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Fibrillary glomerulonephritis associated with hepatitis C viral infection
RENAL BIOPSY CASE
Fibrillary Glomerulonephritis Associated With Hepatitis C Viral Infection Emanuel Coroneos, MD, Luan Truong, MD, and Juan Olivero, MD INDEX WORDS: Fibrillary glomerulonephritis; hepatitis C viral infection; ~x-interferon therapy.
ECENT STUDIES have associated hepati.tis C viral (HCV) infection with glomerular diseases. Both membranous and membranoproliferative glomerulonephritis have been reported, which suggests an immune-mediated mechanism for the renal lesion complicating the HCV infection. Renal biopsy specimens from these patients have shown deposition of irnmunoglobulin (Ig) G, IgM, and C3 in the glomeruli. 1'2 HCV RNA has not been localized in the glomerular lesions; however, the HCV core protein has been identified in patients with HCV-associated glomerulonephritis. 3 We report a case of fibrillary glomerulonephritis (FGN) complicating HCV infection and the favorable response to alpha-interferon treatment (a-IFN). To our knowledge this is the first reported association of fibrillary glomerulonephritis with HCV infection.
R
CASE REPORT A 46-year-old white woman had a medical history of wellcontrolled hypertension with metoprolol 100 mg daily, hypothyroidism treated with L-thyroxine 0.i mg dally, gastritis treated with ranitidine 300 mg daily, and partial-complex seizures treated with depakoate 1,000 mg daily. In April 1988, the patient underwent total abdominal hysterectomy with bilateral salpigoophorectomy, and she received 4 units of packed red blood cells. In August 1992, she presented complaining of headaches and dyspepsia; her blood pressure was 130/70 mm Hg, and the physical examination was only remarkable for bilateral ankle pitting edema. Laboratory findings showed hemoglobin 11.9 g/dL, hematocit 35.5%, albumin 3.2 g/dL, blood urea nitrogen (BUN) 10 mg/dL, creatinine 0.9 mg/dL, aspartate aminotransferase (AST) 65 U/L, and alanine aminotransferase (ALT) 67 U/L (normal values, less than 40 U/L), gamma-glutamyl transpeptidase (GGTP) 130 U/L (normal values, less than 70 U/L). Urine
From the Department of Medicine, Renal Section, and the Renal Pathology Laboratory, Baylor College of Medicine, VAMC, and the Methodist Hospital, Houston, TX. Received May 23, 1996; accepted in revised form August 13, 1996. Address reprint requests to Juan Olivero, MD, 6560 Fannin, Ste 1426, Houston, TX 77030. © 1997 by the National Kidney Foundation, Inc. 02 72-6386/97,/2901-001853.00/0 132
analysis showed hyaline casts and new-onset proteinuria quantitated to 1 g/day and creatinine clearance (CrC1) of 80 mL/min. Additional serological studies showed a serum C3 level of 85 mg/dL (normal value, 60 to 120 mg/dL), a serum C4 level of 39 mg/dL (normal, 15 to 50 mg/dL). Serological tests for human immunodeficiency virus, antinuclear antibody, and rheumatoid factor (RF) were negative; serum cryoglobulins were not detected. Hepatitis B surface antigen (HBsAg) and antibodies to both HBsAg and hepatitis B core antigen (HBcAg) were negative, and HCV antibody was positive by first-generation assay. Urine and serum protein immunoelectrophoresis were normal. The patient was followed without any treatment till June 1995, when she noticed a 4kg weight gain, bilateral leg edema, and recurrence of her hypertension (165/100 mm Hg), requiring the addition of amlodipine 5 mg daily to be controlled. Laboratory findings were remarkable for BUN 18 mg/dL, creatinine 1.5 mg/dL, albumin 2.6 g/dL, ALT 90 U/L, AST 85 U/L, and GGTP 350 U/L. Urine analysis showed hyaline casts and that her proteinuria had increased to a nephrotic range, 4.9 g/day; moreover, her CrC1 had decreased to 54 mL/min. Repeated previously mentioned serological tests were normal or negative except for positive HCV antibody, verified by secondgeneration assay and HCV RNA detected in serum by reverse-transcription polymerase chain reaction (RT-PCR). A renal biopsy was performed, and the patient was subsequently treated with a-IFN (9 million units weekly). After 3 months of treatment, her edema had disappeared, and her hypertension was controlled. Repeated laboratory tests showed BUN 10 mg/dL, creatinine 0.7 mg/dL, albumin 3.6 g/dL, ALT 47 U/L, AST 42 U/L, GGPT 130 U/L, proteinuria had decreased to 2.3 g/day, CrC1 had increased to 94 mL/min, and HCV RNA disappeared from serum assessed by RT-PCR. These findings indicated a favorable response of both her liver and her renal disease to the a-IFN treatment.
