Virus-associated Membranous Nephropathy Research Articles

Prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy: a retrospective study of 420 biopsy-proven cases

Background This retrospective study aims to investigate the prevalence and immunopathologic characteristics of seropositive and seronegative hepatitis B virus-associated membranous nephropathy (HBV-MN). Methods Clinicopathologic and serologic records of 420 patients with histologically confirmed HBV-MN between January 2014 and July 2021 were examined to determine the prevalence of seropositive and seronegative HBV-MN. Serum anti-PLA2R antibody testing was conducted on 280 patients with HBV-associated membranous nephropathy (HBV-MN) from August 2018 to July 2021. Immunopathologic characteristics of HBV-MN patients and anti-PLA2R antibody positivity were analyzed. Results Among 420 pathologically confirmed HBV-MN patients, 230 (54.8%) were seropositive for HBV. The seropositive group exhibited higher blood creatinine values and incidence of liver function abnormalities than the seronegative group (p < .05). Serum anti-PLA2R antibody testing on 280 HBV-MN patients revealed a total positive rate of 44.6%, with the seronegative group showing a significantly higher rate (62.6%) compared to the seropositive group (32.1%) (p < .01). The anti-PLA2R antibody-positive group displayed higher levels of urine protein (p < .05), serum cholesterol (p < .01), and IgG4 subtypes (p < .05) compared to the negative group. Additionally, the positive group had significantly lower levels of serum albumin and IgG than the negative group (p < .01). Conclusions This comprehensive study reveals a significantly higher prevalence of seronegative HBV-MN than previously thought. The blood creatinine values and incidence of liver function abnormalities was higher in the serology-positive group than in the serology-negative group. Notably, the seronegative group displayed a higher positive rate of anti-PLA2R antibodies compared to the seropositive group, indicating distinctive clinical and immunopathologic features.

Spatial-Spectral Density Peaks-Based Discriminant Analysis for Membranous Nephropathy Classification Using Microscopic Hyperspectral Images

The traditional differential diagnosis of membranous nephropathy (MN) mainly relies on clinical symptoms, serological examination and optical renal biopsy. However, there is a probability of false positives in the optical inspection results, and it is unable to detect the change of biochemical components, which poses an obstacle to pathogenic mechanism analysis. Microscopic hyperspectral imaging can reveal detailed component information of immune complexes, but the high dimensionality of microscopic hyperspectral image brings difficulties and challenges to image processing and disease diagnosis. In this paper, a novel classification framework, including spatial-spectral density peaks-based discriminant analysis (SSDP), is proposed for intelligent diagnosis of MN using a microscopic hyperspectral pathological dataset. SSDP constructs a set of graphs describing intrinsic structure of MHSI in both spatial and spectral domains by employing density peak clustering. In the process of graph embedding, low-dimensional features with important diagnostic information in the immune complex are obtained by compacting the spatial-spectral local intra-class pixels while separating the spectral inter-class pixels. For the MN recognition task, a support vector machine (SVM) is used to classify pixels in the low-dimensional space. Experimental validation data employ two types of MN that are difficult to distinguish with optical microscope, including primary MN and hepatitis B virus-associated MN. Experimental results show that the proposed SSDP achieves a sensitivity of 99.36%, which has potential clinical value for automatic diagnosis of MN.

Efficacy of entecavir in treating hepatitis B virus-associated membranous nephropathy.

