitis B (HBV)-associated MN, and 10 with tumor-associated MN. Among patients with idiopathic MN, 49 (82%) had detectable anti-PLA2R autoantibodies using a Western blot assay; an assay with greater sensitivity detected very low titers of anti-PLA2R in 10 of the remaining 11 patients. Using the standard assay, we detected anti-PLA2R antibody in only 1 patient with lupus, 1 with HBV, and 3 with cancer, producing an overall specificity of 89% in this cohort limited to patients with secondary MN. The enhanced assay detected low titers of anti-PLA2R in only 2 additional samples of HBV-associated MN. In summary, these results suggest that PLA2R is a major target antigen in Chinese idiopathic MN and that detection of anti-PLA2R is a sensitive test for idiopathic MN.

Retrospective characterization of the S open reading frame of HBV isolated from children with membranous nephropathy treated with interferon-α2b

A causal relationship exists between HBV infection and membranous nephropathy. The association is especially close in Black children in sub-Saharan Africa. Interferon-alpha2b is commonly used to treat this condition, but is effective in only 30-40% of patients. The reason for the poor response is unknown. The objective of this study was to determine if mutations in the surface gene of HBV isolated from Black children with HBV-associated membranous nephropathy before, during and after interferon treatment, have any effect on treatment response and vice versa. HBV DNA was extracted from a responder, a reverter and a non-responder before and after initiation of 16 weeks of interferon-alpha2b treatment. The preS1/preS2/S region was amplified, cloned and sequenced. The preS2 region was the most variable in the reverter and the non-responder, and the S region was the most variable in the non-responder. Phylogenetic analysis showed that the viral population dynamics between the responder and the reverter/non-responder strains differed as a result of mutations in the surface gene. The presence of mutations in the S region of HBV could be used as predictive markers to differentiate interferon-alpha2b responders from non-responders provided that detailed analysis of further genomes confirms our findings.

Long-term (7-year-) treatment with lamivudine monotherapy in HBV-associated glomerulonephritis

Glomerulonephritis (GN) is an uncommon but well-described complication of chronic hepatitis B virus (HBV) infection. HBV-related membranous nephropathy (MN) may lead to renal failure in 1/3 of the patients and spontaneous remission is rare. There is no standard therapy for HBV-associated MN. We report a case of a 28-year-old man with HBV-associated MN due to pre-core HBV mutant with complete remission under an ongoing 7-year lamivudine monotherapy.

Study on hepatitis B virus pre-S/S gene mutations of renal tissues in children with hepatitis B virus-associated membranous nephropathy

This study aims to clarify the prevalence and significance of the emergence of hepatitis B virus (HBV) pre-S/S mutations in children with hepatitis B virus-associated membranous nephropathy (HBVMN). Direct sequencing of polymerase chain reaction products of renal tissue samples that were obtained via percutaneous renal biopsy from seven children revealed the presence of HBV DNA. Seven adr subtypes were analyzed. Deletions in the HBV pre-S region were observed once per seven patients. The deletions were noted in both the pre-S1 (27 bp) and pre-S2 (60 bp) regions. Various point mutations in the HBV pre-S region were detected in all seven patients and proved to be more frequent in the pre-S1 region than in the S2 region. Point mutations in the HBV S region were detected in six patients. Among these mutations, the mutation in the "a" determinant region was noted in five patients. No deletion, however, was observed in the HBV S region. These observations suggested that deletions and point mutations in the HBV pre-S1 and pre-S2 regions and point mutations in the HBV S region, especially the "a" determinant region, are common frequent findings. These results also suggested that HBV pre-S/S region mutations may be involved in the pathogenesis in children with HBVMN.

HBV and proteinuria in relatives and contacts of children with hepatitis B virus-associated membranous nephropathy

Hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) is an important cause of childhood nephrotic syndrome in regions endemic for the virus, but little is understood of the biosocial context in which the disease develops. We evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated. Thirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of the study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridization and the polymerase chain reaction. Sequencing of the precore region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein/creatinine ratio. Seventy-two (37%) of the 195 family members and household contacts were HBV carriers, and 53 (27%) had a protein/creatinine ratio greater than the physiological limit. The frequency of abnormal proteinuria was not significantly different in those with [22 out of 72 (30.5%)] or without [33 out of 104 (32%)] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; P = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (P = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (P = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than that in community-based controls. The 10 index HBVMN cases and the 14 family members and household contacts who were tested all had HBV of genotype A. These results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria, a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak for HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two covert disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors.

Hepatitis B virus deoxyribonucleic acid in kidney cells probably leading to viral pathogenesis among hepatitis B virus associated membranous nephropathy patients.

In order to investigate the role of hepatitis B virus (HBV) DNA in the pathogenesis of renal lesion in HBV-associated membranous nephropathy (HBVMN) patients, serial studies using an in situ hybridization technique at different time points were performed. Within 6 months after the onset of the disease, 7 of 8 (87.5%) HBVMN patients demonstrated HBV DNA in the glomeruli and tubular epithelia. In contrast to the 14 HBVMN specimens taken later than 6 months after the onset, HBV DNA was detectable in only 3 (21%) in the tubular epithelia but none in the glomerular region. Most of the glomeruli-associated HBV DNA seemed extracellular because they were also positive for both the accumulation of HB e antigen (HBeAg)-anti-HBe antibody (Ab) immune complex and immunoglobulin G. The finding suggested that glomeruli-associated viral DNA is joined with filtered HBeAg-anti-HBeAb immune complexes. In the analysis of follow-up biopsies, HBV DNA in tubular epithelia was detected more frequently in the progressive group (50%) than in the nonprogressive group (0%). HBV DNA was detectable in the tubular epithelia in 2 cases who were progressing to end-stage renal disease and had heavy proteinuria. However, in the cases with mild or no proteinuria, HBV DNA was no longer detectable in the kidney. These findings suggest that HBV disseminates in the kidney and its dynamic changes at different time points may implicate the important role of HBV in the pathogenesis of HBVMN. This needs further study to be clarified.

Treatment of hepatitis B virus-associated membranous nephropathy with adenine arabinoside and thymic extract

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)

Immunoelectron microscopic localization of membrane attack complex and hepatitis B e antigen in membranous nephropathy

Immunoelectron microscopy was used to localize membrane attack complex (MAC) and hepatitis B e (HBe) antigen in renal tissue specimens from a total of 9 patients with membranous nephropathy (MN); 6 with MN associated with a hepatitis B virus (HBV) infection, 2 with idiopathic MN, and 1 with lupus nephritis. All the patients were proteinuric, and 2 patients were classified as stage I-II, 6 as stage II, and 1 as stage IV. MAC, along with IgG and C3, was distributed within the subepithelial electron dense deposits in all the stages. MAC was also stained in the striated membranous structures within the glomerular basement membrane and mesangial matrix of some patients. In HBV-associated MN, HBe antigen was localized in the subepithelial electron dense deposits of 5 patients, while it was absent from the subepithelial deposits in a patient that was sero-positive for hepatitis B s antigen but negative for HBe antigen. This patient also lacked MAC deposition in these loci. These results suggest that MAC is associated with the formation of subepithelial deposits and proteinuria in MN. In HBV-associated MN, HBe antigen-antibody immune complex makes up the subepithelial deposits and is likely to activate the terminal components of complement in situ.

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.