Minimization or Withdrawal of Immunosuppressants in Pediatric Liver Transplant Recipients

Presenter: Chinsu Liu

Coauthors:Niang-Cheng Lin , Hsin-Kai Wang, Yi-Chen Yeh, Chia-Pei Liu , Che-Chuan Loong, Hsin-Lin Tsai, Cheng-Yen

Chen , Taiwai Chin.

Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

National Yang-Ming University, School of Medicine, Taipei, Taiwan

Background

• Calcineurin inhibitor (CNI)-based immunosuppressants greatly improves outcomes of liver transplantation. However, their long-term side effects can cause morbidities.

• In this prospective trial, we aimed to minimize the dose of tacrolimus (CNI) in pediatric patients after liver transplantation.

Inclusion criteria

• Pediatric patients (age<18 y/o)

• Normal liver function after 1 year (transplant at <1 year of age) or 2 years (transplant at> 1 year of age) after liver transplantation without any ongoing complications.

• Baseline sono-guided biopsy proof of no rejection or fibrosis of the liver.

Methods

• The dosage of the tacrolimus was gradually reduced (by half per 4 weeks), and liver function was assessed at outpatient clinical visits.

• Protocol liver biopsies to evaluate the effects of reducing the dosage of the tacrolimus.

• The diagnosis and staging of graft rejection and fibrosis were based on the Banff schema :rejection activity index (RAI) and Ishak fibrosis scoring .

Banff schema : RAI and Ishak fibrosis scoring

RAI more than 3-rejection, Ishak fibrosis more than 3:

moderate fibrosis

Ormondee et al, Liver Transpl Surg 1999

Shiha et al, Liver biopsy

Patient recruitment algorithm

Patients

• From January 2011 to December 2012, 16 patients were recruited, of whom 15 completed

follow-up at a mean 40.75±5.98 months.

Six patients were preliminarily weaned off tacrolimus, and five

remained tacrolimus-free for more than 2 years.

The histologies of liver biopsy in 5 tolerant patients

Of the 10 patients who were not weaned off tacrolimus, six

experienced seven episodes of clinical rejection.

Five patients had a reduction in tacrolimus dosage to an

undetectable trough level, another five to a trough level <4 ng/ml

The patients with metabolic liver disease (p=0.039) and who

were recruited earlier after transplantation (p=0.028) were more

likely to be weaned off tacrolimus

Fibrosis of liver during weaning off tacrolimus

• Five patients noted on post-recruitment surveillance biopsy. • The fibrosis in these five cases were low grade (Ishak grade 3 in one case,

grade 2 in two cases and grade 1 in two cases). • We believe fibrosis of liver caused by • Rejection in two cases (RAI: 2), also elevated AST/ALT • Concurrent de novo hepatitis B in one case • Suspicion of it being related to immunosuppressant withdrawal in two

cases (RAI:1, 2) without elevation of AST/ALT. • In two cases, fibrosis was resolved (Ishak grade: 3 to 1 to 0 in patient 6

and grade 1 to 1 to 0 in patient 14) after the reinstitution of low-dose tacrolimus.

• Considering the findings in the literature and our study, graft fibrosis may result from multi-factorial mechanisms, and surveillance biopsies are important in addition to laboratory tests to monitor the grafts during and after immunosuppressant withdrawal.

Conclusions

• Tacrolimus withdrawal is feasible in select pediatric liver transplant recipients, and long-term follow-up for these patients is suggested.

• As renal function decline is considered to be a long-term concern in pediatric recipients who receive transplants for methylmalonic acidemia and propionic academia, both are of an inborn error on organic acid metabolism, the high incidence of tolerance in our patients with metabolic liver diseases may suggest that early immunosuppressant minimization in these patients may achieve better long-term outcomes.

Thank you for your

attention