tacrolimus and Liver-Failure--Acute

  We report a case series of four children who developed fixed dilated pupils associated with high tacrolimus levels (>30 nanograms/millilitre [ng/mL]) in the immediate post-operative period following isolated liver or liver and small bowel transplantation.

Topics: Child; Cystic Fibrosis; Electroencephalography; Female; Fixation, Ocular; Humans; Immunosuppressive Agents; Infant; Liver Failure, Acute; Liver Transplantation; Male; Pupil; Short Bowel Syndrome; Tacrolimus

Topics: Humans; Immunosuppressive Agents; Infant; Liver Failure, Acute; Liver Transplantation; Tacrolimus; Thrombotic Microangiopathies

To describe the clinical and laboratory profile, natural course, treatment outcome, and risk factors of posttransplant esophageal and nonesophageal eosinophilic gastrointestinal disorders (EGIDs).. All children (aged <18 years) who underwent liver transplantation, between 2011 and 2019, in a single transplant center with a follow-up period of 1 year or more posttransplant and with a history of posttransplant endoscopic evaluation were included in this study.. During the study period, 89 children met the inclusion criteria. Patients were followed for a median of 8.0 years. A total of 39 (44%) patients were diagnosed with EGID after transplantation. Of these, 29 (33%) had eosinophilic esophagitis (EoE), and 10 (11%) had eosinophilic gastritis, gastroenteritis or enterocolitis. In comparison with the non-EGID group, patients with EGID were younger at transplant (P ≤ 0.0001), transplanted more frequently due to biliary atresia (P ≤ 0.0001), and had higher rates of pretransplant allergy (P = 0.019). In the posttransplant period, they had higher rates of mammalian Target of Rapamycin inhibitor use (P = 0.006), Epstein-Barr virus viremia (P = 0.03), post-transplant lymphoproliferative disease (P = 0.005), and allergen sensitization (P ≤ 0.0001). In regression analysis, young age at transplant, age at diagnosis, pretransplant atopic dermatitis, and post-transplant lymphoproliferative disease were associated with an increased risk of EGID or EoE. Laboratory abnormalities such as anemia (P = 0.007), thrombocytosis (P = 0.012), and hypoalbuminemia (P = 0.031) were more commonly observed in the eosinophilic gastritis, gastroenteritis or enterocolitis group than in the EoE group. Following treatment, most patients had symptomatic resolution at 3 months and histologic resolution at 6 months postdiagnosis. Among the patients who had 5 years of follow-up, none recurred.. EGID is a common posttransplant diagnosis, which seems to affect patients who are transplanted earlier and who have pretransplant atopy. Posttransplant EGID is responsive to treatment, but as histologic remission occurs after symptomatic resolution, the decision to perform control endoscopy should be delayed.

Topics: Age Factors; Anti-Allergic Agents; Biliary Atresia; Budesonide; Child; Child, Preschool; Cholestasis, Intrahepatic; Dermatitis, Atopic; Disease Progression; Drug Tapering; Enteritis; Enterocolitis; Eosinophilia; Eosinophilic Esophagitis; Epstein-Barr Virus Infections; Female; Follow-Up Studies; Gastritis; Glucocorticoids; Graft Rejection; Humans; Hypersensitivity; Immunosuppressive Agents; Infant; Ketotifen; Liver Failure, Acute; Liver Transplantation; Lymphoproliferative Disorders; Male; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Viremia

