Sunday Poster Sessions, October 29, 2006

Immunosuppression, Outcomes, Complications

 

 

576. MULTICENTER RANDOMIZED HEPATITIS C (HCV) - THREE TRIAL POST LIVER TRANSPLANTATION (OLT): TWO-YEAR INTERIM REPORT.  C. G.

Fasola; T. G. Heffron; L. Sher; D. Douglas; R. Brown; J. Ham; L. Teperman; M. Hanaway; D. Eckhoff; K. Washburn; M. Millis; J. Roberts; M. Charlton; P. Baliga; T. Pruett; B. Koneru; E. Pomfret; M. Abecassis; G. B. Klintmalm.

 

Aims:  

To assess the efficacy and safety of steroid (Pred)-free immunosuppression (IS) with daclizumab (DAC), tacrolimus (TAC) and mycophenolate mofetil (MMF) to minimize acute cellular rejection (ACR), HCV recurrence (HCVR) and adverse events post OLT.

 

Methods: 

Ongoing open label, prospective, multicenter study involving 312 adult HCV-OLT recipients randomized pre-OLT (1:1:2) to three IS regimens (see Results). Laboratory data and liver histology (local pathologists) done when clinically indicated and, by protocol, at 90, 365 and 730 days. ACR graded by Banff classification. HCVR staged by according to Batts and Ludwig. Primary endpoints: clinically significant ACR (Grade 2 + RAI 4) and/or HCVR (Stage 2 by day 365 and/or stage 3 by day 730 or Grade 3 at any time). Significant statistics: p ≤ 0.05* (Fishers exact test).

 

Results:  

For this abstract, 166 patients were evaluable for 2-year endpoints: Arm 1 (n=42): TAC+Pred; Arm 2 (n=42): TAC+Pred+MMF; Arm 3 (n=82): 3-dose DAC+TAC+MMF (steroid-free). Available data: ACR: 165 (99%) and, HCVR: 155 (93%). Data reported for Arms 1, 2, 3, respectively. Rejection-free incidences: 85%, 89% and 91%; mild ACR: 3 (33%), 4 (50%) and 10 (63%); moderate ACR: 5 (56%), 1 (13%) and 6 (37%); severe ACR: 1 (11%), 3 (38%) and 0 (0%) patients (p < 0.05: 2 vs. 3*). HCV recurrence-free incidences: 11%, 8%, and 20%; moderate HCVR: 2 (40%), 6 (46%) and 8 (50%); severe HCVR: 1 (20%), 2 (15%) and 2 (12%). More aggressive HCVR (greater than 1 stage increase between days 90 and 365 biopsies) progression was observed in Arm 1 (9, 32%) vs. 2 (6, 25%) and 3 (15, 23%). Cox proportional hazards model showed ACR is an independent risk factor for HCVR (HR 8.22, p=0.003). Quantitative HCV-RNA levels similar in all groups as were the incidences of post-transplant diabetes mellitus (PTDM), malignancies, infections, hypertension (HTN) and hyperlipidemia. Graft survival: 71%, 77% and 76% (NS). Patient survival: 75%, 77% and 78% (NS). Similar death causes: HCVR (4, 1, 3), respiratory (0, 2, 5), malignancy (1, 4, 1), sepsis (2, 1, 3); others (3, 1, 4).

 

Conclusions:  

This 2-year interim report suggests that steroid-free IS with DAC/TAC/ MMF is safe and effective, with low incidences of ACR and severe ACR. ACR appears to be a presumptive factor in HCVR. At present doses, steroids seem to be subordinate compared to other IS medications or comorbidities as a risk factor for PTDM or HTN. Updated 2-year data will be presented at the time of the meeting.

 


577. Rates of Special Case MELD Exception Awards and Liver Transplant Waiting List Death Vary by UNOS Region. 

C. K. Argo; C. L. Berg; G. J. Stukenborg; P. G. Northup.

 

Background/Aims:

Introduction of MELD exceptions raised concern about possible “gaming” of the liver allocation system. Request and approval rates for exceptions for reasons such as refractory ascites, termed “special case” exceptions (SCE), vary widely by region. We aimed to confirm regional differences in rates of SCE requests and approvals and to examine correlations of rates of SCE and waiting list deaths (WLD).

 

Methods:

81434 patients were included from the UNOS database of adult OLT candidates during the MELD era (run date 4/24/06). Patients who underwent LDLT, repeat or multiorgan transplant, or who received an HCC-exception were excluded. Rates of SCE requests and approvals and WLD rates were compared using ratios standardized by regional adult population. Organ shortage by region was estimated using the ratio of the number of waiting list patients with MELD > 15 at run date divided by offered organs in 2005. Pearson correlation coefficients (PCC) were calculated to quantify degrees of association between variables across regions.

 

Results:

There was a wide range of regional variation in SCE request and approval rates, WLD rates, and standardized organ shortage ratios (Table). The highest per capita rate of WLD was 64.3/million adults with standardized mortality ratio (SMR) of 2.26 (region 9) and lowest was 9.18/million with SMR of 0.32 (region 6). Regions with higher rates of SCE approvals also had higher rates of WLD (PCC=0.89, p=0.002). The severity of organ shortage varied with WLD in a similar pattern (PCC=0.84, p=0.012), but there was much less association between SCE approval rates and organ shortage (PCC=0.6, p=0.05) and between SCE approval rates and mean lab-based MELD at transplant, another indicator of organ shortage (PCC=0.38, p=0.25).

 

Conclusions:

There is clear regional variation in patterns of requesting and approval of special case MELD exceptions for liver transplant. The differences in the degree of correlation between WLD rates, SCE approval rates, and organ shortage measures, however, suggest that observed rates of SCE approval are not reliant solely on degree of regional organ shortage but also vary due to basic regional differences in philosophy concerning awarding SCE for individual patients. These regional differences likely represent an area of inconsistency in the application of the MELD allocation system that may affect WLD rates.

 


579. Effect of gender mismatch on acute cellular rejection and graft failure in liver transplant recipients. 

M. K. Oh; S. Colquhoun; F. F. Poordad; T. T. Tran.

 

Background:

Previous studies have shown that gender mismatch between liver transplant donor and recipient, in particular female donor to male recipient, may be associated with decreased graft and patient survival. While the mechanism for this is unclear, an increase in acute cellular rejection (ACR) due to immunologic differences in gender could play a role.

 

Aims:

Determine the effect of donor and recipient gender on incidence of acute biopsy proven rejection as well as graft failure.

 

Methods:

Retrospective analysis was done on deceased donor liver transplants performed at Cedars-Sinai Medical Center from 2000-2005. Recipient age, gender, race, type of liver disease, immunosuppression, peak aminotransferases, and liver biopsy data was collected, along with donor age and gender. Graft failure was defined as patient death or retransplantation.

 

Four donor/recipient gender pairs were evaluated: female to female (F/F), male to female (M/F), female to male (F/M), and male to male recipient (M/M). ACR was also evaluated in three specific gender subsets: gender matched vs. gender mismatched; female recipient vs. male recipient; and female donor vs. male donor, using Fischer’s exact test and logistic regression.

 

Results:

A total of 99 deceased donor liver transplants were analyzed. Sample sizes of donor/recipient pairs yielded: F/F=17, M/F= 18, F/M= 26, M/M= 38. Overall incidence of ACR at 1 year was 37%. Recipient age, race, aminotransferases, and donor age did not differ amongst the groups. Incidence of ACR was similar across all four donor/recipient combinations, p=NS: F/F (47%), M/F (39%), F/M (35%), M/M (34%). ACR occurred in 21 of 55 gender matched pairs (37%) and 16 of 44 gender mismatched pairs (36%), p=NS. In the donor gender subset, ACR occurred in 17 of 43 transplants with a female donor (40%) and 20 of 56 transplants with a male donor (36%), p=NS. In the recipient gender subset, ACR occurred in 15 of 35 transplants with female recipients (43%) and 22 of 64 transplants with male recipients (34%), p=NS. Multivariable analysis of gender, race, recipient and donor age, aminotransferases, etiology of liver disease (HCV, PBC, PSC, AIH) failed to reveal gender mismatch as an independent predictor of ACR. Overall incidence of graft failure at 1 year was 15%, occurring in 6 of 55 gender matched pairs (11%) and 9 of 44 gender mismatched pairs (20%), p= NS.

 

Conclusion:

Despite previous reports showing decreased graft and patient survival in female donor to male recipient deceased donor liver transplants, ACR was not observed more frequently in gender mismatched donor/recipient pairs, suggesting another possible mechanism of graft injury.

 


580. Effects on survival of listing vs not listing patients with low MELD scores. 

J. Rai; M. S. Campbell; E. Kozin; J. Markmann; K. Olthoff; A. Shaked; K. Reddy.

 

Introduction:

The survival benefit of listing cirrhotic patients with low MELD for orthotopic liver transplantation (OLT) is not well known.

 

Aim:

Among patients with low MELD scores, we sought to compare survival between patients who were listed and not listed for OLT.

 

Methods:

We identified 1,102 patients evaluated for OLT at our institution (2002-2004). After excluding patients with hepatocellular carcinoma, active alcohol and substance abuse, medical contraindications to OLT, and living donor candidates, we identified 240 patients with MELD scores ≤ 12. 118 subjects were listed and 122 were not listed for OLT. We obtained clinical data (age, race, gender, etiology, diabetes, coronary artery disease, hypertension, hepatic decompensations, presence of TIPS, and history of drug and alcohol use) from our comprehensive, prospectively maintained transplant database. Mortality data were obtained from the social security death index. We compared survival between the two cohorts using Kaplan-Meier survival analysis and Cox proportional hazard modeling.

 

Results:

Among the 122 patients not listed, 69 (56%) were considered too early for listing, and 51 (42%) did not complete listing evaluation. Listed patients tended to have a higher MELD score than those not listed (10.1 +/- 1.5 vs. 9.3 +/- 1.9, p=0.001). Furthermore, listed patients more often had ascites (93 (78%) vs. 66 (54%), p=<0.001) and were more often white (109 (92%) vs. 99 (81%), p=0.01) and male (83 (70%) vs. 64(52%), p=.005). The average follow-up time was 22.6 +/- 11.3 months and was similar in both cohorts (p=0.45). Listing for OLT was associated with a 0.69 (0.36-1.35, p=0.28) hazards ratio for mortality. Adjusting for MELD, ascites, and hepatic encephalopathy, the hazards ratio for mortality in those listed for OLT was 0.45 (0.23-0.90, p=0.026), which was statistically significant. Restricting analysis of not listed patients to only those who were considered too early for liver transplant (well controlled or no hepatic decompensations) did not substantially alter this point estimate. After progressively restricting MELD threshold for study inclusion from 12 to 8, we could not identify a minimal MELD threshold at which a survival difference between listed and not listed patients was lost.

 

Conclusion:

a)     listing patients with low MELD is associated with a statistically significant survival advantage.

b)    we could not identify a minimum MELD to achieve a survival benefit

c)     We speculate that the survival advantage results from additional close follow-up provided to listed patients.

 


581. Impact of MELD Allocation on Post-OLT Renal Failure: Analysis of the UNOS Database. 

D. Batty; N. R. Krieger; Y. Yu; S. Ray.

 

Introduction:

For patients receiving non-renal solid organ transplants, post-transplant renal failure rates are highest in OLT (OLT) recipients. The impact of the MELD allocation system in 2002 has had an unknown impact on this rate of renal failure. With renal function included as one of the three variables in the MELD formula, implementation of this allocation policy could have had the inadvertent impact of greater incidence of post-OLT renal failure. An analysis of the UNOS database for OLT recipients was performed to evaluate this possibility.

 

Methods:

We used the Standard Transplant Analysis and Research (STAR) data from the United Network for Organ Sharing (UNOS) to examine the incidence of renal failure (RF) observed in patients who had liver transplant (OLT) during 1998 - 2006. All patients in the database with OLT between 1/1/1998 and 6/30/2006 were selected. Patients with an OLT before 2/28/2002 were grouped as the pre-MELD cohort, and the remaining patients were grouped as post-MELD cohort. Patients with renal failure were identified as someone who was listed or received a kidney transplant. A minimum follow-up period of 18 months after the liver transplant was required for patients without observed renal failure to be included in the analysis. Rates of renal failure and LKTx were computed at 6, 12, and 18 months post-OLT for the pre-MELD and post-MELD cohorts, and compared using Chi-square test.

