|Year : 2022 | Volume
| Issue : 1 | Page : 1-6
Hepatitis B virus-related nephropathy: Review and update
Elmukhtar Habas1, Fahim Khan1, Khalifa Farfar2, Aml Habas3, Aisha Al Aldab1, Mehdi Errayes4, Eshrak Habas5, Ijaz Kamal4, Amnna Rayani3, Abdel-Naser Elzouki6
1 Internal Medicine, Hamad General Hospital, Doha-, Qatar
2 Alwakar Hospital, Alwakra, Alwakra-, Qatar
3 Department of Medical, Tripoli Medical Center, Tripoli-, Libya
4 Internal Medicine, Hamad General Hospital, Doha, Qatar
5 Tripoli Medical Center, Tripoli University, Tripoli, Libya
6 Hamad Medical Corporation
|Date of Submission||01-Jul-2022|
|Date of Acceptance||03-Jul-2022|
|Date of Web Publication||11-Aug-2022|
Prof. Elmukhtar Habas
Internal Medicine, Hamad General Hospital, Doha
Source of Support: None, Conflict of Interest: None
Viral-associated nephropathy indicates the direct pathogenic relationship between viral status and the development of nephropathy. Hepatitis B virus (HBV) infection (especially chronic) causes different glomerular, tubular, and interstitium damages. Membranous and membranoproliferative are the common HBV-associated nephropathy. The pathogenesis of HBV-associated nephropathy is primarily immune complex mediated; however, direct tubular damage may occur. The virus load and activity are essential risk factors in HBV-associated nephropathy development. Decreasing virus load and early treatment reduce the risk of HBV-associated nephropathy and may prevent the disease progression. Prevention of HBV infection by a worldwide vaccination program governed by the World Health Organization is the prime target to prevent hepatic and extrahepatic HBV-related complications. The authors searched the EMBASE, Google Scholar, Scopus, and Google search engines for articles about HBV-associated nephropathy using phrases, texts, and keywords such as chronic HBV infection and kidney, HBV-associated glomerulonephritis, nephritis in HBV infection, viral nephropathy, and HBV vaccination. Following multiple meetings and discussions, each author was given a section on the topic to search and summarize. Then, this narrative review manuscript has been written and revised to update HBV-associated nephropathy pathogenesis and treatment.
Keywords: Hepatitis B virus, hepatitis B virus-associated nephropathy, membranous glomerulonephritis, membranoproliferative glomerulonephritis, immune complex
|How to cite this article:|
Habas E, Khan F, Farfar K, Habas A, Al Aldab A, Errayes M, Habas E, Kamal I, Rayani A, Elzouki AN. Hepatitis B virus-related nephropathy: Review and update. Libyan J Med Sci 2022;6:1-6
|How to cite this URL:|
Habas E, Khan F, Farfar K, Habas A, Al Aldab A, Errayes M, Habas E, Kamal I, Rayani A, Elzouki AN. Hepatitis B virus-related nephropathy: Review and update. Libyan J Med Sci [serial online] 2022 [cited 2022 Sep 26];6:1-6. Available from: https://www.ljmsonline.com/text.asp?2022/6/1/1/353690
| Introduction|| |
Despite significant advancements in vaccination and antiviral therapy for hepatitis B virus (HBV), more than 30% of the global population shows serological evidence of a previous or present HBV infection. The chronic kidney disease (CKD) global burden is increasing and will become the 5th most common cause of death worldwide by 2040,, with the burden of CKD growing faster in low- and middle-income countries. CKD is a condition affecting >10% of the general population, equating to >800 million people worldwide. Another report in 2010 noted a prevalence range between 10.5% and 13.1%. CKD has become one of the first five leading causes of death and morbidity in the 21st century. In 2017, an estimated 843.6 million people were diagnosed with CKD. This increase is attributed to the increased number of patients with risk factors, such as hypertension, obesity, and diabetes mellitus. The number of people having renal replacement therapy exceeds 2.5 million. It is projected to double to 5.4 million by 2030. A forecasting analysis suggested that by 2040, the number of disability-adjusted life years due to CKD will be 52.5 million, up from about 26 million in 2016. Also, the number of deaths will rise to 3.1 million. Although mortality in people with end-stage renal disease (ESRD) has decreased, CKD has become the most significant cause of increased morbidity, hospitalization, and death worldwide.
