Pediatric LTx Research Articles

Outcome of liver re‐transplantation in children—Impact and special analysis of early re‐transplantation

In case of graft failure, re-LTX is the only life-saving option but it has been associated with inferior results. This study analyzes the outcome following pediatric re-LTX with a main focus on the timely relation between initial transplant and re-LTX. All pediatric LTX at our institution between 2000 and 2010 divided into patients with primary LTX and patients undergoing re-LTX early (≤30days) or late (>30days) after previous LTX were analyzed. Two hundred and ninety-eight primary LTX(79%), 33 early (9%), and 46 late (12%) re-LTX were performed. Patient/graft survival was significantly worse for children undergoing early re-LTX compared to primary LTX and late re-LTX (p=0.024/0.001 and p=0.015/0.03). One-/five-yr graft survival rates were 66%/49% for early re-LTX compared to 86%/76% for late re-LTX and 90%/74% for primary LTX. The inferior results in children undergoing early re-LTX were due to events occurring in the first sixmonths with similar survival thereafter. No difference in outcome was evident after adjustment of the groups for high-urgency status. Outcome was excellent for primary LTX and late re-LTX, supporting late re-LTX in children. Early re-LTX takes an elevated risk of early graft loss and patient death; however, beyond the early postoperative period, the outcome was comparable.

(789) - Acidic Gastroesophageal Reflux and Aspiration Are Not Associated with Earlier Development of Bronchiolitis Obliterans in Pediatric Lung Transplant

Bronchiolitis obliterans (BO) is the leading cause for late morbidity and mortality following lung transplant (LTx). Gastroesophageal reflux (GER) and aspiration are hypothesized risk factors for BO, but fundoplication has been reported to mitigate these effects. We are reporting preliminary data from an ongoing study to determine if acidic GER, aspiration and fundoplication influence development of BO in pediatric LTx.

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The role of donor-specific HLA antibodies (DSA) following liver transplantation (LTx) is not clearly established. Our aim was to assess the presence of DSA in pediatric LTx recipients. We hypothesized that DSA would be detected (+DSA) in patients with late allograft dysfunction due to de-novo autoimmune hepatitis (d-AIH). Serum was collected at routine clinic visits from 50 pediatric LTx recipients a mean of 11.8 ± 5.3 years post LTx, and classified into four clinical phenotypes: non-tolerant with biopsy-proven late acute cellular rejection (n = 6) and/or d-AIH (n = 12); stable with normal liver function on maintenance tacrolimus (n = 25); tolerant with normal liver function off immunosuppression ⩾2 years (n = 7). Samples were blinded and antibody detection was performed using LABScreen HLA Class I and II Single Antigen beads (One Lambda) and Luminex multiplex technology. Descriptive statistics and multivariate logistic regression were performed with results reported as means and odds ratios (OR). HLA antibodies were detected in 28/50 (56%) of patients, with the majority of DSA directed against HLA Class II DR or DQ loci (40% and 52%, respectively). Patients with +DSA had a mean of 1.8 (range 1-4) DSA with a mean MFI of 11681 ± 8227. Patients with +DSA were younger at LTx (2.4 ± 2.9 vs 5.4 ± 5.4 years, p = 0.01). There were no differences in other clinical variables including sex, primary diagnosis, history of re-LTx, and early acute rejection. Age in years at LTx (OR 0.5, p = 0.01), history of post transplant lymphoproliferative disorder (OR 0.1, p = 0.01) and late rejection (OR 27, p = 0.02) are the strongest predictors of +DSA. Patients with d-AIH tended to be +DSA (10/12 patients, p = 0.05), a trend that was not observed in the other phenotypes. +DSA is the strongest multivariate predictor of d-AIH (OR 19, p = 0.03). DSA are common after pediatric LTx and detected more frequently in patients with d-AIH, suggesting d-AIH may be a form of antibody-mediated rejection.

