Sunday Poster Sessions, October 29, 2006

Living Donor and Split Liver Transplantation

Metabolic and Genetic Disease

Pediatric Liver Disease

 

642. HISTOLOGICAL ABNORMALITIES FOUND ON LIVER BIOPSIES OF APPEARENTLY HEALTHY POTENTIAL LIVER DONORS.

N. Savas; I. Uruc; O. Demirhan; H. Sumer; B. Bilezikci; H. Selcuk; G. Gur; U. Yilmaz; H. Karakayali; M. Haberal.

 

Background:

Living donor liver transplantation(LDLT) has acquired widespread acceptance. A through workup of the potential living donor is guided by two objectives.(1) assuring the safety of the surgical procedure for the donor, and(2) identifying donor grafts that pose potential risks for the recipient.

 

Aim/Methods:

Our aim was to evaluate the importance of preoperative donor liver biopsy in the selection of candidates for LDLT at our institution.We retrospectively analyzed the 5 years(2001-2006) data of 305 living related liver donors for 96 liver transplant recipients, at our institution.Our evaluation protocol consisted of 4 steps, the first step being the clinical evaluation with history and physical examination, blood group typing, hematological, biochemical and serological tests for viral hepatitis, abdominal ultrasonography(USG) and also psychological evaluation, second step is consisted of evaluation for cardiological and pulmonary diseases, third step is abdominal computerized tomography(CT) or abdominal magnetic resonance imaging and liver volume measurement, and fourth step is liver biopsy.

 

Results:

Out of 305 living related liver donors, 201 of them were reached to step 4 for liver biopsy.  All of those patients’ liver function tests and serological tests were within normal limits. One hundred and eight(53.7%) and 93( 46.3%) of them were male and female respectively. Mean age of donors was 38.3±10.9 years. Forty-one of 201 patients had steatosis on abdominal USG or CT.Thirty-three of 41 patients had mild steatosis, 2 patients had moderate and 6 patients had severe steatosis. Out of 201 patients’ liver biopsy specimens, 94(46.8%) of them was normal,107(53.2%) of them was with pathological findings. Out of 107 patients with pathological findings on biopsies,60 (56%) patients had hepatocellular injuries, 32(29.9%) patients had fatty change,6 (5.6%) patients had fibrosis, 3(2.8%) patients had hepatitis of unknown etiology, 4(3.7%) patients had steaotohepatitis, and 2 (1.8%) patients had granulomatosis reaction on biopsy. Out of 160(80%) patients with normal abdominal USG or CT findings,84(52.5%) of them had normal findings,76(47.5%) had abnormal findings on liver biopsy.

 

Conclusions:

Our data shows that near half of the living related liver donors, absolutely appearing healthy, had pathological findings on liver biopsies, the most common pathological findings being the hepatocellular injuries and hepatosteatosis.  As it is known that each percentage of steatosis or hepatocellular injuries might reduce the functional mass of the graft, we recommend that liver biopsies should take place in all evaluation protocol of living related liver donors in transplantation institutions.


643. HLA and Living-Donor Liver Transplantation Outcomes – An Analysis of the OPTN Database.

S. Jakab; C. Daskalakis; S. Rossi; S. K. Herrine; B. W. Colombe; V. J. Navarro.

 

Background:

The impact of HLA compatibility on living-donor liver transplantation (LDLT) outcomes is of particular interest because of a higher chance of donor/recipient HLA matching when the graft is from a blood-related donor. Furthermore, in liver diseases of autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis), donor/recipient pairs with similar HLA profiles may trigger immune-mediated recurrence of disease. However, previous studies addressing these issues report contradictory results and often lack subgroup analysis based on the etiology of liver disease.

 

Aim:

To investigate the impact of HLA match/mismatch on 5-year graft survival in adult LDLT, with further analysis of patients with autoimmune versus non-autoimmune etiologies of liver disease.

 

Methods:

OPTN (Organ Procurement and Transplantation Network) database was used to identify first-time adult living-donor liver transplant patients with available HLA A, B, and DR profile. Graft failure was defined as retransplantation or death from a transplant-related cause. 5-year survival was analyzed with the Kaplan-Meier method. Multi-variable Cox proportional-hazard models were used to evaluate the association between the degree of HLA mismatch and graft failure, while controlling for potentially confounding variables (e.g. age, sex, and race for donor/recipient, donor/recipient relationship, medical condition at transplantation, treatment year). Separate analysis was conducted for recipients with autoimmune versus non-autoimmune liver disease.

