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Management of Special Groups:
HCV in Patients with Renal Disease

Renal disease may be present in patients with HCV infection. In many cases, the renal disease is unrelated to HCV (eg, diabetic or hypertensive renal disease).

Several immunologically mediated extrahepatic syndromes that complicate HCV infection may be directly related to HCV infection. They include membranoproliferative glomerulonephritis (MPGN), membranous glomerulonephritis (MGN), essential mixed cryoglobulinemia, porphyria cutanea tarda, Mooren's corneal ulcer, and a lymphoproliferative disorder characterized by monoclonal gammopathy.¹²⁹ Although the link with HCV infection has not been demonstrated for all these extrahepatic manifestations, the association between HCV infection and renal disease is well established.¹²⁹

DIAGNOSIS

HCV infection is a risk factor for renal disease. Also, hemodialysis treatment of end-stage renal disease (ESRD) is associated with exposure to HCV.¹³⁰ Hepatitis C is the most common cause of liver disease among patients with ESRD who are dialysis dependent. The risk of transmission is probably lower with peritoneal dialysis as compared with hemodialysis. Although the exact prevalence of HCV in this patient population is unclear, data from a number of dialysis centers throughout the world suggest prevalence rates ranging between 2% and 60%.¹³¹¹³² Patients who contract HCV while on hemodialysis may be too immunosuppressed to develop anti-HCV antibodies, and testing may yield a false-negative result. Therefore, patients who have a history of hemodialysis should be considered for an HCV RNA assay rather than an EIA. Measurement of ALT will not be useful because ALT levels are lower in patients with ESRD.

The most common renal manifestations of HCV infection are MPGN and MGN.¹³³ These diseases are commonly seen in patients with cryoglobulinemia, although they sometimes occur without it. The diagnosis is made clinically and confirmed by kidney biopsy.
The most common presenting symptoms of MPGN are microscopic hematuria and proteinuria, and the most common presenting symptom of MGN is nephrotic syndrome. The pathophysiology of these manifestations is still unknown, but it probably includes the deposition of circulating immune complexes (containing HCV, rheumatoid factor, anti-HCV antibodies, and complement) in the mesangium and subendothelium, with subsequent complement activation and cellular immune response.

It has been suggested that patients with ESRD may have higher mortality if they are infected with HCV.¹³⁴ In these patients, the stage of liver disease usually cannot be determined without a liver biopsy, unless there are clear indications of portal hypertension (eg, hypersplenism, esophageal varices, porto-systemic encephalopathy). Furthermore, dialysis-dependent patients with HCV seem to have persistently normal liver enzyme levels, even in the presence of significant hepatic fibrosis. The issue of staging liver disease in these patients should be balanced against a theoretically increased risk of bleeding from liver biopsies.^135 136

TREATMENT

The management of renal disease associated with HCV, especially cryoglobulinemia, MPGN, and glomerulonephropathies, has been approached from two different directions: the treatment of the renal immunologic disease and the treatment of the hepatitis C.

Renal immunologic disease has been treated with corticosteroids and/or cyclophosphamide. In the acute setting, plasmapheresis has been used to rapidly decrease the cryoglobulinemia. The problem with this approach is that it does not address the liver disease; in fact, it sometimes hastens it.¹³⁷

The treatment of HCV infection in the setting of cryoglobulinemia is fraught with difficulty; it is usually noncurative, and HCV RNA reappears when therapy is discontinued.¹³⁸ However, treatment is usually effective in improving the renal manifestation of the HCV immunologic disease. Treatment is limited because the decreased renal clearance of ribavirin can worsen hematologic toxicity; in fact, ribavirin is contraindicated in patients whose creatinine clearance is less than 60 mL/min. Therefore, most of these patients should be treated with interferon monotherapy. Numerous small studies of thrice-weekly IFN therapy suggested sustained virologic response rates ranging from 15% to 70%. Additionally, treatment-related side effects seem to be common, requiring dose reduction or discontinuation of therapy.^139-142 Given the convenience of weekly dosing, it may be more appropriate to use PEG-IFN alfa-2a or -2b monotherapy. However, as renal function decreases, there is also less renal clearance of PEG-IFN alfa-2b (normally as much as 30% is eliminated via the renal route).

Patients with HCV infection and MPGN tend to experience recurrences of both conditions following liver transplantation, and they have lower survival rates than do HCV-infected patients who do not have a cryoglobulinemic syndrome or renal disease.

RENAL TRANSPLANTATION

Given the high prevalence of HCV in candidates for renal transplantation, a number of issues must be considered. First, despite normal liver enzyme levels, these patients may have significant liver disease or even cirrhosis. The presence of histologic cirrhosis may influence not only perioperative risks associated with renal transplantation but also the prognosis after transplantation. The use of immunosuppressive medications following renal transplantation usually leads to an elevation in HCV RNA circulating titers by an average of 1 log. Although this increased viral load does not affect fibrosis progression in all patients,¹⁴³ the unequal effect of immunosuppressive therapy on liver disease results in a worse outcome for some patients (but not all), and it reduces survival beginning in the second decade after kidney transplantation. In a study of kidney transplant recipients, Hanafusa et al reported that survival rates in anti-HCV antibody carriers and in an unexposed group were 91% and 93.7%, respectively, at 5 years, 83.7% and 88.9% at 10 years, and 63.9% and 87.9% at 20 years (Figure 10).¹⁴⁴ In this study, the mean patient age at the time of transplant was slightly less than 30 years, which suggests that the duration of HCV infection was less than 10 years.

Other data suggest that HCV-infected patients with ESRD who undergo renal transplantation live longer than those who stay on hemodialysis.¹⁴⁵ On the other hand, the presence of advanced liver disease at the time of kidney transplantation is associated with a reduction in post-transplant survival rates.¹⁴⁶ Patients with cirrhosis should not undergo renal transplantation unless they also receive a liver transplant.

The second important issue for patients undergoing renal transplantation relates to the treatment of HCV infection after transplantation. It is important to remember that transplant recipients receiving a tacrolimus- or cyclosporine-based immunosuppressive regimen may have some degree of renal insufficiency, complicating the use of ribavirin and putting these patients at a high risk for severe anemia. Additionally, IFN may initiate renal allograft rejection and, accordingly, is not often used in renal transplant recipients. Currently, it is prudent to consider treatment of these patients only in a protocol setting designed to establish the safety and efficacy of these regimens.^141 147