HBV prevalence differs according to continent and region. It was noted that it is unknown whether these prevalence differences impact the HBV-associated nephropathy syndrome or not. HBV infection is one of the causes of kidney injuries that can proceed to CKD and may cause ESRD. However, it was reported that the relationship is unclear enough between chronic HBV infection and the increased risk of CKD. Chronic HBV-induced nephropathy is mostly immune complex mediated, but a direct injury to tubules and glomeruli occurs.
The first described lesion associated with HBV infection is membranous glomerulonephritis (MGN), mainly due to Australian–antigen-containing immune complex deposition in the glomeruli. Later, MGN in two children showed HBeAg with IgG and β1C deposits along the glomerular capillary wall. Other glomerular lesions were reported in HBV carriers, although the most common is MGN. HBV-induced nephropathies such as membranoproliferative glomerulonephritis (MPGN) and polyarteritis nodosa (PAN) occur.
| Chronic Hepatitis B Virus Infection-Associated Nephropathies|| |
Chronic HBV cases are increasing progressively. It was estimated that >350 million HBV carriers worldwide, of whom about 6 million die annually due to HBV-associated liver disease. In 2019, about 248 million persons were chronic HBV surface antigen (HBsAg) carriers worldwide. Approximately 240 million individuals have detected HBsAg in their serum, and 20%–30% of those in the inactive HBsAg carrier status can experience spontaneous reactivation of hepatitis B during follow-up. HBV-nephropathy (HBV-GN) is one of the extrahepatic symptoms in patients with persistent HBV infection and nonsymptomatic HBV carriers. In addition to the hepatic complications of chronic and acute HBV, extrahepatic involvement occurs in about 3%–5% of cases, of which 3%–5% may have renal disease, mainly the MGN.
Serologic evidence of persistent HBV infection (HBsAg, HBeAg, or HB core antigen) and the presence of glomerular immune complex deposits are often required to diagnose HBV-GN. The common glomerular pathologies are MGN, MPGN, mesangial proliferative glomerulonephritis, minimal change disease, IgA nephropathy, lupus-associated nephritis, and focal segmental glomerulosclerosis [Table 1].
| Membranous Glomerulonephritis|| |
MGN was described firstly during the 19th century, and then, Gilbert and Wiggelinkhuizen and others demonstrated that MGN has a strong relationship with chronic HBV infection, particularly in children. MGN-associated HBV resolves spontaneously in children, typically in conjunction with the development of free anti-HBeAb in the circulation. However, in adults, MGN cure is uncommon, and most MGNs tend to progress.
MGN is a pathological condition characterized by the thickening of the glomerular basement membrane involving the whole glomerulus. As demonstrated by the presence of HBV DNA and hepatitis B antigen, MGN is typically associated with active viral replication. At the MGN diagnosis, liver enzyme levels may be normal or modestly increased. In almost all cases of MGN, the pathogenesis is mediated by autoantibodies directed against phospholipase A2 receptor or, more seldom, thrombospondin type-1 domain-containing 7A.,
MGN is classified into primary and secondary MGNs. Primary MGN accounts for around 70% of MGN cases. The remaining third of the patients usually have secondary MGN. Secondary MGN has usually defined as underlying causes such as medications, cancer, autoimmune diseases, and viral infections such as hepatitis B and C. The clinical presentation of primary and secondary MGN is usually identical; however, the recognized feature of the primary disease is also present. Differentiation between the primary and secondary MGN is essential. It must be based not only on the patient's history and clinical symptoms but also on immunofluorescence and electron microscopy analysis of the renal biopsy and identifying the circulating antibodies. Furthermore, identifying the pathologic processes underlying secondary MGN is essential, as removal of the etiological causes may be followed by remission or cure of secondary MGN.
