tacrolimus and Liver-Diseases

Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.. A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.. The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD.. Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cholangiocarcinoma; Cholangitis, Sclerosing; Colectomy; Cyclosporine; End Stage Liver Disease; Enzyme Inhibitors; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the longterm administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation include Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance bio-marker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.

Topics: Antilymphocyte Serum; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Mycophenolic Acid; Reproducibility of Results; Sirolimus; Tacrolimus

The purpose of this review is to evaluate the historical and recent literature as it pertains to current immunosuppression regimens in hepatitis C virus (HCV)-positive (+) liver-transplant recipients.. Recent findings suggest that there are unique differences between HCV transplant recipients and non-HCV transplant recipients, not only in the graft's inflammatory response, but also to the treatments used to prevent and combat rejection.. HCV (+) transplant recipients present unique challenges. Over the years, there has been progress but there is clearly no consensus regarding the optimal immunosuppressive medications or drug regimens; however, there continues to be advancements in the management of patients with HCV. Though current studies do not provide clear evidence as to optimal immunosuppression, they do identify questions ideally addressed by large, randomized controlled trials.

Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Azathioprine; Basiliximab; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Daclizumab; Everolimus; Hepatitis C; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Mycophenolic Acid; Receptors, Interleukin-2; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Advances in organ preservation, surgical technique, and postoperative care have permitted the rapid development of liver transplantation in children. Consequently, the applicability of this procedure has gone beyond the treatment of life-threatening complications of chronic liver disease and now includes disabling morbidities and quality-of-life issues. The use of hepatic segments for transplantation with reduced or split cadaveric grafts and living-related donors has decreased the mortality of children awaiting liver transplantation. We are presently armed with a new potent immunosuppressive drug, tacrolimus, and an understanding that the migration and grafting of passenger leukocytes of bone marrow origin is the seminal explanation for allograft acceptance. The next forefront will involve manipulation of the process not only for the transplantation of already successful whole organs--such as the liver, kidney, pancreas, and heart--but also in the development of the intestinal transplantation program. Thus, augmentation of leukocyte traffic in unconditioned recipients of cadaver allografts with concomitant intravenous infusion of donor bone marrow cells under the same immunosuppressive management of tacrolimus-prednisone treatment will be the path into the future.

Topics: Child; Cyclosporine; Humans; Immunosuppressive Agents; Intestines; Kidney Transplantation; Liver Diseases; Liver Transplantation; Tacrolimus; Transplantation Chimera; Treatment Outcome; Vena Cava, Inferior

Orthotopic liver transplant is the only cure for end stage liver disease. Enormous progress has been made in the fields of graft and patient survival since the introduction of cyclosporine and tacrolimus. Scientists involved in basic and clinical research have dedicated their efforts to understanding the mechanisms of action and the side effects of these medications with the goal of finding the perfect balance between the well-being of the patient and the avoidance of rejection. A great deal of work has been done and now we can propose a variety of treatments suitable to different clinical scenarios. The introduction of new medications will offer even more options for the treatment of rejection in liver transplant patients.

Topics: Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Survival Rate; Tacrolimus

DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids).. eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Topics: Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Risk Factors; Tacrolimus

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Steroids; Tacrolimus; Young Adult

We studied whether the use of sirolimus with reduced-dose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000-2003), adult primary liver transplant recipients (n=222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p=0.009) and patient death (20% vs. 8%, p=0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p=0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p=0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

Topics: Adult; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; International Agencies; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Sirolimus; Survival Rate; Tacrolimus; Time Factors; Transplantation Immunology

Use of generic tacrolimus in liver transplantation (LT) could result in cost savings. Generic tacrolimus has been shown to be bioequivalent to innovator tacrolimus in healthy volunteers and renal transplant patients. There are limited data on the de novo use of generic tacrolimus in LT. This study aimed to determine whether the de novo use of generic tacrolimus (Adoport, Sandoz,UK) was associated with differences in outcomes, safety, and cost compared with innovator tacrolimus (Prograf, Astellas, Japan).. Patients were studied before and after a programmatic change from de novo IS with Prograf to Adoport. Outcomes, tacrolimus levels, doses, and costs were compared for the first-yr post-LT.. Ninety-four patients were studied, 46 Prograf, 48 Adoport. No significant differences in rejection, cytomegalovirus infection, acute kidney injury, sepsis, or graft loss were observed between groups. Tacrolimus costs were significantly reduced with the de novo use of Adoport. Day 14 dose normalized levels in Adoport patients showed significant variation but at the day 30 and one yr, there were no significant differences in the doses or levels of tacrolimus between groups.. Adoport is safe and effective compared to Prograf when used de novo in LT patients. Tacrolimus costs were significantly reduced by the use of Adoport.

Topics: Adult; Drugs, Generic; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Japan; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Retrospective Studies; Risk Factors; Tacrolimus

Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection.. This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months.. The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time.. Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Steroids; Tacrolimus; Time Factors

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Function Tests; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Chronic renal dysfunction is a frequent and severe complication in solid-organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty-one liver transplant recipients (19 males, mean age = 60.6 +/- 7.8 years) with chronic renal dysfunction (creatinine >or= 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 +/- 0.39 mg/dL (range = 1.50-2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft-Gault formula, was 54.64 +/- 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow-up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 +/- 0.40 (P = 0.012 with respect to basal values), 1.67 +/- 0.34 (P = 0.107), 1.70 +/- 0.41 (P = 0.521), and 1.57 +/- 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 +/- 16.50 (P = 0.013 with respect to basal values), 59.49 +/- 13.27 (P = 0.028), 59.82 +/- 16.83 (P = 0.124), and 64.46 +/- 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection.

Topics: Adult; Aged; Biomarkers; Calcineurin Inhibitors; Chronic Disease; Creatinine; Cyclosporine; Drug Administration Schedule; Everolimus; Feasibility Studies; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Two-hour postdose cyclosporine (C2) monitoring is becoming an accepted method of therapeutic drug monitoring, although it is not known whether C2 monitoring is superior to tacrolimus (FK)-based immunosuppression. The purpose of this trial was to compare the safety, efficacy, and pharmacoeconomics of cyclosporine A (CsA) monitored by C2 levels versus FK monitored by trough levels in de novo liver transplant recipients. After informed consent, 60 de novo liver transplant recipients were randomized in a 1:1 fashion to receive either FK (trough, 6-10 ng/mL) or CsA (C2, 600-1200 ng/mL) and corticosteroids. The 2 groups were similar for gender, race, indication for liver disease, and age. At 1 year, patient survival was similar (93% for FK versus 90% for C2). One patient in the FK arm was retransplanted because of recurrent hepatitis C virus (HCV). Early acute rejection occurred in 27% of FK-treated patients and 23% of CsA-treated recipients [P = not significant (NS)]. Recurrent HCV occurred in 21% of FK-treated patients and 61% of CsA-treated patient (P = 0.04). The incidence of other infections, new onset diabetes mellitus, requirement for antihypertensives, and requirement for cholesterol medications were similar between the groups. Annual calcineurin inhibitor costs were lower in the C2 arm ($5432 +/- 2091 for C2 versus $8291 +/- 3948 for FK, P = 0.001). Annual pretransplant drug costs ($2292 +/- 2331 for C2 versus $2831 +/- 2358 for FK, P = NS) and 1-year posttransplant drug costs ($17,214 +/- 16,600 for C2 versus $15,151 +/- 11,699 for FK, P = NS) were similar. In conclusion, immunosuppression with CsA, monitored by C2 levels, is safe, effective, and economical in liver transplant recipients and provides immunosuppression at least equivalent to that of FK.

Topics: Adrenal Cortex Hormones; Adult; Cost-Benefit Analysis; Cyclosporine; Drug Costs; Drug Monitoring; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Time Factors

Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine [CsA], sirolimus [SrL], tacrolimus [FK]) and antiretrovirals (ARVs) (e.g. protease inhibitors [PIs] and/or nonnucleoside reverse transcriptase inhibitors [NNRTIs]) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.

Topics: Adult; Anti-Retroviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Female; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pilot Projects; Sirolimus; Tacrolimus

Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.

Topics: Adult; Aged; Antiviral Agents; Biopsy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Growth Substances; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Interferons; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Prednisone; Recombinant Proteins; Ribavirin; Tacrolimus; Time Factors

A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P =.011), acute cellular rejection (6% vs 27%, P =.038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P =.011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P =.007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antigens, Viral; Basiliximab; Cytomegalovirus; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Incidence; Injections, Intravenous; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Receptors, Interleukin-2; Recombinant Fusion Proteins; Tacrolimus

This is the first multicenter, randomized, open-label study to compare the efficacy and safety of cyclosporine A microemulsion (CsA-ME) (Neoral, Novartis, Basel, Switzerland ) with C2 monitoring versus tacrolimus in de novo liver transplant recipients. Patients were stratified according to hepatitis C virus status and randomized to receive CsA-ME (n= 250) or tacrolimus (n= 245) with steroids, with or without azathioprine. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 3 months. Secondary endpoints included death or graft loss and safety evaluations at 6 months. The incidence of BPAR at 3 months was 26% in the CsA-ME group and 24% in the tacrolimus group (not significant). At 6 months, 89% of patients receiving CsA-ME and 88% of patients receiving tacrolimus were alive with a functioning graft. Among the hepatitis C virus-positive patients, there was no difference in BPAR, but death or graft loss was more frequent in those receiving tacrolimus (15% vs. 6%, P <0.05). Diabetes mellitus (14% vs. 7%, P <0.02) and diarrhea (29% vs. 14%, P <0.001) were significantly more often reported in patients receiving tacrolimus. The incidence of hypertension was similar in both groups. At 6 months, the median total cholesterol was 4.7 mmol/L (2.9-7.4 mmol/L) in the CsA-ME arm versus 4.3 mmol/L (2.5-6.4 mmol/L) in the tacrolimus arm; the median serum creatinine was 106 micromol/L (52-238 micromol/L) in the CsA-ME arm versus 103 micromol/L (44-477 micromol/L) in the tacrolimus arm. Efficacy is equivalent with CsA-ME using C2 monitoring or tacrolimus in liver transplant recipients. The incidence of adverse events is comparable except for a significantly higher incidence of diabetes mellitus and diarrhea in the tacrolimus group. Both agents are effective primary immunosuppressants in liver transplant recipients.

