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Original Article
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Volume 328:465-470 February 18, 1993 Number 7
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Membranoproliferative Glomerulonephritis Associated with Hepatitis C Virus Infection
Richard J. Johnson, David R. Gretch, Hideaki Yamabe, Jaime Hart, Carlos E. Bacchi, Peter Hartwell, William G. Couser, Lawrence Corey, Mark H. Wener, Charles E. Alpers, and Richard Willson

 

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Background and Methods Hepatitis C virus (HCV) infection causes both acute and chronic liver disease and is also associated with mixed cryoglobulinemia. Whether HCV is also associated with renal disease, as is the hepatitis B virus, is not known. We describe the clinical, pathologic, virologic, and immunologic features of eight patients with HCV infection who were referred to nephrologists for glomerulonephritis. Four patients were treated with interferon alfa.

Results All eight patients had proteinuria, and seven had decreased renal function. Renal biopsy in all patients revealed membranoproliferative glomerulonephritis, characterized by the deposition of IgG, IgM, and C3 in glomeruli. Electron microscopy of the biopsy specimens showed cryoglobulin-like structures in three of four patients. All eight patients had HCV RNA detected in their serum, elevated serum aminotransferase concentrations, and hypocomplementemia, and the majority had cryoglobulins and circulating immune complexes in their serum. Cryoprecipitates from the three patients who were tested contained HCV RNA and IgG anti-HCV antibodies to the nucleocapsid core antigen (HCVc or c22-3). IgM rheumatoid factors, present in all patients, bound anti-HCV IgG in all six patients tested. Four patients received interferon alfa for 2 to 12 months; all had evidence of decreased HCV replication and improvement of their renal and liver disease.

Conclusions Chronic HCV infection is associated with cryoglobulinemia and membranoproliferative glomerulonephritis. The pathogenesis is unknown, but may relate to deposition within glomeruli of immune complexes containing HCV, anti-HCV IgG, and IgM rheumatoid factors.

Hepatitis C virus (HCV), an RNA virus first identified in 1989,1,2 is a major cause of both transfusion-associated and sporadic non-A, non-B hepatitis3. Persistent infection occurs in approximately 50 percent of patients and may result in chronic active hepatitis, cirrhosis, and possibly, hepatocellular carcinoma3. Chronic HCV infection has also been associated with several extrahepatic syndromes, including mixed cryoglobulinemia, polyarteritis nodosa, and a sicca-like syndrome that resembles Sjogren's syndrome4,5,6,7,8,9,10,11,12,13,14. The relation between HCV infection and mixed cryoglobulinemia is especially strong, with antibodies to HCV present in 42 to 70 percent of patients6,7,8 and with HCV RNA detected in the serum of 86 percent of patients in one study9.

Hepatitis virus infection may be associated with immunologically mediated renal disease. Chronic hepatitis B virus (HBV) infection is associated with membranous glomerulonephritis, membranoproliferative glomerulonephritis, and cryoglobulinemia15. With regard to HCV infection, three patients with glomerulonephritis and antibodies to HCV have been described: one patient with cryoglobulinemia and endocapillary glomerulonephritis,14 one with cryoglobulinemia and membranoproliferative glomerulonephritis,4 and one with membranous nephropathy16. Whether these cases represent a true association or a coincidental finding is not known.

We describe eight patients with membranoproliferative glomerulonephritis and HCV infection. The results of immunologic and virologic studies suggest that the renal disease resulted from the deposition within the glomeruli of immune complexes containing HCV. In four patients treatment with interferon alfa was beneficial.

Methods

We identified eight patients (five at the University of Washington Medical Center in Seattle and three at Hirosaki University School of Medicine in Hirosaki, Japan) during a two-year period who were referred to nephrologists for the evaluation of proteinuria and who had evidence of HCV infection on the basis of a positive screening enzyme immunoassay (Abbott Laboratories, North Chicago, Ill.) for anti-HCV antibody.