 

Results:

635 donor/recipient pairs with complete HLA data were evaluated from a pool of 1845 adult living-donor liver transplants performed between 1991-2005. Of those, 174 patients had autoimmune etiologies of liver disease. The 5-year graft survival was not statistically significant for any HLA match/mismatch category, either overall or in the non-autoimmune subgroup of patients. However, there was a tendency for decreased graft survival in the autoimmune subgroup for the patients with fewer than 3 mismatches, but it was not statistically significant (adjusted HRs of 0.22, 0.49, 0.50, 0.44, for 3, 4, 5, 6 HLA mismatches, respectively, compared to <3 mismatches, p=0.421).

 

Conclusions:

1.     The degree of HLA compatibility does not influence the overall graft survival in adult living-donor liver transplantation.

2.     Patients with autoimmune etiologies of liver disease (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) may benefit from receiving a graft from a donor with more than 3 HLA mismatches, but larger studies in this population are necessary to verify our observation.

 


644. Evaluation for hepatic steatosis in Japanese living liver donors and outcome of dietary intervention. 

N. Yamashiki; Y. Sugawara; S. Tamura; J. Kaneko; N. Kokudo; K. Nojiri; M. Omata; M. Makuuchi.

 

 

Background:

Hepatic steatosis is associated with higher risk of primary non-function and complications after liver transplantation. Lower degree of steatosis is considered suitable for LDLT compared to DDLT. We report our cumulative experience of dietary intervention for living liver donor candidates.

 

Methods:

Between January 2004 and June 2005, 177 potential donors started medical evaluation for 148 adult recipient candidates. Only donors with macrovesicular steatosis less than 10%, conformed by percutaneous liver biopsy (PBL), were accepted for partial hepatectomy for donation at our program. Dietary intervention followed by PBL was indicated when subject met any of followings; AST/ALT ratio less than 1.0, BMI25, and bright liver by ultrasonography. All donor candidates were required total abstinence. Bibliographic and laboratory data of donor candidates meeting dietary intervention criteria (PLB group) were compared with those not meeting criteria (control).

 

Results:

Among 177 potential donors, 92 met our criteria. The median age was 42 (19-64) years at the initial screening. Compared to control, PLB group was male dominant (70% vs 40%), higher ALT value (31±19 IU/ml vs 15±9 IU/ml), and higher BMI (23±2.9 vs 22±2.2). Among PLB group, 58 were otherwise eligible for liver donation, and agreed to start dietary intervention followed by PLB. Among 17 (29.3%) donors with BMI >25, immediate PLB was performed in 3; 2 showed steatosis>10%. After median of 38(16-127) days of dietary intervention, 10 reduced 8±2.2 kg, and met our pathological criteria at their first (n=8) or second (n=2) PLB. 7 abandoned donation due to recipients death during dietary intervention. Among 41 (70.7%) donors with BMI<25, 7 revealed mild steatosis (13%-46%) at the first PLB. 5 of them successfully reduced 4±0.6 kg after 68(37-127) days, and the second biopsy revealed steatosis less than 5%. In other 2, hepatic steatosis was not resolved at the second PLB even after dietary intervention. 31 with BMI<25, PLB was performed 29 (4-325) days after alcohol abstinence and hepatic steatosis<10% was confirmed at the initial biopsy. 3 required emergent LDLT; because ALT level was within normal range, PLB was skipped in these 3 cases. Eventually, 39 among PLB group and 45 among control underwent partial hepatectomy. We encountered no primary non-function after LDLT. Hospital death occurred in 4% and 1 year patient survival was 92%.

 

Conclusions:

Dietary intervention and histological confirmation were effective among Japanese living donor candidates, and lead successful living donor liver transplantation. Our criteria may be applicable for living liver donor evaluation among Asian population.

 


646. Liver regeneration in living donors of right and left liver grafts until 1 year. 

T. Aoki; H. Imamura; T. Kobayashi; Y. Kishi; N. Kokudo; Y. Sugawara; M. Makuuchi.

 

Introduction:

The practice of living-donor liver transplantation (LDLT) has made it possible to study the time-pattern of liver regeneration after major resection of the normal liver. While some previous studies have suggested that rapid liver regeneration occurs within a few weeks, few studies have documented a long-term regeneration process and some differences in the process between right and left liver graft donors.

 

Aim:

The aim of the present study was to clarify the chronological profiles of liver regeneration after donor hepatectomy, focusing on both the early (within 1 month) and the late (until 1 year) postoperative phases.