Topics: Adult; Aged; Biopsy; Cyclosporine; Diabetes Mellitus; Emulsions; Graft Rejection; Hepacivirus; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Diseases; Liver Transplantation; Middle Aged; Monitoring, Physiologic; Tacrolimus; Time Factors; Treatment Outcome

Induction with monoclonal antibodies for prevention of acute cellular rejection (ACR) may avoid many of the adverse events associated with polyclonal antibodies. Basiliximab, a chimeric monoclonal antibody directed against the alpha-chain of the interleukin 2 receptor (CD25), has been extensively evaluated as an induction therapy for kidney transplant recipients, more frequently in combination with a cyclosporine-based regimen. In this study, we assessed the efficacy and safety of basiliximab in combination with a tacrolimus-based regimen after liver transplantation.. Fifty consecutive liver transplants (47 cadaveric donors; 3 living donors) were analyzed. All patients received two 20-mg doses of basiliximab (days 0 and 4 after transplantation) followed by tacrolimus (0.15 mg/kg/day; 10-15 ng/mL target trough levels) and a tapered dose regimen of steroids. Follow-up ranged from 404 to 1,364 days after transplantation (mean 799.89 days, SD+/-257.37; median 796 days).. A total of 88% of patients remained rejection-free during follow-up with an actuarial rejection-free probability of 75% within 3 months. The actuarial patient survival rate at 3 years was 88%, and the graft survival rate was 75%. Twelve (24%) patients experienced one episode of sepsis, requiring temporary reduction of immunosuppressive therapy. There were no immediate side effects associated with basiliximab and no evidence of cytomegalovirus infection or posttransplant lymphoproliferative disorder.. Basiliximab in combination with a tacrolimus-based immunosuppressive regimen is effective in reducing episodes of ACR and increasing ACR-free survival after liver transplantation. In addition, basiliximab does not increase the incidence of adverse effects or infections.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft Survival; Hepatitis, Viral, Human; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Recombinant Fusion Proteins; Survival Analysis; Tacrolimus

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Topics: Adult; Aged; Area Under Curve; Bile; Bilirubin; Chromatography, High Pressure Liquid; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucuronates; Glucuronides; Half-Life; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Serum Albumin; Tacrolimus; Time Factors

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Topics: Adult; Bone Marrow Transplantation; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Infections; Kidney Diseases; Life Tables; Liver Diseases; Male; Methotrexate; Middle Aged; Pilot Projects; Safety; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

To determine the concentrations of FK506 and its metabolites in blood from liver transplant patients and subjects with hepatic dysfunction.. HPLC was combined with an enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of FK506 and its immunoreactive metabolites in human whole blood.. In four liver transplant patient, most of the immunoreactivity was seen in the HPLC fractions where unchanged FK506 eluted. FK506 accounted for about 95% or more of the total immunoreactivity in the first days of posttransplant. Immunoreactivity observed in the nonFK506 fractions ranged from 1.6% to 10.7% of the total immunoreactivity; about 30% of the nonFK506 immunoreactivity was due to M-III(15-O-demethyl FK506). Blood from subjects with mild hepatic dysfunction was examined at 1.5 and 6 hours after an oral and intravenous dose, respectively, by HPLC-ELISA. Regardless of the route of administration, more than 96% of the total immunoreactivity was recovered in the FK506 fraction. M-III was detected in the blood of 3 of 6 subjects after an oral dose, but in none of these after an intravenous dose.. ELISA is an appropriate method for therapeutic drug monitoring of FK506.

Topics: Adult; Child; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Tacrolimus

Tacrolimus (formerly FK506) was first used clinically in 1989 to successfully replace cyclosporine in hepatic transplant recipients who were experiencing intractable rejection or as the baseline drug from the time of operation. After extensive pilot experience, an institutional review board-mandated clinical trial comparing cyclosporine with tacrolimus was performed.. From February 16, 1990 to December 26, 1991, 154 patients were recruited. The competing drugs were combined with equal induction doses of prednisone in both arms of the study for the first 81 patients and with subsequently higher doses of prednisone in the remaining 35 patients who received cyclosporine and were entered into the trial. Drug crossover was permitted for lack of efficacy or adverse events. End points were rejection confirmed by biopsy and treatment failure leading to retransplantation or death.. Seventy-nine patients were randomized to the tacrolimus arm and 75 to the cyclosporine arm during 1990 and 1991. All patients were available for follow-up throughout the trial, which terminated on May 30, 1995. The mean duration of follow-up was four years. Patients randomized to the tacrolimus arm were less likely to experience acute rejection than were those receiving cyclosporine, with 36.2 percent of the patients receiving tacrolimus and 16.8 percent of the patients receiving cyclosporine showing freedom from rejection at one year (p = 0.003, likelihood ratio test). Survival of patients over the course of the study was virtually the same in the two groups.

Topics: Adolescent; Adult; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prednisone; Tacrolimus; Treatment Outcome

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Incidence; Liver Diseases; Liver Neoplasms; Liver Transplantation; Male; Steroids; Survival Rate; Tacrolimus

Tacrolimus (FK 506), a macrolide compound isolated from a bacterium, is a potent immunosuppressant with activity in solid-organ transplants. Most immunosuppressive regimens for liver transplantation are based on cyclosporine.. We conducted an open-label, randomized, multicenter trial to compare the efficacy and safety of tacrolimus-based and cyclosporine-based immunosuppressive regimens for patients receiving a first liver transplant. A total of 478 adults and 51 children (< or = 12 years of age) were randomly assigned at the time of transplantation to receive tacrolimus (n = 263) or cyclosporine (n = 266) and were followed for one year. The primary end points were patient and graft survival at one year. The secondary end points were the incidence of acute rejection, corticosteroid-resistant rejection, and refractory rejection (continued rejection after two courses of corticosteroids and an intervening course of muromonab-CD3).. According to Kaplan-Meier analysis, actuarial patient-survival rates at day 360 were 88 percent for both the tacrolimus and cyclosporine groups (P = 0.85; 95 percent confidence interval for the difference, -5.4 to 6.6 percent), and graft-survival rates were 82 percent and 79 percent, respectively (P = 0.55; 95 percent confidence interval for the difference, -4.8 to 9.7 percent). Acute rejection occurred in 154 patients in the tacrolimus group and 173 patients in the cyclosporine group (P < 0.002), corticosteroid-resistant rejection occurred in 43 and 82 patients, respectively (P < 0.001), and refractory rejection occurred in 6 and 32 patients, respectively (P < 0.001). Tacrolimus was associated with a higher incidence of adverse events requiring withdrawal from the study, primarily nephrotoxicity and neurotoxicity; 37 patients in the tacrolimus group and 13 in the cyclosporine group discontinued the study because of adverse events (P < 0.001).. After one year, immunosuppressive regimens based on tacrolimus and cyclosporine were comparable in terms of patient and graft survival. Tacrolimus was associated with significantly fewer episodes of acute, corticosteroid-resistant, or refractory rejection, but substantially more adverse events requiring discontinuation of the drug.

Topics: Adult; Child; Confidence Intervals; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Liver Diseases; Liver Transplantation; Male; Tacrolimus

Children receive transplants at a younger age, and the period of immunosuppression therapy may extend over decades. However, immunosuppression seems to be responsible for long-term mortality and morbidity. Pediatric liver transplant recipients can benefit from achieving immune tolerance and the opportunity of freedom from lifelong immunosuppression. This study aimed to investigate the frequency of prope tolerance among pediatric liver transplant recipients and the characteristics of these patients.. In this retrospective cohort study of pediatric liver transplant recipients, the medical records of transplant recipients treated at Shiraz Organ Transplant Center between 1994 and 2017 were reviewed. Prope tolerance was defined as normal laboratory values and stable clinical status on low-dose monotherapy. Children treated with low-dose monotherapy were categorized as the prope tolerant group. We compared the characteristics of prope tolerant recipients on low-dose monotherapy with patients on standard immunosuppression, i.e. full-dose tacrolimus plus steroids and mycophenolate mofetil. The data were analyzed with the t-test, chi-squared test, and a Cox proportional hazard model at a 5% significance level in SPSS software version 16.. A total of 585 children with a mean age of 8.32 ± 5.23 years were enrolled. 341 patients were categorized as prope tolerant and 244 comprised the full immunosuppression regimen group. Mean age at transplantation and rejection frequency were lower in the prope tolerant group (p < 0.001, p < 0.001). Based on the underlying diseases, metabolic/genetic, biliary tract, and cryptogenic liver diseases were significantly more prevalent in the prope tolerant group (p < 0.001). However, autoimmune liver disease was found to be more prevalent in the full immunosuppression regimen group. Also, those who received living organs (p = 0.001) and recipients of organs from female donors had a greater likelihood of achieving prope tolerant. According to the multiple Cox regression results, age at transplantation (p = 0.022), rejection frequency (p < 0.001), and autoimmune liver diseases (p = 0.028) had a prognostic effect on prope tolerance.. Factors as underlying disease, age at transplantation, and rejection frequency were factors that were predictive of prope tolerance in this sample of children. However, the risk of rejection should be considered during the tapering period.

Topics: Adolescent; Child; Child, Preschool; Female; Graft Rejection; Humans; Immune Tolerance; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Retrospective Studies; Tacrolimus

This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1 h)-reperfusion (72 h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus.. Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72 h.. The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72 h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001).. Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy.

Topics: Animals; Interleukin-17; Liver Diseases; Male; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tacrolimus

Renal dysfunction is related to short- and long-term survival after liver transplantation. We present herein a retrospective analysis of our experience with liver transplantation in recipients with pretransplant renal dysfunction treated with induction therapy followed by delayed/reduced de novo once-daily tacrolimus.. Liver transplantations performed between April 2008 and August 2011 were included in this study. Pretransplant renal dysfunction was defined as estimated glomerular filtration rate <60 mL/min. Interleukin-2 receptor antagonists were used for induction therapy. Initial once-daily tacrolimus dose was 0.10 mg/kg/day or 0.07 mg/kg/day if combined with mycophenolate mofetil (MMF). Tacrolimus target trough levels were 4 to 6 ng/mL during the first post-transplant year and <4 ng/mL the rest of the follow-up.. Nineteen patients comprised the study cohort with a median follow-up of 56.4 months (range, 11-78). Median day of tacrolimus introduction was 7 (range, 3-12). Once-daily tacrolimus was withdrawn in 6 patients (31.6%) due to evolution of renal dysfunction in all cases. At 5 years, 30% of the patients were under MMF monotherapy. Mean tacrolimus trough levels were maintained under 5 ng/mL. Mean estimated glomerular filtration rate at 5 years was 55.3 ± 12.7 mL/min. No patient needed hemodialysis or renal transplantation over the follow-up. Patient survival at 5 years was 78.9%.. Induction therapy followed by delayed/reduced de novo once-daily tacrolimus and maintenance of low tacrolimus exposition during the follow-up is effective to maintain long-term renal function and to achieve favorable patient survival in liver transplant recipients with pretransplant renal dysfunction.