Pathology Findings A total of 51 glomeruli were present in the biopsy specimen. They showed global diffuse acellular expansion of the mesangium and mild thickening of the capillary walls. There was no endocapillary or mesangial cell hypercellularity (Fig 1). Crescents were not present. There was mild patchy tubular atrophy without significant tubulointerstitial inflammation. Some small arteries and arterioles showed mild intimal thickening. The Congo red and Thioflavin-T stains were negative for amyloidosis. Up to six glomeruli were available for immunofluorescent studies. Using a subjective grading scale (0 to 4; 0 = negative, 4 = very strong), it was found that there was a 3 + global and diffuse mesangial and peripheral staining for IgG and C3 (predominantly IgG4), 1 + mesangial and peripheral staining for kappa and lambda light chains, and a negative staining for IgA, IgM, and C4. The staining for
American Journal of Kidney Diseases, Vol 29, No 1 (January), 1997: pp 132-135
FIBRILLARY GN AND HEPATITIS C VIRUS
133
amyloid fibers (Fig 2, insert). However, measurement of the fiber diameter at high magnification (×35,000) showed a diameter of 16 _+ 2 nm, which is significantly larger than that of amyloid fibrils (10 nm). In summary, the renal biopsy findings were characteristic of fibrillary gtomerulonephritis. DISCUSSION
Fig 1. The glomerulus shows global mesangial expansion by an amorphous eosinophilic material and also segmental thickening of the glomerular capillaries. (Hematoxylin-eosin stain; original magnification x550.)
tubular basement membrane and blood vessels was negative. Electron microscopic examination showed irregular and occasionally prominent thickening of the capillary basement membrane with intramembranous amorphous irregularly outlined deposits, which in higher magnification were composed of arrays of straight nonbranching fibrils (Fig 2). These deposits were even more pronounced within the mesangium. These fibrils had a morphology and arrangement similar to
Fig 2. The mesangium (M) is expanded with electrondense aggregates of fibrillary material. The same material is also identified along the glomerular basement membrane (L = capillary lumen). (Electron microscopy; original magnification x9,000.) Insert, The fibrils are straight, nonbranching, and randomly arranged, measuring 12 _+2 nm. (Electron microscopy; original magnification x35,000.)