 

Results:

A total of 22,796 patients with a mean age of 45.9 (SD=17) years were identified for the analysis, of whom 14,280 (63%) were male. Of the total, 14,903 (65%) patients were classified into the pre-MELD cohort and 7,893 (35%) patients to the post-MELD cohort. The 6-month, 12-month, and 18-month post-OLT incidence of observed renal failure in the pre-MELD cohort were 3.4%, 3.7%, 3.9% respectively. The corresponding 6-month, 12-month, 18-month incidence rates in the post-MELD cohort were 12.8%, 13.6%, 14.0% respectively (p<0.0001 for all 3 differences). The incidence of dual LKTx was 450 (3%) vs. 949 (12%) in the post-MELD cohort (p<0.0001).

 

Summary:

An analysis of the UNOS database for the effect of the MELD allocation policy change for OLT revealed a dramatic increase in the number of patients with renal failure post- OLT. This was primarily driven by a dramatic increase in the number of concomitant LKTx performed. This could result in increased competition between patients awaiting OLT and KTx for a fixed number of kidneys. This would likely result in a significant increase in waiting time for patients listed for KTx. Strategies to address renal failure in OLT are needed to reduce the incidence of post-OLT renal failure.

 


582. Randomized Prospective Study Suggesting Worse Outcomes For Complete Steroid Avoidance in Liver Transplantation. 

A. Magar ; S. J. Pelletier; M. J. Englesbe; T. H. Welling; W. N. Al-Holou; R. J. Fontana; J. D. Punch.

 

Introduction:

Steroids are a mainstay in liver transplantation (OLT) for induction and maintenance immunosuppression but are associated with significant adverse effects.

 

Aims:

While prior studies have successfully limited the use of steroids, whether complete steroid avoidance will improve outcomes remains unclear.

 

Methods:

Patients undergoing OLT between 6/02 and 4/05 were entered into a prospective, randomized trial of complete steroid avoidance and followed until 6/06. Recipients received either standard therapy (tacrolimus, mycophenolate, steroid induction/maintenance; N=50) or complete steroid avoidance (standard therapy without steroid induction/maintenance; N=50). Clinically suspected rejection was confirmed by biopsy and treated with pulse steroids. Donor and recipient characteristics and outcomes were compared on an intention to treat basis.

 

Results:

The mean follow up of all recipients was 774±40 days. Fifteen (23%) recipients randomized to no steroids ultimately did receive steroids for a clinical indication. Recipient characteristics (age, race, gender, MELD score, diagnosis, and comorbidities) and donor characteristics (age, race, gender, and ischemic times) were similar between groups. No difference was observed in the incidence of diabetes or hypertension prior to or after OLT although the steroid group required more antihypertensives at 1 year (0.86±0.15 vs. 0.51±0.10 meds per patient, p=0.05). While the incidence of acute and chronic renal failure was similar, those not receiving steroids had a higher serum creatinine at 6 months (1.60±0.14 vs. 1.24±0.11 mg/dl, p=0.05) and required a longer time on hemodialysis (257±85 vs. 50±31 days, p=0.03) There was no difference in the incidence of acute or chronic rejection. The incidence of recurrent HCV was similar between the steroid avoidance group and standard therapy (56% vs. 43%, p=0.33) but increased graft fibrosis at 1 year was present for those not receiving steroids (3.3±0.4 vs. 1.8±0.4 Ishak score, p=0.02). While early (1 and 2 year) survival rates were similar, comparison of 3 year patient and graft survival rates demonstrated a trend toward decrease survival in the steroid avoidance group (62.5% vs. 81.6%, p=0.13; 60.6% vs. 81.6%, p=0.07; respectively).

 

Conclusion:

Complete steroid avoidance provides liver transplant recipients with minimal benefit, while demonstrating a concerning trend toward increased graft loss, recipient death, and accelerated allograft fibrosis related to recurrent HCV. These data suggest that at least a short course of steroids should be used following OLT.

 


583. MYCOPHENOLATE MOFETYL (MMF) MONOTHERAPY IS AN ATTRACTIVE STRATEGY IN LIVER TRANSPLANT RECIPIENTS WITH SEVERE SIDE EFFECTS OF CALCINEURIN INHIBITORS (CNI). 

S. Dharancy; C. Sammartino; A. Hulin; N. Declerck; A. Iannelli ; P. Mathurin; E. Boleslawski; J. Gugenheim; F. Pruvot.

 

Introduction:

CNI are associated with severe side-effects such as chronic renal failure (CRF). Most of transplant centers decrease CNI doses (sparing strategy) in pts with CNI-induced toxicity (CIT). However it is not sufficient to improve renal function in all pts, therefore, CNI withdrawal and MMF monotherapy has been evaluated in small cohort-size studies which reported 0 to 60% risk of acute rejection.

 

Aim:

to evaluate the results of MMF monotherapy in pts who presented severe CIT.

 

Methods:

We identified all pts treated with MMF monotherapy for severe CIT. 3 periods were considered: 1) period with usual dose of CNI during which CIT has developed, 2) period of CNI sparing strategy and 3) period of MMF monotherapy. The following variables were collected: parameters of liver graft function (prothrombin time, albumin, bilirubin, γGT, ALT, AST) and renal function (calculated creatinine clearance: CrCl). Liver graft and renal functions were the two end-points. Statistical analysis used paired-T tests (Wilcoxon and T tests).

 

Results:

52 pts (9F, 43M, mean age: 57 yrs) were treated with MMF monotherapy. MMF was introduced at a mean of 67 months after liver transplantation (LT) and the mean time of follow-up during MMF monotherapy period was 42 months. The reasons for being treated with monotherapy were CRF in 88% and metabolic disorders in 12% of cases. Indications for LT were 31% alcoholic cirrhosis, 31% HCV cirrhosis, 21% HCC, and 13.5% for other reasons. In term of liver graft function, mean bilirubin, albumin, prothrombin time and γGT did not change significantly between the three periods. Mean AST and ALT decreased from 72 and 73 IU/L to 49 and 40 IU/L (p=0.01 and 0.006 respectively) during the sparing period and to 37 IU/L and 34 IU/L (ns) during the monotherapy period. Only 2 pts experienced acute rejection during MMF monotherapy (incidence of 4%) leading to CNI introduction. Seven deaths were recorded (myocardial infarction, sepsis shock, recurrent alcoholic cirrhosis and cholangiocarcinoma). In term of renal function in pts who developed CRF (n=46), CrCl decreased significantly from 90.1 to 50.4 mL/min during the first period (p<0.000001), remained unchanged during the sparing period (50.4 to 43.7 mL/min, p=0.8) and increased significantly from 43.7 to 50.2 mL/min (p=0.02) during the MMF monotherapy period. Mean variation of CrCl during monotherapy period was +6,6 ml/min (mean gain of 15,4%). Five pts (11%) required dialysis despite CNI withdrawal.

 

Conclusions:

This study showed that MMF monotherapy prevents subsequent CRF without any sign of major graft dysfunction. Further studies are warranted to confirm that MMF monotherapy is an attractive strategy in liver recipient pts with CIT.

 


587. Liver Transplantation for Hepatocellular Carcinoma: Validation of the Milan Criteria using the UNOS database. 

M. Jatoi; S. Puhl; V. Thyagarajan; S. Pelletier; J. Magee; P. Jeffery; F. J. Robert; L. S. Anna; J. Marrero.

 

Introduction:

Liver transplantation (OLT) for hepatocellular carcinoma (HCC) has been shown to be effective if the Milan criteria are applied. Our aim was to evaluate the effectiveness of OLT for HCC in the United States.

 

Methods:

We analyzed the UNOS database since 1998 for all patients listed for HCC. Demographic, laboratory, clinical, and tumor characteristics were obtained at the time of listing. Kaplan-Meier analysis was performed from the time of listing in an intent-to-treat analysis, up to a post-OLT follow up in December 2005.

 

Results:

Since 1998, 7365 patients with HCC were listed for OLT, of these 5106 (69%) were transplanted, 1435 (20%) were removed due to death or tumor progression, and 824 (11%) removed due change in center or lost to follow up. The median waiting time for transplant was 90 days and median time before dropping out was 187 days. 66.3% of patients were listed after the MELD exception was implemented, leading to a lower dropout rate than in the pre-MELD era (9% vs. 19%, p<0.0001). The 1- and 5-year survival for all patients listed for HCC was 81% and 48%, respectively. For patients meeting Milan criteria the 1- and 5- year survival from listing was 86% and 51%, respectively, and for those exceeding the Milan criteria but meeting the expanded UCSF criteria the 1- and 5-year survival was 74% and 16% respectively (p<0.0001 Milan vs. UCSF, Figure). Patients meeting Milan at listing still had a better survival when only evaluating patients that underwent transplant. The dropout rate for those meeting Milan at listing was lower than those exceeding Milan (9% vs. 17%, p<0.0001).

 

Conclusion:

About 20% of patients will dropout from the waiting list due to death or tumor progression. OLT for HCC is effective but the greatest benefit belongs to those that meet Milan criteria. The UNOS data do not support expanding the criteria for transplanting HCC.

 

 


589. Non-standard livers to liver transplant candidates: a fatal combination in liver transplantation. 

A. W. Avolio; S. Agnes; A. Gasbarrini; E. Nure; M. Siciliano; L. Zileri dal Verme; R. Gaspari; M. Castagneto.

 

Background:

The Model for End-stage Liver Disease (MELD) has been adopted by OPTN (Organ Procurement and Transplantation Network) in the 2002 as the standard priority rule for the liver transplantation (LTx) waiting list.

 

Aim:

Aim of the present study is the evaluation using Kaplan-Meier life tables and Cox regressions analysis of graft survivals after liver transplantation in relation to MELD score and to donor characteristics (standard donor vs non-standard donor).

 

Materials and Methods:

MELD and PELD scores of 244 consecutive grafts were retrospectively calculated. The MELD score was calculated for 230 adult cases (age 12-65). The PELD score was calculated for 14 pediatric cases (age 1-11). All stage II HCC cases where classified as MELD 24. No other correction for the etiology of liver disease was performed. Grafts used for re-LTx were not included. Cases were categorized according to the MELD score levels. We retrospectively identified 3 categories: Low MELD (scores <12, N=60); Intermediate MELD (scores between 12 and 24, N=155); High MELD (scores ≥25, N=29). All pts were transplanted using deceased donors (DD). Grafts were categorized also according to donor quality: standard livers (N=188), vs non-standard livers (N=53). Non-standard livers were identified by age >=60, or at least by 2 of the following conditions: a) severe hemo-dynamic instability, b) ultrasound evidence of steatosis, c) levels of Na >=150 mEq/L, d) period of ventilatory support >7 days.

 

Results:

MELD scores of candidates transplanted using standard livers (18.4±6.9) were similar to MELD scores of candidates transplanted using non-standard livers (18.2±7.1). In standard livers, the 6-month graft survival (GS) for the low, intermediate and high MELD classes were 82%, 79% and 78% respectively; differences did not reach a statistical significance. In non-standard livers, the 6-month GS for the low, intermediate and high MELD classes were 90%, 61% and 43%, respectively; differences between low MELD class and both intermediate and high MELD classes were significant (p<0.05). Beside donor quality (χ2=6.424 p=0.011), Cox regression analysis identified 2 independent predictors of graft survival: 1. donor age (χ2=6.005, p=0.014); 2. recipient creatinine (χ2=6.005, p=0.003).

 

Conclusions:

Following the different survival figures obtained for each MELD class at different levels of donor quality, we strongly suggest to avoid the use of non-standard livers for patients with high MELD scores (≥24). Nevertheless, we are indeed in favour of continuing the use of non-standard livers for patients with MELD score <25.