Topics: Aged; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Preoperative Period; Retrospective Studies; Tacrolimus; Treatment Outcome

To evaluate the association between tacrolimus trough levels and dosage in Pakistani patients undergoing live donor liver transplantation (LDLT), and the efficacy and adverse effects at different tacrolimus trough levels and dosages.. An observational study.. Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad and Basic Medical Sciences Institute, Karachi, from September 2016 to October 2018.. Sixty liver transplant recipients were included. Demographics, clinical data, tacrolimus trough levels and doses were monitored as per routine protocol. Electrochemiluminescence immunoassay (ECLIA) was used to measure tacrolimus trough levels. Acute cellular rejection (ACR), sepsis and other adverse events were monitored at different tacrolimus trough levels in early post-transplantation period.. Mean age of transplant recipients was 49.1 ± 10.6 years. Mean tacrolimus trough levels were 6.1 ± 2.2 ng/ml and mean dose was 0.94 ± 0.3 mg. Sepsis (27%) psychosis (20%), seizures (10%), and renal insufficiency (13%) were the most common adverse effects. Acute cellular rejection (ACR) was observed in 15% patients. Patients with sepsis had significantly high mean tacrolimus levels of 7.7 ± 2.5 ng/ml versus 5.5 ± 1.9 ng/ml (p=0.001). Mean tacrolimus trough levels in patients with ACR were significantly lower (4.05 ± 1.6 ng/ml vs. 6.43 ± 2.2ng/ml, p=0.003). None of the patients with a single tacrolimus trough level >10 ng/ml experienced ACR.. A tacrolimus trough level between 5 to 7.5 ng/ml appears to be safe in Pakistani liver transplant recipients significantly minimising the risk of ACR and other adverse events.

Topics: Female; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Pakistan; Prospective Studies; Survival Analysis; Tacrolimus

Generic tacrolimus (Tacrobell. Two hundred sixty-five adult DDLTs were performed in our center between 2003 and 2017. To determine the efficacy and safety of generic tacrolimus, renal function (estimated glomerular filtration rate [eGFR] and creatinine), infectious complications, rejection-free survival rates, and patient survival rates were investigated.. Of 265 patients, 193 were selected and divided into a generic tacrolimus group (n=147) and a brand-name group (n=46). Mean follow-up duration was 63.2 ± 44.3 months. The 1-year, 3-year, 5-year, and 10-year patient survival rates were 89.1%, 86.9%, 84.5%, and 75.2%, respectively, in the generic tacrolimus group and 95.7%, 88.9%, 86.3%, and 83.7% in the brand-name tacrolimus group. There were no statistically significant differences in the infectious complications, new-onset diabetes, and renal dysfunction included mean serum creatinine level or eGFR after DDLT between the two groups. Increased recipient age, continuous renal replacement therapy (CRRT) in the pre-transplant phase, and acute rejection were predisposing factors for patient death.. The present study shows that generic tacrolimus is an alternative comparable to brand-name tacrolimus in adult DDLT patients.

Topics: Adult; Aged; Drugs, Generic; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Recent reports have indicated that the risk of anti-D alloimmunization following D-incompatible platelet (PLT) transfusion is low in hematology and oncology patients. We investigated the rate of anti-D alloimmunization in RhD-negative (D. We reviewed the blood bank database from January 2003 to October 2016. D. Six of the 56 eligible patients (10.7%) had anti-D antibodies. All had received whole blood-derived PCs. Four of 20 patients (20%) untransplanted or transfused before LT and only two of 36 patients (5.6%) transfused during or after LT produced anti-D antibodies. These two patients were on maintenance immunosuppression based on low-dose steroids and tacrolimus. The factors identified as significantly associated with anti-D immune response were the presence of red blood cell immune alloantibodies before D. D

Topics: Aged; Blood Banks; Chronic Disease; Female; Humans; Immunosuppression Therapy; Liver Diseases; Male; Middle Aged; Platelet Transfusion; Rho(D) Immune Globulin; Risk Factors; Steroids; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Diseases; Tacrolimus

Topics: Hepatitis, Autoimmune; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Liver Diseases; Tacrolimus

BACKGROUND Long-term morbidity and mortality in liver transplant recipients is frequently secondary to immunosuppression toxicity. However, data are scarce regarding immunosuppression minimization in clinical practice. MATERIAL AND METHODS In this cross-sectional, multicenter study, we reviewed the indications of immunosuppression minimization (defined as tacrolimus levels below 5 ng/mL or cyclosporine levels below 50 ng/mL) among 661 liver transplant recipients, as well as associated factors and the effect on renal function. RESULTS Fifty-three percent of the patients received minimized immunosuppression. The median time from transplantation to minimization was 32 months. The most frequent indications were renal insufficiency (49%), cardiovascular risk (19%), de novo malignancy (8%), and cardiovascular disease (7%). The factors associated with minimization were older age at transplantation, longer post-transplant follow-up, pre-transplant diabetes mellitus and renal dysfunction, and the hospital where the patients were being followed. The patients who were minimized because of renal insufficiency had a significant improvement in renal function (decrease of the median serum creatinine level, from 1.50 to 1.34 mg/dL; P=0.004). Renal function significantly improved in patients minimized for other indications, too. In the long term, glomerular filtration rate significantly decreased in non-minimized patients and remained stable in minimized patients. CONCLUSIONS Immunosuppression minimization is frequently undertaken in long-term liver transplant recipients, mainly for renal insufficiency. Substantial variability exists regarding the use of IS minimization among centers.

Topics: Age Factors; Cardiovascular Diseases; Cross-Sectional Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Risk Factors; Tacrolimus; Transplant Recipients

Topics: Adult; Atrioventricular Block; Bone Marrow Transplantation; Bradycardia; Electrocardiography; Female; Graft vs Host Disease; Heart Block; Hemorrhage; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Liver Diseases; Lung Diseases; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Mycophenolic Acid; Pneumonia, Staphylococcal; Skin Diseases; Tacrolimus; Transplantation, Homologous

The widespread use of immunosuppressive agents has significantly increased the rates of successful solid-organ and stem cell transplants, especially with liver and kidney. Cyclosporine and tacrolimus are most commonly used for this purpose. Although these agents have different mechanisms of action, both have various adverse effects, including nausea, vomiting, headache, hypertension, nephrotoxicity, and rarely epileptic seizures. In our first case, a patient presented with epileptic seizures and hemiparesis after a liver transplant, and posterior reversible encephalopathy syndrome related to cyclosporine toxicity was considered. Once cyclosporine levels in the blood decreased, the patient had both clinical and radiologic improvements. In our second case, a patient presented with delirium after a liver transplant. Again, when cyclosporine levels in the blood decreased, the patient showed improvement in clinical findings. Neurologic complications may develop after liver transplant, and these complications are encountered most frequently within the first postoperative month. Neurologic complications are multifactorial; insufficient graft function, intracranial bleeding, cerebral infarcts, infections, and immunosuppressive drug toxicity (tacrolimus and cyclosporine) may be considered among these factors. As shown in our presented cases, most neurologic complications can be successfully treated by correcting the underlying factor.

Topics: Cyclosporine; Epilepsy; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Muscle Weakness; Paresis; Postoperative Complications; Reflex, Babinski; Tacrolimus

Tacrolimus is known to have little hepatotoxicity. Nevertheless, a few case studies have shown liver toxicities of tacrolimus, particularly in patients on multiple medications. This study is a retrospective data analysis on the potential of tacrolimus hepatotoxicity.. A data analysis was conducted on the electronic medical records (EMRs) of 2,462 Korean patients taking tacrolimus or cyclosporine from 2002 through to 2008. Alanine aminotransferase (ALT) and total bilirubin level (TBL) were also monitored. The maximum ALT, time to reach ALTmax (TALTmax), and TBL(ALTmax) were compared between the tacrolimus and cyclosporine groups. Other possible factors that may aggravate liver function were also investigated.. ALTmax and TBL(ALTmax) were higher in the tacrolimus group compared to the cyclosporine group (i.e., 50 IU/L vs. 41 IU/L and 1 mg/dL vs. 0.9 mg/dL, respectively), and TALTmax was shorter (i.e., 101 days vs. 142 days) in the tacrolimus group. In addition, the frequency of ALTmax > 3x upper limit of normal (ULN) (i.e., ALTmax > 120) was significantly increased in the tacrolimus group compared to the cyclosporine group (30% vs. 21%). The severity of tacrolimusinduced liver damage was greater in patients with history of liver disease, as indicated by > two-fold greater ALTmax than that of cyclosporine (i.e., 153 IU/L vs. 65 IU/L). Moreover, the ALTmax was significantly lowered by switching from tacrolimus to cyclosporine in patients with a history of liver disease. In patients with preexisting renal disease, neither tacrolimus nor cyclosporine showed any effect on ALTmax.. Results indicate that tacrolimus may have a higher risk of inducing liver injury in Korean patients with a history of liver disease and may require close monitoring.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Bilirubin; Biomarkers; Chemical and Drug Induced Liver Injury; Cyclosporine; Drug Monitoring; Electronic Health Records; Female; Humans; Immunosuppressive Agents; Liver Diseases; Male; Middle Aged; Republic of Korea; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Young Adult

Topics: Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Sirolimus; Tacrolimus

Topics: Adult; Amsacrine; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Cytarabine; Daunorubicin; Drug Therapy, Combination; Egg Hypersensitivity; Etoposide; Female; Food Hypersensitivity; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Humans; Idarubicin; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Liver Diseases; Male; Middle Aged; Nut Hypersensitivity; Seafood; Tacrolimus; Transplantation Conditioning; Vidarabine

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5-5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49-year-old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition-related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12-15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus-associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.

Topics: Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Posterior Leukoencephalopathy Syndrome; Postoperative Complications; Prognosis; Recurrence; Sirolimus; Tacrolimus

Cost of post liver transplant immunosuppression is a major financial burden to patients in developing countries. In India, generic varieties of various immunosuppressants are often used without any definite evidence to their efficacy. This study was aimed at studying the dosage, side effect profile and cost of post-liver transplant immunosuppression using generic products in Indian population following living donor liver transplantation (LDLT).. Data on dose, cost, and toxicity of immunosuppression were retrieved retrospectively from case records of 59 patients who had undergone LDLT at our center.. Adequate immunosuppression was obtained by tacrolimus (Pangraf(®)-Panacea) of 0.04 to 0.05 mg/Kg, and mycophenolate (Mycept(®)-Panacea) of 500 to 1,000 mg; the acute rejection rate was 15% during the first month. Serum tacrolimus levels were 5.4 to 7.3 ng/mL. The cost of immunosuppression varied from Rs. 28,705 in the first month to Rs. 8,820 per month at the end of first year, amounting to an average monthly cost of Rs. 17,250. Approximately 23% and 51% of cost was for mycophenolate and for drug level measurement of tacrolimus, respectively.. Average cost of immunosuppression after LDLT in India is much lower than that reported elsewhere in the world, since lower drug doses are needed and cheaper generic drugs are available. This can be reduced further by decreasing the frequency of tacrolimus drug level measurement.

