Diagnosis
Screening for HCV infection outside of the transplant setting is done using a serological assay that detects antibodies to HCV (anti-HCV). Current third- and fourth-generation anti-HCV enzyme-linked immunoassays (EIA) yield high sensitivity rates up to 100% in immunocompetent patients. However, the "serological window" between acute infection and the detection of specific antibodies takes an average of 8 weeks, and in immunocompromised patients, antibody production may be delayed or absent. Thus, false-negative anti-HCV tests in dialysis units with high HCV prevalence have been reported to be as high as 17.9%. To minimize the risk of nosocomial transmission, hemodialysis patients in high-prevalence units should be tested for HCV RNA directly.
After a positive anti-HCV test, HCV RNA testing should be performed (Figure 1). A positive result confirms infection, either acute (defined as the presence of HCV RNA for <6 months) or chronic (defined as persistence of HCV RNA >6 months). A negative result is considered as a resolved HCV infection (or a false-positive antibody test). Additionally, in the patient tested positive for HCV infection, determination of the genotype and the viral load is helpful to evaluate the likelihood of response and for monitoring of antiviral therapy. However, serial monitoring of viral load in the absence of treatment is not required as there are no demonstrable associations between HCV RNA levels and the severity of histological changes in the liver. The stage of liver disease should be evaluated as discussed below.
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Figure 1.
Algorithm for screening for HCV in patients on hemodialysis. EIA, enzyme-linked immunoassays; HCV, hepatitis C virus; NAT, nucleic acid amplification test; RIBA, recombinant immunoblot assay.
The Question of Occult HCV Infection
"Occult HCV infection," a new entity defined by detection of HCV RNA in peripheral blood mononuclear cells (PBMC) and/or hepatocytes in the absence of HCV RNA in serum, has been a matter of controversy. Detection of such an infection not uncovered by routine diagnostic methods may have potential deleterious consequences. Occult HCV infection was detected in PBMC in up to 45% of 103 anti-HCV- and HCV-RNA-negative hemodialysis patients with abnormal liver enzyme levels of unknown etiology. In contrast, no evidence of occult HCV infection was found in 26 formerly HCV-infected kidney recipients, who had eliminated HCV either spontaneously or after antiviral therapy while on dialysis, or in an HCV-seronegative kidney recipient of an HCV-infected living donor who had been successfully treated with antiviral therapy before nephrectomy.Our recent findings from the largest prevalence study to date in hemodialysis and kidney transplant patients that included >400 patients in each cohort also argue against a clinically relevant occult HCV infection. We found a very low prevalence (<1%) of occult HCV infection in PBMC in both groups of patients, not warranting routine screening for occult HCV infection in this setting.
Evaluation of Liver Disease
An interdisciplinary management by a nephrologist and a hepatologist is essential both before and after kidney transplantation. The evaluation of liver disease should start with a thorough history, physical examination, laboratory testing and an ultrasound for radiological signs of cirrhosis/portal hypertension. However, ultrasound only shows moderate sensitivity in detecting liver cirrhosis, and the level of transaminases may not reflect the severity of the liver disease or may be normal in cirrhosis. Studies have demonstrated that the prevalence of advanced fibrosis and cirrhosis on liver biopsy ranges from 10% up to 25% in kidney transplant candidates with HCV infection. Evaluation of the stage of liver disease before transplantation is important in determining the risk for liver-related complications after transplantation, and combined kidney and liver transplantation (CKLT) might be necessary in some cases. Therefore, liver biopsy is indicated to assess the extent of liver injury unless there are definite clinical, radiological and/or laboratory signs for cirrhosis/portal hypertension. However, there are no definite studies that have evaluated long-term posttransplant outcomes in HCV-infected kidney recipients with or without a pretransplant liver biopsy.
Percutaneous liver biopsy appears not to impose an increased risk in patients with end-stage renal disease (ESRD). To decrease the risk of bleeding, a transjugular instead of a percutaneous approach can be used. An additional benefit of a transjugular biopsy is that during this procedure, the hepatic venous pressure gradient (HVPG) can be measured in patients with suspected cirrhosis. Measurement of HVPG also provides important prognostic information in patients with compensated liver cirrhosis, with an HVPG ≥ 10 mmHg defining clinically significant portal hypertension.
Alternative noninvasive tests for the assessment of the fibrosis stage have been evaluated in patients with chronic hepatitis C. These include imaging tests, such as transient elastography (FibroScan™; Echosens, Paris, France) or blood-based tests, such as the FibroTest™ (Biopredictive, Houilles, France). Though these methods have been shown to be reliable for the diagnosis of cirrhosis, they are less accurate than liver biopsy in discriminating different fibrosis stages in the nontransplant setting. In HCV-infected kidney recipients, small studies comparing the performance of noninvasive tests to liver biopsies have shown inconsistent results. Before transplantation, the liver biopsy remains the gold standard, but after transplantation, serial transient elastography measurements may be relevant for surveillance of fibrosis progression, though this remains to be evaluated in further prospective studies.
Management of the HCV-infected Kidney Transplant Candidate
After initial evaluation of liver disease in the kidney transplant candidate, an individual decision has to be made when to rebiopsy a patient before kidney transplantation. The Kidney Disease Improving Outcomes (KDIGO) guidelines recommend to rebiopsy every 5 years with mild/moderate fibrosis in the baseline biopsy and every 3 years with advanced fibrosis, though this is not supported by prospective studies. At least a yearly evaluation (sonography, laboratory tests) should be done in patients with no cirrhosis. In patients with cirrhosis awaiting transplantation, an ultrasound should be performed at least every 6 months (with or without α-fetoprotein measurement) to exclude a hepatocellular carcinoma (HCC) and the surveillance of esophageal varices also should be done regularly by endoscopy, according to international guidelines.
All HCV-infected kidney transplant candidates should be evaluated for potential antiviral therapy before kidney transplantation. Viral eradication before transplant may not only lower the risk of progressive liver disease after transplantation, but also of HCV-associated extrahepatic complications.