 


590. Post-Transplant Ascites Typically Occurs in the Absence of Significant Fibrosis. 

B. Y. Lan; G. M. Landry; V. O. Tan; A. Bostrom; S. Feng.

 

Introduction:

Ascites (ASC) after liver transplantation (tx) is uncommon but causes substantial morbidity and mortality. Unlike pre-tx ASC which occurs in the setting of cirrhosis, post-tx ASC can occur in the absence of significant fibrosis. We identified risk factors for post-tx ASC and reviewed liver biopsies (bxs) to determine fibrosis stage (st) and characterize histopathology.

 

Methods:  

Records of 372 adult liver txs performed from 1/98 to 12/02 at a single large center were reviewed to find recipients with clinically significant post-tx ASC. Logistic regression identified donor, recipient (R), and tx risk factors for ASC. A pathologist scored all allograft bxs during ASC episodes.

 

Results:  

Of 372 adult liver txs, 23(6.2%) developed post-tx ASC: 18/173(10.4%) of HCV txs and 5/199(2.5%) of non-HCV txs. Logistic regression models identified 4 independent risk factors for ASC (Table 1): R female gender, HCV disease, grade 3 pre-tx ASC, and cold ischemia time ≥ 8 hours. The 23 txs had 25 ASC episodes; 24/25 had allograft bxs. The majority, 17/24 (71%) had fibrosis st ≤2(15=st 0/1; 2=st 2); 7/24 (29%) had fibrosis st ≥3. Bxes without significant fibrosis did not exhibit distinctive parenchymal or vascular histopathology (Table 2). ASC in the absence of significant fibrosis occurred earlier after tx, at a median of 196.5 days (range 13-1174 days) versus 932 days (range 574-1477 days); p=.002. At the time of ASC diagnosis, renal function for those with and without significant fibrosis were comparable (Cr 1.7 ± 1.3 vs 1.6 ± 0.52; MDRD GFR 40.1 ± 18.4 vs 36.6 ± 10.6).

 

Summary:  

Female gender, HCV disease, grade 3 disease pre-tx ASC, and CIT ≥ 8 were strong and independent predictors of ASC which occurred in 6.2% of all liver tx recipients. Intriguingly, the majority (71%) of post-tx ASC episodes occurred without significant fibrosis and distinctive parenchymal or vascular histopathology.

 


592. Outcome of liver transplantation in patients with glutathione S-transferase T1 donor/recipient mismatch and de novo immune hepatitis. 

J. Sousa; I. Aguilera; I. Wichmann; F. Gavilan; J. Pascasio; T. Ferrer; M. Sayago; A. Nuńez-Roldan; J. Marquez; A. Bernardos.

 

Aim:

To evaluate the clinical course of liver transplant patients with glutathione S-transferase T1 (GSTT1) genetic mismatch (positive donor/null recipient) that our group has recently described as a risk factor for the pathogenesis of de novo immune hepatitis (IH).

 

Patients and methods:

280 patients that underwent liver transplantation were followed for a period >6 months. The GSTT1 genotype was determined in recipients and donors. Detection of anti-GSTT1 ab was confirmed in WB with the human recombinant protein. We searched for any association between the four possible combinations of GSTT1 genotypes, production of anti-GSTT1 ab, de novo IH and IgG kappa monoclonal gammopathy (Fisher test). We also analyzed survival of the patients comprising the GSTT1 mismatch that developed de novo IH versus those that did not (Kaplan-Meier curve).

 

Results:

44 of 280 patients (17.5%) belonged into the null recipient/positive donor category. 18 of the 44 (40.9%) produced anti-GSTT1 ab mean 14 (3-82) months after the transplant and 26 did not; 10 of the 18 were diagnosed of de novo IH with a mean of 20 (6-60) months. None of the 239 patients included in the other three categories (+ rec/+ donor, + rec/null donor and null rec/null donor) did ever produce anti-GSTT1 ab or suffered de novo IH (p<0.0001).

 

13 of the 18 (72.2%) with anti-GSTT1 ab revealed monoclonal gammopathy IgG kappa while the 26 without ab did not (p<0.0001). At the time of diagnosis 6/10 (60%) had cirrhosis attributable to de novo IH. They had a good response to steroid treatment with a survival rate of 90% after a median follow-up of 48 months (14-89) from diagnosis. No significant differences were observed in the survival rate of patients with IH compared to those without the disease.

 

Conclusions:

1.     The GSTT1 mismatch + donor/null recipient is a necessary condition but is not sufficient to trigger antibody production and de novo IH after liver transplant.

2.     The IgG kappa monoclonal gammopathy could be used as a marker of anti-GSTT1 ab and de novo IH.

3.     During the follow-up of liver transplant patients with this mismatch, routine exam of antibodies should be performed.

4.     Despite the cirrhosis stage, medium and long-term prognosis of de novo IH is good in patients under steroid treatment.

 

GSTT1 donor /recipient genotype

 

-/+
n=45

+/+
n=178

-/-
n=13

+/-
n=44

No response

45

178

13

20

de novo IH

0

0

0

10

anti-GSTT1 ab

0

0

0

18

 

Distribution of the four possible donor/recipient GSTT1 combinations and specific immune response.

 


593. Post Liver Transplant Quality of Life as a function of pre-transplant MELD score and other variables. 

V. Misra; L. Munsch; R. Mangus; J. Tector; J. Fridell; R. Vianna; S. Liangpunsakul; M. Alsatie; S. Bhardwaj; B. Musick; B. Juliar; P. Kwo.

 

Introduction:

The MELD score was adopted to rank liver transplant recipients based on pretransplant mortality for liver patients using 3 objective variables to improve organ allocation. The optimal MELD score for OLT is unknown but patients(pts) are typically offered transplant with MELD scores >15. One limitation of MELD is the exclusion of variables that may affect QOL (quality of life) including hepatic encephalopathy (HE). Our AIM was to correlate pre-transplant MELD score and other pre-transplant variables with post-transplant QOL score.

 

Methods:  

In this single-center, prospective cohort study, pts who underwent OLT after MELD implementation and were at least one year post-OLT were consented and administered the SF-36 QOL form to assess measure of disease (MOD), psychological distress/well being(PDW), personal function(PF), social/role function(SRF) and general health perception(GHP). MELD score on day of OLT, grade of hepatic encephalopathy(HE), Child Pugh’s Score(CPT), hepatoma(HCC) and etiology of liver disease data were obtained from medical records. Data were analyzed using SAS software. QOL scores were compared between pre-transplant MELD groups(<16 and >16) using t-test. Linear regression was used to test the association between QOL outcomes and other variables adjusted for MELD scores including CPT scores, HE(0-4 based on grade), HCC and different etiologies. In those with HCC, MELD score was calculated rather than using score exceptions.

 

Results:  

We present data from the first 100 pts who completed the QOL questionnaire with mean age 54.3 years (range 19.5-74.3), 66% male. 34% had returned to work either part time or full time. QOL scores by level of MELD score are presented in Table 1 with no differences seen in QOL scores between pre-transplant MELD scores < 16 and > 16. MOD (β=6.86, p=0.007) &SRF (β=1.47, p=0.035)& scores were higher and PF (β=-0.70, p=0.026) scores were lower in pts with HCV related liver disease compared to pts without HCV. GHP scores were lower in pts with higher CTP (β=-0.28, p=0.016) and in marginally associated in pts with higher HE scores (β=-0.44, p=0.069).

 

Conclusion:  

Post transplant QOL scores in various domains were not different in those with pre-transplant MELD scores <16 and > 16. Those who received OLT for HCV related disease had worse QOL. Higher pretransplant CTP scores were also associated with worse QOL post OLT.

QOL

Mean Score (Range) for MELD<16

Mean Score (Range) for MELD 16+

P value

MOD

22(1-55)

17(3-41)

0.076

SRF

4.6(0-15)

4(0-13)

0.864

PF

1.48(0-4)

1(0-4)

0.622

PDW

7(0-17)

5.6(0-18)

0.178

GHP

7(0-10)

7(2-10)

0.466

 

 

 

 

 

 

 


594. Experience with Pre-Recovery Liver Biopsies in Potential Deceased Liver Donors. 

M. Shaughnessy; P. Weber; R. Menza; K. Bradley; D. Kinder; C. E. Freise.

 

Purpose:

As the demand for liver transplantation increases, more marginal donors are being evaluated and their livers recovered for transplant. Unfortunately, the chance of finding a liver at the time of organ recovery that may not be transplantable is greater with marginal donors. We hypothesized that the use of pre-recovery liver biopsies (PBX) in donors thought to be marginal may help decrease aborted recoveries (donor recovery initiated but liver not removed), and may facilitate the placement of livers to the most appropriate patients. We examined the results of our practice over the last 15 months, and compared liver utilization in this era to the previous three years.

 

Methods:

The use of pre-recovery liver biopsies began 1/2005, and the time period of study extends to 4/2006. Indications for biopsy included BMI >/= 32, ultrasound or CT scan suggestive of fatty infiltration of liver, significant ETOH history, positive HCV serology, or clinical indications suggestive of liver disease. Biopsies were performed at the donor hospital, and read by the local pathologist if available, and in many cases re-read at one of the transplant centers. An initial report was available as the liver was being allocated.

 

Results:

In the 15 months since the biopsy protocol was initiated, there were 338 potential liver donors, 80 underwent PBX. The mean age (49.9 vs. 36.2 yrs) and BMI (30.0 vs. 25.5) of donors undergoing PBX was significantly greater than non biopsy donors (p<0.0001). In the group of donors undergoing PBX, there were only 2 aborted donors, 14 livers were not placed, 4 were recovered but not transplanted, 1 was ruled out for other medical reasons, and the remaining 59 livers were transplanted. Macro vesicular fat >30% was the most common finding on livers that could not be placed. With PBX, there was a significant drop in the rate of aborted donors compared to the 3 years prior to initiating the protocol (p<0.0296). There was an increase of 38 livers transplanted in the first year of the PBX protocol, compared with the previous year. The biopsy procedure was also safe, with no serious bleeding complications in this cohort of 80 donors.

 

Conclusion:

A pre-recovery liver biopsy protocol was successfully used in our large donor service area, with a significant decrease in aborted donors. The information available from the biopsies may facilitate placement of livers, and increase livers transplanted.

 


597. Sexual dysfunction in female patients before and after liver transplantation (LT).  

P. Burra; A. Masier; D. Canova; G. Germani; M. D'Aloiso; G. Sturniolo; U. Cillo; F. Montorsi; A. Salonia.

 

Introduction:

Sexual dysfunction has been scarcely investigated in female patients with liver cirrhosis. The aim of this study was to investigate the sexual function in female patients with liver cirrhosis before and after LT.

 

Methods:

27 female patients with liver cirrhosis evaluated for LT and 20 female patients after LT consecutively followed-up in our outclinic were enrolled in this cross-sectional study. The control group comprises 13 age-comparable healthy controls. A medical history and liver disease scores (Child-Pugh-Turcotte-CPT, MELD) were obtained and all patients filled in a set of questionnaires on sexual function: Female Sexual Function Index (FSFI); Beck Depression Inventory (BDI); American Urological Association Symptom Index (AUASI). Statistical analysis was performed by student’s t test and chi square test.

 

Results:

The two groups of patients and the group of controls were age-comparable (mean±se: before LT 54.54±3.08 vs after LT 50.6±5.2 vs controls 54.1±3.6 p=0.48). 24/27 (88.8%) cirrhotic patients and 19/20 (95%) transplanted patients filled in the FSFI. Cirrhotic patients and transplanted patients showed a lower score for sexual desire compared to healthy controls (before LT 2.6±1.2 vs after LT 2.6±1.2 vs healthy controls 4.0±1.2; p=0.01). No urological dysfunction was reported in cirrhotic and transplanted patients. Among cirrhotic patients a significant correlation (p=0.010) between sexual dysfunction and depression but not between sexual dysfunction and urological symptoms was observed. In transplanted patients a significant correlation (p=0.02) between depression, sexual desire and lubrication was observed. BDI, FSFI and AUASI score do not correlate with aetiology or severity (CPT and MELD score) of liver disease.

