Chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) is a significant global health issue and can cause a spectrum of glomerular diseases. Despite its high global burden, glomerular disease only occurs in a subset of patients (3%–5%) (1, 2). These glomerular disorders are largely mediated by the host response of antibody formation with subsequent deposition of immune complexes in the glomerulus.
Hepatitis B
Membranous nephropathy (MN) is the most common pattern of glomerular injury in chronic HBV infection, and a minority of patients may present with membranoproliferative glomerulonephritis (MPGN) (3). In addition, polyarteritis nodosa (PAN), a type of immune complex-mediated necrotizing vasculitis in small- and medium-sized vessels, may occur in the setting of high-burden hepatitis B surface antigen (HBsAg) (3). A global effort of vaccination has significantly reduced childhood MN from perinatal exposures and PAN in endemic areas (3, 4).
With a smaller molecular weight and a predilection to passage, the highly negatively charged glomerular basement membrane, hepatitis B e antigen (HBeAg), is more commonly involved in the pathogenesis of HBV-associated MN (HBV-MN). HBsAg, on the other hand, is more frequently associated with an MPGN pattern of injury, due to its larger size and anionic charge (5). Clinically, the presence of HBeAg is highly correlated with disease activity, whereas the development of anti-HBe antibodies and clearance of HBeAg are typically associated with disease remission (6). HBV-MN typically presents with nephrotic-range proteinuria and occurs more commonly in children, the majority of whom tend to resolve spontaneously. In the adult population, however, spontaneous remission is uncommon, and 30%–50% of patients develop progressive chronic kidney disease that could eventually lead to kidney failure (7, 8).
Treatment of HBV-MN remains a challenge. Historically, before antiviral therapy became widely available, there was a major concern that corticosteroids could lead to activation of viral replication and worsening liver function (7). To date, the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline continues to recommend against the use of immunosuppressive agents, such as rituximab or cyclophosphamide, in HBV-MN given the risk for acceleration of HBV replication (9). However, data from small cohorts suggest that when combined with antiviral therapy, corticosteroids or tacrolimus could be effective in improving proteinuria without triggering viral replication or causing worsening liver or kidney injury (10, 11). Large randomized controlled trials are needed to rigorously evaluate the efficacy and safety of combined therapy. It is important to note that the nucleoside and nucleotide analogues need to be dose adjusted, according to the estimated glomerular filtration rate (eGFR).
Hepatitis C
HCV leads to chronic B cell stimulation and is the most common cause of mixed cryoglobulinemia, which could affect small-sized blood vessels and manifest with purpuric rash, peripheral nerve involvement, arthralgia, and cryoglobulinemic glomerulonephritis (cryoGN). Proteinuria (nephrotic or non-nephrotic range), low complement level (especially C4), various degrees of kidney impairment, and monoclonal immunoglobulin (Ig; almost invariably IgM kappa [IgMk]) are classical laboratory features (12).
The high efficacy of a direct antiviral agent (DAA) for HCV has led to a shift in the management of cryoGN over the past 10 years. An abundance of data suggested the high efficacy of DAA alone (without immunosuppression) in treatment of cryoGN. Currently, DAAs are recommended as the first-line treatment for cryoGN, including those with an eGFR lower than 30 mL/min/1.73 m2, for whom three DAA-based regimens have been recommended (9). Concurrent immunosuppression (rituximab and corticosteroids) should be considered in patients with aggressive, organ-threatening manifestations (rapid, progressive glomerulonephritis or pulmonary hemorrhage) or those who continue to have signs and symptoms of active glomerulonephritis despite achievement of a sustained virological response (~30%). Plasmapheresis may be considered as a bridge therapy for organ-threatening manifestations (13).
Finally, it is important to recognize that clinical presentation of cryoGN may be desynchronized from viral replication, and persistent, de novo, or recurrent cryoGN could occur even after viral eradication (14, 15). Persistent manifestations of cryoglobulinemia should also prompt an evaluation for B cell-proliferative disorders.
Footnotes
References
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Alberts CJ, et al. Worldwide prevalence of hepatitis B virus and hepatitis C virus among patients with cirrhosis at country, region, and global levels: A systematic review. Lancet Gastroenterol Hepatol 2022; 7: 724–735. doi: 10.1016/S2468-1253(22)00050-4
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Gupta A, Quigg RJ. Glomerular diseases associated with hepatitis B and C. Adv Chronic Kidney Dis 2015; 22: 343–351. doi: 10.1053/j.ackd.2015.06.003
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Kupin WL. Viral-associated GN: Hepatitis B and other viral infections. Clin J Am Soc Nephrol 2017; 12: 1529–1533. doi: 10.2215/CJN.09180816
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Liao M-T, et al. Universal hepatitis B vaccination reduces childhood hepatitis B virus-associated membranous nephropathy. Pediatrics 2011; 128:e600–e604 doi: 10.1542/peds.2010-3137
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Neurath AR, Strick N. Host specificity of a serum marker for hepatitis B: Evidence that “e antigen” has the properties of an immunoglobulin. Proc Natl Acad Sci USA 1977; 74: 1702–1706. doi: 10.1073/pnas.74.4.1702
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Gilbert RD, Wiggelinkhuizen J. The clinical course of hepatitis B virus-associated nephropathy. Pediatr Nephrol 1994; 8: 11–14. doi: 10.1007/BF00868249
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Tang S, et al. Lamivudine in hepatitis B-associated membranous nephropathy. Kidney Int 2005; 68: 1750–1758. doi: 10.1111/j.1523-1755.2005.00591.x
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Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021; 100:S1–S276. doi: 10.1016/j.kint.2021.05.021
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Zheng X-Y, et al. Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis. World J Gastroenterol 2012; 18: 821–832. doi: 10.3748/wjg.v18.i8.821
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Li H, et al. Efficacy of adefovir dipivoxil combined with a corticosteroid in 38 cases of nephrotic syndrome induced by hepatitis B virus-associated glomerulonephritis. Ren Fail 2014; 36: 1404–1406. doi: 10.3109/0886022X.2014.952745
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Pouteil-Noble C, et al. Glomerular disease associated with hepatitis C virus infection in native kidneys. Nephrol Dial Transplant 2000; 15 (Suppl 8):28–33. doi: 10.1093/ndt/15.suppl_8.28
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De Vita S, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64: 843–853. doi: 10.1002/art.34331
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Fayed A, et al. Incidence and characteristics of de novo renal cryoglobulinemia after direct-acting antivirals treatment in an Egyptian hepatitis C cohort. Nephron 2018; 140: 275–281. doi: 10.1159/000493807
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Levine JW, et al. Persistent cryoglobulinemic vasculitis following successful treatment of hepatitis C virus. J Rheumatol 2005; 32:1164–1167. PMID: 15940780; https://www.jrheum.org/content/jrheum/32/6/1164.full.pdf
