Immunosupression - A backbone to the success of liver transplantation. - journey from the start

1. Overview of Immunosupressions
in
Adult Liver transplantation
Dr.Bhavin Vasavada
MBBS,MS,Fellow HPB and liver
transplant surgery

2. First extended survival of Liver
Transplant (1 year)

3. Precyclosporin Era
• Corticosteroids and azathioprine were used in
combination by Starzl et al. in his first 5
transplants.
• The majority of the Colorado series from 1963
to 1976 received corticosteroids, azathioprine,
and antilymphocyte globulin.

4. Gastroenterology. 1979 August; 77(2): 375–388. Fifteen Years of Clinical Liver Transplantation
THOMAS E. STARZL
• Survival in the Early and Late Phases of the
Colorado Experience (Follow-up to January
1979)
• Primary cause of death was ACR in 20% of
cases
Time period No of patients One year survival
1963-1976 111 28%
1976-1977 30 50%

5. Cyclosporin
• First successful use of cyclosporin in 2
patients of liver transplant without rejection.

6. • 14 patients who underwent liver transplant were given cyclosporin as Immnosupressant

8. Transplant Proc. 1988 Feb;20(1 Suppl 1):498-504.
Experience in 1,000 liver transplants under cyclosporine-steroid therapy: a survival
report.
Iwatsuki S, Starzl TE, Todo S, Gordon RD, Esquivel CO, Tzakis AG, Makowka L, Marsh JW,
Koneru B, Stieber A, et al.

9. • can be administered intravenously, although it
is usually given orally as a tablet or an oral
suspension
• After oral administration, cyclosporine is
variably absorbed in the jejunum and enters
the lymphatic system.
• Peak blood levels are achieved in two to four
hours.

10. • Cyclosporine levels should be monitored
frequently in the peritransplant period
(typically daily), with decreasing frequency as
graft function stabilizes and rejection becomes
less of a threat.

11. Cyclosporine
• Block Calcineurin→ ↓IL-2 →↓T-Cell Activation
• Initial dosage 10 to 15 mg/kg/day divided into 2 doses.
• Trough Goals
– Week 1-2 250-350 ng/mL
– Weeks 3-4 200-300
– Weeks 5-24 150-250 ng/mL
– Weeks 25+ 100-200 ng/mL
– Distant – can tolerate levels <100

12. Cyclosporine – Adverse Effects
• Hypertension
• Renal dysfunction
• Hirsutism
• Hyperkalemia
• Gingival hyperplasia
• Hypomagnesemia
• Neurologic toxicity
http://jorthod.maneyjournals.org/content/vol30/issue1/images/large/ClocFig1b.jpeg

13. TACROLIMUS

14. • Randomized Control Trial
• Total number of patient: 478 adults , 51
children
• Randomly assigned either tacrolimus (n=263)
and cyclosporin (n=266)
• Follow up period of one year

15. Figure 1. patient survival

16. Figure 2.. Graft survival

17. A. Acute rejection B.Steroid resistant acute rejection

18. Tacrolimus
• MOA same as CsA
• Initial dose 0.1 to 0.15 mg/kg/day orally
• Trough Goals (variable per patient/disease)
– Early Post-OLT – 10-15 ng/ml
– 3-6 Months – 8-10
– >6 Months – 5-7 (variable)

19. • Tacrolimus dosing should be individualized.
• start with a low dose (0.5 to 1 mg every
• 12 hours) on postoperative day one, and aim
for a level of 7 to 10 ng/mL by the end of the
first week.
• Often with the addition of an auxiliary agent
like mycophenolate mofetil or a monoclonal
antibody

22. Tacrolimus – Adverse Effects
• Posttransplant diabetes mellitus
• Nausea, vomiting, diarrhea
• Hyperkalemia
• Tremor
• Hypertension
• Hypomagnesemia
• Headache
• Renal dysfunction

23. Tac vs Csa
• Dyslipidemia and Gingival hyperplasia – more
common in Csa
• Diabetes – more common in Tac
• Rejection – less common in Tac
• Renal Dysfunction – similar

26. Baseline change in creatinine clearence at 52 weeks

28. Calcineurin inhibitors and HCV
• The selection of a specific calcineurin inhibitor
in liver transplant recipients with HCV remains
unclear.
• A theoretical advantage of cyclosporine is that
it inhibits HCV replication in vitro

32. Sirolimus
• Binds to same immunophilin as Tac (FKBP12) but with a
different mechanism of action
• blocks response of T and B Cell Activation by cytokines – prevents
progression at the juncture of G1 and S phase in these cell lines.
• Theoretical (lab based) antineoplastic and antifungal
effects.
• Early excitement about renal protective effect-
subsequent studies have not confirmed this
– Meta-analysis of 11 studies suggests a numerical/non-
significant improvement in renal function.
Hepatology. 2010 Oct;52(4):1360-70.

35. Sirolimus
• Not FDA approved for Liver Transplants –
– The FDA is notifying healthcare professionals of clinical trial
data that suggest increased mortality in stable liver
transplant patients after conversion from a calcineurin
inhibitor (CNI)-based immunosuppressive regimen to
sirolimus (Rapamune). The trial was conducted by sirolimus
manufacturer, Wyeth.

36. • Although sirolimus binds its target (FK-binding
protein) with higher affinity than tacrolimus,
the two drugs act synergistically rather than
competitively to prevent rejection.

39. Sirolimus
• Black Box warning – possible increased risk of
Hepatic Artery Thrombosis in immediate post-
OLT setting – usually wait up to 12 weeks post.
• Recent study of switch from CNI to SRL
suggests possible increased mortality (FDA
ALERT [06/11/2009])
• Currently using in those intolerant to CNIs,
and in some patients for theoretical
antineoplastic and renoprotective
(controversial) effects.

40. Sirolimus – Adverse Effects
• Anemia
• Hypercholesterolemia
• Hypertriglyceridemia
• Leukopenia
• Hyperlipidemia
• Interstitial lung disease
• Thrombocytopenia
• Peripheral edema
• Wound dehiscence
• Hepatic Artery Thrombosis

41. Mycophenylate Mofetil (MMF)/
Mycophenolic Acid (MPA)
• inhibit the de novo purine nucleotide synthesis
via abrogation of the inosine monophosphate
dehydrogenase and the production of guanosine
nucleotides
• Leads to blockage of DNA replication in T and B
lymphocytes (can’t use salvage pathways).
• MPA is a delayed release form of MMF
• Dosing –
– 1000-1500mg bid MMF or
– 360-720 BID MPA

42. Side effects of MMF/MPA
• Nausea, vomiting, diarrhea
• Anemia
• Leukopenia
• Weight loss
• Thrombocytopenia

43. • The role of MMF is similar to that of sirolimus
in that it is used to reduce or discontinue CNI
dosing in order to treat side effects.

47. Steroid

48. • Once the patient is able to take oral
medications, he/she is switched to prednisone
20 mg/day.
• Tapering to zero is usually achieved over three
to six months, although some centers leave
patients on 5 mg/day
• indefinitely.

49. • Given the problems with glucocorticoids,
many centers try to wean from steroids as
early as possible.
• rapid steroid withdrawal can precipitate a
flare of an underlying condition (eg,
autoimmune hepatitis,inflammatory bowel
disease, or hepatitis)

50. Glucocorticoids and HCV
• The ability of steroids to increase HCV replication has
created concern about their use in these patients.
• As a general rule, three options exist with regard to
glucocorticoid use in patients with HCV:
• Maintain low dose steroids indefinitely
(approximately 5 mg/day)
• Taper steroids slowly
• Avoid steroids

55. Steroid free immunosupression

59. Limitation of steroid free regime
• Trials cannot necessarily be compared since steroid dosing
and tapering regimens vary widely.
• We rarely see rejection using the steroid protocol discussed
above.
• shorter tapering protocols have been associated with higher
rates of rejection, including steroid-resistant rejection.
• The steroid-free regimens use expensive drugs that are not
always available. Daclizumab is no longer manufactured.
• Aggressive immunosuppression may have late consequences
such as post-transplant lymphoproliferative disease (PTLD).

60. Baciliximab (Simulact)
IL-2 Receptor Antibodies – induction
Basiliximab (Simulect)
daclizumab (Zenapax).

64. Immunosuppression – Drug Interactions
• Cytochrome P-450 3A
• P-Glycoprotein – cell membrane associated
protein transports drugs and plays a role in
both absorption (bowel) as well as elimination
(liver and kidney)
– carvedilol inhibits p-plycoprotein pathway leading
to increased CNI levels
• Grapefruit – can increase levels of CNIs –
mechanism not totally clear

65. Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003

66. Drug Interactions
American Journal of Transplantation 2009; 9:
1988–2003

67. Antibody Induction
• Antithymocyte Globulin – induction/rejection.
– Polyclonal antilymphocyte globulin – multiple epitopes on
T cell receptor – lead to apoptosis of T-cells
– ATGAM (of equine origin)
– Thymoglobulin (of rabbit origin)
• Monoclonal anti T-Cell antibodies – induction/rejection
– Muromonab-CD3 (OKT3) – binds CD3 Antigen on T-Cell
receptor – inactivates adjacent T-Cell – leads to rapid drop
in T-Cells
• IL-2 Receptor Antibodies – induction
– Basiliximab (Simulect)
– daclizumab (Zenapax).

68. Summary
• CsA, Tac or Sirolimus are the backbone of
maintenance immunosuppresion
• Addition of other agents (Steroids, MMF,
Azathioprine) can be used to decrease risk of
rejection or allow for lower doses of the
primary agents.
• 50% of post-OLT deaths are directly/indirectly
related to immunosuppressive medications.

69. • THANK YOU