The presence of antibodies to HCV was confirmed by a four-antigen (c100-3, 5-1-1, c33-c, and c22-3) recombinant immunoblot assay (Ortho Diagnostics, Raritan, N.J.), and HCV RNA in serum was detected with the polymerase chain reaction (PCR) with primers derived from the 5'-noncoding, highly conserved region of the HCV genome17. The methods, specificity, and sensitivity of each of these assays have been reported earlier17. Semiquantitation of HCV RNA in serum, cryoprecipitates, and urine was achieved by serial end-point dilution of complementary DNAs followed by PCR. To evaluate whether HCV was present in cryoglobulins, cryoproteins were precipitated from the serum of three patients, washed extensively with phosphate-buffered saline at 4 °C, and tested for anti-HCV antibody by recombinant immunoblot assay and for the presence of HCV RNA by PCR.

Serum and cryoprecipitates were also tested for IgM anti-HCV activity with a modification of the recombinant immunoblot assay. The samples were allowed to react with the antigen strips in the recombinant immunoblot assay before peroxidase-conjugated goat antihuman IgM antiserum (Boehringer-Mannheim, Indianapolis) was added. To determine whether reactivity was due to rheumatoid factors, the serum was also tested for IgM anti-HCV after the removal of total IgG by adsorption to a protein G Sepharose column (Pharmacia, Uppsala, Sweden) or by treatment with affinity-purified goat antihuman IgG (Boehringer-Mannheim).

Serum samples were tested for evidence of HBV infection by measuring hepatitis B surface antigen (HBsAg), anti-hepatitis B core antigen (anti-HBc) IgG, anti-hepatitis B surface antigen (anti-HBs) IgG, and HBV DNA according to standard methods (Abbott Laboratories).

The activity and severity of liver disease were assessed in biopsy specimens according to the method of Knodell et al.,18 in which the total index of activity is calculated as the sum of the individual grades (on a scale of 0 to 4, in which 0 indicates the absence of disease and 4 severe disease) for each of four histologic categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis.

After giving informed consent, four patients were treated with recombinant interferon alfa (Intron-A, Schering-Plough, Bloomfield, N.J.) according to protocols approved by the University of Washington Human Subjects Committee or by the Japanese Welfare Ministry.

Results

Patients' Characteristics

Seven of the patients were men, and one was a woman; their average age was 50 years (range, 39 to 72). Five were white, and three were Asian. Most patients had known risk factors for HCV infection as well as a history of abnormal liver function (Table 1). The major findings at presentation were hypertension, hepatomegaly, and peripheral edema (Table 1).

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  		Table 1. Clinical Characteristics of Eight Patients with HCV Infection and Membranoproliferative Glomerulonephritis.

 
Seven of the eight patients had microscopic hematuria, and the urinary sediment of three patients contained red-cell casts. All patients had proteinuria; in five of eight patients this was in the nephrotic range (>3.5 g per day) (Table 2). The creatinine clearance was decreased in seven patients; the mean value was 51 ml per minute (Table 2), with a mean serum creatinine concentration of 1.7 mg per deciliter (150 µmol per liter). Other laboratory findings included mildly elevated serum aminotransferase concentrations, hypoalbuminemia, and rheumatoid factors in all eight patients; normochromic normocytic anemia in seven patients; and cryoglobulinemia and circulating immune complexes in five patients (Table 3). All the patients had low plasma total hemolytic complement concentrations; the majority also had low C1q, C3, and C4 concentrations (Table 3).

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  		Table 2. Renal Function in, Liver Histologic Score for, and Virologic Data on Eight Patients with HCV Infection and Membranoproliferative Glomerulonephritis.

 
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  		Table 3. Results of Laboratory Analyses in Eight Patients with HCV Infection and Membranoproliferative Glomerulonephritis.

 
Virologic Studies

All the patients had HCV antibodies (by recombinant immunoblot assay) and HCV RNA (by PCR) in their serum (Table 2). The immunoblot profiles revealed IgG anti-HCV antibodies to the three nonstructural antigens (c100-3, 5-1-1, and c33-c) in most patients, and antibodies to the nucleocapsid core antigen (HCVc or c22-3) in all. Urine from Patient 5 revealed HCV RNA by PCR at levels approximately 100 times less than those in the serum.

