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Membranoproliferative glomerulonephritis associated with hepatitis C virus infection responsive to interferon-α
Membranoproliferative Glomerulonephritis Associated With Hepatitis C Virus Infection Responsive to Interferon-a! Hideaki Yamabe, MD, Richard J. Johnson, MD, David R. Gretch, MD, PhD, Hiroshi Osawa, MD, Hiroshi Inuma, MD, Takashi Sasaki, MD, Mitsuaki Kaizuka, MD, Naoyuki Tamura, MD, Satoru Tsunoda, MD, Yoshiko Fujita, MD, Atsushi Sato, MD, and Kogo Onodera, MD 0 A 42-year-old man with hepatitis C virus infection, cryoglobulinemia, hypocomplementemia, and nephrotic syndrome is repotted. The kidney biopsy showed membranoproliierative glomerulonephritis. The patient was treated with interferon-e for 2 months. After the treatment, serum hepatitis C virus RNA became negative and nephrotic syndrome remitted. Repeat biopsy of the kidney revealed an improvement in renal histology. This case confirms an association between hepatitis C virus infection and membranoproliferative glomerulonephritis and the usefulness of interferon-a for treatment. 0 1995 by the National Kidney Foundation, Inc. INDEX
WORDS:
Interferon;
membranoproliierative
glomerulonephritis;
A
LTHOUGH it is well known that hepatitis B virus may cause membranous nephropathy and membranoproliferative glomerulonephritis (MPGN),’ glomerulonephritis related with hepatitis C virus (HCV) infection has only been recently reported. We have previously reported that HCV infection is associated with MPGN and that interferon-a may be beneficial, but followup in these patients was limited.* Other investigators have also reported patients with HCV infection and MPGN.‘-5 We describe the long-term follow-up and repeat biopsy results in one of the original cases of MPGN with HCV infection.* CASE REPORT A 42-year-old man who had suffered from nephrotic syndrome and liver dysfunction since 1989 was admitted to the Hirosaki University Hospital in April 1992 because of exacerbation of pretibial edema. The patient had a history of multiple blood transfusions in childhood secondary to a laparotomy performed for abdominal pain. Physical examination revealed pitting edema on his legs and several scars on his abdomen. Blood pressure was 130/ 88 mm Hg. Laboratory findings showed urinary protein 12.3 g/d; the results were negative for urinary sugar and Bence Jones protein. Microscopic hematuria was observed in the urine sediment. Hemoglobin was 12.7 g/dL and white blood cell count was 7,8OO/mm’. Serum protein was 3.6 g/dL, blood urea nitrogen I9 mg/dL, serum creatinine 0.8 mg/dL, serum aspartate aminotransferase 199 Iv/L, and serum alanine aminotransferase 205 ILK. Serum complement component 3 (C3) was 49 mg/dL (normal, 60 to 130 mg/dL) and C4 was 7 mg/dL (normal, 15 to 50 mg/dL). Rheumatoid factor was 99.4 U/mL and cryoglobulins were present. Creatinine clearance was 67 mUmin. The kidney biopsy was performed on May 6, 1992; its findings are described separately.
Virologic Studies Hepatitis B surface antigen and antibody negative; antibody to HBcAg was positive. American
Journal
of Kidney
Diseases,
to HBsAg were Hepatitis C virus Vol 25, No 1 (January),
hepatitis
C virus.
antibody was found to be positive by second-generation assay, and HCV RNA was detected in both serum and cryoprecipitates by the reverse transcriptase polymerase chain reaction.’
Clinical Course One month after admission, treatment with interferon-a (Intron A; Schering-Plough, Bloomfield, NJ) was initiated. The protocol of interferon therapy was approved by the Japanese Welfare Ministry, and the patient gave informed consent. Ten million units of interferon-cr was injected subcutaneously daily for 2 weeks followed by three times per week for 6 additional weeks. One week after initiation of interferon therapy, a reduction in the 24-hour urine protein excretion and an increase in total serum protein were apparent (Fig 1). The patient’s pretibial edema resolved and his body weight decreased by 10 kg. Hepatitis C virus RNA were found to be negative in both serum and cryoprecipitates by polymerase chain reaction and the liver function test was normal (Fig 1). One month after completing the course of interferon, the 24hour urine protein excretion was 2.0 g and total serum protein was 5.7 g/dL (Fig 1). One year after treatment, urinary protein was 0.5 g/d. Serum protein was 7.4 g/dL, blood urea nitrogen 20 mg/dL, serum creatinine 0.8 mg/dL, serum aspartate aminotransferase 26 IU/L, serum alanine aminotransferase 22 IUI L, C3 86 mg/dL, and C4 8 mg/dL. Creatinine clearance was 111.3 mWmin. Rheumatoid factor was 165.0 U/mL. Serum HCV RNA was negative. Cryoglobulins have continuously been detected in the patient, but have been negative for HCV RNA since June 1992. Repeat biopsy of the kidney was performed on July 7, 1993.
