tacrolimus and Liver-Cirrhosis

Hepatorenal syndrome (HRS) was originally defined as a renal dysfunction caused by a decreased renal perfusion due to hemodynamic disturbances in the arterial circulation and an excessive activity of endogenous vasoactive systems in the course of cirrhosis. Considering the latest research, this syndrome may have a more complex pathomechanism. Equally often as in cirrhosis, HRS develops after orthotopic liver transplantation (OLTx) and worsens the prognosis significantly increasing mortality rates in this patient population. The prevalence of renal complications after OLTx and their negative prognostic impact on the survival of both the graft and the recipient prompted the authors of this work to analyze in detail 2 cases of HRS after OLTx to indicate the multiplicity of factors contributing to the pathophysiology of this syndrome. Attention was paid to risk factors for HRS found in the anamnesis before OLTx, especially a pre-existing renal dysfunction. In both cases early post-OLTx complications associated with the transplantation procedure were described: destabilization of the circulatory system, transfusions of blood products, prolonged stay at an intensive care unit, and necessity of introducing continuous renal replacement therapy. In the later period after the OLTx, infections (bacterial, fungal, viral) and drug nephrotoxicity, including the activity of immunosuppressants (tacrolimus), contributed primarily to the renal function impairment.

Topics: Hepatorenal Syndrome; Humans; Kidney; Liver Cirrhosis; Liver Transplantation; Tacrolimus

Recent advances in immunosuppressive drug regimens have changed the outcome after liver transplantation significantly in the last two decades. However, chronic rejection and long-term graft survival remains a major problem. Side effects like drug-induced nephrotoxicity, hypertension, osteoporosis, hyperlipidaemia and neuropathy of some immunosuppressive agents play an essential role in long-term allograft and patient survival. This review outlines the current treatment of short- and long-term immunosuppression in liver transplanted patients, it summarizes the treatment of acute and chronic rejection, describes the complications and side effects of immunosuppressive therapy and points out the current use of immunosuppressive therapy in living-related liver transplantation.

Topics: Azathioprine; Calcineurin Inhibitors; Glucocorticoids; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Living Donors; Mycophenolic Acid; Sirolimus; Tacrolimus

1. Approximately 10% to 25% of hepatitis C virus-infected recipients of liver allografts will develop cirrhosis within 5 years of transplantation; this acceleration of the natural history of hepatitis C is caused in part by immunosuppression. 2. Risk factors for aggressive recurrence, graft loss, and death are treated acute cellular rejection, methylprednisolone pulse therapy, and use of OKT3. There appears to be no consistent difference between cyclosporine and tacrolimus in their effects on hepatitis C. 3. The benefit of steroid withdrawal, although commonly practiced in transplant recipients with hepatitis C, has not been proven. 4. Mycophenolate mofetil may show synergistic antiviral properties when used with interferon; however, posttransplantation use has not been associated with consistent beneficial or deleterious effects. 5. Effects of other agents, such as sirolimus or interleukin-2-receptor antibodies, have not been adequately defined. Early reports suggest that disease activity may be more aggressive when these agents are constituents of the immunosuppressive regimen.

Topics: Cyclosporine; Disease Progression; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Risk Assessment; Sirolimus; Tacrolimus

Hepatitis C virus (HCV) reinfection is almost universal in patients transplanted for HCV-related cirrhosis. The medium-term survival after orthotopic liver transplantation (OLT) is similar to other transplanted patients, but the long-term survival remains uncertain. The prevention and an effective treatment of progressive liver disease are the primary aims in HCV recurrence. Interferon and ribavirin, as monotherapy or in combination, have been tried to treat or prevent HCV recurrence. Preliminary studies suggest a better chance of initial HCV clearance and better results in preventing HCV recurrence with combination therapy. IFN or ribavirin, as monotherapy, may normalize liver enzymes, but only gives rise to a transient virological response, without histological improvement. Combination IFN and ribavirin may be able to prevent progression of HCV-related graft disease, but indications and duration of treatment need further evaluation. No clear association between type and dose of immunosuppressive and outcome of post-transplant HCV recurrence has been found. Strategies to minimize the effects of immunosuppressive drugs include dose reduction of all agents and the selective discontinuation of individual agents. Initial immunosuppression with a single drug may inhibit or delay the severe fibrosis, and further investigation with a single immunosuppressive regimen to evaluate the outcome of recurrent hepatitis C should be performed. The recent evidence that mycophenolate may have an antiviral effect needs a clinical confirmation. Retransplantation survival is better with early retransplantation, and for indications not directly related to viral recurrence.

Topics: Adrenal Cortex Hormones; Antiviral Agents; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferons; Liver Cirrhosis; Liver Transplantation; Ribavirin; Secondary Prevention; Tacrolimus

Topics: Cyclosporine; Follow-Up Studies; Humans; Hypertension; Immunosuppression Therapy; Liver Cirrhosis; Liver Transplantation; Renal Insufficiency; Tacrolimus; Time Factors

The new directly acting antivirals (DAAs) enable all-oral interferon-free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C.. Twenty-one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment.. All patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P<.0001) at the 12-week follow-up. In parallel, the tacrolimus trough level to dose ratio decreased from 4.68 down to 2.72 (P=.0004).. Antiviral treatment with DAAs enabled sustained elimination of recurrent HCV in liver transplant recipients and was associated with a significant improvement of the enzymatic liver function.

Topics: Administration, Oral; Aged; Antiviral Agents; Biopsy; Carbamates; Cohort Studies; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Recurrence; Ribavirin; Simeprevir; Sofosbuvir; Tacrolimus; Transaminases; Valine

Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA).. 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy.. No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted.. Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

Topics: Anti-Inflammatory Agents; Azathioprine; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Hypertension, Portal; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Prednisolone; Recurrence; Tacrolimus; Time Factors

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Topics: Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Survival Rate; Tacrolimus

The purpose of this prospective, randomized, multicenter trial was to evaluate the effects of a steroid-avoiding immunosuppression protocol on hepatitis C virus (HCV)-positive recipients of living donor liver transplantation (LDLT). Seventy-five HCV-positive LDLT recipients were included in this study, and they were randomized to receive tacrolimus (TAC) plus a corticosteroid (ST; n = 35) or TAC plus mycophenolate mofetil (MMF; n = 40). Biopsy-proven acute rejection (BPAR) was treated with steroid pulse therapy in both groups. Protocol biopsy was performed 3, 6, and 12 months after LDLT and annually thereafter. Histological recurrence of HCV (fibrosis stage ≥ F1 according to the METAVIR score), BPAR resistant to 2 sets of steroid pulse therapy, hepatocellular carcinoma (HCC) recurrence, retransplantation, and patient death were defined as events, and the primary endpoint was event-free survival. The median follow-up was 55 months. The event-free survival rates at 1, 3, and 5 years were 38.2%, 11.8%, and 5.9%, respectively, for the ST group and 25.0%, 17.5%, and 14.6%, respectively, for the MMF group (P = 0.45). The overall 5-year patient survival rates were similar for the ST group (82.7%) and the MMF group (81.0%, P = 0.28). Steroid-resistant BPAR occurred in only 1 patient from the MMF group. HCC recurrence occurred for 1 patient from the ST group and 2 patients from the MMF group. HCV recurrence rates with a fibrosis stage ≥ F1 1 and 3 years after LDLT were 59.4% and 85.9%, respectively, for the ST group and 74.2% and 81.9%, respectively, for the MMF group (P = 0.57). In conclusion, our steroid-avoidance regimen had no apparent impact on LDLT outcomes for HCV-positive recipients.

Topics: Adult; Aged; Biopsy; Disease-Free Survival; Female; Follow-Up Studies; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recurrence; Steroids; Tacrolimus; Treatment Outcome; Young Adult

To evaluate the safety and efficacy of steroid-minimization therapy in liver transplantation (LT) recipients with hepatitis B virus-related diseases in China.. From March 2000 to June 2007, 502 adult LT recipients, mostly with hepatitis B (HBV)-related diseases, were enrolled in our study. Four study groups were setup according to the steroid-minimization protocols: tacrolimus (TAC) with 6 months steroids withdrawal (6M SW), TAC with 3 months SW (3M SW), TAC with 14 days SW (14d SW), and TAC with basiliximab induction and steroids avoidance (Bas SA). All patients were followed up for at least 36 months after LT.. There were no significant differences in the overall 3-year survival rates of the patients and graft, and chronic rejection among the four groups (P = 0.092, P = 0.113 and P = 0.684, respectively). There was also no difference in acute rejection within 12 months after LT (P = 0.514). The 3-year recurrence rates of HBV infection and hepatocellular carcinoma (HCC) after LT were significantly different among all the groups (lowest in TAC/Bas SA group; P = 0.037 and P = 0.029, respectively). The overall incidence of infection was significantly higher in the 6M SW group (62.2% vs 56.1% in 3M SW, 30.5% in 14d SW, 20.5% in Bas SA; P < 0.01). By the end of the 3-year follow-up, more than 90% of the surviving patients could safely receive TAC monotherapy.. Bas SA immunosuppressive protocol can be achieved safely in LT and reduce HBV infection and HCC recurrence and side effects of steroids after LT.

Topics: Adult; Antibodies, Monoclonal; Bacterial Infections; Basiliximab; Carcinoma, Hepatocellular; Chi-Square Distribution; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Neoplasm Recurrence, Local; Recombinant Fusion Proteins; Recurrence; Statistics, Nonparametric; Survival Rate; Tacrolimus

study impact of steroid avoidance on HCV recurrence after transplantation.. 35 HCV pats, being part of prospective, randomized, double-blind, placebo-controlled study comparing Tacrolimus (TAC)-Placebo (PLAC) (n = 14) to TAC-short-term (2 mo) low-dose steroid (STER) (n = 21), had 5 years follow-up. Primary endpoint was 1 and 5 years survival; secondary (composite) endpoint comprised HCV related cirrhosis, re-transplantation (re-LT) and death.. 1 and 5-years survival were 93% and 75% in TAC-PLAC group; 91% and 66% in TAC-STER group (p 0.38). Two (14.3%) TAC-PLAC pats died due to HCV cirrhosis at 54 and 72 mo; 7 (33%) TAC-STER pats died due to cholestatic hepatitis at 5.8 and 9 mo, to cirrhosis at 18, 22, 34, 73 and 79 mo (p 0.20). Composite endpoint at 5 years didn't show advantage in favor of TAC-PLAC patients (5/14 [35.7%] vs. 9/21 [42.8%] pts, p.0.69). Early biopsies seemed more favorable in TAC-PLAC pats; at 5 years results were identical for both groups. Only 1 (7.1%) TAC-PLAC and 2 (9.5%) TAC-STER pats needed rejection treatment.. immunosuppression using steroid avoidance or short-term use had similar outcomes. Well documented long-term follow-up, including biopsies, is necessary in order to make conclusions in relation to impact of steroid use on outcome of HCV liver recipients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antiviral Agents; Biopsy; Double-Blind Method; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Monitoring, Immunologic; Secondary Prevention; Survival Analysis; Tacrolimus; Time; Treatment Outcome

We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT).. Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 μg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted.. At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo.. A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

Topics: Antiviral Agents; Cyclosporine; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Induction Chemotherapy; Interferon-alpha; Kidney; Liver Cirrhosis; Liver Transplantation; Logistic Models; Maintenance Chemotherapy; Male; Middle Aged; Placebos; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Treatment Outcome; Viral Load

The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients.. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis C virus (HCV) patients were reevaluated.. After 5 years, the following parameters were comparable in both groups: patient survival (P=0.236), organ survival (P=0.509), and acute rejections (P=0.409). Steroid-free immunosuppression lead to a higher rate of chronic rejections (P=0.023). Six months after OLT, there was a difference in rates of posttransplant diabetes mellitus (PTDM) (P=0.024) and hypercholesterolemia (P=0.002). However, 5 years after OLT, there was no difference in hypertension (P=0.647), PTDM (P=0.453), hypercholesterolemia (P=0.412), and osteoporosis (P=0.624). In HCV patients, we could not find any differences in patient survival (P=0.096), organ survival (P=0.424), time free from recirrhosis (P=0.647). The rate of recirrhosis was influenced by steroid bolus therapy (P=0.01) but not by avoiding continuous steroid therapy.. Early tapering down of steroids to a tacrolimus monotherapy is possible with comparable acute rejection rates. During steroid therapy, PTDM and hypercholesterolemia are cumulative. These side effects are reversible. The recirrhosis in HCV patients is not influenced by continuous steroid therapy but more frequent in HCV patients receiving a steroid bolus therapy.

Topics: Adrenal Cortex Hormones; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Graft Survival; Hepatitis C; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Recurrence; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

There is a paucity of good studies evaluating the impact of calcineurin inhibitors on posttransplantation outcome in hepatitis C virus (HCV)-infected liver transplant (LT) recipients.. We sought to determine whether there are differences on posttransplantation survival and histologic recurrence in HCV-LT recipients based on initial immunosuppression (IS) by conducting a prospective study comparing tacrolimus (Tac) versus cyclosporine-based IS in patients undergoing LT between 2001 and 2007. Protocol liver biopsies were performed.. Baseline characteristics (demographics, liver function at LT, genotype distribution, donor, surgery, and IS except for the type of calcineurin inhibitor) did not differ between groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, or allograft loss or death because of recurrent disease in the first year) was present in 67 of 253 (26.5%) and was equally distributed in the CsA and Tac groups (27% vs. 26%; P=0.68). Two thirds of protocol biopsies performed at 1 year showed some fibrosis without differences between CsA and Tac groups (75% vs. 70%). Advanced fibrosis (bridging fibrosis and cirrhosis) was diagnosed in 30% CsA and 24.5% Tac patients (P=NS). No differences in survival at 1 and 7 years were observed (83% and 67% vs. 78% and 64%, respectively, P=0.4). In summary, in patients undergoing LT for HCV-related liver disease, posttransplantation outcome is not related to the calcineurin inhibitor used.

Topics: Adult; Aged; Antiviral Agents; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Spain; Tacrolimus; Time Factors; Treatment Outcome

Less potent immunosuppression is considered to reduce the severity of hepatitis C virus (HCV) recurrence after liver transplantation. An optimal regimen is unknown. We evaluated tacrolimus monotherapy versus triple therapy in a randomized trial of 103 first transplants for HCV cirrhosis. One hundred three patients who underwent transplantation for HCV were randomized to tacrolimus monotherapy (n = 54) or triple therapy with tacrolimus, azathioprine, and steroids (n = 49), which were tapered to zero by 3 to 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. The time to reach Ishak stage 4 was the predetermined endpoint. All factors documented in the literature as being associated with HCV recurrence and the allocated treatment were evaluated for reaching stage 4 and HVPG >or= 10 mm Hg. No significant preoperative, perioperative, or postoperative differences, including the frequency of biopsies between groups, were found. During a mean follow-up of 53.5 months, 9 monotherapy patients and 6 triple therapy patients died, and 5 monotherapy patients and 4 triple therapy patients underwent retransplantation. Stage 4 fibrosis was reached in 17 monotherapy patients and 10 triple therapy patients (P = 0.04), with slower fibrosis progression in the triple therapy patients (P = 0.048). Allocated therapy and histological acute hepatitis were independently associated with stage 4 fibrosis. HVPG increased to >or=10 mm Hg more rapidly in monotherapy patients versus triple therapy patients (P = 0.038). In conclusion, long-term maintenance immunosuppression with azathioprine and shorter term prednisolone with tacrolimus in HCV cirrhosis recipients resulted in a slower onset of histologically proven severe fibrosis and portal hypertension in comparison with tacrolimus alone, and this was independent of known factors affecting fibrosis.

Topics: Adolescent; Adult; Aged; Azathioprine; Biopsy; Child; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Hypertension, Portal; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prednisolone; Proportional Hazards Models; Recurrence; Risk Assessment; Risk Factors; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction.. Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12-84).. Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (<6 ng/mL) TAC monotherapy (P 0.79).. TAC monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population. The higher incidence of early CRR in the TAC-PL group related to the significantly higher number of patients transplanted while being on artificial organ support. In such condition, this monodrug immunosuppressive strategy needs to be adapted. TAC monotherapy strategy should lay the basis for further large scale minimization studies in liver transplantation.

Topics: Adult; Aged; Cholestasis, Intrahepatic; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Long-term steroid administration may predispose liver transplant recipients to infectious and metabolic complications. Maintaining effective immunoprophylaxis while minimizing the negative consequences of steroid therapy could be a key factor in improving clinical outcomes.. Six hundred two patients were randomized to receive tacrolimus (TAC) immunosuppression with a single-steroid bolus and two doses of daclizumab (DAC) or mycophenolate mofetil (MMF).. The incidence of biopsy-proven acute rejection was 19.7% in the TAC/DAC group and 16.2% in the TAC/MMF group (ns). Three-month patient and graft survival were similar. Steroid use at month-3 was low at 5.5% in the TAC/DAC group and 3.9% in the TAC/MMF group. Significantly higher incidences of causally related adverse events (AEs) and significantly more dose modifications, interruptions, or discontinuations due to an AE were reported with TAC/MMF. Study withdrawal due to leucopenia was significantly higher with TAC/MMF (0.0% vs. 1.7%. Por=2 fasting plasma glucose values >or=7.0 mmol/L) were low at 9.5% (TAC/DAC) and 11.0% (TAC/MMF).. Both TAC-based regimens allowed optimization of immunoprophylaxis while eliminating some of the negative consequences associated with steroids. Efficacy outcomes were comparable; however, TAC monotherapy after DAC induction was associated with significantly less leucopenia and less bacterial infection than a dual regimen incorporating MMF.

Topics: ABO Blood-Group System; Acute Disease; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Mycophenolic Acid; Patient Selection; Survival Analysis; Tacrolimus; Treatment Outcome

Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation.. HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months.. Twenty-seven patients (MT) and 29 (TT)--median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different.. Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Topics: Adult; Aged; Azathioprine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Secondary Prevention; Survival Analysis; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

In this series of 32 adult-to-adult living related liver transplantations, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen. Basiliximab, a chimeric monoclonal antibody directed against the alpha chain of the interleukin-2 (IL-2) receptor (CD25), has been extensively evaluated as induction therapy for cadaveric liver transplant recipients.. Thirty-two adult-to-adult living related liver transplantations were performed in the last 3 years. All patients received two 20 mg doses of basiliximab (days 0 and 4 posttransplantation) followed by tacrolimus (0.15 mg/kg/d; 10-15 ng/mL target trough levels) and steroids (starting with 20 mg IV switched to PO as soon as the patient was able to eat and weaned within 1-2 months). The average follow-up was 395 days after transplantation.. Of the patients, 93.75% remained rejection-free during follow-up with an actuarial rejection-free probability of 92.59% within 3 months. Two patients (6%) had one episode of biopsy-proven acute cellular rejection (ACR). Actuarial patient and graft survival rates at 3 years were 86.85% and 81.25%. One patient (3%) experienced one episode of sepsis. There was no evidence of cytomegalovirus infections or side effects related to the basiliximab. We found zero de novo malignancy but we observed two patients with metastatic spread of their primary malignancy during the follow-up.. Basiliximab in association with tacrolimus and steroids is effective as prophylaxis of ACR among adult living related liver transplant recipients.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Drug Administration Schedule; Drug Therapy, Combination; Family; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Living Donors; Middle Aged; Recombinant Fusion Proteins; Safety; Survival Analysis; Tacrolimus

This is a 4-yr follow-up of a trial using mycophenolate mofetil (MMF) induction in orthotopic liver transplantation (OLT). The goal of this study was to evaluate a multidrug approach that would reduce both early and long-term morbidity related to immunosuppression while maintaining an acceptable freedom from rejection.. This was a prospective, randomized, intent to treat study designed to compare the primary endpoints of rejection and infection, and secondary endpoints of liver function, renal function, bone marrow function, cardiovascular risk factors, and the recurrence of hepatitis C. Ninety-nine consecutive patients with end stage liver disease who underwent OLT were randomized to receive either cyclosporine microemulsion (N) (50 patients) or tacrolimus (FK) (49 patients) starting on postoperative day 2, with MMF and an identical steroid taper begun preoperatively.. Ninety of 99 patients (N 46, FK 44) completed the 4-yr follow-up. The overall 4-yr patient and graft survivals were 93 and 89%, respectively. There was no significant difference in 4-yr patient (N 96% vs. FK 90%, p = ns) or graft (N, 90% vs. FK, 88%, p = ns) survival between groups. The 4-yr rejection rate was not significantly different in either arm (N = 34%, FK = 24%; p = 0.28). There were no differences in infection rates in either arm. The patients with hepatitis C had no differences in the viral titers or Knodell biopsy scores between groups. However, in the hepatitis C subgroup (37 patients), the FK patients had a significantly lower rejection rate (p = 0.0097) and a significantly lower clinically recurrent hepatitis C rate (p = 0.05) than the N patients. No difference was seen in the percent of patients weaned off of steroids after 4 yr (N 51%, FK 49%). There were no differences in the incidences of diabetes mellitus and hypertension. When renal dysfunction was analyzed, a significant difference in the number of patients whose creatinine had increased twofold since transplant was seen (N 63%, FK 38%, p = 0.04).. Use of MMF induction and maintenance following OLT in conjunction with either N or FK and an identical steroid taper, resulted in an acceptable long-term incidence of rejection and infection, without an increase in long-term graft or patient morbidity.

