| Abstract|| |
Renal diseases associated with hepatitis C virus (HCV) infection are a significant problem for clinicians and diagnostic pathologists. A wide variety of disorders, including a spectrum of immune-complex glomerulonephritides, has been reported in association with hepatitis and cirrhosis caused by HCV. For some of these diseases, including membranoproliferative glomerulonephritis type I and cryoglobulinemic glomerulonephritis, plausible links between HCV and the glomerular pathology have been proposed. In other cases, the role of the virus in the pathogenesis of the renal disease is less certain. This communication catalogues the renal manifestations of HCV infection, providing clinical and pathological descriptions of the most prevalent disorders. Where available, evidence implicating HCV in the causation of the disorders is also discussed.
Keywords: Glomerulonephritis, Hepatitis C virus, Cryoglobulinemia, Membranoproliferative glomerulonephritis, Membranous glomerulonephritis.
|How to cite this article:|
Miller SE, Howell DN. Glomerular Diseases Associated with Hepatitis C Virus Infection. Saudi J Kidney Dis Transpl 2000;11:145-60
|How to cite this URL:|
Miller SE, Howell DN. Glomerular Diseases Associated with Hepatitis C Virus Infection. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2019 Nov 12];11:145-60. Available from: http://www.sjkdt.org/text.asp?2000/11/2/145/36671
| Introduction|| |
Since its identification in 1989, hepatitis C virus (HCV), a positive-stranded RNA virus belonging to the family Flaviviridae, has been recognized as a major cause of chronic hepatitis and cirrhosis. , End-stage liver disease associated with HCV infection is currently the leading indication for liver transplantation in many centers, including our own. Though the known primary effects of HCV are confined to the liver, infection with the virus is associated with a number of systemic pathologies. Of these, HCVassociated renal diseases have perhaps the greatest variety and clinical impact.
The interplay between HCV and the kidney is complex. Infection with HCV is particularly prevalent in patients on hemodialysis (HD) and renal transplant recipients;,,,,,,,, almost 70% of active HD patients in the Kingdom of Saudi Arabia reportedly have circulating antibodies against the virus.  These patients are predisposed to the development of HCV infection for a variety of reasons, including spread of virus through blood products and transplant tissues. In a majority of such cases, the HCV infection is presumably an indirect result of therapy for the renal disease rather than its cause. Immunosuppressive therapy for renal transplant recipients may also exacerbate the course of pre-existing HCV infection in some cases.,,, In other instances, a single underlying disorder can predispose to both HCV infection and renal disease. Sickle cell disease, for example, is associated with a variety of renal manifestations as well as an increased risk for transfusion-acquired HCV infection., Both HCV and other viruses with known or suspected effects on the kidney, such as human immunodeficiency virus (HIV), can be acquired by sexual or parenteral routes of transmission.
The central topic of this communication, however, is the role of HCV in the pathogenesis of renal disease. The virus has the theoretical potential to cause renal injury by a number of direct or indirect mechanisms. Circulating immune complexes of anti-HCV antibodies and viral components, often augmented by anti-immunoglobulin rheumatoid factors, have been detected in numerous studies; such complexes may lodge in the renal glomerulus and cause damage.,,,,,, HCV has also been shown to elicit autoimmune responses against several "self" antigens, in some cases by molecular mimicry; some of the resulting autoantibodies have known or suspected associations with renal disease., Hepatic injury caused by HCV has a variety of systemic consequences, including decreased clearance of circulating immune complexes, decreased synthetic function for numerous serum proteins, and hemodynamic perturbations, with known or potential consequences for the kidney. Therapeutic agents used for the treatment of HCV infection or to prevent rejection of hepatic or renal transplants can have toxic effects on the kidney. Although HCV has no documented tropism for the kidney, the virus could also conceivably cause damage by direct infection of renal tissue, a mechanism which has been proposed for HIV.