Further analysis of the cryoprecipitates from Patients 3, 4, and 5 (Table 2) revealed the presence of HCV RNA. In the two patients in whom a comparison was made, the titer of HCV RNA in the cryoprecipitate was equal to or approximately 10 times greater than that in the serum. It is unlikely that any positive signals in the cryoprecipitates represented serum contamination, since the cryoprecipitate washings were either negative or weakly positive relative to a strong signal in the cryoprecipitate. By recombinant immunoblot assay, anti-HCVc (c22-3) and anti-c33-c IgG antibodies were present in the cryoglobulins from all three patients, whereas anti-c100-3 and anti-5-1-1 IgG antibodies were absent.

Both serum and cryoprecipitates contained IgM that bound to the HCVc (c22-3) antigen on the basis of an IgM recombinant immunoblot assay (Table 2). IgM reactivity to other HCV antigens was variably present. We investigated the possibility that the IgM was not binding HCV antigens directly, but rather was binding as rheumatoid factor to anti-HCV IgG present on the immunoblot. All six serum samples with the IgG selectively removed demonstrated a loss of IgM reactivity against the HCV antigens, suggesting that the IgM activity was due to the presence of IgM rheumatoid factors. In contrast, in a control patient with presumed acute HIV infection, removal of the IgG from serum did not inhibit the IgM anti-HCVc activity. In three patients the IgM rheumatoid factor appeared to bind preferentially to anti-HCV IgG as compared with pooled normal human IgG (which is present on the immunoblot as a control), whereas in the other three patients the IgM rheumatoid factor was polyspecific, binding both anti-HCV IgG and nonspecific IgG.

No patient had evidence of active HBV infection, although five patients had evidence of a past infection (Table 2). Cryoprecipitates from two patients were also negative for HBV DNA.

Pathological Analysis

Renal biopsies in all eight patients showed membranoproliferative glomerulonephritis, with increased cellularity in a lobular pattern (Figure 1A). Most biopsy samples contained foci of tubular atrophy and mild infiltration of mononuclear cells in the interstitium. Biopsy samples from three patients showed mild-to-moderate mesangial sclerosis; the biopsy specimen from another patient showed increased numbers (i.e., 40 percent) of sclerosed glomeruli, findings suggestive of a chronic process. Immunofluorescence staining showed heavy staining of the glomerular capillary wall with IgM (seven of eight patients), IgG (seven of seven; no glomeruli were present in one sample), and C3 (eight of eight) (Figure 1B and Figure 1C). IgA staining of capillary wall and mesangium was weakly present in three of seven patients, and C1q was present in the biopsy specimens of two of the five patients in whom it was sought. Electron microscopy of the biopsy specimens of four patients showed occasional interposition of mesangial cells with subendothelial, mesangial, and rarely, intramembranous deposits. Organized annular, finely fibrillar, cylindric, or immunotactoid-like structures, compatible with cryoglobulins, were present in the biopsy samples of three of the four patients (Figure 1D).


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  		Figure 1. Renal-Biopsy Specimens from a Patient with HCV Infection.

In Panel A there is increased cellularity, with expansion of the mesangial matrix and various degrees of thickening and splitting of peripheral-capillary walls (periodic acid-Schiff, x250). In Panel B and Panel C there are capillary-wall deposits of IgG and IgM, respectively (immunofluorescence, x250). In Panel D, electron microscopy of a glomerular capillary shows subendothelial immune deposits organized as tactoids (arrows) and possibly microtubules (arrowhead) characteristic of cryoglobulins (x26,900).

 
Liver biopsies in the five white patients showed varying degrees of chronic active hepatitis (Table 2), and four patients had cirrhosis. One Asian patient had cirrhosis with hepatoma, and two had chronic liver disease. Thus, all the patients had advanced chronic liver disease.