A significant n u m b e r o f patients have been reported with H C V infection and d o c u m e n t e d g l o m e r u l a r diseases that were characterized b y the presence o f i m m u n e deposits, but these glomerulopathies have never been described with the ultrastructural features o f fibrillary g l o m e r u l o n e phritis. This patient presented with nephrotic s y n d r o m e and m o d e r a t e renal insufficiency c o m plicating H C V infection, and the renal b i o p s y specimen showed deposits arranged in the less frequently found fibrillar form consistent with F G N . This finding could b e e x p l a i n e d because o f the I g G 4 p r o m i n e n c e in the deposits, a feature that is generally found to be characteristic of F G N . 4 Previous studies have shown that H C V infection can be associated with renal diseases. 2'5 A l though the association o f H C V infection with
134
mixed cryoglobulimenia is well known, 6'7 it is also apparent that HCV infection may manifest as primary glomerulonephritis without cryoglobulinemia (25%) and occasionally with clinically silent liver disease. 8 Although a variety of types of glomerulonephritis have been described in the context of HCV infection, the most frequent and best characterized form is membranoproliferative glomerulonephritis. ~'s'9 Currently, to prove that a correlation exists between HCV infection and the induction of glomerular lesions, clinical remission as well as disappearance of HCV RNA from serum or cryoprecipitates after a-IFN treatment should be demonstrated. 2,s Another way of proving association of HCV infection with glomerular diseases is by showing either the presence of HCV RNA in the glomerular lesions, which has not been shown, or the existence of HCV proteins in the affected glomeruli. The presence of HCV core protein has been shown in two patients with HCV-associated membranous glomerulonephritis by immunostaining of frozen tissue. 3 Although more than 100 patients with the diagnosis of FGN have been reported, 4'1°-12 no apparent correlation with other systemic diseases known to be involved in the pathogenesis of glomerular diseases has been found. The association of F G N with HCV infection has never been noted, which indicates that the combination is very rare or has not been recognized, perhaps because a number of FGN cases were diagnosed when an accurate HCV test was not yet available and the relation of HCV infection to glomerular diseases was not yet established. Previously reported patients with HCV-associated cryoglobulinemic or noncryoglobulinemic glomerular diseases have been treated with aIFN. s'13 A significant number of them (70%) manifested a favorable clinical response that was associated with suppression of HCV viremia as determined by RT-PCR. In these studies, reduction of urinary protein excretion, normalization of liver function tests, and a modest improvement of the renal function was observed. Our patient had some features that are less frequently encountered in reported patients with renal disease related to HCV infection. She had no detectable cryoglobulins, a negative RF, and normal complement levels, findings commonly seen in patients diagnosed with FGN. 4,u Moreover, treat-
CORONEOS, TRUONG, AND OLIVERO
ment with a-IFN was followed by partial remission of nephrotic syndrome and improvement of renal function as well as suppression of HCV viremia. The magnitude of proteinuria decrement observed in our patient after a-IFN treatment was smaller than expected. However, this level is not surprising because 40% of previously reported patients who were treated with a-IFN for glomerular diseases associated with HCV infection had a similar level of response, and most of them were also noncryoglobulinemic, s The a-IFN was administered at the usual recommended doses, and a higher-dosage regimen may have induced a better response, because this has been observed in few cases. ~4 FGN has been reported to be a disease that is difficult to treat, and it has shown a poor response to current therapeutic regimens, especially for patients who are older than 40 years. H'12 The observation that our patient had a partial improvement of her renal function suggests that the HCV infection was associated with the glomerular disease and furthermore indicated that in some patients with FGN, renal function could be favorably improved from the relentless course to end-stage renal disease (ESRD), as generally observed after biopsy-proven diagnosis in a few years. In conclusion, we report a patient with FGN associated with HCV infection who underwent partial clinical remission of her renal disease after treatment with a-IFN. This represents the first reported case of a potentially treatable cause for FGN, a renal disease with undefined cause, and poor response to any currently applied therapy, which rapidly leads to ESRD. REFERENCES
1, Johnson RJ, Willson R, Yamabe H, Couser W, Alpers C, Wener M, Davis C, Gretch D: Renal manifestations of hepatitis C virus infection. Kidney Int 46:1255-1263, 1994 2. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi C, Hartwell P, CouserW, Covey L, Wener M, Alpers C, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465-470, 1993 3. Okada K, Takishita Y, Shimomura H, Tsuji T, Miyamura T, KuharaT, YasutomoK, KagamiS, Kuroda Y: Detection of hepatitis C virus core protein in the glomeruli of patients with membranous glomerulonephritis. Clin Nephrol 45:71-76, 1996 4. Iskandar SS, Falk RT, Jennette JC: Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int 42:1401-1407, 1992
FIBRILLARY GN AND HEPATITIS C VIRUS
5. Yamabe H, Johnson RJ, Gretch DR, Fukushi K, Osawa H, Miyata M, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Onodera K: Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan. J Am Soc Nephrol 6:220-223, 1995 6. Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M: Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573577, 1992 7. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobnlinemia. N Engl J Med 327:1490-1495, 1992 8. Johnson RJ, Gretch DR, Couser WG, Alpers C, Wilson J, Chung M, Hart J, Willson R: Hepatitis C virus-associated glomernlonephritis: Effect of alpha-interferon therapy. Kidney Int 46:1700-1704, 1994 9. Stehmann-Breen C, Alpers CF, Couser WG, Willson R, Johnson RJ: Hepatitis C virus and membranous glomerulonephritis. Clin Nephrol 44:141-147, 1995 10. Alpers CE, Rennke HG, Hopper J Jr, Biava CG: Fibril-
135
lary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 31:781-789, 1987 11. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 22:367-377, 1993 12. D'Agati V, Sacchi G, Truong L, Venkataseshan S, Kim D, Kim B, Appel G: Fibrillary glomeru!opathy (FG): Defining the disease spectrum. J Am Soc Nephrol 2:591, 1991 (abstr) 13. Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi P, Zilio P, Vemocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti P: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 14. Yamabe H, Johnson R, Gretch D, Osawa H, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Sato A, Onodera K: Membranoproliferative glomerulonephritis associated with hepatitis C virns infection responsive to Interferon-a. Am J Kidney Dis 25:67-69, 1995
Fibrillary Glomerulonephritis Associated With Hepatitis C Viral Infection Emanuel Coroneos, MD, Luan Truong, MD, and Juan Olivero, MD INDEX WORDS: Fibrillary glomerulonephritis; hepatitis C viral infection; ~x-interferon therapy.
ECENT STUDIES have associated hepati.tis C viral (HCV) infection with glomerular diseases. Both membranous and membranoproliferative glomerulonephritis have been reported, which suggests an immune-mediated mechanism for the renal lesion complicating the HCV infection. Renal biopsy specimens from these patients have shown deposition of irnmunoglobulin (Ig) G, IgM, and C3 in the glomeruli. 1'2 HCV RNA has not been localized in the glomerular lesions; however, the HCV core protein has been identified in patients with HCV-associated glomerulonephritis. 3 We report a case of fibrillary glomerulonephritis (FGN) complicating HCV infection and the favorable response to alpha-interferon treatment (a-IFN). To our knowledge this is the first reported association of fibrillary glomerulonephritis with HCV infection.
R
CASE REPORT A 46-year-old white woman had a medical history of wellcontrolled hypertension with metoprolol 100 mg daily, hypothyroidism treated with L-thyroxine 0.i mg dally, gastritis treated with ranitidine 300 mg daily, and partial-complex seizures treated with depakoate 1,000 mg daily. In April 1988, the patient underwent total abdominal hysterectomy with bilateral salpigoophorectomy, and she received 4 units of packed red blood cells. In August 1992, she presented complaining of headaches and dyspepsia; her blood pressure was 130/70 mm Hg, and the physical examination was only remarkable for bilateral ankle pitting edema. Laboratory findings showed hemoglobin 11.9 g/dL, hematocit 35.5%, albumin 3.2 g/dL, blood urea nitrogen (BUN) 10 mg/dL, creatinine 0.9 mg/dL, aspartate aminotransferase (AST) 65 U/L, and alanine aminotransferase (ALT) 67 U/L (normal values, less than 40 U/L), gamma-glutamyl transpeptidase (GGTP) 130 U/L (normal values, less than 70 U/L). Urine
