sirolimus and Liver-Diseases

To evaluate the effects of the COVID-19 lockdown on the self-reported perception of physical and mental health, in a cohort of teenagers. To assess the extent to which these effects are perceived as detrimental.Non-directional Hypothesis - the perception of physical and mental health will change over the duration of the eight weeks, due to the effects of the lockdown, as a result of COVID-19.. This was a prospective longitudinal study evaluating the effects of the COVID-19 lockdown in the UK over the eight week period, against the political timeline during which the study was conducted (April 08, 2020-June 04, 2020).. Participants were all in secondary education, ranging from years 10-13 (ages 15-18).. 55 volunteers have taken part in the study, the group of participants was mixed-sex and of different ethnic groups. Participants were chosen via an opportunity sampling method. All participants stem from a middle to high socioeconomic background. The target demographic of the study was teenagers in secondary education, so participants have been selected from a volunteer sample that is representative of this population.. Physical health and Mental health.. Despite certain positive effects, the overall impact of lockdown during the COVID-19 pandemic has been negative, regarding both physical and mental health, for this cohort of young people.

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Inhalation; Animals; Antifungal Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Azoles; Candida albicans; Carbon Dioxide; Child; Chitosan; Chronic Periodontitis; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Environmental Monitoring; Female; Fluorides; Functional Residual Capacity; Gene Deletion; Genotype; Goats; Gold; Groundwater; Haplotypes; Humans; Infant; Insulin-Like Growth Factor II; Ketoconazole; Linkage Disequilibrium; Litter Size; Liver Diseases; Male; Metal Nanoparticles; Middle Aged; Nanocomposites; Pakistan; Peptides; Periodontal Attachment Loss; Periodontal Index; Plethysmography, Whole Body; Pneumoperitoneum, Artificial; Reference Standards; Remifentanil; Respiratory Function Tests; Respiratory Mechanics; Retrospective Studies; RNA-Binding Proteins; Sevoflurane; Sirolimus; Soot; Tidal Volume; Tumor Necrosis Factor Inhibitors; Water Pollutants, Chemical

Introduction Somatostatin analogues and rapamycin inhibitors are two classes of drugs available for the management of polycystic liver disease but their overall impact is not clearly established. This article systematically reviews the literature on the medical management of polycystic liver disease. The outcomes assessed include reduction in liver volume and the impact on quality of life. Methods The English language literature published between 1966 and August 2014 was reviewed from a MEDLINE(®), PubMed, Embase™ and Cochrane Library search. Search terms included 'polycystic', 'liver', 'sirolimus', 'everolimus', 'PCLD', 'somatostatin', 'octreotide', 'lanreotide' and 'rapamycin'. Both randomised trials and controlled studies were included. References of the articles retrieved were also searched to identify any further eligible publications. The studies included were appraised using the Jadad score. Results Seven studies were included in the final review. Five studies, of which three were randomised trials, investigated the role of somatostatin analogues and the results showed a mean reduction in liver volume ranging from 2.9% at six months to 4.95 ±6.77% at one year. Only one randomised study examined the influence of rapamycin inhibitors. This trial compared dual therapy with everolimus and octreotide versus octreotide monotherapy. Liver volume reduced by 3.5% and 3.8% in the control and intervention groups respectively but no statistical difference was found between the two groups (p=0.73). Two randomised trials investigating somatostatin analogues assessed quality of life using SF-36(®). Only one subdomain score improved in one of the trials while two subdomain scores improved in the other with somatostatin analogue therapy. Conclusions Somatostatin analogues significantly reduce liver volumes after six months of therapy but have only a modest improvement on quality of life. Rapamycin inhibitors do not confer any additional advantage.

Topics: Cysts; Disease Management; Everolimus; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Liver Diseases; Octreotide; Sirolimus; Somatostatin

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

The present review summarizes the existing knowledge on polycystic liver disease (PCLD) and highlights the progress made in medical treatment for this condition in the past year.. PCLD is associated with autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant PCLD. Signaling pathways of adenosine 3',5'-cyclic monophosphate (cAMP) and mammalian target of rapamycin (mTOR) are aberrantly regulated in polycystic livers and promote hepatic cystogenesis. Somatostatin analogues reduce intracellular cAMP, and this might prevent fluid accumulation in hepatic cysts. Several clinical trials published over the last year now show that somatostatin analogues when given for 6-12 months in patients with ADPKD and PCLD decrease total liver volume, attenuate polycystic kidney volume, and improve perception of health. In two recent studies mTOR inhibitors failed to halt the progression of ADPKD. It is still too early to recommend to start somatostatin analogues in PCLD and definitive answers should come from future clinical trials.. Somatostatin analogues are promising new medical drug options in the treatment of PCLD. However, more needs to be elucidated with regard to molecular mechanisms in hepatic cystogenesis, the uncertainty who will respond to therapy and long-term outcomes.

