Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection.

Fibrosing cholestatic hepatitis (FCH) has been described as a specific manifestation of hepatitis B virus (HBV) infection in liver allograft recipients characterized by a rapid progression to liver failure. Only sporadic cases have been reported in other immunocompromised groups infected with HBV and in a few transplant recipients with hepatitis C virus (HCV) infection. We present the occurrence of FCH in 4 HCV-infected renal transplant recipients within a series of 73 renal transplant recipients with HCV infection followed up closely serologically and with consecutive liver biopsies. All 4 patients received the triple-immunosuppressive regimen (azathioprine, cyclosporine A, methylprednisolone). The interval from transplantation to the appearance of liver dysfunction was 1 to 4 months and to histological diagnosis, 3 to 11 months. The biochemical profile was analogous to a progressive cholestatic syndrome in 3 patients, whereas the fourth patient had only slightly increased alanine aminotransferase and gamma-glutamyl transferase (gammaGT) levels. Liver histological examination showed the characteristic pattern of FCH in 2 patients, whereas the other 2 patients had changes compatible with an early stage. All patients were anti-HCV negative at the time of transplantation, whereas 2 patients, 1 with incomplete and 1with complete histological FCH features, seroconverted after 3 and 31 months, respectively. The patients were HCV RNA positive at the time of the first liver biopsy and showed high serum HCV RNA levels (14 to 58 x 10(6) Eq/mL, branched DNA). HCV genotype was 1b in 3 patients and 3a in 1 patient. After histological diagnosis, immunosuppression was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months posttransplantation, whereas the seroconverted patients showed marked improvement of their liver disease, which was histologically verified in 1 patient. In conclusion, FCH can occur in HCV-infected renal transplant recipients. It seems to develop as a complication of a recent HCV infection during the period of maximal immunosuppression and is associated with high HCV viremia levels. There are indications that drastic reduction of immunosuppression may have a beneficial effect on the outcome of the disease.     

The clinical outcome of hepatitis C virus antibody-positive renal allograft recipients.

In order to investigate the prevalence of antibody to hepatitis C virus (anti-HCV) in renal transplant patients, the evolution of anti-HCV status, and clinical outcome in anti-HCV-positive renal allograft recipients, we tested the sera from 120 renal transplant patients for anti-HCV. Thirty-eight patients were hepatitis B surface antigen (HBsAg)-positive. Two patients were anti-delta-positive. A total of 79 patients (65.8%) had at least one serum positive for anti-HCV. Anti-HCV positivity decreased after transplantation for more than 5 years (65.5% at transplantation versus 37.9%, 78.3 +/- 13.4 months later). Among those with positive anti-HCV, the HBsAg-positive group had significantly higher incidence of chronic hepatitis (50% vs. 25.5%, P = 0.026) and liver cirrhosis (21.4% vs. 0%, P = 0.001) than HBsAg-negative group. Among the 82 HBsAg-negative patients, the prevalence of anti-HCV was significantly higher in those with chronic hepatitis than in those without (86.7% vs. 56.7%, P = 0.027). We conclude from this study: (1) anti-HCV positivity is quite prevalent in renal transplant patients; (2) coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV) may lead to aggressive liver disease and cirrhosis; HCV infection alone has a more benign clinical outcome; and (3) HCV infection is an important cause of posttransplant chronic hepatitis in HBsAg-negative patients.     

Outcome of renal graft recipients with hepatitis C virus infection

Abstract  Hepatitis C virus (HCV) is a major cause of posttransplanta-tion chronic liver disease. The aim of this study was to evaluate the prevalence of HCV in renal transplant recipients and to investigate risk and prognostic factors. Of 427 renal transplants carried out between July 1983 and January 1993, we retrospectively studied 66 (15.5 %) HBsAg-negative patients with anti-HCV detected by enzyme-linked immunosorbent assay (ELISA) and recombinant immunoblot assay (RIBA). Patient and graft survivals were estimated. Anti-HCV positive patients had more time on hemodi-alysis and pretransplant blood transfusions ( P = 0.0001) than did the seronegative population. In a mean follow-up of 52.3 ± 27.7 months, 36 patients (54 %) had biochemical evidence of liver disease, predominantly with a persistently high pattern of serum alanine aminotransferase (ALT). Pretransplan-tation ALT elevation was associated ( P = 0.004) with chronic liver disease (CLD) in the graft recipient. None of the other variables studied predicted posttransplantation CLD. Liver failure occurred in two (3 %) and was the cause of death in one of the patients. Death occurred in eight significantly more aged ( P = 0.0001) patients, at 45.5 ± 28.8 months post-transplant. In 50 % of the cases, death was ascribed to sepsis. The biochemical pattern of HCV showed no predictive value for prognosis. The disease had no significant effect on the number of rejections or graft survival. The study revealed lower actuarial survival ( P = 0.004) for HCV-positive patients in comparison with the seronegative population.     

