HBV-related Glomerulonephritis Research Articles

Hepatitis B virus-targeting sodium taurocholate cotransporting polypeptide mediates HBV infection and damage in human renal podocytes.

This study identified for the first time that sodium taurocholate cotransporting polypeptide (NTCP) can mediate HBV direct infection and damage to human podocytes, and the NTCP157-165 locus is the main HBV entry site. The findings provide theoretical support for the pathogenesis of direct infection of HBV with kidney tissue. The findings provide a new target and theoretical basis for the treatment of HBV-related glomerulonephritis (HBV-GN). Blocking NTCP is a new target for the treatment of HBV-GN. We found that tacrolimus, a calcineurin inhibitor that blocks NTCP, can effectively treat HBV-GN. This study also provides a theoretical basis for the effective and safe treatment of immunosuppressant tacrolimus for HBV-GN.

Spectrum of hepatitis B and renal involvement.

Renal involvement in hepatitis B occurs in various spectrums and its knowledge is important for clinicians in management of patients. The renal diseases most commonly associated with hepatitis B virus (HBV) infection include membranous nephropathy, membranoproliferative glomerulonephritis and Polyarteritis nodosa. The widespread use of hepatitis B vaccination has decreased the incidence of HBV-related renal diseases. The incidence of HBV infection in dialysis patients has significantly decreased over the past few decades because of screening of blood products for hepatitis B surface antigen (HBsAg) and hepatitis B core antibody, implementation of infection control measures and hepatitis B vaccination. The definition of acute kidney injury has been recently modified in cirrhotic population, helping in prognosis and prediction of mortality. The most common etiologies of acute kidney injury in this cirrhotic population, which account for 80% to 90% of all cases, include volume depletion, acute tubular necrosis and hepatorenal syndrome. Treatment with oral nucleoside/tide analogues (NA) brought a new paradigm in the management of HBsAg positive glomerulonephritis, kidney transplant recipients and dialysis patients, resulting in effective viral suppression, reduced hepatic complications and improved patient survival, without compromising renal allograft outcome. NAs are cleared by the kidneys and therefore their dosage has to be adjusted in all patients with impaired renal function. This article reviews the recent knowledge of the pathogenesis and treatment of HBV-related glomerulonephritis and discusses the management of hepatitis B in patients on dialysis, kidney transplant recipients and cirrhotics, which is continuously evolving.

A Case of Hepatitis B Virus Related Membranous Glomerulonephritis That Well Responsed to Low Dose Corticosteroid Therapy

©Copyright 2014 by Bezmialem Vakif University Available online at www.bezmialemscience.org ©Telif Hakki 2014 Bezmialem Vakif Universitesi Makale metnine www.bezmialemscience.org web sayfasindan ulasilabilir. Glomerulonephritis (GN) is a common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection, affecting approximately 20% of patients from the Middle East and Far East Asia, where HBV infection is prevalent (1) Recent data show that 30% of patients with HBV-related GN eventually progress to renal failure (2). The major pathogenetic mechanism of HBV-related GN is immune complex deposits in the kidney, leading to destruction of the epithelial side of the glomerular basement membrane and eventually resulting in protein loss into the tubules. Although treatment strategies of HBV and membranous nephropathy are well established, there is still a lack of available data in patients who not respond well to primary intervention or who have failed to sustain the response.

Hepatitis B virus-related glomerulonephritis: not a predominant cause of proteinuria in korean patients with chronic hepatitis B.

Background/Aims. Hepatitis B virus (HBV) can form immune complexes which may result in various types of glomerulonephritis (GN). However, proteinuria can occur because of other kidney diseases besides HBV-related GN (HBV-GN). The aim of this study is to elucidate the causes of proteinuria and report on the clinical outcomes of HBV-GN. Methods. We reviewed the medical records of patients positive for serum hepatitis B surface antigen who underwent renal biopsies due to proteinuria at a tertiary medical center in Korea. Results. A total of 55 patients were included. HBV-GN was diagnosed in 20 (36.4%) of the patients by confirming the presence of immune complexes (12 of 13 membranoproliferative glomerulonephritis, 7 of 8 membranous glomerulonephritis, and 1 of 13 immunoglobulin A nephropathy). Twenty-one patients had other types of GN. A total of 13 (65%) HBV-GN patients were treated with antiviral agents for a median of 11 months. However, the degrees of proteinuria were not significantly reduced in the antiviral intervention group when compared to the control group. Conclusions. Proteinuria can be caused by various glomerular diseases and HBV-GN accounts for one-third of total GN cases. Well-designed prospective study is needed to assess whether antiviral therapy against HBV infection may improve the prognosis of HBV-GN.

