Outcome of pediatric liver transplant recipients in Turkey: single center experience

To summarize the evolution of the pediatric liver transplant program in a developing country. Between April 1997, and September 2003, 32 cadaveric (CD) and 35 living donor (LD) liver transplantations were performed on 61 children (median age 3.8 yr, range 0.5-16) at Ege University Organ Transplantation and Research Center. The patient's charts were reviewed retrospectively. The outcome of patient and graft survival was analyzed and the incidence of graft loss, complications and rejections was calculated. Indications for liver transplantation were metabolic liver disease (n = 17), biliary atresia (n = 14), viral hepatitis (n = 4), autoimmune hepatitis (n = 6), cryptogenic cirrhosis (n = 11), fulminant liver failure (n = 5) and others (n = 5). Seven of 61 children with chronic liver disease had hepatocellular carcinoma concomitantly. Median pediatric end-stage liver disease score was 23 (range 1-54). Seven children (11.4%) were UNOS status I, 44 (72%) were UNOS status II and 10 (16.6%) were UNOS status III. The median follow-up of the study population was 3.6 yr (range 0.5-6). Actuarial patient survival rates at 1, 2, 3 and 4 yr were 86, 86, 71.3 and 65% in the CD group vs. 80, 76, 67 and 67% in the LR group, respectively (p = NS). Patients listed as UNOS status 1 had lower survival rates than patients listed as UNOS status 2 and 3 (p < 0.05). The mortality rate was 26.2%. Graft survival rates were 81, 81, 75 and 64% at 1, 2, 3 and 4-yr respectively. Six patients (9%) underwent retransplantation. The main complications were infections (64.7%) and surgical complications (43.2%) (including biliary complication, vascular problems, postoperative bleeding, small for size and large for size). The incidence of acute cellular rejection was 39.3%, whereas chronic rejection was 7.4%. The result of liver transplantation in Turkish children was slightly inferior to those reported for North American and European children. However, an important characteristic of these patients that distinguishes them from Europe and North America is that most were UNOS status IIa and UNOS status I (44%). Despite technical and medical progress, infectious and biliary problems have continued to be an important cause of mortality in these patients.     

Lipid profile and cardiovascular risk factors in pediatric liver transplant recipients

Cardiovascular diseases induce long‐term morbidity and mortality of adult LT recipients. The aim of this retrospective study was to assess CVRF, lipid abnormalities, and atherosclerosis (appraised by c‐IMT), more than 10 yr after pediatric LT. Thirty‐one children who underwent LT between December 1990 and December 2000 were included. Median age at LT was 14 months (range 4–64), and median follow‐up after LT was 11.9 yr (range 9.0–17.3). In our cohort, obesity (9.7%) and treated hypertension (9.7%) were rare. None of the patients was smoker or diabetic. High TC and TG were both observed in 6.5% of the patients. The mean c‐IMT for male patients was 1.22 ± 1.55 and 1.58 ± 1.23 mm in female patients. Seven patients (22%) had a mean c‐IMT above +2 s.d. Values below the 5th percentile were noted for LDL‐cholesterol (58.1%), HDL‐cholesterol (25.8%), apolipoprotein B (40%), and apolipoprotein A1 (20%). LDL‐cholesterol and apolipoprotein B levels were significantly lower in patients treated by tacrolimus in comparison with CsA (p < 0.05). In conclusion, our results suggest that pediatric LT patients do not present significant CVRF; moreover, instead of hyperlipidemia, hypocholesterolemia (LDL‐C) is frequent and immunosuppressive therapy is probably the cause.     

