| Abstract|| |
Hepatitis C virus (HCV) may have a pathogenic role in several forms of immune complex glomerulonephritis (ICGN), including cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy. HCV infection may also be related indirectly (e.g. secondary to HCV-related liver disease) or coincidentally to glomerulonephritis. These include cases of fibrillary/immunotactoid glomerulopathy, MPGN arising in allografts, allograft glomerulopathy, rapidly progressive glomerulonephritis, focal and segmental glomerulosclerosis, and ICGN arising in individuals coinfected with human immunodeficiency virus (HIV). This review summarizes the clinical and pathologic features of HCV-associated glomerular disease, particularly immune complex glomerulonephritis, and discusses possible pathogenic mechanisms.
Keywords: Immune complex, Glomerular disease, Pathogenesis.
|How to cite this article:|
Stokes MB. Immune Complex Glomerulonephritis in Patients with Hepatitis C. Saudi J Kidney Dis Transpl 2000;11:396-404
| Overview|| |
HCV was first identified in 1989 by molecular cloning and was found to be the agent responsible for most cases of sporadic and transfusion-associated hepatitis, previously referred to as non-A non-B hepatitis. HCV affects an estimated 170 million persons worldwide, and is a major public health concern because of the high rate of chronic infection, and its association with cirrhosis and hepatocellular carcinoma. HCV has also been linked to several forms of immune complex glomerulonephritis (ICGN), in some cases leading to end-stage renal failure and dialysis. This article discusses the reported associations of HCV and glomerular disease, with an emphasis on putative pathogenic mechanisms.
A. HCV-Related Renal Disease: MPGN
A role for HCV in glomerular disease emerged from several fields of study. Firstly, a high prevalence of HCV infection was shown in patients with idiopathic (essential) mixed cryoglobulinemia,  and this was followed by the demonstration that HCV RNA is enriched in the cryoprecipitates in such patients,  strongly suggesting a pathogenic role for HCV in cryoglobulin-related disease. The incidence and classification of glomerular disease in these individuals was not described in detail. Subsequently, the renal pathologic findings in patients with chronic HCV infection undergoing renal biopsy were described. All of these individuals had MPGN, with or without signs of cryoglobulinemia.  Characterization of the cryoprecipitates demonstrated HCV nucleocapsid core antigens bound to specific IgG, which was in turn bound to rheumatoid factor (IgM). The association of HCV infection, cryoglobulinemia, and MPGN, was confirmed in larger retrospective epidemiologic studies and in individual case reports. ,,, Further indirect evidence of a pathogenic role for HCV derives from the clinical observation that treatment with alpha interferon in patients with HCV infection and glomerular disease leads to lowered serum creatinine levels and proteinuria, together with lowering of HCV RNA levels, anti-HCV antibody levels, and cryoglobulin titers. ,
Clinical features of HCV-related MPGN
Patients usually present with moderate to severe proteinuria, persistent hematuria and impaired renal function. , Up to 25% of patients may have the nephrotic syndrome. Most have mildly elevated serum aminotransferase levels. Although they may lack clinical or laboratory evidence of liver disease, liver biopsy frequently shows chronic hepatitis with or without cirrhosis.  Many, but not all patients have cryoglobulinemia, hypocomplementemia, rheumatoid factor, and circulating immune complexes. Some also have other signs suggestive of cryoglobulinemia, including arthralgias and peripheral neuropathies.
Pathologic features of HCV-related MPGN
The renal biopsy findings in HCV-related MPGN consist of diffuse glomerular hypercellularity, accentuation of glomerular tuft lobules, and thickening of peripheral capillary walls with splitting of basement membranes and cellular interposition [Figure - 1],[Figure - 2]. The capillary lumina are frequently narrowed due to the increased cellularity and capillary wall thickening.