 

Conclusions:

Female patients with liver cirrhosis, waiting for LT but also following LT, report a lower sexual desire as compared to healthy controls. Different domains of sexual dysfunction correlates with depression in both, cirrhotic and transplanted female patients. No correlations were found between sexual dysfunction and aetiology or severity of liver disease before liver transplantation. Studies to investigate the role of hormones in causing the sexual dysfunction are ongoing.

 


602. Tacrolimus versus Cyclosporine Based Immunosuppression in Hepatitis C Patients after Liver Transplantation: Long-Term Follow-up of a Randomized Controlled Trial. 

P. G. Northup; T. W. Chong; J. C. Iezzoni; S. E. Kerr; A. S. Burns; T. L. Pruett.

 

Introduction:

Cyclosporine has been recently shown to have significant in vitro effects on the hepatitis C virus and these effects are not seen with tacrolimus. We present long-term follow-up on HCV positive liver transplant recipients randomized to either cyclosporine or tacrolimus based immunosuppression with respect to HCV disease activity and progression.

 

Methods:

57 patients with active hepatitis C infection undergoing liver transplantation participated in a randomized controlled trial comparing immunosuppression with cyclosporine (n=28) or tacrolimus (n=29) in addition to corticosteroids. Recipients who survived more than one year and had at least one biopsy after transplantation were included in the final analysis (n=45). Standardized immunosuppression protocols were followed and corticosteroids were routinely discontinued within six months of transplantation. Protocol liver biopsies and HCV RNA levels were performed on all patients and were analyzed at yearly intervals after transplantation. Blinded pathology review of liver biopsy specimens was performed and HCV grade (0-18) and stage (0-6) were quantified using the modified Ishak scoring system. Clinical outcome variables were also compared between groups.

 

Results:

The mean age was 48y (± 8), 34 (76%) patients were male, and mean follow-up was 48.5 mos (± 28.3). There was no difference in the proportion of patients in each group treated with HCV specific therapy after transplant (p>0.5). There were no statistically significant differences between groups in HCV RNA levels at years 1 through 5 post-transplant. The mean total necroinflammatory grade at the end of follow-up in the cyclosporine group was 4.1 versus 4.5 in the tacrolimus group (p=0.45). The mean fibrosis stage was 2.4 versus 2.2 (p>0.5) in the cyclosporine and tacrolimus groups, respectively. Three patients in the cyclosporine group and 5 patients in the tacrolimus group eventually progressed to cirrhosis (p=0.47). In the patients that had disease progression, the mean days to increase 2 points or more in necroinflammatory score was not different between groups (1502 vs. 1202, cyclosporine vs. tacrolimus, p>0.5) nor were the mean days required to reach at least stage 3 fibrosis (1130 vs. 1861, p=0.22).

 

Conclusions:

This study found no differences in progression of hepatitis C in clinical, viral load, or histopathology endpoints between cyclosporine and tacrolimus treatment groups after liver transplantation. Larger studies are required to further investigate the effect of specific immunosuppression drugs on hepatitis C.

 


603. Growth and final height after pediatric liver transplantation in relation to age and underlying disease. 

R. Scheenstra; R. J. Odink ; W. Gerver ; H. Soest ; P. M. Peeters; P. J. Sauer; H. Verkade.

 

Introduction:

It is still unresolved to what extent liver transplantation (LTx) at pediatric age restores growth velocity and affects final height. In our national program, we have adhered to annual follow up after LTx, which allows assessing its effects on growth and final height.

 

Aim:

To determine the effects of pediatric LTx on growth and final height, in relation to age at LTx, underlying disease (cholestatic vs. noncholestatic) and immuno-suppressive scheme (cyclosporine/prednisolon vs. tacrolimus/prednisolon).

 

Patients and Methods:

Longitudinal data were available of 101 patients for 2 years after LTx at child age (mean age 3.7 ± 5.4 yr), and of 63 patients for 5 years. Data on final height were available for 23 patients. Height was determined just before LTx, and at 2 and 5 years after LTx. Height was expressed as a standard deviation score of the target height of each individual patient, i.e. their genetic potential (SDSth).

 

Results:  

Before LTx, patients were growth retarded (median and range SDSth: -1.6, -6.3 to 1.7), with 40 patients (39%) having a SDSth below 2. Growth during 2 or 5 years after LTx, expressed in ΔSDSth, was significantly, positively correlated with pre-transplant growth retardation (2yr: p<0.001, r=0.63; 5 yr: p<0.001, r=0.62). Nevertheless, at 2 years after LTx, 29 patients had still a SDSth below -2 (29 %) and at 5 years after Ltx, 14 patients had a SDSth below –2 (21%). Twelve of the 23 patients reaching their final height, had a final height < -1.3 SD of their target height SDS, of which 3 even below -2.0 SD. Underlying cholestatic disease was associated with more severe growth retardation before LTx (SDSth -2.0 vs. -1.2, p< 0.05), and with better growth in the first two years after LTx (ΔSDSth +0.6 vs. -0.1, p<0.05), compared with non-cholestatic patients. There was no significant effect of either age at LTx or immunosuppression scheme on growth after LTx.

 

Conclusions:  

Growth retardation is a common finding in children before LTx, particularly in children afflicted by a cholestatic disease. Catchup growth after LTx was only prominent in cholestatic children that had been severely growth retarded before LTx. Our longitudinal data indicate that after LTx at pediatric age, ~50% of patients reach a final height lower than -1.3 SD of their genetic potential.

 


604. MELD-XI: a rational approach to “sickest first” liver transplantation in cirrhotic patients requiring anticoagulant therapy. 

D. M. Heuman; A. A. Mihas; A. Habib; H. S. Gilles; R. Stravitz; A. J. Sanyal; R. A. Fisher.

 

Introduction:

Priority for “sickest first” liver transplantation (LT) in the US is determined by the Model for End stage Liver Disease (MELD). MELD is a good predictor of short-term mortality in cirrhosis, but can overestimate risk when INR is artificially elevated by anticoagulation. An alternate prognostic index omitting INR is needed in this situation.

 

Methods:

We retrospectively analyzed survival data for 554 cirrhotic veterans referred for consideration of LT prior to 12/1/03 (training group). Using logistic regression we derived a predictive formula for 90-day pretransplant mortality incorporating bilirubin and creatinine but omitting INR. We normalized this formula to the same scale as MELD using linear regression. This yielded MELD-XI (for MELD excluding INR) = 5.11 ln(bilirubin) + 11.76 ln (creatinine) + 9.44. Accuracy of MELD-XI was validated in a holdout group of 278 cirrhotic veterans referred after 12/1/03, and in an independent validation dataset of 7,203 cirrhotic adults listed for LT in the U.S. between 5/1/01 and 10/31/01.

 

Results:

MELD-XI and MELD correlated well in training, holdout and independent validation cohorts (r=0.930, 0.954, and 0.902, respectively). In the holdout cohort, c-statistics of MELD vs. MELD-XI for mortality at various time points were, respectively, 30-day: .939 vs .906; 60-day: .860 vs. .841; 90-day: .842 vs .829; 180-day, .795 vs .797. In the independent validation dataset, c-statistics for MELD vs. MELD-XI as predictors of 90-day survival were, respectively, .857 vs. .843 in non-cholestatic liver diseases and .905 vs. .894 in cholestatic liver diseases. Comparable MELD and MELD-XI scores were associated with comparable prognosis.

 

Conclusion:

MELD-XI, despite omission of INR, is nearly as accurate as MELD in predicting short-term survival in cirrhosis. In patients treated with oral anticoagulants, substitution of MELD-XI for MELD may permit more accurate assessment of risk and more rational assignment of “sickest first” priority for LT.

 


605. Racial Differences in Liver Transplantation and Mortality in Hospitalized Cirrhotic Patients with Portal Hypertension. 

G. Nguyen; D. Segev; P. J. Thuluvath.

 

Introduction:  

It has been suggested that there may be racial disparities in the use of liver transplantation (LT) in the United States. In this study, we characterized racial disparities in LT among hospitalized cirrhotic patients with portal hypertension using a large national dataset.

 

Methods:

We queried the Nationwide Inpatient Sample, the largest all-payer dataset of hospital discharges in the U.S., from 1998 to 2003, to identify hospitalized patients with cirrhosis complicated by portal hypertension. International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) diagnosis codes were used to identify individuals with a primary diagnosis of portal hypertension or one of its manifestations: hepatic encephalopathy, ascites, or variceal bleed. ICD-9-CM procedural codes were used to identify LT and portosystemic shunt procedures. Logistic regression was used to determine the influence of race on LT, portosystemic shunt procedure, and in-hospital death while controlling for confounders.

 

Results:  

Baseline characteristics of hospitalized patients with cirrhosis complicated by portal hypertension are shown in the table below. Compared to whites, the odds ratios of undergoing LT were 0.30 (95% CI: 0.18 – 0.52) and 0.48 (95%CI: 0.26 – 0.89) for African Americans (AAs) and Hispanics, respectively, after adjustment for age, gender, calendar year, insurance, comorbidity, disease manifestation, and geographic region. Similarly, the adjusted odds ratio for receiving a portosystemic shunt was 0.36 (95%CI: 0.27 – 0.49) and 0.70 (95% CI: 0.54 – 0.88) for AAs and Hispanics, respectively. Compared to whites, AAs experienced higher in-hospital mortality (OR=1.13: 95%CI: 1.02 –1.3) while Hispanics had a lower risk of death (OR=0.80; 95%CI: 0.72 – 0.88). Among variceal bleeders, the odds ratio for death was 1.8 (95%CI: 1.2 – 2.4) for AAs compared to whites.

 

Conclusions:  

African Americans and Hispanic patients were less likely to receive LT or a portosystemic shunt than whites. Further studies are warranted to elucidate the underlying reasons for these disparities to ensure equitable access to LT for all races.

 

Baseline Characteristics by Race

 

White
(N=41,665)

AA
(N=6,963)

Hispanic
(N=11,894)

Mean Age ±SE

59.2 ± 0.2

54.8 ± 0.2*

57.2 ± 0.4*

Charlson Index ±SE

4.2 ± 0.02

4.3 ± 0.04*

4.3 ± 0.04*

 

N (%)

N (%)

N (%)

Female

16282 (39)

2941 (42)*

4201 (35)*

Medicaid

7038 (17)

2280 (33)*

3660 (31)*

Variceal Bleeding

3911 (9.3)

585 (8.4)*

1090 (9.2)

Encephalopathy

23701 (57)

4429 (64)*

7593 (64)*

Ascites

21166 (51)

3106 (45)*

5283 (45)*

Hepatorenal Syndrome

1145 (2.8)

197 (2.9)

305 (2.6)

* p<0.01

 


606. The Development of De Novo Autoimmune Hepatitis (Immune-Mediated Hepatitis) and its Effect on Outcome in Patients With HCV Post-Liver Transplantation . 

M. Fiel; K. Agarwal; N. Elhajj; N. Kontorinis; C. Stanca; S. Thung; T. D. Schiano.

 

Introduction:

De novo autoimmune hepatitis is increasingly recognized as a complication after liver transplantation (LT) and at times may have an aggressive course. We have observed an increasing frequency of this in LT recipients over the past few years, an entity which we term immune-mediated hepatitis (IMH). We sought to ascertain the natural history and outcome of IMH in HCV patients and its response to treatment.

 

Methods:

The Mount Sinai pathology database covering a 12-year period (1994-2006) was searched for the diagnoses of IMH and/or the terms “liver allograft” and “plasma cells”. After excluding cases with acute or chronic rejection, steatohepatitis and bile duct problem, the remaining biopsies were blindly reviewed by 2 experienced hepatopathologists (MIF & ST). A diagnosis of IMH was made in biopsies demonstrating sheets of plasma cells (3+) or 20-30% plasma cell infiltrate (2+) with associated centrilobular necrosis. Subsequent biopsies were assessed for fibrosis progression and histologic resolution. Clinical data was gathered from chart review. Exact test was used for statistical analysis.