Topics: Antineoplastic Agents; Cysts; Everolimus; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Liver Diseases; Octreotide; Peptides, Cyclic; Sirolimus; Somatostatin; TOR Serine-Threonine Kinases

Topics: Animals; Calcium-Binding Proteins; Caroli Disease; Cholangiopancreatography, Magnetic Resonance; Cysts; Disease Models, Animal; Elasticity Imaging Techniques; Glucosidases; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Liver Cirrhosis; Liver Diseases; Magnetic Resonance Imaging; Membrane Proteins; Molecular Biology; Molecular Chaperones; Octreotide; Peptides, Cyclic; Polycystic Kidney Diseases; Prevalence; RNA-Binding Proteins; Sirolimus; Somatostatin; Tomography, X-Ray Computed

To evaluate the effects of the COVID-19 lockdown on the self-reported perception of physical and mental health, in a cohort of teenagers. To assess the extent to which these effects are perceived as detrimental.Non-directional Hypothesis - the perception of physical and mental health will change over the duration of the eight weeks, due to the effects of the lockdown, as a result of COVID-19.. This was a prospective longitudinal study evaluating the effects of the COVID-19 lockdown in the UK over the eight week period, against the political timeline during which the study was conducted (April 08, 2020-June 04, 2020).. Participants were all in secondary education, ranging from years 10-13 (ages 15-18).. 55 volunteers have taken part in the study, the group of participants was mixed-sex and of different ethnic groups. Participants were chosen via an opportunity sampling method. All participants stem from a middle to high socioeconomic background. The target demographic of the study was teenagers in secondary education, so participants have been selected from a volunteer sample that is representative of this population.. Physical health and Mental health.. Despite certain positive effects, the overall impact of lockdown during the COVID-19 pandemic has been negative, regarding both physical and mental health, for this cohort of young people.

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Inhalation; Animals; Antifungal Agents; Antirheumatic Agents; Arthritis, Rheumatoid; Azoles; Candida albicans; Carbon Dioxide; Child; Chitosan; Chronic Periodontitis; Cohort Studies; Dose-Response Relationship, Drug; Drug Therapy, Combination; Environmental Monitoring; Female; Fluorides; Functional Residual Capacity; Gene Deletion; Genotype; Goats; Gold; Groundwater; Haplotypes; Humans; Infant; Insulin-Like Growth Factor II; Ketoconazole; Linkage Disequilibrium; Litter Size; Liver Diseases; Male; Metal Nanoparticles; Middle Aged; Nanocomposites; Pakistan; Peptides; Periodontal Attachment Loss; Periodontal Index; Plethysmography, Whole Body; Pneumoperitoneum, Artificial; Reference Standards; Remifentanil; Respiratory Function Tests; Respiratory Mechanics; Retrospective Studies; RNA-Binding Proteins; Sevoflurane; Sirolimus; Soot; Tidal Volume; Tumor Necrosis Factor Inhibitors; Water Pollutants, Chemical

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

The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Everolimus; Feasibility Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Sirolimus; Time Factors; Withholding Treatment; Young Adult

Polycystic liver disease (PLD) is associated with autosomal dominant polycystic kidney disease (ADPKD) or autosomal dominant polycystic liver disease (PCLD). The resulting hepatomegaly compromises quality of life. Somatostatin analogues reduce PLD volume by approximately 5% when given for 6-12 months. A pilot trial in 16 ADPKD patients demonstrated that sirolimus, an mTOR inhibitor, reduced PLD volume by 26%. The aim of this study was to assess the PLD volume reducing effect of everolimus and octreotide relative to octreotide monotherapy.. We designed a randomized controlled trial that compared 48 weeks of everolimus 2.5 mg daily, combined with octreotide 40 mg intramuscularly every 4 weeks, to octreotide monotherapy. We included PCLD and ADPKD patients. Exclusion criteria were MDRD-GFR <60 ml/min/1.73 m(2) and liver volume <2500 ml. Primary outcome was change in liver volume measured with CT-volumetry.. We randomized 44 PLD patients (29 PCLD, 15 ADPKD, 89% female) to treatment with octreotide (n=23) or octreotide-everolimus (n=21). Liver volume decreased by 3.5% (p<0.01) in the monotherapy arm, compared to 3.8% with combination therapy (p<0.01). The difference between treatment arms was not significant (p=0.73).. Adding everolimus to octreotide in PLD does not increase the liver volume reducing effect of octreotide.

