BACKGROUND: The systematic application of living-related and cadaveric, in situ split-liver transplantation has helped to alleviate the critical shortage of suitable-sized, pediatric donors. Undoubtedly, both techniques are beneficial and advantageous; however, the superiority of either graft source has not been demonstrated directly. Because of the potential living-donor risks, we reserve the living donor as the last graft option for pediatric recipients awaiting liver transplantation. Inasmuch as no direct comparison between these two graft types has been performed, we sought to perform a comparative analysis of the functional outcomes of left lateral segmental grafts procured from these donor sources to determine whether differences do exist. METHODS: A retrospective analysis of all liver transplants performed at a single institution between February 1984 and January 1999 was undertaken. Only pediatric (<18 years) recipients of left lateral segmental grafts procured from either living-related (LRD) or cadaveric, in situ split-liver (SLD) donors were included. A detailed analysis of preoperative, intraoperative, and postoperative variables was undertaken. Survival was estimated using the Kaplan-Meier method, and comparison of variables between groups was undertaken using the t test of Wilcoxon rank sum test. RESULTS: There were no significant differences in the preoperative variables between the 39 recipients of SLD grafts and 34 recipients of LRD grafts. The donors did differ significantly in mean age, ABO blood group matching, and preoperative liver function testing. Postoperative liver function testing revealed significant early differences in aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, prothrombin time, and alkaline phosphatase, with grafts from LRD performing better than those from SLD. SLD grafts also had significantly longer ischemia times and a higher incidence of graft loss owing to primary nonfunction and technical complications (9 vs. 2, P<0.05). However, six of these graft losses in the SLD group were because of technical or immunologic causes, which, theoretically, should not differ between the two groups. Furthermore, these graft losses did not negatively impact early patient survival as most patients were successfully rescued with retransplantation (30-day actuarial survival, 97.1% SLD vs. 94.1% LRD, P=0.745). In the surviving grafts, the early differences in liver function variables normalized. CONCLUSIONS: Inherent differences in both donor sources exist and account for differences seen in preoperative and intraoperative variables. Segmental grafts from LRD clearly performed better in the first week after transplantation as demonstrated by lower liver function variables and less graft loss to primary nonfunction. However, the intermediate function (7-30 days) of both grafts did not differ, and the early graft losses did not translate into patient death. Although minimal living-donor morbidity was seen in this series, the use of this donor type still carries a finite risk. We therefore will continue to use SLD as the primary graft source for pediatric patients awaiting liver transplantation.

Adult↗

PubMed2001

Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses.

BACKGROUND: We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection. METHODS: Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6). RESULTS: WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium. CONCLUSION: Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.

Amino Acid Sequence↗

PubMed2001

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.

Adult↗

PubMed2001

Evidence of T cell clonality in the infectious tolerance pathway: implications toward identification of regulatory T cells.

We have shown that a rare population of regulatory CD4+ T cells plays a key role in the acquisition of infectious tolerance in rat sensitized recipients of cardiac allografts pretreated with nondepleting anti-CD4 mAb. This study was designed to analyze the TCR Vbeta expression patterns in this transplantation model. First, we used Vbeta-specific RT-PCR to show that there was no differential usage of TCR Vbeta genes by T cells mediating rejection or tolerance. Indeed, graft-infiltrating lymphocytes expressed most of the 22 known rat TCR Vbeta genes in both recipient groups, suggesting unrestricted TCR Vbeta repertoire in alloreactive T cells. Then, we applied CDR3 spectrotyping of TCR beta-chain to assess the clonality of T cells at different anatomic sites. CDR3 size restriction, indicative of the presence of T cell clones, was observed in graft-infiltrating lymphocytes but not in draining lymph nodes or spleen of tolerant hosts. Consisent with the clonal expansion, T cells in tolerated grafts exhibited the memory phenotype at a much higher percentage as compared with peripheral lymphoid organs. Moreover, in tolerated graft-infiltrating lymphocytes, the CD3 size restriction occurred in limited Vbeta gene families, with Vbeta8.1 and Vbeta18 most frequently detected. Hence, T cells at the graft site of tolerant recipients contain T cell clones expressing selective Vbeta genes. This phenotypic characteristics of the tolerogenic GILs may potentially be used as a novel marker to identify operational regulatory T cells in organ allograft recipients.

Animals↗

PubMed2001

A novel iron chelator in combination with a P-selectin antagonist prevents ischemia/reperfusion injury in a rat liver model.

