When Hepatitis B Virus-Associated Glomerulonephritis Mimics Lupus Nephritis: A Case of Adult-Onset Disease With Full-House Pattern

Abstract

Although membranous nephritis represents the classic presentation of hepatitis B virus--associated glomerulonephritis (HBV-GN) in children, adult cases can exhibit quite different features. In 1992, a 41-year-old man with recurrent nephrotic syndrome since 20 years was admitted for renal evaluation and underwent kidney biopsy. Light microscopy showed periodic acid methenamine silver staining with spike formation consistent with membranous nephropathy. However, electron microscopy demonstrated large electron-dense deposits distributed throughout subepithelial, subendothelial, and mesangial areas—an unusual pattern. Immunofluorescence showed a complete “full-house” pattern with positive staining for immunoglobulin (Ig)G (IgG2-IgG4), IgA, IgM, C3, C4, and C1q along the glomerular basement membrane. These findings initially suggested lupus nephritis, but comprehensive autoimmune testing proved negative, including antinuclear antibodies and anti--double-stranded DNA antibodies, with no characteristic clinical manifestations. Further evaluation showed positive serum HBV e antigen and DNA polymerase. Crucially, tissue immunostaining confirmed HBV e antigen deposition along the glomerular basement membrane, with high-magnification electron microscopy revealing virus-like particles, establishing the diagnosis of HBV-GN. Unlike the typical membranous pattern seen in pediatric HBV-GN, this adult case demonstrated lupus-like features with diverse glomerular lesions. To our knowledge, this represents the first English-language publication of this diagnostically challenging case, highlighting the need for heightened awareness of atypical adult HBV-GN presentations.

Introduction

Hepatitis B virus--associated glomerulonephritis (HBV-GN) most commonly presents as membranous nephritis, particularly in pediatric patients. The pathogenesis typically involves immune complex formation between HBV e antigen (HBV-eAg) and corresponding antibodies, leading to subepithelial deposits characteristic of membranous nephropathy (MN). When HBV e antibody levels exceed those of HBV-eAg, viral clearance occurs through seroconversion, often leading to resolution of both viral load and associated renal lesions.1, 2, 3 However, not all patients achieve seroconversion, and some develop persistent chronic hepatitis extending into adulthood. The renal manifestations in these adult cases remain poorly characterized.¹

In this study, we present a diagnostically challenging adult case from 1992 whose HBV-GN exhibited such atypical features that it initially mimicked lupus nephritis. To our knowledge, this case represents the first English-language publication of this phenomenon and demonstrates how adult presentations can diverge significantly from the well-described pediatric phenotype. By examining medical records spanning over 3 decades, we aimed to characterize the distinctive features of adult HBV-GN that differ markedly from childhood presentations.

Case Report

Clinical Presentation

In 1992, a 41-year-old man was admitted for evaluation of proteinuria and hematuria. His medical history was notable for nephrotic syndrome first diagnosed at 20 years, which had responded completely to glucocorticoid therapy. Over the subsequent 2 decades, he experienced 3 additional episodes of nephrotic syndrome, each achieving complete remission with corticosteroid treatment. He denied any history of blood transfusion or intravenous drug use.

Physical examination showed a lean man (height 161 cm and weight 56 kg) with blood pressure 110/80 mm Hg and no peripheral edema. Laboratory studies showed preserved kidney function with serum creatinine 1.0 mg/dL and serum urea nitrogen 11 mg/dL. Other findings included total protein 6.7 g/dL, albumin 3.9 g/dL, normal liver enzymes (aspartate aminotransferase 28 IU/L [reference 10-40 IU/L] and alanine aminotransferase 20 IU/L [reference 5-45 IU/L]), and immunoglobulin (Ig) levels within normal ranges (IgG 874 mg/dL, IgA 244 mg/dL, and IgM 108 mg/dL). Urinalysis showed proteinuria (0.36 g/d) and microscopic hematuria (11-30 red blood cells/high-power field). Cryoglobulins were absent.

Kidney Biopsy Findings

Kidney biopsy was performed according to standard methods previously described.⁴ Of the 11 glomeruli examined, only 1 showed global sclerosis on light microscopy. Periodic acid–Schiff staining showed mesangial matrix expansion (Fig 1A), whereas periodic acid methenamine silver staining demonstrated not only the expected spike formation but also prominent subendothelial deposits (Fig 1B)—an unusual finding for typical HBV-GN.

Figure 1.