Markers of operational immune tolerance after pediatric liver transplantation in patients under immunosuppression

A prospective identification of the estimated 20-50% of pediatric LTX recipients developing operational tolerance would be of great clinical advantage. So far markers of immune tolerance - T-cell subpopulations or gene expression profiles - have been investigated only retrospectively in successfully weaned patients. Fifty children aged 8-265months (median 89) were investigated 1-180months (median 44) after LTX under ongoing immunosuppression. T-cell subpopulations were measured during regular post-transplant visits using FACS (Vδ1- vs. Vδ2-γδ-T cells and Tregs). A Vδ1/Vδ2-γδ-T-cell ratio ≥1.42 previously reported in operational tolerance was found in 12 of 50 (24%) patients. In analogy, a Treg count ≥44 per μL was found in 35 of 50 (70%) patients and a Treg proportion ≥2.23% of CD3(+) -T cells in 39 of 50 (78%) patients. Only 9 of 50 patients (18%) fulfilled both criteria. The parameters Vδ1/Vδ2-γδ-T-cell ratio and Tregs were not significantly correlated to each other or with donor type or immunosuppression. Vδ1/Vδ2-γδ-T-cell ratio was more stable in serial examinations compared with Treg analyses. The observed proportion of 18% pediatric LTX patients with potential operational tolerance is in accordance with previous reports. However, clinical experience shows that rejections may happen even after long-time weaning of immunosuppression. This suggests that operational tolerance is a dynamic process, with uncertain prediction by Vδ1/Vδ2-γδ-T-cell ratio and/or Tregs under immunosuppression.

Center Volume Impacts Survival in Pediatric Lung Transplantation

<h3>Purpose</h3> The effect of center volume on adult lung transplantation (LTx) survival has been reported. Although other institutional and patient factors play a role in determining the overall survival rates, the center volume as a surrogate of experience has also been shown to directly impact the outcomes of LTx. However, this effect has not been demonstrated for pediatric LTx. The purpose of this study was to analyze the effect of center volume on pediatric LTx using a national database. <h3>Methods and Materials</h3> Query of United Network of Organ Sharing database through 06/2012 yielded 1044 pediatric (≤18y) LTx. Multiorgan Tx were excluded. The effect of center volume was analyzed as cumulative experience and yearly median number of LTx, and divided into high and low volume centers ensuring equal division of LTx in both groups. For excluding the era-effect, a sub-analysis of LTx was also performed (2000-2012). Cox-regression was used to calculate the risk of failure related to center volume. <h3>Results</h3> The graft and patient LTx survival was better in high-volume centers (3 centers, 517 LTx) than the low-volume centers (59 centers, 527 LTx) (p<0.006) (figure). The 1y-conditional graft and patient survival was also better for high-volume centers (p<0.001). Sub-analysis of the recent era showed a better graft (p=0.008) and patient (p=0.006) survival for high-volume centers. The yearly median LTx cut-off for improved survival was 4 LTx/year. There was a 40% increased risk of LTx graft failure for low-volume centers (p=0.022). <h3>Conclusions</h3> Center volume has an impact on patient and graft survival in pediatric lung transplantation. Further detailed risk-factor analysis will help in determining the extent of this impact.

Lung transplantation in children following bone marrow transplantation: A multi‐center experience

Allogenic BMT has been successfully performed as a treatment for hematologic diseases with an expected long-term survival. This survival is truncated by respiratory complications including airway obstruction especially BO. Chronic GVHD has been reported to precede almost all cases reported. LTx has become a therapeutic life-saving option for patients with end-stage lung disease that maybe offered for the treatment of GVHD. We report a multi-center experience of pediatric LTx following BMT in 11 patients age- and gender-matched with 11 controls who received LTx for end-stage lung disease secondary to CF. Overall death was 36.4% over a follow-up period of 19months (range 3-36months) for the cases and 27.3% for the control group followed for 17months (range 8-32months). Median FEV1 oneyr post-transplant for the cases was 78% predicted compared with 67.3% predicted for the controls. The median for episodes of infection was comparable at a median of one episode per patient through the entire follow-up period among both groups. Acute rejection episodes were significantly higher in the control group with a median of one episode per patient in the control group compared to none within the cases. Our data suggest that LTx may be a valuable therapeutic option for children with end-stage lung disease post-BMT with comparable survival outcome to that after LTx in children for other indications such as CF. Hospital stay was significantly longer in our case group. Infection rate was comparable between groups albeit type of infection varied. Significantly and of interest is that acute rejection episodes were non-existent in these cases.

