Original Article
Membranous Nephropathy Related to Hepatitis B Virus in Adults
N Engl J Med 1991; 324:1457-1463May 23, 1991
- Abstract
- Abstract
Background.
The natural course of adult hepatitis B virus (HBV)—related membranous nephropathy in areas where HBV infection is endemic (characterized by vertical and horizontal transmission of HBV in early childhood) has not been fully defined.
Methods.
We evaluated the clinical features, pathological findings, serologic profiles, therapeutic responses, and prognoses of 21 patients with adult-onset HBV-related membranous nephropathy. The patients were followed for a mean of 60 months (range, 12 to 108). Only patients with evidence of glomerular capillary deposition of hepatitis B e antigen (HBeAg) in a renal-biopsy specimen were included.
Results.
The clinical features and serologic studies suggested that the patients had acquired chronic HBV infection in early childhood; moreover, other causes of membranous nephropathy had been excluded. All were seropositive for hepatitis B surface antigen and had high titers of antibody to hepatitis B core antigen at first clinical presentation. HBeAg was detected in the serum of 17 patients (81 percent), yet only 3 had even slightly increased plasma alanine aminotransferase levels. The clinical response to therapy with interferon alfa was disappointing; only one of the five patients treated had a complete remission with seroconversion to antibody to HBeAg. Contrary to reports of studies in children, spontaneous remission of the nephrotic syndrome or proteinuria was uncommon in the adults with HBV-related membranous nephropathy whom we studied. Proteinuria and HBV antigenemia persisted in untreated patients. During the follow-up period, 29 percent of the patients had progressive renal failure and 10 percent required maintenance dialysis therapy.
Conclusions.
The course of HBV-related membranous nephropathy in adults in areas where HBV is endemic is not benign. Regardless of treatment, the disease has a slowly but relentlessly progressive clinical course in approximately one third of patients. (N Engl J Med 1991; 324:1457–63.)
Media in This Article
Figure 1
Renal-Biopsy Specimens.Figure 2
Mean Plasma Albumin Concentrations and Urinary Excretion of Protein in Five Patients with HBV-Related Membranous Nephropathy Who Were Treated with a 2-Week Course of Prednisolone Followed by a 12-Week Course of Interferon Alfa.Article Activity
- Article
THE association between chronic hepatitis B virus (HBV) infection, characterized by persistent hepatitis B surface antigenemia, and renal disease was first reported in 1971.1 Since then various morphologic patterns of HBV-related renal disease, including membranous nephropathy, mesangiocapillary glomerulonephritis, and mesangial proliferative glomerulonephritis, have been described.2 3 4 Among them, membranous nephropathy is the best-recognized disorder.1 2 3 The hepatitis B e antigen (HBeAg) has been shown to have an important pathogenetic role in persons with chronic HBV infection who have coexisting membranous nephropathy.5 6 7 Most reported cases in areas where there is a high frequency of chronic HBV infection are in children, but HBV-related membranous nephropathy has also been reported in adults. Despite good documentation of the pathological features of HBV-related membranous nephropathy, the natural history of this disease and the role of therapy with antiviral agents have not been fully delineated.
We describe here the characteristics and course of 21 adults who had persistent hepatitis B surface antigenemia and HBV-related membranous nephropathy. These patients were followed for an average of five years. Eight patients received a short course of prednisolone, five were treated with recombinant human interferon alfa, and the remaining patients received either diuretics or dipyridamole (or both) or no treatment.
Methods
Patients
We studied 21 consecutive patients given a diagnosis of HBVrelated membranous nephropathy between 1981 and 1989. In all the patients, the diagnosis was established by percutaneous biopsy of the kidney. The criteria for patient selection included the following: age of 15 years or more at the first clinical presentation; no history of jaundice or liver disease; no history of blood transfusion; no history of intravenous drug use; no clinical or laboratory evidence of systemic disease known to cause membranous nephropathy; hepatitis B surface antigenemia on repeated testing; proteinuria (> 1 g of urinary protein per day); and evidence of HBV antigens in glomeruli.