Topics: Cyclosporine; Drug Therapy, Combination; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Patient Readmission; Prospective Studies; Remission Induction; Tacrolimus

Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV.

Topics: Adult; Biopsy, Needle; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prospective Studies; Recurrence; RNA, Viral; Tacrolimus; Treatment Outcome

In 2001, we published early results of a prospective randomized trial of 71 patients who received either steroids or rabbit antithymocyte globulin (RATG) for orthotopic liver transplantation (OLT). We now report follow-up on these patients and additional patients undergoing steroid-free OLT.. A total of 119 adult OLT recipients were prospectively randomized to receive either methylprednisolone 1,000 mg followed by a 3-month steroid taper or a steroid-free regimen of RATG 1.5 mg/kg during the anhepatic phase followed by a 1.5 mg/kg dose on posttransplant day 1. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil in both groups. Mycophenolate mofetil was weaned over 3 months in the first 71 patients and over 2 weeks in the last 48 patients, achieving tacrolimus monotherapy by 2 weeks posttransplant. Subsequently, a group of 24 sequential OLT recipients received the steroid-free (RATG) protocol. Endpoints of the study were survival, rejection, infectious complications, posttransplant diabetes, and recurrent hepatitis C virus.. One-year patient survival was 85% in each group of the prospective randomized trial with a mean follow-up of 18.5 months. One-year graft survival was 82% in the RATG group and 80% in the steroid group (P=not significant). Patient and graft survival of the 24 nonrandomized RATG patients was 96% with a mean follow-up of 3 months. The incidence of rejection was not significantly different; however, 50% of the patients in the steroid group required pulse steroids to reverse the rejection compared with only one patient (1.6%) in the RATG group (P=.03). The incidence of cytomegalovirus infection (P<.05) and posttransplant diabetes was higher in the steroid group (P=.03). There was a trend toward decreased severity of hepatitis C virus in the RATG group.. Steroid-free liver transplantation using RATG and early tacrolimus monotherapy effectively reduces immunosuppression-related complications with excellent survival.

Topics: Adult; Animals; Antilymphocyte Serum; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Methylprednisolone; Mycophenolic Acid; Rabbits; Survival Analysis; Tacrolimus

Liver transplant recipients administered gelatin (GEL) rather than human albumin solution (HAS) can become profoundly hypoalbuminemic in the early postoperative period and often have hepatic dysfunction at this time. The combined effect of these two abnormalities could be an increase in the unbound (active) concentration of low-extraction highly albumin-bound drugs, such as tacrolimus (TAC). This may increase the efficacy and/or toxicity of such drugs. We prospectively compared the clinical outcome of 69 de novo liver transplant recipients randomized primarily to TAC or cyclosporine (CYA) and secondarily to HAS or GEL therapy during the first 14 days after liver transplantation. Antipyrine clearance on the 7th postoperative day was used as a measure of liver metabolic function. Serum albumin levels were significantly lower in both GEL arms than HAS arms during the first 14 days (P <.001). Although antipyrine clearance was similar in all four trial arms, it was intermediate between that found in historic healthy controls and patients with cirrhosis (P <.0001). Serum creatinine concentrations were significantly greater in the TAC plus GEL arm than the other three arms (P <.001). The linearized treated acute rejection rate was significantly greater in the TAC plus HAS arm than the other three arms (relative risk, 2.02; 95% confidence interval, 1.07 to 3.78; P =.03). These data indicate that excess nephrotoxicity can occur with TAC in liver transplant recipients with impaired hepatic metabolism who are administered GEL. In addition, supplementary albumin may reduce the efficacy of TAC in liver transplant recipients at a time when the risk for rejection is greatest.

Topics: Adult; Antipyrine; Creatinine; Cyclosporine; Female; Gelatin; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Reference Values; Serum Albumin; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Antilymphocyte Serum; Azathioprine; Creatinine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Safety; Tacrolimus; Time Factors

Cyclosporin A (CsA) is widely used to prevent liver transplantation failure. CsA-induced gingival overgrowth is a common side effect. However, the effect of cirrhotic liver disease, liver transplantation, and immunosuppressive therapy on the periodontium is yet unclear. The aim of the present cross-sectional study was to examine the effect of liver cirrhosis, transplantation, and immunosuppressive therapy on the periodontium.. The experimental group (LC) consisted of 13 liver cirrhosis patients. A second experimental group (PT) included 24 patients, post-liver transplantation, receiving immunosuppressive therapy. Seventeen healthy subjects formed a control group. The Ramfjord index teeth were recorded for plaque index (PI), gingival index (GI), probing depth (PD), clinical attachment level (CAL), and gingival overgrowth (GO).. Mean PI and mean GI for the LC, PT, and C groups were not statistically different (P >0.05). Mean PD for the LC (3.32+/-0.24 mm) and PT group (3.41+/-0.13 mm) was significantly higher (P = 0.0001, ANOVA) compared to the C group (2.45+/-0.16 mm). Likewise, CAL for the LC (4.89+/-0.47 mm) and PT group (4.68+/-0.47 mm) was significantly higher (P = 0.001, ANOVA) than the C group (2.78+/-0.23 mm). Patients in the PT group exhibited the greatest mean GO scores (0.88+/-0.09) compared to the LC group (0.37+/-0.07) and the C group (0.09+/-0.02). All 3 groups were significantly different from each other (P = 0.0001) despite great variability within the groups. GO in the CsA-treated patients (1.1+/-0.09) was significantly higher (P = 0.0001) than in those treated with tacrolimus (0.57+/-0.1).. Liver cirrhosis patients demonstrated greater pocketing and attachment loss compared to healthy matched controls. These same differences were observed in patients post-transplantation. Gingival overgrowth occurred as a result of the immunosuppressive therapy with CsA, while to a lesser degree with tacrolimus. Replacement of CsA by tacrolimus in patients manifesting gingival overgrowth might be recommended whenever possible to overcome this problem.

Topics: Analysis of Variance; Cyclosporine; Female; Gingival Hyperplasia; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Statistics, Nonparametric; Tacrolimus

Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation.. From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens.. There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively.. (a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.

Topics: Adult; Aged; Cyclosporine; Emulsions; Female; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Reoperation; RNA, Viral; Survival Rate; Tacrolimus

Topics: Adult; Cyclosporine; Humans; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Survival Analysis; Tacrolimus

Tacrolimus has a narrow therapeutic index and large individual differences in pharmacokinetics. The distribution of tacrolimus in ascitic fluid and its influence on whole-blood tacrolimus were unclear. In this study, a sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was established and validated for the quantification of tacrolimus in the ascitic fluid of liver transplant recipients. Chromatographic separation was achieved on an Agilent ZORBAX Eclipse Plus Phenyl-Hexyl column (2.1 × 100 mm, 3.5 μm). Mass spectrometry was performed in multiple reaction monitoring conditions of transitions m/z 821.4→768.5 for tacrolimus. The concentrations of tacrolimus in the ascitic fluid range from 0.2 to 3.0 ng/mL, accounting for 1.19-31.87% of whole-blood tacrolimus concentrations. A linear mixed model showed a statistically significant positive correlation between the steady-state trough blood concentration of tacrolimus and the corresponding amount of tacrolimus excreted in the ascitic fluid for 24 consecutive hours, especially after normalization by daily dose per unit body weight. These data suggested that the distribution of tacrolimus in the ascitic fluid has great individual differences. The whole-blood tacrolimus concentration, dose per unit body weight, and other confounding factors may contribute to the excretion of tacrolimus in ascitic fluid, but the influence of tacrolimus excretion in drained ascitic fluid on the whole-blood tacrolimus concentration is negligible.

Topics: Ascitic Fluid; Chromatography, High Pressure Liquid; Chromatography, Liquid; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Tacrolimus; Tandem Mass Spectrometry

Topics: Carcinoma, Hepatocellular; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma, Primary Effusion; Male; Middle Aged; Pleural Effusion; Stomach Ulcer; Tacrolimus

Drug-induced hypersensitivity reactions attributed to the immunosuppressive agent tacrolimus after an organ transplant are rare in the literature. We present 3 cases of male adult patients grafted with a cadaveric liver who developed delayed hypersensitivity reactions to tacrolimus in the form of the prolonged-release capsules (Advagraf). Furthermore, the appropriate drug concentration solutions used for allergy testing are proposed.. All patients received a liver transplant (LT) because of cirrhosis of various etiologies. They were immunosuppressed with tacrolimus once daily. Several months after they had been placed on an immunosuppressive regimen with tacrolimus in the form of prolonged-release capsules (Advagraf), the patients presented with delayed hypersensitivity reactions and torturous pruritic rash that affected the whole body and was unresponsive to treatment with oral ursodeoxycholic acid, cholestyramine, or levocetirizine. Allergy testing that was performed by skin prick testing was negative. Nevertheless, intradermal testing yielded positive results in all 3 patients. Management was by interruption of the culprit agent, which was followed by symptom resolution. The immunosuppressive treatment was continued with alternative drugs.. Appropriate nonirritating drug concentration solutions of the drug used for intradermal testing were highly sensitive and confirmed the clinical diagnosis of tacrolimus allergy in all the affected patients.. Immunosuppressive treatment with tacrolimus in the form of prolonged-release capsules may cause a drug hypersensitivity reaction. A suspicion of allergy warrants a referral for allergy testing. Pruritic rash refractory to treatment in liver transplanted patients should be evaluated by an allergist for possible drug allergy when bile stasis and graft disease have been excluded. Intradermal testing has proven a highly sensitive method for confirming a drug allergy diagnosis, whereas skin prick testing did not.

