Impaired kidney transplant survival in patients with antibodies to hepatitis C virus.

BACKGROUND: With a few exceptions, most published studies do not show an influence of antibodies to the hepatitis C virus (HCV) on the success of a kidney transplant. METHODS: We studied all our renal transplant recipients who had received kidneys from cadaver donors (n = 335) and had been treated with quadruple immunosuppression (steroids, azathioprine, and antilymphocyte antibodies, followed by cyclosporin). We had information on the status of the hepatitis C antibodies before and/or after the transplant in 320 cases (95.5%; in 300, pre-transplant). Patients with HCV antibodies before and/or after the transplant were considered to be HCV positive (HCV+). RESULTS: The HCV+ patients had more time in dialysis and a greater number of transfusions, hyperimmunized cases, and re-transplants. The evolution in the first post-transplant year was similar in both groups, but afterwards, the HCV+ patients had proteinuria more often as well as worse kidney function. The survival rate of the graft was significantly less in the HCV+ cases: 90.6, 68.3 and 51.0% at respectively 1, 5 and 10 years, compared with 91.5, 84.7 and 66.5% in HCV-patients (P<0.01). The patient survival rate was: 96.4, 87.0, and 71.9% in the HCV+ patients at 1, 5, and 10 years, compared with 98.2, 96.0 and 90.0% in the HCV- cases respectively (P<0.01). The differences remained the same in stratified studies according to time spent in dialysis or pre/post-transplant evolution of HCV antibodies, even when immunologically high-risk patients were excluded. In multivariant analysis, the presence of HCV antibodies acted as a independent prognostic factor for the survival of the kidney and the patient: 3.0 (1.8-5.0) and 3.1 (1.2-7.8) odds-ratio (95% of the confidence interval), respectively. The main cause of death among HCV+ patients was cardiovascular; there was no apparent increase in mortality rate due to infections or chronic liver disease. The loss of organs was mainly due to chronic nephropathy or death with a functioning kidney. CONCLUSION: The presence of hepatitis C antibodies, before or after transplantation, is associated with a worse long-term survival rate for both the patient and the transplanted kidney in our patients treated with quadruple therapy.     

Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience

Jain A, Sharma R, Ryan C, Safadjou S, Kashyap R, Mantry P, Maliakkal B, Orloff M. Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience.
Clin Transplant 2010: 24: 104–111. © 2009 John Wiley & Sons A/S.   Abstract: 
Introduction:  Recurrence of hepatitis C virus (HCV) in hepatic allograft is a major concern after successful liver transplant (LTx).
Aim:  To examine the response rate to pegylated interferon (PEG–IFN) and ribavirin in post-LTx patients with HCV recurrence.
Patients and methods:  Between January 2003 and September 2006, 60 patients with biopsy proven HCV recurrence (46 males and 14 females) received PEG–IFN 2a (n = 40) or IFN 2b (n = 20) with ribavirin. All patients were followed until July 2007.
Results:  Fourteen patients (23.3%) tolerated antiviral therapy for less than six months and 10 (16.7%) discontinued therapy between six and 11 months. PEG–IFN dose was reduced in 21 (35%) patients and ribavirin dose was reduced in 16 (26.7%) patients. Overall, 55% patients achieved end of treatment response (EOT) and 35% sustained virological response (SVR). Mean Hepatitis Activity Index and Fibrosis Score pre-therapy was 5.8 ± 1.9 and 1.7 ± 1.3 and post-therapy, it was 4.4 ± 2.1 and 2.4 ± 1.6, respectively. Overall, three yr patient and graft survival was 73.9% and 69.2%, respectively. The patients with SVR had significantly lower viral load compared with other groups (p = 0.028).
Conclusion:  PEG–IFN and ribavirin therapy achieved 55% EOT and 35% SVR; 60% patients tolerated therapy. Biochemical response was observed in all groups of patients irrespective of virological response.     