Growth of liver allografts over time in pediatric transplant recipients

The liver's capacity to grow in response to metabolic need is well known. However, long‐term growth of liver allografts in pediatric recipients has not been characterized. A retrospective review of pediatric recipients at a single institution identified patients who had cross‐sectional imaging at 1, 5, and 10 years post‐transplant. Using volumetric calculations, liver allograft size was calculated and percent SLV were compared across the different time points; 18 patients ranging from 0.3 to 17.7 years old were identified that had imaging at 2 or more time points. Measured liver volumes increased by 59% after 5 years and 170% after 10 years. The measured liver volumes compared to calculated %SLV for these patients were 123 ± 37%, 97 ± 19%, and 118 ± 27% at 1, 5, and 10 years after transplant, respectively. Our data suggest that liver allografts in pediatric recipients increase along with overall growth, and reach SLVs for height and weight by 5 years post‐transplantation. Additionally, as pediatric recipients grow, the livers appear to maintain appropriate SLV.     

A single center experience of donation after cardiac death liver transplantation in pediatric recipients

Bartlett A, Vara R, Muiesan P, Mariott P, Dhawan A, Mieli‐Vergani G, Rela M, Heaton N. A single center experience of donation after cardiac death liver transplantation in pediatric recipients.
Pediatr Transplantation 2010:14: 388–392. © 2009 John Wiley & Sons A/S. Abstract: Many centers are now performing DCD adult LT. There has been a reluctance to transplant pediatric recipients with DCD livers due to concern over the medium to long‐term outcome. We describe the outcome of 14 children (median age seven yr, 8 months–16 yr) that underwent LT with DCD grafts from July 2001 to December 2007. Donors had a median age of 23 yr (10–64), intensive care stay of five d (2–14) and bilirubin of 9 mmol/L (6–60). Median warm and cold ischemic time was 16 min (11–29) and seven h (5.5–8.4). Livers were transplanted as a whole organ (4), reduced graft (8), formal split (1) or auxiliary transplant (1). Compared to DBD recipients AST was significantly higher on the first three post‐operative days and there was no difference in the INR, bilirubin or GGT out to 12 months. There were no biliary or vascular complications and patient and graft survival is 100% at a median follow‐up of 41.8 months (1.7–74 months). LT with DCD grafts in pediatric recipients can be performed with low morbidity and excellent short‐to‐medium term patient and graft outcome.     

Towards minimizing immunosuppression in pediatric liver transplant recipients

Abstract:  Immunosuppression regimens after liver transplantation focus mainly on preventing rejection and subsequent graft loss. However, in children, morbidity and mortality rates from infections exceed those from rejection after transplant, and immunosuppression can hinder growth, renal function, and graft tolerance. We hypothesized that early steroid withdrawal, with a primary aim of TAC monotherapy would yield no penalty in terms of rejection and graft loss, while reducing risks of infection and maximizing growth. We prospectively evaluated 64 consecutive pediatric liver transplant recipients. One yr patient/graft survival was 93/90%, respectively. At one yr post-transplant, 75.4% of patients were on TAC monotherapy. No deaths or graft losses were caused by infection. Sixty-one percent of patients had at least one episode of rejection, most within three months following transplant and 3.8% were treated for chronic rejection. One non-compliant adolescent died from chronic rejection. CMV, EBV, and lymphoproliferative disease rates were 3.1%, 5.3%, 1.8%, respectively. Pretransplant and one yr post-transplant glomerular filtration rates were unchanged. One yr improved catch-up growth was observed. We conclude that immunosuppression minimization after pediatric liver transplant yields no serious complications from rejection, and might confer advantages with respect to infection, renal function, growth, and is deserving of wider application and study.     

The use of everolimus in pediatric liver transplant recipients: first experience in a single center

The role of mTOR inhibitors, such as EVL, has not been established for pediatric liver transplant recipients up to now, although data from adult solid organ graft transplantation are very promising. Major complications following pediatric liver transplantation in the long-term course include chronic graft rejection and CNI-derived nephrotoxicity. The purpose of our study was to report first results using EVL as a rescue therapy in pediatric liver transplant recipients for the following indications: chronic graft dysfunction n=12, suspected CNI toxicity n=3, hepatoblastoma n=2, and recurrence of primary sclerosing cholangitis post-Ltx n=1. Four patients with chronic graft dysfunction developed completely normal liver function tests using EVL, six patients showed partial improvement, and two patients did not respond at all. One patient with CNI-induced nephropathy showed a slightly improved GFR. Both patients with hepatoblastoma did not develop any metastasis post-Ltx. First experience with EVL in pediatric liver transplant recipients shows promising results in patients with chronic graft failure when standard immunosuppression has failed. The future role of EVL in immunosuppressive protocols for children post-Ltx has to be proven by controlled clinical trials.     