Topics: Aged; Delayed-Action Preparations; Drug Hypersensitivity; Exanthema; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Tacrolimus

Post-transplant liver fibrosis (PTLF) is a common and severe complication in liver recipients. In this study, we assessed the impact of donor liver genetics on the development of PTLF. A total of 232 patients undergoing liver transplantation were included. Twenty-two single nucleotide polymorphisms (SNPs) associated with liver fibrosis were analyzed. Univariate analysis revealed seven donor SNPs to be associated with PTLF. In a multivariate analysis, independent risk factors of PTLF were genetic variation of donor GRP78 rs430397 (OR = 8.99, p = 0.003), GSTP1 rs1695 (OR = 0.13, p = 0.021), miRNA-196a rs12304647 (OR = 16.01, p =0.001), and TNF-α rs1800630 (OR = 79.78, p = 0.001); blood tacrolimus levels at maintenance > 7 ng/ml (OR =7.48, p <0.001); and post-transplant diabetes mellitus (OR = 7.50, p = 0.001). A predictive model that included donor SNPs showed better prognostic ability for PTLF than a model with only clinical parameters (AUROC: 0.863 vs 0.707, P < 0.001). Given that donor gene SNPs are associated with an increased risk of PTLF, this model integrated with donor gene polymorphisms may help clinicians predict PTLF.

Topics: Adult; Diabetes Mellitus; Endoplasmic Reticulum Chaperone BiP; Female; Genetic Predisposition to Disease; Glutathione S-Transferase pi; Graft Rejection; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Male; MicroRNAs; Middle Aged; Polymorphism, Single Nucleotide; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Tumor Necrosis Factor-alpha

Topics: Allografts; Biopsy; Carcinoma, Hepatocellular; Cholestasis; Cyclosporine; Graft Rejection; Hepatitis; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Tacrolimus; Ultrasonography, Doppler

Topics: Arthroplasty, Replacement, Hip; Cecal Diseases; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Intestinal Perforation; Liver Cirrhosis; Liver Transplantation; Middle Aged; Periprosthetic Fractures; Peritonitis; Tacrolimus; Therapeutic Irrigation

In the majority of long-term survivors after PLTx, graft fibrosis has been identified. Recently, subtypes of graft fibrosis have been described based on their predominant acinar localization. We aimed to evaluate whether the development of portal, perisinusoidal, and centrilobular distribution of graft fibrosis is related to patient or transplantation-related parameters. We reviewed the histological features in protocol liver biopsies taken at 1 and 5 years after PLTx of 47 children on a tacrolimus-based immunosuppressive regimen. Fibrosis was assessed according to the LAFSc. The prevalence of portal fibrosis increased from 31% to 62%, sinusoidal from 68% to 79%, and centrilobular from 76% to 85%. The presence of portal fibrosis was associated with total bilirubin and γGT levels (each P<.02) and tended to be associated with biliary complications (P=.06). Sinusoidal fibrosis was associated with prior rejection episodes (P<.02) and centrilobular fibrosis with the presence of HLA mismatches (P=.02). In conclusion, using the LAFSc, we found a high incidence of progressive fibrosis in the 1-year and 5-year protocol biopsies after PLTx. Progression of fibrosis was observed in all acinar compartments, and each of the three locations is associated with different clinical conditions.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Disease Progression; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver; Liver Cirrhosis; Liver Transplantation; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Dexamethasone; Drug Substitution; Etoposide; Humans; Ifosfamide; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Living Donors; Lymphoma, Extranodal NK-T-Cell; Methotrexate; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Remission Induction; Tacrolimus; Transplant Recipients

Graft loss because of hepatitis C virus recurrence is a serious problem after liver transplantation (LT), and the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) is poor. The significantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better graft and patient survival rates, but severe drug interactions may limit the usefulness of this therapy for LT patients. We report our single-center experience with a specially developed protocol that involved administering a low daily dose of tacrolimus (TAC) to a cohort of 17 patients with a recurrence of hepatitis C virus genotype 1 after LT.. Patients were treated with TVR, PEG-IFN, and RBV for 12 weeks, followed by 12 or 36 weeks of dual therapy with PEG-IFN and RBV. After TVR administration was initiated, the TAC dosage was skipped until trough levels began to decline; it was then administered at a dose of 0.1 mg once or twice daily. Tacrolimus trough levels and laboratory values were closely monitored during the TVR phase.. Deviations in trough levels were avoided, thus preventing any clinically evident renal toxicity related to TAC. In addition, histologic studies performed at the end of therapy showed that no rejection episodes had occurred. All patients tolerated the medication. Sustained virologic response was documented for 10 of 17 patients (58%) 24 weeks after end of treatment.. In conclusion, substantial dose reduction and daily administration of low doses of TAC compose a safe and efficient immunosuppressive regimen during TVR-based triple therapy.

Topics: Adult; Aged; Antiviral Agents; Drug Monitoring; Drug Therapy, Combination; Feasibility Studies; Female; Genotype; Germany; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferons; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Oligopeptides; Recurrence; Retrospective Studies; Ribavirin; Tacrolimus; Time Factors; Treatment Outcome; Virus Activation

Although cardiovascular disease (CVD) is the leading cause of long-term mortality in liver transplant recipients (LTRs), the role of recently identified biomarkers of CVD risk in liver transplantation is unknown. We aimed to evaluate an extensive CVD risk profile in LTRs. Markers of CVD risk in 65 LTRs with no known history of diabetes mellitus (DM), dyslipidemia, or ischemic heart disease were compared to age-, sex-, and body mass index (BMI)-matched controls with no chronic medical disease. LTRs on corticosteroids or those with graft cirrhosis (GC) were excluded. The effect of calcineurin inhibitors on the CVD risk profile was separately analyzed in LTRs receiving either tacrolimus (Tac) or cyclosporine A (CsA). To evaluate the impact of GC, a comparison was made between LTRs with and without GC. Non-DM LTRs were matched to controls with respect to age, sex, and BMI. LTRs had similar serum high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and total cholesterol in comparison with BMI-matched controls. Proatherogenic small-dense (sd) LDL-C (33.6 ± 14 versus 25.9 ± 9.9 mg/dL; P < 0.001) and %sdLDL-C (30% ± 10% versus 26.4% ± 9%; P = 0.02) were significantly higher in LTRs. In comparison with controls, LTRs had higher apolipoprotein B (apoB; 98 ± 37 versus 88 ± 24 mg/dL; P < 0.01), very low density lipoprotein-particle concentration (VLDL-P; 7.7 ± 6.7 nmol/L versus 3.2 ± 9.1 nmol/L; P < 0.001), and VLDL size (51.1 ± 6.6 versus 46.5 ± 6.9 nm; P < 0.001). In LTRs, VLDL size and VLDL-P were directly related to serum CsA levels (r = 0.53, P = 0.09, and r = 0.63, P < 0.01, respectively) but not to Tac levels. In comparison with controls, LTRs had significantly lower total serum high-density lipoprotein-particle concentration. In comparison with those with preserved graft function, LTRs with GC had lower levels of serum atherogenic markers characterized by low sdLDL-C, apoB, triglycerides, LDL-C, and total cholesterol. In conclusion, LTRs have a proatherogenic lipoprotein profile that is not captured with a traditional lipid panel, and this suggests that a detailed serum atherogenic profile is needed to truly assess CVD risk in LTRs.

Topics: Aged; Atherosclerosis; Biomarkers; Body Mass Index; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Cyclosporine; Female; Humans; Immunosuppression Therapy; Inflammation; Lipoproteins; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Prospective Studies; Risk; Tacrolimus; Transplant Recipients

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Topics: Aged; Antiviral Agents; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin; Simeprevir; Tacrolimus; Treatment Outcome

Topics: Antiviral Agents; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Oligopeptides; Tacrolimus

We aimed to minimize the dose of tacrolimus in pediatric patients undergoing liver transplantation prospectively.. Pediatric liver transplant recipients with stable graft function >1year (transplant at <1year of age), or 2years (transplant at >1year of age) post transplant were screened. After baseline graft biopsy, patients were enrolled into our protocol for elective tacrolimus dose reduction. Patients were assessed by liver function test and protocol biopsy during and after tacrolimus dose reduction.. From January 2011 to December 2012, 16 patients were recruited, of whom 15 completed follow-up at a mean 40.75±5.98months. Six patients were preliminarily weaned off tacrolimus, and five remained tacrolimus-free for more than 2years. Of the 10 patients who were not weaned off tacrolimus, six experienced seven episodes of clinical rejection. Five patients had a reduction in tacrolimus dosage to an undetectable trough level, another five to a trough level <4ng/ml, including one patient who was off the study. At the last patient visit, all of the patients had normal liver function test results with no graft loss. Three patients had low-grade graft fibrosis. The patients with metabolic liver disease (p=0.039) and who were recruited earlier after transplantation (p=0.028) were more likely to be weaned off tacrolimus.. Tacrolimus withdrawal is feasible in select pediatric liver transplant recipients, and long-term follow-up for these patients is suggested.

Topics: Biopsy; Child; Child, Preschool; Drug Administration Schedule; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Tacrolimus; Withholding Treatment

Immunosuppressants are used ubiquitously post-liver transplantation to prevent allograft rejection. However their effects on hepatocytes are unknown. Experimental data from non-liver cells indicate that immunosuppressants may promote cell death thereby driving an inflammatory response that promotes fibrosis and raises concerns that a similar effect may occur within the liver. We evaluated apoptosis within the liver tissue of post-liver transplant patients and correlated these findings with in vitro experiments investigating the effects of immunosuppressants on apoptosis in primary hepatocytes.. Hepatocyte apoptosis was assessed using immunohistochemistry for M30 CytoDEATH and cleaved PARP in human liver tissue. Primary mouse hepatocytes were treated with various combinations of cyclosporine, tacrolimus, sirolimus, or MMF. Cell viability and apoptosis were evaluated using crystal violet assays and Western immunoblots probed for cleaved PARP and cleaved caspase 3.. Post-liver transplant patients had a 4.9-fold and 1.7-fold increase in M30 CytoDEATH and cleaved PARP compared to normal subjects. Cyclosporine and tacrolimus at therapeutic concentrations did not affect hepatocyte apoptosis, however when they were combined with MMF, cell death was significantly enhanced. Cell viability was reduced by 46% and 41%, cleaved PARP was increased 2.6-fold and 2.2-fold, and cleaved caspase 3 increased 2.2-fold and 1.8-fold following treatment with Cyclosporine/MMF and Tacrolimus/MMF respectively. By contrast, the sirolimus/MMF combination did not significantly reduce hepatocyte viability or promote apoptosis.. Commonly used immunosuppressive drug regimens employed after liver transplantation enhance hepatocyte cell death and may thus contribute to the increased liver fibrosis that occurs in a proportion of liver transplant recipients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspase 3; Cell Survival; Cyclosporine; Drug Therapy, Combination; Female; Fluorouracil; Hepatocytes; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Transplantation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Mitomycin; Semustine; Sirolimus; Tacrolimus

The aim of this work was to evaluate the CYP3A5:CYP3A5*1/CYP3A5*3 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients.. This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n = 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use of a TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele ("minor-allele") was analyzed for correlation with the tacrolimus dose-normalized ratio during the 3 months after transplantation.. The following observations were obtained in the population studied: (1) Frequency of the minor allele*1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A5*1/*3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele*1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P < .05).. The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1-polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype.