Pegylated interferon-α-based treatment for chronic hepatitis C in renal transplant recipients: an open pilot study

Treatment of hepatitis C in renal transplant recipients remains a controversial issue, as interferon therapy has been associated with a high risk of rejection and poor efficacy. We report here the use of pegylated interferon-α, alone or in combination with ribavirin, in renal transplant recipients with chronic hepatitis C. Eight renal transplant recipients with chronic hepatitis C were recruited. The mean delay between renal transplantation and antiviral therapy was 198.8 months. Sustained virological response was observed in four of out eight patients. Three patients with sustained virological response were genotype 2, one was genotype 1; fibrosis stages were F1 for one patient, F2 for 2, F3 for one. At baseline, renal dysfunction was moderate in seven patients and severe in one patient. No patient experienced rejection episodes during or after pegylated interferon-α therapy. One patient developed haemolytic uraemic syndrome, which eventually resulted in graft loss and return to dialysis. In conclusion, for renal transplant recipients treated with pegylated interferon-α-based therapy, we observed a low risk of renal dysfunction, acceptable tolerance and significant virological efficacy. This is therefore the first study to suggest that pegylated interferon-α could be proposed late after transplantation to renal transplant recipients.     

Pilot study of pegylated interferon-alpha 2a in dialysis patients with chronic hepatitis C virus infection

AIM: Pegylated interferon (PEG-IFN) combined with ribavirin is recommended for the treatment of chronic hepatitis C virus (HCV) infection in patients without renal failure. The optimal treatment of hepatitis C in dialysis patients remains to be established. A high incidence of adverse effects has been observed with conventional interferon and PEG-IFN alpha-2b in dialysis patients. METHODS: We conducted a prospective study to investigate the tolerability and efficacy of PEG-IFN alpha-2a (135 microg weekly for 48 weeks) in six dialysis patients with chronic HCV infection. RESULTS: Two patients completed 48 weeks of treatment. Treatment was stopped in three patients (beyond 24 weeks) when they developed unrelated complications, and stopped in one patient due to failure of viral clearance. None required treatment discontinuation due to adverse effects, and PEG-IFN alpha-2a was subjectively well tolerated. Marrow suppression with mild anaemia, leucopenia, or thrombocytopenia remained common. Two patients (infected with genotypes 3a and 1b, respectively) had sustained virological response. CONCLUSIONS: Results from this pilot study showed that PEG-IFN alpha-2a appeared relatively well tolerated in dialysis patients with chronic HCV infection, and about one-third of patients could achieve sustained virological response.     

Chronic liver disease in kidney recipients with hepatitis C virus infection

BACKGROUND: The prevalence of anti-hepatitis C virus (HCV) positive test is higher among patients in dialysis and in kidney recipients than in general population. Hepatitis C virus infection is the main cause of chronic liver disease in renal transplant patients. Liver biopsy and virological analysis were performed to clarify the grade of liver damage in kidney recipients. METHODS: Renal recipients patients with at least 5 yr under immunosuppression were submitted to clinical and laboratory analysis. Patients who tested anti-HCV positive were candidates to liver biopsy with no regard to transaminase levels. RESULTS: Forty-five patients tested anti-HCV positive and 42 anti-HCV negative. Twenty-six anti-HCV and RNA-HCV positive patients were submitted to liver biopsy. Seventy-three percentage of these patients presented chronic active hepatitis, from these only one patient presented cirrhosis. Only 29% of the anti-HCV positive group presented elevated alanine aminotransferase levels. Anti-HCV positive patients presented longer previous time on dialysis and less rejection episodes than the group anti-HCV negative (p < 0.05). All anti-HCV positive patients but one tested RNA-HCV positive by polymerase chain reaction (PCR). CONCLUSIONS: In this series the prevalence of anti-HCV positive is 51.7%. Most of the patients presented liver damage in histology caused by HCV. However, we found only mild or minimal fibrosis and inflammatory activity grade, despite 10 yr of HCV infection and 5 yr of immunosuppressive treatment. Only one patient presented cirrhosis (4%). Performing serial liver biopsies in a long-term follow-up is needed to clarify the impact of HCV infection in renal transplant patients.     