Immune checkpoint inhibitors (ICIs), particularly anti-PD-1 antibody, have dramatically changed cancer treatment; however, fatal immune-related adverse events (irAEs) can develop. Here, we describe a severe case of sclerosing cholangitis-like irAE. We report the use of 3 immunosuppressive agents that resulted in the death of the patient due to treatment inefficacy. According to a postmarketing study of nivolumab, the frequency of ICI-related sclerosing cholangitis is 0.27% and that of ICI-related cholangitis is 0.20%. There have been 4 case reports of sclerosing cholangitis-like irAE, with imaging findings, including typical intrahepatic bile duct beaded constriction in primary sclerosing cholangitis. Treatment starts with prednisolone and is combined with an immunosuppressant in refractory cases. There are no reports of severe cases that ultimately led to death.. The patient is a 64-year-old male with Stage IV squamous cell lung carcinoma; he was hospitalized with abdominal pain and elevation of aspartate transaminase and alanine transaminase, approximately 4 months after ICI administration was suspended. This occurred because the patient treated with nivolumab as the second-line chemotherapy and developed type 1 diabetes mellitus after 11 courses.. A grade 3 increase in bilirubin was observed and he was diagnosed with sclerosing cholangitis, based on magnetic resonance cholangiopancreatography imaging and pathological findings of the liver and bile duct.. Prednisolone, mycophenolate mofetil, and tacrolimus combination therapy was administered.. The treatment was difficult and failed. He died from liver failure 8 months after diagnosis. In this case, hepatitis and cholangitis, mainly alanine transaminase-dominant liver disorder, developed in the early stages of irAEs. Although he showed some improvement after prednisolone administration, bilirubin levels began rising again, and sclerosing cholangitis did not improve even with the use of 3 immunosuppressive agents recommended by the ESMO Clinical Practice Guidelines for immune-related hepatotoxicity management. Although the antitumor effect showed a complete response, liver failure led to death.. This is the first case report on the ineffectiveness of triple immunosuppressant combination therapy recommended by the guidelines for immune-related hepatotoxicity. It is necessary to develop more appropriate treatment for severe sclerosing cholangitis-like irAE based on the robust evidence.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Carcinoma, Non-Small-Cell Lung; Cholangiopancreatography, Magnetic Resonance; Cholangitis, Sclerosing; Fatal Outcome; Humans; Immune Checkpoint Inhibitors; Immunosuppressive Agents; Liver Failure, Acute; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Nivolumab; Prednisolone; Tacrolimus; Treatment Failure

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

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

Topics: Acute Disease; Anemia, Sickle Cell; Antisickling Agents; beta-Thalassemia; Bradycardia; Budd-Chiari Syndrome; Cardiopulmonary Resuscitation; Cholestasis, Intrahepatic; Glucocorticoids; Graft Rejection; Heart Arrest; Humans; Hydroxyurea; Immunosuppressive Agents; Liver Failure, Acute; Liver Transplantation; Male; Postoperative Complications; Prednisone; Tacrolimus; Young Adult

Living donor liver transplantation (LDLT) is now an established technique for treating children with end-stage liver disease. Few data exist about liver transplantation (LT) for exclusively young infants, especially infants of <3 months of age. We report our single-center experience with 12 patients in which LDLT was performed during the first 3 months of life and compare the results with those of older infants who underwent LT. All of the patients were treated at the National Center of Child Health and Development, Tokyo, Japan. Between November 2005 to November 2016, 436 children underwent LT. Twelve of these patients underwent LT in the first 3 months of life (median age, 41 days; median weight, 4.0 kg). The indications for transplantation were fulminant hepatic failure (n = 11) and metabolic liver disease (n = 1). All the patients received the left lateral segment (LLS) in situ to mitigate the problem of graft-to-recipient size discrepancy. A reduced LLS graft was used in 11 patients and a segment 2 monosegment graft was used in 1 patient. We compared the results with those of infants who were 4-6 months of age (n = 67) and 7-12 months of age (n = 110) who were treated in the same study period. There were significant differences in the Pediatric End-Stage Liver Disease score and the conversion rate of tacrolimus to cyclosporine in younger infants. Furthermore, the incidence of biliary complications, bloodstream infection, and cytomegalovirus infection tended to be higher, whereas the incidence of acute cellular rejection tended to be lower in younger infants. The overall cumulative 10-year patient and graft survival rates in recipients of <3 months of age were both 90.9%. LDLT during the first 3 months of life appears to be a feasible option with excellent patient and graft survival. Liver Transplantation 23 1051-1057 2017 AASLD.