BACKGROUND: Hepatic ischemia/reperfusion (I/R) injury is associated with early and late graft failure after liver transplantation. A major mechanism is leukocyte adhesion to endothelium followed by release of reactive oxygen intermediates. We examined whether desferriexochelin 772SM (D-Exo), a lipid soluble iron chelator that prevents hydroxyl radical formation, can enhance the capacity of recombinant P-selectin glycoprotein ligand immunoglobulin (rPSGL-Ig), a glycoprotein that binds to P-selectin and inhibits neutrophil adhesion, to protect against I/R injury in an ex vivo rat liver model. METHODS: Rat livers were harvested and stored for 6 hr at 4 degrees C in University of Wisconsin solution and then perfused with oxygenated whole blood for 2 hr. Three groups were studied (n=6 rats/group): an untreated control group; a group that received 0.4 mg/kg rPSGL-Ig intraportally at the time of harvest; and a group that received 0.4 mg/kg rPSGL-Ig plus 1 micromol D-Exo intraportally both at the time of harvest and at the onset of reperfusion. Liver portal venous blood flow was assessed during perfusion, and at the end of each experiment, liver samples were collected for blinded histological evaluation and biochemical analyses. RESULTS: Livers treated with D-Exo + rPSGL-Ig had significantly higher blood flow than livers treated with rPSGL-1Ig alone (P<0.05), and both treatment groups had higher blood flow than controls (P<0.001). Production of carbonyl proteins, a protein oxidation product, was significantly reduced in the D-Exo + rPSGL-1Ig group (P<0.02 vs. controls), but not in the rPSGL-Ig alone group. Total reduced glutathione was significantly higher than controls in the D-Exo + rPSGL-Ig group (P<0.001 vs. controls), but not in the rPSGL-Ig alone group, indicating less oxidative stress in the D-Exo-treated group. Production of malondialdehyde, an index of lipid peroxidation, was significantly less than controls in both treatment groups (P<0.03). Histopathological findings paralleled these results with Banffs scores of 3.3+/-0.5, 1.8+/-0.4, and 1.3+/-0.5 in the control, rPSGL-Ig alone, and D-Exo plus rPSGL-Ig groups, resp. CONCLUSION: rPSGL-Ig provides partial protection against I/R injury to ex vivo rat livers; however, the addition of D-Exo substantially increases protection by reducing oxidative injury. These findings may have clinical relevance in preventing the consequences of I/R injury after liver transplantation.

Animals↗

PubMed2001

Outcome after intestinal transplantation: results from one center's 9-year experience; discussion 1031-2.

HYPOTHESIS: Outcomes after intestinal transplantation have improved during the past decade with refinements in surgical techniques as well as advances in immunosuppression and antimicrobial therapy. DESIGN: Retrospective analysis. SETTING: Tertiary care medical center, August 1991 through December 2000. PATIENTS: Adult (5) and pediatric (12) patients with intestinal failure. All developed complications from long-term total parenteral nutrition therapy. Median age was 8.6 years and median weight was 22 kg. INTERVENTIONS: Primary intestinal transplantation with (n = 14) or without (n = 3) the liver. MAIN OUTCOME MEASURES: Patient and graft survival, viral infections, rejection, and nutritional autonomy. RESULTS: Twenty-one intestinal grafts were transplanted into the 17 recipients. All donors were cadaveric and were matched by ABO blood group and size. Patient survival at 1 and 3 years was 63% and 55%, respectively. Death-censored graft survival at 1 and 3 years was 73% and 55%, respectively. There were 1.5 acute cellular rejection episodes per graft and 3 grafts were lost to rejection. Incidences of infection with the Epstein-Barr virus and cytomegalovirus were negligible with aggressive prophylaxis and preemptive therapy. Nutritional autonomy was achieved in 69% of grafts surviving more than 30 days after intestinal transplantation. CONCLUSIONS: Intestinal transplantation is now the standard of therapy for patients with intestinal failure and complications resulting from total parenteral nutrition. Outcomes have markedly improved since initiation of the program. Aggressive immunosuppression as well as prophylaxis and preemptive antiviral therapy have led to low incidences of acute cellular rejection, Epstein-Barr virus, and cytomegalovirus. Finally, nutritional autonomy can be achieved after successful intestinal transplantation.

Adolescent↗

PubMed2001

Technical challenges of hepatic venous outflow reconstruction in right lobe adult living donor liver transplantation.

A right lobe graft that is drained by the right hepatic vein (RHV) is obtained by transecting the liver on the right side of the middle hepatic vein (MHV). On occasion, a small RHV that only drains a portion of the right lobe, with the predominant outflow achieved by the MHV, is encountered. If such variation is not recognized while performing right lobe liver transplantation and the RHV only is used for reconstruction, venous outflow obstruction with subsequent graft congestion and eventual graft failure will occur. Additionally, preservation of the main MHV and its branch drainage of the left lobe is crucial to avoid outflow blockage to the remaining segment 4 in the donor. We report 4 cases showing a variant type of small RHV and large MHV branch that drain not only segments 5 and 8, but also segments 6 and 7. These variations were simultaneously associated with a large-caliber inferior RHV that also required reconstruction. The methods used to diagnose such anatomic variations and the techniques for reconstruction in the donor and recipient are described.