hepatitis B virus-associated membranous nephropathy (HBV-MN) is the most common pathological type of hepatitis B virus-associated glomerulonephritis. This study evaluated the efficacy of entecavir antiviral therapy for HBV-MN patients due to the intolerable side effects of interferon-alpha and high incidence rate of drug-resistance in lamivudine therapy. thirty-two patients with HBV-MN were identified by biopsy and treated with entecavir for 52 weeks. These patients were followed up to evaluate outcomes of entecavir-treatment. Descriptive statistics were used to summarize patient demographics and treatment outcomes. entecavir treatment reduced 24-h urinary protein excretion. The total probability of partial proteinuria and complete remission at 24 and 52 weeks was 53.1 and 78.1 %, respectively. A decrease of circulating HBV-DNA was observed in all patients with active HBV replication. The significant decrease of 24-h urinary protein began at 12 weeks, as early as the decrease of serum HBV-DNA level. The serum HBV DNA titers at baseline and after 52 weeks of treatment were 4.3 ± 2.8 log10 and 2.3 ± 1.7 log10, respectively. Meanwhile, eGFR increased from 100.3 ± 20.5 ml/min/1.73 m2 at baseline to 107.7 ± 15.9 ml/min/1.73 m2 after 52 weeks of treatment. The serum alanine aminotransferase level (ALT) gradually decreased to normal during entecavir antiviral treatment. entecavir treatment in HBV-MN patients was carefully described. Complete remission and HBV replication suppression were induced by entecavir treatment in HBV-MN patients. Patients with high serum creatinine (Scr), ALT and low eGFR levels benefit more from entecavir treatment. Entecavir therapy is well tolerated by patients and no adverse reactions were observed.

Anti-phospholipase A2 receptor antibody positive hepatitis B virus-associated membranous nephropathy remitted with entecavir after relapse with lamivudine

Background: Phospholipase A2 receptor (PLA2R) is thought to be an intrinsic antigen of idiopathic membranous nephropathy (IMN), and has been widely used for the differentiation from secondary membranous nephropathies. However, the positive expression of PLA2R in the patients with hepatitis B virus associated membranous nephropathy (HBV-MN) is controversial in Asian countries, because co-localization of PLA2R and HBV antigens in glomeruli have been reported. Case Presentation: We report a case of anti PLA2R antibody positive HBV-MN that was remitted with entecavir after a relapse during treatment with lamivudine. In a renal biopsy of the case, we could confirm the co-localized glomerular deposition of HBV surface antigen (HBs-Ag) and PLA2R using double staining of immunofluorescence. We also could observe the relapse of nephrotic syndrome correlated with the increased titer of HBs-Ag, and the remission with the decrease of HBs-Ag by the change of antiviral agents. Conclusions: Our case demonstrated that the renal manifestation of HBV-MN clearly responded to antiviral agents. Furthermore, the co-localized glomerular depositions of PLA2R and HBs-Ag in HBV-MN may be concerned with the etiology of MN patients with chronic HBV infection.

Role of M-type phospholipase A2 receptor and its antibody in hepatitis B virus-associated membranous nephropathy

To examine levels of M-type phospholipase A2 receptor (PLA2R) and its antibody in the patients with hepatitis B virus-associated membranous nephropathy (HBV-MN), and to explore the correlation of PLA2R with laboratory parameters and pathological characteristics. Methods: A total of 49 adult patients with biopsy-proved HBV-MN were enrolled in this study. Levels of anti-PLA2R antibody in serum and PLA2R in renal tissue were detected. Patients were assigned into two groups: a positive PLA2R group and a negative PLA2R group. Differences in laboratory parameters and pathological characteristics were compared between the two groups. Results: Of 49 patients with HBV-MN, 17 had positive PLA2R expression in renal tissues. In the positive PLA2R group, 10 patients were positive for serum anti-PLA2R antibody. Patients with positive PLA2R expression in renal tissues showed higher levels of 24 hour urinary protein [(4.6±3.9) g/d], serum HbsAg (70.5%) and renal HbsAg expression (71%), while lower level of serum albumin [(24.1±7.5) g/L] than those of the negative group. Conclusion: PLA2R is expressed in the renal tissues and serum anti-PLA2R antibody can be detected in some HBV-MN patients. Positive PLA2R expression in renal tissue might be related to HbsAg deposition in serum and renal tissues. Patients with positive PLA2R expression in renal tissue have more severe glomerular sclerosis.

A Meta-Analysis of Antiviral Therapy for Hepatitis B Virus-Associated Membranous Nephropathy.