 

Results:

404 biopsies that contained the specified search terms were found. Non-HCV LT patients (n=336) and HCV LT patients that had concurrent problems like cellular rejection, steatohepatitis, or vascular/biliary complications (n=38)were excluded. 30 patients (20 male, mean age at diagnosis = 54 years) fulfilling IMH criteria were identified. No cases were found prior to 1999. Upon clinical presentation of IMH, median AST was 140 IU/L, ALT 116 IU/L and bilirubin 1.1g/dL. Overall, 16/30 (53%) pts died, developed cirrhosis or required re-LT (negative outcome). IMH occurred 2-141 months post-LT (median 27). 23 pts had follow-up biopsy; 13/23 had fibrosis progression with 8/13 having negative outcome; 6/10 without fibrosis progression had negative outcome (p=NS). Ten pts resolved IMH (3 with negative outcome), while 11/13 pts not resolving IMH did poorly (p=0.01); 9 of these 11 pts were treated with IFN (p=0.02). 6/10 pts not resolving IMH were treated, with 5/6 doing well; 4 of these pts were treated with azathioprine. 23/30 pts (77%) were receiving interferon (IFN) for recurrent HCV or had their immunosuppression lowered during the preceding 3 months. 80% of the remaining pts had autoantibodies suggesting a predisposition to autoimmunity.

 

Conclusions:

The development of IMH in pts with recurrent HCV is associated with an unfavorable prognosis and may accelerate fibrosis progression. IMH may be associated with IFN use or tapering of immunosuppression. Treatment with azathioprine should be considered.

 


608. MELD SCORE AND SERUM SODIUM IN THE PREDICTION OF SURVIVAL OF PATIENTS WITH CIRRHOSIS AWAITING LIVER TRANSPLANTATION. 

M. Londono; A. Cardenas; M. Guevara; D. De las Heras; M. Navasa; A. Rimola; J. García-Valdecasa; V. Arroyo; P. Gines.

 

Background/Aims:

Serum sodium predicts prognosis in cirrhosis and may improve the prognostic accuracy of MELD score, but the available information is limited. We aimed to assess the prognostic value of serum sodium in the prediction of survival at 3 and 12 months after listing in patients with cirrhosis awaiting liver transplantation and compare its predictive value with that of MELD score.

 

Patients and Methods:

Three-hundred and eight consecutive patients with cirrhosis listed for transplantation during a 5-year period were included in the study. 252 were excluded because HCC (15 pts), re-transplantation (48 pts), and diseases other than cirrhosis (52 pts) End-point was survival at 3 and 12 months before transplantation. Variables obtained at the time of listing were analyzed for prognostic value using multivariate analysis. Accuracy of prognostic variables was analyzed by ROC curves.

 

Results:

MELD score and serum sodium concentration were the only independent predictors of survival at 3 and 12 months after listing. Low serum sodium was associated with an increased risk of death in all subpopulations of patients with cirrhosis categorized according to the major complication developed before listing. The area under the ROC curves for serum sodium and MELD score were similar both at 3 months (0.83 vs. 0.79, respectively) and at 12 months (0.70 vs. 0.77, respectively). The addition of serum sodium did not improve significantly the accuracy of MELD score in the prediction of survival at 3 and 12 months.

 

Conclusion:

In patients with cirrhosis awaiting liver transplantation serum sodium concentration shows a good correlation with survival. The addition of serum sodium does not appear to improve the accuracy of MELD score in predicting 3 and 12 month survival in these patients.

 


609. Predictors of Employment in Liver Transplant Recipients. 

S. Saab; C. Wiese; A. B. Ibrahim; F. Durazo; S. Han; H. Yersiz; D. G. Farmer; R. Ghobrial; L. I. Goldstein; M. J. Tong; R. W. Busuttil.

 

Background/Aim:  

In the United States six thousand liver transplants are performed yearly, leading many to focus on the enormous cost of transplantation. Particular attention has been made to the employment status of liver transplant recipients as an indirect measure of society’s ability to regain lost expense, and as a marker of a patient’s mental and physical health. The aim of this study is to determine the factors affecting employment/subemployment after liver transplantation.

 

Methods:

Adult liver transplant recipients who were seen at UCLA’s Pfleger Liver Institute during a nine month period between August 2005 and April 2006 were administered two questionnaires: one regarding work history and insurance coverage, and the second a SF-36 (Short Form 36). Through multivariate analysis, factors significantly associated with employment were identified.

 

Results:  

The mean age of participants was 51 (standard deviation [SD] = ± 13.9). The majority (98/204) were transplanted for viral hepatitis. 98.5% reported having health insurance. 34% had disability coverage. Of 204 subjects, 163 (80%) worked prior to transplantation, and 64 (31%) worked post-transplant. Of those employed post-transplant, most (29%) returned to work greater than 24 months after transplantation. Eight recipients changed jobs after transplantation (12.5% of those employed) and 22% had a salary decrease. Only 4% had an increase in salary post-transplant. Thirteen participants reported having been denied employment secondary to their transplant. In multivariate analysis, higher post-transplant salary (OR=0.55, 95% confidence interval [CI] 0.45, 0.60, p<0.001), lack of disability prior to transplant (OR=0.49, 95% CI 0.30, 0.81, p<0.005), and ability to pay for transplant without insurance (OR=0.53, 95% CI 0.31, 0.89, p=0.017), and matriculation in school (OR=0.25, 95% CI 0.07, 0.89, p=0.032) were independently significantly associated with post-transplant employment. Employment prior to transplantation, age, type of insurance, etiology of the liver disease, and MELD scores were not significantly related to post-transplant employment. In addition, components of SF-36 survey were not associated with employment.

 

Conclusion:  

Liver transplant recipients are more likely to work after transplantation if they are students, have a higher post-transplant salary, did not require disability prior to transplantation, and were able to pay for transplantation without insurance. Mental and physical health status, and type of pre-transplant insurance did not affect employment after transplantation.

 


610. CCR2 V64I Polymorphism: A risk factor for patients suffering HCV after orthotopic liver transplantation? 

J. . Knaak; A. Lautem; C. Moench; G. Otto.

 

Introduction:

CC-Chemokines may play a key role in the recruitment of leukocytes during ischemia-reperfusion damage and acute rejection following orthotopic liver transplantation (OLT). Therefore the CC-chemokine-receptor 2 (CCR2), its functionless CCR2-V64I-polymorphism (amino acid chance at codon 64. valine -> isoleucine) and the ligand CCL2 (MCP-1) might have an influence on the grafts pathology after OLT.

 

Material and Methods:

In 267 patients after OLT between 09/97 and 08/05 the CCR2 was analyzed with regard to the CCR2-V64I by realtime-PCR (Fluorescence resonance energy transfer DNA hybridization – light cycler instrument Roche). CCL2 was measured in patients serum with ELISA .

 

Results:

219 patients (Alter: 50,6 ± 11,6; 16-69) showed a normal receptor whereas 47 patients (Alter: 51,6 ± 10,4; 22-69) suffered from the CCR2-V64I polymorphism (44 heterozygote, 3 homozygote). 5 year graft survival was 80% in CCR2-V64I patients and 60% in CCR2 patients (p = 0,08 log rank). 5-year-patient survival was 88% and 75% in CCR2-V64I and CCR2, respectively (p = 0,11 log rank). Almost all dying patients with the I-Allel died because of HVC recurrence und HCV related liver failure. HCV positive Patients combined with I-Allel had a poor Patient and Organ survival (60 and 50%) versus the HCV positive Patient combined with the V-Allel with an outcome of 75 and 64% (p= 0,11 log rank) . HCV neg Patients had a better outcome. The HCV neg Patient combined with the I-Allel showed great Patient and Organ survival (97 and 95%) versus the V-Allel Patients with 76 and 64% (p=0,02, log rank). MCP-1 levels were significant lower (p<0,01, Wilcoxon/Mann-Whitney-U-test) in patients with CCR2-V64I (Median: 123 pg/ml) compared to CCR2 patients (Median 148,9 pg/ml).

 

Conclusion:

CCR2-V64I leads to excellent 5 year graft survival of 92% following OLT. A significant reduction of MCP-1 levels may lead to a reduced immunoactivation following transplantation and could be reasonable for these results. Futhermore, recently published data from Nakayama et al (Nakayama et al., 2004) propose CCR2 polymorphism to interfere with surface expression of CCR5. On the other hand there might be an induction of tolerance through the I-Allel not only towards the graft. We thought of tolerance towards the HCV virus and more cytotoxic influence from T-Cells to hepatocytes.

 


611. Steroid-free Immunosuppression in Pediatric Liver Transplantation: A pilot study examining efficacy for prevention of graft rejection. 

M. Al Turaiki; N. M. Kneteman; S. M. Gilmour.

 

Introduction:

Corticosteroids have been part of almost all immunosuppression protocols in pediatric liver transplantation. The potential benefits from steroid free pediatric immunosuppression include improved growth and bone density but this must be balanced with the potential risk of increased graft rejection. We report the pilot data on rates of graft rejection in a cohort of children recently transplanted steroid-free, at the Stollery Children’s Hospital, University of Alberta.

 

Patients:

Between July 2004 and February 2006, 21 children were transplanted on a protocol which included intraoperative dacluzimab 2mg/kg and 1mg/kg day 5 post-transplant; tacrolimus 0.1 mg/kg, aiming for trough levels of 8-10 for the first 4 weeks post-transplant; and mycophenolate mofetil 30 mg/kg/day. These patients were compared to a historical cohort of 27 children transplanted between January 2001 and June 2004 who received standard immunosuppression of tacrolimus 0.1 mg/kg and corticosteroids with an intraoperative pulse, and post-operative 1 mg/kg/day with a wean over 2 week to 0.25 mg/kg/day and .1 mg/kg/day by 3 months post-transplant. Corticosteroids were routinely discontinued by 6 months post-transplant.

 

Results:

Both cohorts were comparable in regards to demographic data such as age, gender, etiology and living related donation. Their rates of infection, PTLD, graft loss and death were also comparable.

 

All episodes of rejection in the steroid/tacrolimus cohort occurred within the first 12 months post-transplant. One patient developed chronic rejection, within the first 12 months post-transplant and went on to retransplantation. Biopsy proven acute graft rejection occurred in 11/27 (41%) in the tacrolimus/steroid cohort and 5/21 (24%) in the steroid-free cohort. There was no difference between the two groups. In both cohorts, all episodes of rejection were mild/moderate and graded Banff Criteria 3-5/9.

 

Conclusion:

Steroid-free immunosuppression is safe and does not increase the risk of early acute graft rejection. Further follow-up of this steroid-free cohort will provide data on the potential benefits of improved growth and bone density.

 

Demographic and rejection rates in steroid/tacrolimus cohort (n = 27) versus steroid-free cohort (n = 21)

 

 

Steroid/tacrolimus

Steroid-free

p

Age

4.6 ± 5.5

5.1 ± 5.1

.751

Gender M:F

15:12

9:12

.561

Biliary atresia

56%

48%

.771

Living donor

26%

29%

.355

Acute rejection

41%

24%

.355

 


612. Does indication of alcoholic liver disease influence the long-term results of liver transplantation?

H. Audin; C. Defez; M. Bismuth; F. Chermak; H. Rigole; P. Perney; F. Navarro; D. Larrey; G. Pageaux.

 

Introduction:

In the European liver transplant registry, the 5-years survival rate after liver transplantation (LT) is about 70%. Beyond 5 years, little is known about long-term results. It has been reported that long-term results could be worse in patients transplanted for alcoholic liver disease (ALD).

 

Aim:

To analyze the complications observed beyond 5 years after LT and to assess the influence of indication for LT on long-term results.

 

Methods:

We reviewed records of all patients transplanted between April 1989 and January 2000, and alive 5 years after LT. The following parameters were assessed, on one part for the whole population, on another part comparing patients transplanted for ALD and non ALD: survival, de novo cancer, renal function, arterial hypertension, cardiovascular complications, alcohol onsumption.