Is lung transplantation survival better in infants? Analysis of over 80 infants

There have been >1,600 pediatric lung transplantations (LTx) performed worldwide with a trend toward improved outcomes over the last 25 years. The majority of these LTxs have been in older children and adolescents. Less than 4 infant (defined as ≤ 12 months of age) LTxs per year have been performed over the past 20 years, mostly in the USA. However, infant LTx outcomes have not been well documented in a multi-institutional longitudinal fashion. The United Network of Organ Sharing database was queried from October 1987 to July 2011. Of the 1,003 pediatric LTxs reported, 84 (8%) were infants. All combined transplantations were excluded. Eighty-one infants received 84 LTxs, of which 95% had a bilateral LTx. Median age and weight at LTx was 4 months (range 0 to 11 months) and 5.3 kg (2.7 to 11.8 kg), respectively. Median ischemic time was 5.2 hours (2.0 to 10.8 hours). Overall Kaplan-Meier graft survival was similar for infants compared with other pediatric age group (OPA: >1 to 18 years) LTx recipients (half-life 4.0 years vs 3.4 years, p = 0.7). Conditional 1-year graft survival for infants was significantly higher than OPA (half-life 7.4 years vs 5.0 years, p = 0.024). Early (1987 to 2000, n = 46) and late (2001 to 2011, n = 38) era graft survival was not significantly different. Graft survival in pre-LTx ventilated infants was significantly better than pre-LTx ventilated OPA (half-life 6.1 years vs 0.9 year, p = 0.004) and was not statistically different from pre-LTx infants not on ventilatory support (half-life 6.1 years vs 2.2 years, p = 0.152). Cox regression of 5 variables (weight, donor arterial PO(2), pre-Tx ventilator, organ ischemic time, center experience) showed that survival was associated with increased center experience (p = 0.03). Infants undergoing LTx have outcomes similar to those of all other pediatric LTx patients.

The Unique Immunophenotype of the Adaptive Immune System in Tolerant Pediatric Liver Transplant Recipients

Introduction: The adaptive immune system is known to play a central role in solid organ transplant tolerance and rejection. The aim of this study was to characterize populations of T and B cell subsets in pediatric liver transplant (LTx) recipients via immunophenotyping. We hypothesized that such analysis would identify a unique cellular immune profile of tolerance in pediatric LTx recipients. Methods: Twenty pediatric LTx recipients were classified into 3 clinical phenotypes: tolerant (TOL, n=6) with normal liver function off immunosuppression for ≥2 years; non-tolerant (NON-TOL, n=6) with a history of ≥1 rejection episode ≥1 year post-LTx on double or triple immunosuppression; stable (STA, n=8) on tacrolimus monotherapy with normal liver function and no rejection episodes ≥1 year post-LTx. PBMCs were separated from peripheral blood specimens collected at routine clinic visits. Immunophenotyping was performed with multi-color monoclonal antibody panels. Cell fluorescence was acquired on an LSR FortessaTM cell analyzer. Population measurements were determined using FCS Express V4 analysis software. Non-transplanted, healthy young-adults (n=3) were used as controls to establish and validate flow panels. Statistical analyses included fisher's exact, Kruskal-wallis, and t-tests. Results are reported as mean ± SD. Results: As shown in the Table, TOL patients tended to be younger at the time of LTx and older at the time of sample collection. All TOL patients were males. As also shown in the table, T and B cell populations varied across groups. TOL patients had a significantly greater proportion of naïve CD4+RA+ T cells and smaller populations of central memory CD4+CD197+RA- T cells compared to NON-TOL and STA. TOL patients had a trend towards lower proportions of memory B cells (CD19+CD27+) and higher proportions of transitional (CD27CD-38++IgD+) and unswitched memory (CD27+IgD+IgM+) B cells compared to NON-TOL patients. TOL patients also had increased naïve CD4+CD197+RA+ T cells, CD4+CD25+CD127l0 regulatory T cells, and inducible CD4+CD25+CD127l0RA- T cells (data not shown).Table: [Results for TOL, NON-TOL, and STA LTx recipients]Conclusion: This study represents the most comprehensive analysis of T and B cell immunophenotypes in pediatric LTx recipients to date. We have shown that TOL patients have a unique adaptive immune system cellular profile characterized by smaller populations of central memory T cells and larger populations of naïve and regulatory T cells as well as transitional and unswitched memory B cells. This may lead to fewer effector T cells and increased production of regulatory cytokines, ultimately creating an overall tolerogenic environment. We are currently immunophenotyping a larger cohort of patients to further delineate the unique features of tolerance and discriminate them from the effects of immunosuppression.