 

Methods:

Out of 63 LDLT donors carried out between May 2001 and September 2002, 33 participated in the present study after providing written informed consent. Enhanced abdominal computed tomography (CT) was conducted preoperatively in each donor, and repeated at 1 week, 2 weeks, 1 month, 3 months, 6 months and 12 months after the surgery. The liver volume was calculated using the CT volumetry method. Results: The donors consisted of 22 males and 11 females, with an average age of 36 years. The BMI of all the donors was <23. The hepatectomy procedure in the donors was right hepatectomy in 23 cases, left liver resection in 6 cases, and right lateral sectoriectomy in 4 cases. The former 2 procedures were classified as the Right group (corresponding to resection of approximately 2/3 liver volume), and the latter 2 procedures as the Left group (corresponding to resection of about 1/3 liver volume). The ratios of the regenerated liver volume to the preoperative liver volume at 1 week, 2 weeks, 1 month, 3 months, 6 months and 12 months after the operation (%, mean±SEM,) were 43±5, 50±5, 54±5, 61±7, 71±7, 75±6, and 79±5, respectively, in the Right group, and 62±5, 67±2, 70±2, 77±6, 81±10, 85±10, and 83±8, respectively, in the Left group. The inter-group difference became insignificant at 3 months postoperatively. It is of interest that the mean regeneration ratio in the Right group (median (range)) was 79 % (68-97 %), and exceeded 90 % in only one donor. The regeneration ratio in the Left group was 83 % (68-94 %). The results of univariate analyses revealed that the regeneration ratio was not affected by the gender or age of the liver graft donors.

 

Conclusions:

In liver graft donors for LDLT, 1) about 50 % of the lost liver volume was restored by regeneration within a month of the graft donation. 2) The liver volume was restored to 80 % of the original liver volume within a year. The late phase regeneration is rather slow. We propose to conduct further follow-up of these subjects to evaluate the long-term results over years.

 


648. Comparison of Complication Rates in Recipients of Living Donor and Deceased Donor Liver Transplants: Findings from the Adult to Adult Living Donor Liver Transplantation Cohort Study (A2ALL). 

C. E. Freise; B. W. Gillespie; A. J. Koffron; A. S. Lok; T. L. Pruett; J. C. Emond; J. H. Fair; R. A. Fisher; K. M. Olthoff; J. F. Trotter; R. Ghobrial; S. and the A2ALL.

 

Background:

Comparisons of the incidence and severity of recipient complications of living donor (LDLT) and deceased donor (DDLT) liver transplants have been limited mainly to small, single center evaluations. A2ALL is a multicenter study of potential adult LDLT recipients, of whom a large proportion eventually received DDLT rather than LDLT. This study examined post-transplant morbidity in recipients of LDLT and DDLT from the A2ALL study.

 

Methods:

Candidates were eligible for enrollment in A2ALL if they had a potential donor evaluated. Detailed structured chart reviews were conducted. This report considers all single organ recipients of either DDLT or LDLT at the nine A2ALL centers between 1998 and 2003. Median follow-up was 2.1 years. Complications were recorded and graded using the Clavien grading system.

 

Results:

Among a total of 384 LDLT and 216 DDLT, 16.9% of LDLT and 21.8% of DDLT recipients had no complications. A larger median number of complications per recipient occurred in the LDLT vs. DDLT group (median 3 vs. 2; P=0.0124). Complications occurring at a higher rate (P<0.05) in the LDLT group included biliary leak (32% vs. 10.2%), unplanned re-exploration (26.3% vs. 17.1%), hepatic artery thrombosis (6.5% vs. 2.3%), portal vein thrombosis (2.9% vs. 0.0%), GI bleeding (8.6% vs. 2.8%), recurrence of disease excluding HCV and HCC (5.2% vs. 1.9%), and biliary tract infection (9.4% vs. 3.2%). Complications occurring at a higher rate (P<0.05) in the DDLT group included pulmonary edema (20.8% vs. 12%), respiratory arrest (6.9% vs. 3.1%), hepatic encephalopathy (10.2% vs. 4.7%), pulmonary fungal infection (6.5% vs. 1.8%) and fungal urinary infection (5.6% vs. 1.8%). A significantly greater number of Clavien grade 4 complications (resulting in re-transplant or death) occurred in the LDLT group (16.1% vs. 9.3%; P=0.0184). The adjusted odds ratio (AOR) of a grade 4 complication after LDLT when center case number was ≤20 (LDLT≤20) was significantly higher than DDLT (AOR 2.89; P=0.0004), but not significantly different vs. DDLT after LDLT center case number >20 (LDLT>20) (AOR 1.2; P=0.5357). Overall, LDLT was associated with a higher risk of biliary leak (AOR 4.2; P<0.0001). The excess bile leak risk for LDLT vs. DDLT significantly decreased as center experience increased (LDLT≤20 AOR 5.6; LDLT>20 AOR 3.3; P=0.021).

 

Conclusions:

Compared to DDLT, several complications are more frequent in LDLT recipients, especially biliary leak. Biliary complications in LDLT recipients and complications leading to death or re-transplant occur at a lower rate once centers have more LDLT experience.