Presentation of atopic disease in a large cohort of pediatric liver transplant recipients

Atopic disease occurs in solid organ transplant recipients with an increasingly recognized frequency. The time course for the development of these atopic diseases in liver transplantation has not been described. The objective was to characterize the atopic manifestations of children receiving chronic immunosuppression after orthotopic liver transplantation (OLT). Chart review and follow-up questionnaire were utilized for 176 OLT pediatric recipients at a single institution for manifestations of allergic disease. Atopic disease was present in 25 (14.2%) patients. Median age at transplant was 16 months with a median follow-up of 63 months. Food allergy and non-food related atopic symptoms presented at a median of 11.5 (IQR, 6-28) and 19 (IQR, 5-41) months post-transplantation, respectively. The median age at transplant of the non-atopic children was 72 months, higher than patients with atopy (p < 0.001). Food allergy and atopic skin disease symptoms were present in 40% and 56% of cases, respectively. Asthma, allergic rhinitis, or both were found in 66% of cases. The onset of symptoms of food allergy and eczema (median, 12 months post-transplantation) preceded symptoms of allergic rhinitis and asthma. (median of 27 and 30 months post-transplantation, respectively). Atopy occurs in ～14% of pediatric liver transplant recipients, with manifestations including food allergy, eczema, allergic rhinitis, and asthma.     

Diaphragmatic hernias after pediatric liver transplantation: Experience of a high‐volume transplant center

Diaphragmatic hernias (DHs) are rare complications after pediatric liver transplantation (PLT). It is now widely accepted that DHs after liver transplantation (LT) is a pediatric related condition. PLTs (under of age 18) performed between January 2013 and June 2019 at Malatya Inonu University Institute of Liver Transplantation were retrospectively scanned. Study group consisting DHs and a control group were compared. Among 280 PLTs, 8 of them were complicated with DHs (%2.9). Median age of the patients with DH was 3.0 (0.8‐9.5) years. Median graft recipient weight ratio was 2.5 (0.9‐4.4). Five patients were below 5th percentiles in terms of pediatric weight growth chart at the time of LT. Also, 6 patients were below 5th percentiles in terms of pediatric height growth chart. There was no statistical difference between study and control groups. There are many risk factors mentioned in literature that may be primarily responsible for DHs after PLT. These factors are left lobe and large‐for‐size grafts, malnutrition, trauma or diathermy of diaphragmatic nerve and vessels and immunosuppressants. In our study, we could not specify any reason that differs in DHs. In our aspect, narrow diaphragma and thorax are exposed to high intra‐abdominal pressure from abdomen. Large‐for‐size grafts, which are specific to children, also may contribute to this affect. Excessive diathermy and trauma to diaphragmatic collaterals may aggravate the risk of DH. More patients are needed to make an exact conclusion, in order to evaluate with comparable study on this aspect.     

Evaluating non-adherence to immunosuppressant medications in pediatric liver transplant recipients

Abstract:  Non-adherence with recommended immunosuppressant medications is common post-pediatric liver transplant and is the most important reason for organ rejection in long-term survivors. However, there is currently no validated, standard method to measure adherence, with a well-defined threshold, making it extremely difficult to evaluate interventions to improve adherence. Previous studies have suggested that the degree of fluctuation of medication blood levels over time can provide an idea about how regularly the medication is being taken. The present study, conducted at UCLA medical center, sought to identify a specific threshold value of the s.d. of individual tacrolimus blood levels in pediatric liver transplant recipients which would be associated with rejection episodes in these patients. A threshold of 3.0 has been identified in other studies, and was supported by the analysis of retrospective data from 96 subjects. However, further analysis found that a s.d. of 2.5 appeared to have a better fit with the data. These findings suggest the utility of monitoring the s.d. of routine tacrolimus blood levels in pediatric liver transplant recipients for detecting non-adherence to immunosuppressant medication prior to clinical rejection, allowing earlier interventions.     

