Joseph W. Markmann

Survival following liver transplantation from non-heart-beating donors

Objective:To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts. Summary Background Data:With the growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist. Methods:Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database. Results:NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26,856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications. Conclusions:Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.

Predicting outcome after liver transplantation: utility of the model for end-stage liver disease and a newly derived discrimination function1

Background. The Model for End-Stage Liver Disease (MELD) has been found to accurately predict pretransplant mortality and is a valuable system for ranking patients in greatest need of liver transplantation. It is unknown whether a higher MELD score also predicts decreased posttransplant survival. Methods. We examined a cohort of patients from the United Network for Organ Sharing (UNOS) database for whom the critical pretransplant recipient values needed to calculate the MELD score were available (international normalized ratio of prothrombin time, total bilirubin, and creatinine). In these 2,565 patients, we analyzed whether the MELD score predicted graft and patient survival and length of posttransplant hospitalization. Results. In contrast with its ability to predict survival in patients with chronic liver disease awaiting liver transplant, the MELD score was found to be poor at predicting posttransplant outcome except for patients with the highest 20% of MELD scores. We developed a model with four variables not included in MELD that had greater ability to predict 3-month posttransplant patient survival, with a c-statistic of 0.65, compared with 0.54 for the pretransplant MELD score. These pretransplant variables were recipient age, mechanical ventilation, dialysis, and retransplantation. Recipients with any two of the three latter variables showed a markedly diminished posttransplant survival rate. Conclusions. The MELD score is a relatively poor predictor of posttransplant outcome. In contrast, a model based on four pretransplant variables (recipient age, mechanical ventilation, dialysis, and retransplantation) had a better ability to predict outcome. Our results support the use of MELD for liver allocation and indicate that statistical modeling, such as reported in this article, can be used to identify futile cases in which expected outcome is too poor to justify transplantation.

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 hospitals 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.

Promotion of Allograft Survival by CD4+CD25+ Regulatory T Cells: Evidence for In Vivo Inhibition of Effector Cell Proliferation

Regulatory T cells preserve tolerance to peripheral self-Ags and may control the response to allogeneic tissues to promote transplantation tolerance. Although prior studies have demonstrated prolonged allograft survival in the presence of regulatory T cells (T-reg), data documenting the capacity of these cells to promote tolerance in immunocompetent transplant models are lacking, and the mechanism of suppression in vivo remains unclear. We used a TCR transgenic model of allograft rejection to characterize the in vivo activity of CD4+CD25+ T-reg. We demonstrate that graft Ag-specific T-reg effectively intercede in the rejection response of naive T cells to established skin allografts. Furthermore, CFSE labeling demonstrates impaired proliferation of naive graft Ag-specific T cells in the draining lymph node in the presence of T-reg. These results confirm the efficacy of T-reg in promoting graft survival and suggest that their suppressive action is accomplished in part through inhibition of proliferation.

Factors differentially correlated with the outcome of liver transplantation in hcv+ and HCV- recipients.

Background. Survival following liver transplantation for hepatitis C virus (HCV) is significantly poorer than for liver transplants performed for other causes of chronic liver disease. The factors responsible for the inferior outcome in HCV+ recipients, and whether they differ from factors associated with survival in HCV- recipients, are unknown. Methods. The UNOS database was analyzed to identify factors associated with outcome in HCV+ and HCV- recipients. Kaplan-Meier graft and patient survival and Cox proportional hazards analysis were conducted on 13,026 liver transplants to identify the variables that were differentially associated with outcome survival in HCV- and HCV+ recipients. Results. Of the 13,026 recipients, 7386 (56.7%) were HCV- and 5640 were HCV+. In HCV- and HCV+ recipient populations, five-year patient survival rates were 83.5% vs. 74.6% (P<0.00001) and five-year graft survival rates 80.6% vs. 69.9% (P<0.00001), respectively. In a multivariate regression model, donor age and recipient creatinine were observed to be significant covariates in both groups, while donor race, cold ischemia time (CIT), female to male transplants, and recipient albumin were independent predictors of survival of HCV- recipients. In the HCV+ cohort, recipient race, warm ischemia time (WIT), and diabetes also independently predicted graft survival. Conclusions. A number of parameters are differentially correlated with outcome in HCV- and HCV+ recipients of orthotopic liver transplantion. These findings may not only have practical implications in the selection and management of liver transplant patients, but also may shed new insight into the biology of HCV infection posttransplant.