The renal histopathology spectrum of elderly patients with kidney diseases: a study of 430 patients in a single Chinese center.

The elderly population has significantly increased in China. However, data regarding renal histopathology in this population is lacking. The present study retrospectively analyzed renal disease spectrum of 430 elderly patients who had received renal biopsy at Peking University First Hospital between January 2003 and December 2012.Among 6049 patients receiving renal biopsies during the same period, 430 (7.10%) were elderly (≥65 years). The ratio of male (263 patients) to female (167 patients) was 1.57:1, with an age of 70.29 ± 3.99 (range 65–82) years at the time of biopsy. The most common indication for renal biopsy was nephrotic syndrome (59.53%), followed by acute kidney injury (AKI, 19.53%) and chronic glomerulonephritis (CGN, 16.05%). The most common renal histopathology in primary glomerular disease was idiopathic membranous nephropathy (iMN, 61.02%), followed by IgA nephropathy (18.22%), minimal change disease (MCD, 9.32%) and focal segmental glomerulosclerosis (6.78%). ANCA-associated vasculitis (AAV, 43.95%) was the leading secondary glomerular disease, followed by HBV-related glomerulonephritis (HBV-GN, 24.2%), and amyloidosis (14.01%). In patients with nephrotic syndrome, iMN (50%) was the leading cause, followed by HBV-GN (16.02%), MCD (7.81%), and amyloidosis (7.81%). In patients with iMN, 89.5% presented as nephrotic syndrome, 8.39% as CGN. In patients with AKI, the leading cause was AAV (48.12%), followed by acute interstitial nephritis (20.48%) and acute tubular necrosis (8.43%).In conclusion, in elderly Chinese patients, the most common renal histopathology pattern was iMN in patients with nephrotic syndrome, and AAV in patients with AKI.

Seroconversion of Hepatitis B Envelope Antigen by Entecavir in a Child with Hepatitis B Virus-related Membranous Nephropathy

Membranous nephropathy (MN) is caused by subepithelial deposition of immune complexes in the glomerular basement membrane, with secondary MN arising in association with infection. In secondary MN caused by hepatitis B virus (HBV), seroconversion has been known to occur after the onset of MN, particularly in children. In patients with high serum concentrations of HBV DNA, treatment with interferon-α2b or a nucleoside analog has been reported to induce seroconversion and suppress HBV-DNA levels. We treated a 7-year-old boy who presented with proteinuria and liver dysfunction. He had a history of HBV infection since shortly after birth, as his mother was HBV-positive, and he was neither vaccinated nor treated with immunoglobulin at birth. Chronic hepatitis related to HBV was diagnosed following percutaneous needle biopsy of the liver. Percutaneous renal biopsy revealed HBV-related glomerulonephritis with diffuse global subepithelial and focal segmental mesangial and subendothelial deposits. Therefore, HBV-associated MN was diagnosed. Treatment with the nucleoside analog lamivudine was started to reduce serum HBV-DNA levels, but lamivudine was discontinued and treatment with entecavir was started at a dosage of 0.5 mg/day after 6 weeks because of possible adverse effects. Tests for HB envelope antibody were positive in week 16 of treatment, and proteinuria had resolved by week 22. Elevated levels of aspartate aminotransferase and alanine aminotransferase were seen with both treatments but were probably attributable to the developing immune response to HBV. In the present case, HBV levels needed to be reduced to: 1) lower elevated serum HBV-DNA titers, which put the patient at high risk of hepatocellular carcinoma; and 2) remove the immune complexes causing MN. Use of nucleoside analogs to suppress the HBV load may facilitate early remission of MN, and entecavir therapy did not cause any serious adverse reactions in this case. Given the advent of lamivudine-resistant HBV, entecavir appears promising for patients with elevated serum levels of HBV DNA.

