Conversion from tacrolimus to sirolimus as a treatment modality in de novo allergies and immune‐mediated disorders in pediatric liver transplant recipients

De novo PTAID may develop in pediatric solid organ transplant recipients, have a diverse spectrum, and are occasionally treatment resistant. Previous reports showed resolution of immune cytopenias in solid organ transplant recipients following replacement of the calcineurin inhibitor tacrolimus with the mTOR inhibitor sirolimus. Herein we describe a retrospective review (2000‐2017) of subjects who developed PTAID in whom immunosuppression was changed to sirolimus. Eight recipients (6 males) of either liver (n = 7) or multivisceral transplant (n = 1) suffered from severe, treatment‐resistant PTAID and were switched from tacrolimus to sirolimus. The median age at transplant was 1 year (range 0.5‐2.4 years). Six (75%) recipients developed de novo allergy and 2 immune‐mediated diseases. The median age at presentation of PTAID was 2.7 (1.4‐9) years at a median of 1.3 (0.25‐8) years after transplantation. The median time from PTAID presentation to conversion to sirolimus was 1.8 (0.45‐10) years. Complete resolution of symptoms was seen in 4 (50%) patients after a median of 12 (range 4‐24) months including 2 patients with immune‐mediated disease, 1 eczema, and 1 with eosinophilic colitis. One patient with multiple food allergies had a partial response and 3 (38%) had no response. None of the 8 recipients developed sirolimus‐attributed adverse events or acute rejection during a median follow‐up of 5 (0.6‐8) years after the conversion. Immunosuppression conversion from tacrolimus to sirolimus can be an effective therapy in patients suffering severe or treatment‐resistant PTAID, suggesting a potential role for tacrolimus in the pathogenesis of PTAID.     

Food protein sensitivity with partial villous atrophy after pediatric liver transplantation with tacrolimus immunosuppression

We report three pediatric liver transplant recipients receiving tacrolimus immunosuppression presented with vomiting, heme-positive stools and failure to thrive, who had subtotal villous atrophy in their histology because of food protein sensitivity. Case findings and current literature of the casual relationship between tacrolimus and food allergies briefly reviewed.     

The development of eosinophilic colitis after liver transplantation in children

Tacrolimus-based immunosuppression in pediatric liver transplant recipients is known to be associated with EGID. Our goal was to determine the incidence, risk factors, and characteristics of EGID in our pediatric liver transplantation program. This study was a retrospective analysis of 38 pediatric liver transplant recipients. Rectal mucosal biopsy was performed to evaluate for gastrointestinal PTLD and eosinophilic colitis. There were 14 patients (37%) who were diagnosed with eosinophilic colitis. The mean age at transplantation was 10.8 +/- 1.8 months. Those with eosinophilic colitis had a higher incidence of peripheral eosinophilia (p = 0.003) during the first two months following transplantation and had a higher EBV infection rate. Symptoms, such as diarrhea, hematochezia, and abdominal pain, became apparent after an average of three months; diagnoses were made at 6.9 +/- 2.0 months after transplantation. There were eight patients (57%) with elevated food-specific IgE levels. With food restriction treatment, the symptoms of patients improved. EGID should be considered when clinical symptoms are present, because symptoms of this disorder are similar to those of gastrointestinal PTLD. It should also be considered when peripheral eosinophila is detected or when EBV seroconversion develops during the first two months following transplantation.     

Food allergies developing after solid organ transplant

The development of food allergy is an increasingly recognized form of morbidity after solid organ transplant. It occurs more commonly in liver transplant recipients, although it has also been reported in heart, lung, kidney, and intestinal transplants. Pediatric transplant recipients are more likely to develop symptoms compared to adults, and reports of frequency vary widely from 5% to 38% in pediatric liver transplant recipients. Multiple mechanisms have been proposed in the literature, although no single mechanism can yet account for all reported observations. As food allergy can have at worst potentially fatal consequences, and at best require lifestyle adjustment through food avoidance, it is important for recipients to be aware of the donor's food allergies and particularly in pediatrics, the possibility of completely de novo allergies. This review explores the recent reports surrounding food allergy after solid organ transplant, including epidemiology, proposed mechanisms, and implications for practice.     