Topics: Age Factors; Cyclosporine; Cytomegalovirus Infections; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infant; Infant, Newborn; Japan; Liver Failure, Acute; Liver Transplantation; Living Donors; Male; Retrospective Studies; Severity of Illness Index; Survival Rate; Tacrolimus

A 20-year-old woman presented with acute exacerbation of ulcerative colitis. After treatment with infliximab, she developed a fulminant liver failure. Under supportive therapy and steroid medication, recovery of symptoms and transaminases occurred. A few case reports about hepatic side effects of anti-TNF-α antibodies in patients with inflammatory bowel disease have been published. These side effects ranged from asymptomatic increase of transaminases to fulminant liver failure necessitating transplantation. The pathomechanism is not fully understood; in some case reports autoimmune phenomena have been described.

Topics: Colitis, Ulcerative; Diagnosis, Differential; Disease Progression; Drug Therapy, Combination; Female; Humans; Hydrocortisone; Infliximab; Infusions, Intravenous; Liver Failure, Acute; Liver Function Tests; Prednisolone; Sigmoidoscopy; Tacrolimus; Tomography, X-Ray Computed; Young Adult

Topics: Acetaminophen; Adolescent; Adult; Allografts; Ammonia; Analgesics, Non-Narcotic; Biopsy; Female; Graft Rejection; Hepatectomy; Hepatic Artery; Hepatic Encephalopathy; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Failure, Acute; Liver Transplantation; Portacaval Shunt, Surgical; Portal Vein; Prednisolone; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous; Ultrasonography, Doppler; Vena Cava, Inferior

Immunosuppressive drugs and other medications may predispose patients to oral diseases. Data on oral mucosal health in recipients of liver transplantation (LT) are limited. We, therefore, recruited 84 LT recipients (64 with chronic liver disease and 20 with acute liver failure) for clinical oral examinations in a cross-sectional, case-control study. Their oral health had been clinically examined before transplantation. The prevalence of oral mucosal lesions (OMLs) was assessed in groups with different etiologies of liver disease and in groups with different immunosuppressive medications, and these groups were compared to controls selected from a nationwide survey in Finland (n = 252). Risk factors for OMLs were evaluated with logistic regression. OMLs were more frequent in LT recipients versus controls (43% versus 15%, P < 0.001), and the use of steroids raised the prevalence to 53%. Drug-induced gingival overgrowth was the single most common type of lesion, and its prevalence was significantly higher for patients using cyclosporine A (CSA; 29%) versus patients using tacrolimus (TAC; 5%, P = 0.007); the prevalence was even higher with the simultaneous use of calcium channel blockers and CSA (47%) or TAC (8%, P = 0.002). Lesions with malignant potential such as drug-induced lichenoid reactions, oral lichen planus-like lesions, leukoplakias, and ulcers occurred in 13% of the patients with chronic liver disease and in 6% of the controls. Every third patient with chronic liver disease had reduced salivary flow, and more than half of all patients were positive for Candida; this risk was higher with steroids. In conclusion, the high frequency of OMLs among LT recipients can be explained not only by immunosuppressive drugs but also by other medications. Because dry mouth affects oral health and OMLs may have the potential for malignant transformation, annual oral examinations are indicated.

Topics: Adult; Aged; Calcium Channel Blockers; Case-Control Studies; Cross-Sectional Studies; Cyclosporine; End Stage Liver Disease; Female; Gingival Diseases; Humans; Immunosuppressive Agents; Leukoplakia; Lichen Planus; Liver Failure, Acute; Liver Transplantation; Logistic Models; Male; Middle Aged; Mouth Mucosa; Oral Ulcer; Prevalence; Risk Factors; Tacrolimus

The established procedure for ABO-incompatible liver transplantation (ABO-I LT) was too complicated to be used in case of emergency. We developed a protocol consisting of rituximab and intravenous immunoglobulin (IVIG) for ABO-I LT in patients with acute liver failure (ALF).. The data from 101 patients who had undergone liver transplantation (LT) for ALF were retrospectively analyzed. The patients were divided into two groups: ABO-compatible liver transplantation group (ABO-C LT, n=66) and ABO-I LT group (n=35). All the patients in the ABO-I LT group received a single dose of rituximab (375 mg/m2) and IVIG (0.4 g/kg per day) at the beginning of the operation. IVIG was administered for 10 consecutive days after LT. Plasma exchange, splenectomy and graft local infusion were omitted in the protocol. Quadruple immunosuppressive therapy including basiliximab, corticosteroids, tacrolimus and mycophenolatemofetil was used to reinforce immunosuppression.. The 3-year cumulative patient survival rates in the ABO-I LT and ABO-C LT groups were 83.1% and 86.3%, respectively (P>0.05), and the graft survival rates were 80.0% and 86.3%, respectively (P>0.05). Two patients (5.7%) suffered from antibody-mediated rejection in the ABO-I LT group. Other complications such as acute cellular rejection, biliary complication and infection displayed no significant differences between the two groups.. The simplified treatment consisting of rituximab and IVIG prevented antibody-mediated rejection for LT of blood-type incompatible patients. With this treatment, the patients did not need plasma exchange, splenectomy and graft local infusion. This treatment was safe and efficient for LT of the patients with ALF.

Topics: ABO Blood-Group System; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Blood Group Incompatibility; Drug Administration Schedule; Drug Therapy, Combination; Emergencies; Female; Graft Rejection; Graft Survival; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Failure, Acute; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk Factors; Rituximab; Tacrolimus; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes.. Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 ± 2.5. Median follow-up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression.. Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25).. During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival.

Topics: Adult; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Failure, Acute; Liver Neoplasms; Liver Transplantation; Logistic Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure, Acute; Liver Transplantation; Tacrolimus

Graft rejection and disease recurrence are well-recognized complications of liver transplantation (LT) for autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC). We describe indications and outcome of LT for childhood AIH and AISC.. Twenty-year retrospective review of a cohort of children (n = 101) with AIH, AISC, or AIH/sclerosing cholangitis overlap syndrome from a single center.. AIH type 1 (AIH1, n = 67) was more common than AIH type 2 (AIH2, n = 18), AISC (n = 8), or overlap syndrome (n = 8). Overall, 18 patients (18%) required LT, the indications being failure of medical therapy (n = 16) and fulminant liver failure (n = 2). Patients with AIH who required LT had a more prolonged prothrombin time at presentation compared with those who did not undergo transplantation (P = 0.01). Patients with AIH1 who received LT had a lower aspartate transaminase (P = 0.009) and alanine transaminase (P = 0.02) levels at initial diagnosis compared with those with AIH1 who did not undergo transplantation. Post-LT, 11 patients (61%) had 18 episodes of rejection, most were steroid sensitive. Disease recurrence was observed in 7 patients (39%, median duration post-LT 33 months), more common in AIH2 (80% recurrence rate), and those taking cyclosporine (71%, 5/7 patients) compared with those taking tacrolimus (18%, 2/11 patients; P < 0.05) and in 3 of 3 children who did not have maintenance steroids post-LT. The overall 5- and 7-year post-LT survival rate was 94% and 88%, respectively.. LT is a good therapeutic option for progressive AIH and AISC, although recurrence of the primary autoimmune process limits the outcome.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Child; Cholangitis, Sclerosing; Cyclosporine; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Liver; Liver Failure, Acute; Liver Transplantation; Male; Prothrombin Time; Recurrence; Retrospective Studies; Steroids; Survival Analysis; Survival Rate; Syndrome; Tacrolimus; Treatment Outcome

Posterior reversible encephalopathy syndrome, a serious neurotoxicity, may develop rarely in patients receiving tacrolimus. Because the underlying etiology of posterior reversible encephalopathy syndrome is vasogenic edema, it is generally accepted to be a reversible neurologic condition. Cranial magnetic resonance imaging techniques enable detection of the type of edema, and they are widely used in the differential diagnosis and prognostic prediction of posterior reversible encephalopathy syndrome. Presented here is a case of posterior reversible encephalopathy syndrome in which the patient recovered completely, despite radiologic findings indicating the coexistence of vasogenic and cytotoxic edema secondary to tacrolimus therapy after liver transplantation.

