Clinical relevance and prevalence of polymorphisms in CYP3A5 and MDR1 genes that encode tacrolimus biotransformation enzymes in liver transplant recipients.

OBJECTIVES: To study the prevalence and clinical significance of polymorphisms in the CYP3A5 and MDR1 genes in liver transplant patients and their donors; to determine the relative importance of genes from the donor and the recipient; to assess the relationship of polymorphisms with the variability of concentration/dose of tacrolimus for optimization and individualization regimens. MATERIALS AND METHODS: This prospective study included 53 liver transplant recipients who received tacrolimus de novo. CYP3A5 and MDR1 gene polymorphisms were identified in the donors and recipients using polymerase chain reaction. We collected indicator variables of graft function and the patient for 3 months after the transplantation: days 0, 1, 3, 7, 14, 30, 60, and 90. RESULTS: The frequencies of CYP3A5 polymorphisms were: 90.6% (G/G), 9.4% (G/A) and 0% (A/C) in donors and 88.7% (G/G), 11.3% (G/A), and 0% (A/A) in recipients. For the MDR1 gene, they were: 26.4% (C/C), 50.9% (C/T), and 22.6% (T/T) in donors and 17.0% (C/C), 71.7% (C/T), and 11.3% (T/T) in recipients. In the early days after transplant, G/A recipients from G/A donors did not reach the minimum drug levels. Between days 30 and 60, G/G recipients from G/A donors required higher tacrolimus doses. G/G recipients (CYP3A5) from C/T donors (MDR1) had a lower frequency of renal dysfunction, the same rejection rate, and a higher rate of diabetes than the other groups. CONCLUSIONS: For CYP3A5, the presence of the A allele appeared to be related to greater requirements for tacrolimus in the early days after transplantation. Pharmacogenetics combined with pharmacodynamics may be a useful tool to adjust the concentration of tacrolimus depending on the absorption by the individual patient.

Liver transplantation consequential to Caroli's syndrome: a case report.

Caroli's disease is a rare condition that includes fibrocystic malformations of the bile duct. It consists of multifocal congenital dilatations of the intrahepatic bile ducts, which may be diffuse or limited, presenting in sack form that produces cystic structures which communicate with the biliary tree. Herein we have presented the case of a 44-year-old woman with recurrent cholangitis consequential to Caroli's syndrome. The distinctive feature of this case was that it was the first and only liver transplantation performed to date for this cause at our center among 700 procedures that had been performed over 19 years. The hepatectomy sample from the liver transplantation showed large cystic dilatations at the level of segments VII and VIII. The pathological study reported congenital dilatation of the intrahepatic bile ducts, associated with congenital hepatic fibrosis (Caroli's syndrome). Caroli's syndrome is a complex association of conditions which usually presents together with polycystic kidney lesions. Orthotopic liver transplantation is still the only therapeutic option for diffuse, uncontrollable cases or those with significant portal hypertension, as well as being the final option in the other cases in the event of a lack of response to other therapeutic options or as an alternative to them.

Influence of donor age on survival in liver transplantation due to hepatitis C virus.

Cirrhosis secondary to hepatitis C virus (HCV) is one of the most frequent indications for liver transplantation. During recent years, the age of donors has increased, which has led to a worse prognosis for persons undergoing transplantations because of this virus. In this study, we analyzed the 93 transplantations performed during a 6-year period (2000-2005) due to HCV, dividing them into 2 groups according to donor age: <60 years (group A) and >/=60 years (group B). We examined graft and recipient survivals with a mean follow-up of 34 months. Recipient survival among group A was 61% compared with 57% among Group B, the difference being greater if we excluded the initial months after transplantation, since this eliminated the complications inherent to the intervention. Graft survival, according to the Knodell histological activity index, was summarized as: 55.7% histological recurrence, 16.7% fibrosis, and 21% cirrhosis among group A versus 65.6%, 25%, and 18.7%, respectively, among group B. In conclusion, there was improved survival and disease progression was slower among group A compared with group B, suggesting that donor age was an important factor; patient and graft survivals fell progressively with increased donor age.

