Title: Follow-up liver biopsy as a tool for tailoring immunosuppressive treatment in pediatric liver transplantation

Source: Transplantation 2026, Apr 27. [E-publication]

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Date of publication: April 2026

Publication type: Prospective, single-centre cohort study

Abstract: Background: In pediatric liver transplantation (pLT), follow-up liver biopsies (fLBs) frequently reveal subclinical histological abnormalities, despite normal liver function tests. Findings, including inflammation, fibrosis, and immune-mediated changes, suggest overlapping alloimmune and autoimmune mechanisms with potential long-term consequences.

Methods: We performed a prospective, single-center cohort study at the Vall d’Hebron Barcelona Hospital Campus, including 167 children who underwent 299 liver biopsies (214 protocol, 85 post-immunosuppression modification) from 2018 to 2024. Immunosuppression was adjusted according to a preestablished histology-guided protocol, intensifying therapy in patients with subclinical T cell-mediated rejection (S-TCMR; Banff Rejection Activity Index ≥2) detected in protocol biopsies.

Results: S-TCMR was identified in 71 of 214 (33.2%) protocol biopsies, with fibrosis (Ishak ≥2) in 38 (53.5%). Following protocol-driven immunosuppressive intensification, 57 of 71 (80.3%) achieved S-TCMR resolution at 12 mo, with 8 of 12 showing further improvement at 24 mo. Fibrosis regressed by ≥1 Ishak stage in 21 of 38 (55.3%). Autoantibody responders showed superior S-TCMR (P = 0.006) and fibrosis outcomes (P = 0.05). Donor-specific antibody-positive patients exhibited lower S-TCMR resolution (odds ratio [OR], 3.3; P = 0.1) and a higher risk of persistent fibrosis (OR, 4.8; P = 0.03). Plasma cell-rich S-TCMR (18/71 [25.4%]) strongly correlated with C4d deposition (5-fold increase) and markedly reduced fibrosis regression (OR, 11.0; P < 0.001), indicating resistance to standard immunosuppression.

Conclusions: Histology-guided, protocol-driven immunosuppression intensification effectively reversed most S-TCMR and fibrosis, underscoring the importance of long-term protocol biopsies for individualized therapy in pLT.

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Title: 30-year follow-up of immunosuppression modulation: Impact on graft fibrosis and anti-HLA antibodies after pediatric liver transplantation

Source: Liver Transplantation 2025, Aug 13. [E–publication]

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Date of publication: August 2025  

Publication type: Article  

Abstract: Pediatric liver transplantation, while life-saving, poses long-term challenges in immunosuppression (IS) management. We retrospectively studied 26 pediatric recipients who underwent living donor liver transplantation between 1990 and 1994 and retained their original grafts for over 30 years. Based on IS status at the final follow-up, patients were categorized as IS-free (n=8), IS-resumption (n=9), or IS-continued (n=9). We analyzed liver allograft fibrosis score (LAFSc, range 0-9), donor-specific antibodies (DSA), and liver function tests. At the last follow-up, liver function tests showed no significant differences across groups. The IS-free group had a median IS cessation period of 22.8 years (range: 14.2-26.7) and demonstrated minimal fibrosis (median LAFSc=1) and low DSA prevalence, suggesting potential operational tolerance. The IS-resumption group resumed IS after a median cessation period of 7.9 years (range: 1.3-15.7) due to fibrosis progression and exhibited the highest fibrosis burden (median LAFSc=4) and frequent DSA positivity. Notably, some patients showed a tendency for fibrosis progression despite the restart of IS, suggesting possible subclinical antibody-mediated injury. The IS-continued group experienced fluctuating fibrosis (median LAFSc=1) and multiple late-onset T cell-mediated rejection episodes. Across all groups, high DSA positivity (mean fluorescence intensity >20,000) significantly correlated with advanced fibrosis. In conclusion, the IS-free group’s favorable histology and antibody profile support the possibility of durable immune tolerance. Conversely, persistent fibrosis in the IS-resumption group highlights the limitations of conventional IS strategies. Serial histological evaluations and antibody monitoring would be helpful for long-term IS management in pediatric liver transplant recipients.

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Title: Sirolimus utilization in pediatric liver transplantation: a large high-volume quaternary center experience

Source: Journal of Pediatric Gastroenterology and Nutrition 2025, May 19. [E–publication]

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Date of publication: May 2025

Publication type: Retrospective cohort study

Abstract: Objectives: Optimization of liver transplant (LT) immunosuppression is essential for long-term graft function in children. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus, have not been extensively studied in pediatric LT. We aimed to explore the usage of and indications for sirolimus at a quaternary pediatric LT center in a retrospective cohort analysis.

Methods: Pediatric LT patients who received sirolimus from 2010 to 2018 were included. Their electronic medical records were evaluated for demographic information, clinical data, and laboratory data before and after initiation of sirolimus.

Results: Sirolimus was initiated on 41 pediatric LT recipients at a median of 0.67 years post-transplant (interquartile range [IQR]: 0.13-1.83) at Texas Children’s Hospital. The leading indications for initiating sirolimus were chronic rejection (CR) (n = 12, 29.3%), T-cell-mediated rejection (TCMR) on tacrolimus (n = 8, 19.5%), posterior reversible encephalopathy syndrome (PRES) (n = 8, 19.5%), and unresectable hepatic tumors/malignancies (n = 7, 17.1%). Among patients started on sirolimus for CR, 58% (n = 7/12) demonstrated histological or biochemical improvement. Among those started for TCMR augmentation, 62.5% experienced biochemical improvement. No patients who started on sirolimus for unresectable hepatic tumors/malignancies had malignancy recurrence 1-year post-LT. Median cholesterol and triglyceride levels 1-year post-initiation were higher than values 1-year pre-initiation (p < 0.0001); however, sirolimus-induced anemia, nephrotoxicity, and HAT were not observed.

Conclusions: This study is among the first to review the clinical experience of sirolimus usage in pediatric LT. Our experience suggests sirolimus can be used safely and effectively. Further research is warranted to evaluate long-term benefits, adverse effects, and optimal dosing of sirolimus in pediatric liver transplantation.

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Title: Sex-based differences in rejection among pediatric solid organ transplant recipients

Source: Pediatric Transplantation 2025, 29 (3): e70071

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Date of publication: April 2025

Publication type: Retrospective review

Abstract: Background: Immunosuppression is paramount to prevent acute rejection in solid organ transplant but also poses a risk for infection and malignancy. Identifying factors that influence rejection may allow for personalization of treatment and avoidance of an unnecessary degree of immunosuppression for the vulnerable pediatric population.

Methods: We conducted a retrospective review analyzing public data provided by the Organ Procurement and Transplantation Network for pediatric patients listed for solid organ transplantation (kidney, liver, lung, and heart) from March 1998 to December 2022. Univariate and multivariate logistic regression was used to identify independent risk factors for treated acute rejection at 6 months and/or 1 year for liver, lung, kidney, and heart transplants.

Results: The study population consisted of the following pediatric patients for each organ studied: liver (n = 8993), lung (n = 846), heart (n = 7118), and kidney (n = 14 600). At 1 year, 28.4% and 31.7% of males and females, respectively, were treated for rejection in liver transplant, 24.1% and 34.5%, respectively, for lung, 14.8% and 16.2%, respectively, for kidney, and 25.2% for both in heart transplant. In multivariate analysis, male recipient status was a statistically significant protective factor against rejection in liver transplant, OR = 0.85 (p < 0.001), lung transplant, OR = 0.61 (p = 0.004), and kidney transplant, OR = 0.91 (p = 0.040), but not heart transplant, OR = 0.96 (p = 0.460).

Conclusions: Our study demonstrates that pediatric males may have a lower risk of acute rejection in liver, lung, and kidney transplant yet not in heart transplant. These findings may have implications for the level of maintenance immunosuppression for pediatric male transplant recipients.

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Title: Transplant-acquired food allergy in children

Source: Nutrients 2024, 16 (18): 3201

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Date of publication: September 2024

Publication type: Review article

Abstract: Background: Organ transplantation in children is a vital procedure for those with end-stage organ failure, but it has been linked to the development of post-transplant allergies, especially food allergies. This phenomenon, known as transplant-acquired food allergy (TAFA), is becoming increasingly recognized, though its mechanisms remain under investigation. Pediatric transplant recipients often require lifelong immunosuppressive therapy to prevent graft rejection, which can alter immune function and heighten the risk of allergic reactions. Our review aimed to gather the latest evidence on TAFA.

Methods: We conducted a PubMed search from 25 June to 5 July 2024, using specific search terms, identifying 143 articles. After screening, 36 studies were included: 24 retrospective studies, 1 prospective study, 2 cross-sectional researches, and 9 case reports/series.

Results: Most studies focused on liver transplants in children. The prevalence of food allergies ranged from 3.3% to 54.3%. Tacrolimus, alongside corticosteroids, was the most commonly used immunosuppressive therapy. In addition to food allergies, some patients developed atopic dermatitis, asthma, and rhinitis. Allergic symptoms typically emerged within a year post-transplant, with common allergens including milk, eggs, fish, nuts, soy, wheat, and shellfish. Both IgE-mediated and non-IgE-mediated reactions were observed, with treatment often involving the removal of offending foods and the use of adrenaline when necessary.