Kidney biopsy findings. (A) Periodic acid--Schiff stain showing mesangial matrix expansion (arrow) (original magnification, ×200). (B) Periodic acid methenamine silver stain showing not only glomerular basement membrane (GBM) doubling but also spike formation (black arrow). Large subendothelial electron-dense deposits (EDDs) (white arrow) can also be seen (original magnification, ×600). (C-O) Immunofluorescence study. Fluorophore: fluorescein isothiocyanate; channel: fluorescein isothiocyanate/green (excitation 488 nm, emission 525/50 nm) (original magnification, ×200). Immunofluorescence shows (C) granular positive (2+) stain (arrow) for immunoglobulin (Ig)G along the GBM; (D) positive (2+) IgA stain (in the same location as the IgG staining) (white arrow) and the mesangial area (yellow arrow); (E) positive (2+) IgM stain in the GBM (in the same location as the IgG staining); (F) positive C3 (2+) stain in the GBM (in the same location as the IgG staining); (G) positive C1q (2+) stain in the GBM (in the same location as the IgG staining); (H) positive (2+) C4 stain in the GBM (in the same location as the IgG staining); (I) positive (1+) IgG2 stain in the GBM (in the same location as the IgG staining); (J) positive (1+) IgG3 stain in the GBM (in the same location as the IgG staining); (K) positive (2+) IgG4 stain in the GBM (in the same location as the IgG staining); (L) positive (2+) kappa stain in the GBM (in the same location as the IgG staining); (M) positive (1+) lambda stain in the GBM (in the same location as the IgG staining); (N) positive (2+) IgA1 stain in the GBM (in the same location as the IgA staining); (O) positive (2+) hepatitis B virus (HBV) e antigen stain in the GBM (in the same location as the IgG staining). (P-S) Electron microscopy findings. (P) Large EDDs in the subepithelial area (arrow) of the GBM (original magnification, ×9,000). (Q) Large EDDs in the subendothelial area (arrow) of the GBM (original magnification, ×9,000). (R) Large EDDs in the mesangial area (arrow) (original magnification, ×9,000). (S) Tubuloreticular inclusions (interferon footprints) (arrow) in the cytoplasma of the epithelium. (T) Magnification of the EDDs revealing granular material, which appears to be HBV particles, but the identity of the virus was not confirmed using immunoelectron microscopy, so it is unclear whether they are HBV particles (original magnification, ×12,000). Abbreviation: HBV-eAg, hepatitis B virus e antigen.

Immunofluorescence (IF) microscopy showed the most striking feature, which is as follows: a complete “full-house” pattern with positive granular staining for IgG (Fig 1C), IgA (Fig 1D), IgM (Fig 1E), C3 (Fig 1F), C1q (Fig 1G), and C4 (Fig 1H) along the glomerular basement membrane. Additional analysis confirmed positive staining for IgG subclasses IgG2(1+) (Fig 1I), IgG3(1+) (Fig 1J), and IgG4(2+) (Fig 1K), with IgA1(2+) (Fig 1N) predominating over IgA2(1+). Kappa (Fig 1L) stain was positive (2+), and lambda stain (Fig 1M) was weakly positive (1+). This IF pattern was virtually indistinguishable from active lupus nephritis.

Electron microscopy (EM) confirmed large, granular electron-dense deposits (EDDs) distributed throughout multiple glomerular compartments, which are as follows: subepithelial (Fig 1P), subendothelial (Fig 1Q), and mesangial (Fig 1R). Tubuloreticular inclusions (interferon footprints) (arrow) (Fig 1S) were noted in the cytoplasma of the epithelium. This widespread distribution contrasted sharply with the predominantly subepithelial deposits typical of HBV-MN.

Diagnostic Workup

The combination of full-house IF, widespread EDDs, and diverse histologic changes initially suggested lupus nephritis. However, the clinical picture proved inconsistent with systemic lupus erythematosus. The patient lacked characteristic extrarenal manifestations such as rash, arthritis, or serositis. Moreover, comprehensive autoimmune testing was negative, including antinuclear antibodies, antidouble-stranded DNA antibodies, and anti-Smith antibodies, and complement levels remained normal. Other autoimmune diseases were similarly excluded.

Given the negative autoimmune workup, we pursued infectious etiologies. Testing for syphilis and hepatitis C proved negative, but hepatitis B serology showed positive HBV surface antigen and HBV-eAg. Notably, HBV-e antibodies remained negative, and HBV DNA polymerase was elevated at 3.0 LogIU/mL (reference value 0 LogIU/mL), indicating active viral replication.

The definitive diagnostic breakthrough came with tissue immunostaining for HBV-eAg, performed according to the methods described by Hirose et al.² This proved positive and demonstrated perfect colocalization with IgG deposits (Fig 1O), confirming HBV-eAg involvement in renal pathology. High-magnification EM showed fine granular material within the EDDs, but the identity of the virus was not confirmed using immunoelectron microscopy, so it was unclear whether they were HBV particles (Fig 1T). These findings established the diagnosis of HBV-GN.

Clinical Course

The patient underwent interferon therapy for 5 years in an attempt to achieve seroconversion. Unfortunately, treatment proved unsuccessful—HBV-eAg remained positive throughout, and kidney disease actually progressed with worsening proteinuria and hematuria. The patient was eventually transferred to another institution, precluding long-term follow-up.

Discussion

We presented findings in a 41-year-old man who underwent kidney biopsy because of kidney disease. The analyses led to a diagnosis of HBV-GN. At the time of the analyses in 1992, the present case was not reported in an English-language article; however, we believe that the report should be published in English to make it available to a wider audience and because we assume that this case can be the basis for subsequent reports of HBV-GN in adults.

