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
|
|
-/+ |
+/+ |
-/- |
+/- |
|
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.