Topics: Adult; Alleles; Cohort Studies; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Genotype; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Pharmacogenetics; Polymorphism, Single Nucleotide; Prednisone; Retrospective Studies; Tacrolimus; Tissue Donors; Transplants

Increasingly, food allergy associated with tacrolimus after pediatric living-donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T-helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus-associated food allergy after pediatric living-donor LT. The patient was a 7-year-old Japanese girl who had undergone living-donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post-transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post-transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.

Topics: Cyclosporine; Enzyme Inhibitors; Female; Food Hypersensitivity; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Cirrhosis; Liver Transplantation; Tacrolimus

Topics: Blindness, Cortical; Blood Group Incompatibility; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Confusion; Drug Substitution; Drug Therapy, Combination; Emergencies; Everolimus; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Photopheresis; Plasmapheresis; Sirolimus; Syndrome; Tacrolimus

Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.

Topics: Cyclosporine; Diabetic Nephropathies; Female; Hepatitis B; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Living Donors; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Treatment Outcome

Topics: Aged; Alcoholism; Biopsy; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatitis C; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors

Assessment of renal function 12 months after liver transplantation (LT) predicts chronic renal failure on long-term follow up.. To evaluate pre- and post- LT factors associated with development of renal dysfunction (RD) in cirrhotic patients.. Between June 2005 and June 2010, 104 cirrhotic patients were selected from 268 consecutively transplanted adult patients. RD was defined as a calculated glomerular filtration rate (cGFR) < 50 ml/min/1.73m2 by modification of diet in renal disease (MDRD), 12 months after LT.. Baseline pre-LT creatinine was 1.0 ± 0.7 mg/dL and cGFR was 64 ± 32.8 mL/min. At 12 month follow up, creatinine was 1.3 ± 0.6 mg/dL and cGFR was 47 ± 18 mL/min. The prevalence of RD was 55%. Variables related to RD on univariate analysis were age (P = 0.007), pre-L T GFR (P = 0.012) and 7th day post-L T GFR (P = 0.003). Risk factors associated with RD on multivariate stepwise regression analysis were patient age [Odds ratio (OR) 1.04 (95% confidence interval (CI) 0.99- 1.09, P = 0.06)] and 7 day post-LT GFR [OR 0.97 (95% CI 0.96-0.99, P = 0.013)]. ROC curve analysis for 7th day post-LT GFR was 0.71 (95% CI 0.61-0.81).. The 7th day post-LT GFR in cirrhotic patients may be a useful clinical tool to identify which patients might benefit from earlier nephroprotective immunosuppression.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Period; Renal Insufficiency; Retrospective Studies; Risk Assessment; Sensitivity and Specificity; Tacrolimus; Time Factors

Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen α2(I) mRNA was at normal levels. Collagen α1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into α1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis.

Topics: Animals; Autoantigens; Carbon Tetrachloride; Collagen Type I; Ethanol; Gene Expression Regulation; HEK293 Cells; Hepatic Stellate Cells; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Male; Primary Cell Culture; Rats; Rats, Wistar; Ribonucleoproteins; SS-B Antigen; Tacrolimus; Tacrolimus Binding Proteins; Tissue Culture Techniques

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Topics: Administration, Oral; Biological Availability; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Esophageal Perforation; Esophagectomy; Hepatitis C; Humans; Immunosuppressive Agents; Jejunostomy; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Mediastinitis; Middle Aged; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Immunosuppressant-related hip pain can greatly affect a patient's mobility and increase the number of total hip arthroplasties. We investigated risk factors and causes of hip pain after orthotopic liver transplant.. The medical records of 175 adult orthotopic liver transplant patients, who were followed-up for more than 2 years, were retrospectively reviewed. Data collected from the records included primary disease, medications, biochemical results, Child-Turcotte-Pugh score, death, rejection, and complications related to liver transplant.. A total of 11 patients (6.3%) complained of hip pain, which was diagnosed as calcineurin-inhibitor-induced pain syndrome in 4 patients (2.3%), osteonecrosis of the femoral head in 3 patients (1.7%), and osteoporosis in 2 patients (1.1%). The incidence of calcineurin-inhibitor-induced pain syndrome was related to the dosage of tacrolimus (P > .05) but independent of methylprednisolone use. The occurrence of osteonecrosis of the femoral head was independent of the dosage and early withdrawal of methylprednisolone (P > .05). Patients with methylprednisolone withdrawal within 6 months had significantly longer survival than those using methylprednisolone for more than 6 months (50 ± 15 vs 41 ± 18 mo; P = .007).. Calcineurin-inhibitor-induced pain syndrome and osteonecrosis of the femoral head are main causes of hip pain in adult orthotopic liver transplant patients. Osteonecrosis of the femoral head was not common, but the incidence of hip pain owing to calcineurin-inhibitor-induced pain syndrome was relatively high in orthotopic liver transplant patients. Early withdrawal of methylprednisolone could benefit the patients' survival.

Topics: Adult; Aged; Arthralgia; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Hip Joint; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Osteonecrosis; Osteoporosis; Retrospective Studies; Risk Factors; Tacrolimus

The development of end-stage graft disease is suspected to be partially determined by an individual genetic background. The aim of our study was to determine the prevalence of YKL-40-gene polymorphism in hepatitis C virus (HCV)-positive patients and its impact on the incidence of acute cellular rejection (ACR), graft fibrosis and antiviral treatment response.. A total of 149 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for YKL-40 (rs4950928; G/C) by TaqMan Genotyping Assay. The results were correlated with 616 post-transplant graft biopsies regarding inflammation, fibrosis and evidence for ACR.. No association of YKL-40-genotypes was observed regarding mean inflammation grade (P = 0.216) and antiviral treatment outcome (P = 0.733). However, the development of advanced fibrosis (F3-4) was significantly faster in patients with YKL-40-G-allele: t(CC) = 4.6 versus t(CG/GG) = 2.4 years; P = 0.006. Patients with lower fibrosis (F0-2) compared to advanced fibrosis (F3-4) received significantly more frequent dual immunosuppression (calcineurin inhibitors [CNIs]/mofetile mycophenolate [MMF] vs CNIs; P = 0.003). ACR-occurrence was associated with YKL-40-genotypes (ACR: CC = 60.4%, CG = 25.0% and GG = 14.6% vs non-ACR: CC = 74.2%, CG = 23.8% and GG = 2.0%; P = 0.009) and with gender compatibility between donor and recipient (P = 0.012).. Fibrosis progression and ACR-incidence after transplantation for HCV-induced liver disease seem to be under genetic control. The negative impact of G-allele on post-transplant events observed in our study, deserves attention and should be verified in larger liver transplantation-cohorts.

Topics: Adipokines; Adult; Antiviral Agents; Chitinase-3-Like Protein 1; Cyclosporine; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Female; Genotype; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lectins; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Polymorphism, Single Nucleotide; Recombinant Proteins; Ribavirin; Sex Factors; Statistics, Nonparametric; Tacrolimus; Time Factors; Young Adult

Posterior reversible encephalopathy syndrome (PRES) is a rare disease characterized by altered mental status, seizures, headache, vomiting and visual disturbances, most often described after transplantation and immunosuppressive therapy. PRES is commonly first diagnosed by the neuroradiologist, rather than the clinician, as it is characterized by very typical magnetic resonance imaging (MRI) features, i.e., hyperintense lesions in the territories of the posterior cerebral artery. Here we report our experience in the Intensive Care Unit (ICU) with a case of tacrolimus-related PRES after liver transplant, presenting with sudden neurological deterioration and diffuse and massive hyperintensities upon brain MRI. Discontinuation of tacrolimus, as prompted by the established literature, permitted the patient to eliminate tacrolimus-associated toxicity, whereas its substitution with everolimus and mycofenolic acid allowed the maintenance of immunosuppression while avoiding acute organ rejection and reducing the dosage of corticosteroids. The lowering of blood pressure with drugs reported in the literature for use in PRES proved to be effective but challenging, requiring the use of multiple drugs and only slowly leading to proper control of hypertensive peaks. Nonetheless, hypertension management and supportive therapy allowed for a complete neurological restitutio ad integrum of the patient. In conclusion, tacrolimus-related brain adverse events need to be promptly recognized, especially during the first months after transplantation. When tacrolimus-related PRES occurs, immunosuppressive therapy may be safely and efficiently switched to everolimus and mycofenolic acid. This strategy may help not only to avoid acute organ rejection but also to reduce the dosage of corticosteroids, which might interfere with proper control of hypertension.

Topics: Brain; Critical Care; Electroencephalography; Humans; Immunosuppressive Agents; Intensive Care Units; Liver Cirrhosis; Liver Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Tacrolimus

To investigate the effect of zinc finger protein A20 on chronic liver allograft dysfunction in rats.. Allogeneic liver transplantation from DA rats to Lewis rats was performed. Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer administered intravenously every 10 d starting from POD 10. The recipient rats were injected with physiological saline, rAdEasy-A20 (1 × 10(9) pfu/30 g weight) or rAdEasy (1 × 10(9) pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10. Liver tissue samples were harvested on POD 30 and POD 60.. Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis. A20 overexpression ameliorated the effects on liver function, attenuated liver allograft fibrosis and prolonged the survival of the recipient rats. Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF)-β1, interleukin-1β, caspase-8, CD40, CD40L, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin. A20 treatment suppressed liver cell apoptosis and inhibited nuclear factor-κB activation of Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF-β1 in HSCs.. A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs, LSECs and HSCs.

