Preoperative factors associated with outcome and their impact on resource use in 1148 consecutive primary liver transplants.

BACKGROUND: Hepatic transplantation is a highly effective but costly treatment for end-stage hepatic dysfunction. One approach to improve efficiency in the use of scarce organs for transplantation is to identify preoperative factors that are associated with poor outcome posttransplantation. This may assist both in selecting patients optimal for transplantation and in identifying strategies to improve survival. METHODS: In the present work, we retrospectively reviewed consecutive liver transplants performed at the University of California at Los Angeles during a 6-year period and determined preoperative variables that were associated with outcome in primary grafts. In addition, we used the hospital's cost accounting database to determine the impact of these variables on the degree of resource use by high-risk patients. RESULTS: We found five variables to have independent prognostic value in predicting graft survival after primary liver transplantation: (1) donor age, (2) recipient age, (3) donor sodium, (4) recipient creatinine, and (5) recipient ventilator requirement pretransplant. Recipient ventilator requirement and elevated creatinine were associated with significant increases in resource use during the transplant admission. CONCLUSIONS: Patients at high risk for graft failure and costly transplants can be identified preoperatively by a set of parameters that are readily available, noninvasive, and inexpensive. Selection of recipients on the basis of these data would improve the efficiency of liver transplantation and reduce its cost.

A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients.

OBJECTIVE: To determine the factors affecting the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV) and to identify models that predict patient and graft survival. SUMMARY BACKGROUND DATA: The national epidemic of HCV infection has become the leading cause of hepatic failure that requires OLT. Rapidly increasing demands for OLT and depleted donor organ pools mandate appropriate selection of patients and donors. Such selection should be guided by a better understanding of the factors that influence the outcome of OLT. METHODS: The authors conducted a retrospective review of 510 patients who underwent OLT for HCV during the past decade. Seven donor, 10 recipient, and 2 operative variables that may affect outcome were dichotomized at the median for univariate screening. Factors that achieved a probability value less than 0.2 or that were thought to be relevant were entered into a stepdown Cox proportional hazard regression model. RESULTS: Overall patient and graft survival rates at 1, 5, and 10 years were 84%, 68%, and 60% and 73%, 56%, and 49%, respectively. Overall median time to HCV recurrence was 34 months after transplantation. Neither HCV recurrence nor HCV-positive donor status significantly decreased patient and graft survival rates by Kaplan-Meier analysis. However, use of HCV-positive donors reduced the median time of recurrence to 22.9 months compared with 35.7 months after transplantation of HCV-negative livers. Stratification of patients into five subgroups, based on time of recurrence, revealed that early HCV recurrence was associated with significantly increased rates of patient death and graft loss. Donor, recipient, and operative variables that may affect OLT outcome were analyzed. On univariate analysis, recipient age, serum creatinine, donor length of hospital stay, donor female gender, United Network for Organ Sharing (UNOS) status of recipient, and presence of hepatocellular cancer affected the outcome of OLT. Elevation of pretransplant HCV RNA was associated with an increased risk of graft loss. Of 15 variables considered by multivariate Cox regression analysis, recipient age, UNOS status, donor gender, and log creatinine were simultaneous significant predictors for patient survival. Simultaneously significant factors for graft failure included log creatinine, log alanine transaminase, log aspartate transaminase, UNOS status, donor gender, and warm ischemia time. These variables were therefore entered into prognostic models for patient and graft survival. CONCLUSION: The earlier the recurrence of HCV, the greater the impact on patient and graft survival. The use of HCV-positive donors may accelerate HCV recurrence, and they should be used judiciously. Patient survival at the time of transplantation is predicted by donor gender, UNOS status, serum creatinine, and recipient age. Graft survival is affected by donor gender, warm ischemia time, and pretransplant patient condition. The authors' current survival prognostic models require further multicenter validation.

Sirolimus: continuing the evolution of transplant immunosuppression.

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and economic issues associated with sirolimus, the most recent immunosuppressive agent approved for kidney transplantation. DATA SOURCES: A MEDLINE search (1966-June 2000) was completed to identify primary and review articles. In addition, abstracts from recent meetings on transplantation were reviewed for information and research on sirolimus. STUDY SELECTION AND DATA EXTRACTION: Blinded, randomized, controlled studies were the goal, but, as with most newly approved immunosuppressive agents, a significant amount of information on sirolimus is not available in this optimal form. All articles were assessed and all pertinent information was incorporated in this review. DATA SYNTHESIS: Sirolimus is structurally related to the immunosuppressive agent tacrolimus, and retains a pharmacokinetic and drug interaction profile similar to that of the calcineurin inhibitors, cyclosporine and tacrolimus. However, the novel mechanism of action of sirolimus differs significantly from these agents, as does its adverse effect profile. The most significant adverse reaction is hyperlipidemia. Clinical experience with sirolimus has allowed transplant centers to expand its use into other areas of transplantation as well as certain autoimmune disorders. CONCLUSIONS: The definitive role of sirolimus will continue to be determined; however, sirolimus offers an excellent addition to the transplant immunosuppression armamentarium.