Hepatitis B virus-associated membranous nephropathy (HBV-MN) is the most common renal extra-hepatic manifestation in patients with chronic HBV infection. In September 2015, we searched the MEDLINE, EMBASE, and CENTRAL databases, and the reference lists of retrieved articles, to identify relevant studies. Descriptions of antiviral drugs used to treat HBV-MN were included in our review. Two authors independently screened all relevant articles, extracted data, and assessed the risk of bias. Nine hundred and fifty-four papers have been considered after electronic and manual searching, only five relevant studies were identified. Complete remission (OR = 26.87, 95% CI: 8.06 to 89.52), total remission (OR = 10.31, 95% CI: 3.59 to 29.63) of proteinuria and HBeAg clearance (OR = 20.91, 95% CI: 6.90 to 63.39) increased significantly after antiviral therapy. No significant differences were seen between interferon and nucleoside analog treatments. Our study found that antiviral therapy was an effective treatment in HBV-MN patients; interferon and nucleoside analogs were equally effective at causing proteinuria remission and HBeAg clearance.

Retrospective Study of Phospholipase A2 Receptor and IgG Subclasses in Glomerular Deposits in Chinese Patients with Membranous Nephropathy

Background and objectivesThe research work in the past years showed that detection of phospholipase A2 receptor (PLA2R) antigen and its dominant IgG4 autoantibody in glomerular deposits of patients with membranous nephropathy (MN) was useful for the differentiation between primary MN (PMN) and secondary MN (SMN), but so far such research data from large Chinese patient series is little. Here, we are going to report a research work in a Chinese cohort.Design, setting, participants, & measurementsThis study enrolled 179 patients with PMN, 40 patients with membranous lupus nephritis (LN-MN), 26 patients with hepatitis B virus-associated MN (HBV-MN), 2 patients with malignancy-associated MN (M-MN) and one patient with IgG4-related MN (IgG4-MN). PLA2R and IgG subclasses in glomerular deposits of these patients were examined by immunofluorescence and/or immunohistochemical staining, and the potential value of the above examinations for differential diagnosis of PMN and SMN was evaluated.ResultsGlomerular PLA2R deposition was present in 92.2% patients with PMN and 7.7% patients with HBV-MN, but none of the patients with LN-MN. Predominant/codominant IgG4 deposition was found in 93.3% patients with PMN and 11.5% patients with HBV-MN, but none of the patients with LN-MN. The two M-MN patients both had glomerular PLA2R and predominant/codominant IgG4 deposition. The one IgG4-MN patient had deeply staining IgG4 but no PLA2R in glomeruli.ConclusionsThe glomerular PLA2R and predominant/codominant IgG4 deposition is frequently observed in Chinese patients with PMN. Immunofluorescence and immunohistochemical staining of renal biopsy tissue for detection of glomerular PLA2R and IgG subclasses deposition can help to distinguish PMN from LN-MN and most of HBV-MN.

Effectiveness of sulodexide might be associated with inhibition of complement system in hepatitis B virus-associated membranous nephropathy: An inspiration from a pilot trial

BackgroundThe activation of complement system is associated with the development of hepatitis B virus-associated membranous nephropathy (HBV-MN) and heparin could inhibit the activation of complement system. MethodsThis was a three-center trial. Seventy-nine patients with HBV-MN participated in the study. The follow-up of the study consisted of two periods: Stage 1 (S1) and Stage 2 (S2). All patients received 0.5mg entecavir plus 150–300mg/day of irbesartan but sulodexide was prescribed during S1. They were randomized into 4 groups according to sulodexide dose: blank (Group 1), 250 lipasemic unit (lsu)/day for 1year (Group 2), 500 lsu/day for 1year (Group 3) and 1000 lsu/day for 6months followed by 250 lsu/day for 6months (Group 4). Major clinical outcomes were valid remission (VR): (1) urine albumin/creatinine ratio (UACR) <150mg/mmol and >50% decline of baseline; (2) albumin >35g/L; (3) glomerular filtration rate (GFR) >90ml/(min*1.73m2). Results(1) Groups 3 and 4 had significantly lower UACR and higher albumin than did Groups 1 and 2 at major visits; (2) Groups 3 and 4 achieved more VR compared with Group 1 (42.1% and 60.0% vs. 9.1%, p both<0.05); (3) in Groups 3 and 4, instead of Groups 1 and 2, more C3 deposition in the kidney was observed in those achieving VR; (4) plasma C3a, C5a and C5b-9 decreased significantly in Groups 3 and 4 during S1. Conclusions(1) The prescription of both sulodexide and entecavir could improve the prognosis of patients with HBV-MN but their mechanisms might be different; (2) the renoprotection of sulodexide in HBV-MN might probably relate to the inhibition of complement system.