MGN is the most common cause of proteinuria and nephrotic syndrome. MGN is the most common form of HBV-related nephropathy, occurring in 35% of chronic HCV-infected patients. It was reported that HBV-related MGN histologic changes are challenging to differentiate from the idiopathic MGN because both types have subepithelial immune complex deposits on electron microscopy. However, the MGN-related HBV immune deposits consist of one or more of the three potential viral particles (HBsAg, HBcAg, or HBeAg). Furthermore, the idiopathic MGN patients have circulating anti-phospholipase A2 receptor (anti-PLA2R) antibodies and IgG subtype in the glomerular basement membrane as IgG4; whereas, in HBV-induced MGN, the IgG1 class is the main IgG subtype. Another study reported that immunofluorescent staining and electron microscopy reveal granular IgG, C3, and some IgM staining in the subepithelial region within the glomerular basement membrane. Furthermore, the podocyte foot processes and viral particles in various locations within the glomerulus detected extensive effacements. A minor percentage (<5%) of HBV-related MGN has positive anti-PLA2R; however, another study reported 64% of HBV patients to have anti-PLA2R. Hence, the subside of anti-PLA2R to differentiate between the HBV-related and idiopathic MGNs is not substantiated yet. Tubular reticular inclusions are frequently reported in HBV. The presence of tubular reticular inclusions confirms the upregulation of the local interferon, making the idiopathic MGN unlikely. In adults, about 25%–35% of HBV-related MGNs progress to ESRD adults, while in children, ESRD develops in about <5%.
Mild and nephrotic syndrome range proteinuria is the most common manifestation of HBV-related MGN in adults. Adults with HBV-associated MGN from places where HBV is not common are more likely than children who have a history of acute hepatitis. This might be related to intravenous drug consumption or acquired immunodeficiency syndrome. HBeAg has an essential pathogenetic role in a chronic HBV infection patient who has MGN. Most reported cases are among chronic HBV-infected children, but HBV-related MGNs were also observed in adults., HBV-related MGN course is endemic and is not benign even with active treatment, and has a slowly but persistently progressive clinical course in almost a third of adult patients. After systemic HBeAg clearance, a kidney biopsy detected spontaneous improvement of MGN lesions in children.
| Membranoproliferative Glomerulonephritis|| |
HBV-associated MPGN is an immune complex-mediated glomerulopathy. In chronic HBV infection, MPGN is characterized by circulating antigen–antibody complex deposition in the mesangial and subendothelial space. MPGN has been classified into three subtypes according to the locations of electron antigen–antibody complex dense deposits. Types 1 and III occur in chronic HBV infection, but type II (dense deposit disease) was not reported in HBV-associated nephropathy. The deposits are mainly IgG and C3. HBeAg and HBsAg were implicated in MPGN-related HBV infection, although their exact role remains uncertain. HBV-related MPGN is rarely due to mixed cryoglobulinemia compared to HCV infection.
MPGN is the second most common nephropathy related to HBV carriers. It affects both adults and children. MPGN characterizes by basement membrane splitting and mesangial, subendothelial, and even subepithelial layers of the glomerulus deposits. IgG can only stick to HBsAg and deposits in the subendothelial space. Chronic HBV carriers have both type 1 and type 3 MPGNs. It is marked by the nephritic syndrome with or without nephrotic range proteinuria and decreased levels of serum C, primarily because of the complement classic pathway activation manifesting by low serum C3 and C4.