Efficacy and safety of mycophenolate mofetil monotherapy in liver transplant patients with renal failure induced by calcineurin inhibitors.

OBJECTIVE: To assess the efficacy and safety of mycophenolate mofetil (MMF) monotherapy in liver transplant recipients with renal failure secondary to the use of calcineurin inhibitors (CNIs). MATERIALS AND METHODS: Thirty-one patients on MMF monotherapy with creatinine levels >1.3 mg/dL, previously immunosuppressed with CNIs and MMF, were analyzed. Conversion was started in patients with no acute or chronic rejection episodes and stable liver chemistry. CNI doses were reduced by 25% every 2 to 3 months, or to 50% if the dose was lower than 1 mg/d of tacrolimus or 50 mg/d of cyclosporine. Different variables were recorded from the time that conversion to monotherapy was decided, on the discontinuation day of the calcineurin inhibitor, and during the follow-up. RESULTS: Mean times from transplant to conversion ranged from 14 to 186 months. The minimum follow-up time in monotherapy was 12 months. Renal function improved at 6 months in 70% of cases and at 12 months in 69.6%. Patients with no renal function improvement maintained stable creatinine values. There were no rejection episodes, graft losses, or deaths. No leukopenia occurred, and triglyceride and uric acid values improved. CONCLUSIONS: MMF monotherapy is a safe alternative in patients with posttransplant renal failure secondary to the use of CNIs. Renal function improvement was achieved in almost 70% of patients at 12 months, and creatinine values were maintained in all other patients. The risk of rejection due to the slow tapering of CNIs is minimum.

Laparoscopic aproach in post-traumatic chylous ascites.

Chylous ascites is a rare condition little reported in literature, with even more exceptional traumatic origin. Its production mechanism is not known exactly but has been attributed to hyperflexion or hyperextension of the spine leading to a rupture of lymph ducts. We present a case of post-traumatic chyloperitoneum in a young patient after abdominal blunt trauma. Conservative treatment should be the first therapeutic option, especially if the origin is traumatic, reserving more aggressive possibilities for cases that do not respond after 15 days, if debt is greater than 1.5 litres/day in adult patients or in those with metabolic complications. A laparoscopic approach is indicated to confirm the diagnosis and to rule out other associated injuries that may require other surgical procedures.

Cancers of new appearance in liver transplant recipients: incidence and evolution.

OBJECTIVE: To investigate the incidence, time of appearance, treatment, and evolution of tumors appearing in liver transplant recipients at our hospital. MATERIAL AND METHODS: We undertook a retrospective analysis of our series of liver transplants between 1990 and 2005. Patients who died during the immediate postoperative period were excluded. RESULTS: Of the 515 patients, 25 died during the immediate postoperative period and therefore had no occasion to develop neoplasms. Of the remaining 490, 32 developed cancers (6.5%). The average age was 55.4 +/- 7.17 years. The reasons for transplant were alcoholic cirrhosis (n = 15), hepatitis C virus (2), hepatitis B virus (n = 1), alcoholic and viral cirrhosis (n = 7), primary biliary cirrhosis (n = 1), and cryptogenic cirrhosis (n = 1). Four patients developed multiple neoplasms. Most of the tumors were cutaneous: nine basal cell and six squamous cell carcinomas. Other locations were the lung, urothelium, stomach, thyroid, and brain. Eight patients presented metastasis at the time of diagnosis. The average tumor-free period was 3.36 years. Nine patients died as a result of the tumor. DISCUSSION: Patients with a liver transplant have a high risk of developing cancers as a result of the immunosuppression treatment, which is lifelong. Nevertheless, other factors can be involved, such as infection by cytomegalovirus or the original diagnosis leading to transplantation. The risk for developing cancers is significantly greater than in the general population, with a higher tendency to recurrence and later development of second neoplasms.