649. The Impact of a Donor Advocacy Committee on the Evaluation Process of Living Liver Donors.

K. Shetty; A. Lu; S. Shaneyfelt; L. Johnson.

 

Introduction:

Recent United Network for Organ Sharing (UNOS)guidelines for the selection of living donors recommends appointing an Independent Donor Advocacy Team to safeguard donor well-being. We undertook this study to examine the impact of a recently established institutional Donor Advocacy Committee (DAC)on the selection process.

 

Methods:

Potential living liver donors who approached our program between October 1999 and March 2006 were included. The intake date was the first date on which the potential donor established telephonic contact. The interval between the intake date, and the decision date was denoted as the evaluation time. The rate of non-acceptance was denoted as the percentage of potential donors who were rejected on the basis of medical, psychosocial or anatomical concerns. The Chi square test was used to compare means.

 

Results:

132 potential donors made an initiating phone call;18 did not follow-through or were ABO incompatible, and were excluded from further analyses. Seventy nine individuals were evaluated prior to DAC establishment-27 were excluded because of donor unsuitability, 21 due to recipient issues (death, decompensation, or a deceased donor liver transplant), 8 because of miscellaneous issues, and 4 because of donor reluctance to proceed. A total of 15 living donor liver transplants were performed during this time. After DAC establishment, 30 liver donors were evaluated, of whom 9 were found unsuitable due to donor issues. The mean evaluation time pre-DAC was 111 days, compared to 179 days post-DAC (p = 0.04), but there were no significant differences in rates of donor non-acceptance or in recipient outcome (table 1).

 

Conclusion:

The establishment of a DAC significantly increased the total time period required of the evaluation process in liver donors. However, this did not translate into higher rates of donor non-acceptance,or recipient death/disease progression. We speculate that a longer, and presumably more intensive evaluation process results in a more thorough donor evaluation. This may result in enhanced donor safety, without adversely affecting recipient outcome.

 

Table 1

 

Variable

Pre-DAC
N=79

Post-DAC
N=30

P value

Non acceptance%

32

30

0.07

Evaluation time(days)

111

179

0.04*

Recipient death/ disease progression(%)

12.5

15

0.06

 
653. Hepcidin and Iron Metabolism in Wilson's Disease. 

V. Medici; F. Lamboglia; V. Di Leo; R. D'Inca'; G. C. Sturniolo.

 

Background: 

Iron (Fe) accumulation could be involved in the progression of hepatic damage in Wilson’s disease (WD): hepatic Fe deprivation prevents development of fulminant hepatitis in LEC rats and Fe reduction by phlebotomy ameliorates liver function tests in WD patients.

 

The pathophysiology of Fe accumulation may involve hepcidin, a peptide synthetized by hepatocytes and increased by Fe overload and inflammation. The role of hepcidin in Fe loading in WD patients is unknown.

 

Aim/Methods:

The aim is to determine whether serum and urinary hepcidin levels correlate with markers of hepatic inflammation and Fe status in our patients with WD.

 

We quantified serum and urinary hepcidin and correlated them with AST, ALT, serum Fe, ferritin, transferrin, erythropoietin, liver Fe content, fibrosis, clinical features (hepatic or/and neurological involvement) and type of therapy (zinc and D-penicillamine) in 23 WD patients (14 males, 60.8 %; mean age 33 ± 8.3 years). Nineteen age-matched healthy volunteers (HV) served as controls. Pro-hepcidin was measured by ELISA. Pre and post therapy serum ceruloplasmin was also measured. Hepatic Fe content was measured before starting anti-copper treatment and in 14 follow-up biopsies.

 

Results:  

serum and urinary hepcidin were significantly increased in WD patients compared to HV (445 +/- 164 vs 209 +/- 63 and 455 +/- 69 vs 303 +/- 129 ng/mL respectively; p= 0.001). Serum and urinary hepcidin did not correlate with transaminases, serum Fe (17.8 +/- 5.2 umol/L), ferritin (137 +/- 102 ng/mL), transferrin (2.47 +/- 0.675 g/L), erythropoietin (9.3 +/- 8.4 mU/mL) and liver Fe concentration (690 +/- 108 ug/g d.w.). No differences in hepcidin levels were found based on presence of fibrosis, clinical features and type of therapy (zinc therapy: 18 patients; D-penicillamine: 5). Pre and post ceruloplasmin levels were not significantly different (8.5 vs 10.5 mg/dL). Hepatic Fe content, measured during follow-up biopsies, increased in 8 out of 10 men, while all women (4) had stable or reduced liver Fe concentration.

 

Conclusions:  

Serum and urinary hepcidin were significantly increased in our WD patients compared to the HV, despite a normal biochemical pattern of Fe metabolism. In contrast to other inflammatory conditions, hepcidin was independent of Fe metabolism parameters. The supposed mechanism that underlines the Fe metabolism in WD patients could be represented by hepcidin. Its synthesis is increased in front of increased Fe stores which are possibly determined by long-term anti-copper therapy and persistent hypoceruloplasminemia. WD women could be protected from Fe accumulation by physiological blood loss.

