Orthotopic liver transplantation in U.S. veterans under primary tacrolimus immunosupression.

The evolution and refinement of surgical techniques, per ioperative patient care, and immunosuppression hav~ estab~ished orthoto~ic li~er transplantation (OLTX) as a ~ighly successful therapeutic modality for patients wrth end-stage hver disease. In February 1989,Tacrohmus (Prograf®, formerly FK 506)was first used successfully at the University of Pittsburgh Medical Center to treat patients with rejection refractory to cyclosporine-based immunosuppression." Clinical trials utilizing Tacrolimus in solid organ transplantation followed, and in April of 1994 it was approved for use by the Food and Drug Administration

Hepatitis C virus genotypes in liver transplant recipients: Impact on posttransplant recurrence, infections, response to interferon-α therapy and outcome

Background. End-stage liver disease due to hepatitis C virus (HCV) is the most common indication for liver transplantation in U.S. veterans. We investigated the influence of HCV genotypes on the incidence and timing of recurrent HCV hepatitis, survival, infectious morbidity, and response to interferon-α therapy in this unique patient population. Methods. HCV genotype was determined by direct sequencing of the NS5 region of HCV with type-specific primers. Results. Genotype 1a (66%, 32/47) was the predominant genotype. Type 1b was found in 25% (12/47) of patients and type 2b was found in 9% (4/47). His topathologically recurrent HCV hepatitis developed in 53% (25/47) of the patients after transplantation. This group included 45% (14/31) of the patients with type 1a, 67% (8/12) of the patients with type 1b, and 25% (1/4) of the patients with type 2b (P>0.5). The time to recurrence and the severity of HCV recurrence as defined by aminotransferase levels or Knodell scores were not different among the three genotypes. There was a trend toward a higher incidence of major infections in patients with type 1b (75%) versus type 1a (48%) and type 2b (50%) (P=0.11). The response to interferon-α therapy did not differ significantly among the genotypes. Mortality at 5 years was 16% (5/31) in patients with genotype 1a, 42% (5/12) in patients with genotype 1b, and 50% (2/4) in patients with genotype 2b (P=0.06). Conclusions. The incidence, time to recurrence, and response to interferon-α therapy did not differ be tween the various genotypes in our liver transplant recipients. However, there was a trend toward higher infectious morbidity and overall mortality in patients with genotype 1b after transplantation

Orthopedic liver transplantation in high-risk patients

Background. One of the most controversial area in patients selection and donor allocation in the high-risk patient. Risk factors for mortality and major infectious morbidity were prospectively analyzed in consecutive United States veterans undergoing the liver transplantation under primary tacrolimus-based immunosuppression. Methods. Twenty-eight pro-liver transplant, operative and posttransplant risk factors were examined univariately and multivariately in 140 consecutive liver transplant in 1130 veterans (98% male); mean age 47.3 years) Results. Eighty-two percent of the patients had postnecrotic cirrhosis due to viral hepatitis or ethanol (20% ethanol alone), and only 12% had cholestatic liver disease. Ninety-eight percent of the patients were hospitalized at the time of transplantation (66% Unites Network for Network for Organ Sharing [UNOS] 2, 32% UNOS 1). Major bacterial infection, posttransplant dialysis, additional immunosuppression, readmission to intensive care unit (p=0.0001 for all), major fungal infection, posttransplant abdominal surgery, posttransplant intensive care unit stay length of stay (p<0.005 for all), donor age, pretransplant dialysis, and creatinine (P<0.05 for all) were significantly associated with morality by univariate analysis. Underlying liver disease cytomegalovirus infection and disease, portal vein thrombosis, UNOS status, Childs-Pugh score, patient age, pretransplant bilirubin, bilirubin time, and operative blood loss were not significant predictors of mortality. Patients with hepatitis C (HCV) and recurrent HCV a trend toward higher mortality (P=0.18). By multivariate analysis, donor age, any major infection, additional immunosuppresion, post-transplant dialysis, and subsequent transplantation were significant independent predictors of mortality (P<0.05). Major infectious morbidity was associated with HCV recurrence (P=0.003), posttransplant dialysis (P=0.0001), pretransplant creatine, donor age, median blood loss, intensive care unit length of stay, additional immunosuppression, and biopsy-proven rejection (P<0.05 for all). By multivariate analysis, intensive care unit length of stay and additional immunosuppression were significant independent predictors of infectious morbidity (P<0.03). HCV recurence was of borderline significance (P=0.07). Conclusions. Biologic and physiologic parameters appear to be more powerful predictors of mortality and morbidity after liver transplantation. Both donor and recipient variables need to be considered for early and late outcome analysis and risk assessment modeling

Effect of donor age and sex on the outcome of liver transplantation

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 66% to 78%); and male to female, 78% (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (-60 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category. © 1995

Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression

Objective: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. Summary Background Data: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. Methods: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. Results: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reductions in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. Conclusions: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation