Hepatitis-related Renal Disease

Kar Neng Lai


Future Virology. 2011;6(11):1361-1376. 

In This Article

HCV-related GN

Historical Perspective

In 1966, Meltzer and coworkers first described the clinical manifestations associated with 'mixed' cryoglobulinemia.[47] They described a clinical triad that consisted of palpable purpura, arthralgias and weakness plus variable degrees of GN, lymphadenopathy, and hepatosplenomegaly in some patients. Cryoglobulinemia in these patients had a 'mixed' composition of IgG and IgM rheumatoid factor (RF). The cause of this disease was entirely a mystery in those days, and its association with HCV infection only became increasingly apparent following its discovery in 1989.[48,49] It is now apparent that the classical clinical triad only occurs in a minority of patients. The most common manifestation is the markedly heterogeneous presentations of systemic vasculitis, with purpuric skin lesions that show leukocytoclastic vasculitis on biopsy being an almost constant and predominant feature of HCV virology.

HCV is a small RNA virus of the Flaviviridae family and has been recently classified as the sole member of the genus hepacivirus.[50] The virus is a small double-shelled virus consisting of a lipid envelope (E) with virally encoded glycoproteins (E1 and E2) and an inner nucleocapsid (core) that contains a positive-sense single-stranded RNA genome of 9,500 nucleotides. It has well-defined structural (core, E1 and E2) as well as several nonstructural (NS2–NS5) proteins. The nonstructural proteins encode several proteases, a virus-specific helicase and an RNA-dependent RNA polymerase responsible for replication of the genome. Six major genotypes based on sequence homology, and more than 50 subtypes, have emerged from the evolution of HCV.[51]


To date, WHO has estimated approximately 170–200 million individuals worldwide have chronic HCV infection.[52] HCV infection is not confined to the liver and a wide variety of extrahepatic disease manifestations have been reported. The exact prevalence of extrahepatic diseases is not known but HCV is definitely involved in nonhepatic pathological processes.

There are two immunologic features of HCV that may predispose patients to experiencing manifestations of extrahepatic disease. First, it is known that HCV evades immune elimination, leading to chronic infection and the accumulation of circulating immune complexes exemplified by MCGN associated with HCV infection. The second feature is that HCV stimulates production of monoclonal rheumatoid factors (mRF). This feature causes type II cryoglobulinemia that is responsible for most of the symptomatic cryoglobulinemic vasculitis. Despite its lower occurrence, one should note that extrahepatic involvement of chronic HCV infection is responsible for much of the increased morbidity and mortality accompanying the disease.

The prevalence of mixed cryoglobulinemia increases with the duration of the hepatitis infection. Chronic hepatitis C carriers with mixed cryoglobulinemia have an apparent duration of disease that is almost twice as long as those without cryoglobulinemia.[53] A high prevalence of mixed cryoglobulinemia (35–90%) has been reported for patients with HCV infection.[54,55] However, in assessing the prevalence of mixed cryoglobulinemia, it is important to realize that prevalence has not been determined in populations of unselected HCV-infected patients. Hence, reports of high prevalence of mixed cryoglobulinemia may represent a selection bias (e.g., studies on cirrhotic patients with long-standing HCV infection from gastroenterology centers). Overt symptomatic cryoglobulinemia occurs in 1% or less of patients, and is usually associated with high RF and cryoglobulin titers. The testing of unselected patients with cryoglobulinemia has revealed an anti-HCV antibody-positivity rate of up to 90%. While type I MCGN has been regarded as idiopathic for some time, chronic HCV infection is observed in a considerable proportion of patients. The exact proportion of patients with type I MCGN who are positive for anti-HCV antibody is unknown.

The most frequent form of renal involvement in HCV infection is MCGN, according to data from the USA and Japan.[56,57] The real prevalence of MCGN without detectable cryoglobulinemia is difficult to assess. Such cases might represent a subclinical form of cryoglobulinemia owing to a failure to detect circulating cryoglobulins due to technical issues in laboratory.[58] Furthermore, IgM antibodies with anti-IgG activity may induce immune complexes without cryoprecipitable properties.[58] Lastly, these patients may only develop detectable circulating cryoglobulinemia late in the course of the disease.[59]

Definition of Cryoglobinemia

Cryoglobulinemia is defined as the presence in serum of immunoglobulins that precipitate at reduced temperatures. Therefore, blood samples obtained from patients for detection of cryoglobulins must be stored and transported at 37°C.

