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Background: Tacrolimus has proven to be a potent immunosuppressive agent in orthotopic liver transplantation (OLT). The aim of this study is to examine its long-term efficacy and safety., Methods and Results: One thousand consecutive primary OLTs performed between August 1989 and December 1992 and maintained under tacrolimus-based immunosuppression were followed up until January 2009. Patient and graft survivals with corresponding causes of death and retransplantation, maintenance immunosuppression, and adverse effects were examined. The study population includes 600 males and 400 females comprising 166 children, 630 adults, and 204 seniors. The mean follow-up was 17.83 (range, 16.1-19.50) years. The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively. At the last follow-up, 442 patients were alive; 133 (77.1%) children, 265 (34.5%) adults, and 44 (16.1%) seniors (P=0.0001). After the first post-OLT year, cardiopulmonary events, recurrence of primary disease, and malignancy were the main causes of death. Overall, 183 recipients underwent retransplants; mainly for primary nonfunction, hepatic artery thrombosis, and recurrent primary disease, 180 required dialysis, and 45 underwent kidney transplant. A total of 97.7% of the survivors were on tacrolimus and 26.2% were also receiving adjunctive immunosuppressants at the last follow-up., Conclusions: The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively, with significantly better survival among children. Age-related complications, recurrence of primary disease, and malignancy were the major causes of late graft loss. Graft loss related to immunologic reasons was rare. The prevention of recurrent disease and newer immunosuppressive regimen will further improve these results.

Background: Calcineurin inhibitor nephrotoxicity in nonrenal allograft recipients can lead to end-stage renal disease and the need for kidney transplantation. We sought to evaluate the role of alemtuzumab induction in this population., Patients and Methods: We evaluated 144 patients undergoing kidney transplantation after nonrenal transplantation between May 18, 1998, and October 8, 2007. Seventy-two patients transplanted between January 15, 2003, and October 8, 2007, received alemtuzumab induction and continued their pretransplant immunosuppression. Seventy-two patients transplanted between May 18, 1998, and July 21, 2007, did not receive alemtuzumab induction, but received additional steroids and maintenance immunosuppression. Donor and recipient demographics were comparable., Results: Overall, 1- and 3-year patient survival and renal function were comparable between the two groups. One- and 3-year graft survival was 93.0% and 75.3% in the alemtuzumab group and 83.3% and 68.7% in the no alemtuzumab group, respectively (P=0.051). The incidence of acute rejection was lower in the alemtuzumab group, 15.3%, than in the no alemtuzumab group, 41.7% (P=0.0001). The incidence of delayed graft function was lower in the alemtuzumab group, 9.7%, than in the no alemtuzumab group, 25.0% (P=0.003). The incidence of viral complications was comparable., Conclusion: Alemtuzumab induction with simple resumption of baseline immunosuppression in patients undergoing kidney transplantation after nonrenal transplantation represents a reasonable immunosuppressive strategy.

Background: Chronic liver disease often leads to amenorrhea in women of childbearing age. There are several reports of successful pregnancy after liver transplantation (LTx) with cyclosporine A immunosuppression. Tacrolimus has been increasingly used in solid-organ transplantation, and the effect of the drug on pregnancy is still of interest to clinicians. This study updates our single-center experience., Methods: All pregnancies after LTx with tacrolimus immunosuppression were followed prospectively. Patients' clinical courses during pregnancy and labor along with gestational period and birth weight were catalogued. Changes in liver function, renal function, and immunosuppression also were recorded. The birth weight percentile was calculated on the basis of the gestational period using a standard chart., Results: Thirty-seven mothers delivered 49 babies. Three mothers delivered three times, and six mothers delivered two times. Thirty-six mothers (97%) survived the pregnancy, and 36 allografts (97%) survived. The one death and graft loss was in a patient who demonstrated infra-aortic arterial graft, which clotted by the gravid uterus during labor. The patient developed a gangrenous liver and died before she could undergo retransplantation. The mean gestational period was 36.4+/-3.2 weeks, excluding two premature deliveries at 23 and 24 weeks gestation. Twenty-two babies (46.9%) were delivered by cesarean section, and the other babies were delivered vaginally. In addition to the two premature babies, one baby, who was born to a mother with Alagille syndrome, died from congenital birth defects. The rest of the newborns survived. The mean birth weight was 2,797+/-775 g, with 38 babies (78%) weighing more than 2,000 g. The mean birth weight percentile to gestational period was 54+/-23. Four babies (8.5%) had a birth weight percentile of less than 25, and 28 babies (59.6%) had a birth weight percentile greater than 50. Twelve patients demonstrated an increase in hepatic enzymes without jaundice during the pregnancy. All of them responded to augmentation of immunosuppression., Conclusion: The present report reconfirms the safety of tacrolimus during pregnancy after LTx. Preterm delivery and low birth weight seem to be a persistent problem in all solid-organ transplantation under any form of immunosuppression. However, toxemia of pregnancy and new onset of hypertension seem to be have a low occurrence with the use of tacrolimus.

Background: Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection., Methods: The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months., Results: The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups., Conclusions: This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids.

Background: Vascular complications remain an important cause of postoperative morbidity in liver transplant patients. Herein, we present an unusual case of nonanastomotic inferior vena cava (IVC) stenosis in a patient with a "piggyback" caval anastomosis., Methods: A 59-year-old woman underwent liver transplantation using a piggyback IVC anastomosis. Her postoperative course was complicated by IVC thrombosis. Catheter-directed thrombolysis, followed by balloon angioplasty and intravascular stent placement, was used to recanalize the IVC and treat a severe retrohepatic IVC stenosis., Results: After 46 hr of catheter-directed urokinase infusion, there was clot lysis and identification of a severe stenosis in the retrohepatic IVC. The lesion was extremely resistant to balloon dilatation alone and a 22-mm-diameter intravascular stent was placed. Simultaneous dilatation of three high-pressure balloons was necessary for maximal stent expansion. The patient remains asymptomatic with no evidence of IVC compromise through 20 months of follow-up., Conclusions: IVC stenosis and thrombosis after liver transplantation may be treated favorably in some patients using catheter-directed thrombolytic therapy followed by balloon dilatation and/or stent placement.

We report on the efficacy and safety of FK506 (tacrolimus) compared with a cyclosporine (CsA)-based immunosuppressive regimen after 1 year of treatment in pediatric liver allograft recipients (< 12 years) participating in a multicenter U.S. randomized trial. Patients received either FK506 or CsA as primary immunosuppression following a first ABO-compatible liver transplant. Intravenous FK506 was initiated at 0.1 mg/kg per day, followed by oral FK506 beginning at 0.3 mg/kg per day. The dose was adjusted to maintain plasma trough levels of 0.5-2.0 ng/ml. The CsA group was treated according to each center's usual protocol. Both groups received the same initial doses of corticosteroids. All rejection episodes were biopsy-proven and a standardized algorithm was adopted for the treatment of rejection. Thirty patients were randomized to the FK506 group and 20 to the CsA group. After twelve months of follow-up 20 patients remained in the FK506 group and 13 in the CsA group. Patient survivals were 80% and graft survival 70% in the FK506 group compared with 81% and 71% respectively, in the CsA group. 48% of the FK506 group remained rejection-free compared with 21% of the CsA group, and 79% of FK506-treated patients did not require OKT3 compared with 68% of CsA treated patients. The cumulative corticosteroid dose was less at each time point throughout the first year in the FK506 group. The incidence of serious and minor infections was similar in both groups. Nephrotoxicity, neurotoxicity, and gastrointestinal disturbances were the major toxicities reported. Differences did not reach statistical significance between the two groups although major neurologic events, diarrhea and dyspepsia were more often reported in the FK506 group. There was no difference in mean serum creatinine at 12 months between the two groups. There was a tendency toward lower mean serum cholesterol in the FK506 group. There was no hirsuitism in the FK506 group compared with a 30% incidence in the CsA group. In conclusion, compared with CsA, there is a trend toward less rejection in FK506-treated pediatric allograft recipients, while both drugs have a similar spectrum of side effects.

Several studies have reported the development of antiidiotypic antibodies to anti-HLA alloantibodies in renal allograft transplant recipients, postulating their potential beneficial role in allograft survival. In order to evaluate the role of anti-HLA antiidiotypic antibodies in human liver transplant recipients and to differentiate them from circulating soluble donor HLA antigens, sera obtained from liver recipients, both pre- and posttransplantation, were analyzed for cytotoxicity inhibitory activity against alloantisera to mismatched donor HLA antigens. Prior to cytotoxicity inhibition assays, sera were absorbed with W6/32 coupled sepharose in order to remove circulating HLA antigens. Antiidiotypic antibodies to anti-HLA class I antibodies were detected in the sera of 7 out of 9 recipients, and antibodies to anti-HLA class II were found in the sera of 4 out of 7 recipients. Antiidiotypic antibodies were detected only during the immediate posttransplantation period. The specific inhibitory activity noted against both HLA class I and II mismatches showed no detectable preference for either HLA class or locus. Furthermore, the antiidiotypic antibodies to HLA developed in liver recipients also inhibited alloantisera to HLA-specific public epitopes or crossreactive groups (CREGS). Cytotoxicity inhibition by posttransplant sera was not mediated by circulating HLA antigens since absorption of the sera with monoclonal anti-HLA framework reagents did not change the specific inhibition of the alloantisera. In addition, the immunoglobulin fraction of the posttransplant sera retained its ability to inhibit cytotoxicity by donor-specific alloantisera. Thus these studies indicate that the development of antiidiotypic antibodies to anti-HLA is common during the immediate period following liver transplantation, even though circulating donor HLA antigens are present. The presence of circulating donor HLA antigens and the development of antiidiotypic antibodies to donor-specific anti-HLA during this period may be important for the successful adaptation of mismatched liver allografts.