Mixed cryoglobulinemia is a cause of type 1 MPGN in HBV carriers. Most of these patients (75%) present with mostly type 3 cryoglobulinemia (polyclonal IgM and IgG) after 10 years of HBV infection. In contrast, type 2 cryoglobulinemia (monoclonal IgM and polyclonal IgG) is likely to happen with type 1 MPGN in people who have had chronic HCV infection for more than 10–15 years. Patients with HBV who have cryoglobulinemia may develop nephrotic syndrome, acute kidney injury, and systemic vasculitis along with low C4 (92%) and low C3 (58%). While HBV does not move through the lymph system, the underlying mechanisms that stimulate B-cells to synthesize the cryoglobulin are unknown. Because of this new link between HBV and cryoglobulinemia, it is essential to rule out co-infection with hepatitis C as a cause of MPGN in HBV carriers. Up to 10% of patients worldwide have both viral infections, and the treatment will depend on which virus is causing the renal lesion. HBV-MPGN has a poor prognosis in adults, with an increased mortality rate and ESRD development.
| Mesangioproliferative Glomerulonephritis|| |
Mesangioproliferative GN was reported with predominant mesangial IgA deposits and persistent hepatitis B surface antigenemia. In IgA nephropathy, glomerular HBeAg deposits were not found in renal biopsies, but HBsAg mesangial deposits similar to the IgA immunostaining distribution were noticed in 40% and 21% of renal biopsies by polyclonal and monoclonal antibodies, respectively., Further studies reported a strong association between chronic HBV infection and mesangial IgA nephropathy. Later, Bhimma et al. reported that 26% of the 23 studied children with HBV-associated glomerular disease other than MGN had mesangial proliferative GN. Circulating immune complexes, particularly the large circulating immune complexes, are deposited principally in the mesangial regions and subendothelial space. It is unclear whether IgA present in glomeruli has a specific anti-HBs antibody activity. Lai et al. demonstrated HBcAg by immune peroxidase within the nuclei of mesangial cells in patients with HBV-associated IgA nephropathy. The association may be incidental as the prevalence of the HBsAg carrier state among patients with this lesion is much lower compared to those with MGN or MPGN.
| Polyarteritis Nodosa|| |
HBV-associated PAN shares the same characteristic features as idiopathic PAN. Chronic HBV infection is sometimes accidentally associated with focal segmental glomerulosclerosis and minimal change nephropathy. Chronic HBV infection is reported in approximately 15%–25% of PAN patients. HBV was the cause of up to 30% of PAN cases. Global use of the hepatitis B vaccine has significantly reduced the HBV-PAN incidence, which is recently estimated to account for <8% of all PAN cases.
HBV-associated PAN typically occurs within 4–6 months after the onset of HBV infection; however, it may occur at any time during HBV infection clinical course. HBV infection induces the deposition of antigen–antibody complexes in the medium-sized arteries. The presence of HBV-associated disease is suggested by the findings of HBsAg, HBeAg, and HBV DNA (an indicator of viral replication) in the serum. The deposition of circulating antigen–antibody immune complexes in the medium-sized artery wall triggers downstream inflammatory processes., Renal disease is due to the local inflammatory process of medium-sized arteritis, leading to glomerular ischemia, by a direct effect on the blood vessel wall, and endothelial dysfunction that induces inflammation via the production of adhesion molecule and cytokine. PAN causes different types of GN, including diffuse proliferative and membranous and mesangial proliferative GNs. The activity of HBV-associated PAN is not parallel to the degree of hepatitis, and the presenting symptoms are almost identical to idiopathic PAN. In small studies, there were more gastrointestinal manifestations, malignant hypertension, renal infarction, and orchiepididymitis reported in HBV-PAN than in idiopathic PAN.
The standard PAN treatments, including steroids and cyclophosphamide, improve the disease activity control and prognosis. Nevertheless, these therapies can induce persistent HBV infection and delay the seroconvert of HBs-AB and HBeAg antibodies. Thus, antiviral medications are required in the treatment of these patients. Guillevin et al. studied therapeutic strategies, including steroids, antivirals, and plasma exchange (plasmapheresis), and they concluded that these regimens are not entirely successful in HBV-associated PAN.