Brouet et al. classified three types of cryoglobulins based on their immunoglobulin (Ig) composition.[60] Type I consists of a single monoclonal Ig without antibody activity, and can be found in patients with multiple myeloma, Waldenström's macroglobulinemia, or idiopathic monoclonal gammopathy. Types II and III, or mixed cryoglobulins, consist of polyclonal IgG and monoclonal IgMκ (type II) or polyclonal IgM (type III) with RF activity (Table 3). When no definite disease association is found, the condition is referred to as essential mixed cryoglobulinemia. The observation that up to 90% of unselected patients with cryoglobulinemia have anti-HCV antibody indicates that the disease is not genuinely 'essential', but more likely related to HCV infection. Hence, the term 'essential' may be a misnomer and can no longer be used for the majority of cases, where cryoglobulins consist of complexes of RF, IgG, anti-HCV antibody and HCV virions.[61] The pathogenesis of cryoglobulinemia due to HCV infection is not well understood, but it appears to be related to excessive proliferation of B cells as a result of the chronic antigenic stimulation of HCV infection.[62]

Clinical Findings

Symptoms & SignsHCV-related Cryoglobulinemia Full-blown symptomatic cryoglobulinemia occurs infrequently, and the typical symptoms are fatigue and palpable purpura, which histologically consists of leukocytoclastic vasculitis (with complexes of anti-HCV antibody and HCV in injured tissue). These lesions are usually found on the lower limbs, although they can occur anywhere, and represent small vessel vasculitis. A smaller proportion of patients have fever, arthritis, Raynaud's phenomenon and neuropathy. Peripheral neuropathy is usually characterized by paresthesias and variable degrees of motor deficit. Abdominal pain arises from mesenteric vasculitis, and may mimic an acute abdominal emergency during disease flare. Hepatosplenomegaly is due to chronic liver disease as a result of HCV. Cryoglobulinemia is more common in women than men and typically occurs after a prolonged period, often years or decades, of HCV infection. Although the course of illness tends to wax and wane, occasionally the systemic illness can be severe or even fulminant. For instance, nodular pulmonary infiltrates from deposition of cryoglobulins leading to respiratory failure, and non-Hodgkin's B-cell and splenic lymphomas have been reported to arise in the setting of cryoglobulinemia.[63] In addition, cryoglobulinemia has also been anecdotally reported in association with adenocarcinoma of the liver and stomach in Chinese individuals.[64]

Cryoglobulinemic GN The typical renal manifestation of HCV infection is MCGN type I, usually in the context of cryoglobulinemia.[56] Type II MCGN (e.g., dense deposit disease) has not been reported in association with HCV infection. MCGN associated with type II cryoglobulinemia is the predominant type of GN clinically associated with HCV infection in studies from Italy,[65] USA[66] and Japan.[57] The prevalence of MCGN in HCV-type II cryoglobulinemia is approximately 30%, yet the prevalence of anti-HCV antibody among patients with MCGN is much lower in Chinese populations.[67] MCGN also is occasionally observed in patients with hepatitis C in the absence of cryoglobulinemia.[56]

Renal disease is rare in children; the typical age of disease onset is 40–60 years old, following long-standing infection, and is often associated with mild subclinical liver disease. Patients may have other cryoglobulinemia symptoms, such as palpable purpura and arthralgias. Renal manifestations include nephrotic (20%) or non-nephrotic proteinuria and microscopic hematuria.[68] Acute nephritic syndrome is the presenting feature in 25% of cases. Progression to uremia is associated with male gender and old age. 50% of patients develop renal insufficiency, although this is frequently mild. Over 80% of patients have refractory hypertension at presentation, which may be a cause for the high rate of cardiovascular deaths.