Serologic Tests for HBV
Tests for HBV antigens and antibodies were performed two months before and at the time of the renal biopsy and regularly thereafter. Hepatitis B surface antigen (HBsAg) was measured by reversed passive hemagglutination (Auscell, Abbott, Abbott Park, Ill.) and enzyme immunoassay (Auszyme monoclonal, Abbott). Anti-HBs antibody, antibody to hepatitis B core antigen (HBcAg), antibody to hepatitis delta agents, HBeAg, and anti-HBe antibody were measured by enzyme immunoassay (Corzyme, Ausab, antidelta enzyme immunoassays, and HBe enzyme immunoassay, all from Abbott).
Morphologic and Immunopathological Studies
Renal-biopsy specimens were processed for light-microscopical examination, immunofluorescence studies, and electron microscopical examination by standard methods.4 Frozen sections 4 μm thick were stained for HBsAg, HBcAg, and HBeAg by direct immunofluorescence with use of F(ab')2 fragments of murine monoclonal antibodies obtained from the Jichi Medical School (1:10 dilution) and by indirect immunofluorescence with use of murine monoclonal antibodies obtained from St. Mary's Hospital Medical School (1:5 dilution). Adequate frozen tissue for immunofluorescence studies was not available from five patients; in these cases, 2-μm-thick paraffin sections were prepared and stained by the immunoperoxidase technique for HBsAg, HBcAg, and HBeAg with use of polyclonal antibodies from Behringwerke (Mannheim, Germany), Dakopatts (Copenhagen, Denmark), and Abbott, respectively. The specificity and properties of these monoclonal and polyclonal antibodies have been reported elsewhere.6 7 8 9
Clinical and Laboratory Evaluation
The onset of the disease was defined as the time at which the initial manifestation (nephrotic syndrome, proteinuria, or chronic renal failure) first appeared or was reported. Subsequent deterioration in renal function during the study period was defined as a decrease of 25 percent or more in creatinine clearance from the initial value. Chronic renal failure was defined as a plasma creatinine level of more than 150 μmol per liter, creatinine clearance of less than 1 ml per second per 1.73 m2 of body-surface area (60 ml per minute per 1.73 m2), or both.
All patients had tests for proteinuria, measurements of creatinine clearance, plasma creatinine, urea, and liver enzyme levels, and serologic tests for HBV antigens and antibodies at four-month intervals during the study period.
Treatment
Eight patients were enrolled in a prospective trial of short-term prednisolone therapy for HBV-related membranous nephropathy.10 The criterion for patient selection in this trial was the presence of the nephrotic syndrome or proteinuria (>3.0 g of urinary protein per day). The initial dose was 60 mg of prednisolone per day, which was reduced by half after eight weeks; thereafter, the dose was reduced in stepwise fashion to zero over four months. Only the complete correction of all biochemical abnormalities was designated a remission.
Five patients who had proteinuria in the nephrotic range (>3.0 g of urinary protein per day) that persisted for at least 12 months after diagnosis were randomly selected for a trial of therapy with recombinant human interferon alfa-2b (Intron-A, Schering, Kenilworth, N.J.). Three had previously received prednisolone therapy with no clinical or biochemical improvement; the drug had been discontinued 12 to 18 months earlier. These five patients first received a 2-week course of prednisolone (40 mg per day orally), followed by interferon therapy in a dose of 3 million units given subcutaneously three times a week for 12 weeks. If severe or intolerable side effects occurred, the dose of interferon was decreased by half. During interferon therapy, the patients were seen each month and had monthly serologic and urine tests.
All patients who received either prednisolone or interferon gave written informed consent.
Statistical Analysis
All biochemical results are expressed as means ±SD. The data were analyzed with use of nonparametric statistics and Fisher's exact test, as appropriate.
