Anti-glomerular basement membrane antibody-mediated glomerulonephritis combined with non-fulminant acute viral hepatitis A

Authors


Correspondence

Dr Kwan-Kyu Park, MD, PhD, Department of Pathology, Catholic University of Daegu School of Medicine, 3056-6 Daemyung 4-dong, Nam-gu, Daegu 705-718, Korea.

Email: kkpark@cu.ac.kr

ABSTRACT

Anti-glomerular basement membrane antibody-mediated glomerulonephritis (anti-GBM Ab-mediated GN) is a rare autoimmune disease, characterized by crescentic glomeruli and linear GBM staining with immunoglobulin G (IgG). Exposure to viruses can trigger the formation of autoantibodies to the GBM. We report the first case of anti-GBM Ab-mediated GN associated with hepatitis A virus (HAV) infection. Although the pathogenesis of HAV-related anti-GBM Ab-mediated GN has not been documented, we suggest that the immune complexes produced by HAV infection might be deposited in the glomerular capillary walls and lead to immune complex-mediated glomerular damage, resulting in exposure of the sequestered GBM antigens and the formation of anti-GBM antibodies. Under immunosuppressive and intravenous cyclophosphamide therapy, his renal function has been improving without development of pulmonary symptoms.

INTRODUCTION

Anti-glomerular basement membrane antibody-mediated glomerulonephritis (anti-GBM Ab-mediated GN) is a rare autoimmune disease caused by deposited as well as circulating antibodies against the noncollagenous C-terminal (NC1) domain of α3 chain of collagen type IV (anti-GBM antibody).[1] In some cases, the autoantibodies cross-react with pulmonary alveolar basement membranes to produce pulmonary hemorrhage associated with renal failure, called Goodpasture syndrome.[1] Anti-GBM Ab-mediated GN is characterized by a rapidly progressive glomerulonephritis with crescentic glomeruli and linear deposition of IgG along the GBM.[2] Although what triggers the formation of such autoantibodies is not clear, exposure to viruses has been implicated in some patients.[3]

Hepatitis A virus (HAV) has a worldwide distribution. The World Health Organization estimates 1.4 million cases of hepatitis A annually. The Republic of Korea was categorized as having a high HAV endemicity level.[4] Hepatitis viruses can damage not only liver parenchyma but also renal parenchyma. Several literatures have presented that membranoproliferative glomerulonephritis (MPGN), acute interstitial nephritis (AIN), and acute tubular necrosis (ATN) could be implicated in acute viral hepatitis A.[5-10] To the best of our knowledge, only one case of hepatitis B virus (HBV)-related anti-GBM Ab-mediated GN has been reported, but occurrence of this glomerulonephritis associated with HAV infection has not been reported yet.[11]

In this article, we report HAV-related anti-GBM Ab-mediated GN without any evidence of fulminant hepatitis, suggesting possible pathogenesis.

CASE REPORT

A 52-year-old man without a significant past medical history had suffered from fever, malaise, nausea, and anorexia for 2 weeks. Laboratory examination performed at an outside clinic showed gamma-glutamyl transpeptidase (GGT) 120 IU/L and alkaline phosphatase (ALP) 600 IU/L. However, evaluation for viral hepatitis was not performed. A month later, he visited another clinic with persistent symptoms. The results of the clinic's test showed blood urea nitrogen (BUN) 20 mg/dL, serum creatinine (Cr) 2.3 mg/dL, and total anti-HAV antibody 60 IU/L.