A higher frequency of IL-10-producing B cells in Hepatitis B virus-associated membranous nephropathy.

The purpose of this study is to elucidate the potential role of interleukin (IL)-10(+) regulatory B cells and other B cell subsets in the development of hepatitis B virus-associated membranous nephropathy (HBV-MN). A total of 14 patients with new onset HBV-MN, 12 individuals with immune-tolerant HBV infection (HBV-IT), and 12 healthy controls (HC) were examined for the percentages of CD38(+) , CD86(+) , CD27(+) , CD95(+) and IL-10(+) B cells by flow cytometry. Serum IL-10 concentration was examined by enzyme-linked immunosorbent assay (ELISA). The percentages of CD38(+) CD19(+) , CD86(+) CD19(+) , CD38(+) CD86(+) CD19(+) , and CD95(+) CD19(+) B cells were significantly higher in HBV-MN patients than the HBV-IT and HC. The percentages of CD5(+) CD19(+) , IL-10(+) CD19(+) B cells and serum IL-10 level in HBV-MN patients were significantly higher than the HC, and lower than the HBV-IT. Percentages of CD38(+) CD19(+) , and CD86(+) CD19(+) B cells were reduced after treatment, while the percentages of CD5(+) CD1d(+) CD19(+) , CD5(+) CD1d(+) IL-10(+) CD19(+) , and IL-10(+) CD19(+) B cells were increased. The 24h urinary protein concentration was positively correlated with the percentage of CD38(+) CD19(+) , and negatively correlated with the percentage of IL-10(+) CD19(+) B cells and serum IL-10 level. Similarly, the value of eGFR was negatively correlated with the percentage of CD38(+) CD19(+) , and positively correlated with the percentage of IL-10(+) CD19(+) B cells and serum IL-10 level. Serum IL-10 level and the percentage of IL-10(+) CD19(+) were negatively correlated with the percentages of CD38(+) CD19(+) , and CD86(+) CD19(+) B cells. These results suggest that CD86(+) CD19(+) , CD38(+) CD86(+) CD19(+) , CD95(+) CD19(+) , and especially CD38(+) CD19(+) and IL-10(+) CD19(+) cells may participate in the pathogenesis of HBV-MN.

Renal Phospholipase A2 Receptor in Hepatitis B Virus-Associated Membranous Nephropathy

Objective: This study examined the expression of renal phospholipase A₂ receptor (PLA₂R) in idiopathic and secondary membranous nephropathy (MN). Methods: Patients with biopsy-proven MN and non-MN were enrolled. Renal PLA₂R was examined using an anti-PLA₂R antibody (anti-PLA₂R-Ab), and circulating PLA₂R-Ab was detected by indirect immunofluorescence. Results: Renal PLA₂R was detected along the capillary loop in 84% patients with idiopathic MN but not in those with any other primary glomerulonephritis. Only 1 of 38 patients with class V lupus nephritis showed renal PLA₂R positive. In hepatitis B virus-associated MN (HBV-MN), 64% showed renal PLA₂R positive, and PLA₂R overlapped with HBsAg along the capillary loop. In addition, renal PLA₂R positivity was closely associated with serum PLA₂R-Ab. Renal PLA₂R positive was present in all the patients with serum PLA₂R-Ab positive and in 53% of patients with serum PLA₂R-Ab negative. However, in patients with renal PLA₂R negative, serum PLA₂R-Ab was all negative. Conclusion: Renal biopsy PLA₂R positivity was common in idiopathic MN and HBV-MN but rare in lupus-associated MN, and it was closely associated with serum PLA₂R-Ab production. Further studies examining the association between PLA₂R and HBV-MN may shed light on the mechanism of idiopathic MN or HBV-MN.