Recombinant {alpha}-interferon in renal allograft recipients with chronic hepatitis C

BACKGROUND.: Although chronic hepatitis C infection is one of the factorsthat can lead to morbidity and mortality in renal allograftrecipients, treatment procedures have not been well documented.Interferon treatment has been shown to be effective in the normalizationof biochemical hepatitis C and in the clearing of hepatitisC virus RNA. However, little is known concerning the efficacyand safety of interferon treatment in renal allograft recipientswith chronic hepatitis C. Interferon has also been accused ofincreasing renal allograft rejection. METHODS.: Recombinant -interferon in a dose of 4.5 million units threetimes per week was given to five renal-allograft recipientswith chronic hepatitis C for 6 months. Besides biochemical investigations,liver histopathologies before and after the treatment coursewere also studied. RESULTS.: Interferon treatment was effective in two of the patients, inanother two cases renal function deteriorated during the treatment.In the last case ALT increased again after cessation of interferontherapy. CONCLUSION.: We conclude that interferon seems to be moderately effectivein treating chronic hepatitis C in renal allograft recipients,but a risk of renal functional deterioration and rejection remains.     

Gamma-glutamyltransferase activity in chronic dialysis patients and renal transplant recipients with hepatitis C virus infection

The prevalences of chronic infection by hepatitis C virus (HCV) and its genotypes vary among countries and ethnic groups. Among patients with end-stage renal disease (ESRD) and transplant recipients, the evolution of hepatic disease seems atypical and has not been established. In this study we compared the prevalence and HCV genotypic distribution among Brazilian patients with ESRD on dialysis or with transplantations. Moreover, we sought to compare the behavior of biochemical markers of hepatic activity of HCV infection in both groups. We prospectively evaluated 87 ESRD patients on dialysis and 105 transplant patients. Blood samples were obtained to perform qualitative HCV-RNA, genotyping, and, periodically, serum levels of aminotransferases (ALT, AST), gamma-glutamyltransferase (GGT), alpha-fetoprotein (AFT), and albumin. The prevalence of HCV in ESRD patients was similar to recipients (19.5% vs 25.7%; P = NS) and the most frequent genotype was 1a. There was no difference in the mean values of ALT, GGT, AFT, and serum albumin between both groups with HCV infection. The mean values of aminotransferases were slightly elevated and a high frequency of patients evolved with persistently normal parameters. In contrast, the mean values of the GGT were 3 or 4 times above the reference limit and a greater frequency of patients evolved with values persistently elevated in the 2 groups. In conclusion, in the 2 groups the prevalence of HCV infection was elevated; the most frequent genotype was 1a. Among the biochemical parameters, GGT seemed to be useful as an indirect marker of liver disease.     

Outcome of renal allograft in Turkish patients with pretransplantation hepatitis C virus infection

BACKGROUND: The aim of the present study was to investigate the impact of hepatitis C virus (HCV) infection on the long-term survival of renal transplant recipients. METHODS: Outcomes and survivals among 325 patients who received renal allografts from July 1991 to September 2005 were compared between those known to have pretransplantation HCV infection (Group I, HCV+ group, n = 33) versus a matched cohort of those without this infection (Group II, HCV- control group, n = 33). Allograft performance, liver function, cholesterol, and glucose levels were determined both at transplantation and at a mean of postgrafting year 8. A one-way analysis of variance (ANOVA) statistical method was used for multivariate analysis. RESULTS: Thirty-three patients (10.15%, 19 women and 14 men) were positive for HCV antibody. The mean follow-up period was 8 years (range, 0.5-14 years). The mean survival rates were similar in Groups I and II (96.6% and, 100%, respectively). Although the allograft survival rate was lower in Group I (84.8% vs 90.9%), the rejection rate among the HCV- group was 6%; only 1 patient died of hepatic failure. In spite of a significant rise in both total and direct bilirubin values (P < .01) in both groups, we failed to observe an adverse effect on graft survival. A significant rise in the fasting glucose level was seen in both HCV+ and HCV- patients. CONCLUSIONS: Chronic HCV infection before transplantation did not have a significant impact on graft survival or mortality compared with noninfected patients.     

