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Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients Under Tacrolimus Immunosuppression

2006; Elsevier BV; Volume: 6; Issue: 8 Linguagem: Inglês

10.1111/j.1600-6143.2006.01406.x

1600-6143

Marco Spada, Wanda Petz, Alessandro Bertani, Silvia Riva, Aurelio Sonzogni, M. Giovannelli, Elena Torri, G. Torre, M. Colledan, Bruno Gridelli,

Renal Transplantation Outcomes and Treatments

American Journal of TransplantationVolume 6, Issue 8 p. 1913-1921 Free Access Randomized Trial of Basiliximab Induction versus Steroid Therapy in Pediatric Liver Allograft Recipients Under Tacrolimus Immunosuppression M. Spada, Corresponding Author M. Spada Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, Italy * Corresponding author: M. Spada, mspada@ismett.edu mspada@ismett.eduSearch for more papers by this authorW. Petz, W. Petz Liver and Lung Transplantation UnitSearch for more papers by this authorA. Bertani, A. Bertani Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this authorS. Riva, S. Riva Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this authorA. Sonzogni, A. Sonzogni Pathology UnitSearch for more papers by this authorM. Giovannelli, M. Giovannelli Liver and Lung Transplantation UnitSearch for more papers by this authorE. Torri, E. Torri Liver and Lung Transplantation UnitSearch for more papers by this authorG. Torre, G. Torre Pediatrics Unit, Ospedali Riuniti of Bergamo, ItalySearch for more papers by this authorM. Colledan, M. Colledan Liver and Lung Transplantation UnitSearch for more papers by this authorB. Gridelli, B. Gridelli Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this author M. Spada, Corresponding Author M. Spada Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, Italy * Corresponding author: M. Spada, mspada@ismett.edu mspada@ismett.eduSearch for more papers by this authorW. Petz, W. Petz Liver and Lung Transplantation UnitSearch for more papers by this authorA. Bertani, A. Bertani Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this authorS. Riva, S. Riva Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this authorA. Sonzogni, A. Sonzogni Pathology UnitSearch for more papers by this authorM. Giovannelli, M. Giovannelli Liver and Lung Transplantation UnitSearch for more papers by this authorE. Torri, E. Torri Liver and Lung Transplantation UnitSearch for more papers by this authorG. Torre, G. Torre Pediatrics Unit, Ospedali Riuniti of Bergamo, ItalySearch for more papers by this authorM. Colledan, M. Colledan Liver and Lung Transplantation UnitSearch for more papers by this authorB. Gridelli, B. Gridelli Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione, IsMeTT, University of Pittsburgh Medical Center, ItalySearch for more papers by this author First published: 09 June 2006 https://doi.org/10.1111/j.1600-6143.2006.01406.xCitations: 52AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Avoidance of corticosteroids could be beneficial after pediatric liver transplantation (LTx). To test this hypothesis, we performed a randomized prospective study to compare immunosuppression with tacrolimus (TAC) and steroids versus TAC and basiliximab (BAS) after pediatric LTx. Seventy-two patients were recruited, 36 receiving TAC and steroids and 36 TAC and BAS. The primary endpoint was the occurrence of the first rejection episode. Secondary endpoints were the cumulative incidence and severity of rejection, patient and graft survival, and incidence of adverse events. Overall 1-year patient and graft survival rates were 91.4% and 85.5% in the steroid group, and 88.6% and 80% in the BAS group (p = NS). Patients free from rejection were 87.7% in the BAS group and 67.7% in the steroid group (p = 0.036). The use of BAS was associated with a 63.6% reduction in incidence of acute rejection episodes. Overall incidence of infection was 72.3% in the steroid group and 50% in the BAS group (p = 0.035). We conclude that the combination of TAC with BAS is an alternative to TAC and steroid immunosuppression in pediatric LTx, which allows for a significant