Mycophenolate mofetil: effects on clinical transplantation.

Mycophenolate mofetil (MMF) is the morpholinoethylester prodrug of mycophenolic acid, an agent which inhibits the proliferation of B and T lymphocytes through the noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, itself a key enzyme in the de novo synthetic pathway of guanosine nucleotides. Currently, MMF is approved for the prevention of acute renal allograft rejection when used in combination with cyclosporin and corticosteroids. Several studies have also demonstrated that this drug is useful in the treatment of refractory rejection in renal, heart and liver transplant recipients.

Mycophenolate mofetil.

Mycophenolate mofetil is the morpholinoethylester prodrug of mycophenolic acid, an agent that inhibits the proliferation of B and T lymphocytes through noncompetitive, reversible inhibition of inosine monophosphate dehydrogenase, a key enzyme in the de novo synthetic pathway of guanine nucleotides. Currently, mycophenolate mofetil is approved for the prevention of acute renal allograft rejection when given in combination with cyclosporine and steroids. Several studies also demonstrated that the agent is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection as well.

Coccidioidomycosis in liver transplant patients.

Eight (0.59%) of 1,347 patients who underwent liver transplantation at the UCLA Medical Center (Los Angeles) developed coccidioidomycosis. Whereas only one case occurred during the first 8 years and 10 months of the UCLA Liver Transplant Program (February 1984 to December 1992), seven cases occurred within the following 23-month period (December 1992 to November 1994). The median time of onset for infection after transplantation was 8 weeks (range, 4-312 weeks). Clinical presentations of patients with coccidioidomycosis included pneumonia (six cases), pneumonia with meningitis (one case), hepatitis (one case), and monoarticular arthritis (one case). Despite therapy with amphotericin B alone (six cases) or amphotericin B plus fluconazole (two cases), infection was fatal in four of eight cases. As of this writing, the four surviving patients are receiving chronic maintenance therapy with either fluconazole (three patients) or itraconazole (one patient). These experiences show that coccidioidomycosis can be a serious and frequently fatal infection after liver transplantation and that the incidence of this disease appears to be increasing.

Long-term ganciclovir prophylaxis for successful prevention of primary cytomegalovirus (CMV) disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors.

BACKGROUND: We conducted a trial of long-term ganciclovir prophylaxis for prevention of primary cytomegalovirus (CMV) disease in CMV-seronegative liver transplant recipients with CMV-seropositive donors. METHODS: Patients received intravenous ganciclovir at a dose of 6 mg/kg once a day from day 1 to day 30 after transplant, and then at a dose of 6 mg/kg once a day, Monday through Friday, until day 100. Forty-seven consecutive patients were evaluated. Due to the primary physician's decision or administrative error, 10 patients received less than 7 weeks of ganciclovir (mean duration, 3 weeks). RESULTS: Four of the 10 (40%) patients who received less than 7 weeks of ganciclovir developed CMV disease (hepatitis). In contrast, none of the 37 patients given 100 days of prophylactic ganciclovir developed CMV disease while receiving ganciclovir. Two patients (5.4%) subsequently developed CMV disease (hepatitis) 21 and 88 days, respectively, after completing their ganciclovir prophylaxis. Reversible neutropenia in three patients (8.1%) was the only side effect associated with long-term ganciclovir. Complications from central intravenous catheters did not occur. CONCLUSIONS: These results reaffirm the efficacy and safety of long-term ganciclovir prophylaxis for prevention of primary CMV disease in a large number of high-risk CMV-seronegative liver transplant recipients with CMV-seropositive donors.

Hyperlipidemia after liver transplantation: natural history and treatment with the hydroxy-methylglutaryl-coenzyme A reductase inhibitor pravastatin.

