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.     

Liver allograft pathology in healthy pediatric liver transplant recipients

Liver transplantation offers excellent results for children with end‐stage liver disease, and efforts should be directed toward maintaining long‐term graft health. We evaluate graft pathology in healthy pediatric transplant recipients with low‐maintenance immunosuppressive medications to assess whether protocol biopsies are helpful for adapting immunosuppression and protecting long‐term graft function. Liver biopsies were performed on 60 healthy pediatric liver transplant recipients, and histological findings were correlated with laboratory, serological, and radiological results. Fourteen patients (23%) were diagnosed with acute or early chronic rejection, and immunosuppressive medications were increased in these children. Liver function tests did not correlate with histological findings. The incidence of fibrosis was 36% in transplant recipients five or more years after liver transplantation. We observed an unexpectedly high prevalence of rejection and fibrosis in children with no laboratory abnormalities, which led to changes in their immunosuppressive medications. Scheduled biopsies appear to be useful in pediatric transplant recipients with low immunosuppressive medications for early detection of morphological changes in liver transplants. Further studies are needed to evaluate whether adaption of immunosuppression helps to reduce tissue damage and the incidence of allograft dysfunction in the long term.     

Tacrolimus-associated eosinophilic gastroenterocolitis in pediatric liver transplant recipients: role of potential food allergies in pathogenesis

Tacrolimus is a macrolide agent that is now the primary immunosuppressant used in prevention of graft rejection in transplant recipients. It has been found to be superior to cyclosporine (CSA) for rescue therapy as well as for earlier weaning of steroids. Both tacrolimus and CSA share similar toxicity profiles; however, their gastrointestinal side effects have received little attention. We report three cases of eosinophilic colitis in liver transplant recipients, maintained on tacrolimus as immunosuppressive medication post-liver transplantation. These patients also had high serum immunoglobulin (Ig)E levels, eosinophilia and IgE-positive radioallergosorbent test for milk proteins. The colitis appeared to be mediated by food allergies. Each patient had symptomatic improvement following reduced immunosuppression and an appropriately restricted diet. We conclude that tacrolimus may play a role in the initiation of food allergies, leading to eosinophilic colitis. More studies are needed in a controlled setting to identify the prevalence of similar findings among other pediatric liver transplant recipients.     

Immune cell function assay does not identify biopsy‐proven pediatric renal allograft rejection or infection

Management of pediatric renal transplant patients involves multifactorial monitoring modalities to ensure allograft survival and prevent opportunistic infection secondary to immunosuppression. An ICFA, which utilizes CD4 T‐cell production of ATP to assess immune system status, has been used to monitor transplant recipients and predict susceptibility of patients to rejection or infection. However, the validity of this assay to reflect immune status remains unanswered. In a two‐yr retrospective study that included 31 pediatric renal transplant recipients, 42 patient blood samples were analyzed for immune cell function levels, creatinine, WBC (white blood cell) count, immunosuppressive drug levels, and viremia, concurrent with renal biopsy. T‐cell ATP production as assessed by ICFA levels did not correlate with allograft rejection or with the presence or absence of viremia. ICFA levels did not correlate with serum creatinine or immunosuppressive drug levels, but did correlate with WBC count. The ICFA is unreliable in its ability to reflect immune system status in pediatric renal transplantation. Further investigation is necessary to develop methods that will accurately predict susceptibility of pediatric renal transplant recipients to allograft rejection and infection.     

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.     

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.     

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.     

Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient

Martin T, Schwartz J, Demetris A, Comstock J, Lowichik A, Book L. Plasmapheresis treatment of antibody‐mediated rejection in an A2 donor to O pediatric liver transplant recipient.
Pediatr Transplantation 2011: 15:E15–E18. © 2009 John Wiley & Sons A/S. Abstract: It is safe to transplant kidneys from blood group A2 donors into O recipients if the latter have low titers of anti‐A antibodies. However, in liver transplantation, O and B recipients of A2 donor livers are not routinely screened for anti‐blood group antibodies because of the immuno‐absorptive capacity of the liver and the low incidence of antibody‐mediated rejection. Herein, we report a rare case of combined cell and antibody‐mediated rejection in a pediatric blood group O recipient of an A2 donor liver, and rescue of the allograft using PP and IVIG.     