Development of multiple food allergies in children taking tacrolimus after heart and liver transplantation

Angioedema and chronic diarrhea in patients taking immunosuppressants are not always because of side effects and could be a new onset of food allergy. Our aim is to discuss the pathogenesis and treatment of the post-transplant development of food allergies. The first patient was receiving tacrolimus subsequent to heart transplantation and developed angioedema after consumption of dairy products at 12 months after transplantation. He was found to be allergic to multiple foods by both RAST and ImmunoCAP tests. The second patient with argininosuccinic aciduria, post-liver transplant, also received tacrolimus and developed chronic non-mucoid/bloody diarrhea at seven months following transplantation. ImmunoCAP test was positive only for egg white and peanuts. Biopsy showed eosinophilic infiltration of the mucosa from the stomach to the rectum. Elimination diets in both patients resolved the symptoms. These cases suggest a direct relationship between tacrolimus and development of food allergy.     

Post-transplant food allergy in children is associated with liver and not with renal transplantation: A monocentric comparative study

Food allergy is increasingly reported after paediatric liver transplantation. The underlying physiopathological mechanism remains incompletely understood. Therefore, we aimed to determine the incidence, clinical presentation, possible risk factors, and prognosis of post-transplant food allergy in children currently followed after liver and renal transplantation. The study population consists of 49 liver and 21 renal transplant patients transplanted between the age of 22 months and 15 years. Data were collected retrospectively from medical records and via a doctor’s questionnaire taken from the parents in a monocentric setting. Post-transplant food allergy has developed in 13 liver transplant patients and in none of the renal transplant recipients. Within the liver transplant group, median age at liver transplantation is significantly lower in the food-allergic (10 months) versus non-food-allergic group (3.3 years; p?=?0.002). The use of tacrolimus as primary maintenance immunosuppression is associated with food allergy (p?=?0.032) and mean donor age is significantly lower in the food-allergic group (p?=?0.009). Compared to the renal transplant group, median age at transplantation is significantly lower in the liver patients (p?<?0.001). No significant differences are found in primary immunosuppressive regimens between renal and liver transplant patients. Conclusion: Post-transplant food allergy is an important clinical problem in children after liver transplantation which does not affect renal transplant patients despite similar immunosuppressive regimens. Within the group of liver transplant recipients, tacrolimus use, young age at time of transplant and younger donor age were associated with the development of food allergy.     

Management of tacrolimus‐associated food allergy after liver transplantation

Increasingly, food allergy associated with tacrolimus after pediatric living‐donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T‐helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus‐associated food allergy after pediatric living‐donor LT. The patient was a 7‐year‐old Japanese girl who had undergone living‐donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post‐transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post‐transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.     

Incidence,clinical features,and outcomes of food allergy in children who underwent liver transplant: 16‐year experience

Food allergies often develop after liver transplant, especially in young children. However, data are scarce on clinical characteristics and patient outcomes. When we evaluated our pediatric liver transplant patients over a 16‐year period, food allergy incidence was 8% (19/236 patients). All patients with food allergies were <18 months old, with incidence in this age group of 19.2% (19/99). Two patients had a single food and 17 had multiple food allergies. Five patients showed only non‐IgE‐mediated food allergies. Eggs, milk, nuts, and wheat were the most common allergens. Presenting symptoms included diarrhea, flushing, angioedema attacks, wheezing/chronic cough, and vomiting. Seven patients had EBV, and two patients had CMV infections at time of food allergy diagnosis. Twelve patients had eosinophilia. Seven patients (36.8%) were able to regain tolerance to all food allergens. However, one patient with single nut allergy and three with multiple food allergies were still on allergen‐eliminated diets. Eight patients with multiple food allergies gained tolerance to some of the food allergens. In conclusion, food allergies in our patients were mainly against multiple foods and IgE mediated. Infections like EBV and CMV may play a role in food allergies after liver transplant, especially in pretransplant‐naive patients.     

An objective measure to identify pediatric liver transplant recipients at risk for late allograft rejection related to non-adherence