Topics: Brain Edema; Child; Diffusion Magnetic Resonance Imaging; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure, Acute; Liver Transplantation; Male; Tacrolimus

Fulminant hepatic failure is a rare complication of infection by varicella zoster virus that is favored by immunosuppression. Within 1 week, a 43-year-old male heart transplant recipient who was admitted with epigastric pain successively developed a generalized vesicular rash, hepatitis, and secondary multiorganic failure involving encephalopathy, despite treatment with acyclovir (since Day 2) and varicella zoster virus immunoglobulin (since Day 6). Emergency liver transplantation was performed on Day 9, and 36 months later, his heart and liver function are normal.

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cyclosporine; Heart Transplantation; Hemoglobinopathies; Herpes Zoster; Herpesvirus 3, Human; Humans; Immunosuppressive Agents; Liver Failure, Acute; Liver Function Tests; Male; Postoperative Complications; Prothrombin Time; Tacrolimus; Treatment Outcome

The mortality rate of fulminant hepatic failure (FHF) is high because of retarded liver regeneration. Recombinant human granulocyte colony-stimulating factor (rHuG-CSF) and tacrolimus are known to be immunosuppressive and supportive to liver regeneration. We investigated the effects of their combination therapy in a rat FHF model with a 68% partial hepatectomy and 24% liver necrosis. All rats without drug pretreatment died within 55 h. The median time was prolonged from 37 to 52 h by rHuG-CSF (250 microg/kg/day s.c. on days -5 to 0) and to 46 h by tacrolimus (0.5 mg/kg/day i.m. on days -2 to 0). Notably, the combination therapy facilitated DNA biosynthesis and survival prolongation, with a median of 77 h. The interferon-gamma (IFN-gamma) protein levels and natural killer cell (NK) activity in the liver were low at 12 h, and no further inhibition was detected by any treatment. Tacrolimus significantly upregulated the mRNA levels of insulin receptors and transforming growth factor-alpha (TGF-alpha), whereas rHuG-CSF did not. Regarding tissue remodeling-related factors, rHuG-CSF upregulated mRNA levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase- 9 (MMP-9), whereas tacrolimus did not. The combination treatment upregulated protein levels of both insulin receptors and VEGF. These results suggest that tacrolimus improves the hepatocyte replication and rHuG-CSF contributes to tissue reconstitution, and this combination therapy directly facilitates liver regeneration in the FHF model.

Topics: Animals; Disease Models, Animal; DNA Replication; Drug Therapy, Combination; Granulocyte Colony-Stimulating Factor; Hepatocytes; Immunosuppressive Agents; Interferon-gamma; Killer Cells, Natural; Liver; Liver Failure, Acute; Liver Regeneration; Male; Matrix Metalloproteinase 9; Rats; Rats, Sprague-Dawley; Receptor, Insulin; Recombinant Proteins; RNA, Messenger; Tacrolimus; Transforming Growth Factor alpha; Treatment Outcome; Up-Regulation; Vascular Endothelial Growth Factor A

Since the advent of transplantation as a life-saving procedure for patients with end-stage liver disease, more than 15,000 children and adolescents have received liver transplants. With the improvements in long-term posttransplant survival offered by advances in medical and surgical therapy, the concept of transplantation outcome has expanded beyond simple patient and graft survival rates. The quality of the life years restored, the long-term complications of transplant immunosuppression, and the overall cost of care have been increasingly recognized as important components of liver transplantation outcome. This review focuses on the efforts of a single pediatric transplant center to examine the incidence of, and risk factors for, common posttransplantation complications, to characterize posttransplantation health-related quality of life, to describe the cost of posttransplant care, and to implement novel programs to improve health care delivery. Together, these projects set the future course for research and care improvement initiatives in this population and encourage us to "keep the end in mind" when considering pediatric liver transplantation.