 

Results:

175 patients, alive 5 years after LT were analyzed, 122 male, 53 female, mean age 48.3±10.8 yrs. The mean follow-up was 9±4.3 yrs. The main indications for LT were: alcoholic cirrhosis 56%, post viral cirrhosis B or C 31%, hepatocellular carcinoma 8.8%. For the whole population, the actuarial 10- and 13-yrs survival rates were 80% and 70%, respectively. Among the 33 deaths observed after 5 yrs, the main causes were de novo cancer (n=9) and infections (n=6). The evolution of the prevalence of complications already present at 5 yrs was as follows: hypertension, from 65 to 64%, renal failure, from 40 to 46.8%, severe renal failure, from 4 to 9.1%, de novo cancer, from 9.7 to 20%, cardiovascular complications, from 12 to 19%. When we compared ALD (n=98) and non ALD (n=77) patients, there was no difference concerning actuarial 10- and 13-yrs survival rates: 83 vs. 74%, and 71 vs. 70%, respectively. There was statistically more cardiovascular complications observed in ALD patients: 22% vs. 14% (p=0.02), but no differences concerning hypertension, renal failure, de novo cancer. Beyond 5 yrs, alcohol consumption was described in 34.3% of patients, always mild in 8 non ALD patients, mild in 28, moderate in 8, and severe in 15 ALD patients. The type of alcohol consumption, mild, moderate, or severe, did not influence the occurrence of renal failure, hypertension, de novo cancers, cardiovascular complications.

 

Conclusion:

In this study of 175 liver transplant recipients living more than 5 yrs after LT:

1.     the main causes of death beyond 5 yrs were de novo cancer and infection,

2.     patients transplanted for ALD developed more cardiovascular complications,

3.     the intensity of alcohol consumption was not responsible for poorer outcome.

 


616. Cost Analysis of Liver Transplantation According to MELD Score. 

C. W. Duncan; K. Hess; V. Zacharias; T. Kaiser; L. Trumbell; G. W. Neff.

 

Introduction:

The successes recognized in liver transplantation (LTx) over the last decade have resulted in a marked increase in demand for this operation. The literature is limited in terms of measuring expenses and resource allocation. In the following report, we examine this evolving topic by evaluating costs associated with LTx as they are affected by length of hospital stay stratified over varying MELD scores at the time of transplantation.

 

Methods:

A retrospective analysis from January 2004 to May 2006 (28 months) was performed on adult (> 18 years) liver transplant recipients. Patients were subdivided into four subgroups: MELD < 20, MELD score 20 to 24, MELD score 25 to 29 and MELD scores ≥ 30. Hospital costs were collected from the transplant facility. MELD score groupings were compared based on length of hospital stay and costs for both the intensive care unit and floor ward as well as total hospitalization cost during the inpatient stay for Ltx.

 

Results:

Length of stay and associated costs in the intensive care unit was similar throughout the range of MELD scores. The groups differed when examining length of stay and costs associated with hospital floor ward admission as well as total cost of transplant hospitalization. The varying total costs for the different groups were as follows:

MELD < 20 (n=) = $189,410; MELD 20 to 25 = $182,972; MELD 26 to 29 = $242,609; and MELD ≥ 30 = $253,641. This trend indicates that as MELD scores escalate, especially greater than 25 points, the cost of liver transplantation also rises as overall hospital stays lengthen.

 

Conclusion:

·        When examining aggregated costs of hospitalization, higher MELD scores are associated with greater costs as measured by fees during admission for transplantation.

·        In a health care environment of increasing cost sensitivity, decisions surrounding liver transplantation may soon incorporate MELD score as a relevant factor affecting policy decisions for liver transplantation.

 


617. Comparative Analysis of Ethnic Disparities in Liver Transplantation for Pediatric and Adult population. 

G. W. Neff; N. Kemmer; V. Zacharias; T. Kaiser; R. Neff; M. Thomas; A. Tevar; N. Majoras; P. Dryer; J. Buell.

 

Background:

The reported outcomes between ethnic groups following liver transplantation (LTx) in adults are speculated to be much worse in the African American population. Data on ethnic differences in the pediatric population is lacking. The aim was to evaluate whether there were ethnic disparities in transplantation rate and post transplant survival in adults and pediatric groups.

 

Methods:

A retrospective analysis from the UNOS/OPTN databank between January 1995 and December 2004 was performed on adult and pediatric liver transplant recipients. Patients were subdivided into four ethnic groups: African Americans (AA), Hispanic, Caucasians (Cauc), and other. Patient and graft survival was calculated using the Kaplan Meier method. Log rank test was used to compare the survival rates.

 

Results:

Data from 38,639 Adult and 4,341 Pediatric LTx patients were reviewed. Demographics and survival information was collected. Of the 38,639 adult recipients, 29,432 (76.1%) were Cauc, 4369 (11.3%) were Hispanic, 2963(7.7%) were AA and the remaining 1875 (4.9%) were of other ethnicities. Caucasians had a statistically significantly higher transplantation rate than the other ethnic groups (chi-square test p-value < 0.001). Using the Kaplan Meier estimates (KM) and Cox regression analysis there was a significant ethnic difference in both patient and graft survival, for 1-, 3-, 5- and 10 year, with AA showing a lower rate (p <0.001). Of the 4,341 pediatric recipients, 2461 (56.7%) were Cauc, 797 (18.4%) were Hispanic, 824 (18.9%) were AA and the remaining 259 (5.9%) were of other ethnicities. Caucasians had a statistically significantly higher transplantation rate than the other ethnic groups (chi-square test p-value < 0.001). Unlike the adults, there was no ethnic difference in patient (p=0.31) and graft (p=0.33) survival, for 1-, 3-, 5- and 10 year.

 

Conclusion:

These results show that AA LTx recipients have a reduced transplantation rate and a worse survival when compared to other ethnicities in the adult population. However, the pediatric populations do not have disparity differences. This information suggests that further studies are indicated to identify the causes of racial differences in transplant access and outcomes in the adult patient populations.

 


618. Does pre-transplant abstinence duration influence the results of liver transplantation for alcoholic liver disease : an attempt of meta-analysis. 

P. Cerdan; J. Daurčs; P. Perney; H. Rigole; F. Navarro; D. Larrey; G. Pageaux.

 

Introduction:

After liver transplantation (LT) for alcoholic liver disease (ALD), the main issue is the likelihood of relapse and its influence on outcome, because it is the possibility of returning to alcohol use that separates patients with ALD from those with other forms of chronic liver disease. The majority of transplant teams require 6 months of abstinence before LT. The role of the length of pre-transplant abstinence, the so-called 6-month rule, as predictor of post-transplantation abstinence, is still questionable.

 

Aim:

To perform a meta-analysis of all published studies about LT for ALD, which assessed pre-transplant abstinence and post-transplant relapse in order to objectively evaluate whether they influence patient's outcome.

 

Methods:

MEDLINE and bibliographic searches identified 140 potentially relevant articles. Twenty-four studies reporting data on 1712 patients met our inclusion criteria. A first meta-analysis was performed on 19 studies including 1368 patients to evaluate the risk of post-transplant relapse according to the pre-transplant abstinence. A second meta-analysis was performed on 5 studies including 444 patients to evaluate the impact of relapse on patient's survival. It was impossible to perform a meta-analysis to evaluate the impact of pre-transplant abstinence on graft' and patient's survival, because there were only 2 studies. The pooled odds ratio (OR) and 95% confidence intervals (CI) were calculated from the raw study data using the Yusuf-Peto method. We used a statistical evaluation of heterogeneity by the chi2-test.

 

Results:

The first meta-analysis is in favor of a higher risk of post-transplant relapse when the pretransplant abstinence was < 6 months : OR 28.23, 95% CI : 20.7-38.4. The second meta-analysis is not in favor of an influence of post- transplant relapse on patient's survival at 3 and 5 years : OR 0.62, 95% CI : 0.24-1.56, and OR 1.16, 95% CI : 0.5-2,56, respectively. However, in the two meta-analysis, there was a significant heterogeneity (p<0.01), explained by the different definitions of relapse and methods of detecting relapse.

 

Conclusion:

Using meta-analysis methods:

a)     the potential impact of the duration of pre-transplant abstinence in LT for ALD remains controversial : probably predictor of posttransplant behavior, few workable data concerning patient's survival.

b)    post-transplant relapse does not influence middle-term patient's survival. A multidisciplinary approach, beyond the 6-month rule, is then mandatory to evaluate alcoholic candidates for LT.

 

 
622. Predictors of renal failure in patients undergoing liver transplantation for chronic liver disease. 

R. Malik; K. Cheent; K. Morrison; T. Cross; M. Heneghan; J. O’ Grady; M. Bowles; P. Muiesan; M. Rela; N. Heaton; E. Sizer; W. Bernal; G. Auzinger; J. Wendon.

 

Aim:

We report on the incidence and predictors of renal failure in patients undergoing orthotopic liver transplantation (OLT) for chronic liver disease over a five year period at a single centre.

 

Methods:

A retrospective analysis of 422 patients undergoing liver transplantation for chronic liver disease was undertaken between 2000-2005. Patients were stratified according to their pre-transplant serum creatinine (Gp A < 90µmol/L, Gp B 90-120µmol/L and Gp C >120µmol/L). Renal failure was defined as having a serum creatinine outside the normal range on day 1 and/or day 7 following surgery (normal reference lab. serum creatinine <120µmol/L). We further categorised the renal failure into 2 groups depending on the magnitude of the renal dysfunction following surgery: moderate renal dysfunction was defined as 120µmol/L< Cr <240µmol/L/renal replacement therapy (RRT) and severe renal dysfunction defined as Cr >240/RRT.

 

A variety of pre and post transplant factors were examined using logistic regression analysis to find factors associated with the development of renal failure on day 1 and day 7 following OLT.

 

Results:

There were a total of 202 patients in group A (median Cr - 77µmol/L) in whom 37 developed renal failure (18%). We showed that 26 out of 37 had moderate renal dysfunction, whilst 11 out of 37 had severe renal dysfunction. In group B (median Cr - 101µmol/L) there were 143 patients of whom 75 developed renal failure (52%){p<0.05}. We calculated that 57 out of 75 had moderate renal dysfunction whilst 18 out of 75 had severe renal dysfunction. There were a total of 80 patients in group C (median Cr - 141µmol/L) in whom 71 patients developed renal failure (89%){p<0.05}. A total of 40 patients had moderate renal dysfunction, whilst 31 had severe renal dysfunction.

 

There was significant correlation for developing renal failure on Day 1 with pre OLT factors {serum creatinine, CrCl}, and post OLT factors {APACHE 11 score (on day 1}. A significant correlation for renal failure on Day 7 was seen with pre OLT factors {serum creatinine, CrCl} and post OLT factors {APACHE 11 score (on day 1), lactate (on day 1), albumin, INR and Bili.(all day 7}.

 

Conclusion:

Serum Creatinine and creatinine clearance both performed equally well in predicting subsequent renal failure/dysfunction. However, the normal cut off for serum creatinine in patients with severe chronic liver disease should be lowered to 90µmol/L. We have also shown a number of post transplant factors that correlate with the development of renal failure after OLT.

 


625. A Randomized Controlled Trial of Cyclosporine Vs Tacrolimus Immunosuppression in Patients Receiving Pegylated Interferon and Ribavirin for Recurrence Hepatitis C Virus Infection after Liver Transplantation: The Preliminary Results.. 

R. J. Firpi; C. Soldevila-Pico; G. J. Morelli; V. I. Machicao; C. Levy; R. Cabrera; S. Fujita; A. W. Hemming; A. I. Reed; N. R. David.

 

Introduction:

Cyclosporine(CsA) is an immunosuppressive agent used in the management of liver transplant(LT) recipients. Recent studies have demonstrated an antiviral effect in vitro in the hepatitis C (HCV) replicon culture system.

 

Aim:

To determine the effect of CsA vs tacrolimus(TAC) in viral clearance in LT recipients with recurrence HCV infection during therapy with combination PEG-interferon and ribavirin.

 

Methods:

Patients with progressive HCV recurrence (Ishak Stage≥2) have been enrolled in a single-center study from 2004 to present. Patients are randomized to stay on TAC or to change to CsA for baseline immunosuppression with one-month washout period before starting interferon. Both groups received therapy with PEGα-2a and ribavirin x 48 weeks for genotypes 1, or 24 weeks for genotypes 2/3. Prior to therapy, immunosuppression is tapered to CsA/TAC monotherapy. HCV-RNA is assessed at entry, week 12(EVR), 24, 48-weeks(ETR), and 6-months after ETR(SVR). Liver biopsies are performed at inclusion and at the end of treatment.