Topics: Adult; Cysts; Delayed-Action Preparations; Drug Therapy, Combination; Everolimus; Female; Humans; Kidney; Liver; Liver Diseases; Male; Middle Aged; Octreotide; Organ Size; Polycystic Kidney, Autosomal Dominant; Sirolimus; Treatment Outcome

Polycystic liver disease (PLD) is defined as having more than 20 liver cysts and can present as a severe and disabling condition. Most symptoms are caused by the mass effect of the liver size and include abdominal pain and distension. The somatostatin analogues octreotide and lanreotide have proven to reduce polycystic liver volume. mTOR inhibitors such as everolimus inhibit cell proliferation and might thereby reduce growth of liver cysts. This trial aims to assess the benefit of combination therapy of everolimus and octreotide compared to octreotide monotherapy. In this study we present the structure of the trial and the characteristics of the included patients.. This is a randomized open-label clinical trial comparing the effect of 12 months of everolimus and octreotide to octreotide monotherapy in PLD patients. Primary outcome is change in liver volume determined by CT-volumetry. Secondary outcomes are changes in abdominal symptoms and quality of life. Moreover, safety and tolerability of the drugs will be assessed.. This trial will compare the relative efficacy of combination therapy with octreotide and everolimus to octreotide monotherapy. Since they apply to different pathways of cystogenesis we expect that combining octreotide and everolimus will result in a cumulative reduction of polycystic liver volume.. ClinicalTrials.gov: NCT01157858.

Topics: Adult; Aged; Clinical Protocols; Cysts; Drug Therapy, Combination; Everolimus; Humans; Liver Diseases; Middle Aged; Octreotide; Sample Size; Sirolimus; Tomography, X-Ray Computed

Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 +/- 10.2 mL/minute; controls, 2.3 +/- 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation.

Topics: Adolescent; Adult; Aged; Biopsy; Calcineurin Inhibitors; Everolimus; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Treatment Outcome

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

Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.. We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.. Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.. Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)

Topics: Adult; Angiomyolipoma; Brain; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Male; Middle Aged; Protein Kinase Inhibitors; Protein Kinases; Radiography; Respiratory Function Tests; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis

The immunosuppressive agent sirolimus exerts an antiproliferative effect by inhibiting mammalian target of rapamycin (mTOR). Because excessive proliferation of the biliary epithelium is a prominent feature of the polycystic liver that accompanies autosomal dominant polycystic kidney disease (ADPKD), we hypothesized that sirolimus may benefit patients with this disorder. We retrospectively measured the volumes of polycystic livers and kidneys in ADPKD patients who had received kidney transplants and had participated in a prospective randomized trial that compared a sirolimus-containing immunosuppression regimen to a tacrolimus-containing regimen. Sixteen subjects (seven with sirolimus, nine with tacrolimus) had received abdominal imaging studies within 11 mo before and at least 7 mo after transplantation, making them suitable for our analysis. Treatment with the sirolimus regimen for an average of 19.4 mo was associated with an 11.9 +/- 0.03% reduction in polycystic liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14.1 +/- 0.09% increase. A trend toward a greater reduction in native kidney volume was also noted in the sirolimus group compared with the nonsirolimus group. Regarding mechanism, the epithelium that lines hepatic cysts exhibited markedly higher levels of phospho-AKT, phospho-ERK, phospho-mTOR, and the downstream effector phospho-S6rp compared with control biliary epithelium. In summary, treatment with sirolimus was associated with decreased polycystic liver volume, perhaps by preventing aberrant activation of mTOR in epithelial cells lining the cysts.

Topics: Aged; Epithelium; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Liver; Liver Diseases; Magnetic Resonance Imaging; Male; Middle Aged; Organ Size; Polycystic Kidney, Autosomal Dominant; Protein Kinases; Retrospective Studies; Ribosomal Protein S6; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Nine subjects with severe hepatic impairment (Child-Pugh grade C) and 9 healthy matched control subjects were given a single 15-mg dose of sirolimus by oral solution. Increases (P < or = .002) in mean whole-blood sirolimus t(1/2) (168%), AUC(0-infinity) (210%), and MRT(oral) (261%), together with a decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child-Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter-study comparison. Overall, mean t(1/2), weight-normalized AUC, and MRT(oral) increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.