 


662. Liver Injury From Repeated Dosing of Acetaminophen (APAP) in Pediatric Patients.

J. Bailey; G. M. Bogdan; R. C. Dart.

 

Introduction/Aim:

Controversy exists regarding APAP toxicity at therapeutic (≤4g/d; ≤75mg/kg/d) doses in children. The medical literature describing APAP dosing for ≥24h in children was systematically reviewed.

 

Methods:

MEDLINE (1966–2003) and EMBASE (1980–2003) articles identified by APAP, acetaminophen, paracetamol keywords or the APAP CAS registry number and AAPCC death reports (1983–2004) were screened. English and foreign language articles reporting ≥24h APAP dosing in children were systematically abstracted using a structured data collection tool.

 

Results:

180 articles (33,940 patients) reported dosing ≥24h in children: 85 (33,004 patients) prospective studies; 95 (936 patients) retrospective. LFT is defined as AST or ALT. Prospective study patient outcomes (increased LFT=ALT ≥120IU/L or elevated LFT [level not reported]; death=liver transplant/death from APAP) by dose are described in the table. Of 936 patients in retrospective studies, 251 (27%) received therapeutic doses, 19 of which (8%) reported increased LFT with 4 (2%) deaths/transplants. There were 25 (8%) increased LFTs and 36 (11%) deaths/transplants at supratherapeutic doses and 2 (1%) increased LFTs and 11 (3%) death/transplants at unknown doses.

 

Discussion:

Despite administration to 33,004 children, prospective studies reported few cases of increased LFT and no transplants or deaths related to APAP. The 8 patients who received a therapeutic dose during a prospective study (mean 47.9±15.7 mg/kg/d) and had increased LFTs all had LFT levels ≥100 IU/L (exact level not reported), although the paper stated that the elevations are not likely related to APAP dosing. In contrast, retrospective studies accounted for nearly all adverse effects: 4 deaths/transplants occurred after use of APAP with therapeutic intent, 3 of which had incomplete information provided and 1 that included information indicating a much larger dose of APAP than reported.

 

Conclusion:

Therapeutic doses of APAP have not been associated with liver injury in prospective studies of acetaminophen involving >33,000 children. A small increase in serum LFTs occurs rarely but returns to baseline and has not evolved into acute liver injury. One retrospective report of injury appears to be caused by acetaminophen overdosage despite therapeutic intent.

 

Prospective Study Patient Outcomes

 

 

Increased LFT
N (%)

Death
N (%)

No Increased LFT or Death
N (%)

Therapeutic

8 (0.02)

0 (0)

32,099 (99.98)

Supratherapeutic

0 (0)

0 (0)

640 (100)

Unknown

0 (0)

0 (0)

257 (100)

Total

8 (0.02)

0 (0)

32,996 (99.98)

 
669. Impact of Hepatitis C Virus (HCV) Infection in Children: Quality of Life, Emotional, and Cognitive Outcomes. 

J. R. Rodrigue; W. Balistreri ; B. Haber ; M. Jonas; P. Mohan ; J. P. Molleston ; K. F. Murray ; M. R. Narkewicz ; P. Rosenthal ; L. J. Smith ; K. B. Schwarz ; R. P. González-Peralta.

 

Background:

HCV infection is associated with decreased quality of life (QOL) and neurocognitive dysfunction in adults, but little is known about the impact of this viral infection in children and their caregivers.

 

Aim:

To assess QOL, behavioral, emotional, and cognitive functioning of children with HCV and QOL of the child’s primary caregiver. Methods: We studied 84 children enrolled in a placebo-controlled, randomized, multi-site clinical trial evaluating peginterferon alpa-2a alone or with ribavirin (Peds-C). At time of enrollment, these children underwent a baseline assessment that included the Child Health Questionnaire (CHQ), Child Behavior Checklist (CBCL), Child Depression Inventory (CDI), and Behavior Rating Inventory of Executive Function (BRIEF). Their primary caregivers completed the SF-36. Effect sizes were calculated using Cohen’s d statistic to examine for increased impairment relative to published normative comparison samples.