reduction in the incidence of acute rejection and infectious complications. Introduction Corticosteroids have been part of all immunosuppressive regimens since the early days of transplantation (1). However, steroid avoidance could be beneficial, particularly in pediatric recipients because, when administered for a prolonged period, they are associated with multiple severe side effects including infections, arterial hypertension, glucose intolerance, hyperlipidemia, osteoporosis and growth impairment (2-4). Moreover, work in rodents suggests that the administration of steroids may interfere with the development of immunological tolerance, as well as with the process of hepatic regeneration (5, 6). The theoretical advantages of steroid avoidance must be balanced against its potential hazards and detrimental effects, which can be identified as: (1) acute and/or chronic rejection of the hepatic graft, which may require adjustment of immunosuppression above baseline dosages; (2) secondary rejection that may potentially lead to graft loss and even patient death due to graft insufficiency and its consequences, or to infectious complications in the context of increased immunosuppression; (3) maintenance of higher doses and blood levels of calcineurin inhibitors, with adverse results, particularly in terms of chronic renal toxicity. To test the possibility of steroid avoidance after pediatric liver transplantation (LTx), we conducted an open, randomized, comparative study between a novel tacrolimus (TAC)-based steroid-free immunosuppressive protocol—using an induction treatment with basiliximab (BAS)—and a conventional TAC plus steroids protocol. BAS is a chimeric (human and mouse) monoclonal antibody directed against the human IL-2 receptor that has been successfully used to prevent acute cellular rejection after kidney and LTx (7). The primary aim of this study was to access the effects of prophylactic treatment with BAS on the incidence of acute rejection episodes in the first 12 months after transplantation in pediatric recipients of primary deceased donor-liver transplant. The safety and tolerance of BAS were also monitored during the study. Material and Methods Trial design Patient recruitment occurred between June 2001 and August 2003. Patients were randomly assigned in a 1:1 ratio to receive either two doses of BAS (Simulect®; Novartis, Basel, Switzerland) and maintenance TAC (Prograf®; Fujisawa, Munich, Germany) immunosuppression (study group) or steroid and TAC immunosuppression (control group). The study included patients below the age of 18, for whom parents or guardians gave written informed consent. All patients were recipients of a primary, isolate liver transplant from a deceased donor. All transplants were performed at the Bergamo facility; and some of the authors (MS, AB, SR and BG) transferred to IsMeTT, Palermo at different times before or after the end of recruitment. Patients were excluded from the study if they were receiving antibiotics for severe active infection, had been treated with an investigational drug within 1 month of study entry or were to be so treated within 12 months of transplantation, or were affected by hepatic or extrahepatic malignancy. Reasons for premature patient withdrawal from the study were: withholding of the study drugs for more than 7 days or, in cases of severe renal impairment, for more than 14 days, noncompliance and loss to follow-up. The study was done in accordance with the guidelines for Good Clinical Practice as defined by the European Union (8), and the Declaration of Helsinki concerning medical research in humans (9). Local ethical committee approval was obtained. Treatment protocol Standard surgical techniques for pediatric LTx were used as previously described (10). A total of 20 mg (40 mg in patients weighing more than 35 kg) of BAS was given in two doses of 10 mg each (or 20 mg each), by 10 min intravenous infusion. The first infusion of BAS was administered on day 0, as soon as possible after surgery, but no more than 6 h after graft reperfusion, while the second infusion