HBV Hepatitis and Related Renal Nephropathies: Pathogenesis and Treatment

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Maurizio Salvadori
Aris Tsalouchos


Antiviral treatment; Hepatitis B associated glomerulonephritis; HBcAg; HBeAg; HBsAg


The extrahepatic manifestations of hepatitis B virus (HBV) infection include reactive arthritis, vasculitis (panarteritisnodosa), and primary glomer-ulonephritis (membranous nephropathy, membranoproliferative glomerulonephritis, and, less frequently, IgA nephropathy, focal and segmental glomerulosclerosis, and minimal change disease). No specific histomorphological patterns have been reported in association with HBV infection. The treatment of HBV-related glomerulopathies is essentially antiviral. Peginterferon and nucleos(t)ide drugs are the treatment of choice. Cortico-steroids have been proved to be ineffective (except in panarteritisnodosa), while immunosuppressants can lead to exacerbation of HBV infection.


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1. Centers for Disease Control and Prevention (CDC). Hepatitis B vaccination coverage among adults – United States, 2004. MMWR Morb Mortal Wkly Rep. 2006;55:509–11.
2. Lin CL, Kao JH. Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol. 2017 Jun;31(3):249–55. http://dx.doi.org/10.1016/j.bpg.2017.04.010
3. Gilbert RD, Wiggelinkhuizen J. The clinical course of hepatitis B virus-associated nephropathy.PediatrNephrol. 1994 Feb;8(1):11–14. http://dx.doi.org/10.1007/BF00868249
4. Kusakabe A, Tanaka Y, Kurbanov F, Goto K, Tajiri H, Murakami J, et al. Virological features of hepatitis B virus-associated nephropathy in Japan. J Med Virol. 2007 Sep;79(9):1305–11. http://dx.doi.org/10.1002/jmv.20941
5. Howard CR. The biology of hepadnaviruses. J Gen Virol. 1986 Jul;67(Pt 7):1215–35. http://dx.doi.org/10.1099/0022-1317-67-7-1215
6. Kay A, Zoulim F. Hepatitis B virus genetic variability and evolution. Virus Res. 2007 Aug;127(2):164–76. http://dx.doi.org/10.1016/j.virusres.2007.02.021
7. Jaryal A, Kumar V, Sharma V. Renal disease in patients infected with hepatitis B virus. Trop Gastroenterol. 2015 Oct–Dec;36(4):220–8. http://dx.doi.org/10.7869/tg.295
8. Pyrsopoulos NT, Reddy KR. Extra hepatic manifestations of chronic viral hepatitis. Curr Gastroenterol Rep. 2001 Feb;3(1):71–8. http://dx.doi.org/10.1007/s11894-001-0044-1
9. Gupta A, Quigg RJ. Glomerular diseases associated with hepatitis B and C. Adv Chronic Kidney Dis. 2015 Sep;22(5):343–51. http://dx.doi.org/10.1053/j.ackd.2015.06.003
10. Chen L, Wu C, Fan X, Gao J, Yin H, Wang T, et al. Replication and infectivity of hepatitis B virus in HBV-related glomerulonephritis. Int J Infect Dis. 2009 May;13(3):394–8. http://dx.doi.org/10.1016/j.ijid.2008.08.014
11. Ozawa T, Levisohn P, Orsini E, McIntosh RM. Acute immune complex disease associated with hepatitis. Etiopathogenic and immunopathologic studies of the renal lesion. Arch Pathol Lab Med. 1976 Sep;100(9):484–6.
12. Takekoshi Y, Tochimaru H, Nagata Y, Itami N. Immunopathogenetic mechanisms of hepatitis B virus-related glomerulopathy. Kidney Int Suppl. 1991 Dec;35:S34–S9.
13. Johnson RJ, Couser WG. Hepatitis B infection and renal disease: Clinical, immunopathogenetic and therapeutic considerations. Kidney Int. 1990 Feb;37(2):663–76. http://dx.doi.org/10.1038/ki.1990.32
14. Gregorek H, Jung H, U?anowicz G, Madali?ski K. Immune complexes in sera of children with HBV-mediated glomerulonephritis. Arch Immunol Ther Exp (Warsz). 1986;34(1):73–83.
