Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.

Donor morbidity after living donation for liver transplantation.

BACKGROUND & AIMS: Reports of complications among adult right hepatic lobe donors have been limited to single centers. The rate and severity of complications in living donors were investigated in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). METHODS: A retrospective observational study design was used. Participants included all potential living donors evaluated between 1998 and 2003. Complication severity was graded using the Clavien scoring system. RESULTS: Of 405 donors accepted for donation, 393 underwent donation, and 12 procedures were aborted. There were 245 donors (62%) who did not experience complications; 82 (21%) had 1 complication, and 66 (17%) had 2 or more. Complications were scored as grade 1 (minor; n = 106, 27%), grade 2 (potentially life threatening; n = 103, 26%), grade 3 (life threatening; n = 8, 2%), and grade 4 (leading to death; n = 3, 0.8%). Common complications included biliary leaks beyond postoperative day 7 (n = 36, 9%), bacterial infections (n = 49, 12%), incisional hernia (n = 22, 6%), pleural effusion requiring intervention (n = 21, 5%), neuropraxia (n = 16, 4%), reexploration (n = 12, 3%), wound infections (n = 12, 3%), and intraabdominal abscess (n = 9, 2%). Two donors developed portal vein thrombosis, and 1 had inferior vena caval thrombosis. Fifty-one (13%) donors required hospital readmission, and 14 (4%) required 2 to 5 readmissions. CONCLUSIONS: Adult living liver donation was associated with significant donor complications. Although most complications were of low-grade severity, a significant proportion were severe or life threatening. Quantification of complication risk may improve the informed consent process, perioperative planning, and donor care.

Hepatocellular carcinoma screening in patients waiting for liver transplantation: a decision analytic model.

De novo hepatocellular carcinoma (HCC) may have a large impact on patients waiting for liver transplantation. The presence of HCC can lead to a status upgrade or removal from the waitlist. Our aim is to compare costs and outcomes of different liver cancer surveillance strategies. A Markov-based decision analytic model is created to simulate costs and health outcomes for a hypothetical cohort awaiting liver transplantation undergoing HCC screening. Three strategies of HCC screening are compared with the referent strategy of using alphafetaprotein (AFP) level alone: (1) ultrasound (U/S), (2) AFP plus U/S, and (3) computed tomography (CT). Screening is performed for all strategies at 6-month intervals. Selected tumors are treated locally. Costs and clinical outcomes are discounted. Using baseline assumptions, incremental cost-effectiveness ratios (ICERs) for U/S, U/S plus AFP, and CT are $60,300/life-year saved (LY), $74,000/LY, and $101,100/LY, respectively. The most cost-effective strategy was dependent on the relative costs of each screening modality. U/S screening becomes the dominant strategy when the cost of an AFP test is decreased. Our results show that screening with CT is associated the greatest gain in life expectancy and greatest costs. U/S screening strategy is the preferred screening strategy based on the lowest ICER. Ultimately, costs of the screening modalities determine the most cost-effective strategy.

Operative parameters that predict the outcomes of hepatic transplantation.

BACKGROUND: A growing discrepancy between the number of patients awaiting liver transplantation and the number of organs available mandates the use of even marginal organ donors in whom there is major risk of suboptimal graft function. A comprehensive analysis of operative parameters on the outcomes of liver transplantation has not been reported. STUDY DESIGN: We analyzed the impact of 24 operative variables on the survival of 942 consecutive primary liver allografts performed at a single center from June 1992 through December 1997. Univariate and Cox proportional hazards analysis was used to identify those variables with independent prognostic significance in graft survival. Resource utilization for variables with multivariate significance was also analyzed. RESULTS: Of 12 intraoperative variables found to have significance in univariate analysis, three were significant by Cox multivariate analysis: 1) lack of immediate bile production by the graft intraoperatively, 2) platelet transfusion > or = 20 U, and 3) recipient urine output < or =2.0 mL/kg/h intraoperatively. Each of the three variables was associated with marked increases in hospital and Intensive Care Unit length of stay and hospital charges accrued during the admission for transplantation. CONCLUSION: We identified three operative parameters that predict a poor outcome after liver transplantation. The presence of these indicators suggests that early retransplantation should be considered. Early identification of grafts likely to have poor function might also provide an opportunity for therapeutic intervention to salvage graft function.

Conversion from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine is safe and cost-effective in patients receiving long-term prophylaxis to prevent hepatitis B recurrence after liver transplantation.

Recurrent hepatitis B infection after liver transplantation was previously frequent and associated with significant allograft failure and mortality. Recurrence rates of hepatitis B were improved with the use of passive immunoprophylaxis with hepatitis B immune globulin, and later, lamivudine monotherapy. Combination prophylaxis with intravenous hepatitis B immune globulin and lamivudine substantially decreased rates of hepatitis B recurrence, but intravenous administration of hepatitis B immune globulin was expensive and associated with significant adverse effects. In the current study, 59 patients receiving primary liver transplantation for chronic hepatitis B infection were prospectively followed up after converting from intravenous to intramuscular hepatitis B immune globulin in combination with lamivudine. All patients tolerated intramuscular hepatitis B immune globulin well. At a median follow-up of 511 days after conversion to intramuscular hepatitis B immune globulin, 58 of 59 patients (98.3%) were hepatitis B surface antigen-negative. Twenty-one patients (35.6%) required a median of one supplemental intravenous hepatitis B immune globulin infusion to maintain therapeutic antibody levels. Economic analysis showed an average cost-effectiveness ratio for combination intramuscular hepatitis B immune globulin plus lamivudine of $52,600 per recurrence prevented, which was far below the cost of lamivudine monotherapy and of intravenous hepatitis B immune globulin alone or in combination with lamivudine. These results suggest that intramuscular administration of hepatitis B immune globulin in combination with lamivudine offers a safe, effective, and cost-effective approach to preventing hepatitis B recurrence after orthotopic liver transplantation.