Topics: Administration, Oral; Aged; Alanine Transaminase; Alkaline Phosphatase; Area Under Curve; Aspartate Aminotransferases; Bilirubin; Case-Control Studies; Cholecystitis; Creatinine; Female; Half-Life; Humans; Immunosuppressive Agents; Liver Diseases; Male; Middle Aged; Severity of Illness Index; Sirolimus

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

Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control subjects were given a single 15-mg dose of sirolimus by oral solution. Mean whole-blood sirolimus weight-normalized oral-dose clearances (CL/F) were significantly decreased (P = .02) in subjects with mild to moderate hepatic impairment by -31.8% and -36.0%, respectively, compared with controls. There were no significant differences in mean sirolimus C(max) and t(max) values among groups. The observed decreases in CL/F may be relevant in renal transplant patients with mild to moderate hepatic impairment, based on the close similarity of sirolimus CL/F in controls and previously studied stable renal transplant patients receiving multiple-dose administration of sirolimus and cyclosporine. There was considerable overlap in the CL/F values of hepatic-impaired subjects and controls, suggesting that whole-blood sirolimus trough concentrations in renal transplant patients exhibiting mild to moderate hepatic impairment be initially monitored to assess the need for dose adjustments.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Male; Metabolic Clearance Rate; Sirolimus

Alcohol-related liver disease (ALD) is characterized by accumulation of hepatic free fatty acids (FFAs) and liver injury. The present study aimed to investigate if mechanistic target of rapamycin complex 1 (mTORC1) plays a role in FFA-induced organelle dysfunction, thereby contributing to the development of ALD. Cell studies were conducted to define the causal role and underlying mechanism of FFA-activated mTORC1 signaling in hepatocellular cell injury. C57BL/6J wild-type mice were subjected to chronic alcohol feeding with or without rapamycin to inhibit mTORC1 activation. We revealed that palmitic acid (PA)-induced ER stress and suppression of LAMP2 and autophagy flux were mTORC1-dependent as rapamycin reversed such deleterious effects. C/EBP homologous protein (CHOP) was downstream of ATF4 which partially modulated LAMP2. Supplementation with rapamycin to alcohol-fed mice attenuated mTORC1 activation and ER stress, restored LAMP2 protein, and improved autophagy, leading to amelioration of alcohol-induced liver injury. Induction of mTORC1 signaling and CHOP were also detected in the liver of patients with severe alcoholic hepatitis. This study demonstrates that hepatic FFAs play a crucial role in the pathogenesis of ALD by activating mTORC1 signaling, thereby inducing ER stress and suppressing LAMP2-autophagy flux pathway, which represents an important mechanism of FFA-induced hepatocellular injury.

Topics: Activating Transcription Factor 4; Animals; Autophagy; Cell Line, Tumor; Dietary Supplements; Endoplasmic Reticulum Stress; Ethanol; Fatty Acids, Nonesterified; Hepatitis, Alcoholic; Hepatocytes; Humans; Liver Diseases; Lysosomal-Associated Membrane Protein 2; Mechanistic Target of Rapamycin Complex 1; Mice, Inbred C57BL; Palmitic Acid; Signal Transduction; Sirolimus; Transcription Factor CHOP

The objectives of this study were to address the role of autophagy in the pathogenesis of parenteral nutrition (PN)-associated liver disease (PNALD) and its possible mechanism in vivo.. Five-week-old male Sprague Dawley rats were fed Shoobree chow (Xietong Organism, Jiangsu, China) and administered intravenous 0.9% saline (sham group), PN (PN group), PN plus rapamycin (1 mg/kg; PN + Rapa group), or rapamycin (Rapa group) for 7 days. Before and after study, body weight, biochemical indicators, hepatic histology, level of autophagy, hepatocyte apoptosis, reactive oxygen species (ROS), and endoplasmic reticulum (ER) stress indicators including binding immunoglobulin protein (BIP), spliced X-box-binding protein-1 (sXBP1), and CCAAT-enhancer-binding protein homologous protein (CHOP) were measured.. Autophagy was suppressed in the PNALD model, which was demonstrated by less light chain 3 fluorescence (LC3) puncta and lower LC3II expression. Rapamycin effectively induced hepatic autophagy in PN rats. The PN + Rapa group presented improved hepatic function, decreased pathology scores, and less steatosis than the PN group. In addition, rapamycin treatment decreased terminal deoxynucleotidyl transferase dUTP nick end labeling and cleaved-caspase 3 expression, indicating a lower level of hepatocyte apoptosis. Compared with the PN group, the PN + Rapa group had lower levels of ROS and reduced expression of ER stress-related protein markers, such as BIP, sXBP1 and CHOP.. Autophagy was suppressed in the PNALD model. Rapamycin treatment induced autophagy and protected against PNALD, possibly by suppressing ROS-induced ER stress.