Conclusions: Consistent immunological monitoring, such as skin prick tests and IgE level assessments, is essential for early detection and management of allergies in these patients. Understanding the link between transplantation and allergy development is crucial for improving long-term outcomes for pediatric transplant recipients.

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Title: Impact of early immunosuppression on pediatric liver transplant outcomes within 1 year

Source: Journal of Pediatric Gastroenterology and Nutrition 2024, 78 (2): 328-338

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Date of publication: February 2024

Publication type: Article

Abstract: Objectives: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes.

Methods: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries.

Results: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only.

Conclusions: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

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Title: Live-attenuated vaccination for measles, mumps, and rubella in pediatric liver transplantation

Source: Pediatric Transplantation 2024, 28 (1): e14687

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Date of publication: February 2024

Publication type: Review article

Abstract: Background: Infections are a serious short- and long-term problem after pediatric organ transplantation. In immunocompromised patients, they can lead to transplant rejection or a severe course with a sometimes fatal outcome. Vaccination is an appropriate means of reducing morbidity and mortality caused by vaccine-preventable diseases. Unfortunately, due to the disease or its course, it is not always possible to establish adequate vaccine protection against live-attenuated viral vaccines (LAVVs) prior to transplantation. LAVVs such as measles, mumps, and rubella (MMR) are still contraindicated in solid organ transplant recipients receiving immunosuppressive therapy (IST), thus creating a dilemma.

Aim: This review discusses whether, when, and how live-attenuated MMR vaccines can be administered effectively and safely to pediatric liver transplant recipients based on the available data.

Material and methods: We searched PubMed for literature on live-attenuated MMR vaccination in pediatric liver transplantation (LT).

Results: Nine prospective observational studies and three retrospective case series were identified in which at least 833 doses of measles vaccine were administered to 716 liver transplant children receiving IST. In these selected patients, MMR vaccination was well tolerated and no serious adverse reactions to the vaccine were observed. In addition, an immune response to the vaccine was demonstrated in patients receiving IST.

Conclusion: Due to inadequate vaccine protection in this high-risk group, maximum efforts must be made to ensure full immunization. MMR vaccination could also be considered for unprotected patients after LT receiving IST following an individual risk assessment, as severe harm from live vaccines after liver transplantation has been reported only very rarely. To this end, it is important to establish standardized and simple criteria for the selection of suitable patients and the administration of the MMR vaccine to ensure safe use.

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Title: Diminished measles immunity after paediatric liver transplantation – a retrospective, single-centre, cross-sectional analysis

Source: PLoS One 2024, 19 (2): e0296653

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Date of publication: February 2024

Publication type: Retrospective, single-centre, cross-sectional analysis

Abstract: Liver transplantation in childhood has an excellent long-term outcome, but is associated with a long-term risk of infection. Measles is a vaccine-preventable infection, with case series describing severe courses with graft rejection, mechanical ventilation and even death in liver transplant recipients. Since about 30% of liver transplanted children receive liver transplants in their first year of life, not all have reached the recommended age for live vaccinations. On the contrary, live vaccines are contraindicated after transplantation. In addition, vaccination response is poorer in individuals with liver disease compared to healthy children. This retrospective, single-centre, cross-sectional study examines measles immunity in paediatric liver transplant recipients before and after transplantation. Vaccination records of 239 patients, followed up at Hannover Medical School between January 2021 and December 2022 were analysed. Twenty eight children were excluded due to stem cell transplantation, regular immunoglobulin substitution or measles vaccination after transplantation. More than 55% of all 211 children analysed and 75% of all those vaccinated at least once are measles seropositive after transplantation-48% after one and 84% after two vaccinations-which is less than in healthy individuals. Interestingly, 26% of unvaccinated children also showed measles antibodies and about 5-15% of vaccinated patients who were seronegative at the time of transplantation were seropositive afterwards, both possibly through infection. In multivariable Cox proportional hazards regression, the number of vaccinations (HR 4.30 [95% CI 2.09-8.83], p<0.001), seropositivity before transplantation (HR 2.38 [95% CI 1.07-5.30], p = 0.034) and higher age at time of first vaccination (HR 11.5 [95% CI 6.92-19.1], p<0.001) are independently associated with measles immunity after transplantation. In contrast, older age at testing is inversely associated (HR 0.09 [95% CI 0.06-0.15], p<0.001), indicating a loss of immunity. Vaccination in the first year of life does not pose a risk of non-immunity. The underlying liver disease influences the level of measles titres of twice-vaccinated patients; those with acute liver failure being the lowest compared to children with metabolic disease. In summary, vaccine response is poorer in children with liver disease. Liver transplant candidates should be vaccinated before transplantation even if this is earlier in the first year of life. Checking measles IgG and re-vaccinating seronegative patients may help to achieve immunity after transplantation.