was administered on day 4 after transplantation. A third BAS infusion was administered, on day 8–10 at the same dosage, if the total amount of fluid losses from the abdominal drains exceeded 70 mL/kg of recipient body weight (11). All patients received intravenous methylprednisolone, 10 mg/kg, at graft reperfusion, and baseline TAC immunosuppressive therapy. Oral TAC therapy was started postoperatively, no more than 12 h after skin closure, at the initial dose of 0.04 mg/kg in order to bring whole-blood trough levels of TAC into the therapeutic range as quickly as possible. Blood concentration was maintained at 10–15 ng/mL for weeks 1–4; at 8–10 ng/mL for months 2–3; at 6–8 ng/mL at months 4–6; and at 5–7 ng/mL for the remainder of the study. Control-group patients received steroids: intravenous methylprednisolone, 2 mg/kg/day, maximum dose of 40 mg, was administered on days 1–6. Oral prednisolone was started on day 7 at 1 mg/kg/day, at the maximum dose of 40 mg, and tapered to achieve steroid-free immunosuppression 3–6 months after transplantation, unless the clinical situation dictated otherwise. Rejection Rejection was defined as a rejection episode confirmed by liver biopsy, and for which therapy was given. Severity of rejection was graded with the Banff criteria for histological diagnosis of liver allograft rejection (12). Acute rejection episodes were treated with adjustment of the TAC dose in order to achieve the therapeutic range and with intravenous methylprednisolone boluses for a total cumulative dose of 45 mg/kg over 3–6 days. In case of steroid-resistant rejection, treatment with more potent immunosuppressive agents (e.g. OKT3) was allowed by the protocol. Study assessment and statistical method At scheduled visits, or as clinically indicated, we recorded the patient's medical history, vital signs, laboratory assessment, medication doses, trough drug concentrations in whole blood, graft rejection and side-effects. The minimum follow-up period for patient and graft survival was 12 months, even for those prematurely withdrawn from the study. Follow-up for all other clinical variables was performed up to the time of withdrawal from the study or study completion at month 12. The primary efficacy assessment was a comparison of the time of occurrence of the first rejection episode in each group. Secondary assessment included the proportion of patients who experienced at least one acute rejection episode, histological severity of rejection, the incidence of steroid-resistant rejection, graft loss and safety and tolerability—the latter two including deaths, technical and infectious complications. Sepsis was defined by the presence of clinical signs of infection (fever, tachypnea, tachycardia, leukocytosis, systemic inflammatory response syndrome), with two or more positive blood cultures from peripheral and/or central line. Pneumonia was diagnosed by chest x-ray evidence of pulmonary infiltrate, respiratory symptoms (cough, dyspnea, tachypnea and thoracic pain), decreased pO2 or respiratory acidosis, and positive sputum and/or bronchoalveolar lavage culture. Primary infection with cytomegalovirus (CMV) was defined as such if immunofluorescence showed CMV pp65 antigen in circulating lymphocytes in patients previously negative for the virus. A reactivation or reinfection of CMV was defined by a positive immunofluorescence test within a compatible clinical picture. Primary infection with Epstein-Barr virus (EBV) was defined as such if PCR showed EBV virus in circulating peripheral blood lymphocytes in patients previously negative for the virus. A reactivation or reinfection of EBV was defined by a positive PCR test within a compatible clinical context (13). We diagnosed and typed posttransplant lymphoproliferative disease (PTLD) on the basis of clinical symptoms in conjunction with laboratory findings (PCR showing EBV in circulating lymphocytes, neutropenia and oligoclonal or monoclonal peak of γ globulins), and histological or cytological symptoms (abnormal B-lymphocyte proliferation in blood and biopsy samples from lymph