Determinants of early surgical complications after pediatric liver transplantation: A single center/single surgeon experience over 20 years.

BACKGROUND: The risk of early surgical complications of liver transplantation (LT) is higher in children when compared with adults. The aims of the present retrospective study from a single center cohort/single surgeon were to identify the predictive factors for surgical complications after pediatric LT. METHODS: All children receiving a first LT from October 1990 to October 2010 in our center were included. RESULTS: Included 151 children (boys 55.0%), with a mean age of 4.8 ± 4.8 years, and a mean weight of 17.9 ± 14.4 kg. Thirty-seven patients were transplanted within the first year, and 59 patients had a body weight below 10 kg. The main initial liver disease was biliary atresia (49.0%). Living donor LT was performed in 39 cases (25.8%), cadaveric whole liver LT in 50 cases (33.1%), and cadaveric partial liver LT in 62 cases (41.1%). Early surgical complications included reoperation (37.8%), vascular complications (8.6%), i.e. arterial (3.3%) or portal thrombosis/stenosis (7.3%) within the first month, and biliary complications in the first 90 days occurred in 22.5% of the cases. The main indications for surgical revision were abdominal bleeding, treatment of a biliary complication, and bowel perforation. Multivariate analysis disclosed that only graft type (split and moreover from a living donor) was significantly and independently associated with the occurrence of biliary complication, and that indication for LT, period, graft type, and operative time were significantly and independently associated with the necessity of surgical revision. CONCLUSION: Our results emphasize that surgical complications are frequent and strongly depend on patient/graft characteristics.

Are protocol graft biopsies after pediatric liver transplantation useful? Experience in a single center over 20 years.

BACKGROUND: The role of protocol liver biopsies (PLB) in the follow-up of pediatric liver transplant recipients remains questionable. This single-center retrospective study aimed to evaluate their clinical impact on the long-term management of pediatric liver transplant recipients. METHODS: We described histopathological lesions and clinical consequences for patient management of PLB performed 1, 5, 10, 15, 20, and 25 years after pediatric liver transplantation (LT). RESULTS: A total of 351 PLB performed on 133 patients between 1992 and 2021 were reviewed. PLB found signs of rejection in 21.7% of cases (76/351), and moderate to severe fibrosis in 26.5% of cases (93/351). Overall, 264 PLB (75.2%) did not cause any changes to patient care. Immunosuppression was enhanced after 63 PLB, including 23 cases of occult rejection. The 1-year PLB triggered significantly more changes, while biopsies at 15, 20, and 25 years produced the lowest rates of subsequent modifications. PLB had a significantly higher probability of inducing therapeutic changes if the patient had abnormal biological or imaging results (odds ratio [OR] 2.82 and 2.06), or a recent history of rejection or bacterial infection (OR 2.22 and 2.03). CONCLUSION: Our results suggest that, although it often does not prompt any treatment changes, PLB could be performed because of its ability to detect silent rejection requiring an increase in immunosuppression. PLB could be carried out 1, 5, and 10 years after LT and then every 10 years in patients with normal biological and imaging results and no recent complications, while other patients could be kept on a 5-year protocol.

A structured curriculum and procedure clinic to help family medicine residents diagnose and treat skin cancer.

Melanoma is a potentially deadly type of skin cancer that has been increasing in incidence but is curable if found in the early stages. Family physicians are in an ideal situation to examine the skin during routine visits, but studies indicate they are not well trained to detect or treat skin cancers. We piloted a structured, longitudinal, hands-on procedural curriculum to improve family medicine residents' ability to identify and manage skin cancers. Family medicine residency programs wishing to improve the diagnosis and management of skin cancer by family physicians might consider trialing our structured curriculum and procedure clinic.

Le mélanome est un type de cancer de la peau potentiellement mortel qui est de plus en plus fréquent, mais qui est guérissable sous réserve d'une détection précoce. La visite de routine chez le médecin de famille est l'occasion idéale pour examiner la peau. Les études indiquent toutefois que les médecins de famille n'ont pas le niveau de formation nécessaire pour détecter et traiter les cancers de la peau. Nous avons piloté un programme structuré longitudinal axé sur la pratique visant à améliorer la capacité des résidents en médecine familiale à identifier et à traiter ce type de cancer. Nous invitons les responsables de programmes de résidence en médecine familiale qui souhaitent améliorer le diagnostic et la prise en charge des cancers cutanés par les médecins de famille à expérimenter notre programme structuré sur les procédures cliniques.