 

Results:

Complete baseline assessments were obtained for 84 caregivers. Child mean age was 10.6±3.5 yr, 46% female, and 77% White. Caregiver’s mean age was 44.8 yrs (range 27 to 66), 82% were female, and 81% were White. The most common mode of transmission was vertical/perinatal (80%), HCV genotype was predominantly Type 1 (83%), median infection duration was 31.6 months, median ALT was 50, and children were HCV RNA positive for at least 6 months. There were no significant differences between the study sample and published normative data on the CHQ (physical summary: 51.6±6.2 vs 53.0±8.8, d=0.18; psychosocial summary: 50.7±9.4 vs 51.2±9.1, d=0.05), CBCL (Internalizing: 51.9±9.8 vs 50.0±10.0, d=0.19; Externalizing: 49.5±10.2 vs 50.0±10.0, d=0.05; Total behavior Problem: 50.5±10.6 vs 50.0±10.0, d=0.05), BRIEF (Behavioral Regulation Index: 52.5±10.7 vs 50.0±10.0, d=0.24; Metacognition Index: 54.2±12.2 vs 50.0±10.0, d=0.38; Global Executive Composite: 54.0±11.9 vs 50.0±10.0, d=0.36), and SF-36 (all d’s<0.20). Only 1 child had a CDI score in the clinical range. Age and disease indices (genotype, ALT) were not significantly associated with CHQ summary scores (all p values>0.05).

 

Conclusions:

HCV infection, in its early stages, does not lead to impairment in QOL, emotional, behavioral, or cognitive functioning for infected children or in QOL of their caregivers.

 


672. Predictors of Long-Term Hypertension Following Pediatric Orthotopic Liver Transplantation: A Single Center Longitudinal Study of 419 Patients. 

R. S. Venick; K. Koo; D. G. Farmer; J. H. Vargas; M. E. Ament; R. W. Busuttil; S. V. McDiarmid.

 

Background:

Hypertension(HTN) has been described as a long-term complication in children following orthotopic liver transplantation(OLT). The aim of this study was to evaluate the prevalence of & identify risk factors in the development of HTN in pediatric OLT recipients.

 

Methods:

This was a retrospective, longitudinal study involving all primary pediatric OLT recipients with a minimum survival time of 1 year followed at single center from 1984–2005. Baseline covariates included: age, gender, ethnicity, & primary diagnosis; the following variables were collected from outpatient visits at 1, 3, 5, 8 & 10 years post-OLT: height, weight, BMI, primary immunosuppression type & levels- cyclosporine (CsA) vs. tacrolimus (Tac), prednisone dosage, serum creatinine & calculated GFR using the Schwartz formula. Outcome variables were: HTN defined by the need for anti-HTNsive medication, & blood pressure >95% for age & gender as established by the 2004 4th Report on the Diagnosis,Evaluation & Treatment of High Blood Pressure in Children & Adolescents.

 

Results:

865 liver transplants were performed during this time. 419 patients who received isolated, primary OLTs with follow-up > 1 year were included in the analysis. 53% were female, 49% Latino, & median age at OLT=23 months. Indications for OLT were: cholestatic liver dz 52%, FHF 28%, autoimmune liver dz 6%, cryptogenic cirrhosis 6%, metabolic liver dz 4%, & tumor 4%. Additional results are summarized in Table 1.

 

Conclusions:

HTN, as defined by strict age & gender criteria, is a more prevalent long-term side effect following pediatric OLT than previously reported & requires close clinical surveillance. The proportion of patients requiring anti-HTNsive medication increased significantly over long-term follow-up. There is not a statistically significant difference in long-term HTN with CsA vs. Tac. Prednisone use, ethnicity & calculated GFR < 90 are long-term risk factors for HTN in pediatric OLT recipients.

 

 

Table 1

 

Variable

1 yr

3 yr

5 yr

8 yr

10 yr

Mean SBP

108+/1.6

108+/-1.5

111+/-1.6

118+/-1.9

121+/-2.1

Mean DBP

61+/-1.3

61+/-1.2

63+/-1.4

67+/-1.6

68+/-1.6

Mean BMI (kg/M2)

17.9+/-0.3

17.8+/-0.3

18.0+/-0.4

19.3+/-0.5

20.3+/-0.6

Mean Calc. GFR (ml/min/1.73M2)

120.4+/-4.8

124.6+/-5.1

127.5+/-5.3

128.2+/-5.6

126.0+/-5.8

Mean doses of pred. (mg/kg)

0.18+/-0.01

0.08+/-0.01

0.06+/-0.01

0.05+/-0.01

0.04+/-0.01

Mean Tac level (ng/ml)

7.1+/-0.5

5.7+/-0.4

5.6+/-0.5

5.8+/-0.7

5.6+/-0.8

Mean CsA level(ng/ml)

170.6+/-16.1

166.7+/-16.4

142.9+/-15.4

150.0+/-19.1

125.8+/-17.7

% of pts with BP > 95% for age & sex

47.9%

32.5%

28.0%

36.4%

31.5%

% of pts requiringanti-HTNsive medication

7.4%

2.9%

5.1%

9.9%

13.0%

Significant predictors of requiring an anti-HTNsive

CsA (p=0.03)
Prednisone>0.2mg/kg (p=0.02)