From the Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan; and the Division of Nephrology and the Department of Laboratory Medicine, University of Washington, Seattle, WA. Received April 20, 1994; accepted in revised fom August 15, 1994. Address reprint requests to Hideaki Yamabe. MD, Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki 036 Japan. 0 1995 by the National Kidney Foundation, Inc. 0272-6386/9512501-0013$3.00/O 1995:
pp 67-69
67
YAMABE
68
Cryoglobulin HCV RNA Serum cryo.
+
+
+
+
+(weak)
-
-
-
+piGikqUrinary protein 154 ( g/W)
ET AL
+ -
-
I SerumI protein ( g/4
A@2
May/92
June/92
July/92
Au@2
Fig 1. Daily urinary protein excretion and serum protein levels in patient with interferon-a treatment.
Membranoproliferative glomemlonephritis type I is a primary glomerular disease characterized
by mesangial cell proliferation, the capillary wall deposition of IgM, IgG, and C3, and subendothelial immune deposits by electron microscopy. The pathogenesis has been widely assumed to be due to the deposition of circulating immune complexes. Indeed, MPGNlike lesions have been associated with systemic lupus erythematosus, chronic hepatitis B virus infection, bacterial endocarditis, and other infectious diseases in which chronic antigenemia is common. We recently have described MPGN in patients with active HCV infection.’ These patients may or may not have cryoglobulinemia, and often lack clinical evidence of liver disease despite significant histologic injury on liver biopsy.2 Recent studies from our group suggest that chronic HCV infection may be responsible for 60% of cases of MPGN in Ja-
Fig 2. A glomerulus matoxylin-eosin stain;
Fig 3. A glomerulus from the second (Hematoxylin-eosin stain; magnification
Renal Biopsy Findings Fifteen glomeruli were obtained from the First biopsy. first biopsy. A marked mesangial hypercellularity in a lobular pattern was present in all glometuli (Fig 2). Double contours of the basement membrane due to mesangial cell interposition were observed by silver methenamine staining. Immunoglobulin G (IgG), IgM, and C3 deposition were detected in the glomerular capillary walls by immunofluorescence. Immunoglobulin A was absent. Electron microscopy was not performed because of the lack of a glomerulus in the specimen. Second biopsy. Ten glomeruli were found in the second biopsy. Mesangial cell proliferation with some lobular accentuation of the glomerular tuft was also observed, but its degree was milder than that of first biopsy (Fig 3). Mesangial interposition was also mild in its degree and extent. Glomerular IgG deposition was negative, and IgM and C3 deposition remained positive. DISCUSSION
from the first magnification
renal biopsy. x400.)
(He-
renal biopsy. x400.)
INTERFERON
THERAPY
IN MPGN
WITH
HEPATITIS
C
69
pan.6 In these patients, the pathogenesis of MPGN likely relates to the glomerular deposition of immune complexes containing HCV, anti-HCV IgG, and rheumatoid factors. We’*’ and others* have treated patients with HCV-associated cryoglobulinemic and noncryoglobulinemic MPGN with interferon-a. Most of these patients received a 6- to 1Zmonth course of low-dose interferon-a (ie, 3 million U subcutaneously three times per week). In our series of 14 patients, there was no significant change in serum creatinine, although urinary protein excretion was reduced by 65%.’ In both our series’ and in the series by Misiani et al,* a clinical response was associated with suppression of the HCV viremia as determined by polymerase chain reaction. However, relapse of viremia and renal disease occurred in the majority of the patients after interferon-a therapy was stopped.‘** Studies using similar doses of interferon-a to treat chronic HCV-induced liver disease have also noted a high relapse rate.9.‘o We report here a patient with HCV-induced MPGN who was treated with an intense, high dose and short course of interferon-a (ie, 10 million U daily for 2 weeks followed by every other day for 6 weeks). In this patient, a sustained elimination of the HCV viremia has been documented, and the patient has undergone a complete clinical remission of his nephrotic syndrome. A repeat renal biopsy also showed significant improvement of the MPGN. Despite the clinical remission, the patient has continued to have cryoglobulinemia. However, this is not unexpected as elimination of the HCV RNA should be followed by a slower disappearance of anti-HCV antibodies. Indeed, a decrease in the IgM anti-HCV IgG response was noted over time in our patient (data not shown). This would also explain why some mild evidence of histologic injury was observed in the repeat renal biopsy. In conclusion, we report a patient with HCVassociated MPGN who underwent a sustained clinical remission with elimination of HCV RNA following treatment with high-dose interferon-a. This is in contrast to the high relapse rate of both
