Outcomes In Liver Transplant Recipients Research Articles

No hepatitis recurrence using combination prophylaxis in HBV-positive liver transplant recipients with YMDD mutants

Recurrence of hepatitis B impairs the outcome of liver transplantation (OLT). In serum hepatitis B virus (HBV)-DNA-positive recipients, prophylaxis using lamivudine and immunoglobulins (HBIg) reduces the risk of recurrence, but it is undefined whether this regimen also protects candidates with YMDD mutants. Seventeen OLT viraemic candidates received pre-emptive lamivudine followed by post-OLT prophylaxis with lamivudine and HBIg. Both sera and liver biopsies were prospectively collected and high-sensitive polymerase chain reaction (PCR) assay was applied for HBV-DNA detection. Finally, the presence of YMDD mutants was explored in all PCR-positive samples. All patients remained hepatitis B recurrence-free after a mean follow up of 32 months. By PCR, serum HBV-DNA was detectable in 64.3% of cases at OLT-baseline, in 64.7% under combined prophylaxis and in 58.8% in patients (70.5% of the total) with a minimum follow up of 24 months. At OLT-baseline, YMDD mutants were found in 44.4% of patients. After OLT, mutants were present in 50% of patients but only in 16.6% of cases in the long period. Although 41% of the native livers and 42.8% of the analysed grafts harboured HBV-DNA, YMDD mutants were detected in 57% of the native positive livers. YMDD mutants were largely detected both at OLT-baseline and post-OLT, but their presence decreased over time. Regardless of the presence of YMDD mutants, no hepatitis B recurrence was observed in our OLT recipients using pre-emptive lamivudine followed by continuous prophylaxis with lamivudine and HBIg.

The long—term outcome of liver transplantation recipients with de novo hepatitis B infection who received an anti—HBC graft: Michael B Ishitani, Mayo Clinic, Rochester, MN; David D Douglas, Jorge Rakela, Mayo Clinic Scottsdale, Scottsdale, AZ; Rolland D Dickson, Mayo Clinic Jacksonville, Jacksonville, FL; Russell H Wiesner, Charles B Rosen, Ruud A Krom, Mayo Clinic, Rochester, MN

The long—term outcome of liver transplantation recipients with de novo hepatitis B infection who received an anti—HBC graft: Michael B Ishitani, Mayo Clinic, Rochester, MN; David D Douglas, Jorge Rakela, Mayo Clinic Scottsdale, Scottsdale, AZ; Rolland D Dickson, Mayo Clinic Jacksonville, Jacksonville, FL; Russell H Wiesner, Charles B Rosen, Ruud A Krom, Mayo Clinic, Rochester, MN

Severing the Gordian knot of prevention of cytomegalovirus in liver transplant recipients: The principle is the sword

Severing the Gordian knot of prevention of cytomegalovirus in liver transplant recipients: The principle is the sword

Outcomes in liver transplant recipients with hepatitis B virus: Resistance and recurrence patterns from a large transplant center over the last decade

Hepatitis B virus (HBV) recurrence following liver transplantation (LTx) has been controllable primarily with the use of hepatitis B immune globulin (HBIg) and lamivudine (LAM). However, HBV resistance to LAM and/or HBIg has become an increasing problem prompting the use of newer antiviral agents. The purpose of our study was to investigate the association between therapy, HBV breakthrough, and allograft / patient survival in HBV-positive liver transplant recipients. We performed a retrospective review of the medical records of patients that were transplanted for HBV from June 1994 to May 2003. A total of 92 patients, positive for either hepatitis B surface antigen (HBsAg) or HBV deoxyribonucleic acid (DNA) pretransplant, received LAM monotherapy or HBIg (6 months) plus LAM therapy post-liver transplant. HBV breakthrough post-LTx was noted in 14 patients. All patients had detectable HBV DNA prior to liver transplantation; none of the patients that were HBV DNA negative prior to transplant had detectable HBV DNA posttransplant. Of these 14, 9 patients (64%) were switched from LAM to adefovir dipivoxil (ADF) and 5 patients (36%) to tenofovir disoproxil fumarate (TNV). In conclusion, pre-LTx HBV viremia should be considered in planning post-LTx prophylaxis. Trials to evaluate oral antiviral agents in combination with or without HBIg therapy are needed.