Early kidney dysfunction post liver transplantation predicts late chronic kidney disease

Background. Acute and chronic renal dysfunction (ARD, CRD) are common complications after liver transplantation and are associated with poor outcome. Methods. We reviewed the results of 181 liver transplants performed in our institution between January 1, 1998 and December 31, 2000 in which the recipients were alive with good liver function at the end of the follow-up period (mean 2.7 years). Renal dysfunction was defined as a serum creatinine (Cr) greater than or equal to 2 mg/dL in both acute and chronic settings. Results. The incidence of ARD during the first posttransplant week was 39.2% (n=71), whereas late CRD occurred in 6.0% (n=11) of the patients by the end of the follow-up period. Among the variables we examined for association with CRD, five factors were found to be statistically significant in univariate analysis: pretransplant diabetes (PRTDM) (0.000), Cr greater than or equal to 2 during the first postoperative week (0.003), posttransplant diabetes (POTDM) (0.014), age greater than 50 (0.025), and tacrolimus level greater than 15 ng/mL at postoperative day 15 (0.058). In binary logistic regression analysis, PRTDM (odds ratio [OR]=5.7, 95% confidence interval [CI]) and early postoperative ARD (OR=10.2 95% CI) remained consistently significant. Nine of 11 patients with CRD also had a history of ARD during the first postoperative week. These patients progressed to CRD despite the fact that seven of nine had normalized their renal function by day 90 posttransplant. Conclusion. We suggest that a combination of events during the first postoperative week after liver transplant serve as a physiologic “stress test” for the kidneys. Patients who fail the test (peak Cr ≥2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD. In such cases, conversion to a less nephrotoxic regimen may be beneficial.

CD25+ Immunoregulatory CD4 T Cells Mediate Acquired Central Transplantation Tolerance

Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4+CD25+) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4+CD25− and CD4+CD25+ T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.

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.

Comparison of activation requirements and activation phenotype of allogeneic and xenogeneic rodent responses in vivo and in vitro

Background. Both discordant and concordant xenogeneic responses are dominated by humoral immunity. Recent advances in molecular engineering approaches may largely prevent rejection by means of this pathway, leaving the cellular arm of the immune response as the principal remaining barrier to successful engraftment. Methods. To characterize further the cellular response to xenogeneic tissues, we used the intracellular fluorescent marker CFSE (5-(and-6)-carboxyfluorescein diacetate succinimidyl ester) to track the mitotic record of T cells (and T cell subsets) after either xenogeneic or allogeneic activation in vitro or in vivo. Activation marker expression was monitored by simultaneous labeling with antibodies for either CD25 or CD134. Results. The in vitro and in vivo responses of Lewis lymphocytes were generally similar in magnitude and timing comparing activation with allogeneic or xenogeneic stimulators. However, the xenogeneic T cell precursor frequency was found to be markedly higher than that previously reported and were comparable to that seen in allogeneic responses. Xenogeneic responses were unique in the continued expression of activation markers in later division cycles. In addition, CD4 and CD8 T-cell proliferation was highly dependent on stimulator class II expression, highlighting the importance of CD4 T cells and the indirect pathway in the xenogeneic response. Conclusions. An unexpectedly high precursor frequency was detected for xenogeneic cellular responses in the rat anti-mouse combination and was comparable to that seen in allogeneic responses. Differences in xenogeneic versus allogeneic activation profiles exist that may result from the cellular pathways used for activation.