Clinical course of hepatitis C virus infection in renal transplant recipients

Patients with end-stage renal disease are at high risk for exposure to hepatitis C virus (HCV) infection. Although both viral replication and liver disease progression are accelerated after renal transplantation, the long-term impact of chronic HCV infection is unclear. Our aim was to analyze the course of HCV infection in renal transplant recipients and the effects of HCV reactivation on patient and graft survival. METHODS: We retrospectively examined the 21-year (1985-2006) data of 1274 renal transplant recipients, 43 of whom were anti-HCV positive at the time of transplantation. RESULTS: The mean posttransplant follow-up of 43 patients was 62.0 +/- 7.3 months. At the time of transplantation, HCV RNA was positive in 11 (25.6%) patients and negative in 32 (74.4%) patients. HCV reactivation was seen in 19 (45.2%) patients at a mean time of 20.8 +/- 5.7 months. In 31 (72%) patients, acute rejection occurred, whereas graft loss occurred in 10 (23%) patients. Three (7%) patients died. Among 43 patients, 22 (51.2%) were treated with interferon before transplantation. There was a statistically significant association between pretransplant interferon therapy and pretransplant HCVRNA level (P=.024), but no significant association of HCV reactivation and graft rejection, mortality, or kidney survival. CONCLUSION: HCV reactivation occurred in nearly half of the renal transplant recipients, mostly in the second year. Patient survival and graft survival were not affected by HCV reactivation. Anti-HCV positivity should not preclude chronic renal failure patients from renal transplantation.     

Natural history of hepatitis C virus infection in adult renal graft recipients

AIM: To study the natural history of hepatitis C virus infection in renal transplantation, 464 HbsAg negative patients were prospectively studied from 1989. METHODS: AntiHCV was tested by ELISA II and HCVRNA by Amplicor HCV RNA tests. RESULTS: Two hundred nine patients were antiHCV positive (C+). HCVRNA was confirmed in 89% of C+ patients. Compared with the 255 anti-HCV negative (C-), C+ had undergone longer periods of dialysis (P = .0001), were more transfused (P = .01), and included more retransplants (P = .002). Immunosuppression was azathioprine (AZA) plus steroids in 133 and cyclosporine (CsA) in 331 patients. Liver biopsy showed chronic active hepatitis in 50, cirrhosis in 8, and fibrosing cholestatic hepatitis in 2 patients. Histologic progression of liver disease was confirmed in 18 of 26 patients. The causes of death in 84 patients (51 C+ vs 33 C-) were cardiovascular disease in 49%, sepsis in 13%, liver failure in 14%, neoplasia in 21%, and hepatocarcinoma in 2%. The 14-year patient survival was 75% in C+ and 86% in C- (P = .002). By multivariate analysis, age (>40) (P = .001) and C+ (P = .019) correlated with a worse patient survival. If patients were stratified according to age (<40 vs > or =40), younger C+ patients had a lower survival probability (P = .03). The 14-year graft survival was 44% in C+ vs 60% in C- patients (P = .001) but pure graft survival was similar (68% in C+ vs 72% in C-) (P = .13). CONCLUSION: The presence of C+ significantly reduced both patient and graft survival in the long-term with liver failure being the second most frequent cause of death.     