Calculated GFR < 60 (p=0.02)

None identified

Prednisone > 0.05 mg/kg (p=0.03)
African-American (p=0.03)

Calculated GFR < 90 (p=0.05)
Prednisone > 0.05 mg/kg (p=0.004)
African American (p=0.02)

Significant predictors of BP>95% for age & sex

Prednisone >0.1 mg/kg (p=0.01)
Age > 5 years (p <0.001)

Calculated GFR <60 (p=0.02)

None identified

None identified

None identified

 

* = Statistically significant difference (p<0.05) between % of pts requiring anti-HTNsive at 3, 5, 8 & 10 yrs.

 
673. Growth Patterns in Children Following Liver Transplantation. 

E. M. Alonso; R. W. Shepherd; T. A. Sentongo; K. L. Martz; R. Anand; C. SPLIT Research.

 

Introduction:

Impaired linear growth is a well documented complication of chronic liver disease in children, which may persist following liver transplantation (LT). Single center studies have shown that catch-up growth occurs in the first 2 years post-LT, but mean height standard deviation scores (zH) for this population remain below zero. The type of liver disease, age and zH at LT, and corticosteroid exposure after LT are cited as possible risk factors. To evaluate growth outcomes and predictors of growth impairment, data from the multi-center Studies for Pediatric Liver Transplantation (SPLIT) Registry were analyzed.

 

Methods:

A cross-sectional analysis of 1113 patients aged 0.5 to 8 years at primary LT was used to calculate mean zH measurements at time intervals up to 48mo post-LT. A sub-group of 432 patients were included in a longitudinal analysis of ΔzH and growth impairment at 24 months post-LT, with growth impairment defined as a zH of <-1.28 (10th percentile). Risk factor analysis was confined to 383 children who had complete demographic and medical data available. Univariate Kruskal-Wallis or Chi square analysis were used, as appropriate, and factors significant at <0.20 were included in the final multivariate model

 

Results:

Mean(±SD) zH for the 1113 at LT, and 12, 24, 36 and 48 months post-LT were -1.57(±1.82), and -1.21(±1.37), -0.91(±1.29), -0.80(±1.45) and -0.78(±1.44), respectively. Mean(±SD) ΔzH at 24 months was 0.77(±1.46). 150/432 (34.7%) had growth impairment and 109/432 (25%) had zH < -1.64 (5th percentile) at 24 months. Univariate analysis identified 18 candidate risk factors for growth impairment at 24 months. Independent predictors included; zH and z weight at LT (OR 0.62, 95% CI 0.50-0.77 and 0.71, 95% CI 0.59-0.86), respectively, duration of steroid exposure with children receiving 6 up to 18 mo less likely to be growth impaired (OR 0.40, 95% CI 0.22-0.72), primary liver disease with biliary atresia patients less likely to be growth impaired (other cholestatic OR 3.71, 95% CI 1.69-8.16, metabolic OR 4.20, 95% CI 1.87-9.43 ), living in a one parent household (OR 2.18, 95% CI 1.20-3.95), diabetes (OR 2.57 95% CI 1.03-6.46) and transplant prior to 2001 (OR 2.01 ,95% CI 1.18-3.31).

 

Conclusions:

Despite the occurrence of some catch-up growth, approximately 1/3 of pediatric recipients are growth impaired 24 months post LT, and mean zH scores remain below normal up to 48 months. Growth impairment at LT, steroid exposure, primary liver disease, post-transplant diabetes, era of transplant and social factors such as household composition are important predictors of growth impairment after LT. Supported by U01 DK061693.

 


674. Renal function is decreased after pediatric liver transplantation: an interim report from the Studies In Pediatric Liver Transplantation (SPLIT) renal function working group. 

K. M. Campbell; V. L. Ng; S. Martin; J. C. Magee; K. Martz; R. Anand; J. C. Bucuvalas.

 

Background:

Nephrotoxicity is a well recognized complication following liver transplantation (LT). To date, studies of long-term renal function in the pediatric LT population have been hampered by the limitations and biases associated with small populations, single centers, and insensitive outcome measures. Our aim was to define the prevalence of, and identify risk factors for, post-LT renal dysfunction in a multi-center population.

 

Methods:

We conducted a cross-sectional study of 106 patients ≥1 year post-LT from 4 transplant centers involved in the SPLIT registry. All patients had a measured glomerular filtration rate (mGFR) by radionuclide clearance since July 2005. The primary outcome variable was mGFR < 90 ml/min/1.73m2 (Stage 2 chronic renal insufficiency). Independent variables with a p-value < 0.20 were included in the multivariate logistic regression model.