Topics: Health Care Costs; Humans; Immunosuppression Therapy; Immunosuppressive Agents; India; Liver Diseases; Liver Transplantation; Living Donors; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

To present our experience with simultaneous living donor liver and kidney (SLK) transplantation from two different living donors.. We performed five SLK transplantations from two different living donors from November 2006 to December 2010. Four patients were males and one, female. Their age range was 47 to 66 years (mean, 55 years). The primary liver diseases included hepatitis B virus (n=2), alcoholic liver cirrhosis (n=2), cryptogenic liver disease (n=1), and hepatitis C virus with hepatocellular carcinoma (n=1). All five patients had chronic renal failure: four were on hemodialysis (H/D) and one on chronic ambulatory peritoneal dialysis for 1 to 20 years. Liver implantation was performed first, followed by kidney transplantation. The liver and kidney teams worked closely to shorten the ischemia time.. All surgical procedures were performed uneventfully and all recipients and donors survived the operations. Good liver graft function was noted in all five patients. The patient with both anti-T- and anti-B-cell positive crossmatch tests developed hyperacute rejection of the kidney graft requiring its immediate removal. This patient was maintained on regular H/D afterward. The other four patients displayed good renal function. No evidence of severe acute rejection was noted during the follow-up period (range, 9-55 months) among patients treated with tacrolimus-based immunosuppression.. We suggest that SLK transplantation be performed with organs from two different instead of a single live donor.

Topics: Aged; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Reoperation; Retrospective Studies; Tacrolimus; Taiwan; Time Factors; Treatment Outcome

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

Topics: Adult; Bilirubin; Cystic Fibrosis; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Lung Transplantation; Male; Respiratory Insufficiency; Tacrolimus

In liver transplantation (LT), modern immunosuppressive protocol is focused on early corticosteroid (CS) weaning. The aim of the study was to investigate all early transplant-related complications using Clavien grading system, in order to identify a significant relation in two homogenous groups of consecutive liver transplanted patients, only different for steroid avoidance in immunosuppressive regimen.. One group was treated with a tacrolimus-based CS-free immunosuppressive protocol, the other one underwent tacrolimus plus low dose CS therapy. The preoperative continuous variables analyzed were age, gender, model for end-stage liver disease (MELD) score, and the pre-allocation score for predicting survival following liver transplantation (P-SOFT).. There were 39 patients in Group A (CS free) (37.9%), and 64 patients in Group B (CS on board) (62.1%). No statistically significant differences between the two groups were detected regarding the incidence and Clavien grade of complications (P = 0.116). No significant relation was revealed between Clavien rate of complications and tacrolimus-based CS-free immunosuppressive protocol, comparing the two subgroup of patient with P-SOFT score < 6 and ≥ 6 (P = 0.193). This association was noted comparing the two subgroups on tacrolimus plus low dose CS regimen (P = 0.013).. In this series, the use of CS in sick patient is associated with higher morbidity identified by the Clavien classification.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Young Adult

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Topics: Brain Diseases; Cohort Studies; Cyclosporine; Female; Hepatitis B; Hepatitis C; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome

The objective of this study was to identify the incidence of posttransplantation lymphoproliferative disease (PTLD) among children within 1 year after liver transplantation.. This retrospective review analyzed information in medical charts of pediatric (younger than 18 years of age) recipients of liver transplants between September 2000 and December 2007.. Seventy-one patients underwent a liver transplantation and 7 (9.85%) developed PTLD. Among this group, 6 children were girls and 1 was a boy. The median age at transplantation was 35.14 months. Indications that led the children to have their transplantation were 1 case of hemangioendothelioma, 1 case of autoimmune hepatic cirrhosis, 1 case of alpha-1-antitrypsin deficiency, and 4 cases of biliary atresia. The most frequent symptoms were splenomegaly, diarrhea, and fever. The median time from the first symptoms to the initial treatment was 9.7 days. The standard treatment was withdrawal of immunosuppression and close observation of tacrolimus levels and liver function tests associated with antiviral drugs and chemotherapy. Four among 7 children died; 3 children recovered. All 3 children who recovered has presented at the transplantation center within 5 days of initiation of symptoms (P = .033896).. Despite its rarity, when it occurs, PTLD shows a high mortality rate. Therefore, it is necessary to have interdisciplinary work between the medical team that performs the transplantation and those promoting the primary care to diagnose the disease early and treat it effectively.

Topics: alpha 1-Antitrypsin Deficiency; Biliary Atresia; Child; Child, Preschool; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Splenomegaly; Tacrolimus

New-onset diabetes after transplantation (NODAT) is a frequent complication after liver transplantation and has a negative impact on both patient and graft survival. In analogy with the previous finding of an association between posttransplant hypomagnesemia and NODAT in renal transplant recipients, the relation between both pretransplant and posttransplant hypomagnesemia and NODAT was studied in liver transplant recipients (LTRs). One hundred sixty-nine adult LTRs (>18 years old) without diabetes who underwent transplantation between 2004 and 2009 were studied (mean age = 52.11 ± 12.6 years, proportion of LTRs who were male = 67.5%, body mass index = 25.5 ± 4.4 kg/m², proportion receiving tacrolimus = 90.0%). NODAT was defined according to the American Diabetes Association criteria. The association of NODAT with both pretransplant and posttransplant serum magnesium (Mg) was examined. Overall, 52 of 169 patients (30.8%) developed NODAT, and 57.7% of these (30 patients) were treated with antidiabetic drugs. Both pretransplant Mg levels and Mg levels in the first month after transplantation were lower in patients developing NODAT (P = 0.008 and P = 0.001, respectively). A multivariate regression model (adjusted for weight, pretransplant glucose levels, hyperglycemia in the first week after transplantation, gender, hepatitis C, and corticosteroid dosing) demonstrated both pretransplant Mg levels (hazard ratio = 0.844 per 0.1 mg/dL increase, 95% confidence interval = 0.764-0.932, P = 0.001) and posttransplant Mg levels (hazard ratio = 0.659, 95% confidence interval = 0.518-0.838, P = 0.001) to be independent predictors of NODAT together with age, biopsy-proven acute rejection, and cytomegalovirus (CMV) infection in the first year after transplantation. In conclusion, pretransplant hypomagnesemia and early posttransplant hypomagnesemia are independent predictors of new-onset diabetes after liver transplantation. Other risk factors are age, biopsy-proven acute rejection, and CMV infection.

Topics: Adult; Biomarkers; Case-Control Studies; Cytomegalovirus Infections; Diabetes Mellitus; Female; Graft Survival; Humans; Hyperglycemia; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Magnesium; Male; Metabolic Diseases; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Risk; Risk Factors; Tacrolimus; Young Adult

T(H)17 cells have been recently described to be involved in inflammatory and immune-mediated diseases, but there is no evidence of their role in human liver transplantation. Interleukin (IL)-23 is considered an inducer cytokine, whereas IL-17 is the main cytokine released by T(H)17 cells. The aim of our study was to measure the serum levels of IL-17 and IL-23 in stable liver transplant recipients and examine the influence of immunosuppressant concentrations.. Serum levels of IL-23 and IL-17 were determined in 38 healthy subjects and 35 stable hepatic transplant recipients who were free of rejection episodes for at least 8 years. The results were analyzed according to the simultaneous blood levels of cyclosporine (n = 20) or tacrolimus (n = 15).. No significant differences were observed in the serum levels of IL-17 and IL-23 between healthy subjects and transplanted patients. In addition, patients with low blood levels of tacrolimus (<6 ng/mL), but not cyclosporine, showed significantly lower serum levels of the 2 cytokines.. These preliminary results suggested a lack of activation of the T(H)17 pathway, which was more pronounced among the patient subgroup treated with tacrolimus.

Topics: Aged; Cohort Studies; Cyclosporine; Female; Humans; Immunosuppressive Agents; Interleukin-17; Interleukin-23; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Reference Values; Tacrolimus; Th1 Cells; Th2 Cells

Because morbidity early after hematopoietic cell transplantation (HCT) results in large part from the development of acute graft-versus-host disease (GVHD), we previously proposed that a longitudinal assessment of morbidity involving the skin, liver, and gastrointestinal (GI) tract might provide a more complete, objective approach for comparing 2 arms of open-label randomized clinical trials for acute GVHD prevention. In this study, we determined both morbidity across time and GVHD across time in a retrospective analysis of a database from an open-label randomized clinical trial comparing tacrolimus/methotrexate and cyclosporine/methotrexate after myeloablative conditioning and marrow transplantation from HLA-matched unrelated donors. The results confirm differences in overall morbidity across time in patients with peak grade II-IV GVHD compared with those with grade 0-I GVHD, but no significant differences in morbidity associated with grade II GVHD compared with grade 0-I GVHD. We observed less skin morbidity and a trend toward less liver morbidity across time in the tacrolimus group (P = .04 and .09, respectively), but not for GI morbidity or overall morbidity, despite significantly decreased skin and liver stages and overall grades of GVHD across time in this group. Thus, our objective assessment of differences in morbidity (regardless of cause) as a measure of acute GVHD in a randomized clinical trial of acute GVHD prevention has only limited utility. The difficulty of demonstrating clinical benefits from objective parameters, such as survival and morbidity, and the subjectivity of grading acute GVHD emphasize the need for blinded assessments in clinical trials of GVHD prevention.

Topics: Acute Disease; Clinical Trials, Phase III as Topic; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Liver Diseases; Methotrexate; Organ Specificity; Postoperative Complications; Randomized Controlled Trials as Topic; Retrospective Studies; Skin Diseases; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Increased risk of cardiovascular and cerebrovascular disease in liver transplant recipients results in particular from the side effects of calcineurin inhibitor-based immunosuppressive therapy. Several studies have demonstrated a more favourable outcome for patients receiving tacrolimus (TAC) as compared with ciclosporin (CS).. To investigate the effects of conversion from CS to TAC on cardiovascular risk factors and renal function in liver transplant recipients.. In a prospective study, all except two patients had chronic kidney disease stages 2-4 (n = 80), according to estimated glomerular filtration rate using the abbreviated Modification of Diet in Renal Disease equation.. Conversion was accompanied with a mean decrease of total cholesterol from 194.6 +/- 54.0 mg/dL to 175.8 +/- 44.2 mg/dL (P < 0.001), low density lipoprotein cholesterol from 106.7 +/- 39.2 mg/dL to 90.9 +/- 28.6 mg/dL (P < 0.001) and mean arterial blood pressure values from 102.2 +/- 13.2 mm Hg to 95.9 +/- 11.7 mm Hg (P < 0.001). Renal function remained stable. No cases of de novo diabetes mellitus were identified. The Framingham risk score was significantly reduced from 5.2 +/- 4.4 at baseline to 4.4 +/- 5.3 after 12 months (P = 0.006).. Conversion from CS to TAC has been shown to improve the cardiovascular risk profile and may retard further decline of renal function after liver transplantation.