Topical testosterone treatment for chronic allograft failure in liver transplant recipients with recurrent hepatitis C virus

INTRODUCTION: Liver transplant recipients with allograft failure due to recurrent hepatitis C virus (HCV) infection often develop marked muscle wasting and ascites prior to death and are denied repeat liver transplantation. We sought to determine whether topical testosterone therapy is associated with improved muscle mass and survival in patients with chronic allograft failure post-liver transplant. METHODS: We performed a retrospective review of liver transplant recipients with chronic allograft failure. Group 1 patients were treated for >6 months with testosterone gel 1%; group 2 patients were untreated. RESULTS: Fourteen patients were identified with stage 3 or 4 fibrosis, muscle wasting, and allograft failure due to recurrent HCV. Group 1 (n=9) patients had statistically significant improvement in albumin, testosterone, muscle strength, well-being, and MELD/CTP scores, while there was no improvement seen for any of these parameters in group 2 (n=5). There were no deaths in group 1, while four of five patients in group 2 died on average 84 days posttransplant. Adverse effects of testosterone treatment included lower extremity edema (which resolved upon dose adjustment), hypertension, and pruritus. CONCLUSIONS: Topical testosterone gel appears to increase muscle strength, stimulate albumin synthesis, and improve survival in patients with allograft failure post-liver transplant.     

Treatment of chronic hepatitis B and C with interferon-alpha in renal allograft recipients: preliminary results

Abstract We evaluated the effects of treatment with interferon (IFN) on liver disease and renal allograft function in ten immunosuppressed cadaver kidney recipients. Two females and eight males (mean age 39 years) with biopsy-proven chronic active hepatitis ( n = 8) or persistent hepatitis ( n = 2) and serum positive for hepatitis B surface antigen (HBsAg) and HBe antigen ( n = 5) or serum positive for anti-HCV antibodies ( n = 3) or serum positive for HBsAg, anti-HCV and anti-HDV antibodies ( n = 2) received 3 million units IFN thrice weekly of 6 months. All patients responded with a reduction in serum aminotransferase activity and in five of them liver function completely normalized. Three patients among five infected with HBV cleared HBeAg. During the follow-up period liver function remained stable in 9 patients after discontinuation of IFN therapy. Three patients lost their grafts due to rejection 1, 2, and 4 months after IFN therapy, respectively. In six patients renal function remained stable during and after IFN therapy. We conclude that in selected groups of renal allograft recipients IFN can be used safely and effectively for the treatment of chronic viral hepatitis.     

A prospective study of hepatitis C viremia in renal allograft recipients

In an attempt to study the impact of HCV viremia on renal transplant clinical course and outcome, we prospectively followed 133 HBsAg-negative end stage renal disease (ESRD) patients, in whom HCV-RNA-PCR results were available, from the pre- to post-transplant period. Eighty (60%) ESRD patients tested PCR-positive, of these, 12 (15%) were anti-HCV negative by second generation ELISA. The viremic patients had a longer time on dialysis (p < 0.001), received more blood units (p < 0.001) and had a higher frequency of pre-transplantation liver disease (p < 0.001). Further, 41% of PCR-positive patients gave a history of antischistosomal treatment compared with 23% of PCR-negative ones (p = 0.048). Recipients with and without HCV viremia were followed for a mean of 31.8 +/- 5.8 (range 6-42) months and 29.8 +/- 9 (range 6-41) months respectively, p = 0.14. While the prevalence of HCV viremia increased from 60 to 64% at the last follow-up, the anti-HCV seroprevalence decreased from 63 to 61%. PCR-positive patients had higher rates of both acute (p = 0.005) and chronic (p < 0.001) liver disease after transplantation compared with PCR-negative patients. However, none of our HCV RNA positive recipients developed a fulminant liver disease or hepatic failure until the last follow-up. Stepwise logistic regression analysis identified pre-transplant liver disease (Odds ratio = 2.4; p = 0.07) and a cumulative corticosteroid dose in excess of 15 g at the last follow-up (Odds ratio = 3; p = 0.03) as independent predictors of post-transplant hepatic dysfunction in PCR-positive patients. Azathioprine was discontinued due to hepatic dysfunction in a significantly (p = 0.005) higher proportion of viremic patients compared with the non-viremic ones. There were no significant differences between PCR-positive and -negative patients in terms of frequencies and individual causes of graft and patient losses. Our results demonstrate that HCV infection is extremely prevalent in Egyptian hemodialysis patients and is responsible for most hepatic dysfunctions after transplantation. Although HCV viremia did not negatively affect graft or patient outcome until 31 months post-transplantation, the authors would recommend that a viremic patient should have a liver biopsy before transplantation and be immunosuppressed with caution post-transplantation. A longer follow-up may be required to exclude increased rates of HCV-induced hepatic mortalities. Copyright Copyright 1999 S. Karger AG, Basel