Effect of Treatment with Recombinant Interferon Alfa

Four patients were given interferon alfa for 2 to 12 months as treatment for the HCV infection, liver disease, and renal disease (Table 4). Two patients (Patients 1 and 2) were also given erythropoietin (50 units per kilogram of body weight per week) because of anemia (hematocrit, <30 percent). Urinary protein excretion decreased in all four patients, and returned to the normal range in three patients. The treatment was associated with an improvement in liver function and an increase in the serum albumin concentration, and in all patients HCV RNA was no longer detectable in serum (Table 4). One patient also had resolution of a purpuric rash due to lymphocytic vasculitis. In the two patients who received erythropoietin, the hematocrit increased to 43 percent and 39 percent. Cryoglobulins were present in three patients (Patients 2, 3, and 8) before therapy, but were no longer detected (in two patients) or were detected in only trace amounts (in the remaining patient) during therapy. Hypocomplementemia, however, persisted in three of the four patients.

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  		Table 4. Effect of Interferon Alfa Therapy in Four Patients with HCV Infection and Membranoproliferative Glomerulonephritis.

 
The changes in renal function varied (Table 4). In Patient 1, renal function improved during interferon therapy. In Patient 2, renal function fluctuated initially but had improved by the end of therapy. Renal function worsened in Patient 3, whereas Patient 8 maintained relatively normal renal function throughout therapy. Interferon therapy was also well tolerated, although in Patient 1 the dose was reduced from 3 million units to 2 million units after one month because of insomnia and nightmares.

In all patients interferon therapy was stopped. In Patient 1, the serum became positive for HCV RNA and the serum alanine aminotransferase concentration increased within the first month after therapy was completed. During the next three months the serum creatinine concentration increased from 1.1 to 1.4 mg per deciliter (from 97 to 124 µmol per liter).

Discussion

We report an association of HCV infection with membranoproliferative glomerulonephritis in eight patients. All the patients had hypocomplementemia and proliferative glomerular lesions characterized by the deposition of IgG, IgM, and C3 on capillary walls and subendothelial and mesangial immune deposits. In all the patients, active HCV infection was confirmed by the detection of HCV RNA in the serum. Although the patients' liver function was only mildly abnormal, histologic analysis of the liver, when available, often showed advanced chronic active hepatitis or cirrhosis. Most patients had circulating immune complexes and cryoglobulinemia, despite the fact that nonrenal manifestations were uncommon. In three patients HCV RNA and anti-HCV antibodies were identified in cryoprecipitates. IgM rheumatoid factors were present in all patients and bound anti-HCVc IgG in all six patients tested. These results provide indirect evidence that the immune-complex nephritis in these patients may involve the deposition or formation of immune complexes containing HCV, IgG anti-HCV antibody, and IgM rheumatoid factors.

Since these patients were identified after being referred to nephrologists for evaluation of abnormal renal function, the frequency of membranoproliferative glomerulonephritis in patients with HCV infection cannot be determined. However, among 33 consecutive patients with HCV infection (documented by recombinant immunoblot assay) who were followed in our clinic, microscopic hematuria was present in 3 patients (9 percent) and mild-to-moderate proteinuria (trace to 2+) was present in 9 patients (27 percent), although the serum creatinine concentration was normal in all. In addition, in a separate group of 20 patients with active HCV infection (i.e., HCV RNA-positive), rheumatoid factor was present in 3 (15 percent). Thus, urinary abnormalities or rheumatoid factors are not rare in patients with HCV infection. However, further cross-sectional and prospective studies incorporating renal biopsy will be required to determine the prevalence of membranoproliferative glomerulonephritis in the HCV-infected population.

The pathogenesis of the membranoproliferative glomerulonephritis in these patients may relate to the deposition of immune complexes containing HCV in glomeruli, but other possibilities should be considered. For example, patients with chronic liver disease of any cause often have glomerular disease, although in most cases it resembles IgA nephropathy rather than membranoproliferative glomerulonephritis19,20. Chronic HBV infection is also associated with glomerulonephritis, and although the most common presentation is membranous nephropathy, membranoproliferative glomerulonephritis has also been reported15. Most patients with HBV-associated membranoproliferative glomerulonephritis have circulating HBsAg, which was not the case in any of our patients. Nevertheless, we cannot exclude the possibility that HBV was involved in the pathogenesis of the membranoproliferative glomerulonephritis in the five patients with evidence of a previous HBV infection.