Two weeks later, the patient was referred to our hospital for further evaluation of hematuria and proteinuria with azotemia. He weighed 54 kg and his height was 171 cm. His blood pressure was 110/70 mm Hg. His physical examination was within normal limits except for 4 kg weight loss for a month. On admission, laboratory examination showed hemoglobin 7.7 g/dL, hematocrit 23.1%, white blood cells (WBCs) 11,700/mm3 with normal differential count, platelet 228,000/mm3, serum aspartate aminotransferase 14 IU/L, serum alanine aminotrasferase 18 IU/L, GGT 32 IU/L, ALP 175 IU/L, total bilirubin 0.51 mg/dL, albumin 3.2 g/dL, BUN 43.8 mg/dL, and serum Cr 4.0 mg/dL. Blood glucose and HbA1c were 113 mg/dL and 6.2%, respectively. A urinalysis showed albumin 2+, 1–3 WBC/high power field (HPF), and more than 30 red blood cell/HPF with evident erythrocytic dismorfism. The serological examinations for hepatitis B surface antigen (HBsAg), hepatitis B C antigen (HBcAg) and anti-hepatitis C virus (HCV) antibodies were all negative. Immunglobulin M (IgM) anti-HAV antibodies were not detected. Test for IgG anti-HAV antibodies was not performed. Serum anti-GBM antibodies were positive with a titer of 8.0 AI. Antinuclear antibodies (ANA) were weakly positive but anti-neutrophilic cytoplasmic antibodies were negative. Serum immunoglobulin and complement levels were IgG 1,237 mg/dL, IgA 328.3 mg/dL, IgM 117.5 mg/dL, C3 101.7 mg/dL, C4 42.9 mg/dL and CH50 64.3 U/dL. Chest radiography showed no evidence of pulmonary hemorrhage. Evaluation for other organs revealed unremarkable.

Percutaneous renal biopsy showed six large crescents, eight global sclerosis and three segmental sclerosis in all 21 glomeruli (Fig. 1). Early segmental fibrinoid necrosis with karyorrhexis and ruptured fragments of GBM was also presented and a remaining portion of the glomerulus was intact. The interstitium showed tubular atrophy and advanced periglomerular inflammation and fibrosis particularly around crescentic glomeruli. The immunofluorescent stains revealed strong, linear deposits of IgG along the GBM (Fig. 2). Focal, weak granularity along the glomerular capillary walls for IgG was also present. But there was no staining of tubular BM. Immunofluorescent studies for IgA, IgM, C3, and C1q were all negative. Electron microscopy (EM) showed focal subepithelial electron dense deposits (Fig. 3). The podocytes showed diffuse effacement of foot processes. There were no mesangial deposits. Discrete immune complexes in the GBM or viral particles were not identified.

Figure 1.

Microscopic features of anti-glomerular basement membrane antibody-mediated glomerulonephritis. (a) The collapsed glomerular tufts and crescents formed by proliferation of parietal cells are noted (periodic acid methenamine silver stain, ×400). (b) Global and segmental scleroses are seen (Masson trichrome stain, × 200). (c) Segmental fibrinoid necrosis is present with a remaining intact portion of the glomerulus. (d) The interstitium shows advanced periglomerular inflammation (arrow) and periglomerular fibrosis (arrowhead).

Figure 2.

Immunofluorescent microscopy shows strong, linear glomerular basement membrane staining for immunoglobulin G (IgG). The granularity of the capillary loop deposits is also present weakly and focally (anti-IgG immunofluorescence, ×400).

Figure 3.

Electron microscopic features of anti-glomerular basement membrane (GBM) antibody-mediated glomerulonephritis associated with hepatitis A virus infection. (a) There are a few subepithelial electron dense deposits with overlying foot process effacement (arrows) (transmission electron microscope [TEM], ×1,500). (b) Two subepithelial humps (arrows) are prominent. Mesangial deposits were not present. Discrete immune complexes in the GBM or viral particles were not identified (TEM, ×1,500).

He was treated with pulse methylprednisolone, followed by oral corticosteroid and cyclophosphamide. Under immunosuppressive therapy, his renal function has been improving without development of pulmonary symptoms.

DISCUSSION

Total anti-HAV antibodies are composed of IgM and IgG antibodies, the main serological markers for diagnosis of viral hepatitis A.[12] Anti-HAV IgM detects during only the symptomatic phase and usually persists for 2 or 3 months after the initial infection.[12] However anti-HAV IgG begins to appear early in the symptomatic phase and persists for the person's life-time, giving a lifelong protection against reinfection.[12] In the absence of anti-HAV IgM, detection of total anti-HAV antibodies or anti-HAV IgG indicates either a previous infection with HAV or a successful vaccination.[12] Although evaluation for hepatitis A at an outside clinic was not properly performed at the early stage of symptom development, detection of total anti-HAV antibodies in our patient indicates a previous infection for HAV because of no history of vaccination for HAV.