Topics: Adult; Aged; Cardiovascular Diseases; Chronic Disease; Cyclosporine; Disease Progression; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

The calcineurin inhibitors (CNI) cyclosporine micro emulsion (CyA-ME) and tacrolimus (Tac) both display renal and vascular toxicities. We undertook a single-center retrospective study among 149 surviving liver transplant recipients. The primary outcome was kidney function over 10 years posttransplant, evaluating the glomerular filtration rate (GFR) by the abbreviated Modification of Diet in Renal Disease formula with subsequent Kidney Disease Outcomes Quality Initiative staging. The secondary outcomes included correlations between CNI trough levels (C0), GFR, and items of cardiovascular toxicity. At 1 and 5 years, the mean GFRs were 74.2 and 76.9 mL/min/1.73 m(2) under Tac versus 62.8 and 66.0 mL/min/1.73 m(2) under CyA-ME (P < .001). The mean value in favor of Tac was + 10 mL/min/1.73 m(2). Distribution of GFR stages showed more Tac patients at stage 1 or 2 and more at stage 4 or 5 under CyA-ME. There was no significant correlation between CNI-C0 and GFR. Switches between CNI or to mycophenolate mofetil did not show any significant GFR improvement. Patients under CyA-ME displayed significantly higher blood pressures with 3 requiring dialysis versus none under Tac. In conclusion, we observed that liver transplant patients under Tac maintained significantly better renal function with less progression to dialysis as compared with CyA-ME, indicating a lower renal and vascular (lower BP) toxicity.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Follow-Up Studies; Food, Formulated; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Diseases; Liver Transplantation; Male; Middle Aged; Patient Selection; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Young Adult

Calcineurin-inhibiting immunosuppressive medications are the mainstay of posttransplant immunosuppression. Although these highly beneficial drugs are critical for posttransplant survival, significant numbers of transplant recipients experience side effects, some requiring a switch to a different immunosuppressive regimen. Neurotoxicity is one of the most debilitating side effects because of its impact on mental status and cognition. As our center uses tacrolimus as the initial immunosuppressant for all liver transplant (LTX) recipients, we were interested in those patients who required a switch because of neurotoxic side effects. Over a 5-year period, 827 adult LTX recipients received their first graft at our center. Ninety-four patients were no longer on tacrolimus by 2 months post-LTX (86 switched because of concerns over neurotoxicity, and 8 switched because of renal function concerns). Of those experiencing neurotoxic side effects, the majority (64%) had altered mental status, and 26% had seizures (first onset post-LTX). On the basis of our prior work, we hypothesized that patients with a pre-LTX history of excessive alcohol use would be at higher risk for neurotoxic effects. We also hypothesized that the elderly and those who had more advanced illness (that is, higher Model for End-Stage Liver Disease scores) at LTX would be at risk as well. We found that patients with a pre-LTX diagnosis of alcoholic liver disease were not more likely to be switched from tacrolimus. Furthermore, we found that in addition to older age and higher Model for End-Stage Liver Disease scores, poorer hepatic functioning was significantly associated with a switch from tacrolimus. We discuss the implications of these findings and the relevance for future clinical care in these high-risk patients.

Topics: Adolescent; Adult; Age Factors; Aged; Cohort Studies; Female; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Neurotoxicity Syndromes; Tacrolimus

While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity.. Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion.. Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 +/- 12.48 micromol/L to 130.1 +/- 5.573 micromol/L), and over the next 60 days after conversion (97.86 +/- 11.69 micromol/L to 90.7 +/- 8.95 micromol/L) (P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period.. SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.

Topics: Adult; Aged; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Safety; Sirolimus; Tacrolimus

Topics: Brain Diseases; Female; Graft Rejection; Humans; Intensive Care Units; Liver Diseases; Liver Transplantation; Middle Aged; Syndrome; Tacrolimus

Multiple measurements of lymphocyte subsets in 91 children treated with steroid-free tacrolimus, and rabbit anti-human thymocyte globulin induction demonstrate early reconstitution of T-cytotoxic cells, and gradual reconstitution of all other subsets, which is complete after one yr. Rejection-prone children demonstrate significantly higher counts of lymphocytes and all subsets prior to liver transplantation, and may exemplify one basis for enhanced baseline immunocompetence.

Topics: Adolescent; Adult; Animals; Antilymphocyte Serum; Child; Child, Preschool; Female; Humans; Infant; Liver Diseases; Liver Transplantation; Lymphocyte Subsets; Male; Rabbits; Steroids; T-Lymphocytes, Cytotoxic; Tacrolimus

Hepatic dysfunction is an important determinant of the clearance of tacrolimus; however, the impact of reduced hepatic mass in living donor liver transplant (LDLT) patients on the drug exposure and clearance of tacrolimus is not known. AIM.: The aim of the present study is to compare the dosage, concentration and pharmacokinetics parameters of tacrolimus between LDLT and deceased donor liver transplant (DDLT) recipients.. Daily doses used and trough concentrations measured were compared in 12 LDLT and 12 DDLT patients. Multiple blood samples were taken over one dosing interval after oral tacrolimus administration, and pharmacokinetics differences were compared.. The mean tacrolimus dosage in first 14 postoperative days was (0.06 mg/kg/day) for LDLT and (0.09 mg/kg/day) for DDLT (P=0.0001). Despite the lower doses used, mean trough concentration was significantly greater in LDLT as compared with DDLT (8.8+/-2.5 ng/mL vs. 6.79+/-1.5 ng/mL, respectively, P=0.013). On the day of the pharmacokinetic study, minimum Concentration (Cmin), 12-hr postdose concentration (Clast), and average concentration (Cavg) were significantly greater in LDLT as compared with DDLT (LDLT: 6.6+/-2.4 ng/mL, 7.2+/-1.8 ng/mL, 8.9+/-3.0 ng/mL; DDLT: 4.3+/-1.0 ng/mL, 4.9+/-1.6 ng/mL, 5.9+/-1.4 ng/mL, P=0.02, 0.04, and 0.02, respectively). Dose normalized AUC was 37.7% greater and clearance, 47.5% lower in LDLT as compared with DDLT.. Although not statistically significant, the dose normalized AUC was 37.7% greater and clearance 47.5% lower in LDLT as compared with DDLT. An initial tacrolimus dose reduction of about 30-40% may be prudent in LDLT compared with DDLT recipients.

Topics: Adult; Area Under Curve; Blood Urea Nitrogen; Cadaver; Creatinine; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Living Donors; Male; Middle Aged; Tacrolimus; Tissue Donors

Corticosteroid-free immunosuppression (IS) may be potentially beneficial for transplanted patients, particularly children. The purpose of this study was to evaluate the efficacy and cost of such strategy in primary pediatric liver transplantation (LT). Fifty pediatric LT recipients were prospectively treated with a steroid-free, tacrolimus-basiliximab-based IS (group TB). A group of 34 children transplanted under a conventional tacrolimus-steroids regimen served as control series (group TS). Groups TB and TS were compared regarding patient and graft survival, rejection incidence, infectious complications, and growth, as well as cost of the transplant procedure. Patient and graft survivals at 3 years were 96% and 94% in group TB, versus 91% and 88% in group TS (P = 0.380 and P = 0.370, respectively). Rejection-free graft survival at 3 years was 72% in group TB, versus 41% in group TS (P = 0.007). Patients in group TB had significantly less viral infections than patients in group TS (P = 0.045). Height standard deviation score was significantly enhanced in children from group TB, when compared to group TS. Medical care costs were similar in both groups. Steroid avoidance together with basiliximab immunoprophylaxis was not harmful in terms of allograft acceptance, and even seemed to be beneficial in the long term.

Topics: Adolescent; Adrenal Cortex Hormones; Antibodies, Monoclonal; Basiliximab; Belgium; Child; Child, Preschool; Costs and Cost Analysis; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Topics: Antimetabolites; Calcineurin Inhibitors; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Renal Insufficiency, Chronic; Renal Replacement Therapy; Sirolimus; Tacrolimus; Treatment Outcome

The purpose of this study is to review the clinical experience with sirolimus immunosuppression in liver transplant patients with calcineurin inhibitor-induced chronic renal insufficiency. The study design is a case-control retrospective series. Fifty-seven liver transplant patients with renal insufficiency that were started on sirolimus at greater than 90 days postoperatively and treated for more than 90 days were identified. A control group of 57 patients maintained on low-dose calcineurin inhibitors, matched for gender, year of transplant, and baseline creatinine clearance, was also identified. There were no significant differences in the absolute creatinine clearance values between the sirolimus and control groups from 6 months before sirolimus conversion to 12 months after sirolimus conversion. Patients exposed to calcineurin inhibitors for more than 5 years or those with an initial creatinine clearance of less than 30 mL/minute who were converted to sirolimus did worse than control patients maintained on low-dose calcineurin inhibitors. Progression to renal replacement therapy, episodes of acute and chronic rejection, and death were similar between the sirolimus and control groups. The overall prevalence of side effects was significantly higher in the sirolimus group compared with the control group, although these were generally tolerable in most patients. In conclusion, this study suggests that conversion to sirolimus in liver transplant patients with chronic renal insufficiency is associated with stabilization of renal function but confers no additional benefit to low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of less than 30 mL/minute.

Topics: Adult; Aged; Antimetabolites; Calcineurin Inhibitors; Case-Control Studies; Creatinine; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Renal Insufficiency, Chronic; Renal Replacement Therapy; Retrospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection.

Topics: Adult; Aged; Calcineurin Inhibitors; Diabetes Mellitus; Female; Glucose; Hepatitis C; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Multicenter Studies as Topic; Risk Factors; Tacrolimus

Liver transplantation, which serves as treatment of familial amyloidotic polyneuropathy (FAP), and domino liver transplantation, which utilizes resected livers from patients with FAP for treatment of liver diseases, may induce changes in transthyretin (TTR), a pathogenic FAP-related protein. To evaluate this possibility, we performed a 70% hepatectomy or administered tacrolimus to Dark Agouti (DA) rats for 7 days and then measured changes in liver TTR mRNA levels and changes in serum TTR concentrations. After hepatectomy, TTR mRNA levels decreased by 77%; at day 3, they returned to preoperative levels. Except for slightly elevated serum TTR concentrations 12 h after operation, serum TTR levels remained unchanged. Thus, partial hepatectomy did not influence serum TTR concentrations. After tacrolimus administration, TTR mRNA declined by 56% 12 h after the experiment started; however, after day 3, a rebound phenomenon occurred until day 7. Tacrolimus may facilitate serum TTR degradation, although production of TTR in the liver also increased. This finding -- that TTR, the source of FAP-inducing amyloid, did not increase after transplantation -- may help post-transplantation treatment of patients who have FAP and other liver diseases.