nodes, bone marrow, tonsils and/or liver). Serum creatinine concentrations were assessed and renal function was monitored by estimating corrected glomerular filtration rate (cGFR) using the Schwartz formula (14). Height and weight were recorded at every visit, and Z scores were calculated. Continuous variables were presented as mean (95% confidence interval for mean [CI]) except where otherwise specified, and categorical variables as proportion. The Mann-Whitney U-test was used to compare differences between means, while differences in proportions were tested using Pearson's chi-square test or Fisher's exact test (f-test) if expected frequencies were less than five. Survival analyses were computed using the Kaplan-Meier (product-limit) method and probability curves compared by the log-rank (Mantel-Cox) test. In the analysis of rejection episodes, deaths and graft losses before rejection were censored at the point of occurrence. A p value of less than 0.05 was considered statistically significant. Results Patients Eighty-four consecutive children underwent LTx during the study period. Twelve patients did not meet the inclusion criteria, while 72 were randomly allocated to BAS (n = 36) or steroids (n = 36); of these, 65 children (90%; BAS, n = 32; steroids, n = 33) completed the 12-month assessment period. Baseline patient characteristics are presented in Table 1; no clinically relevant differences exist between the treatment groups. Table 1. Baseline patient characteristics Characteristics Steroids (n = 36) Basiliximab (n = 36) Mean (CI) age (years) Patients 2.8 (1.5–4.2) 2.9 (1.5–4.3) Donors 20.4 (16.0–24.9) 24.7 (17.5–32.0) Mean (CI) Z score height −2.61 (−3.27 to −1.95) −2.27 (−2.94 to −1.60) Mean (CI) Z score weight −2.23 (−2.79 to −1.66) −1.54 (−2.10 to −0.97) Male sex 15 (41.7%) 18 (50.0%) Cause of end-stage liver disease Cholestatic diseases 27 (75.0%) 32 (88.8%) Metabolic diseases 3 (8.3%) 2 (5.6%) Other 6 (16.7%) 2 (5.6%) UNOS status 1 1 (2.8%) 1 (2.8%) 2A 3 (8.3%) 2 (5.6%) 2B 20 (55.6%) 15 (41.6%) 3 12 (33.3%) 18 (50.0%) Median (range) waiting time (days) 44 (1–347) 46 (0–373) CMV positive 20 (60.6%) 19 (59.4%) EBV positive 11 (33.3%) 12 (36.4%) Type of liver graft Whole liver 7 (19.4%) 9 (25.0%) Split liver 29 (80.6%) 27 (75.0%) Mean (CI) cold ischemia time (min) 427 (392–463) 424 (379–468) CI = 95% confidence interval for mean; UNOS = United Network for Organ Sharing; CMV = cytomegalovirus; EBV = Epstein-Barr virus. Rejection episodes The Kaplan-Meier estimates of the percentage of patients free of acute rejection during the study period is presented in Figure 1. At 12 months, patients free from rejection were 87.7% in the BAS group and 67.6% in the control group (p = 0.036). The incidence of rejection episodes 12 months after transplantation is presented in Table 2. BAS induction plus TAC immunosuppressive therapy was associated with a 63.6% reduction in the incidence of biopsy-proven acute rejection, compared with control group (19.5% difference). Median RAI score was 6 (range: 3–7) in the steroid group, and 4 (range: 3–6) in the BAS group. All children who experienced acute rejection in the BAS group had only one rejection episode, while in the steroid group one of the eight patients had two episodes (Table 2). Patients experienced the first episode of acute rejection after a median of 10 days in the steroid group (range: 5–266 days), and after a median of 28.5 days in the BAS group (range: 24–33 days). No children in either group developed steroid-resistant rejection. Figure 1Open in figure viewerPowerPoint Kaplan-Meier analysis of children free from biopsy-proven acute rejection at 12 months. Table 2. Rejection episodes 12 months after transplantation Outcome Steroids (n = 36) Basiliximab (n = 36) p Any rejection episodes 11 (30.6%) 4 (11.1%) 0.042* Number of rejection episodes per patient 0 25 (69.4%) 32 (88.9%) – 1 10 (27.8%) 4 (11.1%) – 2 1 (2.8%) 0 – Severity of biopsy-proven rejection episode (Banff criteria)12† Mild acute (RAI 1–3) 2 (16.7%) 1 (25.0%) – Moderate acute (RAI 4–6) 8 (66.6%) 3 (75.0%) – Severe acute (RAI 7–9) 2 (16.7%) 0 – *Chi-square test. †Steroids, n = 12; basiliximab, n = 4. Immunosuppression and concomitant medication No clinically meaningful differences in the mean daily dose of TAC were observed between treatment groups. Mean daily dose of TAC was 0.56 mg/kg (95% confidence interval for mean [CI] 0.24–0.88) in the BAS group and 0.79 mg/kg (CI 0.16–1.42) in the steroid group on postoperative day 7; 0.13 mg/kg (CI 0.07–0.19) (BAS) and 1.15 mg/kg (CI −2.88 to 5.18) (steroids) 3 months after transplant; and 0.34 mg/kg (CI −0.45 to 1.13) (BAS) and 0.08 mg/kg (CI 0.01–0.14) (steroids) at 12 months. In addition mean whole-blood trough TAC concentrations remained within the protocol-defined ranges without statistically significant differences between treatment groups. Mean TAC whole blood trough level was 9.93 ng/mL (CI 8.52–11.35) in the BAS group and 7.81 n/mL (CI 6.19–9.43) in the steroid group on postoperative day 7; 7.45 ng/mL (CI 6.44–8.46) (BAS) and 9.26 ng/mL g (CI 7.70–10.81) (steroids) 3 months after transplant; and 5.60 ng/mL (CI 4.67–6.53) (BAS) and 5.22 ng/mL (CI 4.16–6.27) (steroids) at 12 months. A third BAS dose was needed in 13 out of 34 children (38%) (two patients who died on postoperative day 4 and 9 were not considered). Of the four patients who developed acute rejection in the BAS group, one received a third BAS dose. Patient and graft survival, technical complications Seven deaths (BAS, n = 4; steroids, n = 3) occurred during the 12-month study (Table 3). In the BAS group, no death was considered to be definitely related to BAS. In one case we considered the cause of death to be possibly related to study medication: a 17-year-old boy transplanted for acute liver failure secondary to liver trauma with a whole liver from a 79-year-old donor died on the 9th postoperative day because of enterococcus sepsis and multiple organ failure. A 9-year-old boy with fulminant hepatic failure of unknown origin, received an urgent whole LTx from a 32-year-old donor, developed primary nonfunction and died 12 days later from multiple organ failure after unsuccessful left lateral segment retransplantation, performed on postoperative day 2. Pathology examination of the primary graft revealed diffuse hepatic necrosis with IgG and IgM deposition, suggestive of humoral hyperacute rejection; autopsy was not performed. A 19-month-old boy affected with biliary atresia underwent split LTx with a large-for-size left lateral segment (graft-to-recipient weight ratio = 8.75) from a 21-year-old donor and died 4 days later from primary nonfunction, while waiting for liver retransplantation. A 1-year-old boy affected with biliary atresia underwent primary split LTx with a left lateral segment graft, developed early postoperative portal thrombosis with delayed graft function, underwent liver retransplantation 26 days later (in critical condition), and died from intraoperative cardiac failure. Table 3. Patient and graft survival 12 months after transplantation Steroids (n = 36) Basiliximab (n = 36) p Patient survival2 33 (91.7%) 32 (88.9%) 0.489 Causes of graft loss Hepatic artery thrombosis 3 1 Primary nonfunction 1 2 DGF with portal vein thrombosis 0 1 DGF 0 1 SFS with portal vein thrombosis 1 0 Secondary biliary cirrhosis 0 1 Sepsis 0 1 Graft survival 31 (86.1%) 29 (80.6%) 0.430 DGF = delayed graft function; SFS = small-for-size syndrome. 1Kaplan-Meier p-values. 2Seven deaths in 12-month study period analyzed, steroids, n = 3; basiliximab, n = 4. In the steroid group a 6-month-old boy affected by biliary atresia died 2 days after a left lateral segment split LTx from acute liver failure caused by hepatic artery thrombosis. A 9-year-old boy affected by biliary atresia underwent split LTx from a 12-year-old donor and died from primary graft dysfunction 6 days later; pathology examination of the transplanted graft revealed confluent necrosis with endothelioangiitis and biliary duct inflammatory infiltrate. A 10-year-old boy affected by Byler's disease underwent split LTx with a small-for-size left lateral segment graft from a 40-year-old