15. Nangaku M, Couser WG. Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol. 2005 Sep;9(3):183–91. http://dx.doi.org/10.1007/s10157-005-0357-8
16. Ren J, Wang L, Chen Z, Ma ZM, Zhu HG, Yang DL, et al. Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus-associated nephropathy. J Med Virol. 2006 May;78(5):551–60. http://dx.doi.org/10.1002/jmv.20575
17. He XY, Fang LJ, Zhang YE, Sheng FY, Zhang XR, Guo MY. In situ hybridization of hepatitis B DNA in hepatitis B-associated glomerulonephritis. Pediatr Nephrol. 1998 Feb;12(2):117–20. http://dx.doi.org/10.1007/s004670050417
18. Diao Z, Ding J, Yin C, Wang L, Liu W. Purified hepatitis B virus induces human mesangial cell proliferation and extracellular matrix expression in vitro. Virol J. 2013 Oct 4;10:300–4. http://dx.doi.org/10.1186/1743-422X-10-300
19. Bhimma R, Hammond MG, Coovadia HM, Adhikari M, Connolly CA. HLA class I and II in black children with hepatitis B virus-associated membranous nephropathy. Kidney Int. 2002 Apr;61(4):1510–15. http://dx.doi.org/10.1046/j.1523-1755.2002.00287.x
20. Park MH, Song EY, Ahn C, Oh KH, Yang J, Kang SJ, et al. Two subtypes of hepatitis B virus-associated glomerulonephritis are associated with different HLA-DR2 alleles in Koreans. Tissue Antigens. 2003 Dec;62(6):505–11. http://dx.doi.org/10.1046/j.1399-0039.2003.00141.x
21. Hui D, Yan X, Wei J, Ruixia M, Guangju G. Significance of mutations in hepatitis B virus X gene for the pathogenesis of HB-associated glomerulonephritis. Acta Virol. 2014;58(3):278–81. http://dx.doi.org/10.4149/av_2014_03_278
22. Bhimma R, Coovadia HM. Hepatitis B virus-associated nephropathy. Am J Nephrol. 2004 Mar–Apr;24(2):198–211. http://dx.doi.org/10.1159/000077065
23. Liu XR, Shen Y, Yang YH. Membranous glomerulopathy associated with hepatitis B infection. J Paediatr (new series). 2008;13(1):23–9.
24. Lai KN, Li PK, Lui SF, Au TC, Tam JS, Tong KL, et al. Membranous nephropathy related to hepatitis B virus in adults. N Engl J Med. 1991 May 23;324(21):1457–63. http://dx.doi.org/10.1056/NEJM199105233242103
25. Li P, Wei RB, Tang L, Wu J, Zhang XG, Chen XM. Clinical and pathological analysis of hepatitis B virus-related membranous nephropathy and idiopathic membranous nephropathy. Clin Nephrol. 2012 Dec;78(6):456–64. http://dx.doi.org/10.5414/CN107615
26. Lee HS, Choi Y, Yu SH, Koh HI, Kim MJ, Ko KW. A renal biopsy study of hepatitis B virus-associated nephropathy in Korea. Kidney Int. 1988 Oct;34(4):537–543. http://dx.doi.org/10.1038/ki.1988.215
27. Collins AB, Bhan AK, Dienstag JL, Colvin RB, Haupert GT Jr, Mushahwar IK, et al. Hepatitis B immune complex glomerulonephritis: Simultaneous glomerular deposition of hepatitis B surface and e-antigens. Clin Immunol Immunopathol. 1983 Jan;26(1):137–53. http://dx.doi.org/10.1016/0090-1229(83)90182-4
28. Conjeevaram HS, Hoofnagle JH, Austin HA, Park Y, Fried MW, Di Bisceglie AM. Long-term outcome of hepatitis B virus-related glomerulonephritis after therapy with interferon alfa. Gastroenterology. 1995 Aug;109(2):540–6. http://dx.doi.org/10.1016/0016-5085(95)90343-7
29. Lai KN, Ho RT, Tam JS, Lai FM. Detection of hepatitis B virus DNA and RNA in kidneys of HBV-related glomerulonephritis. Kidney Int. 1996 Dec;50(6):1965–77. http://dx.doi.org/10.1038/ki.1996.519
30. Xie Q, Yan Li Y, Xue J, Xiong Z, Wang L, Sun Z, et al. Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy. Am J Nephrol. 2015;41(4–5):345–53. http://dx.doi.org/10.1159/000431331
31. Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1137–43. http://dx.doi.org/10.1681/ASN.2010090967
32. Kupin WL. Viral-associated GN: Hepatitis B and other viral infections. Clin J Am Soc Nephrol. 2017 Sep 7;12(9):1529–33. http://dx.doi.org/10.2215/CJN.09180816
33. Lu Y, Shen P, Li X. Re-evaluation of the classification system for membranoproliferative glomerulonephritis. Contrib Nephrol. 2013;181:175–84. http://dx.doi.org/10.1159/000348478
34. Li SJ, Xu ST, Chen HP, Zhang MC, Xu F, Cheng SQ, et al. Clinical and morphologic spectrum of renal involvement in patients with HBV-associated cryoglobulinaemia. Nephrology (Carlton). 2017 Jun;22(6):449–55. http://dx.doi.org/10.1111/nep.12795
35. Ozdamar SO, Gucer S, Tinaztepe K. Hepatitis-B virus associated nephropathies: A clinicopathological study in 14 children. Pediatr Nephrol. 2003 Jan;18(1):23–8. http://dx.doi.org/10.1007/s00467-002-0978-z
36. Sharma A, Sharma K. Hepatotropic viral infection associated systemic vasculitides-hepatitis B virus associated polyarteritis nodosa and hepatitis C virus-associated cryoglobulinemic vasculitis. J Clin Exp Hepatol. 2013 Sep;3(3):204–12. http://dx.doi.org/10.1016/j.jceh.2013.06.001
37. Mouthon L, Deblois P, Sauvaget F, Meyrier A, Callard P, Guillevin L. Hepatitis B virus-related polyarteritis nodosa and membranous nephropathy. Am J Nephrol. 1995;15(3):266–9. http://dx.doi.org/10.1159/000168844
38. Nagy J, Bajtai G, Brasch H, Süle T, Ambrus M, Deák G, et al. The role of hepatitis B surface antigen in the pathogenesis of glomerulopathies. Clin Nephrol. 1979 Sep;12(3):109–16.