Topics: Animals; Aspartate Aminotransferases; Gene Expression Regulation; Immunosuppressive Agents; Liver; Liver Diseases; Liver Transplantation; Male; Models, Statistical; Prealbumin; Rats; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Time Factors

Neuropsychiatric complications are an important source of morbidity following orthotopic liver transplantation. Etiology of liver disease and type of immunosuppression are possible related factors. The aim of this study was to describe the prevalence of neuropsychiatric complications after liver transplantation, the role of immunosuppression, and the association between these and specific liver diseases such as hepatitis C. One hundred twenty-eight patients with liver transplants were studied. Tacrolimus was the primary immunosuppressant in 101 patients and cyclosporine in 27 patients. Seventy-five complications in 49 patients (38.2%) were reported. In 43 patients, the etiology was associated with immunosuppression: 36 on tacrolimus and 7 on cyclosporine (P = 0.34). Seventeen and four-tenths percent of patients with hepatitis C and 4.6% of patients without hepatitis C developed depression (P = 0.02). There is no difference between types of primary immunosuppression and neuropsychiatric complications. There is a significantly greater incidence of depression in patients transplanted for hepatitis C.

Topics: Adult; Aged; Cyclosporine; Depressive Disorder; Female; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Medical Records; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tennessee

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

For cadaveric transplantations, histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solutions have been shown to engender similar outcomes. In September 2004, our institution changed from UW to HTK as the primary preservation solution for liver and kidney transplantations. We reviewed records of living-donor liver transplant recipients from September 2001 to December 2005. This study compared early postoperative outcomes of liver transplantation using the 2 solutions. Perfusion was performed first via the portal vein and then via the hepatic artery until the outflow became clear. Patients were compared based on the organ preservation solution. The analysis included patient demographics, early postoperative complication rates, mortality rates, number of acute rejection episodes, costs for preservation solutions, and results of 1-, 7-, 14-, and 30- day liver function tests. Patients in both groups were managed with similar operative techniques, immunosuppressive regimens, and donor liver criteria. Statistical analyses were performed with chi- square and Mann-Whitney U tests. Donor and patient demographics were similar. No statistically significant differences were observed between the groups with regard to posttransplantation liver biochemistry, complication rates, number of acute rejection episodes, and mortality rates. The mean infused volume of preservation solution was 1000 +/- 400 mL (range, 500-2000 mL) for all patients. These volumes corresponded to a cost savings of US 148 dollars/L when using HTK solution. In conclusion, UW and HTK were equally effective and safe for perfusion of living-donor liver grafts; however, the use of HTK solution provided significant cost savings.

Topics: Adenosine; Adult; Allopurinol; Female; Glucose; Glutathione; Humans; Immunosuppressive Agents; Insulin; Liver; Liver Diseases; Liver Transplantation; Living Donors; Male; Mannitol; Organ Preservation Solutions; Potassium Chloride; Procaine; Raffinose; Retrospective Studies; Tacrolimus

A retrospective chart review of 1065 consecutive liver allograft recipients in 11 centers from January 1997 to September 1998 was performed. Patients were followed for 3 years or until graft loss. Patients received either tacrolimus (n = 594), cyclosporine (n = 450) or no calcineurin inhibitor (n = 21). Model for end-stage liver disease (MELD) scores at time of transplant were similar between the two groups. During follow-up, more patients switched from cyclosporine to tacrolimus (26.7%) than from tacrolimus to cyclosporine (12.8%; p < 0.0001). Patient and graft survival were equivalent. Corticosteroid use was more common in cyclosporine-treated patients (p < 0.00001). Patients receiving tacrolimus experienced lower serum creatinine levels at months 3 through 36 (p < 0.0001). Systolic blood pressure was lower in patients receiving tacrolimus (p < 0.001) despite a reduced requirement for anti-hypertensive agents (p < 0.0001). In addition, tacrolimus was associated with lower total cholesterol and triglyceride levels for months 3 through 24 and 3 through 12, respectively (p < 0.01), despite a reduced requirement for anti-hyperlipidemic agents. The incidence of new-onset diabetes mellitus was similar in both groups. While both calcineurin inhibitors were associated with excellent patient and graft survival, renal function, blood pressure and serum lipid levels were significantly better with tacrolimus treatment.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Blood Pressure; Cardiovascular Diseases; Cardiovascular System; Child; Child, Preschool; Cholesterol; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Ischemia; Kidney; Lipid Metabolism; Liver Diseases; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome; Triglycerides

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recurrence; Registries; Survival Analysis; Tacrolimus; Treatment Outcome

Tacrolimus is widely used for the prophylaxis and treatment of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT) and graft rejection in solid organ transplantation. The metabolism of tacrolimus has been reported to be impaired in association with liver dysfunction, mostly as documented in liver transplant recipients. Hepatic veno-occlusive disease (VOD) is one of the serious complications after allogeneic HSCT. It is characterized by jaundice, fluid retention, and painful hepatomegaly, caused by endothelial cell injury resulting from the toxicity of the conditioning regimen. The impaired metabolism of tacrolimus in hepatic VOD has not previously been reported in the literature. Here, we report the notable alteration in the metabolism of tacrolimus in two patients with hepatic VOD, in whom the half-lives of tacrolimus were markedly prolonged (288 and 146 h).

Topics: Cord Blood Stem Cell Transplantation; Endothelium, Vascular; Female; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Male; Middle Aged; Myelodysplastic Syndromes; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Transplantation Conditioning

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

Topics: Adult; Bilirubin; Cholesterol; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Metabolic bone disease is one of the major long-term complications in liver transplant recipients, but it remains unclear which patients are at highest risk for developing severe bone disease following transplantation.. A total of 46 consecutive, adult patients with chronic liver disease accepted for a liver transplantation waiting list were prospectively included in the study. The patients were classified into two groups: group A--chronic cholestatic liver disease (n = 28), and group B--chronic non-cholestatic liver disease (n = 18). Bone mineral density (BMD) was measured at acceptance for the waiting list and at 3, 12 and 36 months following transplantation. Markers of bone turnover (serum-bone specific alkaline phosphatases (bALP), s-osteocalcin, s-1-collagen-C-terminal telopeptide (1-CTP) and urine N-terminal telopeptides u-Ntx) were measured at acceptance and at 3, 6, 12, 24 and 36 months following transplantation. BMD and markers of bone turnover were compared with similar values in a matched control group of 42 healthy individuals.. BMD decreased significantly during the early post-transplantation period (median bone loss femoral neck (FN) 3 months post-transplant 8.5%). BMD levels declined slightly from 3 to 12 months following transplantation and increased thereafter. The relative bone loss was greatest among group B patients (relative bone loss FN 3 months post-transplant: group A, 8% versus group B, 13%; P = 0.04). At 36 months, 8/17 group A and 2/9 group B patients had BMD levels that exceeded the pretransplant levels (P = 0.12). The early bone loss was positively correlated with an increase in resorption markers (s-1-CTP and u-Ntx). Group B had higher levels of both s-1-CTP and u-Ntx at 3 and 6 months post-transplant than group A patients (P = 0.03). Bone formation markers increased slowly from 6 months post-transplant and onwards. Relative bone loss was positively correlated to total glucocorticoid dose during the first 3 months post-transplant. There were no differences in BMD between patients receiving tacrolimus versus those receiving cyclosporin A.. Bone loss following liver transplantation is considerable in patients with both cholestatic and non-cholestatic liver disease, the first group has the poorest starting-point while the latter group has the greatest bone loss following transplantation. Bone loss is closely correlated with biochemical markers of bone resorption and total dose of glucocorticoids given post-transplant.

Topics: Adult; Aged; Alkaline Phosphatase; Biomarkers; Bone Density; Bone Resorption; Cholestasis; Collagen; Collagen Type I; Cyclosporine; Female; Femur Neck; Follow-Up Studies; Forearm; Fractures, Bone; Glucocorticoids; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Longitudinal Studies; Lumbar Vertebrae; Male; Middle Aged; Norway; Osteocalcin; Osteoporosis; Peptide Fragments; Peptides; Postoperative Complications; Survival Analysis; Tacrolimus; Treatment Outcome; Waiting Lists

With the advent of highly active antiretroviral therapy (HAART), HIV positivity is no longer a contraindication for liver transplantation. Some of the antiretroviral agents, particularly protease inhibitors (e.g., ritonavir, indinavir, and nelfinavir) have been described as potent inhibitors of the metabolism of certain immunosuppressive drugs. In this article we describe a profound interaction between tacrolimus and Kaletra (Abbott Laboratories, Chicago, IL) (a combination of lopinavir and ritonavir) in 3 liver transplantation patients. Patient 1, who was maintained on a 5 mg twice daily dose of tacrolimus with a trough blood concentration around 10.6 ng/mL, required only 0.5 mg of tacrolimus per week after addition of Kaletra to achieve similar tacrolimus blood concentrations, with a half-life of 10.6 days. In patient 2, the area under the blood concentration versus time curve for tacrolimus increased from 31 ng/mL/h to 301 ng/mL/h after addition of Kaletra, with a corresponding half-life of 20 days. When the patient was subsequently switched to nelfinavir, the half-life decreased to 10.3 days. Patient 3, who was maintained with 4 to 8 mg/d of tacrolimus and a corresponding blood concentration of 10 ng/mL before Kaletra, required a tacrolimus dose of 1 mg/wk and tacrolimus concentrations of 5 ng/mL with Kaletra. In conclusion, a combination of lopinavir and ritonavir led to a much more profound increase in tacrolimus blood concentrations than use of single protease inhibitor, nelfinavir. A tacrolimus dose of less than 1 mg/wk may be sufficient to maintain adequate blood tacrolimus concentrations in patients on Kaletra. Patients may not need a further dose of tacrolimus for 3 to 5 weeks depending on liver function when therapy with Kaletra is initiated. Great caution is required in the management of tacrolimus dosage when Kaletra is introduced or withdrawn in HIV-positive patients after liver transplantation, particularly in the presence of hepatic dysfunction.