Cryoglobulinemia may also be associated with chronic liver disease21,22,23,24,25. Chronic HBV infection may be responsible for some cases,25 and HBsAg and anti-HBs have been identified in the cryoprecipitates of some patients25,26. Other studies have not been able to document an increased prevalence of HBV markers in patients with cryoglobulinemia27,28. Since the frequency of liver-function abnormalities in patients with mixed cryoglobulinemia is independent of the presence of HBV infection,25 in some cases HBV infection may be acting as a surrogate marker for HCV.

If membranoproliferative glomerulonephritis results from glomerular deposition of immune complexes containing HCV, then HCV antigens or HCV RNA should be present in diseased glomeruli. However, we were unable to identify HCV antigens or RNA in the glomerular lesions. This may relate to the masking of antigens by antibody or to the presence of small amounts of HCV antigen or RNA. In liver infections, for example, amplification procedures have been necessary to localize HCV RNA by in situ hybridization29. Even if HCV antigens are detected in glomeruli, they cannot be assumed to have a pathogenic role, since the presence of HCV antigens may reflect the trapping of antigens at sites of tissue injury. Nor does the absence of HCV antigens rule out a pathogenic role for HCV in membranoproliferative glomerulonephritis. In this regard, a good example is postinfectious glomerulonephritis, in which the role of streptococcal infection in causing the disease is widely accepted, but in which the demonstration of streptococcal antigens and antibodies in glomeruli has been controversial30.

Four patients were treated with interferon alfa, and all had improvement in their renal and liver disease. Interferon has immunomodulating, antiproliferative, and antiviral effects31 and has been used to treat patients with chronic HCV infection with some success, although many patients relapsed after therapy was discontinued32,33. Interferon alfa therapy has also been reported to benefit patients with HCV infection and cryoglobulinemia,10,34 HBV-associated membranous nephropathy,35 and essential mixed cryoglobulinemia36. In our patients, interferon alfa therapy reduced the proteinuria, but had variable effects on renal function. In addition, one of our patients had a clinical relapse, with worsening of renal function, after treatment was discontinued. These results emphasize the importance of performing studies to determine whether interferon therapy is superior to the usual immunosuppressive regimens used to treat patients who have cryoglobulinemic glomerulonephritis37.

Note added in proof: Since this paper was submitted, we have identified six additional patients with membranoproliferative glomerulonephritis and HCV infection (three of whom had cryoglobulinemia) and one patient with membranous nephropathy and HCV infection. We have also screened serum samples from 10 patients with membranoproliferative glomerulonephritis type I (kindly provided by J.C. Jennette, University of North Carolina, Chapel Hill) and detected HCV RNA and antibody in two patients. Misiani et al.38 have also recently described a series of patients with cryoglobulinemic glomerulonephritis and HCV infection. These results suggest that HCV infection may be an important cause of both cryoglobulinemic and noncryoglobulinemic membranoproliferative glomerulonephritis.

Supported by a grant (DK 43422) from the Public Health Service, a grant from the Northwest Kidney Foundation, and a grant-in-aid from Schering Corporation.

We are indebted to Henry Akiyama, M.D., Daniel Doornink, M.D., Jamshid Honari, M.D., J. Hamilton Licht, M.D., Leonard Quadracci, M.D., Alexandra E. Read, M.D., and Catherine Thompson, M.D., for providing the primary care to these patients and permitting us to study and report on them, and to Ms. Phyllis Davie, Ms. Janice Morihara, Ms. Corazon dela Rosa, Mr. Jeffrey Wilson, and Ms. Willa Lee for their technical assistance.


Source Information

From the Divisions of Nephrology and Gastroenterology, Departments of Medicine (R.J.J., J.H., P.H., W.G.C., L.C., M.H.W., R.W.), Laboratory Medicine (D.R.G., L.C., M.H.W.), and Pathology (C.E.B., C.E.A.), University of Washington Medical Center, Seattle, and the Division of Nephrology, Department of Medicine, Hirosaki University School of Medicine, Hirosaki, Japan (H.Y.).

Address reprint requests to Dr. Johnson at the Division of Nephrology, BB-1257 Health Sciences, University of Washington Medical Center, Seattle, WA 98195.

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