Non-adherence to a prescribed immunosuppressive regimen increases risk for late allograft rejection (LAR). We implemented a protocol for immunosuppression management which decreased variation in calcineurin inhibitor blood levels in pediatric liver transplant recipients by controlling for confounders such as physician practice variability. We hypothesized that patients with increased variation in tacrolimus blood levels despite implementation of the immunosuppression management protocol were at increased risk for LAR. We conducted a single center retrospective cohort study of 101 pediatric liver transplant recipients who were at least one year post liver transplantation and receiving tacrolimus for immunosuppression. The primary outcome variable was biopsy proven allograft rejection. Primary candidate predictor variables were the standard deviation (SD) of tacrolimus blood levels (a marker of drug level variability), mean tacrolimus blood level, age, and insurance type. SD of tacrolimus blood levels was determined for each patient from a minimum of four outpatient levels during the study period. Unadjusted and adjusted logistic regression models were used to determine the prognostic value of candidate predictors. The median and interquartile range of the SD of tacrolimus blood levels was 1.6 (1.1, 2.1). Eleven episodes of LAR occurred during the study period. Ten of the 11 episodes occurred in patients with tacrolimus blood level SD > 2. Insurance type, mean tacrolimus blood level and SD of tacrolimus blood levels were significantly related to LAR in the unadjusted analyses (p<0.05). A multivariable model including age, insurance type, mean and SD of tacrolimus blood levels was significantly associated with LAR (validated C-statistic = 0.88, p = 0.012). The adjusted odds of rejection for a one unit increase in the SD of tacrolimus blood level was 3.49 (95% CI 1.31 to 9.29). Effects of age and insurance status on LAR did not provide independent prognostic value after controlling for SD. Variation in tacrolimus blood levels is associated with an increased risk of LAR in pediatric liver transplant recipients. Despite standardized management of tacrolimus levels to control for confounders, some patients were found to have significant variability of tacrolimus blood levels. This may be due to non-adherence and amenable to targeted psychosocial and behavioral interventions to prevent LAR.     

Sirolimus in pediatric gastrointestinal transplantation: the use of sirolimus for pediatric transplant patients with tacrolimus-related cardiomyopathy

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.     

Fatty liver due to high levels of serum tacrolimus after liver transplantation

Tacrolimus has been used extensively for immunosuppressive therapy in pediatric liver transplant recipients. However, patients who are exposed to high levels of serum tacrolimus tend to be associated with a higher incidence of significant nephrotoxicity, neurotoxicity, pruritus, alopecia, diabetes and infection. We herein report a child who developed increased serum transaminase levels and liver steatosis as a result of raised trough blood level of tacrolimus (30 ng/ml for 3 days) in association with rotavirus gastroenteritis.     

Efficacy and pharmacokinetics of tacrolimus oral suspension in pediatric liver transplant recipients

The use of tacrolimus in small pediatric graft recipients may require the availability of a suspension formulation for appropriate dose titration and easier administration. The pharmacokinetics (Pk) of an extemporaneously prepared oral suspension of tacrolimus (OST) was investigated in 15 pediatric liver transplant recipients, and was compared with the corresponding data with tacrolimus capsules (TC). Graft and patient survival rates were 100%. Acute rejection and steroid-resistant rejection were encountered in 9/15 and 3/15 patients, respectively. Comparison of Pk data showed a lower oral absorption of OST when compared with TC. No significant correlation could be made between the Pk parameters and rejection. Despite the lower bioavailability of OST when compared with TC, the rejection incidence was similar with both formulations (60% vs. 55%, respectively). Accordingly, the use of OST may constitute an alternative option for tacrolimus administration in low body weight organ recipients, to allow dosage titration in the early post-transplant weeks.     

Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children

Late graft rejection impairs the long-term function of organ transplants in children. Previous studies suggest patients with wide variation in tacrolimus levels may have higher rates of late kidney and liver graft rejection. The reproducibility of this finding and impact on graft and recipient survival have not been reported. We investigated factors associated with late rejection > 6 months post-transplant in 144 heart, kidney, liver, and lung transplant recipients (ages 8-18, ≥ 1-yr survivors, receiving tacrolimus-based immunosuppression), comparing late rejectors (n = 61, 42%) to non-rejectors (no rejection > 6 months); groups had similar mean tacrolimus concentrations ≤ 6 months post-transplant. For all organ types, increased standard deviation in intrapatient tacrolimus blood levels was an independent risk factor for late rejection (OR 1.6 [CI 1.1-2.1]; p = 0.02). Each 1-point increase in s.d. > 2 of tacrolimus level > 6 months post-transplant associated with 1.58 increase in hazard of graft loss (p = 0.003). Graft survival (conditional on one-yr survival) was significantly better for those with s.d. < 2 at > 6 months post-transplant: 98% at three and five yr, versus 88%, 70%, at three and five yr, in patients with s.d. > 2 (p = 0.003). In conclusion, high s.d. in serial tacrolimus concentrations associated with increased risk of late rejection and graft loss in pediatric organ transplant recipients, providing opportunities for screening and interventions.     