Topics: Adult; Drug Interactions; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir; Tacrolimus

Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience.. All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart.. Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression.. The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Topics: Abnormalities, Multiple; Adolescent; Adult; Anti-Inflammatory Agents; Birth Weight; Diabetes Mellitus, Type 1; Female; Fludrocortisone; Graft Survival; Humans; Hypertension; Immunosuppressive Agents; Infant, Newborn; Kidney; Liver; Liver Diseases; Liver Transplantation; Pre-Eclampsia; Prednisone; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy Outcome; Prospective Studies; Survival Rate; Tacrolimus; Transplantation, Homologous

Topics: Adolescent; Age Distribution; Biliary Atresia; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Liver Diseases; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Reoperation; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

Topics: Adolescent; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Male; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Time Factors

Tacrolimus is a potent immunosuppressive agent and has been used in liver transplantation (LTx) for nearly a decade. More than 70% of children can be maintained on tacrolimus monotherapy, without steroids, by the end of 1 yr post-Tx. This freedom from steroids does not appear to change significantly in subsequent years. The use of steroids has obvious metabolic and cosmetic disadvantages, besides affecting linear growth in children. The present study identifies why some children still require steroid therapy after successful LTx. One hundred and sixty-six consecutive pediatric patients who had undergone primary LTx between October 1989 and December 1992, were included in this study. Follow-up ranged from 6 to 9 yr (mean 7.5 +/- 0.8 yr). One hundred and forty-one children were alive in November 1998 and these patients constituted the study group. Their current rate of prednisone use, reason for prednisone use, and prednisone dose were examined retrospectively. Of the 141 patients, 139 (98.5%) had stopped taking steroids at some time-point after LTx. Thirteen patients (9%) were off immunosuppression altogether (group I), 97 were undergoing tacrolimus monotherapy (group II), and the remaining 31 were receiving therapy with steroids and tacrolimus (group III). The mean prednisone dose at the last follow-up was 6.5 +/- 4.9 mg/day (median 5.0 mg/day). In group III, two children were never weaned off steroids because of inadequate follow-up (both lived outside the country), and the remaining 29 children completely stopped steroid therapy at some time-point after LTx; however, prednisone was re-introduced for clinically suspected or biopsy-proven rejection in 24. Seven children in group III had completely stopped immunosuppressive therapy either as part of an immunosuppression reduction protocol (n = 3) or for suspected or proven post-transplant lymphoproliferative disorder (PTLD) (n = 4). In eleven of the 18 children in group III, requirement of steroid for rejection was thought to be related, in part, to non-compliance. In three children in group III, steroids were re-introduced for renal dysfunction, and two of these patients subsequently received a kidney Tx. In one child with cerebral ischemia, steroids were used to reduce brain edema, and another child had features of auto-immune hepatitis. Hence, almost all children can be weaned off steroids when tacrolimus is used as primary immunosuppression after primary LTx. However, approximately 22% of children may

Topics: Adolescent; Anti-Inflammatory Agents; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Prednisone; Tacrolimus; Time Factors

This study was carried out to compare echocardiographic findings of children taking tacrolimus and cyclosporin A (CsA) after orthotopic liver transplantation (OLT). Echocardiograms of 19 children were reviewed during hospitalizations after OLT, and echocardiograms were performed on 23 children who returned to the clinic for a routine follow-up visit after OLT. Measurements were made of the left ventricle (LV) end-diastolic dimension, and of the thickness of the LV free wall (LVFW) and the inter-ventricular septum (IVS). From these measurements, the LV mass was calculated. LV outflow gradient was measured by using Doppler interrogation. Comparisons were made between patients on CsA and patients on tacrolimus. Children with hypertrophic cardiomyopathy (HCM) were identified. Two patients from the in-patient tacrolimus group were found to have HCM. These two patients had asymmetric septal hypertrophy with dynamic LV outflow obstruction and were successfully treated with propranolol, with or without discontinuing tacrolimus. In the out-patient studies, there was no difference in LVFW and IVS thickness, or LV mass index, between children on CsA and children on tacrolimus. Hence, tacrolimus is associated with the development of HCM in children. The effect of tacrolimus on HCM development may be acute and temporary. More data are needed to determine the incidence of HCM in children on tacrolimus therapy and to establish guidelines for clinicians who follow-up these children.

Topics: Adolescent; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Cyclosporine; Female; Graft Rejection; Heart Ventricles; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Male; Tacrolimus; Ultrasonography; Ventricular Function, Left

The calcineurin inhibitors cyclosporine and tacrolimus are both known to be nephrotoxic. Their use in orthotopic liver transplantation (OLTX) has dramatically improved success rates. Recently, however, we have had an increase of patients who are presenting after OLTX with end-stage renal disease (ESRD). This retrospective study examines the incidence and treatment of ESRD and chronic renal failure (CRF) in OLTX patients.. Patients receiving an OLTX only from June 1985 through December of 1994 who survived 6 months postoperatively were studied (n=834). Our prospectively collected database was the source of information. Patients were divided into three groups: Controls, no CRF or ESRD, n=748; CRF, sustained serum creatinine >2.5 mg/dl, n=41; and ESRD, n=45. Groups were compared for preoperative laboratory variables, diagnosis, postoperative variables, survival, type of ESRD therapy, and survival from onset of ESRD.. At 13 years after OLTX, the incidence of severe renal dysfunction was 18.1% (CRF 8.6% and ESRD 9.5%). Compared with control patients, CRF and ESRD patients had higher preoperative serum creatinine levels, a greater percentage of patients with hepatorenal syndrome, higher percentage requirement for dialysis in the first 3 months postoperatively, and a higher 1-year serum creatinine. Multivariate stepwise logistic regression analysis using preoperative and postoperative variables identified that an increase of serum creatinine compared with average at 1 year, 3 months, and 4 weeks postoperatively were independent risk factors for the development of CRF or ESRD with odds ratios of 2.6, 2.2, and 1.6, respectively. Overall survival from the time of OLTX was not significantly different among groups, but by year 13, the survival of the patients who had ESRD was only 28.2% compared with 54.6% in the control group. Patients developing ESRD had a 6-year survival after onset of ESRD of 27% for the patients receiving hemodialysis versus 71.4% for the patients developing ESRD who subsequently received kidney transplants.. Patients who are more than 10 years post-OLTX have CRF and ESRD at a high rate. The development of ESRD decreases survival, particularly in those patients treated with dialysis only. Patients who develop ESRD have a higher preoperative and 1-year serum creatinine and are more likely to have hepatorenal syndrome. However, an increase of serum creatinine at various times postoperatively is more predictive of the development of CRF or ESRD. New strategies for long-term immunosuppression may be needed to decrease this complication.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors

The aim of this study is to evaluate the hemodynamics and pregnancy outcome of women with prior orthotopic liver transplantation. Hemodynamic measurements by Doppler technique were performed on pregnant subjects with prior orthotopic liver transplantation. Maternal characteristics, renal function, pregnancy complications, delivery indications, delivery mode, and neonatal outcomes were evaluated. Six pregnancies occurred in 5 women after orthotopic liver transplantation at the University of Washington Medical Center (Seattle, WA) between 1991 and 1999. Four of the 6 pregnancies were complicated by chronic hypertension, fetal growth restriction, and preterm delivery. Two pregnancies had worsening hypertension characterized by vasoconstriction in the second trimester despite antihypertensive therapy. These 2 subjects were administered cyclosporine for maintenance immunosuppression and had greater mean arterial pressures preconception and in the first trimester than the other subjects. One of these pregnancies resulted in fetal demise at 25 weeks' gestation. The other subject was delivered at 28 weeks' gestation for nonreassuring fetal status and superimposed preeclampsia. All pregnancies were complicated by renal insufficiency; however, the 2 subjects with poor obstetric outcome had preconception serum creatinine levels greater than 1.5 mg/dL and creatinine clearances less than 40 mL/min. Pregnancies complicated by second-trimester vasoconstriction and moderate renal insufficiency are at risk for preeclamspia, fetal growth restriction, and fetal demise. Good obstetric outcome can occur in women with mild renal insufficiency and well-controlled chronic hypertension. Improved hypertensive control preconception may decrease the risk for preeclampsia and poor obstetric outcome.

Topics: Adolescent; Adult; Cesarean Section; Creatinine; Female; Hemodynamics; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Renal Insufficiency; Tacrolimus

Concanavalin A (Con A) stimulation induces T-cell activation-associated hepatic injury. This study is designed to show the involvement of microcirculatory disturbance in the pathogenesis. Con A administration led to prominent intrasinusoidal hemostasis, which consisted of erythrocyte agglutination, lymphocyte/neutrophil sticking to endothelial cells, and platelet aggregation and degranulation, resulting in a marked decrease in the intrahepatic blood flow and elevation of portal perfusion pressure. After hemostasis, confluent hepatic necrosis occurred within the congested area of liver parenchyma. Reduction in the extent of hemostasis by the treatment with heparin (thrombin inhibitor) or cyproheptadine (serotonin inhibitor) decreased hepatic injury. Pretreatment with either anti-tumor necrosis factor alfa (TNF-alpha) or anti-interferon gamma (IFN-gamma) monoclonal antibody (MAb) moderately decreased hemostasis and hepatic injury, whereas combined use of two MAbs almost perfectly protected mice from these disorders. Complete obliteration of hemostasis and hepatic injury was also accomplished by the pretreatment with FK506 which suppressed TNF-alpha and IFN-gamma production. Intrasinusoidal accumulation of leukocytes and platelets was, however, not blocked by FK506, indicating that Con A activities other than the stimulation of cytokine production are responsible for this event. The administration of anti-CD3 MAb, a T-cell stimulant without agglutination activities, which elevated plasma cytokine levels in a comparable degree without inducing prominent leukocyte infiltration, did not induce hepatic congestion and injury. These findings indicate that the agglutination activities of Con A and T-cell activation mediated TNF-alpha/IFN-gamma production are both required for the induction of intrasinusoidal hemostasis, which is indispensable for the development of hepatic injury.

Topics: Animals; Antibodies, Monoclonal; CD3 Complex; Chemical and Drug Induced Liver Injury; Concanavalin A; Cyproheptadine; Cytokines; Female; Hemostasis; Heparin; Interferon-gamma; Liver Diseases; Mice; Mice, Inbred BALB C; Mice, Nude; Microscopy, Electron; Tacrolimus; Time Factors; Tumor Necrosis Factor-alpha

One of the most controversial areas in patient selection and donor allocation is the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing liver transplantation under primary tacrolimus-based immunosuppression.. Twenty-eight pre-liver transplant, operative, and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplants in 130 veterans (98% male; mean age, 47.3 years).. Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% United Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (P=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (P<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with mortality by univariate analysis. Underlying liver disease, cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, ischemia time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV had a trend towards higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppression, posttransplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatinine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurrence was of borderline significance (P=0.07).. Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling.