Effects of an acute, outpatient physiotherapy exercise program following pediatric heart or lung transplantation

This prospective interventional study investigated the impact of a three-month, ambulatory HA or HB, semi-individualized, PT-prescribed exercise program following pediatric HTx or LTx. SMW distance, strength, and flexibility were assessed at start and completion of the program and one yr after enrollment. Subjects received either an HB or HA exercise program three times per week. The cohort demonstrated clinically and statistically significant improvements in SMW distances at three months (425.7 ± 109.4-500.6 ± 93.6 m, p < 0.001) and at one yr (528.5 ± 66.6 m, p = 0.001), although there was no difference between the two groups at any time. Similar improvements were also observed in strength and flexibility measures. Correlates with higher SMW distance at three months and one yr included older age, male gender, and underlying diagnosis other than CHD. Male gender and diagnosis other than CHD were associated with a slower improvement in the SMW distance. This is the first report of institutionally based, outpatient exercise rehabilitation in the recovery following pediatric thoracic transplantation. We found similar improvements to HB interventions up to one yr after surgery. Further study of the role of exercise rehabilitation and long-term fitness outcomes is needed.

Survival of Cystic Fibrosis Patients Undergoing Liver and Liver-Lung Transplantations

BackgroundWe evaluated the outcome of combined liver-lung transplantation (L-LTx) in cystic fibrosis (CF) patients with liver transplantation (LTx) for CF liver disease. MethodsThe United Network for Organ Sharing (UNOS) data were analyzed from October 1987 to August 2009. ResultsOf 294 patients (210 children), 265 (90.1%) received an LTx and 29, an L-LTx. Patient survival was: adult LTx, 80%, 74%, and 67% at 1, 3, and 5 years, and L-LTx, 72%, 61.4%, and 61.4% (P = .7); pediatric LTx, 85%, 82%, and 74% at 1, 3, and 5 years, and L-LTx, 83%, 83%, and 83% (P = .4). Pediatric patients had a slight survival advantage over adults for LTx (P = .08). Graft survival, not affected by immunosuppression regimens, was similar to patient survival. ConclusionsThe outcome of L-LTx appears similar to LTx in CF providing support for the prospect of a combined transplant.