Pharmacokinetics of tacrolimus granules in pediatric de novo liver,kidney, and heart transplantation: The OPTION study

Tacrolimus granules were developed for patients who are unable to swallow capsules. Therapeutic drug monitoring (TDM) is required to optimize efficacy and safety, which is based on C_trough for tacrolimus capsules. Pharmacokinetic (PK) data for tacrolimus granules are required to establish the basis for TDM in those who are unable to swallow capsules. In this phase IV study (NCT01371331) of children undergoing liver, kidney, or heart transplantation, patients received tacrolimus granules 0.15 mg/kg twice daily; first dose was administered within 24 hours of reperfusion. PK analysis samples were collected after reperfusion, after first dose of tacrolimus (Day 1), and at steady state (Day 7; >4 days stable dose). Of the 52 transplant recipients enrolled, 38 had two evaluable PK profiles. Mean AUC_tau after first dose of tacrolimus was 211, 97, and 224 hour*ng/mL in liver, kidney, and heart transplant recipients, respectively; corresponding mean AUC_tau at steady state was 195, 208, and 165 hour*ng/mL. C_trough and AUC_tau were positively correlated after first dose of tacrolimus and at steady state (Pearson's coefficients: r = 0.81 and r = 0.87, respectively). This study demonstrated that C_trough is a reliable marker for TDM in pediatric transplant recipients treated with tacrolimus granules, consistent with TDM for other tacrolimus formulations.     

Peripheral eosinophilia and eosinophilic gastroenteritis after pediatric liver transplantation

Reports indicate peripheral eosinophilia (PE) and gastrointestinal eosinophilic inflammation can occur after pediatric liver transplantation. The incidence of these conditions, potential risk factors, and the impact of PE and gastrointestinal eosinophilic inflammation on liver transplant outcome were determined in this pediatric liver transplant program. Medical records of liver transplant recipients from 1 to 97 and from 12 to 99 were reviewed. Fifty-seven transplants on 54 patients were performed during the study period. Fifty-three patients were evaluated; all had normal pre-transplantation peripheral eosinophil counts. PE of > 10% developed in 28% of patients. Using this definition, all such identified patients had absolute eosinophil counts of > 350/mm3. History of immediate hypersensitivity did not differ between patients with or without eosinophilia. Gastrointestinal endoscopy and biopsy was performed in 23 patients with gastrointestinal complaints. Of those, six had eosinophilic gastroenteritis and all six had PE. Compared with patients without eosinophilia, those with PE were younger at the time of transplantation (p < 0.05), had more frequent rejection (p < 0.01), were more commonly managed with tacrolimus-based immunosuppression (p < 0.001), and experienced more frequent episodes of detectable EBV viral load (p < 0.04). Patients with eosinophilic gastroenteritis were more frequently retransplanted (p < 0.006). PE associated with symptomatic eosinophilic gastroenteritis is common after pediatric liver transplantation. Age at transplant, frequency of rejection episodes, tacrolimus-based immunosuppression, and EBV viral load may be associated with the development of this condition. There may be higher rates of graft loss in such patients. Whether innate immune responsiveness or an acquired immune dysregulation accounts for these findings merits further evaluation.     

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 C_maxand 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.     

Supra‐therapeutic tacrolimus concentrations associated with concomitant nicardipine in pediatric liver transplant recipients

Tacrolimus is prescribed to prevent allograft rejection in pediatric liver transplant recipients; however, its metabolism through the cytochrome P‐450 enzyme system presents a multitude of challenges in regard to drug interactions. Here, we describe four children (ages 1.4–8.7 yr) who acutely developed supra‐therapeutic serum tacrolimus trough concentrations, despite standard dosing, while on concomitant nicardipine therapy following liver transplantation. Even though tacrolimus regimens were altered (dosage reductions and held doses), serum tacrolimus concentrations remained elevated. Resolution of high tacrolimus concentrations was achieved only after the discontinuation of nicardipine. Following the termination of nicardipine, all children eventually required dosage increases in their tacrolimus regimens to re‐achieve target serum concentrations. We conclude that concomitant use of tacrolimus and nicardipine can result in high tacrolimus concentrations due to the inhibition of cytochrome p450 enzymes responsible for the metabolism of tacrolimus. We encourage clinicians to consider alternative antihypertensive options in children on tacrolimus therapy. If nicardipine therapy is necessary, we recommend a 50% reduction in tacrolimus dose and daily serum concentration monitoring.     

