Liver Transplant Patient Carriers of Polymorphism Cyp3a5*1 Donors May Need More Doses of Tacrolimus From the First Month After Transplantation.

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

Incidence of development of obesity after heart transplantation according to the calcineurin inhibitor.

BACKGROUND: Development of obesity after heart transplantation (HT) is a common complication, largely attributed to immunosuppressive therapy. The objective of this study is to compare the incidence of development of obesity after HT, according to the calcineurin inhibitor (CNI) used (cyclosporine [CsA] vs tacrolimus [Tac]). METHODS: We studied 101 consecutive HT patients from November 2006 to December 2010. A diagnosis of overweight-obesity was made by a body mass index of ≥25 kg/m(2), which was assessed before HT and at 1 year after HT. Patients were randomly assigned to the administration of CsA or Tac by a simple randomization method using a computer program (56% received CsA and 44% Tac). RESULTS: Of the 101 patients, 77% were men, and ischemic heart disease was the most common indication for HT. At baseline, there were no differences in weight between groups treated with CsA or Tac. The mean weight for each group was 71.5 ± 12 and 75 ± 14 kg, respectively (P = .2). The weight increase was greater among CsA patients: after HT, the weight gain was 6.9 ± 11 kg in the CsA group, whereas a minimal weight loss of 0.03 ± 14 kg (P = .008) was experienced in the group treated with Tac. The multivariate analysis showed that only CsA treatment was an independent predictor of development of obesity 1 year after HT (odds ratio, 3.84; 95% CI, 1.04-14.21; P = .01). CONCLUSION: Weight gain after HT may be related to the CNI used and CsA seems to be the CNI that produces the greatest increase.

Everolimus in clinical practice in long-term liver transplantation: an observational study.

INTRODUCTION: Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been used in acute and chronic treatment of kidney and heart transplants. There is scarce information regarding its use in liver transplant recipients, although everolimus may be a useful alternative for selected cases. OBJECTIVE: The objective of this study was to study the clinical, biochemical, and pathological features of patients to whom everolimus was added based upon defined clinical profiles. STUDY DESIGN: This study was prospective observational ongoing study to evaluate the effectiveness and safety of everolimus alone or in combination with low doses of a calcineurin inhibitor (CNI). Chronic liver transplant recipients without contraindications to everolimus were defined based upon 7 profiles of complications. The initial everolimus dose (0.25 mg every 12 hours) was overlapped during conversion, measuring blood levels and evaluating clinical tolerance. Routine monitoring was performed to obtain immunosuppressant blood levels near the lower limit of the therapeutic range. RESULTS: The 35 patients' including 17 men and 18 women, had an overall mean age of 61 ± 10 years with a mean follow-up of 34 months. The everolimus treatment lasted 20 months (range, 6-60). The indication for everolimus conversion were as follows: renal insufficiency (45.7%), no response to hepatitis C virus (HCV) treatment (42.9%), autoimmune hepatitis associated with interferon (8.5%), de novo autoimmune hepatitis (25.5%), de novo tumor (37.1%), neurotoxicity (14.3%), or side effects to rapamycin treatment (5.7%). Patients may have presented more than one indication. Effectiveness was assessed based upon improved liver (48.6%) or renal function (31.25% with renal insufficiency) or withdrawal of prednisone (100% of 10 patients receiving prednisone). CNI was withdrawn from 48.6% of patients due to de novo tumors or neurotoxicity. The side effect were as follows: anemia, leukopenia, or thrombocytopenia (11.4%) or dyslipidemia (27.3%). The survival rate was 94.3%. CONCLUSIONS: Administration of everolimus to chronic liver transplants enhanced therapeutic options in the long term recipients when applied for predefined clinical indications and administrated with dose adjustments based on serial monitoring of exposure.

Effectiveness and safety of everolimus in the treatment of autoimmune hepatitis related to anti-hepatitis C virus therapy after liver transplant: three case reports.

Treatment of recurrent hepatitis C after liver transplantation is indicated in selected cases. During the combined treatment with pegylated interferon and ribavirin, some patients develop immune-mediated liver dysfunction similar to the previously described "de novo" autoimmune hepatitis. Herein we have presented three liver transplant patients who during or after combined antiviral treatment were diagnosed as autoimmune hepatitis related to interferon based on their clinical, biochemical, and liver histology features. There were two women and one man, of ages 49, 52, and 49 years who were transplanted due to cirrhosis related to hepatitis C virus genotype 1. In two patients, elevated liver enzymes occurred during antiviral therapy and in the third, after the therapy. The diagnosis of autoimmune hepatitis was reached after excluding other possible causes. One patient had a sustained viral response; and two cases were nonresponders. Antinuclear antibodies were present in two subjects and antinuclear antibodies and anti-smooth muscle antibodies in the other case. First-line treatment of autoimmune hepatitis with prednisone and azathioprine stabilized clinical and biochemical parameters'. In order to avoid the long-term use of prednisone, everolimus was introduced in the three patients. Interestingly, hepatitis C did not progress and clinical, biochemical, as well as histological parameters stabilized. In one patient, the liver fibrosis stage as assessed by histology showed improvement. However, one subject experienced repeated cerebral hemorrhage and died. Although this is heterogeneous population with partially known characteristics, with a difficult differential diagnosis, the objectives of preserving liver function and avoiding recurrent progressive hepatitis C seemed to be achieved by adding everolimus. In addition, we totally stopped prednisone therapy. In conclusion, treatment with everolimus in combination with cyclosporine achieved a partial remission in two liver transplan cases of autoimmune hepatitis related to interferon therapy.

[Assessment of fetal maturity by measurement of the phospholipids in the amniotic fluid. Comparison of the results with the lecithin/sphingomyelin ratio]. / Appréciation de la maturité foetale par la mesure des phospholipides du liquide amniotique. Comparaison des résultats avec le rapport lécithine/sphingomyéline.

The authors explored the possibility of assessing fetal lung maturity by measuring the phospholipids in the amniotic fluid by the enzymatic technique of Takayama et al. [8]. The study was conducted on 41 pregnancies. The results obtained were evaluated comparatively with the lecithin/sphingomyelin ratio (L/S). The authors found that the L/S ratio can be used to determine fetal lung maturity in 93% of cases with 2/14 false maturities and 1/27 false immaturities. The assay of the phospholipids containing choline by the method of Takayama et al. [8] gives a much less precise assessment of fetal lung maturity: only 68% of the results were concordant; 5/14 false maturities and 8/27 false immaturities. These differences can be explained by the fact that the method of Takayama et al. [8] takes into account substances which are not related to process of fetal lung maturation.