Replication and infectivity of hepatitis B virus in HBV-related glomerulonephritis

To examine the presence of hepatitis B surface antigen (HBsAg), hepatitis B core antigen (HBcAg), and hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in renal tissues from patients with HBV-related glomerulonephritis. Renal tissue biopsies taken from patients with HBV-related glomerulonephritis and two control groups were prepared for immunocytochemical detection of HBsAg and HBcAg. HBV cccDNA was examined using a nested PCR. Of the 63 HBV-related glomerulonephritis patients studied, HBsAg was present in the renal tissues of 48 (76.2%) and HBcAg in the renal tissues of 27 (42.9%). The HBsAg and HBcAg positive rates in HBV-related glomerulonephritis patients were higher than those of the 20 patients with non-HBV-related glomerulonephritis (p<0.05). However, there was no significant difference when the HBV-related glomerulonephritis patients were compared with 12 patients with renal tuberculosis, renal atrophy, renal calculus, and renal tumor with positive serum HBV markers. In patients with HBV-related glomerulonephritis, there was no significant difference in HBsAg and HBcAg positive rates in renal tissue between patients with and without serum hepatitis B e antigen (HBeAg). By nested PCR, two of five patients with HBV-related glomerulonephritis were positive for HBV cccDNA. The location and replication of HBV in renal tissue make the kidney a potential reservoir for HBV. HBV cccDNA may be key in the search for anti-HBV drugs.

Detection of hepatitis B virus DNA and RNA in kidneys of HBV-related glomerulonephritis

Glomerular deposition of hepatitis B virus (HBV) antigens are observed in chronic HBsAg carriers with different glomerulonephritides yet the etiologic role of HBV remains uncertain. We examined the paraffin section of kidney biopsies from 40 chronic HBsAg carriers with membranous nephropathy (MGN), mesangiocapillary glomerulonephritis (MCGN) or IgA nephropathy (IgAN) for HBV DNA and HBV RNA using in situ hybridization (ISH). Glomerular HBV antigens were present in all biopsies by immunofluorescence. HBsAg or HBcAg mRNA was also studied in RNA extracted from frozen renal tissue using a two-step polymerase chain reaction (PCR) following reverse transcription (RT). HBcAg DNA was not easily detected with ISH alone, but was readily found in 31 biopsies (78%) following PCR. HBV DNA was detected mainly in the cytoplasm of proximal tubular epithelia but not in glomerular cells. HBsAg and/or HBcAg mRNA were detected by RT-PCR in extracted RNA from 13 biopsies (33%). The PCR findings were further confirmed by (a) Southern blot hybridization using a cloned HBV probe and (b) absence of PCR product following treating RNA with RNase or omitting the RT. It is plausible that HBV DNA in renal tubules represents endocytosis of HBV DNA in the urinary filtrate and the HBV RNA extracted from kidney biopsies could derive from infiltrating cells bearing HBV RNA. Hence, ISH with specific HBV core gene RNA probe was performed subsequently. HBcAg RNA, localized in the nuclei and cytoplasm of glomerular and tubular cells, was detected in 56%, 20%, and 36% of renal biopsies in chronic HBsAg carriers with MGN, MCGN, and IgAN, respectively. Our findings indicate the presence of viral transcription in glomerular cells and renal tubular epithelia, supporting an etiological role of HBV in some chronic HBsAg carriers who develop coexisting glomerulonephritides.

Long-term outcome of hepatitis B virus-related glomerulonephritis after therapy with interferon alfa

Background & Aims: Glomerulonephritis is an uncommon complication of chronic hepatitis B virus (HBV) infection in adults. A high percentage of patients seem to have short-term response to interferon therapy with improvement of proteinuria. The aim of this study was to assess the long-term response of patients with HBV-related glomerulonephritis to interferon alfa therapy. Methods: All patients with chronic hepatitis B and glomerulonephritis who were treated with interferon alfa at the National Institutes of Health between 1985 and 1993 were assessed. Results: Of the 15 patients treated, 8 (53%) had a long-term serological response with sustained loss of serum hepatitis B e antigen and HBV DNA. After 1–7 years of follow-up, all 8 responders have normal serum aminotransferase levels and 5 are hepatitis B surface antigen negative. Seven of the responders also showed a gradual but marked improvement in proteinuria. In contrast, the 7 nonresponders continued to have evidence of active renal disease and 1 required long-term dialysis therapy. All 8 responders had membranous glomerulonephritis, whereas 4 of 7 nonresponders had membranoproliferative glomerulonephritis. Conclusions: Interferon alfa therapy resulted in long-term remission in liver disease in 8 of 15 patients with chronic hepatitis B and glomerulonephritis. This response was accompanied by significant improvement in markers of renal disease in the majority of patients.