 

Results:

Median age at LT was 29 months (mean 45, range 1.2 to 173). Primary diagnoses were biliary atresia (48%), fulminant liver failure (11%), metabolic liver disease (15%), chronic cholestatic liver disease (11%) and other (14%). At time of LT, mean calculated GFR (cGFR) using the Schwartz formula was 154 ml/min/1.73m2. At 30 days post-LT, 21% of patients were receiving cyclosporin (CSA) and 67% were receiving tacrolimus (TAC), while at one year post-LT 19% were receiving CSA and 78% TAC. Sixty-one percent of patients experienced an episode of rejection in the first year post-LT. At a mean of 4.9 years post-LT (range 1 to 10), 22% of patients had a mGFR < 90 ml/min/1.73m2. In univariate analysis, factors associated with this outcome were cGFR < 90 at LT (p=0.007), increased time since LT (p=0.006), ≥ 2 episodes of rejection in the first year post-LT (p=0.04), CSA use at 30 days post-LT (p=0.07), and renal complications at 30 days post-LT (p=0.07). In multivariate analysis, independent variables associated with a mGFR <90 ml/min/1.73m2 at follow-up were increased time since transplant (odds ratio 1.4, p=0.005) and renal complications in the first 30 days post-LT (odds ratio 7.85, p=0.02).

 

Conclusions:

In this multi-center study of pediatric patients ≥ 1 year post-LT, the prevalence of a mGFR <90 cc/min/1.73m2 was 22%. Time since transplant and renal complications in the immediate post-LT period were predictors of outcome. Assessment of the role of potential contributing factors such as genetic predisposition, exposure to other nephrotoxic drugs, hypertension and others remains to be determined, and requires future multi-center prospective studies.

 


778. Sustained Viral Response Using Peg IFN alfa-2b Plus Ribavirin in Patients with Recurrent Hepatitis C after Liver Transplantation.

R. Ghalib; C. Levine; B. Hollinger; R. Stribling; T. Box; W. Hutson; A. Post; S. Joshi; J. Weinstein; B. Husberg; A. Mejia; S. Cheng

 

Purpose:

To identify factors predictive of viral response to 2 different dosages of PEG IFN alfa-2b plus ribavirin in the OLT patient with recurrent hepatitis C.

 

Methods:

This is a multi-center randomized clinical trial of post OLT patients with histologic recurrent HCV. All patients were started on PEG IFN alfa-2b 0.5 mcg/kg/week plus ribavirin 600 mg/day. At week 4, patients tolerating therapy increased ribavirin to 800 mg/day and according to baseline randomization either remained at 0.5 mcg/kg/wk (low dose arm) or increased to 1.5 mcg/kg/week (high dose arm). Therapy continued for 48 more weeks unless HCV RNA was positive at week 24.

 

Results:

59 patients were enrolled with 27 (46%) in the low dose arm and 32 (54%) in the high dose arm. A total of 28 (47%) completed treatment (28 in high dose vs. 5 in low dose), 20 (34%) discontinued at week 24 with nonresponse (3 in high dose vs. 17 in low dose), 1 from each group withdrew at week 24 with genotype 2/3, and 9 (15%) discontinued for adverse events (5 in high dose vs. 4 in low dose) including 2 (3%) deaths in the high dose arm.

 

The age range was 37-67 years (mean 51.4 6.0) (20 females; 39 males) with a range of 0.3-5.1 years post OLT (mean 1.6 1.2). HCV was genotype 1 in 43 patients (73%). Mean HCV RNA at baseline was 3.9 million IU/mL (range 0.04-15.0 million IU/mL). Significantly more patients achieved an SVR in the high dose arm (19/32, 59.4%) vs. low dose arm (5/27, 18.5%; p<.001). SVR was higher with a non-1 genotype (low dose-67% vs 75% in the high dose arm) vs. genotype 1 (low dose-13% vs. 50% in the high dose arm).  Logistic regression for SVR identified the higher PEG IFN dose and genotype non-1 as significant variables (-2 log likelihood 64.9; model Chi-square 14.8, df=2, p< .001).

 

Conclusions:

Intention to treat analysis of SVR in this post liver transplant population with recurrent hepatitis C shows that the 2 most predictive factors were dose of PEG IFN alfa-2b comparing 1.5 mcg/kg/week to 0.5 mcg/kg/week (56% and 19%, respectively) and genotype 1.  As in the non-transplant population, patients with genotype 2/3 and White race had higher SVR rates.  No significant5 relationship was found for gender, body weight, BMI>30, mean ribavirin dose (mg/kg), average weekly ribavirin dose for the first 12 to 24 weeks of treatment, or baseline viral load.  Further investigation of predictive factors of viral response are needed in the liver transplant population to guide selection of appropriate treatment candidates and therapies.