Determinants of short-term outcomes after pediatric liver transplantation: a single centre experience over 20 years.

BACKGROUND: Liver transplantation (LT) is a standard-of-care therapeutic modality for selected patients with life-threatening liver disease, including children. In addition to specific clinical characteristics of pediatric LT recipients due to initial liver disease (and related comorbidities) and level of liver failure, early postoperative outcome may be dependent on the surgical technique used, related to the type of organ donor and graft. Therefore, the aims of the present retrospective study from a large single centre cohort were to identify the prognostic factors for both 1-year patient and graft survival. METHODS: Between October 1990 and October 2010, 151 children underwent a first LT in our centre. RESULTS: The mean age was 5.3 ±â€¯7.4 years, and the main indication was biliary atresia (BA) (49.0%). Living donor liver transplantation (LDLT) was performed in 39 cases (25.8%). Cadaveric liver graft was a whole liver in 50 cases (33.1%) and a partial liver (reduced or split) in 62 cases (41.1%). One-year patient and graft survival rates were 88.7% and 86.1%, respectively. Multivariate analysis disclosed that initial liver disease, location at time of LT, donor/recipient (D/R) delta age, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with patient survival and that D/R delta age, primary non-function, early post-transplant hemodialysis and initial immunosuppression (induction) were significantly associated with graft survival. CONCLUSION: The results of our single-centre experience of pediatric LT emphasize that early patient and graft survivals depend on pre-operative/operative factors such as initial liver disease, D/R delta age and immunosuppressive regimen. Awareness of these factors can help in the decision making for children requiring LT.

Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus - a Phase 2, open-label, single-arm, one-way crossover study.

There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.

Comparative pharmacokinetics of tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus to prolonged-release tacrolimus formulation.

This study was a Phase II, open-label, multicenter, single-arm, cross-over study comparing the pharmacokinetics (PK) of tacrolimus in stable pediatric kidney, liver, or heart allograft recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). In Days -30 to -1 of screening period, patients received their IR-T-based regimen; during Days 1-7, patients received study IR-T (same dose as screening). On Day 7, the first 24-hours PK profile was taken; patients were then converted to PR-T (1 mg:1 mg), with a second 24-hours PK profile taken on Day 14. The primary end-point was tacrolimus area under the blood concentration-time curve over 24 hours (AUC24 ); secondary end-points were maximum concentration Cmax and concentration at 24 hours C24 . The predefined similarity interval for confidence intervals (CIs) of least squares mean (LSM) ratios was 80%-125%. The PK analysis set comprised 74 pediatric transplant recipients (kidney, n = 45; liver, n = 28; heart, n = 1). PR-T:IR-T LSM ratio (90% CI) was similar overall for AUC24 , max , and C24 , and for kidney and liver recipients for AUC24 (LSM ratio, kidney 91.8%; liver 104.1%) and C24 (kidney 90.5%; liver 89.9%). Linear relationship was similar between AUC24 and C24 , and between PR-T and IR-T (rho 0.89 and 0.84, respectively), suggesting that stable pediatric transplant recipients can be converted from IR-T to PR-T at the same total daily dose, using the same therapeutic drug monitoring method.

Pregnancy and donor-specific HLA-antibody-mediated rejection after liver transplantation: "Liaisons dangereuses"?

BACKGROUND: Risk factors for the development of anti-HLA antibodies include blood transfusion, organ transplantation, and pregnancy. Humoral rejection, mediated by donor-specific anti-HLA antibodies (DSA), has been studied in all kind of solid organ transplantations, and several studies have suggested that post-liver transplantation (LT) DSA may play a role in acute and chronic rejection. OBJECTIVE: The aim of the present study was to assess the impact of pregnancy on the occurrence of DSA and the impact of DSA in a large population of young female LT recipients. METHODS: This single center retrospective study included all female patients who underwent a first LT between January 1990 and December 2010 and who were of childbearing age during post-LT follow-up (i.e. 18 to 40 years old). RESULTS: The study population consisted in 73 patients, and the mean age at LT was 20.9 years (0.6-39.9); 32 patients were transplanted during childhood. The global incidence of de novo DSA was 42.5% (31/73), after a median delay of 15.5 years (1-25) of follow-up after LT. Most de novo DSA were anti-class II alone (90.3%), and included anti-DQ for 80.6%. From the 73 patients, 33 presented at least one pregnancy after LT (45.2%) and before DSA screening. Multivariate analysis disclosed that history of pregnancy (OR = 6.37; 95%CI, 2.17-18.63, p = 0.001) and younger age at LT (OR = 0.96; 95%CI:0.92-0.99, p = 0.033) were significantly associated with de novo DSA. Among the 31 patients who had de novo DSA, the diagnosis of antibody-mediated rejection was made in 8 patients (25.8%), after a median delay of 74 months after LT; 6/8 (75.0%) had history of pregnancy. During follow-up, 3 of these 8 patients lost their liver graft and died. CONCLUSION: The results of the present study suggest that close monitoring of DSA in young women with history of pregnancy should be recommended regarding the risk of DSA-mediated rejection.

mTOR inhibitors in pediatric liver transplant recipients.

BACKGROUND: During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. METHODS: All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. RESULTS: The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 µg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. CONCLUSION: Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.

Liver disease related to alpha1-antitrypsin deficiency in French children: The DEFI-ALPHA cohort.

BACKGROUND & AIMS: To identify prognostic factors for liver disease in children with alpha-1 antitrypsin deficiency, irrespective of phenotype, using the DEFI-ALPHA cohort. METHODS: Retrospective, then prospective from 2010, multicentre study including children known to have alpha-1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as "severe" (portal hypertension, liver failure, liver transplantation or death); "moderate" (persistent abnormal liver biology without portal hypertension); and "mild/none" (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model. RESULTS: In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow-up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty-eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0-11.6): diagnosis of alpha-1 antitrypsin deficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIMlike Z in 1, 15 children underwent liver transplantation, 1 child died at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007). CONCLUSION: Alpha-1 antitrypsin-deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non-homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications.

Relative exchangeable copper: A valuable tool for the diagnosis of Wilson disease.

BACKGROUND & AIMS: Measuring of the relative exchangeable copper seems to be a promising tool for the diagnosis of Wilson disease. The aim of our study is to determine the performance of REC for the diagnosis of Wilson disease in a population of patients with chronic liver diseases. METHODS: Measuring of exchangeable serum copper levels and relative exchangeable copper was performed in a group of Wilson disease patients at diagnosis or at clinical deterioration because of non-compliance (group 1, n=9), a group of stable WD patients (group 2, n=40), and two groups of patients (adult and paediatric) followed for non-Wilsonian liver diseases (group 3, n=103 and group 4, n=49 respectively). RESULTS: Exchangeable serum copper (N: 0.6-1.1 µmol/L) was significantly higher in group 1 (mean 2.2±0.7 µmol/L) compared to the other three groups: group 2=0.9±0.4 µmol/L, group 3=1.2±0.4 µmol/L, group 4=1.1±0.3 µmol/L (P<0.05). Relative exchangeable copper was significantly higher in Wilson disease patients group 1 and 2 (mean 52.6% and 43.8%) compared to patients suffering from other liver diseases (mean 7.1% and 5.9%) (P<0.05). CONCLUSIONS: Our study confirms that the determination of relative exchangeable copper is a highly valuable tool for the diagnosis of Wilson disease.

Deleterious impact of C3d-binding donor-specific anti-HLA antibodies after pediatric liver transplantation.

BACKGROUND: The prevalence and clinical impact of anti-HLA donor-specific antibodies (DSA) after liver transplantation (LT) have not been extensively studied, especially in pediatric population. METHODS: The present cross-sectional study included 100 patients who underwent a first LT in childhood. Anti HLA immunization study was performed at a single time point during routine follow-up using Luminex® single antigen tests with classical anti-IgG conjugate and anti-C3d conjugate. RESULTS: The main indication for LT was biliary atresia (52%) and median age at LT was 4.6years. The median time between LT and DSA assessment was 7.8years (range 1-21years). DSA was identified in twenty-four patients (24%) after LT, with a prevalence of 8%, 28%, 33%, 50%, respectively 0-5years, 5-10years, 10-15years and >15years after LT. DSA were mainly class II (23/24) with a mean MFI of 9.731±5.489 and 18 (79.3%) were C3d-binding DSA. Multivariate analysis disclosed that time elapsed since LT (p<0.01) and history of fulminant hepatitis (p=0.04) were significantly associated with a higher rate of DSA. Liver function tests (at time of DSA assessment) were not different according to the presence or not of DSA (or C3d-binding DSA). Regarding histology, the DSA group had a higher rate of chronic rejection, cirrhosis and centrilobular fibrosis or cirrhosis. In addition, patients with C3d-binding DSA and high MFI (>10,000) had a significant poorer long-term graft survival (p=0.03). CONCLUSION: In our pediatric cohort of LT, prevalence of DSA was high and increased regularly with time. Presence of C3d positive-DSA with high MFI was associated with a higher rate of graft loss.

Donor-Related Coccidioidomycosis Transmitted Through Left-Liver Transplant to a Child Recipient in a Nonendemic Area.

This first observation of donor-transmitted coccidioidomycosis in a pediatric liver-transplant recipient underlines a rare condition in transplanted patients in a nonendemic area. This transmission was observed after a liver split, the patient being contaminated by the left liver while the right-liver recipient was not.

Sertraline as an Additional Treatment for Cholestatic Pruritus in Children.

OBJECTIVES: Pruritus is a severe symptom accompanying chronic cholestasis. It can be debilitating and difficult to control. In children, first-line treatments are ursodeoxycholic acid and rifampicin. Refractory pruritus may require invasive therapies including liver transplantation. Clinical trials based on small samples of adult patients suggest that serotonin reuptake inhibitors can improve pruritus in cholestatic or uremic disease. We performed a prospective, multicenter study to assess efficiency and safety of the serotonin reuptake inhibitor sertraline in treating children with refractory cholestatic pruritus. METHODS: Twenty children experiencing refractory cholestatic pruritus related to Alagille syndrome or progressive familial intrahepatic cholestasis were included from 4 centers between 2007 and 2014, and treated with sertraline at a starting dose of 1 mg ·â€Škg ·â€Šday and thereafter individually adapted up to 4 mg ·â€Škg ·â€Šday. Before and after 3 months with therapy, pruritus was assessed using a visual itching scale graded on 10 points, a skin scratch marks score and a sleeping impairment score. RESULTS: Sertraline was prescribed at a median daily dose of 2.2 mg ·â€Škg ·â€Šday. After 3 months, pruritus improved in 14 out of 20 treated patients, and the median itching score decreased significantly from 8/10 (5-10) to 5/10 (2-10). Likewise, skin scratch marks and sleep quality improved in 9 of these 14 patients. Nonsevere adverse events were reported in 6 children, leading to treatment discontinuation in 3. CONCLUSION: Our data suggest that sertraline may constitute a useful drug in the management of refractory cholestatic pruritus in children.

Pediatric combined liver-kidney transplantation: a single-center experience of 18 cases.

BACKGROUND: Experience in combined liver-kidney transplantation (CLKT) in children is limited. METHODS: We conducted a retrospective study of all pediatric CLKTs performed at our medical institution between 1992 and 2013. RESULTS: We identified 18 pediatric patients (9 girls) who had undergone CLKT at our institution during the study period. The median age [range] and body weight [range] of this patient group was 3.6 [1.0-18.6] years and 13 [10-40] kg, respectively; 11 patients weighed <15 kg at the time of CLKT. Indications for CLKT were primary hyperoxaluria (PH1; n = 14), association of hepatic fibrosis and end-stage renal disease (n = 3) and methylmalonic acidemia (n = 1). In the early postoperative period, eight patients required dialysis. Median stay in the pediatric intensive care unit was 10 [6-29] days. One patient died from cardiovascular disease 10 years after CLKT. There were no liver graft losses despite six acute liver rejection episodes, whereas four kidney grafts were lost. At last follow-up (6 [0.5-21] years) for patients with a functioning renal graft, the glomerular filtration rate was 71 [26-146] mL/min/1.73 m(2). In PH1 patients, urine oxalate normalized in six patients within 3 years after CLKT, but three patients still presented with elevated oxaluria at 1, 2 and 3 years after CLKT. CONCLUSIONS: Pediatric CLKT provides encouraging results in the long term, even in the youngest 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.

Pediatric combined liver-kidney transplantation: a 2015 update.

PURPOSE OF REVIEW: The experience of combined liver-kidney transplantation (CLKT) is limited in pediatric populations. This strategy is, however, required in specific diseases such as metabolic diseases (namely primary hyperoxaluria type one and methylmalonic acidemia), autosomal recessive polycystic kidney disease, miscellaneous ciliopathies and atypical hemolytic uremic syndrome. RECENT FINDINGS: Different series and registry studies have confirmed the feasibility of pediatric CLKT with encouraging results in the long term, even in the youngest and smallest patients, provided that highly trained multidisciplinary teams are involved in this global management. As such, the long-term outcomes after CLKT are currently comparable to that of isolated liver or kidney transplantations, even though the immediate postoperative period remains challenging. SUMMARY: Some questions remain nevertheless unanswered, such as the respective place of combined versus sequential liver-kidney transplantation, especially in primary hyperoxaluria and autosomal recessive polycystic kidney disease. The aim of this review was therefore to provide a 2015 update on pediatric CLKT. In the future, international collaborative studies and registries may help to improve our knowledge of this rare and still highly challenging technique.

Acute leukemia presenting as acute hepatitis without liver failure.

A diagnosis of acute lymphoblastic or myeloblastic leukemia was made in 6 children ages 4 to 14 years who presented with a clinicobiochemical picture of acute hepatitis without liver failure. Standard chemotherapy, including 1 week pretreatment with steroids in children with lymphoblastic leukemia, allowed complete remission of the leukemia and normalization of serum liver tests.

Severe dysphagia in children with eosinophilic esophagitis and esophageal stricture: an indication for balloon dilation?

BACKGROUND: Esophageal stricture is one of the most severe complications in eosinophilic esophagitis (EoE). Clinical practice is based on limited data and some treatments are still considered controversial. We report on our experience in the treatment of severe dysphagia and esophageal strictures in EoE, especially using balloon dilation, showing the clinical practice in our pediatric population. PATIENTS AND METHODS: This was a single-center retrospective study between December 2002 to November 2007, identifying all of the pediatric patients with severe dysphagia in the context of EoE. Demographic data and the results of various treatment regimens were reviewed. RESULTS: Severe dysphagia was identified in 13 cases (77% male, mean age 12.8 +/- 4.4 years). Endoscopic findings were mucosal edema (62%), long segment strictures, esophagitis, and off-white appearance in 31%. Histologically, >20 eosinophils per high-power field were present in all of the patients. Medical treatment consisted of proton pump inhibitor PPI (77%), montelukast (31%), local corticosteroids (54%), systemic corticosteroids (8%), elemental diet (15%), and food elimination diet (61%). A combined therapeutic approach was performed in all of the cases, due to clinical relapse or no response to monotherapy. Good response was obtained clinically in 70%, endoscopically in 62%, and histologically in 75%. Relapses were observed in 46% of the cases. Balloon dilation was necessary in 31% of the cases (mean dilation sessions 3.3 +/- 0.95), being effective in 100% of patients, without complications. CONCLUSIONS: In our pediatric series, combined medical (corticosteroids, elemental diet, and food elimination diet) and endoscopic approach (repeated balloon dilation) were effective and safe in patients with severe EoE and esophageal stricture.

Age-related variability of mycophenolate mofetil exposure in stable pediatric liver transplant recipients and influences of donor characteristics.

Despite the increasing use of mycophenolate mofetil (MMF) in pediatric liver transplantation recipients, data on MMF pharmacokinetics in this population are relatively scattered. This pilot study was performed to explore whether recipient age-related factors, in conjunction with donor factors, can explain variability in mycophenolic acid (MPA) exposure. Thirty-four MPA pharmacokinetic profiles were performed in 20 stable pediatric liver transplantation recipients (median age, 12 years; range, 1-18 years; median delay after liver transplant, 88 months; range, 3-179 months). Ten children were converted to MMF; the others received MMF as a primary immunosuppressive regimen. MMF was used in combination with tacrolimus. Plasma MPA concentrations were analyzed samples collected at 0, 1, 3, and 6 hours after MMF administration using the enzyme multiplied immunotechnique immunoassay. The median MMF dose was 431 mg/m2 per day (range, 189-833 mg/m2 per day) leading to a median estimated MPA-AUC0-12h of 27 mg/h/L (range, 17-79 mg/h/L). Dose-normalized MPA-AUCs were characterized by high interpatient variability. Young children receiving a liver from a pediatric donor had lower MPA exposure compared with those receiving liver from an adult donor. No correlation was seen between MPA-C0 and MPA-AUC 0-6h in infants, whereas this correlation was significant but moderate in older children. The interpatient variability of MPA exposure observed with this pilot study is an argument for developing therapeutic drug monitoring-based dose adaptation strategies in pediatric liver transplantation recipients. A marked MPA underexposure was observed among young children receiving livers from pediatric donors, indicating that higher doses (mg/m2 of body surface area) might be required to reach the same MPA exposure as in adolescents.