Overview of kidney disease associated with hepatitis C virus infection

INTRODUCTION — There is a strong and likely causal association between chronic hepatitis C virus (HCV) infection and glomerular disease [1-5]. Several types of kidney disease have been recognized including mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy [6-12], and polyarteritis nodosa (PAN). Crescentic glomerulonephritis may be superimposed on any of these glomerular lesions.

Less commonly, other glomerular lesions have been reported in HCV-infected patients, including focal segmental glomerulosclerosis (FSGS) [13-15], proliferative glomerulonephritis [16-18], and fibrillary [19-21] and immunotactoid glomerulopathies [20]. In some patients, glomerular disease may be clinically silent [22,23]. (See 'Types of glomerular disease associated with hepatitis C infection' below.)

Glomerular diseases associated with HCV can also occur in kidney allografts. These issues are presented in detail elsewhere. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

This topic provides an overview of the kidney diseases associated with chronic HCV infection. The diagnosis of HCV infection, treatment of HCV infection in patients with kidney disease, and evaluation and management of HCV-associated kidney disease following kidney transplantation are discussed in other topics:

●(See "Screening and diagnosis of chronic hepatitis C virus infection".)

●(See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)

●(See "Hepatitis C infection in kidney transplant candidates and recipients".)

TYPES OF GLOMERULAR DISEASE ASSOCIATED WITH HEPATITIS C INFECTION — The major glomerular diseases associated with HCV infection include the following:

●Mixed cryoglobulinemia syndrome (see 'Mixed cryoglobulinemia syndrome' below)

●Membranous nephropathy (see 'Membranous nephropathy' below)

●Polyarteritis nodosa (PAN) (see 'Polyarteritis nodosa' below)

In addition to symptomatic kidney disease, clinically silent glomerular disease has been described in patients with HCV infection, primarily in those who have undergone liver transplantation for cirrhosis due to chronic HCV infection [22,23]. In a series of 48 such patients, 30 had a kidney biopsy during surgery; the remaining patients either did not consent or were considered at risk for complications from kidney biopsy [22]. The following findings were noted:

●Immune complex glomerulonephritis was present in 25, which was classified as membranoproliferative glomerulonephritis (MPGN) in 12, immunoglobulin A (IgA) nephropathy in 7, and mesangial glomerulonephritis in 6 patients.

●A clinical kidney abnormality (elevated serum creatinine, hematuria, and/or proteinuria) was noted in only 10 patients, most of whom had MPGN.

Posttransplant follow-up was not reported. Thus, the impact of clinically silent glomerular disease at the time of transplant upon kidney and other outcomes following liver transplantation is unknown. (See "Hepatitis C infection in kidney transplant candidates and recipients".)

Mixed cryoglobulinemia syndrome — Mixed cryoglobulinemia syndrome is a systemic vasculitis. Affected patients typically present with nonspecific systemic symptoms, palpable purpura, arthralgias, fever, kidney disease, neuropathy, and other manifestations [24]. The clinical manifestations of the kidney disease may include hematuria, proteinuria (which may be in the nephrotic range), and kidney function impairment. A detailed discussion of the kidney manifestations, including histologic findings, in patients with mixed cryoglobulinemia syndrome is presented elsewhere. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Kidney involvement'.)

Laboratory studies indicate the presence of hypocomplementemia and circulating cryoglobulins. The complement components, C3, C4, and C1q, are usually low; reductions in C4 are usually greater than reductions in C3. Cryoglobulins are most commonly type II, characterized by a polyclonal immunoglobulin G (IgG) and monoclonal immunoglobulin M (IgM) kappa rheumatoid factor directed against the Fc portion of IgG. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Most patients with mixed cryoglobulinemia syndrome have HCV infection, and there is strong evidence that HCV-containing immune complexes are directly involved in the pathogenesis of disease. HCV RNA and HCV IgG antigen-antibody complexes are highly concentrated in the cryoprecipitate. In addition, HCV antigens have been detected along the glomerular capillary walls and in the mesangium of patients with HCV-related glomerulonephritis, mainly in those with MPGN and positive HCV RNA. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Tissue biopsy in selected patients' and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Infections'.)

Although HCV infection is primarily associated with type II mixed cryoglobulinemia, it may also be responsible for some cases of type III mixed cryoglobulinemia. Type III cryoglobulinemia is characterized by circulating cryoglobulins comprised of polyclonal IgG and polyclonal IgM. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Terminology'.)

Histologic examination of kidney biopsies demonstrates glomerular infiltration by activated macrophages. The glomerular basement membrane shows double contours caused by the interposition of monocytes between the basement membrane and the endothelium. Subendothelial deposits of IgM, IgG, and complement components are observed by immunofluorescence and electron microscopy. Vasculitis of small renal arteries is sometimes present. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Tissue biopsy in selected patients'.)

Membranoproliferative glomerulonephritis without cryoglobulins — The association of HCV infection with MPGN type I in the absence of cryoglobulinemia is controversial. Although such patients have been described [13,25-27], most of these patients subsequently developed measurable cryoglobulins, although not necessarily in conjunction with extrarenal manifestations of cryoglobulinemia [6,10,18]. Circulating cryoglobulins are often difficult to detect, and cryoglobulinemia may be unrecognized in many patients. (See "Overview of cryoglobulins and cryoglobulinemia".)