Topics: Adenoviridae; Animals; Apoptosis; Biomarkers; Cells, Cultured; Chronic Disease; Cysteine Endopeptidases; Cytokines; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hepatic Stellate Cells; Immunosuppressive Agents; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Kupffer Cells; Liver; Liver Cirrhosis; Liver Diseases; Liver Transplantation; Male; NF-kappa B; Rats; Rats, Inbred Lew; Tacrolimus; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor alpha-Induced Protein 3

Among patients after renal transplantation (NTx), hepatitis C virus (HCV) infection is a risk factor for graft loss and patient death caused by hepatic decompensation. Also, HCV has been implicated in the pathogenesis of glomerular diseases in native and transplanted kidneys. Therefore, the aim of this retrospective cohort study was to determine the effects of the widely used calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus (Tac) on hepatitis C virus replication, inflammatory activity, development of liver fibrosis, and long-term renal graft function.. A cohort of 71 patients with HCV infection after kidney transplantation under immunosuppression with either CsA or Tac were analyzed for viral kinetics and serum transaminases. In addition, presence of liver fibrosis was detected by non-invasive measurements using the FibroScan. Graft function was determined biochemically. Patients with interferon therapy prior to transplantation were excluded from the study in order to avoid any impact of the antiviral therapy on outcomes.. In the early period after transplantation, hepatitis C viral load was lower in patients treated with Tac as compared to CsA. This effect became negligible 3 months after transplantation. However, hepatic inflammatory activity was reduced in the CsA-treated group. Extent of liver fibrosis was similar in both groups of HCV-infected patients as well as in a control group of non-HCV-infected patients after renal transplantation (NTx), respectively. Renal function and glomerular filtration rate, as calculated by the modification of diet in renal disease (MDRD) formula, were significantly better in patients treated with Tac.. During long-term immunosuppression, the CNIs cyclosporine A versus tacrolimus showed no significant differences in HCV-infected patients after renal transplantation with respect to viral replication and development of liver fibrosis. However, function of the renal graft is significantly better preserved in patients receiving tacrolimus.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Germany; Graft Survival; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Retrospective Studies; RNA, Viral; Tacrolimus; Time Factors; Transaminases; Treatment Outcome; Viral Load; Virus Replication

Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.. We retrospectively investigated 205 patients who had a living-donor liver transplantation performed at our institution between August 1998 and October 2008.. Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immunosuppression after their living-donor liver transplantation. The underlying diseases were alcoholic cirrhosis in 3 cases, viral cirrhosis in 2, biliary atresia in 1, and Wilson disease in 1. Time to clinical onset after tacrolimus medication was 15.6 days (range, 6-30 days). The neurologic symptoms included headache, confusion, myoclonus, seizures, and visual disturbances. The mean serum trough level of tacrolimus at clinical onset was not very high (11.7 ng/mL [range, 6.0-14.2 ng/mL]). T2-weighted magnetic resonance imaging in all cases showed diffuse high signal in the white matter of the frontal, parieto-occipital, and temporal lobes. Treatment with antihypertensives, anticonvulsants, and withdrawal of tacrolimus resulted in amelioration of symptoms and magnetic resonance imaging abnormalities. Six patients showed complete recovery, while the seventh had residual rigidity and cognitive impairment caused by hypoxia during a convulsion.. Tacrolimus neurotoxicity can occur despite low trough levels; it depends on variations in pharmacokinetics, such as absorption and maximum concentration level. Early diagnosis and treatment of leukoencephalopathy syndrome should contribute to complete remission.

Topics: Anticonvulsants; Antihypertensive Agents; Biliary Atresia; Child; Contraindications; Female; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Syndrome; Tacrolimus; Treatment Outcome

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Although an LDLT can successfully treat biliary atresia (BA), some patients develop liver fibrosis or inflammation. To study the incidence and risk factors associated with these complications, we performed serial protocol biopsies. Twenty-four patients with BA who received a pediatric LDLT underwent protocol biopsies. All patients received standard tacrolimus-based immunosuppression and steroids. The last available biopsies were assessed. The mean age at the time of transplant was 4.8yr and the follow-up period ranged from 1.2 to 12.3yr. The GRWR ranged from 0.8% to 4.5%. The mean time from transplantation to the latest biopsy was 4.7yr. No complications occurred with the biopsy protocol. The last available biopsies for 13 (54%) and 4 (17%) patients indicated grade 1 and grade 2 portal fibrosis, respectively, and 14 patients (54%) had inflammation. No ductopenia was detected. A younger age at LDLT was significantly correlated with graft fibrosis (p=0.036). These results indicate that biopsy-proven fibrosis can be detected in patients with BA after LDLT, even in the context of normal liver function blood tests. Therefore, a serial biopsy is a safe and effective follow-up procedure for pediatric LDLT.

Topics: Adolescent; Adult; Biliary Atresia; Biopsy; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Inflammation; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Tacrolimus

Neurologic complications are a significant cause of morbidity in children after liver transplant. In this study, we sought to evaluate the neurologic complications in children after liver transplant.. All children aged younger than 18 years old who had undergone liver transplant between June 2004 and June 2007 were included in this prospective study. There were 30 boys (62.5%) and 18 girls (37.5%) (mean age, 9.6 -/+ 4.3 years; mean duration of follow-up, 21.6 -/+ 9.4 months). The most common indications for liver transplant were biliary atresia (n=12, 25%), Wilson disease (n=7, 14.6%), tyrosinemia (n=7, 14.6%), progressive familial intrahepatic cholestasis (n=6, 12.5%), and autoimmune cirrhosis (n=5, 10.4%).. Immunosuppressive medication consisted tacrolimus (n=44, 91.7%) or cyclosporine (n=4, 8.3%) combined with mycophenolate mofetil (n=33, 68.7%) and prednisolone (n=18, 37.5%). The most-common neurologic complications were tremor (n=8, 16.7%), convulsions (n=6, 12.5%), insomnia (n=6, 12.5%), headache (n=5, 10.4%), muscle cramps (n=5, 10.4%), paresthesia (n=3, 6.2%), and weakness (n=3, 6.2%).. We conclude that the most-common neurologic complication after liver transplant in children in contrast to other studies is tremor, same as adult patients. This may be due to higher rate of use of tacrolimus in our patients.

Topics: Adolescent; Autoimmune Diseases; Child; Child, Preschool; Cholestasis, Intrahepatic; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Transplantation; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome; Tremor

Cytomegalovirus (CMV) infection represents one of the most frequent opportunistic infections following solid-organ transplantation. The incidence and severity of CMV infection depend on the immunosuppressive regimen, the CMV serostatus of donor and recipient, and the type of transplant.. We evaluated CMV infection rates during the last 2 years in our center: March 2007 to March 2009. We enrolled 55 patients-13 females and 42 males-who underwent liver transplantation (OLT) due to hepatitis C virus (HCV) cirrhosis (n = 9), hepatitis B virus (HBV) cirrhosis (n = 5) HCC both on HCV and HBV cirrhosis (n = 37), or autoimmune disease (n = 4). Fifty percent of the patients received tacrolimus (TRL) and the others cyclosporine (CsA), both dosed according to weight. All patients received oral acyclovir (400 mg/td or less, adapted to renal function) as herpes simplex prophylaxis for 6 months. CMV prophylaxis prescribed CMV- hyperimmunoglobulin on postoperative days 1 and 7. CMV infection was monitored using polymerase chain reaction (PCR <1000 IU/mL) according to the following schedule: every week for the first month, every 2 weeks from month 2 to 3 and monthly from month 4 to 6. Patients were treated when three positive PCR results not affected by immunosuppressive dose reduction or when the PCR showed DNA greater than three times the limit of detection. CMV treatment stipulated valgancyclovir (900 mg twice daily) until three consecutive PCRs were negative or for 3 months dosed according to renal function. PCR was measured every 2 weeks during treatment.. Among the patients who were all D(+)/R(+) (CMV-Immunoglobulin G [IgG](+)/IgG(+)). 10 required treatment (18%) within 3 months from OLT. There subjects were prescribed TRL (n = 4) or CsA (n = 6). No renal impairment was observed among treated patients. Of those having the infection, one died due to other causes-sepsis from candida at 5 months after OLT.. CMV-hyperimmunoglobulin on postoperative days 1 and 7 did not confer protection for CMV among OLT patients. Preemptive treatment with intravenous gancyclovir plus valgancyclovir per os seemed to be useful and safe in infected patients requiring treatment.

Topics: Acyclovir; Antiviral Agents; Corticosterone; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Retrospective Studies; Tacrolimus

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.

Topics: Cyclosporine; Disease Progression; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Antiviral Agents; Fatal Outcome; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Jaundice; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Ribavirin; Tacrolimus

To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.. A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.. Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.. Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Topics: Acute Kidney Injury; Anticholesteremic Agents; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Rhabdomyolysis; Simvastatin; Tacrolimus

Topics: Body Mass Index; Creatinine; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Liver Cirrhosis; Liver Transplantation; Tacrolimus

The improvement of pre-existing inflammatory bowel disease after orthotopic liver transplant might be anticipated. However, both the exacerbation of inflammatory bowel disease and de novo inflammatory bowel disease after orthotopic liver transplant (despite sufficient allograft immunosuppressive therapy) have been described.. We present a case of ulcerative colitis in a pediatric liver transplant recipient.. A 13-year-old boy with cryptogenic liver cirrhosis received an orthotopic liver transplant from a deceased donor. Five months later, he presented with watery diarrhea and abdominal distention. He was treated with the immunosuppressive agents tacrolimus (0.15 mg/kg/d) and mycophenolate mofetil (20 mg/kg/d). A general physical examination revealed a boy with stable vital signs and without fever. The only positive finding was enlargement of the abdomen without tenderness. Many pus cells and a few red blood cells were detected in the patient's stool, but the results of a stool culture for bacteria were negative. Because of his chronic diarrhea, this patient underwent colonoscopy, which revealed diffuse erythematous mucosa, multiple ulcers, exudate, and pseudopolyps with a diffuse loss of vascularity. Those findings are indicators of colitis. The results of histopathologic examination of the colonic mucosa suggested ulcerative colitis. The patient was treated with mesalamine and prednisolone, and a repeat colonoscopy revealed an improvement in his bowel disease.. De novo inflammatory bowel disease should be considered in patients in whom chronic diarrhea develops after an orthotopic liver transplant. We suggest that colonoscopy and biopsy should always be performed if other causes of diarrhea have been excluded.