Hepatitis B Virus-Related Polyarteritis Nodosa and Membranous Nephropathy

We report the case of man with a history of post-transfusion chronic persistent hepatitis due to hepatitis B virus (HBV), who secondarily developed polyarteritis nodosa (PN) and membranous nephropathy (MN) simultaneously. At that time, liver biopsy yielded the diagnosis of active chronic hepatitis, and serological tests showed a high replication rate of HBV. PN was due to HBV infection, but the etiology of MN was uncertain, as it has never been described in PN, even in its microscopic form. There was no evidence of paraneoplastic syndrome or other causes of MN. Although the renal biopsy did not give any indication of HBV-related glomerulonephritis, the patient was considered to have an association of classic PN and MN, both related to HBV. Treatment combined plasmapheresis and interferon-alpha.

Primary glomerulonephritis with detectable glomerular hepatitis B virus antigens.

The glomerular pathology and hepatitis B virus (HBV) antigens in renal biopsies were investigated in 100 consecutive patients with both primary glomerulonephritis and positive serology for hepatitis B surface antigen (HBsAg). Glomerular HBV antigens including HBsAg, hepatitis B core antigen (HBcAg), and hepatitis B e antigen (HBeAg) were examined in frozen tissue using both polyclonal and monoclonal antibodies. HBV serology and glomerular antigens were correlated. Using monoclonal antibodies, at least one of the three HBV antigens was detectable in glomeruli in 39% of the cases. These findings correspond mainly to detectable glomerular HBsAg and HBeAg in 22.3 and 28.4% of cases, respectively. A good correlation was found between glomerular and serum HBeAg but not observed for HBsAg. Serum HBcAg was not examined and not correlated with glomerular staining. When the diagnosis of HBV-related glomerulonephritis was based strictly on detectable glomerular antigens, three distinctive morphologies were identified: membranous nephropathy, mesangiocapillary glomerulonephritis, and mesangial proliferative glomerulonephritis with immunoglobulin A (IgA) deposits (IgA nephropathy). Each of these lesions may be seen in pure form or occasionally in overlapping form leading to double glomerulopathies. Glomerular HBeAg and HBsAg were associated with subepithelial and mesangial immune complexes, respectively. Rare overlap between membranous nephropathy and IgA nephropathy further emphasized the distinctive pathology of HBV-related glomerulonephritis and the independent etiological role of HBeAg and HBsAg. In other glomerulonephritis, which rarely demonstrated glomerular HBV antigens, the pathogenetic role of chronic HBV infection remains to be proven.

Glomerulonephritis Caused by Chronic Hepatitis B Virus Infection: Treatment with Recombinant Human Alpha-Interferon

To assess the efficacy of alpha-interferon therapy in patients with hepatitis B virus (HBV)-related glomerulonephritis. Prospective, nonrandomized study. Five patients with persistence of hepatitis B surface antigen, hepatitis B e antigen (HBeAg) and HBV DNA in serum for at least 6 months and histologic changes of chronic hepatitis on liver biopsy as well as persistent proteinuria of greater than 2 g/d and histologic changes of glomerulonephritis on renal biopsy. Patients received a 4-month course of recombinant human alpha-interferon (alfa-2b) beginning at a dose of 5 million units administered subcutaneously each day. Serum levels of HBV DNA decreased in all patients and fell to undetectable levels during treatment in four of five patients. In the four responding patients, serum HBeAg disappeared, aminotransferases fell into the normal range, and a follow-up liver biopsy showed an improvement in the hepatocyte necrosis and inflammation. Urine protein excretion also decreased during treatment. In the four responding patients, urine protein excretion gradually fell to less than 1 g/d and serum albumin levels rose into the normal range. Resolution of the biochemical and serologic evidence of chronic hepatitis and glomerulonephritis was accompanied by disappearance of signs and symptoms of liver and kidney disease. A high proportion of patients with HBV-related glomerulonephritis will respond to a 4-month course of alpha-interferon with a clinical, biochemical, and serologic remission.

Hepatitis B virus-related glomerulopathy in patients with systemic lupus erythematosus.

The clinical data and renal pathologic information from three patients with systemic lupus erythematosus (SLE), active glomerular disease, and hepatitis B virus (HBV) antigenemia are presented. All three patients fulfilled the American Rheumatism Association criteria for the diagnosis of SLE. However, the renal pathologic results excluded the diagnosis of lupus nephritis. The common findings shared by these patients included the following: presence of hepatitis B surface antigen (HBsAg) in both serum and glomeruli and of glomerular hepatitis B core antigen (HBcAg), and the absence of polyclonal immunoglobulins, C1q and C4, deposition in renal tissue. These common features and the renal pathologic results indicated that the glomerulopathy was associated with HBV antigenemia. The cases described here may represent a subset of patients with SLE in whom expression of lupus nephritis was altered by the concomitant HBV-related glomerulonephritis.