Other types of HBV-associated nephropathy are reported. HBV viral transcripts have been found in patients with IgA nephropathy and renal mesangial cells of patients with focal segmental glomerulosclerosis, implying that HBV could cause both disorders. In anecdotal cases, antiviral medication resulted in glomerular disease remission, substantiating the putative causal involvement of HBV in a subset of IgA and focal segmental glomerulosclerosis patients. Furthermore, case reports of minimal change disease in children with HBV who achieved clinical remission only with antiviral medication suggest a new kidney lesion with possible linkage to persistent HBV viremia.
| Treatment of Hepatitis B Virus-Related Nephropathy|| |
The Food and Drug Administration approved different agents for HBV therapy for adults. The effect of these agents is to lower the serum level of HBV. Nucleoside/nucleotide analogs such as interferon-(standard interferon-2b and longer-acting peginterferon-2a) (lamivudine, adefovir, entecavir, tenofovir, and telbivudine) are approved in the USA. Emtricitabine is readily in use in Europe.
Kidney Disease Improving Global Outcomes recommends IFN or oral antiviral medicines containing either nucleotide (tenofovir and adefovir) or nucleoside (lamivudine, entecavir, and telbivudine) reverse transcription inhibitors for HBV patients with MGN. Lamivudine (a cytidine analog) has been the most often utilized medication in treating hepatitis B-associated MGN, with initial remission of viremia and complete clearance of the MGN lesion in 75%–80% of patients. On the other hand, lamivudine is associated with a 20% annual resistance rate due to a somatic mutation of the HBV reverse transcription gene at the YMDD motif (tyrosine [Y], methionine [M], aspartate [D], and aspartate [D]) motif of RNA-dependent DNA polymerase. As a result, either entecavir or tenofovir is currently recommended as first-line therapy, as neither is associated with clinically significant acquired resistance. Steroids alone or combined with other immune-suppressive drugs are an ineffective treatment and may increase the risk of virus replication. They may increase the risk of HBV viremia and insignificantly affect morbidity or mortality rates.
The treatment of HBV-related MPGN with type 3 cryoglobulinemia differs from the treatment of HCV type 2 cryoglobulinemia in that it focuses on HBV viremia control rather than direct-acting antivirals. Rituximab, plasmapheresis, and cytotoxic therapy are rarely utilized, because cryoglobulinemia rarely occurs with HBV infection.
Treatment with pegylated interferon alpha-2b is reported to be effective in complete clinical remission of the nephrotic syndrome and nephrotic syndrome cases induced by HBV infection. HBV viremia load was lowered in some reported cases of IgA nephropathy caused by HBV the interferon therapy. Furthermore, the patients were in clinical remission for the following 5 years.
HBV vaccination reduces HBV MGN caused by horizontal virus transmission. Still, it has no effect on HBV MGN caused by vertical HBV acquisition, which remains a vital transmission vector in third-world countries.
| Conclusion|| |
Research studies have been scarce about HBV-associated pathogenesis in the recent 5 years. HBV infection during the acute and chronic phases can affect the kidneys and lead to kidney function abnormality. The pathogenesis is primarily due to an immune-mediated mechanism; however, direct damage to the glomeruli and tubular cells may happen. Different histopathological lesions were detected by renal biopsy in HBV patients, although the common lesions are MGN and MPGN. Worldwide HBV vaccination to prevent HBV infection is the prim method to prevent HBV-linked hepatic and extrahepatic complications. It seems therapies targeting HBV load are the cornerstone of kidney involvement prevention rather than treatment; however, some case reports noted improvement in kidney involvement following virus load reduction. Further research projects are needed to evaluate HBV-associated GN occurrence rate and their response to the available therapies.
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Conflicts of interest
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