39. Lai KN, Lai FM, Tam JS, Vallance-Owen J. Strong association between IgA nephropathy and hepatitis B surface antigenemia in endemic areas. Clin Nephrol. 1988 May;29(5):229–34.
40. Sun IO, Hong YA, Park HS, Choi SR, Chung BH, Park CW, et al. Clinical characteristics and treatment of patients with IgA nephropathy and hepatitis B surface antigen. Ren Fail. 2013;35(4):446–51. http://dx.doi.org/10.3109/0886022X.2013.775659
41. Khaira A, Upadhyay BK, Sharma A, Das P, Mahajan S, Makhariya G, et al. Hepatitis B virus associated focal and segmental glomerular sclerosis: Report of two cases and review of literature. Clin Exp Nephrol. 2009 Aug;13(4):373–7. http://dx.doi.org/10.1007/s10157-008-0124-8
42. Zhou TB, Jiang ZP. Is there an association of hepatitis B virus infection with minimal change disease of nephrotic syndrome? A clinical observational report. Ren Fail. 2015 Apr;37(3):459–61. http://dx.doi.org/10.3109/0886022X.2014.1001711
43. Lai FM, Lai KN, Tam JS, Lui SF, To KF, Li PK. Primary glomerulonephritis with detectable glomerular hepatitis B virus antigens. Am J Surg Pathol. 1994 Feb;18(2):175–186. http://dx.doi.org/10.1097/00000478-199402000-00007
44. Lightfoot RW Jr, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990 Aug;33(8):1088–93. http://dx.doi.org/10.1002/art.1780330805
45. Zhang Y, Zhou JH, Yin XL, Wang FY. Treatment of hepatitis B virus-associated glomerulonephritis: A meta-analysis. World J Gastroenterol. 2010 Feb 14;16(6):770–7. http://dx.doi.org/10.3748/wjg.v16.i6.770
46. Fabrizi F, Lunghi G, Dixit V, Martin P. Meta-analysis: Anti-viral therapy of hepatitis C virus-related liver disease in renal transplant patients. Aliment Pharmacol Ther. 2006 Nov 15;24(10):1413–22. http://dx.doi.org/10.1111/j.1365-2036.2006.03151.x
47. Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: Reading between the (guide)lines – Application to the individual patient. Kidney Int. 2012 Oct;82(8):840–856. http://dx.doi.org/10.1038/ki.2012.280
48. Okuse C, Yotsuyanagi H, Yamada N, Ikeda H, Takahashi H, Suzuki M, et al. Successful treatment of hepatitis B virus-associated membranous nephropathy with lamivudine. Clin Nephrol. 2006 Jan;65(1):53–6. http://dx.doi.org/10.5414/CNP65053
49. Tang S, Lai FM, Lui YH, Tang CS, Kung NN, Ho YW, et al. Lamivudine in hepatitis B-associated membranous nephropathy. Kidney Int. 2005 Oct;68(4):1750–8. http://dx.doi.org/10.1111/j.1523-1755.2005.00591.x
50. Lapinski TW, Flisiak R, Jaroszewicz J, Michalewicz M, Kowalczuk O. Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation. World J Gastroenterol. 2005 Jan 21;11(3):400–2. http://dx.doi.org/10.3748/wjg.v11.i3.400
51. Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al. Peginterferon alpha-2a (40 kDa): An advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003 Jul;10(4):298–305. http://dx.doi.org/10.1046/j.1365-2893.2003.00450.x
52. Haria M, Benfield P. Interferon-alpha-2a. A review of its pharmacological properties and therapeutic use in the management of viral hepatitis. Drugs. 1995 Nov;50(5):873–96. http://dx.doi.org/10.2165/00003495-199550050-00007
53. Di Bisceglie AM. Long-term outcome of interferon-alpha therapy for chronic hepatitis B. J Hepatol. 1995;22(1 Suppl):65–7.