The impact of cytokine gene polymorphisms on Epstein–Barr virus infection outcome in pediatric liver transplant recipients

BackgroundEpstein–Barr virus (EBV) is associated with most cases of the post-transplant lymphoproliferative disorders developed during the first year after transplantation. The high EBV DNA load constitutes a major risk for the development of EBV-related lymphoproliferations. However, among transplant recipients there are patients with a chronically high viral load (CHVL) who do not develop lymphoproliferations. The polymorphism within cytokine genes might influence the susceptibility to, and contribute to the pathogenesis of the disease. ObjectivesThe aim of this study was to analyze the genetic polymorphism in the selected cytokines with regard to EBV infection outcome in children after liver transplantation (LTx). Study DesignThirteen cytokine/cytokine receptor polymorphisms were genotyped in 170 children after LTx, and related to: EBV DNAemia, CHVL onset and the length of CHVL carriage. ResultsThe study revealed: the protective effect of rare homozygous and heterozygous IL-1β-511 and IL-1 receptor antagonist (IL-1RN VNTR) genotypes against viremia within the first year after LTx (OR=0.28, p=0.0007 and OR=0.35, p=0.009, respectively); the protective effect of CC chemokine ligand 2 (CCL2)+1543CT and TT genotypes against CHVL onset (OR=0.38, p=0.042); and the prolonged CHVL-resolution in IL12B 3’untranslated region (3′UTR) AC individuals (p=0.034). ConclusionsThis data suggests that carriage of IL-1β-511CT/TT and/or IL-1RN VNTR 1.2/2.2 genotype may be beneficial for combating EBV infection. This is the first study reporting the association of CCL2 and IL12B gene polymorphisms with the CHVL carriage in pediatric LTx recipients.

The impact of hepatic portoenterostomy on liver transplantation for the treatment of biliary atresia: Early failure adversely affects outcome

The most common indication for pediatric LTx is biliary atresia with failed HPE, yet the effect of previous HPE on the outcome after LTx has not been well characterized. We retrospectively reviewed a single-center experience with 134 consecutive pediatric liver transplants for the treatment of biliary atresia from 1 May 1995 to 28 April 2008. Of 134 patients, 22 underwent LTx without prior HPE (NPE), while 112 patients underwent HPE first. HPE patients were grouped into EF, defined as need for LTx within the first year of life, and LF, defined as need for LTx beyond the first year of life. NPE and EF groups differed significantly from the LF group in age, weight, PELD, and ICU status (p < 0.05) with NPE having the highest PELD and ICU status. Patients who underwent salvage LTx after EF following HPE had a significantly higher incidence of post-operative bacteremia and septicemia (p < 0.05), and subsequently lower survival rates. One-year patient survival and graft survival were as follows: NPE 100%, EF 81%, and LF 96% (p < 0.05); and NPE 96%, EF 79%, and LF 96% (p < 0.05). Further investigation into the optimal treatment of biliary atresia should focus on identifying patients at high risk of EF who may benefit from proceeding directly to LTx given the increased risk of post-LTx bacteremia, sepsis, and death after failed HPE.

Pre transplant serum magnesium level predicts outcome after pediatric living donor liver transplantation

Hypomagnesaemia is a frequent complication after liver transplantation (LTx) however; magnesium is not routinely replaced in the perioperative period. The incidence of hypomagnesaemia before and after pediatric LTx was studied in 673 pediatric patients who underwent living-donor liver transplantation (LDLT). The mean serum Mg levels before LTx was normal, 2.03 ± 0.28 mg/dl, exhibited marked decrease on 5th postoperative (PO) day, 1.79 ± 0.45, p<0.001, comparing with the pre-transplant value. It reached its nadir in the 1st PO month, p<0.001. Up to the 5th PO year, serum Mg did not achieve the lower limit of normal, 1.77 ± 0.24, p<0.001 and incidence of hypomagnesaemia was 60.7% (242/399). Univariate analyses of variables that can predict graft loss and patient death after LDLT demonstrated that recipient factors, pre and post transplant serum Mg and blood product transfusions were potentially risk factors significantly affected the outcome. Multivariate analysis of potential risk factors showed that pre transplant serum Mg <1.8 mg/dl, (Hazard ratio (HR) 2.362 [confidence interval (CI) 1.350-4.133]; p=0.003) and pre transplant BUN, (HR 1.046 [CI 1.014-1.079]; p=0.005) were independent predictors of graft loss and patient death. hypomagnesaemia is common before and after pediatric LDLT. Pre transplant hypomagnesaemia and high BUN are independent risk factors for graft loss or patient death. Pre transplant hypomagnesaemia patients exhibited decreased survival of their graft. Post transplant hypomagnesaemia was a potentially risk factor for graft loss.