Topics: Animals; Apoptosis; Autophagy; Caspase 3; Endoplasmic Reticulum Stress; Fatty Liver; Hepatocytes; Liver; Liver Diseases; Male; Microtubule-Associated Proteins; Parenteral Nutrition; Rats, Sprague-Dawley; Reactive Oxygen Species; Sirolimus

Transfusion of umbilical cord-derived mesenchymal stem cells (UC-MSCs) is a novel strategy for treatment of various liver diseases. However, the therapeutic effect of UC-MSCs is limited because only a few UC-MSCs migrate towards the damaged regions. In this study, we observed the effects of autophagy on the migration of UC-MSCs in vitro and in a model of liver ischaemia/reperfusion (I/R) injury.. We investigated the effects of autophagy on the status of the cell, release of anti-inflammatory factors and migration of UC-MSCs in vitro. The therapeutic effects and in vivo migration of rapamycin-preconditioned UC-MSCs were observed in a C57/B6 mouse model of liver I/R injury.. Induction of autophagy by rapamycin enhanced the ability of UC-MSCs to migrate and release anti-inflammatory cytokines as well as increased expression of CXCR4 without affecting cell viability. Inhibition of CXCR4 activation markedly decreased migration of these cells. In a mouse model of liver I/R injury, we found significantly upregulated expression of CXCR12 in the damaged liver. More rapamycin-preconditioned UC-MSCs migrated towards the ischaemic regions than 3-methyladenine-preconditioned or non-preconditioned UC-MSCs, leading to improvement in hepatic performance, pathological changes and levels of inflammatory cytokines. These effects were abolished by AMD3100.. Preconditioning of UC-MSCs by rapamycin afforded increased protection against liver I/R injury by enhancing immunosuppression and strengthening the homing and migratory capacity of these cells via the CXCR4/CXCL12 axis.

Topics: Animals; Cell Movement; Cells, Cultured; Chemokine CXCL12; Humans; Immunosuppressive Agents; Ischemic Preconditioning; Liver; Liver Diseases; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Receptors, CXCR4; Reperfusion Injury; Signal Transduction; Sirolimus; Umbilical Cord

Although rapamycin (RPM) have been studied extensively in ischemia models, its functional mechanisms remains to be defined.. We determined how RPM impacted the pathogenesis of ischemia-reperfusion injury (IRI) in a murine liver partial warm ischemia model, with emphasis on its regulation of hepatocyte death.. Rapamycin protected livers from IRI in the presence of fully developed liver inflammatory immune response. Rapamycin enhanced liver autophagy induction at the reperfusion stage. Dual mammalian (mechanistic) target of rapamycin (mTOR)1/2 inhibitor Torin 1, despite its ability to induced autophagy, failed to protect livers from IRI. The treatment with RPM, but not Torin 1, resulted in the enhanced activation of the mTORC2-Akt signaling pathway activation in livers after reperfusion. Inactivation of Akt by Triciribine abolished the liver protective effect of RPM. The differential cytoprotective effect of RPM and Torin 1 was confirmed in vitro in hepatocyte cultures. Rapamycin, but not Trin 1, protected hepatocytes from stress and tumor necrosis factor-α induced cell death; and inhibition of autophagy by chloroquine or Akt by Triciribine abolished RPM-mediated cytoprotection.. Rapamycin protected livers from IRI by both autophagy and mTORC2-Akt activation mechanisms.

Topics: Animals; Autophagy; Cell Line; Cytoprotection; Disease Models, Animal; Endoplasmic Reticulum Stress; Enzyme Activation; Hepatocytes; Liver; Liver Diseases; Male; Mechanistic Target of Rapamycin Complex 2; Mice, Inbred C57BL; Multiprotein Complexes; Naphthyridines; Protective Agents; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Reperfusion Injury; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha; Warm Ischemia

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Topics: Acetylcysteine; Adult; Alanine Transaminase; Antibodies, Antinuclear; Aspartate Aminotransferases; Azathioprine; Biomarkers; Cohort Studies; Complement System Proteins; Cyclosporine; Diabetes Mellitus; Female; Free Radical Scavengers; Humans; Immunosuppressive Agents; Liver Diseases; Longitudinal Studies; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prevalence; Retrospective Studies; Severity of Illness Index; Sex Distribution; Sirolimus

The mTOR pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct the innate and adaptive immune responses. MDSCs are a heterogeneous cell population that plays a crucial regulatory effect in immune-related diseases. However, whether mTOR signaling affects the functions of MDSCs remains largely unknown. Here, we show that mTOR signaling is a pivotal negative determinant of MDSC recruitment in IMH disease. In the context of IMH, inhibition of mTOR with rapamycin in CD11b⁺Gr1⁺ MDSCs mediates protection against IMH and serves as a functional, suppressive immune modulator that results in increased CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment to inflammatory sites. In agreement with this, mTOR down-regulation promotes CD11b⁺Gr1⁺Ly6C(high) MDSC migration in vitro and in vivo. Mechanistically, mTOR activity down-regulation in MDSCs induced iNOS expression and NO production. Pharmacologic inhibition of iNOS completely eliminated MDSC recruitment. This study identifies MDSCs as an essential component for protection against IMH following rapamycin treatment. Rapamycin treatment or mTOR inhibition promotes CD11b⁺Gr1⁺Ly6C(high) MDSC recruitment and is critically required for protection against hepatic injury. This study further validates the targeting of mTOR signaling as a potential therapeutic approach to IMH-related diseases.

Topics: Animals; Antigens, Ly; CD11b Antigen; Cell Movement; Immune Tolerance; Liver Diseases; Mice; Myeloid Cells; Nitric Oxide; Receptors, Chemokine; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

Topics: Cysts; Everolimus; Female; Humans; Liver Diseases; Male; Octreotide; Sirolimus

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

Activation of the mTOR pathway has been implicated in the mediation of the progression of polycystic kidney disease (PKD). Whereas targeted inhibition of mTOR has been proven to be effective in various animal models of autosomal dominant PKD, its efficacy in autosomal recessive PKD (ARPKD) remains to be elucidated. We examined the effects of sirolimus in PCK rats, an orthologous animal model of human ARPKD.. Weaned PCK rats (n = 85) and SD-control rats (n = 72) received drinking water without and with sirolimus (corresponding to a daily intake of 2 mg/kg body weight) for 4, 8 and 12 weeks, respectively. The renal and hepatic functions were monitored throughout the treatment periods. Kidneys and livers were harvested and investigated with respect to progression of fibrosis, and number and size of cysts using the QWin image analysis programme. Expression of Akt, mTOR and its downstream target pS6K were assessed by immunohistochemistry.. Five out of 43 sirolimus-treated PCK rats, but none of the controls, died during the study. Sirolimus treatment resulted in slightly reduced weight gain. In PCK rats, grossly enlarged kidney and livers as well as hepatic fibrosis together with enlarged bile ducts were readily detectable. Whereas activation of Akt/mTOR signalling was hardly detectable in the kidneys of SD rats, strong signals were seen in the kidneys of PCK rats. Despite a significantly reduced relative kidney weight after 12 weeks of treatment (P < 0.05), neither fibrosis and cyst area nor renal function improved during treatment. Sirolimus-treated PCK rats showed only a minor inhibition of renal mTOR-specific phosphorylation of S6K. Male PCK rats on sirolimus presented with increased concentrations of bile acids and bilirubin compared with controls (each P < 0.05 at 12 weeks). Similar, albeit non-significant, effects were noted in female PCK rats.. Sirolimus failed to attenuate progression of kidney and liver disease in PCK rats. The lack of a protective effect might be due to intrinsic or acquired rapamycin resistance in this animal model of ARPKD.

Topics: Animals; Blotting, Western; Disease Progression; Female; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Liver Diseases; Male; Polycystic Kidney Diseases; Rats; Sirolimus; TOR Serine-Threonine Kinases

Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)-dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1alpha)-dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2-knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1alpha, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1alpha accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026.. These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2-defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1alpha-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation.

Topics: Animals; Cysts; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin-Like Growth Factor I; Intracellular Signaling Peptides and Proteins; Liver Diseases; Mice; Polycystic Kidney, Autosomal Dominant; Protein Serine-Threonine Kinases; Sirolimus; TOR Serine-Threonine Kinases; TRPP Cation Channels; Vascular Endothelial Growth Factor A

Topics: Disease Progression; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Liver; Liver Diseases; Octreotide; Polycystic Kidney, Autosomal Dominant; Sirolimus; Somatostatin; Treatment Outcome

Alpha-1-antitrypsin (a1AT) deficiency is caused by homozygosity for the a1AT mutant Z gene and occurs in one in 2000 Americans. The Z mutation confers an abnormal conformation on the a1AT mutant Z protein, resulting in accumulation within the endoplasmic reticulum of hepatocytes and chronic liver injury. Autophagy is one of several proteolytic mechanisms activated to cope with this hepatocellular protein burden, and is likely important in disposal of the unique polymerized conformation of the a1AT mutant Z protein, which is thought to be especially injurious to the cell. Recent data indicate that rapamycin may more efficiently upregulate autophagy when given in weekly dose pulses, as compared with a daily regimen. Therefore, we evaluated the effect of rapamycin on PiZ mice, a well-characterized model which recapitulates human a1AT liver disease. Daily dosing had no effect on autophagy, on accumulation of a1AT mutant Z protein or on liver injury. Weekly dosing of rapamycin did increase autophagic activity, as shown by increased numbers of autophagic vacuoles. This was associated with reduction in the intrahepatic accumulation of a1AT mutant Z protein in the polymerized conformation. Markers of hepatocellular injury, including cleavage of caspase 12 and hepatic fibrosis, were also decreased. In conclusion, this is the first report of a successful in vivo method for reduction of intrahepatic a1AT mutant Z polymerized protein. Application of this finding may be therapeutic in patients with a1AT deficiency by reducing the intracellular burden of the polymerized, mutant Z protein and by reducing the progression of liver injury.

Topics: alpha 1-Antitrypsin; Animals; Autophagy; Disease Models, Animal; Enzyme Activators; Humans; Liver Cirrhosis; Liver Diseases; Mice; Mutant Proteins; Sirolimus

Renal dysfunction, primarily related to long-term use of calcineurin inhibitor-based immunosuppression, is the most common complication after liver transplantation.. To evaluate whether liver transplant recipients with impaired kidney function at transplantation can benefit from early conversion to mammalian target of rapamycin inhibitor therapy (mTORi) compared with patients with late induction of mTORi-based therapy.. Between 2003 and 2008, therapy was changed to an mTORi-based regimen in 57 patients. Patients were divided into 4 groups: group 1, early conversion (≤3 months after orthotopic liver transplantation) to mTORi therapy, and with impaired perioperative renal function; group 2, early conversion to mTORi therapy, and with normal perioperative renal function; group 3, late conversion to mTORi therapy, and with impaired perioperative renal function; and group 4, late conversion to mTORi therapy, and with normal perioperative renal function.. One month after conversion, the mean (SD) increase in calculated glomerular filtration rate in groups 1 (early conversion) and 3 (late conversion) was comparable: 8 (9) mL/min vs 7 (10) mL/min. At month 3, the increase in calculated glomerular filtration rate between groups 1 and 3 was significant (15 [11] mL/min vs 9 [15] mL/min; P = .04), an effect that persisted at month 6 (16 [12] mL/min vs 10 [12] mL/min; P = .05) and month 12 (22 [14] mL/min vs 12 [15] mL/min; P = .04).. In liver transplant recipients with perioperatively impaired renal function, early conversion to mTORi therapy should be performed because this approach seems to be more effective in improving long-term renal function.

Topics: Adult; Aged; Creatinine; Everolimus; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Sirolimus; TOR Serine-Threonine Kinases

Most patients with high MELD scores have impaired renal function prior to transplantation.. A retrospective case control study was conducted with initial low immunosuppression, which was increased when patients rejected or were clinically stable beyond day 30 ('bottom-up').. Thirty patients with impaired renal function were included. Fifteen were treated with de novo cyclosporine A (CsA; group A), and 15 had 'bottom-up' immunosuppression (group B). Baseline renal function was similar: serum creatinine (SCr) median 1.8 mg/dl (range: 1.5-4.0 mg/dl; group A) versus 2.4 mg/dl (range: 1.5-4.0 mg/dl; group B; p = 0.24). The requirement for renal replacement therapy was significantly lower in group B (p = 0.032). Ten received 'bottom-up' immunosuppression [4 CsA/1 sirolimus (Sir) 'on demand' after rejection, 5 Sir (stable)] beyond day 30. By months 6 and 12 (1.6 mg/dl vs. 1.2 mg/dl), SCr values were significantly better in group B (p = 0.006). Renal function in group B did not differ between patients receiving CsA or Sir. Overall complication rates, survival and biopsy-proven acute rejection were similar, although BANFF scores were higher in group B (p = 0.004).. Successful implementation of 'bottom-up' immunosuppression in liver transplant recipients with high lab-MELD scores and renal dysfunction at the time of transplantation has the potential to substantially improve short- and long-term outcomes.

Topics: Adult; Aged; Case-Control Studies; Creatinine; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Pilot Projects; Renal Insufficiency; Retrospective Studies; Sirolimus; Treatment Outcome

Liver injury induced by concanavalin A (Con A) is often used as a model to study the pathophysiology of immune mediated liver injury. Rapamycin (Rapa) is an effective immunosuppressant widely used for preventing immune activation and transplant rejection. However, the effect of Rapa on liver injury caused by Con A has not been carefully examined. In the present study, we examined the effect of Rapa on liver injury caused by Con A.. Mice received intraperitoneal Rapa injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the level of cytokines was detected by enzyme linked immunosorbent assay (ELISA).. In the present study, we examined the effect of Rapa on liver injury after Con A injection in mice. We found that the treatment of mice with Rapa protected the liver from Con A-induced injury. Pretreatment with Rapa dramatically ameliorated Con A-induced mortality. This protection was associated with reduced transaminase levels in the blood and further confirmed by liver histology. ELISA showed that Rapa suppressed pro-inflammatory cytokines IFN-gamma and TNF-alpha production as compared with the untreated controls. Furthermore, intrahepatic lymphocyte proliferation was significantly inhibited.. These findings suggested that Rapa has the therapeutic potential for treatment of immune-mediated liver injury in the clinic.