Hepatic venous reconstruction in pediatric living-related donor liver transplantation--experience of a single center

In pediatric patients submitted to living related liver transplantation, hepatic venous reconstruction is critical because of the diameter of the hepatic veins and the potential risk of twisting of the graft over the line of the anastomosis. The aim of the present study is to present our experience in hepatic venous reconstruction performed in pediatric living related donor liver transplantation. Fifty-four consecutive transplants were performed and two methods were utilized for the reconstruction of the hepatic vein: direct anastomosis of the orifice of the donor left or left and middle hepatic veins and the common orifice of the recipient left and middle hepatic veins (group 1-26 cases), and wide triangular anastomosis after creating a wide triangular orifice in the recipient inferior vena cava at the confluence of all the hepatic veins with an additional longitudinal incision in the inferior angle of the orifice (group 2-28 cases). In group 1, eight patients were excluded because of graft problems in the early postoperative period and five among the remaining 18 patients (27.7%) presented stricture at the site of the hepatic vein anastomosis. All these patients had to be submitted to two or three sessions of balloon dilatations of the anastomoses and in four of them a metal stent had to be placed. The liver histopathological changes were completely reversed by the placement of the stent. Among the 28 patients of the group 2, none of them presented hepatic vein stenosis (p = 0.01). The results of the present series lead to the conclusion that hepatic venous reconstruction in pediatric living donor liver transplantation must be preferentially performed by using a wide triangulation on the recipient inferior vena cava, including the orifices of the three hepatic veins. In cases of stenosis, the endovascular dilatation is the treatment of choice followed by stent placement in cases of recurrence.     

Timed Pediatric Risk of Mortality Scores predict outcomes in pediatric liver transplant recipients

More reliable methods are needed to identify children at risk for poor outcomes following liver transplantation. The Pediatric Risk of Mortality (PRISM) Score is a physiology-based scoring system used to quantify risk of mortality in pediatric intensive care unit (ICU) populations. We evaluated the PRISM Score as a predictor of outcomes including survival in the pediatric liver transplant (LT) population. We retrospectively reviewed the records of 67 consecutive LTs performed between August 1997 and February 2000 at an urban, tertiary children's hospital in Chicago, IL, USA. Four PRISM Scores were calculated to determine which periods were most meaningful. A Classic PRISM Score was calculated during first 24 h of ICU admission, and three PRISM Scores were timed with the patient's transplant: a pre-LT PRISM Score (24 h prior to transplant whether in ICU or not), a 24-h post-LT PRISM Score and a 48-h post-LT PRISM Score. These PRISM Scores and other predictors including transplant number, UNOS status and PELD Score were compared with outcomes including survival using univariate methods. The pre-LT, the 24- and the 48-h PRISM Score were associated with the post-LT number of ventilated days (p < 0.05), ICU days (p < 0.05) and with 1-yr survival (p < 0.04). The PRISM Scores were not related to the post-LT hospital length of stay (LOS) or to 1-yr re-transplantation. The PELD Score correlated with the post-LT hospital LOS, but was not associated with mortality or with the ICU LOS. A patient's UNOS status and Classic PRISM Score were not associated with any of the outcomes measured. PRISM Scores are valid predictors of outcome including survival in pediatric LT recipients. These findings help to demonstrate the importance in this population of a patient's general physiologic condition and its influence on the overall hospital course and survival.     