Frequency of CD4+CXCR5+ TFH cells in patients with hepatitis b virus-associated membranous nephropathy.

The frequency of different subsets of CD4(+)CXCR5(+) TFH cells and serum cytokine levels were analyzed in a total of 14 patients with newly diagnosed hepatitis B virus-associated membranous nephropathy (HBV-MN), 12 individuals with immune-tolerant HBV infection (HBV-IT) and 12 healthy controls (HC). Serum cytokine levels were measured before and 10-12 weeks after treatment. Significantly higher frequency of CD4(+)CXCR5(+), CD4(+)CXCR5(+)ICOS(+) and CD4(+)CXCR5(+)PD-1(+) TFH cells, and higher serum levels of IL-17A, IFN-γ, IL-2, IL-10, IL-4 and IL-21 were detected in HBV-MN patients compared to the HC. The percentage of CD4(+)CXCR5(+) TFH cells and serum IL-21 level in HBV-MN patients were also higher than the HBV-IT. The percentage of CD4(+)CXCR5(+) TFH cell was negatively correlated with the value of eGFR, and the percentage of CD4(+)CXCR5(+)ICOS(+) TFH cells was positively correlated with the 24-h urinary protein concentration. Notably, the percentage of CD4(+)CXCR5(+)PD-1(+) TFH cells was positively correlated with serum IL-21 level and 24-h urinary protein concentration. Treatment with prednisone or/and immunosuppressive drugs significantly reduced the frequency of CD4(+)CXCR5(+), CD4(+)CXCR5(+)PD-1(+) TFH cells and serum IL-21 level, but increased IL-4 and IL-10 levels in the patients. CD4(+)CXCR5(+) TFH cells, especially CD4(+)CXCR5(+)PD-1(+) TFH cells may participate in the pathogenesis of HBV-MN.

Experience of Anti-Viral Therapy in Hepatitis B-Associated Membranous Nephropathy, Including Lamivudine-Resistant Strains

Background/AimsChronic hepatitis B infection is a common cause of secondary membranous nephropathy (MN) in endemic areas. Lamivudine treatment improves renal outcome in patients with hepatitis B virus-associated MN (HBV-MN), but prolonged use leads to the emergence of lamivudine-resistant variants. We describe our experience treating lamivudine-resistant and other strains of HBV-MN with new antiviral drugs.MethodsOf the 89 patients biopsied and diagnosed with MN from 1996 to 2011, 10 positive for hepatitis B surface antigen were recruited for this study. We investigated the clinical courses, therapeutic responses, and prognoses of patients with HBV-MN.ResultsThe incidence of HBV-MN among the original 89 patients was 11.2%. Of these patients, four were treated with supportive care and six with antiviral drugs. One of the four patients treated with supportive care had a spontaneous remission. Four of the six patients treated with antiviral drugs were given lamivudine, and the other two were given entecavir. Two of the four patients treated with lamivudine achieved complete remission with seroconversion (i.e., development of anti-hepatitis B e antigen antibodies), whereas the other two had lamivudine-resistant strains, which were detected at 22 and 23 months after lamivudine treatment, respectively. We added adefovir to the treatment regimen for one of these patients, and for the other patient we substituted clevudine for lamivudine. Both of these patients experienced complete remission, as did the two patients initially treated with entecavir, neither of whom showed resistance to the drug.ConclusionsNew nucleoside analogues, such as entecavir, adefovir, and clevudine, can be effective for treatment of HBV-MN, including lamivudine-resistant strains.

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.

Successful treatment of hepatitis B virus-associated membranous nephropathy with lamivudine

We present a case of chronic hepatitis B with membranous nephropathy, that was improved by lamivudine treatment. A 37-year-old man was admitted to our hospital for the evaluation of proteinuria. He was diagnosed as having chronic glomerulonephritis associated with chronic hepatitis B. Histopathological findings of the renal biopsy specimen indicated membranous nephropathy. He suffered from nephrotic syndrome associated with leg edema, which was parallel to the exacerbation of hepatitis. Lamivudine was started for the treatment of hepatitis, which caused the disappearance of serum hepatitis B virus DNA and the normalization of ALT level in 4 weeks. Additionally, proteinuria disappeared 120 weeks after the treatment was started. Lamivudine treatment may remit HBV-associated nephropathy.