54. European Association for the Study of the Liver. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370–98.
55. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009 May;49(5):1503–14. http://dx.doi.org/10.1002/hep.22841
56. World Health Organization (WHO). Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva, Switzerland: WHO; 2015 March; pp. 74–6.
57. Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003 Feb 27;348(9):808–16. http://dx.doi.org/10.1056/NEJMoa020681
58. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med. 2003 Feb 27;348(9):800–7. http://dx.doi.org/10.1056/NEJMoa021812
59. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HB eAg-negative chronic hepatitis B. N Engl J Med. 2005 Jun 30;352(26):2673–81. http://dx.doi.org/10.1056/NEJMoa042957
60. Izzedine H, Hulot JS, Launay-Vacher V, Marcellini P, Hadziyannis SJ, Currie G, et al. Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: Two double-blind, randomized, placebo-controlled studies. Kidney Int. 2004 Sep;66(3):1153–8. http://dx.doi.org/10.1111/j.1523-1755.2004.00866.x
61. Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al. 2-Year GLOBE trial results: Telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009 Feb;136(2):486–95. http://dx.doi.org/10.1053/j.gastro.2008.10.026
62. Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007 Dec 20;357(25):2576–88. http://dx.doi.org/10.1056/NEJMoa066422
63. Fung J, Seto WK, Lai CL, Yuen MF. Extrahepatic effects of nucleoside and nucleotide analogues in chronic hepatitis B treatment. J Gastroenterol Hepatol. 2014 Mar;29(3):428–34. http://dx.doi.org/10.1111/jgh.12499
64. Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, et al. 96?weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018 Apr;68(4):672–81. http://dx.doi.org/10.1016/j.jhep.2017.11.039
65. Viganò M, Loglio A, Grossi G, Lampertico P. Tenofovir alafenamide (TAF) treatment of HBV, what are the unanswered questions? Expert Rev Anti Infect Ther. 2018 Feb;16(2):153–61. http://dx.doi.org/10.1080/14787210.2018.1428561
66. Westin J, Aleman S, Castedal M, Duberg AS, Eilard A, Fischler B, et al. Management of hepatitis B virus infection, updated Swedish guidelines. Infect Dis (Lond). 2020 Jan;52(1):1–22. http://dx.doi.org/10.1080/23744235.2019.1675903
67. Igarashi T, Shimizu A, Igarashi T, Hanaoka K, Yoshizaki K, Shigemori T, et al. Seroconversion of hepatitis B envelope antigen by entecavir in a child with hepatitis B virus-related membranous nephropathy.J Nippon Med Sch. 2013;80(5):387–95. http://dx.doi.org/10.1272/jnms.80.387
68. Mahajan V, D’Cruz S, Nada R, Sachdev A. Successful use of entecavir in hepatitis B-associated membranous nephropathy. J Trop Pediatr. 2018 Jun 1;64(3):249–52. http://dx.doi.org/10.1093/tropej/fmx058
69. Yang YF, Xiong QF, Zhao W, Zhong YD. Complete remission of hepatitis B virus-related membranous nephropathy after entecavir monotherapy. Clin Res Hepatol Gastroenterol. 2012 Oct;36(5):e89–92. http://dx.doi.org/10.1016/j.clinre.2012.03.033
70. Lai KN, Tam JS, Lin HJ, Lai FM. The therapeutic dilemma of the usage of corticosteroid in patients with membranous nephropathy and persistent hepatitis B virus surface antigenaemia. Nephron. 1990;54(1):12–7. http://dx.doi.org/10.1159/000185802
71. Hamada T, Kumashiro R, Koga Y, Hino T, Furudera S, Sakisaka S, et al. Fatal acute hepatitis B virus infection while receiving immunosuppressants after renal transplantation. Intern Med. 1993 Jul;32(7):547–51. http://dx.doi.org/10.2169/internalmedicine.32.547
72. Lai MK, Huang CC, Chu SH, Chuang CK, Fong MT. Renal transplantation in hepatitis B carriers: Comparison of azathioprine- and cyclosporine-treated recipients. Clin Transpl. 1989:281–6. PMID: 2487573
73. Guillevin L, Mahr A, Callard P, Godmer P, Pagnoux C, Leray E, et al. Hepatitis B virus-associated polyarteritis nodosa: Clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005 Sep;84(5):313–22. http://dx.doi.org/10.1097/01.md.0000180792.80212.5e