Membranous nephropathy — It is not clear whether there is an association between membranous nephropathy and HCV infection. Several small studies have suggested that membranous nephropathy may be induced by chronic HCV infection, although the data are conflicting [6,10,13,26,28,29]. In one study, the prevalence of membranous nephropathy was significantly higher in HCV-positive compared with HCV-negative kidney transplant patients [30]. However, in another study of 19 patients with membranous nephropathy, only 1 (5 percent) had anti-HCV antibodies, which was not different than that observed in control patients with diabetic nephropathy [13].

Overall, these findings suggest but do not prove a possible role of HCV in the development of membranous nephropathy. However, in contrast to the findings in mixed cryoglobulinemia syndrome or MPGN, complement levels tend to be normal, and neither cryoglobulins nor rheumatoid factor is present in HCV-associated membranous nephropathy [28].

Polyarteritis nodosa — PAN is well described in patients with hepatitis B virus infection, but it also occurs in association with HCV in the absence of cryoglobulins [31-34]. In one series, among 161 patients with HCV-related vasculitis, 31 (19 percent) were diagnosed with PAN [34]. This disorder is called secondary PAN.

In a review of 78 cases, the onset of PAN occurred at a mean of two years after the diagnosis of HCV infection [32]. The patients had typical symptoms of PAN and necrotizing inflammation of medium or small arteries in biopsy specimens. Twenty-six percent of tested patients were also positive for hepatitis B surface antigen. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)'.)

Patients infected with HCV who develop PAN may have more severe systemic manifestations of vasculitis compared with those HCV patients who develop mixed cryoglobulinemia vasculitis. In the study cited above, compared with patients with HCV-related mixed cryoglobulinemia syndrome, patients with HCV-related PAN more commonly had fever, weight loss, hypertension, gastrointestinal tract involvement, severe mononeuropathy, and elevated C-reactive protein levels [34].

DIAGNOSIS — The association of HCV infection with the glomerular diseases discussed above suggests that all patients with mixed cryoglobulinemia syndrome, membranoproliferative glomerulonephritis (MPGN) type I, membranous nephropathy, and polyarteritis nodosa (PAN) should be evaluated for possible underlying HCV infection. (See "Screening and diagnosis of chronic hepatitis C virus infection" and "Glomerular disease: Evaluation and differential diagnosis in adults".)

In addition, HCV-infected patients should be evaluated for proteinuria, hematuria, hypertension, and a reduced glomerular filtration rate (GFR). Patients who are found to have kidney abnormalities should undergo testing for cryoglobulins, hypocomplementemia, and a positive rheumatoid factor. A kidney biopsy should be considered in the setting of significant proteinuria and/or impaired kidney function.

TREATMENT — Patients with kidney disease infected by HCV should be offered antiviral therapy. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Patient selection for treatment'.)

In general, patients with severe and progressive HCV-associated glomerulonephritis should undergo antiviral treatment. Most patients with less severe glomerular disease associated with HCV should also have antiviral therapy provided they do not have decompensated cirrhosis. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis", section on 'Hepatitis C infection'.)

In patients who are selected for antiviral therapy, the specific regimen depends upon the estimated glomerular filtration rate (eGFR). These issues are discussed elsewhere in detail. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment", section on 'Regimen selection and dosing'.)

In addition to antiviral therapy, patients with severe and progressive mixed cryoglobulinemia and polyarteritis nodosa (PAN) are frequently treated with immunosuppressive drugs. Specific immunosuppressive regimens and the timing of antiviral therapy in such patients are presented separately. (See "Mixed cryoglobulinemia syndrome: Treatment and prognosis" and "Treatment and prognosis of polyarteritis nodosa".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

SUMMARY

●There is a strong and likely causal association between chronic hepatitis C virus (HCV) infection and glomerular disease. (See 'Introduction' above.)

●The major glomerular diseases associated with HCV infection include the following (see 'Types of glomerular disease associated with hepatitis C infection' above):

•Mixed cryoglobulinemia syndrome (see 'Mixed cryoglobulinemia syndrome' above)

•Membranous nephropathy (see 'Membranous nephropathy' above)

•Polyarteritis nodosa (PAN) (see 'Polyarteritis nodosa' above)

●All patients with mixed cryoglobulinemia syndrome, membranoproliferative glomerulonephritis (MPGN) type I, membranous nephropathy, and PAN should be evaluated for possible underlying HCV infection. In addition, HCV-infected patients should be evaluated for proteinuria, hematuria, hypertension, and a reduced glomerular filtration rate (GFR). Patients who are found to have kidney abnormalities should undergo testing for cryoglobulins, hypocomplementemia, and a positive rheumatoid factor. A kidney biopsy should be considered in the setting of significant proteinuria and/or impaired kidney function. (See 'Diagnosis' above.)

●In general, patients with severe and progressive HCV-associated glomerulonephritis should undergo antiviral treatment. Most patients with less severe glomerular disease associated with HCV should also have antiviral therapy provided they do not have decompensated cirrhosis. In patients who are selected for antiviral therapy, the specific regimen depends upon the estimated GFR (eGFR). These issues are discussed elsewhere in detail. (See "Treatment of chronic hepatitis C infection in adults with kidney function impairment".)