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. Nuñez-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.