renal disease and viremia observed with treatment using standard doses of interferon for chronic HCV infection, suggesting that the dosage and duration of treatment with interferon-a may need to be re-evaluated in these patients. ACKNOWLEDGMENT thank Dr Charles Alpers (Department of Pathology, University of Washington) for reviewing the kidney biopsy specimens from our patient. The
authors
REFERENCES 1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease: Clinical, immunopathogenetic and therapeutic considerations. Kidney Int 137663-676, 1990 2. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WC, Corey L, Wener MH, Alpers CE, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465470, 1993 3. Doutrelepont JM, Adler M, Willems M, Durez P, Yap SH: Hepatitis C infection and membranoproliferative glomerulonephritis. Lancet 341:317, 1993 4. Gonzalo A, Barcena F, Mampaso F, Zea A, Ortuno J: Membranoproliferative glomerulonephritis and hepatitis C virus infection. Nephron 63:475-476, 1993 5. Pasquariello A, Ferri C, Moroconi L, La Civita L, Longombardo G, Lombardini F, Greco F, Zignego AL: Cryoglobulinemic membranoprohferative glomendonephritis associated with hepatitis C virus. Am J Nephrol 13300-304, 1993 6. Yamabe H, Fukushi K, Osawa H, Miyata M, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Onodera K: Hepatitis C virus infection may be an important cause of membranoproliferative glomendonephritis. J Am Sot Nephrol 4:291, 1993 (abstr) 7. Johnson RJ, Gretch DR, Couser WG, Alpers CE, Willson J, Chung M, Hart J, Willson R: Hepatitis C virus associated membranoproliferative glomendonephritis. Effect of alpha-interferon therapy. Kidney Int (in press) 8. Misiani R, Bellavita P, Fenili D, Vicari 0, Marchesi D, Sironi PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 9. Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J Goodman Z, Banks SM, Hoofnagle JH: Recombinant interferon alfa therapy for chronic hepatitis C: A randomized, double-blind, placebocontrolled trial. N Engl J Med 321:1506-1510, 1989 10. Davis GL, Balart LA, Schiff ER, Linsay K, Bodenheimer HC, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, van Thiel DH, Tamburro C, Lefkowitch J, Albrecht J, Meschievitz C, Grtego TJ, Gibas A: Treatment of chronic hepatitis C with recombinant interferon alfa. N Engl J Med 321:1501-1506, 1989
WORDS:
Interferon;
membranoproliierative
glomerulonephritis;
A
LTHOUGH it is well known that hepatitis B virus may cause membranous nephropathy and membranoproliferative glomerulonephritis (MPGN),’ glomerulonephritis related with hepatitis C virus (HCV) infection has only been recently reported. We have previously reported that HCV infection is associated with MPGN and that interferon-a may be beneficial, but followup in these patients was limited.* Other investigators have also reported patients with HCV infection and MPGN.‘-5 We describe the long-term follow-up and repeat biopsy results in one of the original cases of MPGN with HCV infection.* CASE REPORT A 42-year-old man who had suffered from nephrotic syndrome and liver dysfunction since 1989 was admitted to the Hirosaki University Hospital in April 1992 because of exacerbation of pretibial edema. The patient had a history of multiple blood transfusions in childhood secondary to a laparotomy performed for abdominal pain. Physical examination revealed pitting edema on his legs and several scars on his abdomen. Blood pressure was 130/ 88 mm Hg. Laboratory findings showed urinary protein 12.3 g/d; the results were negative for urinary sugar and Bence Jones protein. Microscopic hematuria was observed in the urine sediment. Hemoglobin was 12.7 g/dL and white blood cell count was 7,8OO/mm’. Serum protein was 3.6 g/dL, blood urea nitrogen I9 mg/dL, serum creatinine 0.8 mg/dL, serum aspartate aminotransferase 199 Iv/L, and serum alanine aminotransferase 205 ILK. Serum complement component 3 (C3) was 49 mg/dL (normal, 60 to 130 mg/dL) and C4 was 7 mg/dL (normal, 15 to 50 mg/dL). Rheumatoid factor was 99.4 U/mL and cryoglobulins were present. Creatinine clearance was 67 mUmin. The kidney biopsy was performed on May 6, 1992; its findings are described separately.