Outcome of infections caused by multiple drug–resistant bacteria in liver transplant recipients

Objective To evaluate the impact of infections caused by multiple-drug-resistant (MDR) bacteria on the clinical outcome of liver transplant recipients. Methods Retrospective study including all episodes of bacterial infection diagnosed in patients undergoing liver transplantation from January 19, 1999, to June 30, 2002. The diagnosis of bacterial infection required microbiological documentation. Mortality associated with episodes of infection by MDR bacteria was compared to that observed after antibiotic-susceptible bacterial infections. Results Among 99 patients undergoing liver transplantation during the study period, there were 57 episodes of bacterial infections. Gram-negative bacilli were the predominant etiologic agents (76%) and Pseudomonas aeruginosa was the most frequent bacterial species found in these cases (23 isolates, 28%). Thirty-six episodes of infection (63%) were caused by MDR bacteria. Mean time after transplantation to the diagnosis of infection was 17 days. Mortality associated with episodes of MDR bacterial infections (nine deaths, 25%) was not significantly different from that observed during episodes of antibiotic-susceptible bacteria (five deaths, 24%; P = .92). Conclusion These data suggest that resistance to multiple antimicrobial agents does not have an impact on the mortality associated to bacterial infections in liver transplant recipients.

Cytochrome P-450 3A4, 3A5, and MDR-1 as pharmacogenomic predictors of tacrolimus pharmacokinetics and clinical outcomes in liver transplant recipients

Tacrolimus is a macrolide immunosuppressant used to prevent allograft rejection in organ transplantation. CYP3A4, CYP3A5, and P-glycoprotein (MDR1) may play significant roles in drug disposition of xenobiotics including tacrolimus. Single nucleotide polymorphisms (SNPs) in CYP3A4 (A-290G), CYP3A5 (A22893G), and MDR1 (C3435T) may result in altered in vivo catalytic activity. This study explored the pharmacogenomic impact of CYP3A4, CYP3A5, and MDR1 on tacrolimus dosing and clinical outcomes in liver transplant recipients. In 45 patients, phenotypic data were collected for the first 10 days post-transplant and at Month 4. Genomic DNA was isolated from human liver tissue with genotypic determination done via PCR-based detection methods. Unpaired T-tests compared two genotype groups with P<0.05 considered significant. Significantly, CYP3A4 AA genotype had higher mean tacrolimus trough concentrations than AG/GG (11.8±2.7 vs 9.7±2.9 mcg/dL, p=0.027), and individuals with CYP3A5*3/*3 required higher tacrolimus doses than those with a CYP3A5*1 allele (0.054±0.02 vs 0.040±0.02 mg/kg/d, p=0.040). Renal clearance significantly declined from transplant to Month 4 in all groups (p<0.0001), but no genotype interactions were identified. Thus, genetic variants of CYP3A4 and CYP3A5 may be useful predictors of tacrolimus requirements and outcomes in liver transplant patients and may contribute to the construction of clinically relevant pharmacogenomic models in transplantation. Clinical Pharmacology & Therapeutics (2004) 75, P39–P39; doi: 10.1016/j.clpt.2003.11.149

Subclinical reactivation of hepatitis B virus in liver transplant recipients with past exposure

Transmission of hepatitis B infection has been reported in liver transplant recipients whose donor livers were negative for hepatitis B surface antigen (HBsAg) and positive for antibody to hepatitis B core antigen (anti-HBc). These infections usually have a mild clinical course and no adverse effects on survival. However, the outcome of liver transplant recipients with serologic evidence of past infection to hepatitis B virus (HBV) is unknown. The prevalence of HBV DNA positivity by polymerase chain reaction (PCR) pretransplantation in HBsAg-negative, anti-HBc-positive people is reported to be 0% to 32%. To assess the prevalence of HBV DNA in pretransplantation serum and liver tissue and to determine the clinical outcome of HBsAg-negative, anti-HBc-positive recipients, we retrospectively reviewed the first 693 orthotopic liver transplantations performed at Mayo Clinic between March 19, 1985, and May 25, 1996. Pretransplantation specimens of frozen serum and liver tissue were available for HBV DNA by PCR for 35 of 56 HBsAg-negative, anti-HBc-positive recipients. Twenty-two recipients had positive serologic findings for anti-HBc alone, and 13 were positive for anti-HBc and antibody to HBsAg (anti-HBs). Pretransplantation prevalence of HBV DNA in HBsAg-negative, anti-HBc-positive recipients was 6% (serum) to 29% (liver). Of those recipients whose liver was HBV DNA-positive pretransplantation, 40% also had evidence of HBV DNA in posttransplantation liver biopsy specimens, and this finding was more common in patients co-infected with hepatitis C. None of the recipients became antigenemic (HBsAg-positive) or developed clinical hepatitis B posttransplantation. Thus, prophylactic intervention (eg, antiviral or antinucleoside analog therapy) is not warranted after liver transplantation in HBsAg-negative, anti-HBc-positive recipients. In our experience, infected donor livers are the most common source of de novo posttransplantation hepatitis B infection in transplant recipients.

