Hepatitis in Renal Transplant Recipients K.P. Cheng and T.M. Chan
EPATITIS is an important cause of morbidity and mortality in long-term renal transplant recipients (RTR). It can occur following bacterial and fungal sepsis and from drug-induced hepatotoxicity but by far the most important cause of hepatitis in the long-term RTR is viral infection, especially with parentally transmitted viruses.
PREVALENCE OF HEPATOTROPIC VIRUS INFECTION AMONG RTR
The prevalence of parentally transmitted hepatotropic virus infection (HVI) varies in different centers and in different parts of the world. It correlates with the prevalence in the dialysis and the general population and with the selection bias of using organs from infected donors and accepting infected recipients for transplantation. With the adoption of effective procedures that reduce nosocomial exposure and with the availability of effective vaccines, the prevalence of hepatitis B virus (HBV) among RTR has been declining steadily over the last decades. This trend, however, is more obvious in the United States and Europe but less so in Asia. This is because of the high prevalence rate of HBV infection in the general population in Asia. With a declining prevalence of HBV infection, hepatitis C virus (HCV) has become the most prevalent HVI among RTR. In selected studies reported in the 1990s in which prevalences of both HBV and HCV among RTR area available, the rate varies from 4 to 32% for HBV and 6 to 49% for HCV. Hepatitis G (GBV-C) virus (HGV) is a recently identified parentally transmitted virus. It has a prevalence rate of between 44 to 55% and is therefore as common as HCV among RTR, but studies so far have failed to demonstrate a significant independent impact of HGV on liver biochemistry and histology and on patient or graft survival. Hepatitis D virus (HDV superinfection in HBV-infected RTR is uncommon and infrequently reported. DETECTION OF HVI IN RTR
Liver enzyme abnormality is an insensitive index of HVI in RTR because significant histologic abnormality may be present despite normal liver biochemistry. Measurement of viral antigens is now standard practice for detecting HBV infection, but no such assay is available for the detection of HCV, HDV, or HGV infection, the detection of which either relies on antibody assay or molecular assay for viral nucleic acids. Second or third generation enzyme-linked
immunosorbent assay (ELISA), preferably in combination with a recombinant immunoblot assay (RIBA), which measure antibodies against multiple recombinant HCV peptides are generally recommended for detecting HCV infection. Molecular techniques that detect viral nucleic acids include dot-blot hybridization, solution hybridization method, and polymerase chain reaction (PCR) in increasing order of sensitivity. Between 74 to 95% of anti-HCV positive RTR were also HCV-RNA positive by PCR, and all HBsAg positive RTR are HBV-DNA positive by PCR. Quantitative measurement of viral nucleic acids levels is useful for identifying the infectivity of donors and RTR and for monitoring of the response to treatment. IMPACT OF HVI IN RTR
There is now increasing evidence that HVI in RTR is associated with increased liver-related morbidity and mortality. The evidence is particularly strong for HBV1 and is increasing for HCV.2 It also appears that there is an increased incidence of infections among HVI patients. There is no consistent data on the effect of HVI on the incidence of rejection episodes. An increased incidence of de novo glomerulonephritis (GN) including membranoproliferative GN, membranous GN, transplant GN, and most recently renal thrombotic microangiopathy have been reported among HCV-infected patients. Despite these negative impacts, controversy still exists on whether HVI affects patient or graft survival. The reason for this is likely to be due to heterogeneity with regard to viral infectivity and liver disease activity of the patient populations under study and the “quality and completeness” of the studies. Of note is a recent single-center study by Mathurin et al3 that retrospectively and prospectively compared the 10-year outcome of 128 HBsAg-positive and 216 anti-HCV-positive patients with a control population matched for age, sex, year of transplantation, and immunosuppressive regimes. They showed that compared to control, patient survival was decreased in both HBV- and HCV-infected RTR, that on multivariant analysis HBV and HCV infection were independent risk factors for patient survival in the respective From the Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Pokfulam, Hong Kong. Address reprint requests to Room 904, Takshing House, 20 Des Voeux Road Central, Hong Kong.
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populations, and that liver-related death mainly accounted for the decrease in patient survival.
PREVENTION OF HVI AND HEPATITIS IN RTR
As the majority of parentally transmitted HVI are acquired during dialysis prior to transplantation, measures that reduce exposure during dialysis are an important first step in preventing HVI in RTR. Before a patient is considered for transplantation, detailed clinical, biochemical, and virologic workup, including measurement of serum nucleic acid levels, must be performed. All HBV- or HCV-infected patients should preferably have a pretransplant liver biopsy done. All dialysis patients on the waiting list for transplantation who are not immune should be vaccinated against HVI as this infection, if acquired posttransplant, is associated with a worse prognosis. Dialysis patients with active HBV or HCV infection may be considered for antiviral therapy. Interferon-␣ (IFN-␣) has been shown to induce 20 to 30% sustained remission in dialysis patients, but its use is associated with a high incidence of side effects.4 Lamivudine, a nucleoside analogue, is highly effective in HBV clearance and is relatively free from side effects. It has been shown to prevent recurrent HBV following liver transplantation, but its prophylactic use in RTR is hampered by the incremental emergence of mutant strains with increased treatment duration. Therefore, at present, prophylactic antiviral therapy can only be considered in the living donor transplant setting where the timing of transplant and prophylactic antiviral therapy can be planned. At the time of transplantation, matching of donor and recipient viral status would reduce the chance of disease transmission through the transplant organs, and this has been firmly established in HBV and to a lesser extent in HCV because of the greater difficulty in matching different strains of this virus between recipient-donor pairs. While most transplant physicians would agree not to transplant a kidney from an infected donor to a nonimmune recipient, recent evidence suggests that it may be safe to transplant a kidney from a healthy HBV carrier to an immune recipient5 or from an anti-HBc-positive donor to an anti-HBc-negative individual. Since reactivation of replication of HVI occurs following immunosuppression therapy and patients who become chronic carriers of these viruses are likely to be low immune responders, it is logical to use immunosuppressive therapy judiciously in these patients.