Comparison of liver stiffness, fibrotest and liver biopsy for assessment of liver fibrosis in kidney-transplant patients with chronic viral hepatitis

To assess the accuracy of the noninvasive tools, fibrotest (FT) and liver stiffness measurement (LSM) for assessing liver fibrosis in kidney-transplant patients with chronic hepatitis virus B (HBV) or C (HCV) infection. Thirty-eight consecutive kidney-transplant patients with HCV ( n  =   26) or HBV ( n  =   12) underwent liver biopsies followed by a FT and LSM. Liver biopsies gave the following fibrosis-grade distribution using METAVIR scores: F0/F1, n  =   10 (26.9%); F2, n  =   14 (36.8%), F3, n  =   7 (18.42%); F4, n  =   7 (18.4%). The area under the receiver-operating characteristic curve for mild fibrosis stage 相似文献   

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.     

Longer survival of liver transplant recipients with hepatitis virus coinfections

Hepatitis virus coinfections [HBV plus HCV coinfection (HBV/HCV) or HBV plus HDV coinfection (HBV/HDV)] may progress more rapidly to cirrhosis than hepatitis B or C monoinfections in immunocompetent patients. Only limited information is available on the outcome of coinfected patients after liver transplantation. We studied survival rates of 204 patients with viral hepatitis transplanted at our center between 1972 and 1997. HBV/HDV and HBV/HCV coinfections were present in 23 and nine individuals, respectively, while 97 patients had monoinfection by HCV and 75 had HBV monoinfection. Survival of coinfected patients was significantly longer than that of monoinfected patients (14.4 +/- 0.9 vs. 8.5 +/- 0.6 yr; p = 0.0003). The same was true for graft survival (p = 0.0002). In Cox's regression, viral coinfection (p = 0.0001), absence of hepatocellular carcinoma (HCC) (p = 0.00001) and no retransplantation (p = 0.02) were independently associated with patient survival. After exclusion of patients with HCC (n = 62), survival of coinfected patients was still significantly longer than that of monoinfected individuals (p = 0.002). The improved outcome was similar for both HBV/HDV and HBV/HCV coinfections. In contrast to immunocompetent patients, individuals with multiple hepatitis virus infections had an improved outcome after liver transplantation. Thus, viral coinfections may be associated with ameliorated courses of diseases under certain conditions.     

Liver,simultaneous liver-kidney,and kidney transplantation from hepatitis C-positive donors in hepatitis C-negative recipients: A single-center study

Transplantation of organs from hepatitis C virus (HCV)-antibody (Ab) and -nucleic acid test (NAT) positive donors into HCV-negative recipients has been proposed to expand the donor pool and shorten waiting times. Data on early single-center outcomes are lacking. Nineteen liver (LT, including seven simultaneous liver-kidney [SLKT]) and 17 kidney transplant (KT) recipients received organs from HCV (+) donors; of these, 13 were HCV NAT (+) in each group. All patients who received organs from HCV NAT (+) donors developed HCV viremia post-transplant except for 2 KT recipients. Patients were treated with a variety of direct-acting antiviral regimens, with high rates of sustained virologic response among those with at least 12 weeks of follow-up past the end of treatment: 12/13 (92%) and 8/8 (100%) among LT/SLKT, and KT recipients. Median time to treatment start was 42 days (interquartile range [IQR] 35-118 days) and 40 days (IQR 26-73) post-LT/SLKT and KT, respectively. One death occurred in a SLKT recipient unrelated to HCV or its treatment. There was no significant increase in rejection, proteinuria, or changes in immunosuppression in any group. Organs from HCV-viremic donors can be utilized for HCV-uninfected recipients with good short-term outcomes.     