390 Bronchiolitis Obliterans Syndrome (BOS) Is Not Specific for Bronchiolitis Obliterans (BO) in Pediatric Lung Transplant (LTx)

BO is the leading cause of mortality beyond the first year after transplant in pediatric LTx recipients. Since BO is a histologic diagnosis it often mandates performing an open lung biopsy. BOS is a clinical diagnosis based on spirometric data that is the accepted standard for staging chronic allograft dysfunction. The use of predicted values for pediatric recipients has not been validated. We determined the sensitivity, specificity, positive and negative predictive values (PPV and NPV) of the BOS stages for predicting BO in children.

Pediatric patients receiving ABO-incompatible living related liver transplantation exhibit higher serum transforming growth factor-β1, interferon-γ and interleukin-2 levels

ABO-incompatible liver transplantation (LTx) is becoming more common in response to the paucity of liver allografts. Several studies have expressed concern about the effect of ABO compatibility on graft survival. To evaluate the differences in serum cytokine levels between ABO-incompatible (ABO-i) and ABO-compatible (ABO-c; includes ABO-compatible and identical) pediatric LTx recipients during regular outpatient follow-up. Note that, in the field of organ transplantation, transplants are categorized as incompatible, compatible or identical; accordingly, these are the terms we use in the paper. A clinical outpatient study measuring serum transforming growth factor (TGF)-β1, interferon (IFN)-γ, interleukin (IL)-2 and IL-10 in 43 living related liver transplantation (LRLT) recipients, of whom 36 received ABO-c LRLT (34 were ABO-identical and 2 were non-identical) and 7 ABO-i LRLT. Serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase and bilirubin were measured as part of the patients' regular follow-up visits. There were no differences between the ABO-c and ABO-i groups in terms of recipient's age [mean 12.6 vs. 11.1years (y)], post-LTx duration (mean 7.3 vs. 7.3y), donor's age (mean 35.5 vs. 34.6y), body weight (28.9±2.9 vs. 27.9±6.9kg), or gender (19 female and 17 male vs. 4 female and 3 male). Serum TGF-β1, IFN-γ and IL-2 were significantly higher in the ABO-i group than in the ABO-c group. IL-10, however, did not differ between the two groups. There was a tendency toward higher γGTP levels in the ABO-i group, but this difference did not reach significance. ABO-incompatible LRLTx patients have higher serum TGF-β1, IFN-γ and IL-2 levels as measured at regular outpatient visits. As a result, they face a higher risk of T-helper 1 cell polarization, which could make graft rejection more likely.

Size reduction of donor organs in pediatric lung transplantation

Lobar transplantation and peripheral segmental resection allow downsizing of larger lungs for use in smaller recipients, particularly with regard to pediatric patients on the high urgency waiting list. We studied the safety and outcome of these techniques in children. All pediatric patients who underwent reduced size LTx between January 2000 and March 2009 were retrospectively reviewed and compared with pediatric patients who underwent full size LTx during the same period. Patient characteristics, intra-operative variables, and post-operative morbidity and mortality were compared. Among 28 primary LTxs, 16 (57%) were performed in reduced size technique. Preoperatively, there was a trend toward a higher rate of mechanical ventilation and a higher capillary pCO(2) in the reduced size group. Surgical procedures tended to be longer in that group. Post-operative complications, survival and functional parameters were comparable between both groups. Our study demonstrates that reduced size LTx in children is a reliable therapeutic option that provides results comparable to full size LTx. This technique might help to reduce waiting list mortality by expanding the donor pool in pediatric LTx.

Calcineurin inhibitor minimization in pediatric liver allograft recipients

The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.