Topics: Animals; Cell Proliferation; Chemical and Drug Induced Liver Injury; Concanavalin A; Cytoprotection; Disease Models, Animal; Down-Regulation; Enzyme-Linked Immunosorbent Assay; Immunosuppressive Agents; Inflammation Mediators; Injections, Intraperitoneal; Interferon-gamma; Interleukin-4; Liver; Liver Diseases; Lymphocyte Activation; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Sirolimus; Time Factors; Transaminases; Tumor Necrosis Factor-alpha

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

Long-term supplementation of branched-chain amino acids (BCAA) improves hypoalbuminemia in patients with cirrhosis. Our previous findings have suggested that the binding of polypyrimidine-tract-binding protein (PTB) to rat albumin mRNA attenuates its translation. The aim of the present study was to investigate the role of PTB in the regulation of albumin synthesis by BCAA in human hepatoma cells. HepG2 cells were cultured in a medium containing no amino acids (AA-free medium), a medium containing only 1 amino acid (a BCAA: valine, leucine or isoleucine) or a medium containing all 20 amino acids (AA-complete medium). HepG2 cells cultured in AA-complete medium secreted much more albumin than cells cultured in AA-free medium, with no difference in albumin mRNA levels. In cells cultured in AA-free medium, nuclear export of PTB was observed, and the level of the albumin mRNA-PTB complex was greater than in cells cultured in AA-complete medium. Addition of amino acids stimulated nuclear import of PTB. However, addition of amino acids with rapamycin inhibited the nuclear import of PTB. The addition of leucine, but not of valine or isoleucine, to AA-free medium increased albumin secretion and stimulated the nuclear import of PTB. These data indicate that the mammalian target of rapamycin is involved in the regulation of PTB localization and that leucine promotes albumin synthesis by inhibiting the formation of the albumin mRNA-PTB complex.

Topics: Amino Acids, Branched-Chain; Cell Line; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Liver Diseases; Polypyrimidine Tract-Binding Protein; Protein Transport; RNA, Messenger; Serum Albumin; Sirolimus

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

Everolimus is a new immunosuppressant with antitumoral properties and few side effects, but limited use in liver transplantation. The aim of the present study was to evaluate the effect on survival and safety of everolimus in post liver transplantation neoplasms in a single center. Ten liver transplant recipients with a posttransplant diagnosis of neoplasm received everolimus during a median of 12.7 (5.5-27.5) months; median survival was 21.3 (7.5-40.5) months. The probability of survival of everolimus group was significantly greater than the observed in a historical cohort of 14 liver recipients with comparable tumors who did not receive everolimus (100%, 90%, 72% vs. 50%, 29%, 14%) at 6, 12, and 24 months, respectively (HR=4.6, 95% confidence interval: 1.3-16.4; P=0.008). During everolimus therapy no patients showed rejection. Renal function improved in three patients. Furthermore, severe adverse effects and infections were infrequent. In summary, everolimus seems safe for liver transplant recipients with cancer and may improve short-term survival, but further studies are needed to determine long-term benefits and safety.

Topics: Adult; Aged; Everolimus; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Neoplasms; Sirolimus; Survival Analysis

Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described.. To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients.. Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101).. One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar.. Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted.

Topics: Blood Cell Count; Calcineurin Inhibitors; Creatinine; Female; Graft Rejection; Graft Survival; Hemoglobins; Humans; Immunosuppressive Agents; Kidney; Liver Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Care; Retrospective Studies; Sirolimus; Treatment Outcome

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Topics: Autoantibodies; Azathioprine; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Infant, Newborn; Liver; Liver Diseases; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sirolimus; Time Factors; Transaminases; Treatment Outcome

We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125-labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy.. Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P > .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis.. Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.

Topics: Creatinine; Drug Therapy, Combination; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Diseases; Liver Transplantation; Retrospective Studies; Sirolimus; Time Factors

Topics: Adult; Aged; Calcineurin Inhibitors; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Retrospective Studies; Sirolimus

We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use.. In this open-label, single-dose, case-control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child-Pugh score, 7-9) and 8 demographically matched healthy control subjects received a single oral 2-mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding.. The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 +/- 3.1 versus 19.4 +/- 5.8 L/h). This was manifested by a 115% higher area under the blood concentration-time curve (AUC) (245 +/- 91 versus 114 +/- 45 ng. h/ml) and 84% prolonged half-life (79 +/- 42 versus 43 +/- 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (C(max)) and time to reach C(max) (t(max)). Protein binding was similar in the two groups (73.8% +/- 3.6% versus 73.5% +/- 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed.. The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child-Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.

Topics: Adult; Area Under Curve; Aryl Hydrocarbon Hydroxylases; Case-Control Studies; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Everolimus; Female; Humans; Immunosuppressive Agents; Liver Diseases; Male; Middle Aged; Oxidoreductases, N-Demethylating; Sirolimus

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