Mycophenolate mofetil as

an Adjuvant
Immunosuppressant in
Liver Transplant
Otty Mitha Sevianti
20090712

Introduction

Objective

To search the evidence of efficacy and safety profile of

MMF + TAC + steroid versus TAC + steroid to minimize
the adverse reactions/toxicity of calcineurin inhibitor in
post liver transplant children

CASE
A 5 years 1 months old boy
Chief complain: jaundice since birth
Oct 16th 2012

Oct 20th 2012

PICU
episode of hypothermia,

Came to Child
Health Dept private
clinic
Good vital sign
Complete
examination
Preparation for liver
transplant

12 hours operation
Stable condition
post op ICU

Other histories
Had effusion fluid tapped
Had ascites drainaged

tachycardia, tachypneu
Hyperglycemia
Hypertension
Pleural effusion
Localized ascites + bile
leakage

CASE
Physical
examination

Laboratory
examination
Normocytic normochromic anemia
Hypomagnesemia
Hypophasphatemia
Increased septic marker
Ascites fluid culture : K. pneumoniae
Pleural effusion analysis : exudates

Chest X-ray
Right pleural effusion
Abd CT-scan
Fluid collection at upper quadrant

abdomen sub diaphragma

Localized ascites

CASE
Diagnosis
Post liver transplant ec Alagille
syndrome
Sepsis ec K. pneumoniae
Hyperglycemia ec steroid + TAC
Hypertension ec steroid
Mid malnourished
Short stature

Management
Antibiotics
Tacrolimus
Methylprednisolone
Valganciclovir
Ranitidine
Captoprile
Amlodipine
Insulin

Improved hepatic marker

Uncontrolled hyperglycemia

PICO

Search Method
Keywords
Mycophenolate mofetil

Tacrolimus

Liver transplant

Online search
Pubmed

Highwire

Google

Human, English, Children (0-18 years old)

36 articles
4
2 RCT

1 retrospective study

1 casecontrol

Gonwa et al (2003)
Methods

RCT in 223 children (age 12-18 years)

Treatment groups:
- Group A received TAC + MMF
- Group B received TAC + AZA
- Group C received CsA + MMF
All regimens contained corticosteroid
Dose given : TAC 0.15 0.2 mg/kg/d, CsA 8-10 mg/kg/d, AZA 1.5 2 mg/kg/d

Measurements
Kidney function
Blood glucose and insulin
Followed up for 3 years
.

LoE
1b

Gonwa et al (2003)

LoE
1b

Bansal et al (2006)

LoE
1b

Methods

RCT 40 children

Measurements
Acute rejection, bacterial
infection, fungus, virus, renal
function, survival rate

TAC + MMF + steroid

TAC + steroid

Bansal et al (2006)

LoE
1b

Aw et al (2008)

LoE
2b

Methods

Cohort retrospective 28 children (4 mos 14 yo)

Primary immunosuppression CsA based triple in 22 and TAC based dual therapy in 6.
MMF dose 10/mg/kg/d up to 40 mg/kg/d in divided dose for 2 weeks

Measurements

- Positive response to the addition of MMF normalization of serum aspartate

aminotransferase (AST; 50 U/L) or a decrease in AST to less than
twice the upper limit of normal (AST 50-100 U/L).
- Renal function

Haywood et al (2011)

LoE
3b

Methods

Retrospective case control 101children (4 mos 14 yo)

MMF 2000 mg/d, TAC targeting trough levels of 810 ng/mL in the first three months, and
corticosteroids for 36 months (MMF + TAC group)
control patients (TAC group) received only TAC , corticosteroid tapering identical to
Measurements
the
MMF + TAC group..

renal function
TAC + steroid

TAC + MMF + steroid

MMF+TAC group :
decrease in Cr
(1.65 1.361.22
0.37,
p = 0.02) and an
increase in GFR
(56.6 29.3
64.7 21.2, p =
0.04

Immunosuppresive agents

Corticosteroids

The most widely used non CNI

immunosuppresant in liver transplant
Act on T cell by inhibiting the production of
T cell cytokines IL-2, IL-6, and interferongamma, enhance the response of
lymphocytes and macrophages to allograft
antigens.

Corticosteroids

Suppress antibody and complement

binding and stimulate the migration of T
cells intravascular compartment to
lymphoid tissue.

Corticosteroids

MMF

Morpholinoethyl ester of mycophenolate which is

produced by several species of the fungus
Penicillium
MoA : block de novo purine nucleotide synthesis
by inhibiting type 2 inosine monophosphate
dehydrogenase (IMPDH) and the production of
guanosine nucleotides such a
guanosinemonophosphate (GMP)

MMF

Side effect : gastrointestinal (anorexia,

abdominal pain, gastritis, diarrhea in up
to 30%) and hematological (neutropenia
in up to 3%) usually dose-related

Tacrolimus

Inhibits calcineurin, a calcium-dependent

phosphatase
Dephosphorylation activated T cells
promoter regions of important cytokines
response to activating signals T cell
receptor

Tacrolimus

Side effect : nephrotoxicity, neurotoxicity,

hyperglycemia, hyperlipidemia, anemia,
thrombocytopenia

CASE

Dose, Administration & Side effect

Qureshi AI. J Neurosurg. 1999;44:1055-63.

Upadhyay P. J Pediatr Neurosci. 2010;5:18-21.

Yildizdas D. Indian Pediatr. 2006;43:771-9.

Sakellaridis N. J Neurosurg. 2011;114:545-8.

CONCLUSION

MMFmore effective in reducing side effect of calcineurin inhibitor, especially

nephrotoxicity

Systemic adverse effects rarely reported

Cost effective

Futher study still needed to determine the most effective and the safest
concentration of MMF especially in children