Virologic Studies Hepatitis B surface antigen and antibody negative; antibody to HBcAg was positive. American
Journal
of Kidney
Diseases,
to HBsAg were Hepatitis C virus Vol 25, No 1 (January),
hepatitis
C virus.
antibody was found to be positive by second-generation assay, and HCV RNA was detected in both serum and cryoprecipitates by the reverse transcriptase polymerase chain reaction.’
Clinical Course One month after admission, treatment with interferon-a (Intron A; Schering-Plough, Bloomfield, NJ) was initiated. The protocol of interferon therapy was approved by the Japanese Welfare Ministry, and the patient gave informed consent. Ten million units of interferon-cr was injected subcutaneously daily for 2 weeks followed by three times per week for 6 additional weeks. One week after initiation of interferon therapy, a reduction in the 24-hour urine protein excretion and an increase in total serum protein were apparent (Fig 1). The patient’s pretibial edema resolved and his body weight decreased by 10 kg. Hepatitis C virus RNA were found to be negative in both serum and cryoprecipitates by polymerase chain reaction and the liver function test was normal (Fig 1). One month after completing the course of interferon, the 24hour urine protein excretion was 2.0 g and total serum protein was 5.7 g/dL (Fig 1). One year after treatment, urinary protein was 0.5 g/d. Serum protein was 7.4 g/dL, blood urea nitrogen 20 mg/dL, serum creatinine 0.8 mg/dL, serum aspartate aminotransferase 26 IU/L, serum alanine aminotransferase 22 IUI L, C3 86 mg/dL, and C4 8 mg/dL. Creatinine clearance was 111.3 mWmin. Rheumatoid factor was 165.0 U/mL. Serum HCV RNA was negative. Cryoglobulins have continuously been detected in the patient, but have been negative for HCV RNA since June 1992. Repeat biopsy of the kidney was performed on July 7, 1993.
From the Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki, Japan; and the Division of Nephrology and the Department of Laboratory Medicine, University of Washington, Seattle, WA. Received April 20, 1994; accepted in revised fom August 15, 1994. Address reprint requests to Hideaki Yamabe. MD, Second Department of Internal Medicine, Hirosaki University School of Medicine, Hirosaki 036 Japan. 0 1995 by the National Kidney Foundation, Inc. 0272-6386/9512501-0013$3.00/O 1995:
pp 67-69
67
YAMABE
68
Cryoglobulin HCV RNA Serum cryo.
+
+
+
+
+(weak)
-
-
-
+piGikqUrinary protein 154 ( g/W)
ET AL
+ -
-
I SerumI protein ( g/4
A@2
May/92
June/92
July/92
Au@2
Fig 1. Daily urinary protein excretion and serum protein levels in patient with interferon-a treatment.
Membranoproliferative glomemlonephritis type I is a primary glomerular disease characterized
by mesangial cell proliferation, the capillary wall deposition of IgM, IgG, and C3, and subendothelial immune deposits by electron microscopy. The pathogenesis has been widely assumed to be due to the deposition of circulating immune complexes. Indeed, MPGNlike lesions have been associated with systemic lupus erythematosus, chronic hepatitis B virus infection, bacterial endocarditis, and other infectious diseases in which chronic antigenemia is common. We recently have described MPGN in patients with active HCV infection.’ These patients may or may not have cryoglobulinemia, and often lack clinical evidence of liver disease despite significant histologic injury on liver biopsy.2 Recent studies from our group suggest that chronic HCV infection may be responsible for 60% of cases of MPGN in Ja-
Fig 2. A glomerulus matoxylin-eosin stain;
Fig 3. A glomerulus from the second (Hematoxylin-eosin stain; magnification
Renal Biopsy Findings Fifteen glomeruli were obtained from the First biopsy. first biopsy. A marked mesangial hypercellularity in a lobular pattern was present in all glometuli (Fig 2). Double contours of the basement membrane due to mesangial cell interposition were observed by silver methenamine staining. Immunoglobulin G (IgG), IgM, and C3 deposition were detected in the glomerular capillary walls by immunofluorescence. Immunoglobulin A was absent. Electron microscopy was not performed because of the lack of a glomerulus in the specimen. Second biopsy. Ten glomeruli were found in the second biopsy. Mesangial cell proliferation with some lobular accentuation of the glomerular tuft was also observed, but its degree was milder than that of first biopsy (Fig 3). Mesangial interposition was also mild in its degree and extent. Glomerular IgG deposition was negative, and IgM and C3 deposition remained positive. DISCUSSION
from the first magnification
renal biopsy. x400.)
(He-
renal biopsy. x400.)