TREATMENT OF HVI IN RTR
Currently, there are two main types of antiviral therapy for HVI in RTR: IFN-␣ and nucleoside analogues. In RTR, IFN-␣ activates the expression of major histocompatibility complex antigens in the graft and may induce acute rejection. In the study by Rostaing, a nonsustained virologic and
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biochemical response to treatment was obtained, but 5 of 14 treated patients developed acute renal failure. Of them, only two were responsive to pulse steroid treatment.6 Most nucleoside analogues, not being immune modulators, are free of such a side effect. A number of nucleoside analogues have been shown to be effective for the treatment of HBV and HCV infection in non-RTR, and these include ribavirin, vidarabine, famciclovir, and lamivudine. In RTR with chronic HBV hepatitis, the most promising is lamivudine, which is highly effective against HBV when given orally and is relatively free of side effects. This has been confirmed in RTR in two recent short-term pilot studies.7,8 In a longterm study of 23 patients over a median of 22 (2–33) months, we observed that HBV-DNA decreased to below detection limit by solution hybridization assay in all patients. One of eight patients had HBe conversion and none had HBs conversion. Liver enzyme normalized in 12 of 13 patients with abnormal baseline values, but 8 of 22 surviving patients developed the YMDD mutation, which confers partial drug resistance. In RTR with chronic HCV hepatitis, a recent pilot study on seven patients has shown that ribavirin normalized liver enzymes and reduced HCV-RNA in four patients but anaemia and haemolysis limited the daily dose to 400 to 800 mg.9 To increase the efficacy of treatment and to prevent the emergence of drug-resistant mutants without increasing the side effects, combination therapy is emerging and holds promise as the future antiviral therapy in RTR. One such combination is IFN-␣ and ribavirin, which has recently been shown to be highly effective in treating recurrent HCV hepatitis in liver transplant recipients. Another strategy that would improve the efficacy of treatment is to use a preemptive approach as in both HBV and HCV, one of the predictors of response to treatment is low baseline viral load. In this approach, serum viral nucleic acid level is regularly monitored, and treatment is started when the level shows a rising trend. We observed that a rapid rise of HBV-DNA predicts and predates the onset of fulminating or subfulminating hepatitis,10 while others have shown that an increasing HBVDNA level more frequently occurs with the development of chronic active hepatitis. The development of fulminating or subfulminating hepatitis in a RTR is an ominous sign and implies imminent death without a liver transplantation. In recent years, a subfulminating form of hepatitis, known as fibrosing cholestatic hepatitis, has been increasingly reported in RTR. This form of hepatitis is uniquely observed in immunosuppressed patients and may occur with HBV and HVC infection. The clinical picture is dominated by severe cholestasis with rapid evolution into hepatic failure, and the histologic picture is characterized by periportal fibrosis, cell ballooning, cholestasis, and relatively mild inflammatory infiltrate. Liver damage in this condition is thought to be due to massive accumulation of viral protein in the hepatocytes rather than to the host immune response. It is important to recognize this condition because we and
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others have shown that this condition shows a good response to viral therapy if timely treatment is instituted.11,12
6. Rostaing L, Izopet J, Baron E, et al: Transplantation 59:426, 1995
8. Jung YO, Lee YS, Yang WS, et al: Transplantation 66:733, 1998
1. Huang CC: J Gastroenterol Hepatol 12(suppl):S236, 1997 2. Vosanides GG: Kidney Int 52:843, 1997 3. Mathurin P, Mouquet C, Poynard T, et al: Hepatology 29:257, 1999 4. Chan TM, Wu PC, Lau JYN, et al: Nephrol Dial Transplant 12:1414, 1997 5. Cheng IKP: Transplant Proc 24:2435, 1993
7. Rostaing L, Henry S, Cistern J-M, et al: Transplantation 64:1624, 1997
9. Garnier J-L, Chevallier P, Dubernard J-M, et al: Transplant Proc 29:783, 1997 10. Cheng IKP, Ho SKN, Fang GX, et al: Transplant Proc 28:1493, 1996 11. Chan TM, Wu PC, Li FK, et al: Gastroenterology 115:177, 1998 12. Toth CM, Pascual M, Chung RT, et al: Transplantation 66:1254, 1998