Survival Outcomes in Liver Transplantation With Elderly Donors: Analysis of Andalusian Transplant Register.

Recently, there has been a large discrepancy between the number of patients on the waiting list for a liver transplant and the availability of deceased donors, with an increase in annual wait list mortality rates. Elderly donor livers are thought to be marginal grafts; however, in recent years, their utilization has constantly increased. The aim of this study is to evaluate the utilization of elderly donors in Andalusia and post-transplant outcomes. This retrospective observational study of 2408 liver transplants, performed in Andalusia between 2000 and 2014, analyzes the outcomes from donors aged 70 plus (n = 423) in terms of survival rates of the graft and the recipient, the type of transplant, donor age, and D-MELD score (product of donor age and preoperative Model for End-stage Liver Disease score). The most frequent indications for transplant were alcoholic cirrhosis (49.2%), hepatitis C cirrhosis (13%), and hepatocellular carcinoma (12.5%). The overall survival at 5 years was 64%, with a significant fall in survival for recipients with a D-MELD greater than 1500 (57%; P = .045). In the 70-year-old-plus donor group, the overall patient survival was 58.4%. The retransplant rate increased proportionately with donor age. In the alcoholic cirrhosis recipient subgroup, the overall survival at 5 years was 67.6% (P < .05) compared with 33.5% in patients with hepatitis C. Use of elderly donors is a safe strategy to reduce the scarcity of donors, provided that a D-MELD score below 1500 is obtained. Retransplant rates increase progressively with donor age. It is necessary to carefully screen recipients of older organs, taking into account that the best results are obtained for alcoholic cirrhosis, negative viral load hepatitis C, and a D-MELD score below 1500.

Antitumoral gene-based strategy involving nitric oxide synthase type III overexpression in hepatocellular carcinoma.

Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO) synthase type III (NOS-3) overexpression induces cell death in hepatoblastoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. The first-generation adenoviruses were designed to overexpress NOS-3 or green fluorescent protein, and luciferase complementary DNA under the regulation of murine alpha-fetoprotein (AFP) and Rous Sarcoma Virus (RSV) promoters, respectively. Both adenovirus and Hepa 1-6 cells were used for in vitro and in vivo experiments. Adenoviruses were administered through the tail vein 2 weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8, -9 and -3 activities in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by Nω-nitro-l-arginine methyl ester hydrochloride, p53 and CD95 small interfering RNA. AFP-NOS-3/RSV-luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

Modigraf administration through jejunostomy in liver transplant recipient: case report.

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Outcomes of liver transplantation in candidates with portal vein thrombosis.

OBJECTIVE: The objective of the present study was to analyze the incidence of portal vein thrombosis (PVT), comparing morbidity and mortality rates among those affected with and those free of this complication. In the PVT group, we also analyzed mortality related to partial (PPVT) and total (TPVT) thrombosis. METHODS: We undertook a retrospective study of orthotopic liver transplantations from deceased donors in 617 recipients from January 1991 until October 2008. Recipients were classified according to whether they had PVT. In all cases, we considered age, sex, Model for End-stage Liver Disease score, Child-Pugh score, indication for transplantation, type of thrombosis, surgical technique blood product transfusion, and survival rate. RESULTS: There were 48 patients with PVT (7.78%) among 670 transplantations in 617 recipients in our institution. Concerning the type of thrombosis, 28 (58.3%) were partial and 20 (41.7%) total with complete occlusion of the portal vein lumen. CONCLUSION: PVT in liver transplant candidates is a rare event (7.8%) that entails greater difficulty in the procedure, expressed as a longer operative time, greater consumption of blood products, and complex surgical techniques. The prognosis for these patients depends on the type of thrombosis: patients with TPVT showed a higher mortality, whereas those with PPVT had survival rates comparable to those of candidates with a permeable portal vein.

Outcomes of domino liver transplantation: a single institution's experience.

AIMS: Domino liver transplantation (DLT) is a strategy to increase the donor pool. Explanted liver from patients with familial amyloidotic polyneuropathy (FAP) are often used as domino grafts, because the liver is normal apart from the production of the mutated transthyretin variant. We present the outcomes for both donors and recipients of DLT. MATERIALS AND METHODS: Retrospective analysis of initial DLT for 16 consecutive adult patients performed between July 2004 and July 2009. All cases of FAP donor to grafts were removed preserving the cava vein with reconstruction of the hepatic veins, except the first and seventh cases, where in we removed the retrohepatic vena cava with the liver without venovenous bypass. The postoperative follow-up period for surviving DLT recipients at the end of September 2009 was 2-62 months (mean, 26). RESULTS: Two patients out of 8 FAP donors died due to pulmonary thromboembolism on the 31st postransplant day, or sepsis at 35 days namely, an overall survival of 75%. One patient out of 8 recipients died namely, an early portal thrombosis on the 22nd postransplant day) with a crude survival of 87.5% in the recipient group (P = no significant [NS]). Four grafts from 8 FAP donors were lost-2 deaths and 2 retransplants due to thrombotic events on the first and second postransplant day-with a crude survival of 50%. Two of 8 recipients lost their grafts: 1 death and 1 retransplantation for an acute Budd-Chiari syndrome on the first postransplant day with a crude survival of 75% in the recipient group (P = not significant [NS]). CONCLUSION: We believe that the FAP liver graft is an excellent option for selected patients. Special care must be taken with thrombotic events.

Influence of mycophenolate mofetil on preservation of kidney function in liver transplant patients.

BACKGROUND: There are numerous studies on the effect of immunosuppressive therapy with mycophenolate mofetil (MMF) on preservation of kidney function in liver transplant (OLT) patients with chronic kidney damage. However, we have noted few studies that evaluate the role of this drug prescribed from induction on kidney function. PATIENTS AND METHODS: This prospective observational multicenter study included 296 OLT performed from 2005 to 2007. The collected variables were; gender, and age, Child-Pugh stage, Model for End-Stage Liver Disease (MELD) score, transplant indication, induction immunosuppressive therapy, and baseline and 1 year posttransplant values of creatinine and glomerular filtration rate. Patients were classified into 4 groups: group 1 received MMF from induction; group 2 was never treated with MMF; group 3 started MMF in the first month posttransplant, and group 4 started MMF therapy in the third month posttransplant. We used Wilcoxon and Mann-Whitney U statistical tests. RESULTS: There was a difference of 0.18 mg/dL in baseline creatinine values between groups 1 and 2 (P < .01). However, although patients who consistently had MMF in their treatment started with worse creatinine values, they were able to maintain them within normal ranges at 12 months. In contrast, patients in group 2 showed a significant worsening of 0.28 mg/dL in the first month that persisted throughout the study. Group 3 displayed worse baseline creatinine values than group 2 (P < .05), and also suffered an increase of 0.29 mg/dL (P < .01) versus baseline at 1 month. When MMF was added to their immunosuppressive therapy, the creatinine values reduced versus 1 month by 0.18 mg/dL (P < .05). Creatinine values remained stable at the other study assessments. Group 4 showed a normal creatinine value at baseline, but were altered at 1 and 3 months (P < .01), with increases versus baseline of 0.46 and 0.35 mg/dL, respectively. However, when MMF was introduced kidney function was restored and maintained over the study. CONCLUSION: Early introduction of MMF improved creatinine values among patients with impaired kidney function, maintaining them at stable levels. Furthermore, patients with altered creatinine values at baseline did not worsen their kidney function if they receive MMF from induction.

Evaluation of clinical safety of conversion to Advagraf therapy in liver transplant recipients: observational study.

OBJECTIVE: To present the correlation between dosage and plasma concentration of tacrolimus and the consequences for short-term hepatorenal function of conversion to Advagraf (tacrolimus extended-release capsules) in liver transplant recipients. PATIENTS AND METHODS: This observational study on adult liver transplant recipients examined tacrolimus levels after conversion to Advagraf therapy. Mean (SD) patient age was 51 (44-59) years. Conversion occurred at 43 (19-85) months posttransplantation, and follow-up was 193 (106.5-243.25) days. Dosage was adjusted milligram for milligram. Levels of tacrolimus, total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, and creatinine were recorded on the day before conversion to Advagraf and 1, 3, 6, and months afterward. RESULTS: Of the 79 patients in whom therapy was converted to Advagraf, 31 (39.2%) had alcoholic cirrhosis, 19 (24.1%) had viral disease, 10 (12.7) had mixed disease, 8 (10.1%) had cholestatic disease, 4 (5.1%) had metabolic disease, and 7 (8.8%) had other diseases. Despite no modification of Advagraf dosage during follow-up in most patients, mean tacrolimus levels decreased from the first month after conversion; however, at 6 months after conversion, they tended to equal the initial value. Renal function and liver biochemistry values demonstrated no significant change during follow-up. CONCLUSION: Although tacrolimus levels decreased initially after conversion to Advagraf therapy, 1:1 conversion is safe for hepatorenal function in liver transplant recipients.

Use of mycophenolate mofetil in liver transplantation: Andalusian Liver Registry.

OBJECTIVE: To evaluate the safety and efficacy of various immunosuppressant regimens using mycophenolate mofetil (MMF). PATIENTS AND METHODS: This prospective, observational, multicenter study of 226 patients undergoing liver transplantation was carried out in 2005-2006, with 24-month follow-up. Studied variables were as follows: indicators of kidney, liver, and blood function; intercurrent infections; cardiovascular risk; acute and chronic episodes of rejection; recurrent hepatitis C virus infection; de novo tumors; and survival. Patients were classified into 4 groups according to treatment: no MMF (group 1, n = 91); MMF from induction (group 2, n = 83); late administration of MMF (group 3, n = 30); and MMF at induction, with early withdrawal (group 4, n = 22). RESULTS: Biodemographic characteristics were similar in all 4 groups. The MMF groups were at higher risk and had worse Model for End-Stage Liver Disease and Child-Pugh scores and worse pretransplantation blood and kidney function values. Significant differences were observed in creatinine concentration between groups 2 and 3: 0.45 mg/dL at 1 month (P < .01), 0.27 mg/dL at 3 months (P < .01), and 0.3 mg/dL at 6 months (P < .05). In contrast, differences of 0.34 mg/dL (P < .01) were observed between groups 1 and 3 at 1 month and 0.17 mg/dL (P < .05) between groups 1 and 2 at 3 months. No differences were noted in white blood cell counts, episodes of acute rejection (19%) and chronic rejection (5%), graft survival (80%), and rate of recurrent hepatitis C virus infection (75%) between the 4 groups. The infection rate at 3 months in groups 2 and 4 was 34.5%, and in groups 1 and 3 was 34.5% (P < .05). CONCLUSIONS: Use of MMF at induction and introduction of MMF in the first 3 months posttransplantation helps to preserve and restore creatinine levels in patients with worsened kidney function, and aids in keeping them stable, without increasing the risk of rejection while optimizing the anticalcineurin dosage.

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.

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.

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.

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.