This communication reviews the current literature on renal manifestations of HCV infection, with particular emphasis on immune-complex glomerulonephritis (GN). Other forms of renal disease that have been reported in the context of HCV infection are also discussed, as are renal complications of drug therapies and transplantation. Biopsy findings in several of the more common glomerular disorders are illustrated. For additional information, the reader is directed to several previous reviews on the subject.,,
The glomerular disorder most frequently associated with HCV infection is membranoproliferative glomerulonephritis (MPGN) type I (also referred to occasionally as mesangiocapillary glomerulonephritis type I) ,,,,,,,,,, Patients with MPGN type I generally present with proteinuria (often with the nephrotic syndrome), microscopic hematuria, and varying degrees of renal insufficiency. A majority (up to 100% in some series) have evidence of circulating cryoglobulins, which are reportedly present in up to 50% of patients with HCV infection. , The cryoglobulins are almost invariably of the mixed type (type II or III), containing an anti-globulin rheumatoid factor (usually of the IgM class) directed against polyclonal IgG, though rare examples of MPGN type I associated with type I cryoglobulins (containing a single monoclonal paraprotein) have been reported.  As a result, tests for serum rheumatoid factors are often positive. Both type II mixed cryoglobulins (in which the rheumatoid factor is monoclonal, generally an IgMk) and type III mixed cryoglobulins (in which the rheumatoid factor is polyclonal) have been detected in patients with HCV infection, but virtually all patients with significant renal disease reportedly have cryoglobulins of the type II variety. ,,,,, Other forms of autoantibody, including anti-neutrophil cytoplasmic antibodies, anti-nuclear antibodies, and anti-microsomal antibodies, have been detected in patients with HCVassociated MPGN.  Hypocomplementemia, particularly involving early components of the classical pathway, is also common.
Light microscopic examination of renal biopsy tissue from patients with MPGN type I reveals extensive, generally diffuse, mesangial expansion and hypercellularity with capillary loop thickening and basement membrane reduplication, the latter best visualized on silver-stained sections [Figure - 1]A and B. These findings are due in part to proliferation of mesangial cells, some of which extend into capillary lumens and elaborate a new layer of basal lamina material ("mesangial cell interpositioning"). Some studies, however, have suggested that much of the observed glomerular hypercellularity is due to an influx of circulating macrophages.  Glomerular changes of a more acute nature, including neutrophil infiltrates, tuft necrosis, and cellular crescents, are encountered in a minority of cases. ,, Cryoglobulin deposits, when present, can occasionally be seen as large, hyaline, "thrombus-like" objects within capillary loops [Figure - 1]C. , Occasional patients have accompanying vasculitic changes involving small and medium-sized arteries. , Varying degrees of interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration are often present; dense interstitial lymphoid aggregates have been encountered in a few patients. 
Immunofluorescence microscopy generally reveals diffuse or segmental deposition of IgG, IgM, and complement components (particularly C3; [Figure - 1]D) along capillary loops. Since the monoclonal rheumatoid factor in type II cryoglobulins is generally of the IgMK class, immunostains for kappa and lambda light chains occasionally reveal a preponderance of the former in type II cryoglobulin deposits [Figure - 1]E and F. Other immunoreactants, including IgA, are variably present, and mesangial staining is occasionally seen.
By electron microscopy, subendothelial deposits of granular, electron-dense immune-complex material are seen in the majority of cases, sometimes accompanied by mesangial and/or intramembranous deposits. The subendothelial deposits are frequently associated with interposed mesangial cell processes and reduplicated basal lamina [Figure - 2]A.
Occasional biopsies also contain subepithelial deposits [Figure - 2]B, a combination referred to as "MPGN type III" by some authors. ,, Mixed cryoglobulins are classically described at the ultrastructural level as microtubular structures measuring 25-32 nm in diameter, often with a curved and/or paired configuration; deposits fitting this description are often encountered in patients with HCV-associated MPGN [Figure - 2]C and D. ,,, Many patients with clinical evidence of circulating cryoglobulins lack such microtubular deposits. Conversely, the deposits are occasionally seen in patients without demonstrable circulating cryoglobulins. 