Topics: Adolescent; Biliary Atresia; Bone Density; Bone Diseases; Calcineurin Inhibitors; Case-Control Studies; Child; Child, Preschool; Cross-Sectional Studies; Cyclosporine; Enzyme Inhibitors; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Information Services; Kidney Failure, Chronic; Length of Stay; Liver Failure, Acute; Liver Transplantation; Male; Ohio; Postoperative Complications; Quality of Life; Risk Factors; Tacrolimus; Treatment Outcome

The objective of this study is to evaluate the effect of acute renal or hepatic failure on the intestinal absorption of tacrolimus. Simultaneous perfusion study in rat small intestine revealed that the extent of absorption into blood vessels was decreased in the jejunum and the ileum of rat of acute renal failure due to the decrease in the uptake of tacrolimus into enterocytes. In contrast, there observed no significant changes in tacrolimus absorption in rat of acute hepatic failure. Since it has been reported that tacrolimus absorption is regulated mainly by Cytochrome P-450 (CYP) mediated metabolism in the jejunum, but by P-glycoprotein (P-gp) mediated efflux in the ileum, these factors might contribute to the changes in intestinal absorption of tacrolimus in rat of acute renal failure. Enzyme inhibitor, ketoconazole, was co-perfused with tacrolimus to specify the effect of CYP and P-gp. However, since ketoconazole failed to recover the permeability in the jejunum and ileum of rat of acute renal failure, it is considered that the changes in CYP or P-gp functions might not be involved in the decreased uptake of tacrolimus. This type of kinetic study in rats should be valuable to identify the precise mechanisms of drug absorption and the effects of various diseases on it, such as acute renal or hepatic failure.

Topics: Acute Kidney Injury; Animals; Intestinal Absorption; Intestine, Small; Liver Failure, Acute; Male; Rats; Rats, Wistar; Tacrolimus

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Creatinine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Function Tests; Liver Failure, Acute; Liver Transplantation; Middle Aged; Postoperative Complications; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus

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

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

The aim of the study was to investigate the effect of the immunosuppressant FK 506 (tacrolimus hydrate) on acute liver injury induced by Propionibacterium acnes and lipopolysaccharide (LPS). Acute liver injury was induced in male Wistar rats by injecting the animals with P. acnes (10 mg/rat), and administering LPS (10 microg/rat) seven days later. One group was given FK 506 (1 mg/kg) 24 and 2 hr before administration of LPS, and the other group was given the same dose of saline. The 24-hr survival rate, serum alanine aminotransferase (ALT) concentration, and tumor necrosis factor (TNF) -alpha mRNA and protein concentrations in the liver and spleen were then compared. Hepatic macrophages were also isolated from rats seven days after P. acnes injection, LPS, and FK 506 or saline were added to the culture supernatant, and TNF-alpha production was studied. The 24-hr survival rate was 100% in the FK 506-treated group, in contrast with 16.6% in the saline group. Four hours after LPS injection, the serum ALT concentration was 755 +/- 401 in the saline group versus 119 +/- 42 units/ml (P < 0.01) in the FK 506-treated group. The serum TNF-alpha concentration was lower in the FK 506-treated group (1,419 +/- 957 pg/ml) than in the saline group (9205 +/- 2215) (P < 0.01). The mRNA and protein concentrations in the liver and spleen in the two groups did not differ significantly 1 hr after LPS injection but were significantly lower in the FK 506-treated group after 4 hr. FK 506 did not directly inhibit TNF-alpha production by isolated cultured hepatic macrophages. FK 506 is unable to inhibit initial TNF-alpha production by hepatic macrophages (or probably that by splenic macrophages either) stimulated by injection of LPS in P. acnes + LPS-induced acute liver injury. However, the immunosuppressant does limit hepatic damage by inhibiting subsequent aggravation of inflammation by the cytokine network.

Topics: Alanine Transaminase; Animals; Hepatitis, Autoimmune; Immunosuppressive Agents; Lipopolysaccharides; Liver; Liver Failure, Acute; Macrophages; Male; Propionibacterium acnes; Rats; Rats, Wistar; Tacrolimus; Tumor Necrosis Factor-alpha

Topics: Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver Failure, Acute; Liver Transplantation; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome