Randeep Kashyap

OBJECTIVE: To evaluate the long-term survival outcomes of a large cohort of liver transplant recipients and to identify static and changing factors that influenced these outcomes over time. SUMMARY BACKGROUND DATA: Liver transplantation has been accepted as a therapeutic option for patients with end-stage liver disease since 1983, with continual improvements in patient survival as a result of advances in immunosuppression and medical management, technical achievements, and improvements in procurement and preservation. Although many reports, including registry data, have delineated short-term factors that influence survival, few reports have examined factors that affect long-term survival after liver transplantation. METHODS: Four thousand consecutive patients who underwent liver transplantation between February 1981 and April 1998 were included in this analysis and were followed up to March 2000. The effect of donor and recipient age at the time of transplantation, recipient gender, diagnosis, and year of transplantation were compared. Rates of retransplantation, causes of retransplantation, and cause of death were also examined. RESULTS: The overall patient survival for the entire cohort was 59%; the actuarial 18-year survival was 48%. Patient survival was significantly better in children, in female recipients, and in patients who received transplants after 1990. The rates of retransplantation for acute or chronic rejection were significantly lower with tacrolimus-based immunosuppression. The risk of graft failure and death was relatively stable after the first year, with recurrence of disease, malignancies, and age-related complications being the major factors for loss. CONCLUSION: Significantly improved patient and graft survival has been observed over time, and graft loss from acute or chronic rejection has emerged as a rarity. Age-related and disease-related causes of graft loss represent the greatest threat to long-term survival.

By using specific anti-ACAT-1 antibodies in immunodepletion studies, we previously found that ACAT-1, a 50-kDa protein, plays a major catalytic role in the adult human liver, adrenal glands, macrophages, and kidneys but not in the intestine. Acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity in the intestine may be largely derived from a different ACAT protein. To test this hypothesis, we produced specific polyclonal anti-ACAT-2 antibodies that quantitatively immunodepleted human ACAT-2, a 46-kDa protein expressed in Chinese hamster ovary cells. In hepatocyte-like HepG2 cells, ACAT-1 comprises 85-90% of the total ACAT activity, with the remainder attributed to ACAT-2. In adult intestines, most of the ACAT activity can be immunodepleted by anti-ACAT-2. ACAT-1 and ACAT-2 do not form hetero-oligomeric complexes. In differentiating intestinal enterocyte-like Caco-2 cells, ACAT-2 protein content increases by 5-10-fold in 6 days, whereas ACAT-1 protein content remains relatively constant. In the small intestine, ACAT-2 is concentrated at the apices of the villi, whereas ACAT-1 is uniformly distributed along the villus-crypt axis. In the human liver, ACAT-1 is present in both fetal and adult hepatocytes. In contrast, ACAT-2 is evident in fetal but not adult hepatocytes. Our results collectively suggest that in humans, ACAT-2 performs significant catalytic roles in the fetal liver and in intestinal enterocytes.

BACKGROUND: Survival after liver transplantation has improved significantly over the last decade with pediatric recipients faring better than adults. The 20-year experience of pediatric liver transplantation at Children's Hospital of Pittsburgh is reported in terms of patient survival; graft survival in relation to age, gender, and immunosuppressive protocols; causes of death; and indications for retransplantation. METHOD: From March 1981 to April 1998, 808 children received liver transplants at Children's Hospital of Pittsburgh. All patients were followed until March 2001, with a mean follow-up of 12.2+/-3.9 years (median=12.6; range=2.9-20). There were 405 female (50.2%) and 403 male (49.8%) pediatric recipients. Mean age at transplant was 5.3+/-4.9 years (mean=3.3; range 0.04-17.95), with 285 children (25.3%) being less than 2 years of age at transplant. Cyclosporine (CsA)-based immunosuppression was used before November 1989 in 482 children (50.7%), and the subsequent 326 recipients (40.3%) were treated with tacrolimus-based immunosuppression. Actuarial survival was calculated using the Kaplan-Meier statistical method. Differences in survival were calculated by log-rank analysis. RESULTS: Overall patient survival at 1, 5, 10, 15, and 20 years was 77.1%, 72.6%, 69.4%, 65.8%, and 64.4%, respectively. There was no difference in survival for male or female patients at any time point. At up to 10 years posttransplant, the survival for children greater than 2 years of age (79.5%, 75.7%, and 71.6% at 1, 5, and 10 years, respectively) was slightly higher than those at less than 2 years of age (72.6%, 66.9%, and 65.3% at 1, 5, and 10 years, respectively). However, at 15 and 20 years posttransplant, survival rates were similar (>2 years=67.3% and 65.8%; <2 years=64.1% and 64.1%). A significant difference in survival was seen in CsA-based immunosuppression (71.2%, 68.1%, 65.4%, and 61%) versus tacrolimus-based immunosuppression (85.8%, 84.7%, 83.3%, and 82.9%) at 1, 3, 5, and 10 years, respectively (P=0.0001). The maximum difference in survival was noted in the first 3 months between CsA and tacrolimus; thus, indicating there may have been other factors (nonimmunological factors) involved in terms of donor and recipient selection and technical issues. The mean annual death rate beyond 2 years posttransplant was 0.47%, with the mean annual death rate for patients who received tacrolimus-based immunosuppression being significantly lower than those who received CsA-based immunosuppression (0.14% vs. 0.8%; P=0.001). The most common etiologies of graft loss were hepatic artery thrombosis (33.4%), acute or chronic rejection (26.6%), and primary nonfunction (16.7%). Of note, retransplantation for graft loss because of acute or chronic rejection occurred only in those patients who received CsA-based immuno-suppression. CONCLUSION: The overall 20-year actuarial survival for pediatric liver transplantation is 64%. Survival has increased by 20% in the last 12 years with tacrolimus-based immunosuppression. Although this improvement may be the result of several factors, retransplantation as a result of acute or chronic rejection has been completely eliminated in patients treated with tacrolimus.

OBJECTIVE: To summarize the long-term efficacy and safety of tacrolimus in orthotopic liver transplant (OLT) recipients, as well as to examine the factors that influence long-term morbidity and mortality rates. BACKGROUND: Tacrolimus (FK506, Prograf) was introduced as primary immunosuppression for primary liver transplantation in 1989; many subsequent trials have verified the association of tacrolimus with decreased rates of acute rejection and steroid-resistant rejection after OLT. Cumulative experience with tacrolimus has also defined its short- and intermediate-term toxicity. METHODS: One thousand consecutive patients undergoing primary OLT at a single center from August 1989 to December 1992, under tacrolimus immunosuppression, were followed until January 1999. Patients were categorized by age. Mean follow-up was 93.4+/-11 months after OLT. Patient survival, graft survival (with corresponding causes of death and retransplantation), and rejection rates (and corresponding doses of immunosuppression) were examined as efficacy parameters. Hypertension, renal function, incidence of malignancies, incidence of diabetes, and other toxicities were examined as safety parameters. RESULTS: Actual 6-year overall patient survival rate was 68.1% and graft survival rate was 62.5%, with significant differences in the patterns of survival among the different age groups. After the first post-OLT year, infection, recurrence of disease, de novo malignancies, and cardiovascular events were the main causes of graft loss and death during the long-term follow-up. Graft loss related to either acute or chronic rejection was rare. The rate of acute rejection beyond 2 years was approximately 3% per year, and most were steroid-responsive. Approximately 70% of the patients were receiving tacrolimus monotherapy beyond year 1; at the latest follow-up, 74.2% were maintained on tacrolimus alone. In 6.1% of the survivors, end-stage renal disease developed during the follow-up period, requiring either dialysis or kidney transplantation. Hyperkalemia and hypertension was observed in approximately one third of the patients. Insulin-dependent diabetes mellitus (including patients who had diabetes before the transplant) was observed in 14% in year 1, dropping to 11% in year 7. In 82 patients, de novo malignancies developed; in 41 patients, lymphoproliferative disorders developed during the entire follow-up period. CONCLUSIONS: Long-term patient and graft survival rates are excellent under tacrolimus immunosuppression. Pediatric patients have a better long-term outcome than adults, in part because of the limited recurrence of the original disease, which was the most common cause of late graft loss (other than patient death, most commonly the result of late de novo malignancies and cardiovascular events). Graft loss from late rejection was rare.

BACKGROUND: Liver transplantation (LTx) for alcohol-related liver disease (ALD) is an accepted modality of treatment and is one of the most common indications for LTx in the United States. The present report examines the long-term patient survival, graft survival, rates of recidivism, and development of de novo cancers in this group, and compares these results with a contemporaneous group of patients who were transplanted for non-ALD indications. METHODS: Between August 1989 and December 1992, 185 adults received LTx for ALD (group I). During the same time interval, 649 adults received LTx for non-ALD (group II). The mean follow-up time was 94+/-10.7 months for group I vs. 92+/-11 months for group II. Kaplan-Meier survival estimates and the incidence of cancers using Surveillance Epidemiologic End Result data were compared in both groups. RESULTS: At 5 years after orthotopic LTx, the overall patient survival and graft survival for group I were 72.0% and 66.5% vs. 66.5% and 60.3% for group II, respectively. After 5 years, the patient survival and graft survival for the alcoholic group were significantly lower (P=0.001) compared to the non-alcoholic group. The rate of de novo oropharyngeal cancer and lung cancer was 25.5 times and 3.7 times higher, respectively, in ALD group compared with the general population matched for age, sex, and length of follow-up (P=0.001), whereas this was not higher in the non-ALD group. Prior pretransplant length of sobriety and alcohol rehabilitation was not associated with the rate of post-LTx rate of recidivism, which was 20%. Out of 79 deaths in group I, only 1 was attributed to recidivism and 3 to noncompliance with recidivism. The other deaths occurred from de novo cancer (n=13), posttransplant lymphoproliferative disorder (n=5), age-related complications (n=23), and other infection or miscellaneous causes (n=34). CONCLUSIONS: Patient and graft survival past 5 years after orthotopic LTx is significantly lower for ALD for a variety of reasons (P=0.001). The rate of upper airway malignances was significantly higher in ALD patients than for non-ALD post-LTx patients and the general public. Graft loss/death related to recidivism or chronic rejection was extremely low. More attention is needed for early diagnosis of de novo cancer and prevention of cardiorespiratory and cerebrovascular complications.