Biliodigestive anastomosis in liver transplantation: review of 13 years.

Hepaticojejunostomy is a good alternative technique for biliary reconstruction in liver transplantation. Among 517 liver transplants performed between March 1992 and July 2005, 33 involved hepaticojejunostomy, namely, 18 men and 12 women of average age: 44.8 years. The main cause for this technique was retransplant (n = 10), secondary biliary cirrhosis (n = 5), alcoholic cirrhosis (n = 5), HCV cirrhosis (n = 2), primary biliary cirrhosis (n = 1), cryptogenic cirrhosis (n = 1), sclerosing cholangitis (n = 3), fulminant liver failure (n = 1), autoimmune cirrhosis (n = 1), and insulinoma metastasis (n = 1). Choledochojejunostomy was performed for all Roux-en-Y loops, with an average cold ischemia time of 361.16 minutes (180-780). The biliary complications were biliary fistula in four cases (13.3%), including two who required surgery; stenosis of the anastomosis in two cases (6.6%) including one diagnosed by HIDA that resolved with medical treatment and the other, diagnosed by cholangio-MRI, requiring a new hepaticojejunostomy; and biliary peritonitis in three cases (10%), all of whom required surgery. The vascular complications were thrombosis of the hepatic artery (n = 1), which required retransplantation, and pseudoaneurysm of hepatic artery (n = 1). No biliary complications occurred. The 6-month patient survival was 80% and the 6-month graft survival was 77%; no patient died due to biliary complications. Hepaticojejunostomy is a technique with higher morbidity than choledocho-choledochostomy, but it is the best alternative when the latter is not possible.

Scoring guide when deciding to accept an organ for a liver transplant.

UNLABELLED: Our objective was establish a scoring system that allows a donor to be evaluated quickly and easily using a set of variables that are evaluated prior to the donation and another set that are evaluated during surgery. MATERIALS AND METHODS: Prior to the donation we analyzed age, medication requirements, natremia, hepatic biochemistry, gas levels, days in ICU, history of hypertension, and weight. A value of 40% was allocated to this group of factors. During the transplant we assessed the characteristics of the organ-shine, consistency, surface, edge, color, presence of steatosis, and atheromatosis. A value of 60% was allocated to this set. We established a scale of 1 to 10, only accepting organs scoring 5 or more points. Those grafts that received a score between 5 and 7.5 points were called suboptimal and those with over 7.5 points, optimal. We prospectively analyzed 133 donors whose organs were implanted. RESULTS: The survival rate at 1 year was 85%, and the rejection rate was 12%. The incidence of primary graft dysfunction was 8.2% (n = 11) and that of primary graft nonfunction 2.2% (n = 3). The incidence of primary graft dysfunction was greater within the group with fewer points (suboptimal). There were no differences between the optimal and suboptimal groups in terms of primary malfunction, survival, or rejection rate. CONCLUSIONS: The score provided a guide to decide whether to accept viable organs for implantation, given that the point system was obtained quickly and easily. When greater than 5, it correlated with low rates of primary nonfunction (<3%) and of primary graft dysfunction (<15%), with acceptable survival at 1 year (>80%) and acute rejections rate (<15%).

Efficacy and safety of mycophenolate mofetil as part of induction therapy in liver transplantation.

