Complete Remission of Hepatitis B Virus-Associated Nephrotic Syndrome from IgA Nephropathy Following Peginterferon Therapy

Abstract

Hepatitis B virus (HBV) infection is a major cause of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV has also been associated with various common and uncommon glomerular diseases, including IgA nephropathy (IgAN). We report a patient with chronic HBV infection who presented with atypical features of IgAN with management and long-term follow-up. Much of the data on the treatment of HBV-associated glomerular diseases come from patients with membranous nephropathy, whereas the information on treatment of other glomerulopathies remains largely anecdotal. To the best of our knowledge, treatment of an adult patient with HBV-associated nephrotic syndrome from IgAN with pegylated interferon has not been previously reported. Treatment with pegylated interferon alfa-2b in our patient resulted in complete clinical remission of the nephrotic syndrome as well as a dramatic decrease in HBV viral load. Patient continued to remain in clinical remission 5 years after treatment.

• Hepatitis B virus infection
• IgA nephropathy
• peginterferon therapy
• glomerulonephritis
• nephropathy

INTRODUCTION

Glomerulonephritis remains an important extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. Since Combes et al.¹ first reported the association between hepatitis B surface antigen (HBsAg) and membranous nephropathy (MN) in 1971, HBV has also been associated with other glomerular diseases, mainly membranoproliferative glomerulonephritis (MPGN), mesangial proliferative glomerulonephritis, post-infectious glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, and IgA nephropathy (IgAN).^2–4 In adult patients, HBV-associated nephropathies are usually considered progressive with resolution of proteinuria being relatively uncommon without appropriate medical therapy.^2,5 Antiviral drugs have been recommended for treatment of HBV-associated glomerulonephritis because they can inhibit HBV replication and reduce proteinuria.^2,6,7 However, optimal treatment of HBV-associated IgAN has not been established. We report a patient with chronic HBV infection who presented with abrupt onset nephrotic syndrome. Kidney biopsy revealed IgAN. Treatment with peginterferon alfa-2b in our patient was followed by complete clinical remission of the nephrotic syndrome as well as a dramatic decrease in HBV viral load. Patient remains in clinical remission several years after treatment with peginterferon.

CASE

A 47-year-old Taiwanese man with chronic HBV infection was referred by his primary care physician for evaluation of proteinuria. He presented with a 1 week history of generalized swelling, abdominal distension,and scrotal edema. He stated that he was in his usual state of health until 2 months ago, when he noticed “foamy urine,” which was subsequently followed by 5 kg weight gain, decreased appetite, and edema. He was diagnosed with hepatitis B many years ago in Taiwan and denied any history of blood transfusion, jaundice, or hepatitis C. He denied any history of dyspnea, rash, arthralgia, fever, chills, or sweats. He denied use of any medications, including nonsteroidal antiinflammatory drugs and herbal medications. He had been married for 17 years and there was no history of intravenous drug use or multiple sexual partners. There was no past history of diabetes or hypertension.

On physical examination, his blood pressure was 120/80 mmHg and there was 3+ pitting edema of his lower extremities. At the time of presentation, serum creatinine was 0.8 mg/dL, total protein was 4.8 g/dL, serum albumin was 2.0 g/dL, aspartate aminotransferase (AST) was 36 IU/L, alanine aminotransferase (ALT) was 32 IU/L, alkaline phosphatase was 99 IU/L, cholesterol was 589 mg/dL, hematocrit was 47.6%, and prothrombin time was normal. Urinalysis showed 3+ proteinuria and 2+ blood, and random urine protein/creatinine ratio was 8.8. Serum complement C3 was 195 mg/dL (normal was 79–152 mg/dL) and C4 was 26 mg/dL (normal was 16–38 mg/dL) and antinuclear antibody was negative. Hepatitis B surface antibody (HBsAb) and hepatitis C antibody were negative. HBsAg was positive.

Hepatitis B e antigen (HBeAg) was negative and hepatitis B e antibody (HBeAb) was positive. Quantitative HBV polymerase chain reaction (PCR) assay was greater than 200,000 DNA copies/mL. Ultrasound-guided kidney and liver biopsies were subsequently performed.

BIOPSY FINDINGS

On renal biopsy, nine glomeruli were identified. The glomeruli had normal cellularity and the capillary walls were of normal thickness. On electron microscopy, a few areas of mesangium were moderately enlarged and mesangial electron-dense deposits were noted (Figure 1). Immunofluorescence showed positive staining in the basement membrane and mesangium for IgA and C3. The findings were consistent with IgAN.

Figure 1. Electron microscopy showing moderately enlarged mesangium and a mesangial electron-dense deposit (arrow).

Liver biopsy showed grade I, stage 0 chronic hepatitis.

CLINICAL FOLLOW-UP

The patient required furosemide 80 mg twice daily with metolazone 5 mg twice daily for edema management and was started on ramipril 2.5 mg daily and atorvastatin 20 mg daily. After the results of the kidney and liver biopsies were reviewed, the patient was prescribed peginterferon alfa-2b 150 μg subcutaneously weekly for 6 months. At follow-up after 3 months of therapy, the patient had a complete clinical remission of nephrotic syndrome. Serum creatinine was 0.7 mg/dL, serum albumin increased to 3.9 g/dL, cholesterol decreased to 138 mg/dL, random urine protein/creatinine ratio was 0.1, and quantitative HBV PCR assay was less than 200 DNA copies/mL. All medications were eventually discontinued. At follow-up after 5 years, the patient continued to remain in clinical remission from nephrotic syndrome.

DISCUSSION

Over 2 billion individuals have already been infected with hepatitis B, and it is estimated that 50 million people are infected with HBV annually.⁸ Approximately 350 million people in the world are carriers of HBV.⁸ The prevalence of persistent HBV infection varies markedly depending on the geographic location. HBV infection is endemic in China, Southeast Asia, and sub-Saharan Africa, where 8–15% of the population is HBsAg positive; in Western Europe and North America, HBV is rare, affecting less than 2% of the population.^2,8 The true incidence of HBV-associated nephropathies remains unknown. In countries like the United States where the HBV carrier rate in low, HBV-associated nephropathies are rare and frequently seen in African-Americans,⁹ and in high-risk groups, including intravenous drug abusers.² In countries where HBV infection is endemic, the frequency of HBV-associated nephropathies is much higher, particularly in Southeast Asia where most patients acquire HBV as infants from symptom-free HBV-carrier mothers.² A recent study analyzing previous reported cases of HBV-associated glomerular diseases in the literature showed that HBV was more frequently associated with IgAN in adults, while MN is more likely to be seen in children.³

In Asia, where the prevalence of IgAN is among the highest in the world and HBV infection is endemic, it can be debated whether chronic HBV infection is pathogenetically linked with IgAN or merely a coincidental association. Various studies have shown that HBV infection might play an important role in both occurrence and progression of IgAN.^10–12 Wang et al.¹⁰ have shown that in addition to the humoral immune-mediated damage by HBV antigen–antibody immune complex, the renal tissues of some IgAN cases are directly infected with HBV and express HBV antigens in situ. Thus, cellular mechanism mediated by HBV originating from renal cells in situ might also be involved in the pathogenesis of IgAN.¹⁰ In a retrospective study, Lai and coworkers reported 21 patients with hepatitis B surface antigenemia and IgAN; clinical presentations included macroscopic hematuria in four patients (19%), nephrotic syndrome in four patients (19%), microscopic hematuria in five patients (24%), asymptomatic proteinuria and hematuria in three patients (14%), and chronic kidney disease in one patient (5%); 19% of these patients developed progressive renal failure over a mean follow-up period of 40 months.¹³

The role of HBV in the pathogenesis of different types of glomerulonephritis has yet to be clearly elucidated. HBV-associated glomerulonephritis is felt to be an immune complex-mediated disease induced by three distinct HBV antigens: HBsAg, HBeAg, and hepatitis B core antigen (HBcAg). These HBV-associated antigens promote the formation of circulating immune complexes and eventually deposition in the glomeruli, evoking complement activation and cytokine production. It is unclear why certain patients develop IgAN instead of MN or MPGN. A combination of HBV antigen status and the size and charge properties of the various HBV antigens and their antibodies is hypothesized to determine which type of HBV-associated nephropathy develops. There is evidence that HBsAg, HBeAg, and HBcAg localize to different parts of the glomerulus.¹⁴ Immunofluorescence studies suggest that HBeAg and/or HBcAg localizes to the capillary wall basement membrane in MN. Studies of renal biopsies in patients with HBV-associated IgAN have shown mesangial deposits of HBsAg in addition to IgA deposits on immunofluorescence studies; however, HBeAg deposits in the majority of cases were not seen.¹⁴ Patients with mixed HBV-associated IgAN and MN have been reported. These patients showed both localized HBeAg capillary wall deposits and HBsAg mesangial deposits.¹⁴ Hence, the different localization of these HBV antigens within the glomerulus may explain the pathogenesis of various HBV-associated nephropathies. Our patient had HBsAg viremia with a negative HBeAg; findings that suggest HBsAg rather than HBeAg is pathogenetically linked to IgAN. This is consistent with the observation that the development of IgAN in HBV-infected patients was significantly associated with a negative result for HBeAg, while MN was represented with HBeAg positivity.³

HBV-associated nephropathies are associated with considerable morbidity and mortality with about 30% of adult patients progressing to renal failure and as many as 10% of these patients requiring maintenance dialysis.² The natural history of HBV-associated IgAN is not well defined. Much of the data on the treatment of HBV-related glomerular diseases come from patients with MN, whereas the data on management of other HBV-associated glomerular diseases remain unknown. Optimal treatment of HBV-associated IgAN has not been established. No controlled trial has been reported on the use of corticosteroids in HBV-associated IgAN, but evidence exists that corticosteroids may increase viral replication and precipitate hepatic flares.¹⁵ In a recent meta-analysis, corticosteroid monotherapy did not significantly improve proteinuria in HBV-associated glomerulonephritis.⁷ However, favorable effects of glucocorticoids in reducing proteinuria have been reported in HBV-associated mesangial proliferative glomerulonephritis and MN.⁴ Recently, Zheng et al.¹⁶ in their meta-analysis have shown that combined antiviral and immunosuppressant therapy is an effective and safe regimen for HBV-associated nephropathies with overall estimated rate for proteinuria remission of 83%. This study, however, did not include patients with IgAN.

Antiviral drugs have been recommended for treatment of HBV-associated glomerulonephritis because they can inhibit HBV replication and reduce proteinuria.^6,7,17 Adult HBV-associated nephropathy cases treated with interferon therapy that have been reported so far have had either MN, MPGN, or mesangial proliferative glomerulonephritis.^6,7,16,17 A meta-analysis reported in 2006 by Fabrizi et al.¹⁷ showed the efficacy and safety of antiviral therapy (interferon or lamivudine) in HBV-associated MN with overall estimate for remission of nephrotic syndrome of more than 60%. There are very little available data on the role of alfa-interferon in the treatment of HBV-associated IgAN. A case of a pediatric patient with HBV-associated IgAN treated with interferon alfa-2a and lamuvidine has been reported to achieve both clinical remission and marked decrease in HBV DNA titer.¹⁸ A study in patients with HBeAg-negative chronic HBV infection showed that either peginterferon monotherapy or combination therapy with lamivudine was more effective than lamivudine monotherapy in reducing HBV DNA levels.¹⁹ However, the addition of lamivudine to peginterferon in this study did not improve post-therapy response rates.¹⁹ Hence, we decided to treat our patient who had HBeAg-negative chronic HBV infection with peginterferon monotherapy. Treatment with peginterferon alfa-2b induced complete clinical remission of our patient’s nephrotic syndrome as well as a dramatic decrease in HBV viral load. We therefore believe that IgAN in our patient was associated with HBV infection. To the best of our knowledge, this is the first reported adult case of HBV-associated nephrotic syndrome from IgAN to be successfully treated with pegylated interferon alfa-2b. Our patient remains in clinical remission 5 years after peginterferon therapy. Based on our experience, one can consider peginterferon therapy in patients who develop HBV-associated nephrotic syndrome from IgAN. Nevertheless, the treatment of HBV-associated IgAN with pegylated interferon will require further study.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.