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Title: A longitudinal study of long-term renal outcome after pediatric liver transplantation in relation to CNI exposure

Source: Pediatric Transplantation 2023, Dec 27. [E-publication]

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Date of publication: December 2023

Publication type: Retrospective single centre study

Abstract: Background: Chronic kidney disease (CKD) is reported in 20%-30% of children after liver transplantation (LT). One of the proposed underlying causes is the long-term exposure to tacrolimus, a calcineurin inhibitor (CNI), which is the main immunosuppressive drug used after LT. Variation in tacrolimus absolute exposure and relative dose requirements are believed to be important risk factors for developing CNI-associated nephrotoxicity.

Aim: To describe the long-term renal outcome of pediatric LT recipients and determine the effects of tacrolimus exposure on renal outcome parameters.

Methods: Retrospective single center study of renal function (GFR, proteinuria) and pharmacokinetic parameters (C₀ , AUC_0-12h ) obtained during annual follow-up in children after liver transplantation, between 1998 and 2019. Relevant pharmacogenetic variants for tacrolimus disposition (CYP3A5 and ABCB1) were determined in recipients and donors. The evolution of individual renal function and tacrolimus exposure was evaluated using linear mixed models for repeated measurements.

Results: Twenty-six children were included (mean follow-up: 10.4 years (range 2-18.9)). Mean estimated GFR was 109.3 (SE: 7.4), vs. measured: 91.3 mL/min/1.73 m² (SE: 6.3), which remained stable during follow-up. CKD stage ≥2 was observed in 32.8% of the visits based on eGFR versus 50.0% on mGFR. CKD stage ≥3 was uncommon (4.1% and 6.2% resp.). Mean tacrolimus C₀ was 5.3 ng/mL (SE: 2.5) with a AUC_0-12h of 72.7 ng*h/mL (SE: 30.3), which demonstrated a small decrease during follow-up. There was a negative correlation between C₀ and mGFR (r_S = -0.3; p < .001). We found no correlation between GFR and tacrolimus dose requirements ((ng/mL)/(mg/kg)) or pharmacogenetic background.

Conclusion: Renal function during long-term follow-up after pediatric LT remained stable for the majority of our cohort. However, mild CKD was relatively common, warranting follow-up into adulthood. Although absolute tacrolimus exposure has a small depressing effect on concurrent GFR, there is no progressive deterioration of GFR due to long-term exposure, dose requirements or genetic background under the current target levels. These findings should be confirmed in a larger sample set, ideally including data from multiple centers.

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Title: Immunosuppression minimization is safe and associated with good long-term success in pediatric liver transplant recipients

Source: Liver Transplantation 2023, Nov 8. [E-publication]

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Date of publication: November 2023

Publication type: Article

Abstract: Immunosuppression reduction after liver transplant is an important strategy to mitigate long-term medication side effects. We describe our center’s experience with immunosuppression minimization to once daily calcineurin inhibitor dosing. Success was defined as continuing daily calcineurin inhibitor monotherapy with normal transaminases and no rejection. We performed a retrospective review of eligible children who received a liver transplant between 2009-2016, had a surveillance biopsy, and were on twice daily calcineurin inhibitor monotherapy. Twenty eight of 51 eligible patients were minimized with calcineurin inhibitor goal 12-hour trough detectable. Nineteen patients (68%) had 1-year success, and 17 (61%) had long-term success at median follow-up of 5.0 years (interquartile range (IQR) 2.9-6.6). Minimization failure occurred at a median of 0.6 years (IQR 0.3-1.0) after dose reduction. Patients with long-term success had lower aspartate aminotransferase levels prior to minimization compared to those who failed with median 28.0 IU/L (IQR 20.5-32.0) versus 32.0 IU/L (IQR 30.0-37.0), p=0.047. The long-term success group demonstrated a trend toward greater living donor recipients (53% vs. 18%, p=0.07). At time of last follow up at median 5.0 years (IQR 2.9-6.1) after surveillance biopsy, most (73%) patients who failed had returned to twice daily calcineurin inhibitor monotherapy, all had liver enzymes less than 2-times upper limit of normal, and there were no patient deaths or graft losses. In conclusion, immunosuppression minimization is safe in pediatric liver transplant recipients and should be considered to reduce long-term medication side-effects and improve patient quality of life. Future studies are necessary to follow long-term outcomes and develop biomarkers to predict minimization success.

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