Additional findings in some cases include prominent acellular "hyaline thrombi" in capillary loops, which stain intensely with periodic acid-Schiff reagent (PAS) and correspond to precipitated cryoglobulins [Figure - 2]. Variable, sometimes marked, accumulations of mesangial matrix accompany the increased cellularity. The morphologic features of MPGN are easily identified with PAS or silver stains. Sometimes, the peripheral capillary wall changes are obscured by the intense hypercellularity, and this appearance may lead to confusion with diffuse proliferative glomerulonephritis, as seen in post-streptococcal glomerulonephritis. However, polymorphonuclear leukocytes are not prominent in cases of MPGN. There may be varying degrees of glomerulosclerosis, interstitial fibrosis, and arteriosclerosis, related to the chronicity of the disease process. Rarely, vasculitis of the small or medium sized arterial vessels is observed. Immunofluorescence microscopy demonstrates peripheral capillary wall staining for C3, with or without IgG and IgM. Massive accumulations of C3 and other immune reactants are seen in "hyaline thrombi". Similar, nonspecific immunofluorescence staining may be found in areas of hyalinosis or segmental sclerosis. Electronmicroscopy demonstrates cellular interposition in peripheral capillary walls, and the presence of varying numbers of discrete immune type electron dense deposits. The latter typically occur on the subendothelial side of peripheral capillary walls, and may also be present in the mesangium. In cases of cryoglobulinemic MPGN, the deposits may show a peculiar array of substructures, including annular, tubular, fibrillar, or cylindrical forms.  The findings of HCVrelated MPGN are nonspecific, and resemble MPGN from other causes. MPGN is not equivalent to HCV-disease, and HCV infection is uncommon in some groups of patients with MPGN e.g. in children.  Clinico-pathologic correlation is essential to correctly diagnose HCV-related MPGN.
Pathogenesis of HCV-related MPGN
The combined clinical and pathologic evidence points to a mechanism involving deposition of immune complexes containing anti-HCV antibodies, HCV antigens, and C3, in glomerular capillary walls. This leads to activation of the complement system and generation of pro-inflammatory and chemotactic signals, followed by an influx of monocyte/macrophages, release of proteases and oxidants, and damage to the glomerular filtration barrier, causing proteinuria and renal insufficiency. Chronic HCV infection is believed to stimulate production of polyclonal anti-HCV antibodies and monoclonal rheumatoid factor in mixed cryoglobulins, but whether or not cryoglobulin production is necessary in all cases is uncertain. Likewise, not all cases tested show HCV antigen or RNA at sites of immune complex deposition. However, the absence of HCV-containing immune complexes, either in the circulation or in glomeruli, does not exclude a pathogenic role. It is possible that HCV infection of lymphocytes elsewhere in the body e.g., in lymph nodes, leads to an overproduction of IgM (with polyclonal and, later, monoclonal rheumatoid factor), that subsequently deposits in the glomeruli. The presence of liver disease in many of these individuals may also have a pathogenic role, perhaps via reduced clearance of circulating immune complexes.
B. HCV-Associated Glomerular Disease
Membranous nephropathy: clinical and pathologic features.
The clinical presentation of HCVassociated membranous nephropathy is dominated by proteinuria, sometimes with microscopic hematuria. Most patients have the nephrotic syndrome, and renal function is generally normal, although mild renal insufficiency may be present in some cases. The first reported description of glomerular disease in an HCV infected individual was a case of membranous nephropathy.  Rollino et al retrospectively examined 27 patients with idiopathic membranous nephropathy for serologic evidence of HCV infection, using a first-generation enzyme linked immunoassay.  One patient who tested positive for HCV presented with nephrotic range proteinuria, normal renal function, and abnormal liver function tests. Cryoglobulins were not reported. Following steroid therapy, the patient's proteinuria remitted and serum transaminases returned to normal, suggesting a possible link between HCV-liver disease and membranous nephropathy. Davda et al described two patients who developed membranous nephropathy following bone marrow transplantation for hematolymphoid malignancies.  Both patients tested positive for HCV infection and had signs of hepatitis prior to, or accompanying the onset of nephrotic proteinuria. HCV RNA was identified in their renal biopsy tissues by reverse transcription polymerase chain reaction (RT-PCR). However, it is not possible to exclude a role for malignancy and/or bone marrow transplantation in the pathogenesis of membranous nephropathy in these two cases. Stehman-Breen et al described four patients with HCV infection and renal biopsy findings of membranous nephropathy. 1 In one case with chronic liver disease, renal biopsy also showed features of mesangial sclerosis and focal segmental sclerosis. All four presented with the nephrotic syndrome, and none had cryoglobulins or rheumatoid factor. Of three patients who were treated with alpha interferon, two showed some improvement in renal signs, suggesting a pathogenic role for HCV in membranous nephropathy. Another group, however, reported no remission in nephrotic proteinuria in HCVpositive individuals with membranous nephropathy following interferon therapy, despite improvement in hepatic function.  Okada et al, described two patients who presented with nephrotic proteinuria, one of whom also had microhematuria, chronic active hepatitis, and hypocomplementemia. Neither individual had rheumatoid factor or cryoglobulinemia. In both cases, HCV RNA was detected in circulating immune complexes, and HCV core antigen was demonstrated immunohistochemically in glomerular basement membranes. The renal pathologic features in cases of HCVassociated membranous nephropathy are indistinguishable from those of primary membranous nephropathy i.e. immunofluorescence microscopic findings of granular peripheral capillary wall deposits of IgG, with or without C3, confirmed electronmicroscopically by the finding of immune type electron dense deposits in subepithelial locations. Of note, mesangial immune deposits, which are commonly encountered in hepatitis B associated membranous nephropathy, have only rarely been described in HCV-associated membranous nephropathy. 
Pathogenesis of HCV-associated membranous nephropathy
The pathogenesis of HCV-associated membranous nephropathy is unclear. As mentioned above, Okada et al were able to demonstrate HCV antigens in the glomeruli of two patients with HCV-associated membranous nephropathy, both of whom also had HCV RNA in circulating immune complexes. This suggests a possible role for immune complex deposition involving HCV proteins,  analogous to the demonstration of hepatitis B immune complexes in membranous nephropathy.  Other investigators were unable to identify viral proteins within glomeruli. , However, the absence of detectable HCV protein (or HCV RNA) in diseased glomeruli does not exclude a pathogenic role. Experimental evidence (e.g. from the Heymann nephritis model) suggests that membranous nephropathy may result from an autoimmune reaction to antigens on the surface of visceral epithelial cells, and not from deposition of antigen-containing immune complexes from the circulation. HCV infection is associated with a high prevalence of extrahepatic immunological abnormalities, including synthesis of autoantibodies, rheumatoid factor, and antismooth muscle antibodies,  suggesting a possible link to the development of membranous nephropathy via an autoimmune mechanism. Regardless of the mechanism involved, these findings are suggestive that at least some cases of membranous nephropathy may be pathogenically related to HCV. At this point in time the number of reported cases is too small to draw any firm conclusions. As there are no specific pathologic features that allow us to distinguish HCV-associate membranous nephropathy from other causes, it is probably advisable to seek serologic evidence of HCV infection in all cases of biopsy-proven membranous nephropathy.
Although not generally considered a form of ICGN, this interesting group of glomerular diseases is characterized by accumulation of Congo red-negative fibrillar proteins that contain immunoglobulins and other serum proteins, including fibronectin. The fibrils may represent polymerized polyclonal immunoglobulins deposits.  In contrast to fibrillary glomerulonephritis, which is usually idiopathic, with fibrils measuring 16-24 nm in width, immunotactoid glomerulopathy shows thicker (32-50 nm) microtubular fibrils, and is frequently associated with lymphoproliferative disorders and collagen vascular diseases. The origin of the fibrils in these cases is unknown, but may be related to deposition of a serum precursor(s). Rostagno et al performed biochemical and immunochemical studies on a serum fibrillar cryoprecipitate obtained from a patient with fibrillary glomerulonephritis, that formed on prolonged storage in the cold.  The cryoprecipitate contained fibrillar proteins that had similar properties to the fibrillar proteins in the glomeruli, suggesting a role for immunoglobulinfibronectin complexes in the pathogenesis of fibrillary glomerulonephritis. The similarities to the putative mechanism of HCVrelated cryoglobulinemic glomerulonephritis are obvious. Subsequently, HCV infection was found in five of eleven patients with fibrillary/immunotactoid glomerulopathy at one institution.  One patient had a low titer of cryoglobulin whereas the others were negative. The authors noted the overlapping histologic and clinical features of patients with organized glomerular immune depositscryoglobulinemic glomerulonephritis, fibrillary glomerulonephritis and immunotactoid glomerulopathy and suggested that organized immune deposits may be a feature of HCV-related glomerular disease in general. It is therefore probably worthwhile to test for HCV infection in all patients whose renal biopsies show organized deposits, to test the validity of this interesting hypothesis.
| IgA nephropathy|| |
Two patients were described who presented with cryoglobulinemia (including vasculitis and arthralgias), microscopic hematuria, nonnephrotic proteinuria, mild renal insufficiency, and elevated serum transaminases.  Liver biopsies in both patients showed chronic active hepatitis and micronodular cirrhosis respectively. Renal biopsies demonstrated mesangial IgA deposits, mesangial hypercellularity, and focal and segmental glomerulosclerosis (in one case). Following treatment with alpha interferon, one patient showed improvement in liver function, cryoglobulins, and HCV RNA levels, but renal function and proteinuria were unchanged. It is possible that IgA deposition in these cases may be related indirectly to HCV infection, secondary to liver dysfunction. Alternatively, these and other  reported cases could represent superimposed HCV infection on a background of underlying IgA nephropathy, particularly in populations in which IgA nephropathy is highly prevalent. 
| HCV and transplantation|| |
HCV infection has been associated with de novo or recurrent membranoproliferative glomerulonephritis and acute transplant glomerulopathy in transplanted kidneys. , More recently, a hemolytic uremic syndrome associated with anti-cardiolipin antibodies in HCV-positive renal allograft recipients has been described.  Renal biopsies in these individuals showed thrombotic microangiopathy.
HCV-associated glomerulonephritis may complicate liver transplantation in conjunction with the production of increased amounts of IgM specific for HCV antigens. Davis et al, described three patients who developed glomerular disease following liver transplantation. One patient developed mixed cryoglobulinemia and MPGN.  The other two biopsies showed mesangial proliferative glomerulonephritis and a sclerosing glomerulopathy.
Other glomerular lesions associated with HCV infection
A single case of a young woman developing rapidly progressive glomerulonephritis during the course of acute HCV infection has been described.  Renal biopsy showed crescentic glomerulonephritis without evidence of immune complex deposition. A high rate of HCV infection (50%) has been described in black intravenous drug users (IVDU) with renal biopsy findings of idiopathic focal and segmental glomerulosclerosis,  reflecting the efficiency of parenteral transmission of HCV. Indeed, Cosio et al, have provided evidence that HCV infection is most often related to intravenous drug use in individuals undergoing native kidney biopsy, at least in their study population. 
C. ICGN in patients with HCV/HIV infection
A high rate of HCV coinfection exists in patients with HIV and renal biopsy findings of ICGN, , reflecting the high prevalence of IVDU in this population. In a series of 12 HIV-HCV co-infected IVDU, renal biopsy showed MPGN (five), mesangial proliferative glomerulonephritis (five), membranous glomerulopathy (one), and collapsing glomerulopathy with immune complex deposits (one). The majority of patients had hypocomplementemia, and five had cryoglobulinemia. HCV RNA was detected by RT-PCR in the renal biopsy tissue and/or serum of these patients and in four of eight HIV-infected IVDU with non-immune complex glomerular disease, in whom serologic testing for HCV was not performed. These results suggest that: (a) HCV may be a important cause of ICGN in HIV-infected patients, (b) the predictive value of identifying HCV RNA in tissue for diagnosing HCV related renal disease may be diminished in populations with a high rate of HCV (e.g. IVDU). HCV RNA in these tissues could be related to circulating HCV-infected leukocytes. Cheng et al, described the clinical and pathologic findings in 14 HIV-HCV co-infected IVDU.  Eleven patients had MPGN, including five with feature of both MPGN and membranous nephropathy (MPGN type 3). Cryoglobulins were identified in four of 12 individuals tested. The overlapping clinical features with HIV-associated nephropathy (HIVAN), and the frequently poor renal outcome in these patients underscores the necessity for renal biopsy examination to accurately diagnose glomerular disease in HIV-HCV co-infected individuals. Two small studies (8 and 12 patients, respectively) have shown that alpha interferon therapy for HCV-related hepatitis is well tolerated in HIV-infected patients, at least in the short term, suggesting that this therapy might also be useful for MPGN in HIV/HCV co-infected patients. ,
D. Treatment of HCV-related renal disease
The role of alpha interferon in the treatment of HCV-related renal disease is uncertain, with only a few reported studies and mixed outcomes. ,,,, In one study, four patients treated for two to 12 months showed reduced protein excretion, but with variable effects on serum creatinine; renal function improved in one, worsened in one, fluctuated in one, and remained normal in the fourth patient.  Similarly, in a series of 40 cases,  proteinuria decreased by 65%, but improvements in serum creatinine did not reach statistical significance. Another controlled trial of alpha interferon demonstrated improved creatinine levels in 60% of treated patients,  but renal disease recurred in both of these studies after therapy was stopped. As mentioned above, two of three patients with membranous nephropathy and HCV infection showed improved renal function and diminished proteinuria following alpha interferon therapy.  However, another group reported no remission in nephrotic proteinuria in three HCV-positive individuals with membranous nephropathy, despite improvement in hepatic function with interferon therapy. 
| Summary|| |
In the past decade, HCV has emerged as a major infectious disease that impacts many aspects of medicine, including public health policy, blood product safety, transplantation, hepatology, and nephrology. The identification of HCV as a cause of mixed cryoglobulinemia provides convincing evidence for a role for HCV in the pathogenesis of cryoglobulinemic MPGN. HCV may also be associated with other forms of immune complex/immunoglobulin-related glomerular disease, including membranous nephropathy and fibrillary/immunotactoid glomerulopathies. Whether these and other renal disease associations indicate an etiologic role, or an indirect pathogenic role, remains to be determined. Evidence of HCV infection should be sought in all patients presenting with immune complex glomerular disease, to help answer these questions.
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Michael Barry Stokes
Department of Pathology, TH 480, New York University Medical Center, 560 First Avenue, New York, NY 10016
[Figure - 1], [Figure - 2]