Adult↗

PubMed2001

Liver transplantation for cholangiocellular carcinoma: analysis of a single-center experience and review of the literature.

Cholangiocellular carcinoma (CCC) is a biliary malignancy that frequently presents in advanced unresectable stages. The role of liver transplantation (LT) as a surgical modality is unclear. The goal of this study is to evaluate outcomes of patients with CCC undergoing LT. A retrospective analysis of all patients undergoing LT was undertaken. Only those patients with the pathological diagnosis of CCC were included on the study. Patients were divided into two groups based on primary tumor location: extrahepatic (EH)-CCC and intrahepatic (IH)-CCC. The Kaplan-Meier method was used to calculate overall and recurrence-free survival. Log-rank analysis was used to determine the significance of prognostic variables. Twenty-five patients were identified: 9 patients with EH-CCC (5 patients, Klatskin-type; 2 patients, the middle third; and 2 patients, the distal third) and 16 patients with IH-CCC. Mean age was 47.1 +/- 10.6 years. There were 14 men and 11 women. Tumor stage was local (stages I and II; n = 9) or advanced (stages III and IV; n = 16). Overall and disease-free survival rates were 71% and 67% at 1 year and 35% and 32% at 3 years, respectively. Analysis of variables showed statistically significant improved outcomes (P < .05) for the absence of contiguous organ invasion at LT, small tumor size, and single tumor foci. This study indicates that early survival after LT for CCC is acceptable. Three-year disease-free survival is achieved in approximately 30% of patients. These outcomes can be improved by applying strict selection criteria based on prognostic variables identified in this study.

Adult↗

PubMed2001

Technical and logistical considerations of in situ split-liver transplantation for two adults: Part I. Creation of left segment II, III, IV and right segment I, V-VIII grafts.

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Adult↗

PubMed2001

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.

Adult↗

PubMed2001

Heme oxygenase-1 overexpression protects rat livers from ischemia/reperfusion injury with extended cold preservation.

This study analyzes the effects and mechanisms of heme oxygenase-1 (HO-1)-mediated cytoprotection in rat livers exposed to cold preservation. In the first series, rats were pretreated with cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP), HO-1 inducer and antagonist, respectively. Livers were stored at 4 degrees C for 24 h, and then perfused ex vivo for 2 h. Livers pretreated with CoPP had significantly higher portal venous blood flow and increased total bile production, as compared with the ZnPP group. This correlated with histologic (Banff) criteria of hepatocyte injury/liver function. In the second series, rat livers were stored at 4 degrees C for 24 h or 40 h, and then transplanted into syngeneic recipients. After 24 h of preservation, 80% of rats bearing CoPP-pretreated liver grafts survived 21 days (vs. 50% in controls). After 40h of cold preservation, liver transplant survival at day 1, 7 and 21 for the CoPP group was: 100%, 71% and 57%, respectively (vs. 50%, 50% and 33% in controls). This correlated with improved hepatic function/histologic (Suzuki) criteria of hepatocyte injury after HO-1 overexpression (immunohistology/Western blots) by infiltrating macrophages. This study documents the potential utility of HO-1-inducing agents in preventing ischemia/reperfusion injury resulting from prolonged storage of liver transplants.

Animals↗

PubMed2001

A cost-effectiveness analysis of biliary anastomosis with or without T-tube after orthotopic liver transplantation.

Biliary reconstruction continues to be a major source of morbidity following orthotopic liver transplantation. We wished to determine if choledochocholedochostomy without a T-tube was associated with fewer biliary complications and was less costly than choledochocholedochostomy with a T-tube. A retrospective cohort study of patients who underwent liver transplantation was performed. Patients were stratified into two groups: group I had bile duct reconstruction with T-tube and group II did not have a T-tube. The results were interpreted on an intention-to-treat analysis. We identified 147 adult patients who underwent initial liver transplantation. There were 76 patients in group I and 71 patients in group II. There were no statistical differences between the two groups regarding underlying cause of liver disease, patient age, gender or United Network for Organ Sharing status. As the decision to use a T-tube was made at the time of surgery, the two groups may not be strictly comparable. The mean hospital stay was longer in group I (31.1 +/- 27.9d) than in group II (18.8 +/- 15.5d) (p = 0.001). Biliary complications were statistically more frequent in patients from group I patients (25/76, 32.9%) than in patients from group II (11/71, 15.5%) (p = 0.01). There was a trend for the costs associated with diagnostic and therapeutic procedures for the management of biliary complications to be greater for group I than for group II, although this was not statistically significant (p = 0.235). Our study suggests choledochocholedochostomy without T-tube reconstruction is the preferred strategy for biliary reconstruction in orthotopic liver transplantation. It is not only associated with fewer biliary complications, but also less costly than using choledochocholedochostomy over a T-tube. Randomized prospective studies are needed to confirm our results.

Anastomosis, Surgical↗