Topics: Adult; Aged; Analysis of Variance; Female; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Military Personnel; Morbidity; Multivariate Analysis; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus; United States

Topics: Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prednisolone; Reoperation; Survival Rate; Tacrolimus; Time Factors

The orthotopic liver transplantation (OLT) program of the University of Liège was initiated in 1986. Between 1986 and December 1998, 150 adult OLT have been performed in our institution, including 18 liver retransplantations, 1 combined heart and liver transplantation and 3 combined liver and kidney transplantations. The aim of this study was to report the last 3 years of our experience. From January 1996 to November 1998, we performed 50 OLT on 49 patients. Three were retransplantations and two were combined liver and kidney transplantations. Fourty-three patients were transplanted for chronic liver disease and 6 for acute or subacute hepatopathy. Mean waiting time on the list was 4 weeks. Immunosuppression was based on triple therapy (cyclosporin A/tacrolimus, steroids, azathioprine), with steroid and azathioprine withdrawal in most of the patients after 3 months. In the chronic liver disease group, operative (< 30 days) survival was 95% (peroperative myocardial infarction in 2 patients). In the acute liver disease group, postoperative survival was 66%. No perioperative death occurred in 1997 and 1998. Actuarial one year survival was 87%. In our experience, OLT has become a safe procedure.

Topics: Actuarial Analysis; Acute Disease; Adrenal Cortex Hormones; Adult; Azathioprine; Belgium; Chronic Disease; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Transplantation; Myocardial Infarction; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Time Factors; Waiting Lists

Exclusion of occult diseases in the donor organ and prevention of infectious disease transmission are minimal requirements in organ transplantation. We report here a case of hepatic graft tuberculosis, which was most likely transmitted by the graft from the living-related donor. The course of the recipient included tuberculosis, rejection, and other infections, which led to vanishing bile duct syndrome. Due to various infections and tuberculosis, as well as a strong interaction between rifampicin and tacrolimus, the patient died of pneumonia on day 273 after transplantation. This case emphasizes the importance of care in the selection of a living-related donor for liver transplantation.

Topics: Adult; Drug Interactions; Fatal Outcome; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Function Tests; Liver Transplantation; Living Donors; Mothers; Postoperative Complications; Rifampin; Tacrolimus; Tuberculosis

Topics: Demyelinating Diseases; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Peripheral Nervous System Diseases; Tacrolimus

Transplant immunosuppression using either cyclosporine (CsA) or FK506 leads to renal vasoconstriction. To examine the role of endothelin (ET) in this process, we measured plasma and urinary ET before and at intervals for two years after liver transplantation. Urinary prostacyclin (as 6-keto-PG-F1 alpha), thromboxane, glomerular filtration rate and renal plasma flow were also measured. Forty-four patients were treated with CsA-based regimens and 31 patients with FK506-based regimens. Prednisone doses after one year were lower with FK506 (5.5 +/- 0.5 vs. 10.5 +/- 0.5 mg/day) by study design. Circulating plasma ET remained above normal, but not different from pre-transplant levels. Urinary ET was elevated before transplant (24.6 +/- 3.4 ng/day vs. normal 16 +/- 1.5 ng/day, P < 0.05) and rose further after transplantation (48.5 +/- 13 ng/day, P < 0.05), remaining elevated for two years. 6-keto-PG-F1 alpha fell from 2567 +/- 338 ng/day to subnormal levels and remained suppressed (1158 +/- 128 ng/day, P < 0.01). Over the same period GFR fell (84 +/- 3 ml/min to 60 +/- 3 ml/min, P < 0.01) and renal vascular resistance index rose (11,119 +/- 561 to 23,279 +/- 1692 d.s.cm-5.m-2, P < 0.01). Similar changes were observed both with CsA and FK506-based immunosuppression. No changes in ET were attributable to dihydropyridine calcium channel blockers. These results demonstrate that urinary ET changes independently from plasma ET after transplantation. Elevated ET and suppression of endothelium-derived prostacyclin persist with intense renal vasoconstriction for at least two years after transplant.

Topics: Cyclosporine; Dihydropyridines; Eicosanoids; Endothelins; Female; Hemodynamics; Humans; Liver Diseases; Liver Transplantation; Male; Middle Aged; Radioimmunoassay; Renal Circulation; Retrospective Studies; Tacrolimus; Vasoconstriction

Topics: Adolescent; Adult; Aged; Animals; Autoimmune Diseases; Bone Marrow Transplantation; Child; Child, Preschool; Cricetinae; Demography; Female; Forecasting; Graft Enhancement, Immunologic; Graft Survival; Graft vs Host Disease; Hospitals, University; Humans; Immunosuppression Therapy; Infant; Life Tables; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pennsylvania; Rats; Reoperation; Retrospective Studies; Risk Factors; Survival Analysis; Tacrolimus; Transplantation, Heterologous; Treatment Outcome

FK506 undoubtedly improved the survival advantage of hepatic allotransplantation. Hepatic-intestinal and multivisceral transplantation has also become a feasible therapy for patients with combined intestinal and liver failure. With better understanding of the immunologic and metabolic aspects of allo- and xenotransplantation, further clinical attempts to transplant animal organs to humans may be considered with the hope for a better outcome in the very near future.

Topics: Academic Medical Centers; Adolescent; Adult; Aged; Animals; Female; Graft Survival; Humans; Intestines; Liver Diseases; Liver Transplantation; Male; Middle Aged; Papio; Pennsylvania; Randomized Controlled Trials as Topic; Survival Rate; Tacrolimus; Transplantation, Heterologous

The authors performed 20 liver transplantations from living related donors between June 1990 and July 1991. The 20 pediatric patients (14 biliary atresia, two Budd-Chiari syndrome, one liver cirrhosis after hepatitis C viral infection (HCV hepatitis), 1 progressive intrahepatic cholestasis, 1 liver cirrhosis, 1 protoporphyria) were transplanted with 11 left lobes, eight left lateral segments, and one right lobe. The choice of donors was restricted to the parents of the recipients. The immunosuppressive treatment consisted of FK 506 and steroids. Seventeen recipients are alive, 15 of whom are well and at home. Two recipients, who underwent emergency transplantation, died of postoperative complications. Another recipient died of accidental asphyxia at 6 months after the transplantation. All 20 donors had uneventful postoperative courses and were able to resume their normal social lives. The arterial ketone body ratio (AKBR) increased to above 1.0 within 2 days after the transplantation in all cases. Relatively mild rejection episodes were encountered in only two cases transplanted with ABO-compatible grafts, and these were treated successfully with steroids and FK 506.

Topics: Adolescent; Biliary Atresia; Child; Child, Preschool; Female; Graft Rejection; Humans; Infant; Liver Diseases; Liver Transplantation; Male; Methylprednisolone; Parents; Postoperative Complications; Survival Rate; Tacrolimus; Tissue Donors

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.

Topics: Adolescent; Adult; Aged; Biopsy; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Cyclosporine; Female; Graft Rejection; Hepatic Artery; Hepatitis; Humans; Immunity, Cellular; Infant; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Tacrolimus

Topics: Adult; Antibody Formation; Female; Graft Rejection; Humans; Immunosuppression Therapy; Liver Diseases; Liver Transplantation; Tacrolimus

Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; Blood Group Antigens; Body Weight; Child; Cyclosporins; Female; Hepatitis, Viral, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Sex Factors; Survival Analysis; Tacrolimus

FK 506 therapy with low doses of steroids was adequate to control rejection in most liver recipients. Rejection episodes were readily reversed with single IV doses of methylprednisone or hydrocortisone. Short courses of OKT3 (3 to 5 days 5-10 mL) controlled severe rejections. The rate of retransplantation directly due to rejection was low (1.6%). There was a limited need for steroids either early or out to 6 to 12 months.

Topics: Anti-Bacterial Agents; Antibodies, Monoclonal; Graft Rejection; Humans; Hydrocortisone; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Methylprednisolone; Muromonab-CD3; Survival Analysis; Tacrolimus

Orthotopic liver transplantation is now a widely used treatment for patients with end-stage liver disease. Lifelong pharmacologic immunosuppression renders these patients susceptible to many infections. The purpose of this article is to provide guidelines for treating the patient with end-stage liver disease, both before and after transplantation. In addition, we shall discuss some of the medical implications associated with end-stage liver disease and their clinical presentations and appropriate presurgical management. Adverse side effects of long-term immunosuppression and their effect on the oral and maxillofacial region shall also be discussed. Last, a brief discussion of FK506, the latest immunosuppressant, will be presented together with the implications of its use on our surgical treatment of these patients.

Topics: Anti-Bacterial Agents; Candidiasis, Oral; Chronic Disease; Cyclosporins; Gingival Hyperplasia; Humans; Immunosuppression Therapy; Liver Diseases; Liver Transplantation; Partial Thromboplastin Time; Prothrombin Time; Tacrolimus

The effect of FK 506 on regeneration of the liver was studied in rats after a two-thirds partial hepatectomy after 60 min of ischemia of the unresected liver. The animals were divided into three distinct groups of 10 rats each. Group 1 (controls) received 0.5 ml saline solution intravenously 30 min after the induction of ischemia. Groups 2 and 3 were injected with FK 506 (0.3 mg/kg) intravenously 30 min after and 24 min before the induction of hepatic ischemia, respectively. The hepatic content of ATP and serum levels of ALT and lactate dehydrogenase were determined on each animal. In addition, the histological appearance and mitotic activity of the remnant liver was determined at regular 24-hr intervals after hepatic ischemia. All 10 control animals died within 72 hr. Treatment with FK 506 resulted in improved survival in groups 2 and 3 (30% and 80%, respectively). The improved survival seen in the FK 506-treated animals was reflected by a restoration of hepatic ATP content, a reduction in the serum levels of ALT and lactate dehydrogenase, an amelioration of hepatic necrosis and neutrophilic infiltration and an increase in the mitotic activity of the liver. These results suggest that FK 506 ameliorates the hepatic injury associated with ischemia/reperfusion and has a potent stimulatory effect on liver cell regeneration that may make it valuable as a hepatoprotective agent when administered to organ donors before graft harvesting.

Topics: Adenosine Triphosphate; Alanine Transaminase; Animals; Anti-Bacterial Agents; Immunosuppressive Agents; L-Lactate Dehydrogenase; Liver; Liver Diseases; Liver Regeneration; Male; Mitosis; Necrosis; Rats; Rats, Inbred Lew; Reperfusion Injury; Tacrolimus

Topics: Amino Acid Isomerases; Animals; Carcinoma, Hepatocellular; Carrier Proteins; Cell Line; Cyclosporins; DNA Replication; Gene Expression; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Liver Neoplasms; Liver Neoplasms, Experimental; Organ Specificity; Peptidylprolyl Isomerase; Polyenes; Rats; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Transcription, Genetic

Topics: Administration, Oral; Anti-Bacterial Agents; Bile; Biological Availability; Humans; Immunosuppressive Agents; Infusions, Intravenous; Liver; Liver Diseases; Liver Transplantation; Tacrolimus

Topics: Adolescent; Alanine Transaminase; Anti-Bacterial Agents; Aspartate Aminotransferases; Child; Child, Preschool; Cyclosporins; Drug Evaluation; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Liver Diseases; Liver Transplantation; Male; Tacrolimus