 

Results:

37 patients have been enrolled in the study to date, and 31 patients have reached 24 or 48 weeks of therapy. Of the 31, 24(80%) are men, 24(80%) Caucasian, and 27(90%) genotype 1. The mean age is 53 ± 6 yrs. 27 patients have completed 6-month follow-up after end-of-treatment. EVR was achieved in 12 patients(8 undetectable, 4 two-log drop) on CsA vs 8 patients(7 undetectable, 1 two-log drop) on TAC(p=0.08). The mean drop in HCV-RNA during the first month on CsA before initiation of interferon was 2.9 million IU/ml(p=0.3). The mean drop in HCV-RNA at EVR for CsA and TAC was similar (3.1 vs 3.4 million IU/ml), respectively. ETR was achieved by 8 patients on CsA and 6 on TAC(p=0.23). SVR data was available for 27 patients, 4 patients in each arm achieved SVR. See table below. One patient died in the CsA arm due to chronic rejection after initiation of interferon therapy. Overall adverse events were similar in each group.

 

Conclusions:

Change from TAC to CsA led to a significant HCV RNA drop and improvement in EVR; however, no significant changes in SVR at the time of the analysis. CsA may offer an advantage to TAC in those patients undergoing PEG-based therapy. Larger randomized-controlled studies are needed to further investigate these findings.

 

 

TAC

CSA

Baseline HCV RNA IU/mL (mean)

3.8 x 106

3.2 x 106

Baseline ALT U/L (mean)

150 ± 123

125 ± 78

Initial Ishak Fibrosis Score (mean)

2.1

2.9

Early Virological Response

8/16 (50%)

12/15 (80%)

End of Treatment Response

6/16 (38%)

8/14 (57%)

Relapse

0/14 (0%)

3/14 (21%)

Sustained Virological Response

4/14 (29%)

4/14 (29%)

 


626. Renal Insufficiency after Liver Transplantation in the MELD Era Compared to the Pre-MELD Era. 

Z. Feng; J. Tang; M. Abouljoud; J. Arenas; K. Brown; S. Gordon; D. Kim; M. Sherbondy; A. Yoshida; T. Pham; G. Divine; D. Moonka.

 

Background:

The model for end-stage liver disease (MELD) score for patients awaiting orthotopic liver transplant (OLT) was implemented in 2002. Because the MELD system gives priority to patients with a higher creatinine, and because pre-OLT renal function is an important determinant of post-OLT renal function, the current study compares the burden of renal insufficiency in the pre-MELD and MELD eras.

 

Method:

We identified all OLT patients at our center from 1995 to March 2005 who underwent an initial liver transplant with graft and patient survival of at least one year. A total of 354 patients were divided into 211 patients in the pre-MELD cohort and 143 patients in the MELD cohort. We compared renal function in the two groups using the glomerular filtration rate (GFR) as calculated by the validated Modification of Diet and Renal Disease formula. Data on sirolimus conversion, end-stage renal disease (ESRD), and death were also evaluated. Patients with a combined kidney-liver transplant were excluded.

 

Results:

Comparisons between the pre-MELD and the MELD cohorts were similar in baseline characteristics including age, sex, HCV infection, BMI, diabetes, and hypertension. Hepatocellular carcinoma was more common in the MELD cohort than the pre-MELD cohort (21% vs. 6%, P<0.001). The laboratory MELD score was similar between the two groups. The GFR (ml/min/1.73m2) at the time of transplant, discharge, and 12 months was significantly higher in the MELD cohort than the pre-MELD cohort (see table). Actuarial analysis showed no difference in the two groups in incidence of ESRD. There was improved overall survival (P=0.045) and a higher rate of sirolimus use (P=0.001) in the MELD era. While patients who had a combined liver-kidney transplant were excluded from the analysis, patients were more likely to have a combined transplant in the MELD era (6.2% vs 2.6%, P=0.071).

 

Conclusions:

o       The concern about greater renal insufficiency in the MELD era was not realized at our institution.

o       Our comparison of renal insufficiency actually demonstrated an improvement in renal function in the MELD era at the time of transplant, discharge and month 12.

o       Potential explanations for this include:

o       A lack of difference in the calculated MELD scores in the pre-MELD and MELD ears

o       A higher rate of transplants for hepatic cellular carcinoma in the MELD eara (21%) compared to the pre-MELD era (6%)

o       An earlier and greater use of sirolimus in the MELD era

o       A greater use of kidney-liver transplants in the MELD era (6.2%) compared to the Pre-MELD eara (2.6%) for patients with advanced renal insufficiency (P=0.071)   

o        a higher rate of transplants for HCC, an earlier and increased use of sirolimus and a greater use of kidney-liver transplants in the MELD era for patients with advanced renal insufficiency.

 

 

Pre-MELD

MELD

P-valve

GFR at Transplant

85.3

95.5

0.041

GFR at Discharge

77.4

90.4

0.002

GFR at 12 Months

60.3

66.8

0.028

GFR at 18 Months

58.8

63.6

NS

GFR at 24 Months

59.3

64.0

NS


627. Evidence that an extension of Milan criteria to 5-5 criteria does not impact survival nor HCC recurrence after liver transplantation for hepatocellular carcinoma. 

H. M. Badran; C. Meyer; R. Adam; A. Plessier; F. Durand; O. Boillot; J. Dumortier; S. Dharancy; M. Hilleret; T. Decaens; D. Cherqui; C. Duvoux.

 

Background and Aim:

We recently suggested on a large cohort of pts transplanted for HCC between 1988 and 1998 that 5-year survival rates were similar (61% vs 55%, p=0.2) between pts within Milan criteria or fulfilling the following extended criteria : tumors < 5 in number and with max. diameter of the largest nodule < 5cm*, i.e. the 5-5 criteria.

 

The aim of this study was to reassess the results of these extended criteria on a more recent cohort of pts transplanted for HCC in France.

 

Patient and methods:

A retrospective analysis of 168 patients transplanted between 1999 and 2001 for HCC without venous obstruction in 7 French centers comprised 133 Milan + pts, and 35 Milan – pts fulfilling the 5-5 criteria. The survival and recurrence rates, and the tumor features of these 2 groups were compared.

 

Results:

The 5-year survival rates were similar in the Milan+ pts and 5-5 pts (79.5% vs 80.0% , p=0.46, Log rank test), with a similar rate of post-operative mortality (6.2% vs 5.7%). HCC recurrence rate did not differ between the 2 groups (8.9% vs 11.8% p=0.26).

 

These results were observed despite the following significant differences between pre-LT tumors characteristics in Milan + and 5-5 pts : pre-LT AFP : 111.3±439 ng/ml vs 388.2±839.3 p=0.015, pre-LT number of nodules : 1.6±0.8 vs 3.2±1.2, p<0.0001, pre-LT diameter of largest nodule : 2.4±0.9 cm vs 3.5±1.0 cm, p<0.0001, pre-LT sum of diameters : 3.2±1.3cm vs 6.2±1.4 cm, p<0.0001. On the explanted liver, all the aforementioned criteria were comparable between the 2 groups: post-LT number of nodules: 3.1±5.3 vs 4,5±3.6, p<0.07, post-LT diameter of largest nodule : 3.0 ±2 cm vs 3.5±1.7 cm, p<0.23, post-LT sum of diameters : 5.5±3.9cm vs 6.8±3.9 cm, p<0.14. The prevalence of well differentiated tumors were comparable in both groups (64% vs 63%=0.88) and no difference was noted in the rate of micro-vascular invasion (24.8% vs 32.3%, p=0.54)

 

Multiple regression analysis revealed that only micro-vascular invasion (p=0.04, OR 7.8) and degree of differenciation (p=0.03, OR=12.4) were independently related to recurrence but not the pre or post-LT size and tumors number, whereas independent factors related to mortality were age at LT (p=0.028, OR=1.1) and degree of differenciation (p=0.003, OR=7.0).

 

Conclusion:

This study shows that a moderate extension of transplantation criteria to HCC < 5 nodules and largest< 5 cm does not impact tumor recurrence rates and confers an excellent post-transplant survival comparable to that of Milan positive patients, close to 80%. The 5-5 criteria can therefore be proposed as extension criteria for LT for HCC.

 

* Duvoux et al. AASLD 2005

 


629. Transjugular Intrahepatic Portosystemic Shunts (TIPS) are Associated with a High 1-year Mortality in Liver Transplant Recipients. 

J. J. Kim; R. J. Fontana; N. L. Dasika.

 

Background:

Complications of portal hypertension and graft failure are increasingly being reported amongst liver transplant (LT) recipients with recurrent liver disease and cirrhosis. The utility of TIPS for post-LT ascites and variceal bleeding is not well described. The primary aim of our study was to determine the efficacy and safety of TIPS in LT recipients with advanced portal hypertension.

 

Methods:

Between 8/85 and 12/04, 14 of 1266 LT recipients (1.1%) at a single center underwent TIPS for recurrent variceal bleeding or refractory ascites. Pre-TIPS laboratory and clinical features as well as post-TIPS outcomes were retrospectively reviewed.

 

Results:

14 LT recipients with median age 52 years (r: 13-68 years) underwent attempted TIPS but 3 were unsuccessful due to technical failure (2 PV thromboses, 1 IVC stent). 64% were male, 57% had HCV infection, and the median time from LT was 46 mon (r: 3-183 mon). Amongst the 11 patients undergoing successful TIPS, the mean lab MELD score was 17.1 ± 5.8 and 6 (55%) had biopsy proven cirrhosis. Indications for TIPS included refractory ascites in 7 and bleeding varices in 4. The mean pre-TIPS hepatic portal venous gradient (HVPG) of 18.3 ± 6.1 mm Hg was significantly reduced to 9.0 ± 3.5 mm Hg post-TIPS (P <0.01) and 8 (73%) patients achieved an HVPG <12 mm Hg.

 

However, only 50% of the varices patients had no further bleeding and 57% of the ref ractory ascites patients required no further paracenteses. In addition to peri-procedural complications of death in 1 patient and renal failure in 3 others, 4 patients (29%) developed infection.

 

During follow-up, 9 patients (82%) developed new onset or worsening encephalopathy at a median of 11 days (r: 2-73 days) post-TIPS. None of the 14 patients were retransplanted and the actuarial 3-month and 1-year patient survival was 57% and 14%, respectively. 8 of the 10 deaths (80%) were liver related while 2 patients died of other causes.

 

Conclusion:

Liver transplant recipients with refractory ascites and bleeding can achieve adequate portal decompression post-TIPS but the rate of peri-procedural complications is higher than that reported in non-LT patients. Over 50% of patients experienced improved control of ascites or bleeding but 82% developed new onset encephalopathy. The low 1-year survival following TIPS placement of 14% indicates that LT recipients with complications of portal hypertension have a very poor short-term prognosis in the absence of retransplantation.

 


631. Prevalence and predominant factor of low bone mineral density among patients awaiting liver transplantation. 

T. Liang; X. Bai; L. Wu; J. Li; S. Zheng.

 

Introduction:

Hepatic osteodystrophy occurs in the majority of patients with advanced chronic liver disease and transplant patients experience rapid loss of bone leading to high fracture rates early after liver transplantation. BMD is currently recommended method to determine bone mass.

 

Aim:

The goal of this study was to investigate the frequency and predictors of low bone mineral density (BMD) among patients awaiting liver transplantation. BMD of the lumbar vertebrae (L) and femoral neck (F), measured by dual-energy X ray absorptiometery, were obtained in 64 pre-transplant patients between September 2005 and March 2006. Markers of bone metabolism including serum calcium, phosphorus, parathyroid (PTH), bone alkaline phosphatase, olsteocalcin, and urinary hydroxyproline were assessed as well. Osteoporosis was defined according to the World Health Organization criteria for osteoporosis as a T score of less than –2.5 and osteopenia as a T score between –1 and –2.5.