Direct‐acting antiviral regimens are safe and effective in the treatment of hepatitis C in simultaneous liver–kidney transplant recipients

Hepatitis C (HCV) remains the single most common etiology of end‐stage liver disease leading to simultaneous liver/kidney transplant (SLKT) and has worse post‐transplant survival compared to non‐HCV patients. We aim to assess the effectiveness and tolerance of the all‐oral direct‐acting antiviral (DAA) agents with or without ribavirin (RBV) in the treatment of HCV recurrence post‐SLKT. Thirty‐four patients were studied retrospectively, composed predominantly of treatment‐naïve (73.5%) non‐Caucasian (61.8%) males (82.4%) infected with genotype 1a (64.7%). 94.1% reached a sustained virologic response (SVR) after 24 weeks (32/34 patients), without difference between 12 and 24 weeks of therapy. 64.7% had no clinical side effects. Three deaths occurred, all unrelated to treatment. One patient had liver rejection; tacrolimus was increased and prednisone was initiated while HCV treatment was continued and the patient ultimately achieved SVR. No liver graft losses. No kidney rejection or losses. We demonstrated that DAA combinations with or without RBV result in a remarkable SVR rate and tolerated in the majority of the studied SLKT patients. It is safe to wait to treat until post–kidney transplant and therefore increase the donor pool for these patients. Our cohort is ethnically diverse, making our results generalizable.     

Carvedilol treatment of kidney graft recipients with chronic rejection

Carvedilol is an antihypertensive drug with properties that may be potentially beneficial for kidney graft recipients. The purpose of the study was to investigate if progression of an established chronic rejection may be attenuated or reversed by carvedilol. An open, single-centre, phase II, pilot study, with a 2-yr follow-up, was performed in 25 kidney graft recipients with chronic rejection or accelerated transplant atherosclerosis. Seventeen patients had stable graft function assessed by serum creatinine levels. Eight patients withdrew from the study due to lack of efficacy (increase in serum creatinine 174-477 micromol/L (46-191%) from the initial levels). However. these patients had higher serum creatinine levels and proteinuria already at the start of the study. Both systolic and diastolic blood pressure, as well as heart rate, were stable in all study patients. Low density lipoprotein (LDL)/high density lipoprotein (HDL) cholesterol ratio decreased from 4.7 +/- 1.9 at 1 month to 3.5 +/- 1.2 at 18 months (p < 0.05), and MDA plasma levels decreased from 0.714 +/- 0.119 to 0.493 +/- 0.073 micromol/L after 3 months of carvedilol treatment (p < 0.05). No attenuation of progression of chronic graft rejection by carvedilol treatment was observed in the study. It is suggested that the process of chronic rejection could not be reversed by carvedilol because the patients included in the study already had severe morphological and functional changes of the graft. In conclusion, our study demonstrated that carvedilol provides a good control of blood pressure in renal transplanted patients. Carvedilol treatment had a beneficial effect on lipid pattern and reduced lipid oxidation, but there was no obvious effect on progression of chronic rejection.     

Transplantation in the patient with hepatitis C

Hepatitis C virus (HCV) infection is the most frequent cause of liver disease after renal transplantation. Its clinical course is irrelevant in the short term, except for rare cases of fibrosing cholestatic hepatitis. However, in the long run, HCV infection can lead to major liver complications. Because interferon (IFN) is generally contraindicated in renal transplant patients, the best approach is to treat patients on dialysis. Until more information with pegylated-IFN is available, the use of alpha-IFN monotherapy is recommended. Most of the patients with sustained virological response remain HCV RNA negative after transplantation. HCV-positive renal transplant patients have a higher risk for proteinuria, chronic rejection, infections and post-transplant diabetes (PTDM). Long-term patient- and graft-survival rates are lower in HCV-positive patients. Mortality is higher, mainly as a result of liver disease and infections. HCV can contribute to the development of certain neoplasias such as post-transplant lymphoproliferative disease (PTLD). HCV infection is also an independent risk factor for graft loss. PTDM, transplant glomerulopathy and HCV-related glomerulonephritis can contribute to graft failure. Despite this, transplantation is the best option for end-stage renal disease in HCV-positive patients. Several measures to minimize the consequences of HCV infection have been recommended. Adjustment of immunosuppression and careful follow up in the outpatient clinic for early detection of HCV-related complications are mandatory.     