Utility of liver biopsy culture in pediatric liver transplant recipients

Abstract: The purpose of our study was to determine the utility of the practice of culturing percutaneous liver biopsy specimens obtained from pediatric LT recipients for evaluation of fever and/or elevated serum aminotransferases. Accordingly, a retrospective analysis was done of the 101 liver biopsies obtained during an eight-year period which had been submitted for bacterial, fungal and/or viral culture (out of a total of 174 biopsies in 38 patients). The purpose of the analysis was to ask three questions. (1) What organisms were cultured? (2) Were there clinical profiles that were characteristic of the type of organism? (3) Was the practice cost-effective? The analysis indicated that 34/86 biopsy cultures were positive for bacteria, 4/75 for fungus and 2/81 for virus. Clinical and laboratory data for children with cultures positive for enteric flora (n = 9) were compared to those with cultures positive for Gram-positive organisms (n = 17), laboratory contaminants (n = 8), and those with negative cultures (n = 52). Children with biopsies positive for enteric flora had a ‘cholestatic profile’: mean direct bilirubin 7 mg/dl, ALT 78 IU/l, direct bilirubin/ALT 0.09, in comparison to children with biopsies positive for Gram-positive flora. These children had a ‘hepatocellular profile’: mean direct bilirubin 4 mg/dl, ALT 332 IU/l, direct bilirubin/ALT 0.01 (p = 0.04 versus the enteric flora values) and a high percentage of polymorphonuclear leukocytes (mean 69% versus 38% for those with negative cultures, p = 0.001.) The charge for performing each bacterial culture was $28 (total $28 × 86 = $2408: $268 per enteric flora-positive biopsy; $93 per biopsy positive for either enteric flora or Gram-positive flora). The charge for each fungal culture was also $28 (total $28 × 75 = $2100: $525 per positive culture), while the cost for each viral culture was $140 (total $140 × 81 = $11 340: $5670 per positive culture). Thus, discounting the eight cultures positive for laboratory contaminants, a total of $15 848 was spent for 32 positive cultures. Given the high cost of liver transplantation, this information suggests that discretion should be used in submission of liver biopsy samples for culture in pediatric transplant patients. We recommend that when liver biopsies are performed for evaluation of elevated serum aminotransferases and/or fever, culture of biopsy specimens for bacteria should be considered in children with a ‘cholestatic profile’: direct bilirubin ≥ 7 mg/dl and direct bilirubin/ALT > 0.08, or a ‘hepatocellular profile’: direct bilirubin ≤ 4 mg/dl and direct bilirubin/ALT < 0.05, together with polymorphonuclear leukocytes > 70%. Following these guidelines might provide valuable information pertinent to patient management (especially since Gram-negative organisms can sometimes be cultured from the liver and not from blood) while reducing costs. Fungal cultures should be restricted to critically ill children. However, our data suggest that the practice of obtaining fungal and viral cultures of the liver in most pediatric transplant patients has an unacceptably high cost/benefit ratio, particularly since recovery of the organism from the peripheral blood is likely.     

Immediate tracheal extubation of pediatric liver transplant recipients in the operating room

Keeping patients on mechanical ventilation after orthotopic liver transplantation (OLT) has been a standard anesthetic approach since the first utilization of liver transplantation. Advances in anesthetic management, surgical techniques and patient preparation, in addition to improved postoperative care and the reported advantages of early postoperative tracheal extubation of liver recipients. encouraged us to extubate most recipients at the end of the operation. The aim of the present study is to evaluate the pediatric liver recipients who were extubated immediately at the end of transplantation, in terms of respiratory complications and allograft function during their stay in the ICU. We retrospectively reviewed the records of 40 pediatric recipients who had undergone OLT at the Ege University Organ Transplantation Center between December 1997 and July 2002. Twelve out of 40 patients who had consecutively undergone OLT were extubated immediately at the end of the operation and were included this study. Mean Child Pugh scores of the patients were 9 +/- 2.3 (range 6-12) and the mean PELD score was 23.1 +/- 12.3 (range 7-41). The mean age of the patients was 8.4 +/- 5.2 (range 0.8-16.8 yr). Five of the 12 extubated patients received a cadaveric and seven a living donor liver graft. The mean ICU stay of the patients was 49.1 +/- 24.2 h (6-120 h). No patients required reintubation or mechanical ventilation in the ICU. Respiratory complications diagnosed in the 12 extubated patients were hypercapnia without hypoxemia in three, atelectasis in one and pleural effusion in two. No primary non-function or delayed graft function was detected. The aspartate transaminase (AST), alanine transaminase (ALT) and protrombin time (PT) were normalized within a week. We believe that immediate tracheal extubation in the operating room is a safe procedure for selected cadaveric and living-related liver transplant recipients and will facilitate the patients' recovery and mobilization leading to reduction in complications and a reduced ICU stay.     