The value of immunoprophylaxis for cytomegalovirus infection with intravenous immunoglobulin in pediatric liver transplant recipients receiving a low-dose immunosupressive regimen

The incidence of CMV infection following pediatric Ltx is particularly high, which can be attributed to the increased number of patients at high risk for primary infection (donor CMV+, recipient CMV-). Current approaches to cope with this complication producing post-operative morbidity include prophylactic or preemptive ganciclovir therapy. As the risk for symptomatic CMV infection is directly correlated with the intensity of immunosuppression, the aim of our study was to assess the value of IVIG in order to protect children receiving low-dose immunosuppression from CMV disease. Twenty-eight consecutive children (median age 62.2 months) at high risk prospectively received three infusions of IVIG on days four, 14, and 28 post-transplant and were monitored for six months post-Ltx. Immunosuppression consisted of cyclosporine (initial trough levels 170-200 microg/L) and prednisolone (starting dose 15 mg/m(2)) as well as basiliximab induction therapy. Patient survival was 100% and graft survival was 92.9%. Two subjects developed laboratory findings of CMV infection (8%) and one child suffered from tissue invasive CMV disease (4%). Three patients were excluded from the study because of protocol violations. We conclude that there was a low incidence of CMV disease among a prospective cohort receiving low-dose immunosuppression and a standard IVIG product.

Short‐ and long‐time effects of pediatric liver transplantation on serum cholesterol and triglyceride levels – The Vienna Cohort

Hyperlipidemia is common in patients after LTX. Although immunosuppressive protocols have changed, there are only few data after pediatric LTX. Aim of our study was to evaluate short- and long-time effects of LTX on serum cholesterol and triglycerides in children with different immunosuppressive regimen. We retrospectively analyzed 24 children (seven boys) who underwent LTX since 1987 and were followed for at least one yr at the Medical University of Vienna. Serum lipids, liver function and records of immunosuppressive therapy were evaluated at first referral, shortly before and three, six, nine and 12 months after LTX, and at last visit (mean 6.6 yr after LTX). At first referral, serum lipids were significantly related to underlying disease and age. Following LTX, prevalence of hypercholesterolemia was 25% and of hypertriglyceridemia 90% after the first year. Long-term follow-up showed an overall decrease of serum lipids. Significant decreases in serum triglycerides were directly related to discontinuation of steroids. There was no effect of calcineurin inhibitors. Our study confirms the high prevalence of hyperlipidemia before and after pediatric LTX and suggests a major role of steroid-withdrawal for the control of post-transplant hypertriglyceridemia.

Graft fibrosis after pediatric liver transplantation

Previously we reported the presence of portal fibrosis in 31% (n = 84) of the grafts in protocol biopsies 1 year after pediatric liver transplantation (LTx). To assess the natural history of graft fibrosis after pediatric liver transplantation, we extended the analysis of graft histology in follow-up protocol biopsy specimens obtained 5 and 10 years after transplantation. We correlated histological results with clinical parameters at the time of LTx and during follow-up, to allow identification of risk factors for the development of fibrosis. From 1 year to 5 years after LTx, the prevalence of fibrosis increased from 31% to 65% (n = 66) but remained stable thereafter (at 10 years, 69%, n = 55). At 10 years after LTx, however, the percentage of patients with severe fibrosis had increased from 10% (at 5 years) to 29%. Of the 69% of children without fibrosis at 1 year post-transplantation, 64% (n = 39) had developed some degree of fibrosis at 10 years. Fibrosis was strongly related to transplant-related factors such as prolonged cold ischemia time, young age at the time of transplantation, high donor/recipient age ratio, and the use of partial grafts (P < 0.05). Fibrosis was not significantly related to rejection, chronic hepatitis, or the nature of the immunosuppressive therapy. Biopsies after pediatric LTx show that most grafts developed fibrosis within 5 years. At 10 years after LTx, the graft fibrosis had progressed to severe fibrosis in at least 25% of the patients. Development of fibrosis, starting either before or after the first year post-LTx, was strongly related to transplant-related factors, indicating the importance of these factors to long-term graft prognosis.