Survival and resource utilization in liver transplant recipients: the impact of admission to the intensive care unit

The organ allocation system for liver transplantation was recently changed to address criticisms that it was too subjective and relied too heavily on total waiting time. The new system, Model for End-Stage Liver Disease and Pediatric Model for End-Stage Liver Disease (MELD/PELD), stratifies patients based on the risk of 3-month pretransplant mortality, allocating livers thereby. There is concern that such a scheme gives priority to the sickest patients, who may not enjoy good posttransplant outcomes. The aim of the present study was to compare the outcomes of liver transplant recipients who had been admitted to the intensive care unit (ICU) to those who had not. Admission to the ICU is considered here to be another indicator of the severity of illness. Patients who underwent liver transplantation at the Cleveland Clinic between January 1, 1993 and October 31, 1998 and were at least 18 years of age were coded for liver transplantation as status 2, 2A, and 2B ( n = 112). These patients fell into three groups: those who had been admitted to an ICU before transplantation (group A, n = 16), those who had been admitted to the hospital but not to an ICU (group B, n = 63), and those who were living at home and had undergone an elective transplant (group C, n = 33). Clinical and demographic information (age, sex, race, disease severity, disease etiology, and cold ischemia time) were associated with patient survival, patient/graft survival, and posttransplant resource utilization (hospital length of stay and hospital charges). Age, sex, race, etiology of disease, and cold ischemia time were similar among the three groups. Patient survival, patient/graft survival, and hospital charges were not statistically different between the three groups. The median length of stay was statistically different only between groups B and C ( P = .006). Our data support the idea that if severely ill patients with end-stage liver disease are selected appropriately, liver transplant outcomes are similar to those observed among subjects who are less ill and are transplanted electively from home.

Pregnancy Outcome in Liver Transplant Recipients

Pregnancy Outcome in Liver Transplant Recipients

The long-term outcome of liver transplant recipients with de novo hepatitis B infection who received an anti-HBC graft

The long-term outcome of liver transplant recipients with de novo hepatitis B infection who received an anti-HBC graft

Quality of life and employment after liver transplantation.

1. In general, the health-related quality of life (QOL) of transplant recipients is impaired before and improves after liver transplantation. 2. Transplant recipients report largest gains in those aspects of QOL most affected by physical health and smaller improvements in areas affected by psychological functioning. 3. No utility-based measures have been used with liver transplant recipients; therefore, the necessary QOL weights for use in cost-effectiveness evaluations of liver transplantation are lacking. 4. Pretransplantation, the percentage of candidates with alcoholic liver disease (ALD) who work is less than that of candidates without ALD. However, there is no difference in rates of employment posttransplantation. 5. No study has described types of wages and benefits associated with jobs before or after transplantation or the extent to which health insurance benefits associated with employment motivate changes in work status. 6. Many studies in this field used non-validated heterogeneous instruments to measure QOL and employment, thus limiting the opportunity to combine results across studies and compare outcomes for liver transplant recipients with other patient populations.

Quality of life, employment, and alcohol consumption after liver transplantation

This article reviews the main results and describes the most prevalent design characteristics of the 89 studies included in our comprehensive meta-analysis of quality of life, employment, and alcohol consumption after liver transplantation. In general, the health-related quality of life of recipients was impaired before and improved after transplantation. Recipients reported large gains in those aspects of quality of life most affected by physical health and smaller improvements in areas affected by psychologic functioning. No utility-based measures have been used with liver transplant recipients, so the necessary quality-of-life weights for use in cost-effectiveness evaluations of liver transplantation are lacking. Before transplantation, the percentage of candidates with alcoholic liver disease who worked was lower than that of candidates with nonalcoholic liver disease; after transplantation, however, there was no difference in the rates of employment. None of the included articles described the types of wages and benefits associated with jobs before or after transplantation or the extent to which health insurance benefits associated with employment motivated changes in work status. No difference was found in the proportion of recipients with alcoholic and nonalcoholic liver disease that reported using alcohol after transplantation. Posttransplantation abstinence from alcohol use was greater among those patients who had been abstinent for longer than 6 months before transplantation. No difference was found between the rates of posttransplantation employment of alcohol users and nonusers; however, few studies directly evaluated this question. Because the studies in this meta-analysis used nonvalidated heterogeneous instruments to measure quality of life, employment, and alcohol consumption, the ability to combine results among studies and to compare the outcomes for liver transplant recipients with other patient populations was limited. Additional heterogeneity in the selection of control groups prevented comparisons of results among groups of transplant recipients. Because of these design limitations, clinically important questions regarding the quality of life and functional status of liver transplant recipients remain unanswered.

Posttransplantation dialysis-associated infections: Morbidity and impact on outcome in liver transplant recipients

The aim of this study is to assess the predictors, impact on infectious morbidity, and outcome of posttransplantation dialysis in liver transplant recipients and to compare the results with data from patients who did not require dialysis after transplantation. The study sample included 176 consecutive patients undergoing liver transplantation; the median follow-up was 4.3 years. All patients were administered tacrolimus as primary immunosuppression. Overall, 16% (28 of 176 patients) of the patients required dialysis after transplantation. Patients requiring dialysis had significantly greater pretransplantation creatinine levels (2.4 v 1.2 mg/dL; P =.009), were more likely to require pretransplantation dialysis (21% v 1%; P =.0001), and had a greater rate of biopsy-proven rejection episodes (50%, 14 of 28 episodes v 20%, 30 of 148 episodes; P =.0009) and longer posttransplantation intensive care unit lengths of stay (P =.0001). The incidence of infections (91% v 41%; P =.0001) and episodes of infection per patient (2.4 v 0.7 episodes; P =.0001) were significantly greater in patients undergoing dialysis compared with those not undergoing dialysis. There was no difference in the frequency of cytomegalovirus (CMV) infection or disease; however, bacterial infections (87% v 31%; P =.0001) and invasive fungal infections (39% v 7%; P =.0001) were significantly more likely to occur in patients requiring dialysis. In logistic regression, dialysis (P =.0006) and CMV infection (P =.007) were independent significant predictors of major infections. Overall survival (assessed by Kaplan-Meier probability) was less in patients undergoing dialysis compared with those not undergoing dialysis (P =.0001). Among dialyzed patients, only 10% of those who survived had an invasive fungal infection compared with 46% of those who died (P =.08); 5 of 6 patients died within 1 month of the fungal infection. The need for dialysis portended a grave outcome in liver transplant recipients and identified a subgroup of patients at a significantly greater risk for major infections, particularly fungal infections, after liver transplantation.

102Improved clinical outcomes for liver transplant recipients using cyclosporin blood level monitoring two hours post dosage

102Improved clinical outcomes for liver transplant recipients using cyclosporin blood level monitoring two hours post dosage

Long-term outcome of liver transplant recipients followed exclusively outside the surgical transplant center

Long-term outcome of liver transplant recipients followed exclusively outside the surgical transplant center

Thrombocytopenia in liver transplant recipients: predictors, impact on fungal infections, and role of endogenous thrombopoietin.