Hypogammaglobulinemia in pediatric liver transplant recipients

Hypogammaglobulinemia has been reported after solid organ transplantation in adults, however immunoglobulin replacement [intravenous immunoglobulins (IVIG)] is only necessary in a minority of affected patients. We here present three pediatric patients with severe post-transplant hypogammaglobulinemia following liver transplantation (LTx) receiving a cyclosporine-based standard immunosuppression. Patient 1 was transplanted at the age of 10 months for biliary atresia. Eight weeks post-Ltx the serum IgG was 1.7 g/L. Patient 2 was transplanted at the age of 12 yr for acute liver failure. Four weeks post-Ltx the IgG dropped to 2.6 g/L. Patient 3 was transplanted at the age of 4 months for biliary atresia. Ten weeks post-Ltx severe hypogammaglobulinemia (IgG < 1.48 g/L) was diagnosed during a severe infectious complication. Patients 1 and 3 received a steroid bolus therapy for acute graft rejection. All patients had normal IgG concentrations prior to Ltx and lymphocyte subsets were post-operatively in the normal range. There was no extensive loss of protein by ascites. IGIV were replaced in the three patients monthly without further complications. In two of the patients (1 and 3) IVIG therapy was discontinued 8 and 10 months after Ltx when the immunosuppression has been reduced and serum IgG concentrations were found in the normal range without further immunoglobulin replacement. Severe hypogammaglobulinemia is a rare phenomenon following pediatric LTx and seems to be mainly caused by immunosuppressive drugs, however, the exact underlying mechanisms are unclear. A screening for hypogammaglobulinemia is useful after pediatric LTx, especially in patients with an intensified immunosuppression. Moreover, further immunologic research in affected patients is necessary.     

Investigation of impaired carbohydrate metabolism in pediatric liver transplant recipients

Abstract:  OGTT was performed in 28 liver transplants maintained with tacrolimus to investigate carbohydrate metabolism and assess risk factors for development of PTDM. None had PTDM that was detected by OGTT. Early PTDM in four cases (14.3%) resolved in follow-up. Five new cases (17.9%) demonstrated DCM (DCM  = IGT ± hyperinsulinemia). Fasting measurements were normal in two hyperinsulinemic cases. With one (20%, p > 0.05) exception none of the children with DCM were overweight or had a family history of diabetes. All five (100%) children with DCM had been given high cumulative dosage of steroids 18 (78.3%) – without DCM (p > 0.05). The median age of children with DCM was greater [4.3 (12.7–18.0) vs. 7.0 (2.3–18.0) yr, p < 0.01] and duration of follow-up longer [5.3 (2.3–7.0) vs. 2.5 (0.7–7.3) yr, p < 0.05]. Four children (80%) with DCM were pubertal (p < 0.05). However, neither age nor duration of follow-up or pubertal stage had significant effect on DCM development. Early PTDM is a transient phenomenon and is not predictive for future development of diabetes. DCM is frequently observed in liver transplanted children. Albeit the children with DCM were given high cumulative dose of steroids, were older, mostly were pubertal, and had longer duration of follow-up, we cannot draw firm conclusions on effects of the risk factors on carbohydrate metabolism because of the small sample size and relatively short duration of follow-up. Unlike fasting measurements, OGTT can detect all children with DCM.     

Outcome of pediatric liver transplant in grafts with multiple arteries

Abstract:  Young age, small diameter of the hepatic artery, presence of multiple arteries, and the selected technique are risk factors for hepatic arterial complications. We report the outcomes of pediatric liver transplant (LT) patients who had received a liver graft with multiple arteries. Since April 2001, 89 pediatric LTs have been performed at our center. Twenty-six liver grafts (29.2%) that had multiple hepatic arteries were analyzed retrospectively. Twenty-five grafts had 2, and 1 graft had 3, hepatic arteries. In 17 grafts with double arteries, and in 1 graft with 3 arteries, the adjacent edges of the hepatic arteries were sutured together at the back table to create a single opening, and the recipient's common hepatic artery was then anastomosed to that orifice. In 8 grafts with double arteries, 2 separate anastomoses were performed between the graft hepatic arteries and the recipient's hepatic artery branches. The mean age of the recipients was 7.9 ± 5.4 years (range, 0.6–17 years). During the early postoperative period, hepatic arterial thromboses occurred in 3 recipients. Two of these 3 recipients were treated with transcatheter arterial thrombolysis using streptokinase or recombinant plasminogen and intraluminal stent placement, and the remaining recipient was treated with a re-anastomosis using a polytetrafluoroethylene graft. Three recipients died during follow-up, which ranged from 1 to 71 months. In conclusion, multiple graft arteries did not increase the incidence of hepatic arterial complications in our series.     

Effect of treatment with prostaglandin E1 and N-acetylcysteine on pediatric liver transplant recipients: a single-center study

Prostaglandin E1 (PGE1) and N-acetylcysteine (NAC) have been used as single agents to decrease reperfusion injury and improve outcome after solid-organ transplantation (Tx). We hypothesized that combined treatment with NAC and PGE1 would be safe and reduce reperfusion injury. We therefore carried out a pilot study to assess the safety of this drug combination and gain information regarding the efficacy of treating pediatric liver transplant recipients with NAC and PGE1. The pilot study took the form of an open-label study incorporating 25 pediatric liver transplant recipients (12 children in the treatment group and 13 children as controls). NAC (70 mg/kg) was given intravenously over 1 h following reperfusion and then every 12 h for 6 days. PGE1 (0.4 mg/kg/h) was given as a continuous intravenous infusion for 6 days, starting after the first NAC dose. The primary outcome was the safety of combined treatment with NAC and PGE1. Patient survival, graft survival, allograft rejection within the first 90 days after Tx, peak post-transplant serum alanine aminotransferase (ALT) concentration, post-transplant length of hospitalization, and post-operative complications were secondary outcomes. Post-operative complications occurred at similar rates in both control and treated groups. No complications or adverse events occurred in the treated group as a result of study drugs. The 3-month patient survival rate was 100% for both groups. For the group treated with NAC and PGE1, peak serum ALT was lower and median length of stay was shorter but the differences did not reach statistical significance. The proportion of patients with allograft rejection was not significantly different between the two groups. However, rejection was more severe in the control group than in the treated group. In summary, infusions of NAC and PGE1 were safely administered to pediatric liver transplant recipients. However, a randomized controlled study is needed to determine the efficacy of treatment with NAC and PGE1.     