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.     

Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.     

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.     

Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.     

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.     

Safety and efficacy of tacrolimus in pediatric liver recipients

Pediatric liver transplantation is now so successful that we expect more than 80% of children to survive into adolescence and adulthood. As the focus of care shifts toward long-term patient management, immunosuppressive regimens should, in addition to preventing acute and chronic rejection, promote good quality of life and be free of significant long-term side effects. Historically, the most effective immunosuppressive regimens have been based on induction with a combination of calcineurin inhibitors (cyclosporin or tacrolimus) and steroids. Usually, maintenance is monotherapy with cyclosporin or tacrolimus or dual therapy with low-dose alternate-day steroids to encourage growth. A number of studies, including long-term follow-up, have shown significantly lower incidences of rejection, hypertension, hyperlipidemia and cosmetic side effects in patients treated initially with tacrolimus compared with cyclosporin. The use of anti-interleukin-2 inhibitors as induction therapy, with low-dose tacrolimus or in combination with mycophenolate mofetil, has a key role in preventing significant renal dysfunction and reducing infection and rejection. Steroid-free immunosuppression is also proving to be an effective option for the management of pediatric liver recipients. The main challenges now facing pediatricians include ensuring long-term quality of life, optimizing immunosuppression while preventing associated adverse events, and managing a smooth transition from childhood to adolescence and adulthood.     

Conversion from cyclosporin A to tacrolimus in pediatric liver transplantation

The dosing regimen for conversion from cyclosporin A (CsA) to tacrolimus immunosuppression was studied in 12 pediatric liver allograft recipients. Patients were stratified according to their age. Tacrolimus was started orally at a dosage of 0.05 mg/kg b.i.d., 12 h after stopping CsA administration and increased thereafter if needed. Tacrolimus and CsA concentrations were assayed by immunoassay using, respectively, an IMx and a TDx autoanalyzer (Abbott-France). Mean CsA concentration was in the therapeutic range 12 h prior to and at the time of introduction of tacrolimus. After 72 h of tacrolimus therapy, CsA concentrations were undetectable whereas mean tacrolimus concentration was 10.4 ng/mL with a mean dose of 0.09 mg/ kg b.i.d. The decline of CsA concentration was clearly biphasic. A slower decline in CsA concentration was detected after initiation of tacrolimus therapy, suggesting an inhibition of CsA metabolism by tacrolimus. No nephrotoxicity was observed. This dosage regimen allowed effective immunosuppression while avoiding additive nephrotoxicity.     

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.     

Buccal vs. nasogastric tube administration of tacrolimus after pediatric liver transplantation

Tacrolimus is an important drug for immunosuppression after liver transplantation. Bioavailability of enterally administered tacrolimus is poor, and further reduced by gastric residuals or by enteral nutrition. Buccal administration might be an alternative route especially in children. Tacrolimus trough levels (TTLs) obtained after buccal administration of tacrolimus after liver transplantation have not been reported. The aim of this study was to determine whether buccal administration of tacrolimus is feasible and to compare TTLs after nasogastric tube (NGT) administration with buccal administration. TTLs after NGT or buccal administration during the first week after pediatric liver transplantation were analyzed from 28 cadaveric liver transplants in 23 pediatric recipients between June 2002 and March 2004. Each level was scored within, under or above the target range. Buccal administration was well tolerated in all patients. A total of 149 TTLs were obtained of which nine were excluded because of incomplete information on target levels. Overall 27% of TTLs was adequate. The percentage of levels under, within and above the target range were comparable in both groups (chi-square test; p = 0.64). Both groups had a decrease in percentages within the target range on day 3 and 4 after liver transplantation with a subsequent rise. Buccal tacrolimus administration is feasible. Similar TTLs are achieved compared with NGT tacrolimus administration during the first week after pediatric liver transplantation.     