INTERFERON
THERAPY
IN MPGN
WITH
HEPATITIS
C
69
pan.6 In these patients, the pathogenesis of MPGN likely relates to the glomerular deposition of immune complexes containing HCV, anti-HCV IgG, and rheumatoid factors. We’*’ and others* have treated patients with HCV-associated cryoglobulinemic and noncryoglobulinemic MPGN with interferon-a. Most of these patients received a 6- to 1Zmonth course of low-dose interferon-a (ie, 3 million U subcutaneously three times per week). In our series of 14 patients, there was no significant change in serum creatinine, although urinary protein excretion was reduced by 65%.’ In both our series’ and in the series by Misiani et al,* a clinical response was associated with suppression of the HCV viremia as determined by polymerase chain reaction. However, relapse of viremia and renal disease occurred in the majority of the patients after interferon-a therapy was stopped.‘** Studies using similar doses of interferon-a to treat chronic HCV-induced liver disease have also noted a high relapse rate.9.‘o We report here a patient with HCV-induced MPGN who was treated with an intense, high dose and short course of interferon-a (ie, 10 million U daily for 2 weeks followed by every other day for 6 weeks). In this patient, a sustained elimination of the HCV viremia has been documented, and the patient has undergone a complete clinical remission of his nephrotic syndrome. A repeat renal biopsy also showed significant improvement of the MPGN. Despite the clinical remission, the patient has continued to have cryoglobulinemia. However, this is not unexpected as elimination of the HCV RNA should be followed by a slower disappearance of anti-HCV antibodies. Indeed, a decrease in the IgM anti-HCV IgG response was noted over time in our patient (data not shown). This would also explain why some mild evidence of histologic injury was observed in the repeat renal biopsy. In conclusion, we report a patient with HCVassociated MPGN who underwent a sustained clinical remission with elimination of HCV RNA following treatment with high-dose interferon-a. This is in contrast to the high relapse rate of both
renal disease and viremia observed with treatment using standard doses of interferon for chronic HCV infection, suggesting that the dosage and duration of treatment with interferon-a may need to be re-evaluated in these patients. ACKNOWLEDGMENT thank Dr Charles Alpers (Department of Pathology, University of Washington) for reviewing the kidney biopsy specimens from our patient. The
authors
REFERENCES 1. Johnson RJ, Couser WG: Hepatitis B infection and renal disease: Clinical, immunopathogenetic and therapeutic considerations. Kidney Int 137663-676, 1990 2. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE, Hartwell P, Couser WC, Corey L, Wener MH, Alpers CE, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465470, 1993 3. Doutrelepont JM, Adler M, Willems M, Durez P, Yap SH: Hepatitis C infection and membranoproliferative glomerulonephritis. Lancet 341:317, 1993 4. Gonzalo A, Barcena F, Mampaso F, Zea A, Ortuno J: Membranoproliferative glomerulonephritis and hepatitis C virus infection. Nephron 63:475-476, 1993 5. Pasquariello A, Ferri C, Moroconi L, La Civita L, Longombardo G, Lombardini F, Greco F, Zignego AL: Cryoglobulinemic membranoprohferative glomendonephritis associated with hepatitis C virus. Am J Nephrol 13300-304, 1993 6. Yamabe H, Fukushi K, Osawa H, Miyata M, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Onodera K: Hepatitis C virus infection may be an important cause of membranoproliferative glomendonephritis. J Am Sot Nephrol 4:291, 1993 (abstr) 7. Johnson RJ, Gretch DR, Couser WG, Alpers CE, Willson J, Chung M, Hart J, Willson R: Hepatitis C virus associated membranoproliferative glomendonephritis. Effect of alpha-interferon therapy. Kidney Int (in press) 8. Misiani R, Bellavita P, Fenili D, Vicari 0, Marchesi D, Sironi PL, Zilio P, Vernocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti A: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 9. Di Bisceglie AM, Martin P, Kassianides C, Lisker-Melman M, Murray L, Waggoner J Goodman Z, Banks SM, Hoofnagle JH: Recombinant interferon alfa therapy for chronic hepatitis C: A randomized, double-blind, placebocontrolled trial. N Engl J Med 321:1506-1510, 1989 10. Davis GL, Balart LA, Schiff ER, Linsay K, Bodenheimer HC, Perrillo RP, Carey W, Jacobson IM, Payne J, Dienstag JL, van Thiel DH, Tamburro C, Lefkowitch J, Albrecht J, Meschievitz C, Grtego TJ, Gibas A: Treatment of chronic hepatitis C with recombinant interferon alfa. N Engl J Med 321:1501-1506, 1989