Withdrawal of immunosuppressants in pediatric liver transplant

1. 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

2. 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.

3. 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.

4. 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 .

5. 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

6. Patient recruitment algorithm

7. 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.

8. Six patients were preliminarily weaned off tacrolimus, and five
remained tacrolimus-free for more than 2 years.

9. The histologies of liver biopsy in 5
tolerant patients

10. Of the 10 patients who were not weaned off tacrolimus, six
experienced seven episodes of clinical rejection.

11. Five patients had a reduction in tacrolimus dosage to an
undetectable trough level, another five to a trough level <4 ng/ml

12. 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

13. 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.

14. 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.

15. Thank you for your
attention