Topics: Adolescent; Anti-Inflammatory Agents; Biopsy; Chronic Disease; Colitis, Ulcerative; Colon; Colonoscopy; Diarrhea; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Intestinal Mucosa; Liver Cirrhosis; Liver Transplantation; Male; Mesalamine; Mycophenolic Acid; Prednisolone; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10-100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation.

Topics: Aged; Calcineurin; Calcineurin Inhibitors; Concanavalin A; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Cirrhosis; Liver Transplantation; Lymphocyte Activation; Male; Middle Aged; Tacrolimus

Topics: Adult; Antiviral Agents; Critical Care; Diagnosis, Differential; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Intensive Care Units; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Opportunistic Infections; Oseltamivir; Postoperative Complications; Prednisone; Respiratory Insufficiency; Tacrolimus

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.

Topics: Adult; Aged; Biopsy; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Tacrolimus; Treatment Outcome

This report describes a patient who developed human T-cell leukemia virus type I-associated myelopathy (HAM) following a living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus (HCV) infection. Both the recipient and the living donor (his sister) were human T-cell leukemia virus type I (HTLV-I) carriers. Since the LDLT, he had been treated with immunosuppressive drugs such as tacrolimus and steroids as well as interferon-alpha to prevent rejection and a recurrence of the HCV infection, respectively. Even though the HTLV-I proviral load had decreased upon interferon treatment, he developed a slowly progressive gait disturbance with urinary disturbance 2 years after the LDLT and was diagnosed with HAM. This appears to be the first report of HAM development in an HLTV-I-infected LDLT recipient.

Topics: Antiviral Agents; Drug Therapy, Combination; Gait Disorders, Neurologic; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Middle Aged; Paraparesis, Tropical Spastic; Recombinant Proteins; Steroids; Tacrolimus; Treatment Outcome; Urination Disorders

To determine the efficacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH).. Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records.. Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P=0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P=0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P=0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P=0.016), while the degree of fibrosis tended to decrease (P=0.049).. The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of fibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Female; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Male; Middle Aged; Retrospective Studies; Tacrolimus

To evaluate the outcome of pediatric patients who underwent liver transplantation between Oct. 2002 and May 2005 in the Pediatric Hospital.. Eight cases aged from 4 to 67 months who underwent liver transplantation were analyzed retrospectively. Four of the patients were boys and 4 girls, whose body weight at the time of liver transplantation was 6-19 kg. The underlying diseases were biliary atresia, congenital cholestasis, drug-induced cholestatic cirrhosis and cryptogenic cirrhosis. These patients had been followed up for blood routine examinations, liver and renal function, serum electrolytes and blood concentration of tacrolimus for 16 to 43 months after liver transplantation. Results of serological studies for viral etiology, liver biopsy, growth and mental development were also recorded.. One-year survival rate was 75.0% with the longest survival time being 43 months after transplantation. One patient died from renal failure due to postoperative bleeding 24 hours after the surgery and another case died of variceal hemorrhage 8 months after transplantation. Posttransplantation complications included acute cellular rejection, viral infection and hypoalbuminemia. Viral infections included cytomegalovirus infection in 3 cases, Epstein-Barr virus infection in 1 and hepatitis B virus infection in 1. Surgical complications of portal vein thrombosis and stenosis of inferior vena cava and hepatic vein occurred in 2 cases respectively. Side effects of tacrolimus including hypertension, renal damage, liver damage and diarrhea were observed. Significant growth-retardation was not often seen. A self-reported high quality of life was common.. Close follow-up and management of patients after liver transplantation may significantly increase the survival rate and improve quality of life in children with end-stage liver diseases.

Topics: Biliary Atresia; Child; Child, Preschool; Constriction, Pathologic; Female; Graft Rejection; Hepatitis B; Herpesvirus 4, Human; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Pediatrics; Postoperative Complications; Survival Rate; Tacrolimus; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

Successful immunosuppressive therapy is critical for liver transplantation. However, a considerable number of patients show clinical resistance to the therapy and experience rejection episodes, or alternatively exhibits serious adverse effects of drugs. We examined the in vitro response of peripheral blood mononuclear cells (PBMCs) to immunosuppressive drugs in cirrhosis patients awaiting liver transplantation. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the in vitro blastogenesis of PBMCs obtained from 22 cirrhosis patients and 31 healthy subjects. In vitro drug concentrations giving 50% inhibition of PBMC blastogenesis (IC50s) were calculated. Two out of these 22 patients received liver transplantation from living donors, and their clinical courses were surveyed until 5 weeks after operation. The median IC50 values for prednisolone, cyclosporine, and tacrolimus against blastogenesis of PBMCs from cirrhosis patients were significantly lower than those of PBMCs from healthy subjects (p < 0.01). However, large individual differences were observed in the IC50 values of the immunosuppressive drugs examined, especially in the cirrhosis patients. One recipient exhibiting high PBMC sensitivity to tacrolimus (IC50 = 0.001 ng/ml) showed good clinical course without rejection until 5 weeks after liver transplantation. The other recipient exhibiting relatively low PBMC sensitivity to taclolimus (IC50 = 0.30) showed allograft rejection at 1 week after operation. We concluded from these observations that PBMCs of cirrhosis patients are vulnerable to the immunosuppressive effects of prednisolone and calcineurin inhibitors. However, large individual variations in the IC50 values suggest that patients exhibiting relatively lower sensitivity to these drugs may have risks of rejection, whereas highly sensitive patients are possibly able to reduce the dose of immunosuppressive drugs to avoid serious drug-adverse effects, after liver transplantation.

Topics: Adult; Cyclosporine; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Leukocytes, Mononuclear; Liver Cirrhosis; Liver Transplantation; Lymphocyte Activation; Male; Middle Aged; Prednisolone; Tacrolimus

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.

Topics: Adult; Age Factors; Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Glucocorticoids; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recurrence; Tacrolimus

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

Topics: Adult; Calcineurin Inhibitors; Deafness; Follow-Up Studies; Hearing Aids; Hearing Loss; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Retrospective Studies; Sirolimus; Surveys and Questionnaires; Tacrolimus; Time Factors

Induction therapy with T-cell depleting drugs in liver transplantation is controversial. This study examined the use of rabbit antithymocyte globulin (RATG) with delayed introduction of tacrolimus in liver transplant recipients. Additional subgroup analysis compared patients with or without hepatitis C (HCV) cirrhosis. Over 17 months, 116 adults received 120 liver allografts. Four patients who died before receiving RATG were excluded. Immunosuppression included steroids, 3 doses of RATG (2 mg/kg), and tacrolimus started on postoperative day 3 to 4. Ninety-six percent of patients were alive with a mean follow-up of 12.9+/-4.5 months. No graft was lost to rejection. Two patients developed hepatic artery thrombosis. Six percent of patients had acute rejection. No patient had steroid resistant or recurrent rejection. RATG related drug events were limited to fever, chills, tachycardia, and oxygen desaturation. There were no cases of lymphoproliferative disease. Forty-two percent of patients were transplanted for HCV. Thirty-two percent of HCV-patients had biopsy proven hepatitis C recurrence occurring at 4 weeks to 10 months posttransplant. RATG induction therapy is associated with good patient and graft survival, a low incidence of rejection, and minimal side effects. In addition, RATG induction is safe in patients transplanted for HCV.

Topics: Adult; Antilymphocyte Serum; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases; Liver Transplantation; Methylprednisolone; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

Steroids can increase hepatitis C virus (HCV) replication. After liver transplantation (LTx), steroids are commonly used for immunosuppression and acute rejection is usually treated by high steroid dosages. Steroids can worsen the outcome of recurrent HCV infection. Therefore, we evaluated the outcome of HCV infected liver recipients receiving initial steroid-free immunosuppression.. Thirty patients undergoing LTx received initial steroid-free immunosuppression. Indication for LTx included 7 patients with HCV related cirrhosis. Initial immunosuppression consisted of tacrolimus 2X0.05 mg/kg.d po and mycophenolate mofetil (MMF) 2X15 mg/kg.d po. The tacrolimus dosage was adjusted to trough levels in the target range of 10-15 microg/L during the first 3 mo and 5-10 microg/L thereafter. Manifestations of acute rejection were verified histologically.. Patient and graft survival of 30 patients receiving initial steroid-free immunosuppression was 86% and 83% at 1 and 2 years. Acute rejection occurred in 8/30 patients, including 1 HCV infected recipient. All HCV-infected patients had HCV genotype II (1b). HCV seropositivity occurred within the first 4 mo after LTx. The virus load was not remarkably increased during the first year after LTx. Histologically, grafts had no severe recurrent hepatitis.. From our experience, initial steroid-free immunosuppression does not increase the risk of acute rejection in HCV infected liver recipients. Furthermore, none of the HCV infected patients developed serious chronic liver diseases. It suggests that it may be beneficial to avoid steroids in this particular group of patients after LTx.

Topics: Adult; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Tacrolimus

Liver disease and transplantation affect bone turnover. The role of cylosporin A (CsA) in aggravating bone loss is controversial. The aim of the present study was to examine the effect of liver cirrhosis, transplantation, and immunosuppressive therapy with either CsA or tacrolimus on alveolar bone height.. The experimental group consisted of 13 liver cirrhosis (LC) patients. A second experimental group included 24 post-liver transplantation patients (PT) receiving CsA or tacrolimus. Seventeen healthy subjects formed a control group. Panoramic x-rays were taken and digitized using a computer-based measurement software to assess alveolar bone height of all available teeth.. Bone loss in the PT group (4.57+/-0.56 mm) was significantly higher than the control (C) (2.73+/-0.38 mm); however, it was significantly lower (P = 0.0005) than the LC (6.47+/-0.75 mm). Likewise, alveolar bone loss showed a trend for negative correlation (R = 0.404, P = 0.06) with the duration of immunosuppressive therapy post-liver transplantation.. Liver cirrhosis patients demonstrated greater bone loss compared to healthy controls. Restoration of liver functions following transplantation seems to have the potential to reverse some of these radiographic changes. Further longitudinal studies will be necessary to substantiate these findings.

Topics: Alveolar Bone Loss; Analysis of Variance; Case-Control Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Radiography; Statistics, Nonparametric; Tacrolimus

To evaluate the impact of acute and chronic liver disease and single immunosuppression (cyclosporine A [CSA] or FK506) on insulin sensitivity and glucose effectiveness in liver-grafted patients, we performed a frequently sampled intravenous glucose tolerance test (FSIGTT) in nondiabetic patients after orthotopic liver transplantation (OLT) with acute liver failure ([ALF] group, n = 9, with CSA therapy), in patients after OLT with chronic liver disease (CSA group, n = 8; FK506 group, n = 8), and in 9 healthy control subjects. Insulin sensitivity and glucose effectiveness were determined by analyzing glucose and insulin data from the FSIGTT with Bergman's minimal model technique for glucose. The intravenous glucose tolerance index ([KG] ie, the slope of the regression of the logarithm of blood glucose concentration) was not different between the ALF group (2.17 +/- 0.16 min(-1)) and controls (2.29 +/- 0.13 min(-1)), but was lower (P < .05) in both groups with chronic liver disease (CSA group, 1.46 +/- 0.1; FK506 group, 1.61 +/- 0.11 min(-1)) compared with the ALF group (P < .05). A positive relation for the KG and glucose effectiveness was found in all liver-grafted patients and controls. Insulin sensitivity was not different between all liver-grafted patients and controls. The body mass index (BMI) was the overall determinant of insulin sensitivity in all groups. Single immunosuppressive therapy does not impair insulin sensitivity in liver-grafted patients. The lower glucose effectiveness in liver-grafted patients with chronic liver disease but not in patients after ALF points to a defect in the regulation of glucose-mediated glucose uptake in peripheral tissue.

Topics: Adult; Blood Glucose; Cholesterol; Cyclosporine; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Immunosuppressive Agents; Insulin; Liver Cirrhosis; Liver Failure, Acute; Liver Transplantation; Male; Models, Biological; Postoperative Complications; Reference Values; Tacrolimus; Triglycerides

A 49-year old male patient with severe hemophilia A, coinfected with HIV and HCV, who underwent orthoptic liver transplantation because of hepatitis C cirrhosis is presented. We describe a strong interaction between nelfinavir and tacrolimus postoperatively, that caused a reduction of the dose of tacrolimus by a factor 70 compared with normal, to achieve therapeutic blood concentrations and to avoid toxic side effects. We suggest that nelfinavir inhibits the metabolism of tacrolimus because both compounds are well-known substrates for the cytochrome P450 isoenzyme CYP 3A4. The nelfinavir serum concentrations were not affected by the institution of tacrolimus. Although the interaction dramatically changed the tacrolimus dose-concentration relationship, the situation was manageable by frequent monitoring of blood concentrations of tacrolimus.

Topics: Drug Interactions; Drug Monitoring; Hemophilia A; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Nelfinavir; Tacrolimus

Topics: Adult; Aged; Bone Density; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Mandible; Maxilla; Middle Aged; Regression Analysis; Tacrolimus; Time Factors

Five cases that were referred to the Division of Transplantation at NYU School of Medicine for consideration for liver transplantation were discussed among a panel of hepatitis B and liver transplant experts. Opinions were obtained on the management at every stage of treatment of patients with the following initial information: Case one: young Asian woman in stage IV hepatic coma; intubated; prothrombin time (PT): 30 s; serum glutamic oxaloacetic transaminase (SGOT): 8,000 IU; total bilirubin: 25 mg/dL; hepatitis B surface antigen (HBsAg) positive. Case two: 70-yr-old woman, native of Greece; decompensated cirrhosis with encephalopathy; Child-Pugh Class C; HBsAg positive; hepatitis B surface antibody (HBsAb) negative; hepatitis B e antigen (HBeAg) positive; hepatitis B e antibody (HBeAb) negative; hepatitis B virus (HBV) DNA titer: 10,000. Case three: Muscular detective working full-time; cirrhosis; Child Pugh Class B; ascites controlled with spironolactone and furosemide; PT: 19s; HBsAg positive; HBsAb negative; HBV DNA titer: 50,000; low platelet count. Case four: 45-yr-old baker; cirrhosis and resectable 4-cm hepatoma; Child-Pugh Class B; PT: 16 s; Blood type O; United Network for Organ Sharing (UNOS) 2B; HBV DNA titer: 3,000. Case five: 40-yr-old Indian man; 300 pounds with massive ascites; Child Pugh Class C; PT: 17 s; HBsAg positive; HBV DNA titer: 22,000; transplanted with intra-operative hypotension; tacrolimus; graft functioning; HBIg 10,000 IU intra-operative and around the clock during the first post-operative week; required huge doses of hepatitis B immune globulin (HBIg) to maintain adequate HBsAb level; daily loss of 5 6 L of ascites fluid; post-operative day 8: anuric, blood urea nitrogen (BUN) 127, creatinine 3, mental status changes.

Topics: Adult; Aged; Antiviral Agents; Ascites; Carcinoma, Hepatocellular; Female; Hepatic Encephalopathy; Hepatitis B; Humans; Immunization, Passive; Immunoglobulins; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged; Tacrolimus

Topics: Cyclosporine; Electrocardiography; Female; Follow-Up Studies; Heart Rate; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Long QT Syndrome; Male; Tacrolimus

Topics: Cyclosporine; Electrocardiography; Female; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Tacrolimus

Topics: Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Liver Cirrhosis; Liver Transplantation; Tacrolimus; Trimetazidine; Vasodilator Agents

Autoimmune liver diseases (AILD) may progress to liver failure, requiring liver transplantation as definitive therapy, and these immune-mediated disorders may predispose the patient to more frequent graft rejection. The objective of this study was to determine the effect of preexisting AILD on the incidence of allograft rejection after liver transplantation. Sixty-three patients who underwent liver transplantation between March 1988 and December 1994 for AILDs that included autoimmune hepatitis (AIH; n = 33) and primary biliary cirrhosis (PBC; n = 30) were retrospectively compared with 47 patients who underwent liver transplantation for alcoholic cirrhosis during the same time period. There was a lower incidence of acute allograft rejection in patients with AILD who received tacrolimus-based compared with cyclosporine-based immunosuppression (50% v 85.5%; P = .02). However, patients with AILDs overall had a higher incidence of acute rejection than patients with alcoholic cirrhosis (81% v 46.8%; P < .001), regardless of the type of immunosuppression. In addition, steroid-resistant rejection occurred more frequently in patients with AILDs than in patients with alcoholic cirrhosis (38.1% v 12.8%; P = .003). There was also a trend toward a higher incidence of chronic rejection in patients with AILDs compared with patients with alcoholic cirrhosis (11.1% v 2.1%), but this difference did not reach statistical significance. Patient and graft survivals at 1 and 3 years were similar between patients with AILDs and alcoholic liver disease. Compared with alcoholic cirrhosis, preexisting AILDs are associated with a higher incidence of acute allograft rejection and a trend toward more frequent chronic rejection.

Topics: Adult; Autoimmune Diseases; Case-Control Studies; Chi-Square Distribution; Cyclosporine; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Statistics, Nonparametric; Tacrolimus; Transplantation, Homologous

Topics: Antibodies, Monoclonal; Cyclosporine; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Methylprednisolone; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Acute vanishing bile duct syndrome is a rare but established cause of progressive cholestasis in adults, is most often drug or toxin related, and is of unknown pathogenesis. It has not been reported previously in children. Stevens-Johnson syndrome is a well-recognized immune complex-mediated hypersensitivity reaction that affects all age groups, is drug or infection induced, and has classic systemic, mucosal, and dermatologic manifestations. A previously healthy child who developed acute, severe, rapidly progressive vanishing bile duct syndrome shortly after Stevens-Johnson syndrome is described; this was temporally associated with ibuprofen use. Despite therapy with ursodeoxycholic acid, prednisone, and then tacrolimus, her cholestatic disease was unrelenting, with cirrhosis shown by biopsy 6 months after presentation. This case documents acute drug-related vanishing bile duct syndrome in the pediatric age group and suggests shared immune mechanisms in the pathogenesis of both Stevens-Johnson syndrome and vanishing bile duct syndrome.

Topics: Acute Disease; Adult; Bile Duct Diseases; Biopsy; Child; Cholestasis; Female; Humans; Ibuprofen; Liver; Liver Cirrhosis; Prednisone; Stevens-Johnson Syndrome; Tacrolimus; Time Factors; Ursodeoxycholic Acid

An 8-month-old child with an immunodeficiency disorder characterized by abnormal lymphocyte function and by low IgG and IgA levels had combined liver and small bowel transplantation under tacrolimus and steroid immunosuppression for the treatment of short gut syndrome and hepatic cirrhosis. The patient developed an early postoperative episode of Pneumocystis carinii pneumonia, and a subsequent surgical complication, prompting discontinuance of tacrolimus. A skin rash eventually shown to be graft-versus-host disease (GVHD) developed in the flank on the 12th post-transplant day and gradually became generalized. Peritonitis, sepsis, multisystem organ failure including the liver allograft led to death on the 23rd post-operative day. The mechanisms leading to post-transplant GVHD under the specific circumstances in this case are discussed.

Topics: Exanthema; Fatal Outcome; Female; Glucocorticoids; Graft vs Host Disease; Humans; IgA Deficiency; IgG Deficiency; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Infant; Intestine, Small; Ischemia; Liver; Liver Cirrhosis; Liver Transplantation; Lymphocytes; Methylprednisolone; Multiple Organ Failure; Peritonitis; Pneumonia, Pneumocystis; Sepsis; Short Bowel Syndrome; Tacrolimus

Topics: Adolescent; Adult; Blood Transfusion; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Intestine, Small; Liver Cirrhosis; Middle Aged; Parenteral Nutrition, Total; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Drug Interactions; Erythromycin; Humans; Liver Cirrhosis; Liver Transplantation; Male; Tacrolimus

Topics: Cyclosporine; Drug Monitoring; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Incidence; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Transplantation; Muromonab-CD3; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Female; Fetal Blood; Graft Rejection; Humans; Infant, Newborn; Liver Cirrhosis; Liver Transplantation; Male; Maternal-Fetal Exchange; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Tacrolimus

Topics: Adult; Carcinoma, Hepatocellular; Cyclosporine; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Tacrolimus