Department of Internal Medicine, Pathology, and General Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea Republic
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Abstract |
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Methods. From July 1994 to August 2000, seventeen HBsAg-positive patients (M:F=15:2) received renal allografts (13:4=living:cadaveric donors). Liver function tests at the time of transplantation were normal in all patients. Pre-transplant liver biopsies performed in 15 patients demonstrated minimal inflammatory histology, except in three patients showing pathological and clinical signs of active hepatitis. Lamivudine was started pre-operatively in these three subjects. Another seven patients were treated with lamivudine for post-operative hepatic dysfunction. The remaining seven patients did not develop hepatic dysfunction after transplantation.
Results. Lamivudine was initially effective in decreasing serum HBV DNA titres, and in normalizing hepatic enzymes. Lamivudine was well tolerated without significant side effects for 35.5±8.9 months after initiation of treatment. HBV DNA became negative in nine patients but remained positive in one patient. Among the nine patients with initial negative conversion of HBV DNA, two developed transient positive conversion of HBV DNA and two demonstrated persistent positive conversion. Among the patients with normal liver histology in the pre-transplant period, 41.6% (5/12) developed liver pathology progression after immunosuppression. All 17 patients had functioning grafts, except for one patient who developed relapsed IgA nephropathy.
Conclusions. Our data showed relatively favourable outcomes in hepatitis B-positive renal transplant recipients receiving lamivudine treatment, even though two patients developed lamivudine resistance.
Keywords: hepatitis B; lamivudine; liver biopsy; prognosis; renal transplantation
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Introduction |
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Antiviral therapies such as adenine arabinoside, acyclovir, and interferon- have been used to treat chronic hepatitis B [5]. To date, interferon-
may represent the best treatment option for the management of chronic hepatitis B. However, this treatment may not be safe in the setting of kidney transplantation because interferon-
therapy has been reported to cause deterioration of graft function [5,6].
Lamivudine, the (-) enantiomer of 3'-thiacytidine, is a potent inhibitor of HBV replication in patients with chronic HBV infection [7]. Successful results of lamivudine trials examining advanced and decompensated liver disease or recurring chronic hepatitis B after liver transplantation have been reported [7,8]. Lamivudine was also a safe and effective therapy for activated hepatitis B in renal transplant recipients in short-term follow-up [911]. It is likely that lamivudine therapy may produce more favourable outcomes for renal graft recipients with HBsAg.
In this study, we retrospectively investigated the outcome of renal graft recipients with HBsAg after lamivudine had become available. We also evaluated the usefulness of pre-transplant liver biopsy and serological viral markers, such as HBV DNA and HBeAg, in predicting the risk of liver dysfunction after renal transplantation.
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Subjects and methods |
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Thirteen patients received renal grafts from living related donors who were HBsAg-negative. The remaining four patients received renal grafts from HBsAg-positive cadaveric donors, which would have been abandoned if the patients and their families had not accepted the grafts. All patients were treated with cyclosporine A based triple immunosuppressants.
In our centre, the immunosuppressive protocol includes an initial maintenance of cyclosporine A trough levels at 250350 ng/ml (radioimmunoassay, Cyclo-Trac® SP-Whole blood, Diasorin, Monesota) up to 2 months post-operatively, followed by 200250 ng/ml during post-operative months 2 through 6. After 6 months, cyclosporine A levels were maintained at 150200 ng/ml for 1 year post-operatively, and thereafter were maintained at 100150 ng/ml. Methylprednisone was given 500 mg intravenously during the operation and was then tapered by 2.55.0 mg daily, from an initial 60 mg/day to 20 mg/day. Thereafter, prednisone was tapered more slowly. Azathioprine was given 5075 mg/day and was adjusted according to white blood cell count. In certain cases who developed hepatic dysfunction, cyclophosphamide was temporarily substituted for azathioprine. Monoclonal and polyclonal antibodies were not used for prophylactic therapy or antirejection therapy. Detailed clinical features are shown in Table 1.
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Liver biopsy
Hepatic pathology was scored by grade and stage, according to the method of Ludwig [12].
Statistics
Data are expressed as means±SD. Non-parametric tests (Wilcoxon signed rank test or Wilcoxon rank sum test and Fisher's exact test) were used to compare the values. Comparisons were considered statistically significant at P<0.05.
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Results |
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Group II
Fourteen patients were included in this group. Among these, seven patients maintained normal ALT levels up to the last follow-up (42.8±13.4 months, range: 1862 months, group IIa) (Table 3), but the remaining seven developed biochemical signs of hepatic dysfunction during follow-up (49.5±17.3 months, range: 2974 months, group IIb) (Table 4
). There was no difference in follow-up duration between groups IIa and IIb.
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In group IIb, HBV DNA was positive in all patients with deterioration of liver function. The titre of HBV DNA ranged from 72.5 pg/ml to >4000 pg/ml (Table 4). Four of seven patients were pre-core mutants (patients 11, 12, 13, 17). Post-transplant liver biopsies showed progressive changes in all patients. Mild to severe limiting plate necrosis and bridging necrosis were found, as well as periportal or septal fibrosis (Table 4
). Lamivudine was started at 100150 mg/day 631 months post-operatively. By three months after therapy, ALT levels decreased significantly from 147±103 to 34.7±6.9 IU/l (P<0.05), and at the end of follow-up, ALT was 47±59 IU/l in these seven patients. HBV DNA was undetectable 18 months later, except in one patient (patient 11) having a DNA titre that decreased from 1760 pg/ml to 4 pg/ml at 3 months after therapy. At the last follow-up, the titre increased to 139 pg/ml. After a negative conversion in patient 13, HBV DNA reappeared at 9 months after therapy due to non-compliance and his renal function declined to dialysis level because of biopsy confirmed-relapsed IgA nephropathy. Until haemodialysis, HBV DNA was persistently positive with elevations in ALT. In two other patients (patients 14, 15), HBV DNA became transiently positive due to non-compliance, but was restored to negative levels at 2 and 8 months after restarted lamivudine therapy. Lamivudine was well tolerated in all patients without significant side-effects during follow-up.
Renal functions in 17 patients
Four episodes of acute rejection were observed in three patients and they were treated with steroid pulse therapy. Among our seventeen patients, only one lost his graft because of relapsed IgA nephropathy and the remaining 16 patients maintained functioning grafts in the follow-up period of 44.2±14.5 months (range: 1874 months). The mean serum creatinine of the 16 patients was 1.3±0.4 mg/dl (range: 0.72.3 mg/dl). No patient died during follow-up.
Viral markers and liver histology
For the entire study period, HBsAg was persistently positive in 17 patients. Lamivudine therapy had no effect on the negative conversion of HBsAg. Four patients (patients 1, 6, 7, 15) received grafts from HBsAg-positive cadaveric donors and they were included in groups I, IIa, and IIb.
In cases of deteriorating liver function, HBV DNA was positive in each patient (10/10), and HBeAg was positive in 5/10 patients. These results were the same when compared with patients having normal ALT levels (group IIa). HBeAg and HBV DNA were positive in 5/7 patients in group IIa.
Among the 12 patients having normal to minimal inflammatory pre-transplant liver biopsies, five (patients 11, 12, 13, 14, 17) developed an aggravation of liver pathology at 623 months post-operatively. Pre-operative histology revealed positive HBsAg in 8/11 patients and positive HBcAg in 5/11 patients. Unfortunately, HBsAg and HBcAg were not available in one patient. In post-operative liver biopsies from the latter five patients, all showed positive HBsAg and HBcAg. When lamivudine was not given, fibrosing cholestatic hepatitis (grade/stage: 2/2) was found at 8 months post-operatively (patient 12), and liver cirrhosis (grade/stage: 4/4) was found at 23 months post-operatively (patient 17) despite a near normal pre-operative histology. In patient 15, a post-operative second liver biopsy showed fibrosing cholestatic hepatitis (grade/stage: 4/3), and diminishing liver function because of non-compliance. Interestingly, acute rejection developed post-operatively in patients 12 and 15. In these three patients, liver function stabilized and DNA was converted to negative after lamivudine therapy. Figures 1 and 2
show the clinical course of patients 12 and 15 with developing fibrosing cholestatic hepatitis.