Novel influenza (H1N1) infection in pediatric renal transplant recipients: a single center experience

In 2009, novel influenza A H1N1 caused significant morbidity and mortality worldwide, particularly in children. Because they are immunocompromised, pediatric transplant recipients are presumed to be at high risk. This study assessed epidemiological characteristics, presenting symptoms, and clinical course among pediatric renal transplant recipients with confirmed H1N1 infection. A retrospective review was conducted in renal transplant recipients followed at The Hospital for Sick Children (Toronto) who contracted H1N1 infection between June and November, 2009. Epidemiological, clinical, and laboratory features at presentation, and clinical course were analyzed. Of 59 children, 14 (23.7%) developed H1N1 infection. Children with H1N1 infection had undergone kidney transplantation more recently than their uninfected counterparts. The most common symptoms included fever (92.9%), cough (85.7%), headache (42.9%), and vomiting (42.9%). Fifty percent of patients required hospitalization, of median duration 3.0 (1.0-5.0) days. No child required intensive care treatment. Half the H1N1-infected children had acute renal dysfunction, with serum creatinine elevated >10% above basal values (median increase 21.6 [14.3-46.2]%). In five of the seven children, serum creatinine returned to baseline within two wk. These findings indicate that H1N1 influenza infection in pediatric kidney transplant recipients followed at our center was surprisingly mild, and produced no lasting sequelae.     

Cyclosporine monitoring in the early post-transplant period in pediatric liver transplant recipients

Monitoring of CsA blood levels two h post-dose (C2) has shown a higher correlation to drug exposure than monitoring of trough levels (C0) at least in adults, but initial doses and target blood levels of CsA have yet to be established in pediatric transplant patients. The objectives of the study were to describe the pharmacokinetics of CsA administered by NGT in the first days after transplantation and the dose of Sandimmun Neoral required to achieve minimum therapeutic range blood levels. This study included 20 pediatric liver transplant recipients (mean age of 3.2 yr) treated with CsA administered by NGT from day one post-transplant until they were able to ingest oral medication. The study was continued until one yr of post-transplant follow-up. Eight h pharmacokinetic profiles were performed on days one, three, and five post-transplant to determine the minimum dose required to achieve the therapeutic range. All children received an initial dose of 15 mg/kg/day of CsA by NGT. Mean CsA doses administered on days one, three, and five were 16.8, 29.5, and 36.5 mg/kg/day, respectively. Mean C0 levels of 119, 310, and 337 ng/mL and mean C2 levels of 213, 753, and 888 ng/mL were obtained. No correlation was found between C0 and C2 levels and the AUC(0-8 h). Intravenous administration of CsA was required in 55% of patients. The biopsy-confirmed acute rejection rate was 45%, with graft and patient survival rates of 95 and 100%, respectively. CONCLUSIONS: Poor absorption of CsA in small children requires a considerable increase in dose. CsA exposure cannot be estimated by single C0 or C2 determinations in the early post-transplant period.     

Fatigue in pediatric liver transplant recipients and its impact on their quality of life

The aim of the study was to investigate the occurrence of fatigue in 100 pediatric liver transplant recipients aged 2‐18 years and its impact on their health‐related quality of life (HRQL). HRQL and fatigue were measured using the PedsQL 4.0 Inventory and the PedsQL Multidimensional Fatigue Scale, which encompasses three subscales: general fatigue, sleep/rest fatigue, and cognitive fatigue. The impact of the different domains of fatigue and of clinical and sociodemographic factors on the HRQL was identified with stepwise multiple regression analyses. Parent proxy‐reports were available for all 100 participants (2‐18 years), and child self‐reports were available for 71 patients (8‐18 years). Across all domains, participants and their parents reported significantly more fatigue than healthy peers in a large PedsQL validation study. Thirty‐seven percent of patients and 57% of parents scored clinically relevant levels of fatigue. In the multiple regression analyses, none of the clinical and sociodemographic factors contributed to the HRQL for child self‐report. Only general and cognitive fatigue were significant predictors of patients' HRQL, explaining 66% of the variance in the PedsQL total score. For parent proxy‐report, general and cognitive fatigue also significantly predicted child's HRQL. Further predictors were child's age and family income. The regression model explained 65% of the variance. These findings demonstrate the importance of assessing fatigue during regular follow‐up examinations. Further research is urgently needed to better understand the underlying mechanisms of fatigue. Improvement of fatigue symptoms is essential for better HRQL, for cognitive functioning, and for school achievement.