Rapid steroid withdrawal in hepatitis C virus-positive kidney transplant recipients

The effects of rapid steroid withdrawal (SW) on kidney transplantation (KT) outcome were investigated in 12 HCV+ patients in a prospective cohort study. These results were compared with 17 HCV+ patients who received KT in the prior 2 yr and treated with a standard prednisone taper protocol. SW patients received only 6 d of steroid treatment after transplantation. Eleven received Thymoglobulin and one Basiliximab induction treatment along with a calcineurin inhibitor and mycophenolate mofetil. Patient and graft survival was 92% in SW group (median follow-up 12 months, range 6-17), and 92 and 82% in the historic control group respectively (median follow-up 21 months, range 11-27). In the SW and control group, acute rejection rates were 9 and 18%, and mean creatinine levels at last follow-up 1.30 +/- 0.36 and 1.68 +/- 0.58 mg/dL respectively. Only two SW patients had an increase in liver function tests during follow-up (18%), compared with six patients in the control group (43%). This study demonstrates that rapid SW is safe for HCV+ KT recipients, without an increase in acute rejection episodes or liver function abnormalities in the short term.     

Efficacy and tolerance of interferon-alpha(2b) in the treatment of chronic hepatitis C virus infection in haemodialysis patients. Pre- and post-renal transplantation assessment.

BACKGROUND: Hepatitis C virus (HCV) infection represents an important problem for the dialysis population due to its high prevalence and the long-term development of chronic liver disease, particularly following renal transplantation. METHODS: In order to assess the efficacy and tolerance of interferon (IFN) in the treatment of chronic hepatitis C in haemodialysis (HD) patients and their clinical course following renal transplantation, a multicentre, randomized, open-label study was conducted to compare IFN therapy vs a control group. RESULTS: Nineteen HCV RNA-positive patients received 3 x 10(6) U of IFN s.c., three times a week (post-HD), and 17 HCV RNA-positive patients were assigned to the control group. Tolerance to IFN therapy was good in nine patients, while treatment was discontinued in the other 10 due to the occurrence of side effects. HCV RNA was negative at the end of treatment in 14 out of 19 patients (74%) receiving IFN and in one patient (5%) in the control group. Six out of the 14 patients who initially responded to IFN therapy had a virological relapse (43%). Eight patients (42%) remained HCV RNA-negative, three of them until the day that renal transplantation (RT) was performed (7, 12 and 27 months, respectively), as did five patients on HD during the follow-up (27+/-5 months). Eight out of the nine patients (89%) who completed therapy were HCV RNA-negative at the end of treatment, and seven of them (78%) remained HCV RNA-negative during the follow-up on dialysis (21+/-8 months). Mean transaminase (ALT) values were significantly decreased following IFN therapy, while no changes were observed during the follow-up period in the control group. Fifteen patients (10 in the treatment group and five in the control group) underwent RT. Three patients in the treatment group were HCV RNA-negative at RT, and one of them had a virological relapse 20 months after RT, while the other two remained HCV RNA-negative at 3 months and 24 months after RT, respectively. In contrast to the control group, transaminase (ALT) remained within normal limits in all patients in the treatment group. Finally, during the post-RT follow-up, the transaminase mean values were significantly lower in treated patients vs patients in the control group (P<0.05). CONCLUSIONS: It is concluded that the biochemical and virological response to IFN therapy is good in HD patients. In addition, IFN therapy appears to exert a beneficial effect on the course of liver disease following RT, regardless of the virological response. Despite the fact that IFN therapy was discontinued in 10 out of the 19 patients due to the occurrence of side effects, these disappeared following discontinuation of therapy. Therefore, IFN therapy is advisable for HCV-infected dialysis patients who are candidates for RT.     