 

Patients with osteoporosis and osteopenia were included in the group of low BMD. Both univariate and multivariate models were utilized for statistical analysis. P values < 0.05 were considered statistically significant. No patient had history of fracture in this series. The mean BMD at L and F were 1.035+0.132 and 0.962+0.150, respectively.

 

Results:

The mean T score at L and F were -1.2+1.1 and 0.2+1.1, respectively. Low BMD was found in 36 patients (36/63, 56.2%), including osteoporosis in 6 (6/64, 9.3%) and osteopenia in 30 (30/64, 46.9%). Of all variables (gender, age, primary disease-cholestatic versus non-cholestatic, Child-Tucotte-Pugh classification, model for end liver disease score, serum calcium, phosphorus, parathyroid (PTH), bone alkaline phosphatase, olsteocalcin, and urinary hydroxyproline), cholestatic liver disease and high level of PTH were found to be significantly associated with low BMD by univariate analysis. Only PTH was identified as an independent risk factor of low BMD by multivariate analysis. Median PTH was 55.6 pg/ml (range 7.8~337 pg/ml) in the low BMD group compared with 33 pg/ml (range 3~162 pg/ml) in the non-low BMD group (P< 0.05).

 

Conclusion:

This study revealed high incidence of low BMD among liver transplant recipients preoperatively and high PTH was predominant factor associated with low BMD. Both BMD and PTH should be routinely measured to identify statues of bone mass and bone metabolism in recipients prior to liver transplantation, being a guide of prevention and therapy for bone loss posttransplantation.

 


633. The Development of Hepatic Granulomas in Patients Receiving Pegylated Interferon Therapy for Recurrent HCV Post Liver Transplantation. 

M. Fiel; D. Shukla; N. Saraf; R. Xu; T. D. Schiano.

 

Introduction:

Infrequently hepatitis C (HCV) appears to be the cause of hepatic granulomas. Interferon (Ifn) therapy for HCV has been increasingly associated with the development of sarcoidosis.

 

Aims:

We sought to determine the incidence of hepatic granulomas in patients with recurrent HCV post-LT and to ascertain their potential significance in response to antiviral treatment.

 

Methods:

Between 1994-2005, 820 patients were transplanted for HCV at our institution. The pathology database was searched for patients having recurrent HCV and granulomas. At Mount Sinai, protocol biopsies have been performed for the last two years in patients receiving pegylated-Ifn-α-2b and ribavirin (PEG) for recurrent HCV. Number, location, size of the granulomas and presence of fibrosis were noted. Review of slides from explanted livers, pre- and post-perfusion biopsies and all biopsies of the allograft livers were re-evaluated. Lipogranulomas were excluded because of their frequent association with steatosis. Patient demographics, and duration of PEG treatment if any, were recorded.

 

Results:

10,225 liver biopsies were performed on HCV patients and 25 (0.24%) showed noncaseating epithelioid granulomas. Hepatic granulomas were detected in 14 post-LT HCV patients; nine patients received PEG. Typically only one lobular granuloma was found. The granuloma was small, poorly-formed and often showed entrapment of hepatocytes. None of these patients had granulomas in the native liver or in any biopsy prior to Ifn therapy; 6/9 patients had undetectable HCV-RNA levels and 4 had sustained viral response. No other cause for granuloma formation was identified in the six patients.

 

Conclusions:

Hepatic granulomas are infrequently found in HCV liver biopsies and rarely found in post-LT biopsies with recurrent HCV. When present, they occur more commonly in patients receiving and virologically responding to PEG therapy. The presence of granulomas in patients with HCV being treated with PEG does not warrant an extensive etiologic workup for granulomatous hepatitis unless otherwise clinically indicated.

 

Patients with granulomas that had virological response to Ifn

Case

Ifn/Riba dose
ug/mg

Duration of therapy
(mos)

Viral Response

Time to treatment response

Genotype

Time to HG formation (mos)

Protocol biopsy?

1

180/800

12

SVR

8

3a

7

yes

2

180/1200

12

SVR

8

1a

8

yes

3

135/1200

12

ETR

6

1a

12

yes

4

120/800

20

SVR

19

1a

30

yes

5

135/800

42

SVR

39

unk

35

yes

6

180/400

8

Currently remains negative

2

1b

4

yes

ETR = end of treatment response SVR = sustained viral response

 


636. Age, creatinine and liver function but not MELD predict 6-month survival after liver transplantation: clinical and economic considerations. 

T. Weismueller; H. Barg-Hock; M. P. Manns; J. Klempnauer; T. Becker; C. P. Strassburg.

 

Introduction:

Liver transplantation (OLT) is substantially burdened by the significant shortage of organs. In the Eurotransplant zone (ET) the severity of liver disease is grouped into medical urgency criteria (MUC) to ensure necessity-oriented OLT. The group of T2-patients exhibiting 11 Child-Pugh points or more with a reduced post OLT survival is increasing. Pre-OLT management therefore requires parameters capable of predicting short term outcome in an attempt to optimize preoperative management.

 

Methods:

104 consecutive OLT patients (May 2004 - April 2005) were analyzed retrospectively and represent a homogeneous cohort without changes in graft allocation or transplant procedures. Statistical analyses were performed using Mann-Whitney-test and multiple logistic regression.

 

Results:

104 patients (61.5% men, mean age 46.3±12.1 years) were transplanted: 25% viral Hepatitis (10.6% Hepatitis B, 14.4% Hepatitis C), 20.2% primary sclerosing cholangitis, 13.5% alcoholic liver disease, 10.6% metabolic liver disease (5.8% hemochromatosis), 6.7% primary biliary cirrhosis. 13.5% had developed hepatocellular carcinoma. 56.7% were ET status T2, 33,7% were T3, 9.6% underwent high urgency OLT. Overall 6-month-survival was 84.6%. The majority of deaths were because of multi organ failure. T2-patients had a lower 6-month-survival (T2: 81.4%, T3: 91.4%), longer pre-OLT hospitalization (26.8+-3.7 vs 11.3+-3.1 days, p=0.002) leading to higher costs (€9015.69 vs. €4276.57, p=0.005). Patients who died within 6 months of OLT were older (52.4 ± 2.5 vs. 45.2 ± 1.3 years, P= 0.041) with lower choline esterase (2.3±0.4 vs. 3.7±0.2 kU/l, P=0.004). Body mass index was not significantly different (24.8±1.3 vs. 24.5±0.5 kg/m2). Serum-creatinine (P=0.034), sodium (P=0.048) and choline esterase (P=0.019) but not pre-OLT MELD were independent parameters of 6-month survival. Pre-OLT creatinine >140 mM/L and choline esterase <2kU/L predicted a 6-month-survival of 70% and 68%, respectively.

 

Discussion:

The allocation of organs to patients with severe liver failure has lead to an increase of OLT in patients with a reduced prognosis (ET T2). Pre-OLT age, creatinine and choline esterase but not MELD are predictors of short term post-OLT survival. In view of an increased utilization of resources, higher costs, lower survival rates, and a resulting increase of waiting time for less critically ill patients (T3) these parameters may be helpful as a simple bedside score for pre-OLT clinical management, outcome prediction and decision making.

 


637. Rate Of Progression Of Portopulmonary Hypertension Over A Short Time Interval In Patients Awaiting Liver Transplant. 

S. Khara; A. Samanta; B. Koneru; D. O'Hare; A. Fisher; A. De la Torre; D. Wilson; M. DebRoy.

 

Introduction:

Development of pulmonary artery hypertension in patients with portal hypertension, also called portopulmonary hypertension (PPHTN), carries significant perioperative mortality with increasing pulmonary artery (PA) pressure in patients undergoing liver transplant (OLT). New-onset PPHTN in patients awaiting OLT has recently been reported despite normal PA Pressure at initial evaluation. This raises important questions about the rate of progression of PPHTN, which may shed light on its pathophysiology and influence our assessment of PPHTN. To our knowledge, there are no studies on the rate of progression of PPHTN using mathematical model of progression of PA hypertension.

 

Aim:

Present study is an analysis of patients with PPHTN including calculation of the rate of progression of PA hypertension.

 

Material and Methods:

Of 503 patients evaluated by 2D echocardiography from November 1999 to March 2003, nine had right heart catheterization for PPHTN. Of these, cardiac catheterization data was available for seven patients, and five had follow-up 2D echocardiography with sequential PA pressure measurements over subsequent 3-24 months for calculating the rate of progression of PPHTN. A linear regression model (y=m x + c, m is the slope and c is the y intercept) was used to correlate measured PA Pressure against time with slope of the regression providing the rate of progression of PA hypertension.

 

Results:

There were 5 females and 2 males. Mean age was 49.3 + 2.8 years (range 42-59). Etiology of liver disease was primary sclerosing cholangitis, alcoholism and autoimmune hepatitis in one each, chronic hepatitis C in 2 and cryptogenic in 2. MELD score was 13.2 + 1.3 (range 9-17). Cardiac output was 7.0 + 1.0 L/min (range 4.6-11.4), base line PA systolic mean pressure was 56.5 + 6.1 mm Hg (range 30-90), pulmonary vascular resistance was 277 + 52.5 dynes.s.cm-5 (range 178-357) and all had tricuspid regurgitation. Based on our mathematical model, the rate of progression of PPHTN was 1.06 + 0.3 mm Hg/month and ranged from 0.25 to 2.15 mm Hg/month. There was no correlation between the rate of progression of PPHTN and either the severity of liver disease (MELD score) or the hyperdynamic cardiac output.

 

Conclusion:

The study shows an appreciable rate of progression of PPHTN in patients awaiting OLT, which is not related either to the severity of liver disease or to hyperdynamic systemic hemodynamics. Our findings confirm that PPHTN can be progressive even over a short time interval and support the role of altered vasomotor tone in the pathophysiology of the disease. The rate of progression of PPHTN may influence our future practice of assessing PPHTN in patients awaiting OLT.

 


640. Liver transplantation for hepatocellular carcinoma over two decades. A single center experience. 

R. Goldstein; S. Chinnakotla; G. Narasimhan; D. Orr; T. Uemura; L. W. Jennings; D. Chase; R. Ruiz; G. McKenna; H. Randall; E. Sanchez; M. Levy; G. Klintmalm.

 

Introduction:

This is a report of our 20 years of experience in liver transplantation (LTx) for hepatocellular carcinoma (HCC) with emphasis on recent multi-modality approach and results.

 

Methods:

Between January 1985 and January 2005, 248 primary orthotopic liver transplants were performed for HCC in patients with coexisting liver disease who met the UNOS criteria and were not resectable. 163 patients also received systemic chemotherapy (doxorubicin 10mg/M2) intraoperatively and postoperatively for 20 weeks. From the year 2000, we added tumor ablative treatment (chemoembolization; radiofrequency thermoablation, alcohol ablation or cryoablation) in patients (n=86) awaiting liver transplantation.

 

Results:

Patients and recurrence-free survival are shown in the Table. Use of any form of ablative treatment in patients waiting for LTx significantly improved recurrence-free survival (p=0.0035). Implementation of MELD system for organ allocation significantly has reduced the waiting times.

 

Univariate analysis showed that solitary tumors (p=0.0009) and unilobar tumors (p=0.004) had a significantly higher recurrence-free survival (Table). Vascular invasion (p=0.0001) had a negative impact on survival. Tumor size (p=0.0001) correlated with the recurrence-free survival. Well differentiated tumors (p<0.05) (Grade I & II) had a significantly better survival than poorly differentiated tumors (Grade III and IV). The higher the number of nodules (p=0.001) the worse the recurrence-free survival.

 

Conclusions:

The results of liver transplantation have significantly improved over the last 2 decades. The shorter waiting period and use of ablative treatment have significantly contributed to improved results.

 

 

1985-1989
(N=24)

1990-1994 (N=49)

1995-1999 (N=53)

2000-2004 (N=122)

P

% Patient Survival 1yr/2yr/5yr

79/71/37

63/53/32

73/66/52

91/88/77

<0.001

% Recurrence-free survival 1yr/2yr/5yr

67/50/33

57/45/24

70/58/47

91/89/74

<0.001

Median waiting period in days

10 ± 8

38 ± 78

224 ± 160

94 ± 333