From the Department of Medicine, Renal Section, and the Renal Pathology Laboratory, Baylor College of Medicine, VAMC, and the Methodist Hospital, Houston, TX. Received May 23, 1996; accepted in revised form August 13, 1996. Address reprint requests to Juan Olivero, MD, 6560 Fannin, Ste 1426, Houston, TX 77030. © 1997 by the National Kidney Foundation, Inc. 02 72-6386/97,/2901-001853.00/0 132
analysis showed hyaline casts and new-onset proteinuria quantitated to 1 g/day and creatinine clearance (CrC1) of 80 mL/min. Additional serological studies showed a serum C3 level of 85 mg/dL (normal value, 60 to 120 mg/dL), a serum C4 level of 39 mg/dL (normal, 15 to 50 mg/dL). Serological tests for human immunodeficiency virus, antinuclear antibody, and rheumatoid factor (RF) were negative; serum cryoglobulins were not detected. Hepatitis B surface antigen (HBsAg) and antibodies to both HBsAg and hepatitis B core antigen (HBcAg) were negative, and HCV antibody was positive by first-generation assay. Urine and serum protein immunoelectrophoresis were normal. The patient was followed without any treatment till June 1995, when she noticed a 4kg weight gain, bilateral leg edema, and recurrence of her hypertension (165/100 mm Hg), requiring the addition of amlodipine 5 mg daily to be controlled. Laboratory findings were remarkable for BUN 18 mg/dL, creatinine 1.5 mg/dL, albumin 2.6 g/dL, ALT 90 U/L, AST 85 U/L, and GGTP 350 U/L. Urine analysis showed hyaline casts and that her proteinuria had increased to a nephrotic range, 4.9 g/day; moreover, her CrC1 had decreased to 54 mL/min. Repeated previously mentioned serological tests were normal or negative except for positive HCV antibody, verified by secondgeneration assay and HCV RNA detected in serum by reverse-transcription polymerase chain reaction (RT-PCR). A renal biopsy was performed, and the patient was subsequently treated with a-IFN (9 million units weekly). After 3 months of treatment, her edema had disappeared, and her hypertension was controlled. Repeated laboratory tests showed BUN 10 mg/dL, creatinine 0.7 mg/dL, albumin 3.6 g/dL, ALT 47 U/L, AST 42 U/L, GGPT 130 U/L, proteinuria had decreased to 2.3 g/day, CrC1 had increased to 94 mL/min, and HCV RNA disappeared from serum assessed by RT-PCR. These findings indicated a favorable response of both her liver and her renal disease to the a-IFN treatment.
Pathology Findings A total of 51 glomeruli were present in the biopsy specimen. They showed global diffuse acellular expansion of the mesangium and mild thickening of the capillary walls. There was no endocapillary or mesangial cell hypercellularity (Fig 1). Crescents were not present. There was mild patchy tubular atrophy without significant tubulointerstitial inflammation. Some small arteries and arterioles showed mild intimal thickening. The Congo red and Thioflavin-T stains were negative for amyloidosis. Up to six glomeruli were available for immunofluorescent studies. Using a subjective grading scale (0 to 4; 0 = negative, 4 = very strong), it was found that there was a 3 + global and diffuse mesangial and peripheral staining for IgG and C3 (predominantly IgG4), 1 + mesangial and peripheral staining for kappa and lambda light chains, and a negative staining for IgA, IgM, and C4. The staining for
American Journal of Kidney Diseases, Vol 29, No 1 (January), 1997: pp 132-135
FIBRILLARY GN AND HEPATITIS C VIRUS
133
amyloid fibers (Fig 2, insert). However, measurement of the fiber diameter at high magnification (×35,000) showed a diameter of 16 _+ 2 nm, which is significantly larger than that of amyloid fibrils (10 nm). In summary, the renal biopsy findings were characteristic of fibrillary gtomerulonephritis. DISCUSSION
Fig 1. The glomerulus shows global mesangial expansion by an amorphous eosinophilic material and also segmental thickening of the glomerular capillaries. (Hematoxylin-eosin stain; original magnification x550.)
tubular basement membrane and blood vessels was negative. Electron microscopic examination showed irregular and occasionally prominent thickening of the capillary basement membrane with intramembranous amorphous irregularly outlined deposits, which in higher magnification were composed of arrays of straight nonbranching fibrils (Fig 2). These deposits were even more pronounced within the mesangium. These fibrils had a morphology and arrangement similar to
Fig 2. The mesangium (M) is expanded with electrondense aggregates of fibrillary material. The same material is also identified along the glomerular basement membrane (L = capillary lumen). (Electron microscopy; original magnification x9,000.) Insert, The fibrils are straight, nonbranching, and randomly arranged, measuring 12 _+2 nm. (Electron microscopy; original magnification x35,000.)
A significant n u m b e r o f patients have been reported with H C V infection and d o c u m e n t e d g l o m e r u l a r diseases that were characterized b y the presence o f i m m u n e deposits, but these glomerulopathies have never been described with the ultrastructural features o f fibrillary g l o m e r u l o n e phritis. This patient presented with nephrotic s y n d r o m e and m o d e r a t e renal insufficiency c o m plicating H C V infection, and the renal b i o p s y specimen showed deposits arranged in the less frequently found fibrillar form consistent with F G N . This finding could b e e x p l a i n e d because o f the I g G 4 p r o m i n e n c e in the deposits, a feature that is generally found to be characteristic of F G N . 4 Previous studies have shown that H C V infection can be associated with renal diseases. 2'5 A l though the association o f H C V infection with
134
mixed cryoglobulimenia is well known, 6'7 it is also apparent that HCV infection may manifest as primary glomerulonephritis without cryoglobulinemia (25%) and occasionally with clinically silent liver disease. 8 Although a variety of types of glomerulonephritis have been described in the context of HCV infection, the most frequent and best characterized form is membranoproliferative glomerulonephritis. ~'s'9 Currently, to prove that a correlation exists between HCV infection and the induction of glomerular lesions, clinical remission as well as disappearance of HCV RNA from serum or cryoprecipitates after a-IFN treatment should be demonstrated. 2,s Another way of proving association of HCV infection with glomerular diseases is by showing either the presence of HCV RNA in the glomerular lesions, which has not been shown, or the existence of HCV proteins in the affected glomeruli. The presence of HCV core protein has been shown in two patients with HCV-associated membranous glomerulonephritis by immunostaining of frozen tissue. 3 Although more than 100 patients with the diagnosis of FGN have been reported, 4'1°-12 no apparent correlation with other systemic diseases known to be involved in the pathogenesis of glomerular diseases has been found. The association of F G N with HCV infection has never been noted, which indicates that the combination is very rare or has not been recognized, perhaps because a number of FGN cases were diagnosed when an accurate HCV test was not yet available and the relation of HCV infection to glomerular diseases was not yet established. Previously reported patients with HCV-associated cryoglobulinemic or noncryoglobulinemic glomerular diseases have been treated with aIFN. s'13 A significant number of them (70%) manifested a favorable clinical response that was associated with suppression of HCV viremia as determined by RT-PCR. In these studies, reduction of urinary protein excretion, normalization of liver function tests, and a modest improvement of the renal function was observed. Our patient had some features that are less frequently encountered in reported patients with renal disease related to HCV infection. She had no detectable cryoglobulins, a negative RF, and normal complement levels, findings commonly seen in patients diagnosed with FGN. 4,u Moreover, treat-
CORONEOS, TRUONG, AND OLIVERO
ment with a-IFN was followed by partial remission of nephrotic syndrome and improvement of renal function as well as suppression of HCV viremia. The magnitude of proteinuria decrement observed in our patient after a-IFN treatment was smaller than expected. However, this level is not surprising because 40% of previously reported patients who were treated with a-IFN for glomerular diseases associated with HCV infection had a similar level of response, and most of them were also noncryoglobulinemic, s The a-IFN was administered at the usual recommended doses, and a higher-dosage regimen may have induced a better response, because this has been observed in few cases. ~4 FGN has been reported to be a disease that is difficult to treat, and it has shown a poor response to current therapeutic regimens, especially for patients who are older than 40 years. H'12 The observation that our patient had a partial improvement of her renal function suggests that the HCV infection was associated with the glomerular disease and furthermore indicated that in some patients with FGN, renal function could be favorably improved from the relentless course to end-stage renal disease (ESRD), as generally observed after biopsy-proven diagnosis in a few years. In conclusion, we report a patient with FGN associated with HCV infection who underwent partial clinical remission of her renal disease after treatment with a-IFN. This represents the first reported case of a potentially treatable cause for FGN, a renal disease with undefined cause, and poor response to any currently applied therapy, which rapidly leads to ESRD. REFERENCES
1, Johnson RJ, Willson R, Yamabe H, Couser W, Alpers C, Wener M, Davis C, Gretch D: Renal manifestations of hepatitis C virus infection. Kidney Int 46:1255-1263, 1994 2. Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi C, Hartwell P, CouserW, Covey L, Wener M, Alpers C, Willson R: Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 328:465-470, 1993 3. Okada K, Takishita Y, Shimomura H, Tsuji T, Miyamura T, KuharaT, YasutomoK, KagamiS, Kuroda Y: Detection of hepatitis C virus core protein in the glomeruli of patients with membranous glomerulonephritis. Clin Nephrol 45:71-76, 1996 4. Iskandar SS, Falk RT, Jennette JC: Clinical and pathologic features of fibrillary glomerulonephritis. Kidney Int 42:1401-1407, 1992
FIBRILLARY GN AND HEPATITIS C VIRUS
5. Yamabe H, Johnson RJ, Gretch DR, Fukushi K, Osawa H, Miyata M, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Onodera K: Hepatitis C virus infection and membranoproliferative glomerulonephritis in Japan. J Am Soc Nephrol 6:220-223, 1995 6. Misiani R, Bellavita P, Fenili D, Borelli G, Marchesi D, Massazza M: Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 117:573577, 1992 7. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobnlinemia. N Engl J Med 327:1490-1495, 1992 8. Johnson RJ, Gretch DR, Couser WG, Alpers C, Wilson J, Chung M, Hart J, Willson R: Hepatitis C virus-associated glomernlonephritis: Effect of alpha-interferon therapy. Kidney Int 46:1700-1704, 1994 9. Stehmann-Breen C, Alpers CF, Couser WG, Willson R, Johnson RJ: Hepatitis C virus and membranous glomerulonephritis. Clin Nephrol 44:141-147, 1995 10. Alpers CE, Rennke HG, Hopper J Jr, Biava CG: Fibril-
135
lary glomerulonephritis: An entity with unusual immunofluorescence features. Kidney Int 31:781-789, 1987 11. Fogo A, Qureshi N, Horn RG: Morphologic and clinical features of fibrillary glomerulonephritis versus immunotactoid glomerulopathy. Am J Kidney Dis 22:367-377, 1993 12. D'Agati V, Sacchi G, Truong L, Venkataseshan S, Kim D, Kim B, Appel G: Fibrillary glomeru!opathy (FG): Defining the disease spectrum. J Am Soc Nephrol 2:591, 1991 (abstr) 13. Misiani R, Bellavita P, Fenili D, Vicari O, Marchesi D, Sironi P, Zilio P, Vemocchi A, Massazza M, Vendramin G, Tanzi E, Zanetti P: Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 330:751-756, 1994 14. Yamabe H, Johnson R, Gretch D, Osawa H, Inuma H, Sasaki T, Kaizuka M, Tamura N, Tsunoda S, Fujita Y, Sato A, Onodera K: Membranoproliferative glomerulonephritis associated with hepatitis C virns infection responsive to Interferon-a. Am J Kidney Dis 25:67-69, 1995