病毒性肝炎合并慢性胆囊炎疗效观察

３１例血清谷雨转氨酶（ＡＬＴ）持续不降的病毒性肝炎患者．２０例经Ｂ超证实合并慢性胆囊炎．经抗感染治疗．２８例患者症状消失或明显改善．ＡＬＴ正常或明显下降。提示慢性胆囊炎是ＡＬＴ持续异常的原因之一．正确使用抗生素治疗．有助于肝功能的恢复。     

Chronic hepatitis C virus infection in renal transplant: treatment and outcome

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a common cause of liver disease in post-renal transplant period and causes poor patient and graft survival. We analyzed the effects of antiviral therapy using ribavirin monotherapy or ribavirin in combination with interferon (IFN)-alpha in our kidney transplant recipients with chronic hepatitis C. METHODS: Total of 14 patients received antiviral therapy, all of whom had stable graft function, raised aminotransferases and positive HCV viremia at the start of treatment. Eight patients received ribavirin alone for a period of six months to two yr, in doses of 400-800 mg daily. Five patients received IFN-alpha therapy for a period of two months to 1.5 yr, in doses of 1.5 million units daily or three million units thrice weekly with ribavirin. One patient received pegylated IFN 50 microg once weekly in combination with ribavirin. The response was seen in terms of biochemical and virological improvement at the end of study period. RESULTS: In patients treated with ribavirin alone (n = 8), mean alanine aminotransferase (ALT) levels before and after treatment were significantly different (198.4 +/- 147.6 and 104.8 +/- 66.5 IU/L respectively; p < 0.05). ALT levels normalized completely in three patients at the end of treatment, improved in three patients and deteriorated in two. Only in one of eight patients on ribavirin alone, HCV-RNA became negative after six months of treatment while in the rest (n = 7) HCV-RNA continued to be positive. In subjects on IFN plus ribavirin (n = 6), the mean ALT levels decreased significantly (from 280.2 +/- 114.9 IU/L at baseline to 71 +/- 49 IU/L at end of therapy; p < 0.05). Two patients had sustained remission (33.3%) on IFN plus ribavirin (persistently negative HCV-RNA), two patients relapsed after initial remission and in two patients treatment was stopped after two months because of graft dysfunction. Totally four patients developed graft dysfunction at some time during the course of IFN therapy (66.6%), but it was discontinued in only two (33.3%). All patients regained normal creatinine levels after discontinuation of IFN, although one patient developed chronic allograft nephropathy as shown by kidney biopsy. Four patients in IFN group developed leucopenia. Two patients developed severe anemia one of whom required blood transfusion and one developed severe flu-like syndrome requiring stoppage of therapy. CONCLUSION: Ribavirin monotherapy in renal transplant recipients with chronic hepatitis C infection results in good biochemical response but is not associated with virological clearance. IFN in combination with ribavirin is effective in two-thirds of patients after a minimum therapy of six months, but it is poorly tolerated, results in graft dysfunction in significant number of patients, and relapse can occur after stopping treatment.     

Prevalent immunosuppressive strategies in liver transplantation for hepatitis C: results of a multi-center international survey

To determine current immunosuppression regimens and strategies for acute cellular rejection in hepatitis C virus (HCV) patients after liver transplantation (LT), questionnaires were sent to 264 LT programs worldwide. Surveys from 81 programs were reviewed. In 27 centers (33.8%) the immunosuppression protocol used in HCV differed from non-HCV patients. Tacrolimus-based immunosuppression is utilized in 70 centers (86.42%). Triple therapy using tacrolimus, mycophenolate mofetil and steroids is the most common regimen (41%). Six programs (7.4%) use steroid-free protocols. In nine centers (11%) steroids are discontinued within a week, 56% within 3 months, and 98% within the first year. At 75% of centers, mild rejection is treated by increasing baseline immunosuppression. Moderate rejection is treated by increasing baseline immunosuppression in 38% of centers, steroid bolus in 44%, and either in 16%. For severe rejection, 46% of centers give bolus steroid, and 16% administer antibodies. Among respondents, non-US programs use significantly more cyclosporine than US programs (35.6% vs. 2.8%, P  < 0.001). Duration of steroid therapy is significantly shorter in US programs than non-US (10.8 vs. 29.4 weeks, P  < 0.001). There is no consensus regarding the best immunosuppressive regimen and rejection treatments in HCV patients after LT. Our results reveal the most prevalent management practices in this difficult group of patients.