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Discussion |
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In the present study, we experienced a similar incidence of liver disease progression: seven out of 14 HBsAg-positive patients developed clinical and pathological signs of active hepatic dysfunction. This occurred even though they showed normal to minimal inflammatory histology and/or normal liver function at the time of transplantation. These results suggest that HBsAg-positive renal transplant recipients have a significant risk of developing hepatic dysfunction. However, lamivudine treatment effectively controlled hepatic inflammation in the 7 HBsAg-positive patients (group IIb) and in the three patients showing active inflammation in pre-transplant liver biopsies (group I).
Although lamivudine effectively suppressed the replication of HBV, it was not effective in clearing the virus from our patients. HBV DNA was initially converted to negative after lamivudine therapy in all but one of our patients. Kletzmayr et al. [11] reported that HBV DNA was still positive in 20% of patients after 3 months of lamivudine treatment, and Rostaing et al. [9], using HBV DNA hybridization, found that one of six patients was persistently HBV DNA positive after 6 months of therapy. In the present study, HBV DNA titres decreased in one patient from 1760 pg/ml to 4 pg/ml after therapy, however, it gradually increased to 139 pg/ml at the last follow-up.
The presence of HBV DNA, HBeAg, or both prior to transplantation has been thought to be associated with increased mortality from liver disease [15]. However, in our study, among patients who maintained stable liver function part-operatively, nearly 70% of patients had positive pre-operative HBeAg and HBV DNA. Our data may, therefore, suggest that HBeAg and HBV DNA have no relationship to the later development or aggravation of hepatitis. These results are similar to those of Huang et al. [16], showing that the presence of HBV DNA did not correlate with the later development of chronic hepatitis. Both CD4+ and CD8+ T cell responses to viral antigens are important factors for hepatocyte damage caused by HBV [17]. The balance between helper T cells and cytotoxic T cells may be crucial for the regulation of liver injury and viral clearance. The important mechanism of hepatic cell damage involves the T cell response, and not merely the presence of replicating viral markers.
Rao et al. [1] argued that histological diagnosis may be a useful marker for predicting the course of chronic liver disease after renal transplantation. In our study, among the 12 patients with near normal initial liver biopsy, five (41.6%) developed clinical and pathological signs of progressive liver disease. Therefore, it is fair to state that normal to minimal inflammatory changes in pre-operative liver biopsy do not guarantee normal hepatic function after immunosuppression.
The emergence of HBV resistance to lamivudine remains a major concern during prolonged therapy [18,19]. A rebound in HBV DNA after initial suppression may be explained by non-compliance or lamivudine resistance [18]. In renal transplant recipients, the incidence of rebound was reported to be 15.7% or 30.8% [11,19]. The most resistant patients carried YMDD (tyrosine-methionine-aspartate-aspartate) mutations in viral replicate, which is the target of lamivudine. Therefore, a combination therapy including lamivudine plus another antiviral that prevents lamivudine resistance would be optimal for these patients. In the present study, HBV DNA was persistently positive in one patient. Two other patients developed resistance to lamivudine, and another two non-compliant patients developed a transient HBV DNA rebound. Although we did not perform genotype analysis, we believe that our population included YMDD mutations, a possibility that merits further investigation.
In the study by Dienstag et al. [7], HBV reactivation was observed in 71% of patients who discontinued lamivudine treatment. Fortunately, in the present study, liver function was relatively stable during continuous or resumed lamivudine therapy in patients with final rebound. Severe flare-up leading to fulminant hepatic failure, as reported by Peters et al. [20], was not observed in our study. Kletzmayr et al. [11] reported similar findings to our results. Although we postulate that HBV rebound does not always predict deteriorating liver function, larger prospective studies are needed to confirm this possibility.
Important issues regarding lamivudine introduction in renal transplant patients with HBsAg include whether the therapy should be started as prophylaxis or whether treatment should be continued on a lifelong basis.
In conclusion, careful pre-transplant evaluation of patients including liver biopsy and lamivudine therapy before or after transplantation may lead to favourable outcomes in HBsAg-positive renal transplant patients.
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Notes |
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Correspondence and offprint requests to: Su-Kil Park, MD, Department of Internal Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Song-Pa, PO Box 145, Seoul 138-736, Korea Republic. Email: skpark{at}www.amc.seoul.kr
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References |
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