Induction for Kidney Transplant

Wisit Cheungpasitporn

Induction Therapy

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

Three signal model

Halloran NEJM 2004

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

Induction agents Monoclonal (Daclizumab, Basiliximab,

Alemtuzumab, OKT3)

Polyclonal (Thymoglobulin, atgam)

Depleting agents (Thymoglobulin, Alemtuzumab,

OKT3)

Non-depleting agents (Daclizumab, Basiliximab)

Trends in use of induction agents

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.

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.

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

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

Anti cd25 antibodies

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.

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.

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%).

Kdoqi guidelines1.1: 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 lymphocyte- depleting agent, rather than an IL2RA, for KTRs at high immunologic risk. (2B)

• 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.

• 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).

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.

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