Though some authors have argued, on statistical grounds, that no causal link exists between HCV infection and glomerular disorders, there is considerable circumstantial evidence supporting an etiologic association between the virus and MPGN type I/cryoglobulinemic glomerulonephritis.  Circulating immune complexes and cryoglobulins in patients with HCV-associated MPGN type I have been shown in a number of studies to contain HCV RNA and/or nucleocapsid proteins. ,,,,,, It has been suggested that HCV may induce formation of IgM rheumatoid factors by infecting and polyclonally activating B lymphocytes. 
Complexes of antibodies with HCV antigens may also activate rheumatoid factorproducing B lymphocytes by binding to their surface immunoglobulins.  One recent study has reported the presence of HCV proteins in glomerular deposits from patients with MPGN type I as assessed by immunohistochemistry with monoclonal antibodies. An etiologic link between HCV infection and MPGN type I is also suggested by the fact that treatment of the infection with interferon-α (IFN- α) has led in many cases to abatement of proteinuria and/or improvement in renal function.,,, Cessation of therapy is frequently associated with simultaneous recurrence of viremia and renal dysfunction.
Several studies have reported the development of membranous glomerulonephritis (MGN) in patients with HCV infection.,,,,, The clinical presentation in these patients has been similar to that of idiopathic MGN, usually with heavy proteinuria or the nephrotic syndrome. In contrast to patients with MPGN, individuals with HCVassociated MGN have been reported to lack circulating cryoglobulins and rheumatoid factors,,,, and hypocomplementemia is usually absent., The clinical course has been variable; therapy with steroids (with or without chlorambucil) or IFN- α has led to remission of proteinuria in some cases.,,
The biopsy features of MGN in patients with HCV infection are similar to those of idiopathic MGN. By light microscopy, diffuse thickening of capillary loop basement membranes is observed [Figure - 3]A, a consequence of subepithelial immunecomplex deposition accompanied by progressive deposition of reactive basal lamina. In later stages, irregularity of the basal lamina ("spike and dome pattern") can be seen on silver-stained sections [Figure - 3]B; the deposits can also sometimes be visualized on Masson's trichrome stain as epimembranous, fuchsinophilic globules [Figure - 3]C. Although glomerular cellularity is often normal, some authors have noted mild mesangial hypercellularity similar to that reported for other secondary forms of MGN.  Immunofluorescence microscopy typically shows granular capillary loop deposits containing IgG [Figure - 3]D and C3, occasionally with an admixture of other immunoreactants. By electron microscopy, granular, electron-dense, immune complex deposits are seen on the subepithelial faces of capillary loop basal lamina, accompanied as the disease progresses by increasing amounts of reactive basal lamina material [Figure - 3]E. The subendothelial deposits typical of MPGN are absent, although occasional mesangial deposits have been detected.  In the cases described to date, the deposits in MGN have lacked the microtubular substructure typical of mixed cryoglobulins.
The pathogenesis of HCV-associated MGN is unclear. Although a lack of statistical correlation between HCV seropositivity and MGN has been reported, the occasional improvement in MGN-related proteinuria with IFN- α antiviral therapy in HCV-infected patients suggests a possible etiologic link between HCV and MGN. , This possibility is supported by a study in which two patients with HCV-associated MGN were found to have circulating immune complexes containing HCV RNA and glomerular deposits containing HCV core protein.  HCV genomic material has also been detected in renal tissue from patients with MGN by reverse transcriptase polymerase chain reaction (RT-PCR).