Acquired renal cysts after pediatric liver transplantation: association with cyclosporine and renal dysfunction

Abstract:  ACKD has been observed in children on dialysis and with chronic renal insufficiency. In one report, ACKD was observed in 30% of pediatric liver transplant recipients after 10 yr. We retrospectively reviewed all renal imaging and measurements of GFR of 235 childhood liver transplant recipients with no known risk for renal cyst formation, no evidence of renal cyst(s) at the time of transplantation and renal imaging at least one yr post-transplant. Twenty-six patients (11%) developed one or more cyst(s). Mean GFR was significantly lower in patients with renal cyst(s). Two (1.4%) of the 146 patients treated with tacrolimus and 24 (27%) of the 89 patients treated with CsA acquired renal cyst(s) (p < 0.001). CsA-treated patients had significantly lower GFR. Multivariate analysis identified CsA as the only independent variable associated with ACKD. These results confirm that ACKD can be a late complication of pediatric liver transplantation. Those at most risk are at least 10-yr post-liver transplantation, have been treated with CsA and have impaired renal function. We speculate that ACKD in these patients is the result of calcineurin inhibitor nephrotoxicity. Whether patients with ACKD will be prone to develop solid renal tumors is unknown.     

Long-term evaluation of cyclosporine and tacrolimus based immunosuppression in pediatric liver transplantation

Both calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, are widely used in pediatric liver transplant recipients and currently data are limited with regards to long-term results using the one drug or the other in comparable low doses. We conducted the present study to assess the advantages and disadvantages of both drugs in children at least five yr post-liver transplantation. A total of 129 children were enrolled in the study. Thirty-eight of the children were switched to tacrolimus monotherapy for different reasons [steroid resistant graft rejection (n = 15), chronic rejection (n = 5), severe acute rejection (n = 4), repetitive acute graft rejection (n = 5), dysfunction of the transplant (n = 3), insufficient CsA metabolism (n = 3), hypertrichosis (n = 2), and CsA toxicity (n = 1)], four patients had primary tacrolimus therapy, and 87 patients are receiving cyclosporine. Mean trough levels were 5.3 +/- 2.3 ng/mL (tacrolimus) and 73.6 +/- 44.5 micro/L (cyclosporine), respectively at least five yr post-orthotopic liver transplantation (OLT). There was no significant difference in the calculated glomerular filtration rate between children on cyclosporine and tacrolimus (142.7 + 39.5 mL/min/1.73 m(2) vs. 151.1 +/- 44.1 mL/min/1.73 m(2)). The incidence of arterial hypertension was 7.1% vs. 9.2%, that of hepatotoxicity was 0% vs. 2.3%. Cosmetic changes were found in more than one-third of the patients on cyclosporine and in 4.8% of the patients receiving tacrolimus. Quality of life was excellent in both groups (self assessment). The impact of CNIs on chronic graft dysfunction cannot be assessed by our present study. We conclude from the results that cyclosporine and tacrolimus are both excellent drugs for maintenance immunosuppression in the long-term course following pediatric liver transplantation. However, this retrospective analysis is limited by the bias between children on CsA as compared with patients receiving tacrolimus. A prospective randomized controlled trial is needed in order to assess which CNI is the best for children following OLT.     

Improving adherence to medications in pediatric liver transplant recipients

Abstract:  We describe results from a clinical program, which aimed at improving adherence to medications in children who had a liver transplant. We followed the medical outcomes of 23 children and adolescents who participated in a clinical adherence-improvement protocol during the years 2001–2002. The protocol included identification of non-adherent patients by examining tacrolimus blood levels and intervention by increasing the frequency of clinic visits for non-adherent patients. In the two-yr preintervention (1999–2000), there was no improvement in any of the outcomes. After the intervention, the number of patients with high alanine aminotransferase levels (100 and above) decreased significantly, from eight before the intervention to four afterwards. Other outcomes, including the number of rejection episodes (three before, none after) and the degree of adherence to tacrolimus, also improved, but the improvement did not reach statistical significance. Although non-adherent patients were called to clinic more often under the protocol, the intervention did not lead to increased outpatient costs. This adherence--improvement intervention appears to be promising in improving outcomes in pediatric liver transplant recipients. Larger, controlled studies are needed to establish the efficacy of this or other approaches.