This study was designed to determine the frequency of hyperlipidemia after orthotopic liver transplantation and whether treatment with a hydroxy-methylglutaryl coenzyme A reductase inhibitor was safe and efficacious. Cholesterol levels were assessed in 45 consecutive adult liver transplants (mean +/- SE). Four of 22 patients on cyclosporine (CsA) (18%) and three of 23 patients on FK506 (13%) had levels >225 mg/dl at 12 months (cholesterol levels for patients on CsA [total n=22]: pre-Tx = 140+/-11, 1 month = 183+/-36,3 months = 221+/-12, 6 months = 211+/-11, 12 months = 202+/-14 [P<0.01 vs. pre-Tx]; FK506 [total n=23]: Pre-Tx = 151+/-13, 1 month = 187+/-22, 3 months = 188+/-10, 6 months = 184+/-13, 12 months = 164+/-9 [P=0.02 vs. CsA]). A separate cohort of patients with stable graft function, cholesterol >225 mg/dl, and two additional risk factors for coronary artery disease were started on pravastatin. Ninety-eight patients were enrolled. Sixteen patients (16%) discontinued the drug because of subjective complaints. No episodes of rhabdomyolysis or hepatotoxicity occurred (cholesterol levels for patients on CsA [total n=65]: pretreatment = 251+/-7, 6 months = 220+/-7 [P=0.01 vs. pretreatment], 12 months = 224+/-8 [P=0.01 vs. pretreatment]; FK506 [total n=17]: pretreatment = 251+/-17, 6 months = 219+/-17, 12 months = 208+/-17 [P=0.08 vs. pretreatment]). Natural killer cells isolated from normal volunteers (n=14) exhibited 27+/-9% specific lysis. Patients on FK506 or cyclosporine-based immunosuppression alone (n=11) exhibited 20+/-4% specific lysis. Standard immunosuppression plus pravastatin (n=10) decreased lysis to 0.2+/-10% (P<0.02 vs. controls and standard immunosuppression). We conclude: (1) posttransplant hyperlipidemia occurs less frequently in liver transplant patients than in renal or cardiac transplants; (2) pravastatin is safe and efficacious for cholesterol reduction in liver transplant patients; and (3) pravastatin coadministered with standard immunosuppression reduces natural killer cell-specific lysis in these recipients.

Advances in medical and antibiotic management of infective endocarditis.

Infective endocarditis remains a serious medical problem despite advancements in laboratory detection, echocardiographic techniques, and newer antibiotic agents. This article summarizes the microbial agents in infective endocarditis, in addition to developments in medical and antibiotic management.

Long-term ganciclovir prophylaxis eliminates serious cytomegalovirus disease in liver transplant recipients receiving OKT3 therapy for rejection.

We conducted a trial of long-term ganciclovir prophylaxis for prevention of cytomegalovirus (CMV) disease in liver transplant recipients receiving OKT3 therapy for rejection. Intravenous ganciclovir (6 mg/kg once a day, Monday through Friday) was initiated on the same day OKT3 therapy was started and continued for 4 or more weeks. Fifty-one consecutive adult patients (80% CMV seropositive, 20% CMV seronegative) were evaluated. Due to the patient's noncompliance or the primary physician's decision, 6 patients received less than 2 weeks of ganciclovir. Three of these 6 (50%) developed CMV disease (hepatitis 1, CMV syndrome 2). In contrast, of 45 patients receiving 4 or more weeks of prophylactic ganciclovir, only 1 (2.2%) developed CMV disease (hepatitis). There were no cases of CMV disease among 29 patients who received 6 or more weeks of ganciclovir. Reversible neutropenia in 2 patients (4.4%) was the only side effect associated with long-term ganciclovir. Complications from central intravenous catheters did not occur. These results suggest that CMV can be eliminated as a significant pathogen in liver transplant recipients receiving OKT3 for rejection by the long-term administration of prophylactic gnaciclovir, which is safe.

Role of liver transplantation in patients with hepatitis B infection.

Liver transplantation is currently considered definitive therapy for end-stage liver disease (1-4). The hepatitis B virus (HBV) affects a large group of candidates for liver transplantation (1-4), however, liver transplantation for HBV is associated with unique and serious problems due to post-transplant predisposition for HBV re-infection of the allograft (5-10, 12-14). Patients with actively replicating HBV infection, as demonstrated by positive pre-transplant hepatitis surface antigen (HBsAg), hepatitis e antigen (HBeAg), and HBV-DNA, patients retransplanted for HBV infection, patients not receiving long term hepatitis B immunoglobulin (HBIG) therapy (5-10, 12, 14), and patients of Asian descent (15), appear to be most likely to experience clinically significant recurrent hepatitis (2, 3, 6-14). Recurrent HBV can produce acute or chronic liver disease leading to graft failure, retransplantation, or death (2, 3, 5, 13, 14). For these reasons, liver transplantation for HBV remains controversial. In this review, we describe the proposed mechanisms, predisposing factors, and clinical presentation associated with HBV recurrence in liver allograft recipients. We also discuss current and potential methods of prevention of HBV infection following liver transplantation.