A handful of studies have documented the development of IgA nephropathy (IgAN) in patients with HCV infection.,, Presenting signs and symptoms have been variable, including hematuria, proteinuria, and the nephrotic syndrome. Serologic findings have not been consistent, although serum cryoglobulins have been detected in one patient and elevated levels of serum IgA in another.,
The biopsy features of IgAN associated with HCV infection are similar to those encountered in other forms of IgAN. Light microscopy reveals mesangial expansion accompanied by varying degrees of mesangial hypercellularity. By immunofluorescence microscopy, mesangial deposits containing IgA and C3, often admixed with other immunoglobulins, are seen. The deposits frequently have a coarse-granular or clumped appearance. Mesangial, paramesangial, and occasionally subendothelial deposits of granular, electron-dense material are identified by electron microscopy.
The pathogenetic link between HCV infection and IgAN is uncertain. One autopsy study of IgAN in cirrhotic patients failed to demonstrate an association between HCV and IgAN, but cannot be viewed as conclusive, as it included only two HCV-positive patients. Cirrhosis, regardless of etiology, is thought to predispose to the development of IgAN via impaired hepatic clearance of circulating IgA-containing immune complexes, with consequent deposition of the complexes in the kidney ("cirrhotic glomerulopathy"). This mechanism has been invoked as an explanation for HCV-associated IgAN. Circulating immune complexes containing IgA and HCV antigens have not been reported. It should be noted, however, that circulating complexes of IgA and HIV antigens have been detected in a small number of patients with IgAN and the acquired immunodeficiency syndrome, suggesting that at least one RNA virus can play a direct role in the formation of IgA containing immune complexes.,
Other immune-complex glomerulonephritides
Renal biopsies from occasional patients with HCV infection have been interpreted as showing "acute proliferative and exudative GN" or "endocapillary GN"., It is not clear whether these patterns, often associated with post-infectious GN, represent variants of MPGN type I with unusually acute features or distinct entities. We have encountered one biopsy from an HCVinfected patient that showed features typical of post-infectious GN, including subepithelial "hump-like" immune complex deposits (D.N. Howell, unpublished observations). The GN in this patient, however, was most likely associated with an intercurrent bacterial infection rather than the underlying viral hepatitis.
A single patient with an otherwise unspecified mesangial proliferative GN arising in the setting of HCV infection and IgA deficiency has been described. The exact nature of the glomerular disease in this patient is unclear, but it was presumably not IgA nephropathy.
Fibrillary glomerulonephritis/immunotactoid glomerulopathy
A small number of patients with HCV infection have developed non-amyloidotic fibrillary glomerulopathies, including fibrillary glomerulonephritis and immunotactoid glomerulopathy., Both conditions involve mesangial and/or capillary loop deposition of non-congophilic fibrillary material containing IgG. In fibrillary glomerulonephritis, the fibrils measure ~20 nm, approximately twice the diameter of amyloid fibrils. In immunotactoid glomerulopathy, they are larger (30-50 nm) and often have a microtubular substructure. The ultrastructure of immunotactoids has substantial overlap with that of mixed cryoglobulins, and it has been suggested that immunotactoid glomerulopathy is, in some cases, an early form of cryoglobulinemia. , This supposition is of interest in view of the documented association of cryoglobulins with HCV infection. Cryoglobulins were detected in one of two reported patients with immunotactoid glomerulopathy in the setting of HCV infection, although they were described as being of low titer and inconsistently present. 
Other disorders without immune deposits
The development of focal and segmental glomerulosclerosis (FSGS) in patients with HCV infection has been described in several studies. ,, The clinical presentation, like that of idiopathic FSGS, has included the nephrotic syndrome accompanied by varying degrees of renal failure. In addition to segmental sclerosis of glomeruli, biopsies in several cases have shown tubulointerstitial inflammatory changes. , The immunofluorescence findings are generally limited to nonspecific localization of reactants (particularly IgM and C3) to sclerotic segments. Electron microscopy typically shows widespread disruption of visceral epithelial cell foot processes. The combination of segmental glomerulosclerosis and tubulointerstitial inflammation has been reported in patients with "heroin nephropathy," and five of six patients in the largest series of HCV-associated FSGS had a history of intravenous drug abuse, casting some doubt on the role of HCV in the pathogenesis of the glomerular disorder.  Of the other two reported cases, one was attributed by the authors to therapy with IFN-α, and the second occurred in a renal transplant recipient several decades following transplantation, a setting in which FSGS occasionally develops as a result of hyperfiltration., The association between HCV and FSGS is therefore somewhat speculative.