donor (graft-to-recipient weight ratio = 0.89), developed portal vein thrombosis with delayed graft dysfunction, and underwent successful split liver retransplantation with an extended right graft (segments I + IV − VIII) from a 19-year-old donor; he died 57 days after primary transplantation from acute and incontrollable gastrointestinal bleeding. Graft survival rates 12 months after transplantation were similar in the two treatment groups (Table 3). The overall incidence of vascular complications was equal in the two groups (five patients in both groups; p = 0.633). Arterial thrombosis occurred in one child in the BAS group, and in three children in the steroid group, while portal vein thrombosis developed in four and three patients, respectively. Biliary complications did not differ between groups (six patients [16.7%] in the BAS group vs. 8 [22%] patients on steroids; p = 0.383). Adverse events and infections The tolerance of BAS was excellent, with no evidence of cytokine-release syndrome (i.e. fever, hypertension, lung edema or headache). The overall incidence of infection was higher in the steroid group 26 of 36 (72.2%), than in the BAS group 18 of 36 (50%) (p = 0.035). The breakdown of the type of infection was as follows: bacterial 44 (BAS, 14; steroids, 30); viral 15 (BAS, 7; steroids, 8); fungal 3 (BAS 1; steroids, 2); parasites 1 (steroids 1). Symptomatic EBV infection occurred in six patients (17%) of the BAS group (diarrhea, fever, pharyngitis, lymphadenopathy, ascites and hepatitis), and in four patients (11%) of the steroid group (diarrhea, lymphadenopathy, pharyngitis and hepatitis) (p = 0.367). In all these patients immunosuppression was reduced, resulting in symptoms resolution in eight patients (five in the BAS group, and three in the steroid group). Symptoms of PTLD were reported in one patient (3%) in each group, 4 and 9 months after transplantation, respectively. Both patients had confirmed EBV infection and evidence of polyclonal lymphoproliferation. The BAS child had TAC withdrawn, while immunosuppressive medications were reduced in the steroid patient resulting in PTLD resolution in both cases. In the BAS group, incidence of infection was not different among those who received a third BAS dose (6 out of 14 [43%]), compared to those who did not (12 out of 22 [50%]). New onset hypertension requiring antihypertensive medication was observed in three patients (8.3%) in the BAS group and eight (16.7%) patients in the steroid group (p = 0.094). Renal function, as assessed by mean cGFR, was similar in both groups throughout the study. Mean cGFR was 102.3 mL/min × 1.73 m2 (CI 87.2–117.4) in the BAS group and 112.7 mL/min × 1.73 m2 (CI 91.2–134.2) in the steroid group before transplant, and 94.1 mL/min × 1.73 m2 (CI 79.2–109.0) (BAS) and 88.3 mL/min × 1.73 m2 (CI 70.5–106.0) (steroids) at 12 months. Four patients, three (8%) in the BAS group and one (3%) in the steroid group, had acute renal failure requiring dialysis or ultrafiltration during the study. Liver function after transplantation was similar in both groups. Mean total bilirubin was 15.8 mg/dL (CI 11.1–20.5) (BAS) and 20.6 mg/dL (CI 16.1–25.0) (steroids) at baseline; the corresponding values were 5.0 mg/dL (CI 3.4–6.7) and 4.4 mg/dL (CI 2.8–6.0), respectively, at day 7; 2.3 mg/dL (CI 0.9–3.7) and 1.6 mg/dL (CI 0.7–2.5), respectively, at day 30; and 1.0 mg/dL (CI 0.3–1.7) and 1.1 mg/dL (CI 0.4–1.8), respectively, at the end of the study. Similarly, liver enzymes (alanine and aspartate aminotransferase) were similar in both groups. Fasting serum glucose levels remained within the normal range and were similar in the two treatment groups (data not shown), with the exception of the early postoperative period (p.o.d. 7), when glucose levels were higher in the steroid group (BAS, 89.3 mg/dL [CI 79.4–99.3]; steroids, 113.6 mg/dL [CI 91.9–135.2]). No patients in our series developed insulin-dependent diabetes mellitus. Mean fasting total serum cholesterol and triglycerides were similar in both groups at screening (BAS group 174 mg/dL [CI 132–216] and 141 mg/dL [CI 100–183], respectively; steroid group 237 mg/dL [CI 169–305] and 146 mg/dL [CI 115–178], respectively), and at the end of the study (BAS group 131 mg/dL [CI 123–139] and 122 mg/dL [CI 95–150], respectively; steroid group 136 mg/dL [CI 113–158] and 101 mg/dL [CI 85–117], respectively). No patients in either groups received antihyperlipidemic medications. Patient growth At baseline, mean height and weight of the participating children were below average for their age (Table 1). Mean height and weight Z scores for patients who completed the study improved in both groups: month-12 weight Z scores were −0.01 (CI −0.49 to −0.48) and −0.63 (CI −1.25 to −0.02), month-12 height Z scores were −0.56 (CI −1.14 to 0.01) and −1.15 (CI −1.80 to −0.50) for patients in the BAS and steroid group, respectively. Two-year follow-up In addition to study design, which was intended to follow up patients for 1 year after transplantation, 2-year follow-up data are available for all recruited patients who survived more than 1 year. No patient death or graft failure occurred during the second year after transplantation. In the basiliximab group, 28 out of 32 patients (87.5%) were on tacrolimus monotherapy with normal liver function. During the second year post-transplant, a girl who previously experienced PTLD that was successfully treated with temporary tacrolimus withdrawal, developed PTLD recurrence that required immunosuppression discontinuation. At the 2-year follow-up, she was on steroid monotherapy with mildly elevated liver function tests. Thirteen months after LTx, a boy developed severe sepsis from pneumococcus associated with meningitis and endocarditis, which necessitated immunosuppression discontinuation; 2 months later, he experienced acute rejection and immunosuppression was restored. At 2 years, he was on TAC, steroids and mycophenolate mofetil with mildly elevated liver function tests and signs of early chronic rejection at liver biopsy. A third child developed late graft dysfunction 14 months after transplantation; liver biopsy showed lobular inflammatory infiltration. The child was successfully treated with steroids and at 2 years he was on double immunosuppressive therapy with normal liver function. Finally, a girl, transplanted for Byler's syndrome with occasional finding of hepatocellular carcinoma, underwent post transplant chemotherapy and 21 months later developed chronic rejection; at 2-year follow-up, she was on tacrolimus plus mycophenolate mofetil immunosuppression with elevated liver function tests. In the steroid group, 25 out of 33 patients (75.8%) were on tacrolimus monotherapy with normal liver function. At 2-year follow-up, four children on tacrolimus monotherapy had elevated liver function because of biliary complications. Two girls developed EBV infection 13 months later and had their immunosuppression temporarily interrupted. At 2 years they both had early signs of chronic rejection and mildly elevated liver function tests; the first was treated with TAC and steroids while the second was on TAC, mycophenolate mofetil and steroid immunosuppression. PLTD requiring immunosuppression withdrawal developed 14 months after transplantation in a child who, at 2 years, was on triple immunosuppression with signs of early chronic rejection and with mildly elevated liver tests. Finally, elevated liver function tests with vanishing bile duct syndrome were present at 2-year follow-up in a boy on tacrolimus, mycophenolate mofetil and steroid immunosuppression. Discussion After improvement of overall patient and graft survival one of the most important goals in LTx is now to reduce or even avoid morbidity related to immunosuppressive therapy. The recent introduction of new immunosuppressive drugs with different mechanisms of action and clinical profiles has opened up new therapeutic options that can be used to improve patient morbidity and quality of life (15). In pediatric LTx this concept has translated into the attempt to optimize immunoprophylaxis with steroid withdrawal and steroid avoidance in order to avoid long-term overimmun