Thrombocytopenia is a frequent and potentially serious complication in liver transplant recipients. The role of endogenous thrombopoietin level in posttransplant thrombocytopenia, has not been fully defined in liver transplant recipients. Additionally, there is accumulating evidence to suggest that platelets play a important role in antimicrobial host defense. There were 50 consecutive liver transplant recipients studied. Variables predictive of thrombocytopenia, its impact on infectious morbidity and outcome, and serial thrombopoietin (TPO) serum concentration were assessed. The median pretransplant platelet count was 67 x 10(3)/cmm. After the liver transplantation, the median nadir platelet count was 33 x 10(3)/cmm and was reached a mean of 6 days after the transplant. A lower pretransplant platelet count (r= +.068, P=.0001), lower serum albumin before the transplants (r=+0.39, P=.014), longer operation time (r=0.27, P=.05), higher intraoperative packed red cells (r=0.28, P=.049) and fresh frozen plasma transfusions (r=0.42, P=.004), higher bilirubin at Day 7 (r=-.386, P=.005), and higher serum creatinine at Day 7 after the transplants (r=-.031, P=.025) correlated significantly with a lower nadir in platelets after the transplant. Nadir in platelet count was significantly lower in nonsurvivors compared with survivors (16 vs. 36 x 10(3)/cmm, P=.0001). Forty-three percent (9 of 21) of the patients with nadir platelet counts of < or =30 x 10(3)/cmm had a major infection within 30 days of the transplant compared with 17% (5 of 29) with nadir platelet counts > 30 x 10(3)/cmm (P=.04). Fungal infections occurred in 14% of the patients with nadir platelet counts of < or =30 x 10(3)/cmm versus 0% in those with nadir platelet counts of > 30 x 10(3)/cmm (P=.06); all patients with fungal infections had nadir platelet counts of < or =30 x 10(3)/cmm before fungal infection. Nadir in platelet count preceded the first major infection by a median of 7 days. Pretransplant TPO level did not differ between survivors (mean 103 pg/ml) or nonsurvivors (mean 144 pg/ml). After the transplantation, TPO levels increased in both groups. TPO level peaked at Day 7 and subsequently declined in survivors. Nonsurvivors had persistent thrombocytopenia despite a progressive rise in TPO level; TPO level was significantly higher at Day 7 (P=.02), Day 9 (P=.0019), and Day 14 (P=.04) in nonsurvivors compared with survivors. Persistent thrombocytopenia portended a poor outcome in liver transplant recipients and was not related to low TPO levels. Thrombocytopenia preceded infections and identified a subgroup of liver transplant patients susceptible to early major infections; its precise role in fungal infections warrants validation in larger studies.

Detection of Graft Nonfunction After Liver Transplantation by Assessment of Indocyanine Green Kinetics

Detection of Graft Nonfunction After Liver Transplantation by Assessment of Indocyanine Green Kinetics

Association of pregnancy complications and choice of immunosuppressant in liver transplant patients.

The purpose of this study was to identify factors associated with antenatal complications for an ongoing series of pregnant women who have undergone orthotopic liver transplantation. We reviewed Magee-Womens Hospital records from 14 pregnancies in 13 women in whom a liver had been transplanted before pregnancy. We collected and analyzed data regarding the primary liver disease, allograft status, liver function at conception and during pregnancy, immunosuppressive medications, associated medical conditions, time from transplant to conception, cytomegalovirus serostatus, and maternal and fetal outcome. Seven patients had evidence of renal dysfunction (creatinine, 1.3-2.0 mg/dl), five of whom also were hypertensive at their first prenatal visit. The complications of preeclampsia, worsening hypertension, and small for gestational age occurred only in women with renal dysfunction at conception. Renal dysfunction was more often associated with cyclosporine than tacrolimus use. Renal dysfunction is the primary determinant of adverse pregnancy outcome in liver transplant recipients. Immunosuppression with cyclosporine during pregnancy was more often associated with antenatal complications than with the use of tacrolimus.

Incidence, prevalence, and clinical outcome of hepatitis GB-C virus infection in liver transplant patients.

A novel RNA virus of the Flaviviridae family has been discovered recently and designated hepatitis GB-C virus (GBV-C). Previous studies have reported that GBV-C is associated with posttransfusion hepatitis, chronic viral hepatitis, and cryptogenic hepatitis. However, the clinical significance of GBV-C infection has been questioned increasingly in patients not undergoing transplantation. To investigate whether GBV-C infection under immunosuppression affects the clinical or the histological outcome in liver transplant recipients, we determined the prevalence and incidence of GBV-C infections and the clinical and histological signs in patients after orthotopic liver transplantation (OLT). The presence of GBV-C was tested in sera from patients before and in regular intervals up to 6 years after OLT by nested reverse transcription-polymerase chain reaction using primers derived from the NS3 region. A total of 72 patients were studied. Before OLT, 8 of 72 (11.1%) patients were positive for GBV-C. After OLT, 7 of 8 (87.5%) remained positive. Of 64 patients who were negative for GBV-C before OLT, 23 became positive after OLT, resulting in a de novo rate of GBV-C infection of 35.9%. We could not detect a higher rate of histologically proven hepatitis in GBV-C-positive patients (29.1%) than in GBV-C-negative patients (14.6%, P > 0.057). Comparing GBV-C-positive with GBV-C-negative liver transplant patients, we could not find any differences in age, gender, liver function tests, number of blood transfusions, histological degree of hepatitis, or number of rejection episodes. Survival was not negatively influenced by GBV-C positivity. In conclusion, the presence of GBV-C did not influence the clinical or histological outcome in liver transplant patients.