The natural history of HCV-related cryoglobulinemia remains poorly defined. The clinical course can vary dramatically. The renal disease tends to have an indolent course without significant renal deterioration despite the persistence of urine abnormalities in the majority of patients. Around 15% of patients eventually require dialysis according to an Italian study.[69]

Laboratory Findings

The diagnosis of HCV-related MCGN is established by laboratory testing coupled with renal biopsy. Most patients are seropositive for anti-HCV antibody and HCV RNA. 70% have raised serum transaminase levels. Cryoglobulins are detected in 50–70% of patients. Serum electrophoresis and immunofixation reveals type II mixed cryoblobulins, in which the mRF, almost invariably an IgMκ, is a distinguishing feature of cryoglobulinemic GN. Their amount, usually measured as a cryocrit, varies from one patient to another, and varies from time to time in a given patient (ranging between 2% and 70%). It is common for urine κ light chains to be present. Clinical activity has little effect on the serum complement pattern, which is also discriminative. Low or even undetectable levels of the early complement components (C4 and C1q) and CH50 is characteristic, while the C3 level tends to remain normal or only slightly reduced.

Pathologic Findings

Renal histological evaluation typically shows evidence of immune complex deposition in glomeruli and changes in MCGN.[56] MCGN refers to a pattern of glomerular injury characterized by diffuse mesangial proliferation and thickening of the capillary wall, hence the synonym of membranoproliferative GN. In cryoglobulinemic MCGN, light microscopy reveals an increased number of mesangial cells, expansion of the mesangial matrix, and diffuse accentuation of glomerular tufts, which gives a lobular appearance to the glomeruli (Figure 2A). Glomerular capillary walls appear thickened because of the interposition of mesangial matrix between the GBM and the endothelium. Staining of the GBM with periodic acid-Schiff or silver stain shows splitting ('double contour') or 'tram-tracking' due to insertion of the mesangial matrix (Figure 2B). Immunofluorescence reveals granular deposits of C3 and IgG in the mesangium and in peripheral capillary loops (Figure 2C). A similar morphological appearance may be seen with infective endocarditis and infected ventriculoatrial shunts (shunt nephritis). In addition, glomerular capillaries may have marked inflammatory cell infiltrates with mononuclear cells and polymorphonuclear leukocytes, a distinguishing feature from noncryoglobulinemic MCGN. Intracapillary globular accumulations of eosinophilic material representing precipitated immune complexes or cryoglobulins may also be present. Viral HCV-containing antigens had been previously detected in glomerular structures using a three-stage indirect immunohistochemical monoclonal antibody technique,[70] but this was not confirmed by subsequent studies. Electron microscopy shows subendothelial deposits that may have a tactoid pattern, size, and distribution suggestive of cryoglobulin deposition. These tend to be of 15–30 µm in size, distinguishing them from the smaller fibrillary deposits (12–25 µm) (Figure 2D). The presence of immunotactoid GN in a viral disease confirms the association of immunotactoid GN with a systemic disease, while fibrillary GN is more frequently a 'primary' condition.[71] Fibrillogenesis may be favored by circulating paraproteins interacting with matrix proteins in the glomerulus, such as fibronectin.[72] The animal model of MCGN derived from induction of mixed cryoglobulinemia strongly suggests the pathogenetic role of cryoglobulin rather than a direct etiological role of HCV infection.[73] Of interest, however, and again in the animal model, both RF and cryoglobulinemic properties may be necessary for the development of skin vasculitis, but cryoglobulin activity alone is sufficient to induce glomerular lesions.[74]

Figure 2.

Pathology of cryoglobulin-related mesangiocapillary glomerulonephritis type 1. (A) Glomerulus exhibits diffuse increase in mesangial cellularity and matrix with accentuation of lobulation of tuft architecture, obliteration of capillary lumens and leukocytic infiltrate (hematoxylin and eosin stain, ×200). (B) Periodic acid-Schiff and methenamine silver staining reveals prominent double contours or tram-tracking (arrows) of glomerular basement membrane (×400). (C) Immunofluorescence reveals granular IgG deposits in mesangium and in peripheral capillary loops (×100). (D) Electron microscopy shows markedly increased glomerular cellularity and subendothelial deposits, indicative of cryoglobulin deposition. The thickened glomerular basement membrane also incorporates cell processes (arrowhead), indicative of mesangial interpositioning (×10,500).

Other uncommon forms of glomerular injury associated with HCV infection include membranous GN, IgA nephropathy, focal and segmental glomerulosclerosis, fibrillary GN, immunotactoid GN rapidly progressive GN, exudative–proliferative GN, and lupus nephritis.[75] Membranous nephropathy in HCV carriers is characterized by absence of cryoglobulin and male predominance.[76]


In general, two-stage therapy is considered: removal of cryoglobulins by plasmapheresis and the use of either corticosteroid/cytotoxic agent-mediated immune response attenuation or interferon/ribavirin-mediated viral replication suppression to inhibit their synthesis.

Before HCV and cryoglobulinemic MCGN were discovered to be associated, the mainstay of treatment was corticosteroid and cyclophosphamide. High dose pulse methylprednisolone (1 g/day for 3 consecutive days), followed by oral steroid, were used to control the systemic illness. Plasmapheresis may be applied to remove circulating cryoglobulins, thus preventing their deposition in glomeruli and blood vessel walls. Cyclophosphamide ameliorates the vasculitic injury and inhibits the production of mRFs by B-lymphocytes.[77]

Our current understanding of the association between mixed cryoglobulinemia and HCV infection has allowed a more rational approach to the treatment of this condition. Controlled trials reveal that antiviral therapy with IFN-α improves the systemic symptoms of immune complex disease.[78,79] However, post-therapy relapse occurs in a large proportion of patients, particularly when short-term interferon monotherapy is used. The introduction of combination therapy with IFN-α2b plus ribavirin was an important milestone in chronic hepatitis C treatment,[80] and for the treatment of acute hepatitis C after renal transplantation.[81] Such cocktail therapy has also produced favourable results in mixed cryoglobulinemia, although nonresponses and relapses after initial improvements still occur.[82] In some instances in which sustained viral eradication was unsuccessful, long-term maintenance interferon therapy has led to amelioration of disease. The introduction of pegylated forms of interferon (peginterferon) in the year 2000 represented another breakthrough in the treatment of chronic hepatitis C.[83] Pegylation refers to the covalent attachment of a large inert molecule of polyethylene glycol (PEG) to a protein to yield a molecule that retains biological activity, but has delayed absorption and clearance, allowing for weekly rather than daily or three-times weekly administration. Delayed clearance also led to greater, more potent and longer-lasting antiviral effects. Recent data on peginterferon and ribavirin combination therapy in treating HCV infection are encouraging.[84,85] Furthermore, the higher treatment failure rate of HCV carriers with genotype 1 is recognized.[86] A recent meta-analysis studying 11 clinical trials involving 225 patients revealed that antiviral therapy based on IFN-α can significantly decrease proteinuria and stabilize serum creatinine, and therefore, should be undertaken in patients with HCV-related GN. The improvement in protein excretion is greater in those who achieve HCV RNA clearance, a finding in line with a causal role for HCV in GN.[87]

Despite reports that antiviral therapy can occasionally be associated with a worsening of renal disease or variable response,[88,89] there are increasing numbers of observational studies suggesting the beneficial value of peginterferon and ribavirin combination therapy in treating HCV-related cryoglobulinemic MCGN. A drawback of this therapeutic approach is the complication of hemolysis in ribavirin therapy, especially for patients with renal impairment. This therapeutic issue has been resolved, however, taking glomerular filtration rate into account when determining dosage instead of basing it on body weight alone, as well as administering recombinant erythropoietin to overcome anemia.[90–92] Monitoring the serum ribavirin levels may reduce hemolytic complication, yet serum ribavirin level is not available in most clinical laboratories.[91] Post-treatment renal biopsy showed histological improvement in two of the three patients who received combination therapy for 12 months.[92] In another study in which the viral genotypes were documented, genotype 1 was again associated with a lower sustained VR rate even with combined IFN-α and ribavirin therapy.[93] In severe acute flares of cryoglobulinemia with GN or vasculitis, an appropriate approach is to include corticosteroids and cyclophosphamide as needed to control severe cryoglobulinemic symptoms in addition to combination antiviral therapy. In the most severe cases, plasmapheresis (three to four times weekly exchanges of 3 l of plasma for 2–3 weeks) can be helpful. For refractory cases, monoclonal antibody against the B-cell surface antigen CD20 (rituximab) has been reported to be efficacious with a favorable side-effect profile.[94]


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