Thrombotic microangiopathy (TMA) has been described in occasional patients with HCV infection, including renal transplant recipients. , The biopsy findings in this disorder are similar to those in other forms of TMA, including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, and include thrombosis and fibrinoid change of small extraglomerular vessels and glomerular capillaries. Serum components, accumulated beneath damaged capillary endothelium, can often be visualized by electron microscopy as flocculent material expanding the lamina rara interna, and may potentiate dissolution of the adjacent mesangial matrix ("mesangiolysis"). The renal transplant recipients with TMA and HCV infection were all found to have anti-cardiolipin antibodies, which may potentiate TMA.  This finding is of particular interest in view of the known association of HCV infection with other forms of autoantibody.  It should be noted, however, that most (but not all) of the transplant recipients were being treated with cyclosporin A, a drug whose use is also occasionally associated with TMA. The ultrastructural findings in TMA also overlap to some extent with those of transplant glomerulopathies.
Several studies have documented an association between HCV infection and non-insulin-dependent diabetes mellitus, including one study of a Middle-Eastern patient cohort. ,, Development of diabetic nephropathy in the setting of HCV infection has been reported in two patients, both of whom had concurrent MPGN type I and/or cryoglobulinemic glomerulonephritis.  We have encountered four patients with HCV infection and diabetes whose renal biopsies showed changes consistent with diabetic nephropathy, with or without superimposed immune-complex GN (D.N. Howell, unpublished observations). The histologic features of diabetic nephropathy include diffuse and nodular glomerulosclerosis, usually without conspicuous hypercellularity [Figure - 4]A and hyaline arteriolar sclerosis; ultrastructural findings include diffuse thickening of capillary loop basement membranes and mesangial matrix expansion [Figure - 4]B. Biopsies from patients with chronic MPGN type I frequently show capillary loop thickening and lobular expansion with only limited hypercellularity, findings that could potentially be misinterpreted as diabetic changes. The potential etiologic link between HCV and diabetes is unclear. Though HCV infection is associated with development of a variety of autoimmune responses, there is currently no evidence for anti-islet autoimmunity in this setting.  In HCV-infected transplant recipients, steroid immunosuppressive therapy may contribute to the development of diabetes. 
Development of rapidly progressive, pauci-immune, crescentic GN has been described in one patient with HCV infection.  Serologic studies, including tests for cryoglobulins and anti-neutrophil cytoplasmic, anti-glomerular basement membrane, and anti-nuclear antibodies, were all negative. The relationship between the glomerular disease and viral hepatitis in this patient is unclear.
A final form of renal dysfunction encountered in occasional patients with HCV-induced cirrhosis is the hepatorenal syndrome. 70 The development of this condition appears to involve hemodynamic and/or toxic factors associated with hepatic failure; HCV plays no direct role in its pathogenesis. Renal biopsies are rarely performed in patients with hepatorenal syndrome. Histologic alterations are generally minimal, and in most cases are limited to the presence of occasional bile-stained tubular casts.
Renal manifestations associated with therapeutic agents
Drugs used in the treatment of HCV infection or for immunosuppression of transplant recipients have been associated in some instances with renal abnormalities. Drug-related renal disorders must be included in the differential diagnosis of renal dysfunction in patients with HCV infection, including HCV-infected transplant recipients. Several renal disorders, including acute renal failure, acute interstitial nephritis, , minimal change glomerulopathy,, and thrombotic microangiopathy (TMA) have been reported in patients undergoing therapy with IFN-α for hematopoietic malignancies. As mentioned above, FSGS has also been attributed anecdotally to IFN- α therapy for HCV infection.  In some cases, it has been unclear whether the renal dysfunction was a result of the therapy, the underlying disease process, or a combination of the two.
IFN- α can also stimulate the development of tubuloreticular inclusions (TRI); clusters of branched microtubular structures within the cytoplasm of affected cells., In renal tissue, TRI are most commonly detected in capillary endothelium [Figure - 5]A. Although they are occasionally encountered in a wide variety of renal disorders, and can be seen in untreated HCV-associated GN [Figure - 5]A, they are most prevalent and numerous in the setting of IFN-α therapy, HIV infection, or systemic lupus erythematosus. Though TRI have no known injurious effects on cells containing them, their presence in a patient undergoing therapy with IFN- α could conceivably lead to a misdiagnosis of HIV-associated renal disease or lupus nephritis.
Immunosuppression of transplant recipients with cyclosporin A or tacrolimus (FK506) is occasionally complicated by TMA [Figure - 5]B. As noted above, TMA has also been postulated to occur as an indirect consequence of HCV infection. The relative contributions of immunosuppressive drugs and HCV infection to the development of TMA in HCV-infected transplant recipients are unclear. Withdrawal of cyclosporin A or reduction in its dose has been advocated in this setting, but the clinical outcome has generally been unfavorable. 
Diagnosis of HCV-associated renal disease in the setting of renal transplantation is particularly complex. Many of the disorders discussed above, including MPGN type I, , MGN, , IgAN,  FSGS,  TMA,  and diabetes mellitus  have been reported to recur or occur de novo in HCV-infected renal transplant recipients. To this differential must be added the wide variety of renal and systemic disorders inherent to the transplant setting, including various forms of transplant rejection, drug toxicities, and opportunistic infections.
Several forms of allograft rejection, including acute and chronic vascular rejection and acute allograft glomerulopathy, have been reported to occur with increased frequency in HCV-seropositive renal transplant recipients. , Acute allograft glomerulopathy, typified by diffuse glomerular infiltrates of mononuclear inflammatory cells, endothelial cell injury with capillary lumen compromise, and mesangiolysis, has also been reported in HCV-seronegative recipients of kidneys from HCV-seropositive donors.  Chronic allograft glomerulopathy, whose features include expansion of the lamina rara interna by electron-lucent material and mesangial cell interpositioning, has been reported anecdotally in HCV-infected renal transplant recipients.  Since mesangial cell interpositioning is also a cardinal feature of MPGN type I, potential exists for confusion of these two disorders. The distinction rests primarily on the presence (in MPGN type I) or absence (in chronic allograft glomerulopathy) of immune-complex deposits as assessed by immunofluorescence or electron microscopy.
| Summary|| |
We have reviewed an array of renal diseases, most involving the glomerulus, which have been reported in association with HCV infection. For some of these disorders, particularly MPGN type I and cryoglobulinemic glomerulonephritis, there is considerable circumstantial evidence for an etiologic link, at least indirectly, between the viral infection and the renal injury. For many of the others, it could be argued that the reported cases represent chance associations of relatively common maladies rather than examples of causal linkage. Nonetheless, given the wide variety of renal abnormalities that have been reported in the context of HCV infection, we recommend that all HCV-infected patients with evidence of renal dysfunction receive a careful and thorough clinical evaluation, including renal biopsy where clinically feasible.
| Acknowledgments|| |
The authors are indebted to Ms. Susan Reeves and Mr. Steven Conlon for assistance with photomicroscopy and to Dr. Timothy Fields for critical review of the manuscript.
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David N Howell
Duke University Medical Center, Department of Pathology, Box 3712, Durham, North Carolina 27710
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5]