Induction therapy is used to prevent or delay acute rejection in kidney transplant recipients. Common induction agents include antithymocyte globulin (Thymoglobulin), basiliximab, alemtuzumab, and corticosteroids. Induction agents are either monoclonal antibodies like daclizumab and basiliximab, or polyclonal antibodies like Thymoglobulin. Depleting agents like Thymoglobulin and alemtuzumab cause T-cell depletion, while non-depleting agents do not. High-risk patients may benefit more from depleting induction to improve graft survival. However, depleting agents also carry higher risks of infections and side effects. Current guidelines recommend IL-2 receptor antagonists like basil

1. Induction for Kidney Transplant
Wisit Cheungpasitporn

2. Induction Therapy
•
•
•
•
Anti-thymocyte globulin (Thymoglobulin®)
Alemtuzumab (Campath®)
Basiliximab (Simulect®), Daclizumab (Zenapax ®)
Corticosteroids

3. Three signal model
Halloran NEJM 2004

4. Background
• Multiple trials show that induction agents
either prevent or delay the development
of acute rejection.
• As of 2008, induction agents were
administered in 82% of kidney recipients.
N Engl J Med 364;20

5. Induction agents
Monoclonal
(Daclizumab, Basiliximab,
Alemtuzumab, OKT3)
Polyclonal
(Thymoglobulin, atgam)
Depleting agents
(Thymoglobulin, Alemtuzumab,
OKT3)
Non-depleting agents
(Daclizumab, Basiliximab)

6. Trends in use of induction agents

7. Depleting agents
Eg. Thymoglobulin, OKT-3, Alemtuzumab
• These agents cause T-cell lysis and/or clearance
with a resultant depletion in circulating
lymphocytes.
• Causes extensive release of cytokines due to cell
destruction that may cause significant adverse
events.
• Reconstitution of the immune system can take a
long time.
• The depleting action is responsible for many
adverse reactions like infections and malignancy.

8. Depleting agents
• Advantages of using Depleting Antibodies:
–
–
–
–
–
Improved graft survival for high-risk patients.
Shortening of period of DGF.
Onset of first rejection is delayed.
Obviates early use of CNI
May permit less aggressive maintenance regimens
• Disadvantages:
–
–
–
–
–
Risk of first dose reactions.
May prolong hospital stay
Greater cost
Higher incidence of CMV infection
May increase short term and long term mortality.

9. High risk factors for acute rejection
• The number of human leukocyte antigen
(HLA) mismatches
• Younger recipient age.
• Older donor age.
• African-American ethnicity.
• PRA >0%
• Presence of a donor-specific antibody.
• Blood group incompatibility.
• Delayed onset of graft function.
• Cold ischemia time >24 hours.
KDOQI Transplant Guidelines

10. Antithymocyte globulin
• Polyclonal antibodies produced by
immunizing horse(Atgam) or
rabbits(Thymoglobulin & ATG-Fresenius)
with lymphoid tissue and then harvesting
and stabilizing the resultant immune sera.
• Initially approved for the treatment of
acute cellular rejection but is also used as
induction agent.
• Most widely used polyclonal induction
agent in the US

12. Anti cd25 antibodies

13. Anti cd25 antibodies side effects
• Hypersensitivity reactions is the only
significant side effect (<1%) with both the
agents.
• There is no increased risk of CMV infections
and malignancies.

14. ALEMTUZUMAB
• It is a humanized monoclonal antibody directed
against CD52.
• CD52 is present on virtually all B- and T-cells as
well as macrophages, NK cells, and some
granulocytes.
• The depletion of lymphocytes is so marked that it
takes several months to a year post
administration for the immune system of a
patient to be fully reconstituted.

15. ALEMTUZUMAB
Side Effects:
• The depleting efficiency of alemtuzumab is so
profound that it is invariably associated with
side effects viz. neutropenia
(70%), thrombocytopenia (52%), anemia
(47%), nausea (54%), vomiting (41%), diarrhea
(22%), headache (24%), dysthesias
(15%), dizziness (12%), and AIHA(<5%).

16. Kdoqi guidelines
1.1: We recommend starting a combination of
immunosuppressive medications before, or at the time
of, kidney transplantation. (1A)
1.2: We recommend including induction therapy
with a biologic agent as part of the initial
immunosuppressive regimen in KTRs. (1A)
1.2.1: We recommend that an IL2-RA be
the firstline induction therapy. (1B)
1.2.2: We suggest using a lymphocytedepleting agent, rather than an
IL2RA, for KTRs at high immunologic
risk. (2B)

17. • Induction Therapy Rabbit antithymocyte
globulin (rATG; Thymo- globulin) and
basiliximab (Simulect) continue to be the most
widely used antibody induction agents in the
United States, although the latter is the only
US Food and Drug Administration (FDA)–
approved drug for this indication.
Daclizumab, a basiliximab competitor, was
withdrawn from the market in 2009 due to
diminished market demand.

19. • The primary endpoint was a composite of acute rejection,
delayed allograft function, allograft loss, and death. At one
year, the following results were reported:
– No difference between rATG-thymoglobulin and basiliximab in
the incidence of the composite endpoint, allograft loss, delayed
allograft function, and death.
– rATG-thymoglobulin was associated with a significantly lower
acute rejection rate (16 versus 26 percent), and incidence of
acute rejection that required antibody treatment (1.4 versus 8
percent).
– Although overall adverse event and serious adverse event rates
were similar, rATG-thymoglobulin was associated with a higher
incidence of infection (86 versus 75 percent) but lower
incidence of cytomegalovirus disease (8 versus 18 percent).

20. Alemtuzumab induction
• Alemtuzumab relatively spared regulatory T
cells, resulting in a rise in their numbers. In
spite of this profound lymphopenia, 20% of
patients developed DSA.
• Associated with higher graft failure risks in
patients with panel reactive antibody (PRA)
>20%, recipients of expanded criteria donor
kidneys, and kidneys with cold ischemia time
>24 hours.

21. Alemtuzumab induction
• Associated with higher patient death risks in
recipients of expanded criteria donor kidney
and kidneys with cold ischemia time >24
hours.
• Conceptually, profound, prolonged
lymphopenia/leucopenia may mitigate the
ability to provide concurrent antimetabolite
immunotherapy and antiviral pro- phylaxis.
• ?late acute rejection