HLA class I and II in black children with hepatitis B virus-associated membranous nephropathy

The pathogenetic mechanisms by which individuals with chronic hepatitis B virus (HBV) infection develop membranous nephropathy (MN) are probably dependent on interactions between viral, host and environmental factors; some evidence suggests a genetic predisposition. HBVMN constitutes a major etiological group in black children with nephrotic syndrome. We therefore explored the HLA associations in black children with HBVMN. Thirty black children, age range 2 to 16 years, with biopsy-proven HBVMN, were the subjects of the study. HBV status was determined using third generation ELISA. HLA A, B and C antigens were determined using a two-stage lymphocytotoxic test. HLA DRB1* and DQB1* typing was done using sequence-specific primers. HLA class 1 and II antigen frequencies of the study subjects were compared to controls that were randomly chosen healthy blood donors from the same population. HLA DQB1*0603 was increased in patients with HBVMN compared to controls (chi2 = 13.65, RR = 4.3). DRB1*07 and DQB1*02 were increased in frequency in the study subjects but failed to reach statistical significance. There was no significant difference in the frequencies of class 1 antigens in the study group compared to controls. To our knowledge, this is the first report of HLA associations in black patients with HBVMN in whom Class 1 and 11 antigens were determined using molecular methodology. There was a high frequency of DQB1*0603 in subjects compared to controls, suggesting a possible genetic predisposition to the development of HBVMN.

Characterization of proteinuria in asymptomatic family members and household contacts of children with hepatitis B virus-associated membranous nephropathy

The biosocial background in which the hepatitis B virus (HBV) carrier state with membranous nephropathy (MN) develops was studied by evaluating HBV carriage and proteinuria among 195 family members and household contacts of 31 index HBV carrier children with MN. Unrelated individuals from the communities of these index cases who were negative for HBV served as controls (n = 123). HBV was determined by using third-generation enzyme-linked immunosorbent assay, slot-blot hybridization, and nested polymerase chain reaction. Patterns of proteinuria were determined by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis; immunoglobulin G and haptoglobulin were suggestive of MN. Seventy-two members (36.9%) of the study group (n = 195) were HBV carriers; 21 of these carriers (29.2%) had proteinuria. Twenty-eight members (41.2%) of the study group who were HBV negative (n = 68) and 26.8% of the controls showed proteinuria. This lack of association between HBV carriage and proteinuria remained when controlled for sex and family relationship. HBV was not protective against the development of proteinuria. Proteinuria suggestive of MN was strongly associated with an abnormal protein-creatinine ratio (P: = 0.001), but was not significantly different between subjects and controls (8.7% versus 6.5%; P: = 0.5). Genetic influences or environmental exposures in these subjects may be responsible for the proteinuria, suggesting underlying glomerular basement membrane damage. Discordance between the HBV carrier state and patterns of proteinuria in the study group suggest that HBV and MN may not be causally related or may reflect exceptional interaction between specifically vulnerable individuals and HBV.

Influence of antiviral therapy on the natural history of hepatitis B virus recurrence after liver transplantation: retrospective study of 14 cases

Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon. An open, randomized trial study on the therapeutic effect of recombinant α-interferon (IFNα) 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 IFNα (5 subjects, body wt < 20 kg; 8 subjects, body weight ≥ 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. Flu-like symptoms were found in all patients during the first two weeks of IFNα treatment and disappeared spontaneously. Psychiatric problems were late side-effects found in 30% of patients which disappeared when the dosage of IFN was reduced. These results suggest that IFNα therapy is of value in complete resolution of heavy proteinuria, and provides some benefit in seroconversion of HBeAg (+)/HBsAg (+) 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.

Treatment of hepatitis B virus-associated membranous nephropathy with recombinant alpha-interferon

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)

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)