Results
Initial Clinical, Biochemical, and Serologic Findings
The study group consisted of 17 male and 4 female patients with persistent hepatitis B surface antigenemia who had HBV-related membranous nephropathy as defined above (Table 1Table 1
Clinical, Serologic, and Therapeutic Data on 21 Patients with HBV-Related Membranous Nephropathy.*). Their age at clinical presentation varied from 15 to 53 years (mean, 30). Twelve patients had the nephrotic syndrome, seven had asymptomatic proteinuria, and two were referred for investigation of chronic renal failure. Three patients had a history of ankle swelling in childhood, but no biochemical evidence that they had the nephrotic syndrome was obtained at the time. A history of liver disease among the parents and siblings of nine patients was documented, and in 8 of the 10 families that were screened there was serologic evidence that one or more family members was a carrier of HBV or had previously had HBV infection. The duration of symptoms before biopsy in the 21 patients varied from 1 to 36 months. The mean urinary protein excretion (based on two consecutive tests) was 4.1 g per day (range, 1.0 to 12.5). None of the patients had anti-DNA antibody, rheumatoid factor, or a positive Venereal Disease Research Laboratory test for syphilis, and all had normal serum complement levels. None of the patients had clinical evidence of cancer or lymphoma or were taking medications known to induce membranous nephropathy. Five patients (24 percent) had chronic renal failure at the first presentation, and seven patients (33 percent) had hypertension (blood pressure, > 150/95 mm Hg).Eighteen patients had normal plasma bilirubin, gamma-glutamyltransferase, and alanine aminotransferase concentrations, and three patients had slightly increased plasma alanine aminotransferase concentrations (Patients 5, 6, and 19) (Table 1). All patients were seropositive for HBsAg and had high titers of anti-HBc antibody. HBeAg was detected in the serum of 17 patients (81 percent), and 4 patients were seropositive for anti-HBe.
Pathological Findings
The renal-biopsy specimens of 16 patients had uniform thickening of the glomerular basement membrane on light microscopy with a "spike" pattern evident on silver staining (Fig. 1Figure 1
Renal-Biopsy Specimens.). The biopsy specimens of four patients had only mild thickening of the glomerular basement membrane and no obvious spike pattern, and that of one patient with chronic renal failure had evidence of global sclerosis in more than half the glomeruli. Crescent formation and tubular atrophy were infrequent pathological findings.Diffuse granular deposition of IgG and C3 along the glomerular capillary walls was observed in all the specimens, and ultrastructural examination revealed subepithelial electron-dense deposits. Virus-like particles of 40 to 50 nm in diameter were not seen except in one biopsy specimen obtained at follow-up from a patient who received prednisolone therapy.
Immunofluorescence studies with use of monoclonal antibodies revealed granular deposits of HBeAg along the glomerular capillary wall in the renal-biopsy specimens from 16 patients (Fig. 1). HBcAg was found in the specimens from the remaining five patients by the immunoperoxidase technique with use of polyclonal antibodies against HBV antigens. The HBV antigen in these five specimens was probably HBeAg, since the polyclonal anti-HBc antiserum was shown to contain both anti-HBc and anti-HBe activities.9
Response to Prednisolone
The therapeutic effect of prednisolone in eight patients with HBV-related membranous nephropathy has been reported previously.10 Briefly, three of the eight patients had a complete remission of the nephrotic syndrome after prednisolone therapy, but one patient relapsed after therapy ended. Four patients had persistent proteinuria. Nevertheless, the biochemical and serologic findings suggested that prednisolone could be harmful, since viral replication was activated in some patients during steroid therapy.