The most common cause of virus-associated nephropathies is hepatitis virus, especially HBV or HCV.[5] Combes et al.[13] described the first case of membranous nephropathy with HBV infection in 1971. Johnson et al.[14] first introduced eight patients with MPGN and HCV infection in 1993. In contrast, the histomorphological pattern of glomerulonephritis associated with viral hepatitis A has not been well recognized, because hepatitis A is relatively rare and a self-limited disease without chronic progression. However, several literatures have suggested that MPGN, AIN and ATN could be implicated in acute viral hepatitis A, even in acute non-fulminant hepatitis A.[6-10] Especially, Zikos et al.[6] described the first relationship between biopsy-proven immune complex mediated MPGN and HAV infection. Several studies demonstrate that ANA is detected during the course of acute hepatitis A, even more in the absence of IgM antibody against HAV, as shown in our case.[15, 16]

Anti-GBM Ab-mediated GN may be caused by circulating or deposited antibodies against the GBM after exposure to viruses.[1, 3] Although the pathogenesis of HAV-associated anti-GBM Ab-mediated GN has not been mentioned, an immune complex-mediated mechanism is thought to play a central role in the occurrence of the disease in our patient. In his renal biopsy, the granularity by immunofluorescence and subepithelial deposits by EM raise suspicion of membranous nephropathy. However, we could not find extensive subepithelial deposits. HAV infection might produce immune complexes which circulate within the bloodstream, eventually the complexes will deposit in the glomerular capillary walls. As a result, this will cause subepithelial deposit. The deposits were visualized as focal granular staining along the capillary wall by immunofluorescence and a few subepithelial deposits by EM.

The following observations support the occurrence of HAV-associated anti-GBM Ab-mediated GN in our patient. First, the patient had no history of previous glomerular disease. Second, he showed no evidence of systemic disease with potential renal disease such as diabetes, hypertension and any other infectious diseases or nephrotoxic agents. Third, he developed nephrotic syndrome only after he exhibited symptoms and signs of HAV infection. Fourth, immunofluorescence studies showed focal granular staining along the glomerular capillary wall, unlike diffuse, global granularity of the capillary loop in membranous nephropathy. Fifth, there are a few subepithelial deposits by EM, unlike extensive subepithelial deposits in membranous nephropathy. Sixth, anti-GBM antibodies were detected in serum, as the most important finding. Therefore we propose the possible pathogenesis of anti-GBM Ab-mediated GN associated with HAV infection as follows: the immune complexes produced by HAV infection might deposit in the glomerular capillary walls and lead to immune complex-mediated glomerular damage, resulting in the exposure of the sequestered GBM antigens and the formation of anti-GBM antibodies.

Recommendation for therapy of anti-GBM Ab-mediated GN has not been formulated due to the limited clinical data existing so far. However, the main treatment to maximize the recovery of renal function in rapidly progressive glomerulonephritis includes plasmapheresis to remove the pathogenic circulating antibodies, extensive immunosuppressive therapy to suppress the underlying immune response, or intravenous cyclophosphamide therapy to reduce proliferative lesions and to stabilize renal function. Some authors insist that plasmapheresis and extensively immunosuppressive therapy should be carried out as soon as possible right after diagnosis based on the renal biopsy.[17] On the other hand, others have insisted that plasmapheresis is not more beneficial than only extensive immunosuppressive therapy.[18] Others have insisted that pulse immunosuppressive therapy and intravenous cyclophosphamide is more effective than only steroid treatment in reducing cellular crescents, karyorrhexis, and endocapillary proliferation.[19] Our patient was treated with pulse methylprednisolone, followed by oral corticosteroid and cyclophosphamide, focused on the treatment of anti-GBM Ab-mediated GN, because acute hepatitis A is self-limited disease.

In conclusion, HAV infection produces formation of immune complexes. The immune complexes circulating within the bloodstream might deposit in the glomerular capillary walls and lead to immune complex-mediated glomerular injury, resulting in the exposure of the sequestered GBM antigens and the formation of anti-GBM antibodies. Although either anti-GBM Ab-mediated GN or acute viral hepatitis A associated glomerular disease has been rare, we should be aware of the potential glomerular involvement of HAV, especially in the Republic of Korea with a high prevalence of HAV.

Ancillary