AIMS: To report our experience with mycophenolate mofetil (MMF) for induction and maintenance therapy to prevent acute liver transplant rejection. METHODS: A retrospective analysis of 66 elective, noncombined liver transplant patients treated beginning de novo MMF and follow for a minimum of 2 years. Thirty-nine of the 66 cases received MMF, calcineurin inhibitors, and steroids. In 11 cases daclizumab was added; in 16 daclizumab was added without steroids. RESULTS: The global survival rate was 91% at 6 months, 89.4% at 1 year, and 87.9% after 2 years. Acute rejection episodes were observed in six patients (9.1%). All episodes responded to corticoids. Toxicity possibly, probably, or partially related to MMF was observed in 35 patients (53%) with definitive suspension required in 13 cases (20%), with dose reduction or temporary suspension in 22 (33%). Hematological toxicity associated with MMF was observed in 12 patients (18%), leading to definitive suspension in two patients (3.03%), temporary suspension in two cases (3.03%), and dose reduction in eight cases (12%). Opportunistic infection was observed in seven cases (10%). Gastrointestinal toxicity was mild and infrequent (five cases, 7.5%). CONCLUSION: Regimens containing MMF reduce rejection episodes with high survival rates and low toxicity.

Switching from mycophenolate mofetil to enteric-coated mycophenolate sodium in liver transplant patients with gastrointestinal complications.

OBJECTIVE: Our aim was to safely and effectively reduce adverse gastrointestinal (GI) events resulting from the use of mycophenolate mofetil (MMF) in liver transplant patients by switching to enteric-coated mycophenolate sodium (EC-MPS). PATIENTS AND METHODS: We studied 19 patients on maintenance therapy presenting with GI intolerance to MMF whose therapy was switched to EC-MPS. The variables recorded were: calcineurin inhibitor (CNI) dose levels, MMF/EC-MPS dose levels, lipid profile, hematology, renal and hepatic function markers, and rejection episodes. These variables were recorded at the visit prior to the day of conversion, on the day of conversion, and 1, 3, 6, and 9 months thereafter. RESULTS: Of the 19 patients, 16 were men (mean age, 56.6 +/- 15.9 years) and 3 were women (58.3 +/- 12.1 years). While 31.6% were on MMF monotherapy, 52.6% were on combined therapy with tacrolimus and 15.8% with cyclosporine. On the day of conversion, 21% were not on MMF, 36.8% were on 1000 mg/d, 26.3% were on 1500 mg/d, 5.3% were on 750 mg/d, and 10.6% were on 500 mg/d. The starting daily doses of EC-MPS were: 360 mg (26.3%), 720 mg (31.6%), 540 mg (26.3%), 1080 mg (10.5%), and 1440 mg (5.3%). GI complications were significantly reduced from the first month postconversion (P < .01), as 57.2% of patients did not display any symptoms; however, at 9 months, this incidence rose by 12% relative to month 1 (P < .05). There were no changes in the other variables and there were no reported rejection episodes. Treatment was suspended in 2 patients due to dyspnea and nervousness. CONCLUSION: In liver transplant patients with GI complications from chronic MMF use, the use of EC-MPS was safe and efficacious, as it significantly reduced their incidence.

Causes and predisposing factors of de novo tumors in our series of liver transplant recipients.

INTRODUCTION: Liver transplant recipients suffer a high risk of developing cancer, mainly as a consequence of immunosuppressant treatment, although a variety of other factors are involved. Our purposes were to evaluate the frequency of de novo tumours and to determine predisposing factors. MATERIAL AND METHODS: We analyzed all of the transplantations performed during 1990, with a total of almost 700 cases. We analyzed the frequency of de novo tumors, their location, time since transplantation, survival, and recurrence rates and factors that may influence their appearance. RESULTS: The series included 64 cases in 50 patients with a frequency of 7%. Skin tumors were the most frequent (39.06%), followed by those in the otolaryngologic (ear, nose, and throat) region (15.62%) and the lung (14.06%). The average time to progression between the transplantation and diagnosis was less than 4 years (47.74 months). The recurrence rate was 16%. The factors with the greatest influence on their appearance were age and gender of the recipient, alcohol consumption, and Child-Pugh score. Plasma transfusion was statistically, although not clinically, significant. DISCUSSION: Our frequency of de novo tumors was consistent with that described in the literature. Despite some factors that influence their appearance, the main predisposing factor was immunosuppression and its duration.