Response to Interferon Alfa
Proteinuria diminished in four of the five patients treated with interferon alfa during the initial two-week period of prednisolone therapy. The mean protein excretion in all five patients fell progressively from a pretreatment mean (±SD) value of 3.1 ± 1.5 g per day to 1.8±1.3 g per day after 6 weeks of therapy, 1.3±1.2 g per day after 8 weeks, 2.0±1.5 g per day after 10 weeks, and 1.6±1.5 g per day after 12 weeks (P<0.05 by the Wilcoxon signed-rank test). There was no increase in the plasma albumin concentrations during the therapy (Fig. 2Figure 2
Mean Plasma Albumin Concentrations and Urinary Excretion of Protein in Five Patients with HBV-Related Membranous Nephropathy Who Were Treated with a 2-Week Course of Prednisolone Followed by a 12-Week Course of Interferon Alfa.). The plasma creatinine concentrations and endogenous creatinine clearance rates did not change during therapy with interferon alfa (Fig. 3Figure 3
Mean Plasma Creatinine Concentrations and Endogenous Creatinine Clearance (Glomerular Filtration Rate [GFR]) in Five Patients with HBV-Related Membranous Nephropathy Who Were Treated with Interferon Alfa.). Plasma alanine aminotransferase concentrations did not change except in one patient who had an elevation of the plasma alanine aminotransferase level to 754 U per liter (normal, <58) 10 weeks after commencing interferon alfa therapy. This patient seroconverted from HBeAg to anti-HBe 4 weeks later, and he remained asymptomatic thereafter, with urinary protein excretion of less than 0.5 g per day in the 24 months after interferon therapy. Four patients had one or more side effects, including fatigue and myalgia (two patients), neutropenia (two patients), and thrombocytopenia (one patient).All five patients were reassessed one year after the discontinuation of interferon therapy. All were seropositive for HBsAg at this time. One (Patient 4) had a remission with seroconversion to anti-HBe. Two (Patients 3 and 13) had persistent proteinuria exceeding 2 g per day; neither had the nephrotic syndrome at that time. The remaining two (Patients 2 and 8) remained asymptomatic, with urinary protein ranging between 0.5 and 1.5 g per day. None had evidence of deterioration on tests of renal and liver function.
Clinical Course and Outcome
The average follow-up period for these 21 patients was 60 months (range, 12 to 108). Of the eight patients who received a short course of prednisolone therapy, three had complete remission of the nephrotic syndrome, although only one (Patient 9) had seroconversion to anti-HBe. Two of these three patients died, one and four months after clinical remission; one (Patient 10) died of intracerebral hemorrhage due to a ruptured aneurysm, and the other (Patient 11) of septic peritonitis. Four other patients had persistent proteinuria, and one had relapsing nephrotic syndrome. Three of the five were subsequently treated with interferon alfa. Of the five patients who received interferon therapy, one had a complete remission with seroconversion to anti-HBe. The remaining four patients had persistent proteinuria. Among the 11 patients who received only symptomatic treatment such as diuretics, none had a complete remission. Three of these patients had persistent proteinuria within the nephrotic range and in the remaining eight the proteinuria decreased from 4.0±1.5 to 2.3±1.8 g of urinary protein per day. One had hepatic failure after 24 months of follow-up.
Six patients (29 percent) (Patients 2, 14, 15, 16, 20, and 21) had progressive deterioration of renal function during an average follow-up of 73 months (Fig. 4). Two (10 percent) required continuous ambulatory peritoneal dialysis for maintenance, and one will probably need it soon. Hypertension was slightly but not significantly more common in these patients than in those who had no deterioration in renal function (67 vs. 20 percent).
All patients were persistently seropositive for HBsAg. Of the 17 patients who were seropositive for HBeAg, only two seroconverted to anti-HBe antibody after treatment with either prednisolone or interferon. Spontaneous complete remission of the nephrotic syndrome after seroconversion to anti-HBe was uncommon among these adult patients with HBV-related membranous nephropathy.
Discussion
The prevalence of the HBsAg carrier state varies widely from 0.3 to 1.0 percent in North America, 1 percent in Western Europe, 7 percent in Africa, and 10 percent in Southeast Asia.11 In developed countries the patients are usually adolescents or adults infected through intravenous drug abuse or sexually,12 but in regions where HBV is endemic, vertical transmission from mothers to their children or horizontal transmission between siblings may be important in maintaining the high rate of infection.13
Membranous nephropathy is the most common form of HBV-related nephropathy. We found it in 35 percent of the patients in our earlier study of HBVassociated renal disease.4 The clinical manifestations of HBV-related membranous nephropathy tend to be different in children and adults. In children, it occurs primarily in boys3 , 6 , 7 , 14 and is often detected by routine urine tests and serologic screening.4 , 14 , 15 The other common clinical presentation in children is the nephrotic syndrome, which may be relapsing. Proteinuria and the nephrotic syndrome are the most common manifestations of HBV-related membranous nephropathy in adults, and males are less apt to predominate among adults than among children with this disorder.15 , 16 Adults from areas where HBV is not endemic who have HBV-related membranous nephropathy are more likely than children to have a history of acute hepatitis, which in turn could be related to intravenous drug abuse,17 homosexuality,18 or the acquired immunodeficiency syndrome.19 In contrast, adult patients from areas where HBV is endemic who have HBV-related membranous nephropathy often have no known exposure to HBV, and the disease is probably caused by chronic HBV infection acquired in childhood.4 , 20
The natural history of this disease is not fully defined in children and has rarely been described in adults. Retrospective data from six studies of a total of 66 boys and 16 girls showed that spontaneous regression of the nephrotic syndrome occurred in 60 percent of patients within 12 months after diagnosis.3 , 5 , 7 , 21 22 23 The remaining patients had persistent proteinuria, six (7.3 percent) had chronic renal failure, and two (2.4 percent) had end-stage renal failure.
We found that the sex ratio among adult patients with HBV-related membranous nephropathy was similar to that among children. Most patients had a strong family history of HBV infection but no history of transfusion or drug abuse — suggesting they might have been carriers since childhood. Other than three patients with ankle swelling in childhood, most first presented with the disease between 20 and 35 years of age. Contrary to the findings in children, spontaneous remission of proteinuria or the nephrotic syndrome did not occur, although proteinuria tended to decrease with time. Complete remission occurred after prednisolone treatment in three patients and after interferon treatment in one. Complete remission was associated with seroconversion to anti-HBe. There was a slow and relentless progression to chronic renal failure in 29 percent of patients after an average of six years, and 10 percent of patients may require dialysis therapy.
Spontaneous resolution of HBV-related membranous nephropathy does not often occur, and complications related to overt nephrotic syndrome are common. The frequency of progression to chronic renal failure3 , 4 , 24 and the anecdotal observation of improved renal and liver function after the successful treatment of HBV infection6 , 25 make it worthwhile to consider treating this disease actively. We have recently reported on a prospective trial in which prednisolone had deleterious effects, inducing viral replication in the liver.10 The initial case reports on the effects of interferon alfa on HBV-related membranous nephropathy were not promising.26 , 27 Complete remission occurred in one patient,26 and the remaining two had clinical relapses.27 Recently, Lisker-Melman et al.28 reported a clinical, biochemical, and serologic remission in four adult patients with HBV-related membranous nephropathy who were treated with interferon alfa for four months. Three of these four patients had acquired HBV infection during adulthood by either sexual or intravenous transmission; immunofluorescence staining of glomerular deposits of HBeAg was not carried out in their renal-biopsy specimens. In our patients, who probably acquired chronic HBV infection in childhood and whose renal-biopsy specimens contained evidence of the deposition of HBeAg, the clinical efficacy of interferon alfa was disappointing. Only one of the five patients we treated had a complete remission. An earlier randomized controlled trial of interferon alfa suggested that it was ineffective in the long-term suppression of viral replication in carriers of HBsAg in areas where HBV is endemic,29 and data from England indicated that carriers of HBsAg from the Far East had almost no response to interferon.30 The discrepancy between the clinical response of patients with HBV-related membranous nephropathy from areas where HBV is endemic and the response of those from nonendemic areas could be due to the integration of HBV DNA into host-cell chromosomal DNA in patients who acquired the infection in early childhood, thus rendering the interferon therapy less effective.
In conclusion, we found that spontaneous remission was uncommon among adults with HBV-related membranous nephropathy who lived in an area where HBV infection was endemic and that the disease followed a slow, relentless course often leading to chronic renal failure. Further clinical assessment of therapy with antiviral agents such as interferon, in studies with longer duration and using a higher dosage, is strongly indicated.
We are indebted to Professor M. Mayumi, Jichi Medical School, and Dr. J. Waters, St. Mary's Hospital Medical School, for providing the monoclonal antibodies.
Source Information
From the Departments of Medicine (K.N.L., P.K.T.L., S.F.L.), Microbiology (J.S.L.T.), and Pathology (F.M.M.L.), Prince of Wales Hospital, Chinese University of Hong Kong, and the Medical Unit, Princess Margaret Hospital, Hong Kong (T.C.A., K.L.T.). Address reprint requests to Dr. K.N. Lai, Reader in Medicine, Chinese University of Hong Kong, Shatin, Hong Kong.
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