NTproBNP as a marker of rejection in pediatric heart transplant recipients

Acute rejection is a major morbidity in heart transplant recipients; diagnosis is difficult, and rejection must often be treated reactively. Various serum biomarkers have been investigated for non-invasive monitoring of the cardiac allograft. NTproBNP is produced by the ventricular myocardium and may increase with evolving rejection allowing earlier diagnosis. Retrospective review of serum NTproBNP levels in pediatric heart transplant recipients has been carried out to evaluate the association with episodes of acute rejection. Repeated measures logistic regression was used to model associations for variables with first rejection and within an individual for change in NTproBNP and first rejection. Odds ratios for rejection risk given an increase in serum NTproBNP were calculated. Correlation of NTproBNP levels with renal function as estimated by modified Schwartz equation was performed to look for confounding. Higher serum NTproBNP level was associated with increased risk of rejection, but intersubject variability was wide. However, increase in an individual subject's serum level showed increased risk of rejection, greater with greater rise. Serum NTproBNP levels appear not greatly affected by renal function. NTproBNP shows promise in surveillance for pediatric heart transplant recipients. The greatest use appears to be in following trends for an individual instead of using an absolute value.     

Transition to adult care for pediatric liver transplant recipients: the Western Australian experience

Transition to adult care is a vulnerable period for pediatric transplant recipients and is associated with reduced medication compliance, graft loss, and increased mortality. Psychosocial outcomes in young adults differ between pediatric transplant recipients and their healthy peers. We conducted a single‐center, retrospective cohort study of all pediatric liver transplant recipients who were transitioned through our center. This study aimed to assess the outcomes of transitioned pediatric liver transplant recipients at an Australian center, including mortality, adherence, and psychosocial morbidity. The 1‐ and 5‐year survival rates following transition were 100% and 92%, respectively. There were no episodes of late rejection. In total, 66.7% of patients were compliant with immunosuppression and 61.1% of patients were compliant with clinic attendance. There was a significant relationship between medication compliance and clinic attendance, as well as presence of psychological issues with clinic non‐attendance. Psychosocial outcomes were in keeping with age‐matched data from the general population. All patients were employed or studying following transition. This is the first study of its kind in the Australian population, and outcomes were superior to published international data. Despite the demonstrated good outcomes, transition programs may improve healthcare engagement in this cohort.     

Analysis of rabbit anti‐thymocyte globulin vs basiliximab induction in pediatric liver transplant recipients

Literature is limited comparing induction immunosuppression in pediatric liver transplant (LTx) recipients. This is a single‐center, retrospective cohort study of primary pediatric liver transplants at our center between 2005 and 2016 who received either basiliximab (BSX) or rabbit anti‐thymocyte globulin (rATG) induction. Maintenance immunosuppression consisted of tacrolimus ± a corticosteroid taper. Exclusions included receipt of an ABO‐incompatible graft, retransplantation, and multi‐organ transplantation. Primary outcomes were incidence of treated biopsy‐proven acute rejection (tBPAR) and PTLD within the first year and infections within 90 days of LTx. Secondary outcomes included graft and patient survival, time to first tBPAR, and incidence of steroid‐resistant rejection (SRR) within the first year post‐LTx. A total of 136 patients were included in the final analysis of which 57 patients (42%) received BSX induction. Patients who received rATG induction with or without a 2‐week corticosteroid taper experienced significantly more tBPAR compared to those who received BSX induction with a 6‐month corticosteroid taper (55.7% vs 33.3%, P = .01). There were no differences in the incidence of PTLD, infections, SRR, graft or patient survival, or time to first tBPAR between the two groups . Induction with rATG either with or without a short corticosteroid taper was associated with significantly more tBPAR in primary pediatric LTx recipients when compared to BSX induction with a prolonged corticosteroid taper in the setting of maintenance immunosuppression with tacrolimus.