Chronic hepatitis occurs when autoantibodies against the HBV antigen in liver cells attack not only the virus but also the liver cells. If the antibody response is too strong, patients can develop fulminant hepatitis. Kidney damage is known to occur in patients with hepatitis B although HBV does not directly attack the kidney: antibodies against HBV antigens (hepatitis B surface, e, and core antigens) are thought to form immune complexes in the blood that are deposited in the glomeruli, triggering inflammation and resulting in HBV-GN. In such cases, HBV-GN is confirmed when hepatitis B antigen is found in kidney tissue.

At present, hepatitis B can be diagnosed by measuring markers in blood, so HBV-eAg staining in liver tissue is no longer necessary; in fact, staining of HBV-eAg is no longer possible because the materials required for its measurement are no longer produced. However, in 1992, when the kidney biopsy of this case was performed, staining for HBV-eAg was performed on the liver tissue of patients with chronic hepatitis because of HBV.

In the case described in this study, renal tissue was stained for HBV-eAg according to a method described by Hirose et al.² In their study, Hirose et al² primarily included patients with pediatric-onset MN and reported positive staining of HBV-eAg in renal tissue in patients diagnosed with MN who had positive results for HBV-eAg in circulating blood. The location of renal staining of HBV-eAg was consistent with the location of granular deposition of IgG along the glomerular basement membrane. However, staining for HBV surface and core antigens was negative. In a patient with seroconversion MN and a negative blood test for HBV-eAg, the authors no longer found HBV-eAg staining in renal tissue. They also reported that the rate of positive HBV-eAg measurements in blood was consistent with the rate of positive HBV-eAg measurements in renal tissue. Unfortunately, they did not have detailed data on cases that had progressed to adulthood.²

MN is a well-known renal complication of HBV, but other complications such as membranoproliferative glomerulonephritis (MPGN), IgA nephropathy, and many other kidney diseases have been reported. To date, the question whether each condition exists alone or as a complication of another condition is unclear, and there is little evidence that kidney disease is directly related to HBV-eAg.¹

We reported the case of a patient diagnosed with HBV-GN at 41 years and noted that the kidney biopsy findings differed from those of patients with pediatric MN, in which EDD was found only in the subepithelium on EM. In this patient, the presence of large, IgG-positive subepithelial EDD on EM was consistent with MN. However, the presence of IgA deposits on EM and EDD in the mesangial region on IF was also consistent with IgA nephropathy. Furthermore, the presence of large subendothelial EDD on EM suggested a possible diagnosis of MPGN-like disease. In addition, the presence of various deposits on EM and of positive IgG, IgA, IgM, C1q, C3, and C4 findings on IF was similar to lupus nephritis.^5,6 In adult HBV-MN, Lai et al⁷ noted the presence of various deposits in addition to subepithelial deposits on EM. They compared lupus MN with HBV-MN in multiple cases and found similar variability in renal histologic findings in both diseases, making differentiation on the basis of renal tissue impossible. Consequently, they concluded that differentiation is difficult without serological test information and that HBV-MN resembles lupus MN.⁷ In a case of HBV-MN experienced by Roy et al,⁸ light microscopy showed diffuse endocapillary glomerulonephritis, IF confirmed deposition of IgG, IgA, IgM, C3, and C1q, and EM showed mesangial and subendothelial deposits; unlike typical MN and MPGN, which are primarily characterized by IgG and C3 deposition on IF, this case resembled renal histologically lupus nephritis and was therefore reported as lupus-like glomerulonephritis.

Based on the above reported cases, HBV-MN can be summarized as follows: although some cases resemble primary MN and MPGN, some have diverse deposits, and some are better classified as lupus-like glomerulopathy rather than MN or MPGN.

Next, we considered why HBV-GN and lupus nephritis are similar. HBV-GN is characterized by DNA polymerase, which is the main body of HBV antigens. In addition, immune complexes comprising HBV-eAg and HBV e antibody, which are related to DNA polymerase, are the main components of HBV-GN. On the other hand, in lupus nephritis, immune complexes are mainly composed of double-stranded DNA antigens and antibodies. Therefore, we speculated that immune complexes with DNA as the antigen are common to both HBV-GN and lupus nephritis and present similar renal histology.

In an autopsy study, Endo et al⁹ demonstrated that renal involvement in liver disease, including hepatitis B and alcoholic hepatitis, is diverse, and they speculated that in addition to the underlying disease, cirrhosis may be involved.

In summary, HBV-MN presents as MN in children, but in adults, a variety of unclassifiable histologic findings may be present in addition to typical histologic findings of MN. In this study, we presented an adult case in which EM showed subepithelial deposits, large subendothelial deposits, and deposits in the mesangial region, and IF showed positive results for IgG, IgA, IgM, C3, C1q, and C4. Because serological factors such as antinuclear antibodies, which are necessary for the diagnosis of lupus nephropathy, were negative, lupus-like glomerulopathy was considered as the most appropriate diagnostic term. HBV-GN cases that fail to seroconvert in childhood but persist into adulthood may result from viral mutations or specific host immune responses.