Seminar on Induction agents in renal transplantation. Author: Vishal Golay, DM trainee in Nephrology, IPGMER

1. DM SEMINARINDUCTION AGENTS in renal transplantation Dr. Vishal Golay 24/06/2011

3. Three signal model

4. Topic overview Need for induction agents. Various agents used in transplantation. Trials of various agents used for induction. Newer agents and future therapies.

5. Background The risk of acute rejection is maximum in the initial weeks to months. Herein lies the need for strong initial immunosuppressant to deplete or modulate T-cell responses at the time of antigen presentation. Induction therapy can mean any agent used perioperatively but it is now synonymous with the use of antibodies against various components of the immune system

6. 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

8. WHY induction therapy ? Many trials showing decreased rejection rates and 1 yr post transplant survival. Vital role in patients at high risk for poor short-term outcomes. Prevention of CNI related damage by decreasing the dose or delaying the initiation of CNIs. These benefits of induction agents come with the risk of increased infections and malignancy.

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

10. Induction agents Monoclonal agents are produced using murinehybridoma techniques and sometimes are genetically engineered to create chimeric or humanized modifications. Polyclonal agents generally are produced by harvesting serum from animals previously inoculated with human thymocytes or lymphocytes.

11. Monoclonal antibodies-nomenclature Random Target class Prefix- Substem A - Substem B - Suffix Species on which mab Ig sequence is based

12. DAC-LI-ZU-MAB immunomodulatoryhumanized PREFIX SUBSTEM A SUBSTEM B SUFFIX immunomodulatorychimeric BASI-LI-XI-MAB

13. Trends in use of induction agents

14. 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.

15. 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.

16. 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

17. 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

19. Mechanism of action of ATG Rapid T-cell– depleting agent in both the blood and peripheral lymphoid tissues. The major pathways for T-cell depletion are complement-dependent cell lysis in the blood compartment and apoptotic cell death in the lymphoid tissues. Also modulates cell surface molecules that regulate T-cell activation as well as adhesion molecules and chemokine receptors involved in leukocyte-endothelial interactions. Repopulation leads to expansion of specific T-cell subsets that have been shown to exhibit regulatory-suppressor functions, such as CD8+CD57+CD28- T cells.

20. DOSING of ATG The “optimal” dose - 6 mg/kg, Typical regimen of Thymoglobulin for induction consists of 1.5 mg/kg for 3 to 5 days. However, dosing protocols have a wide range from 1 to 6 mg/kg/dose for a duration of 1 to 10 days. Infusion in 500ml of dextrose or NS over 4-8 hours into a central vein/AVF with premedications is preferred. Side Effects: allergic reactions, cytopenias, infections (CMV), lymphomas.

21. Evidence on ATG use as induction agent

22. Anti cd25 antibodies

23. Anti cd25 antibodies dosing Daclizumab: 1 mg/kg within 24 hours of transplantation plus an additional four doses of 1 mg/kg at a schedule of every two weeks after surgery. Causes receptor saturation that lasts up to 120 days reduced dosing schedule with an initial dose of 1 mg/kg on the day of transplant and POD 4 is equally efficacious and safe compared with the 5-dose regimen. Basiliximab: 20 mg IV given two hours prior to the transplant, followed by a second 20 mg dose on POD 4. causes a complete saturation of the CD25 receptor for 5-8 weeks

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

25. Withdrawal of zenapax Feb 1999-introduced in the EU 22 April 2008- Roche notified the EU of its decision to voluntarily withdraw the marketing authorization for Zenapax for commercial reasons. This decision was not supposedly to any safety concerns with Zenapax. 1 January 2009- officially withdrawn from the EU

26. Evidence of anti CD25 antibodies as induction agents

27. Evidence of anti CD25 antibodies as induction agents

28. Evidence of anti CD25 antibodies as induction agents

29. 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. When the alemtuzumab antibody binds to CD52, it is thought to trigger an antibody-dependent lysis of the cell. 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.

30. ALEMTUZUMAB Dosing: 20-30 mg on the day of transplantation. A second dose on POD 1 or 4 can also be given. 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%).

31. Renewed interest in alemtuzumab “prope tolerance,” a state in which maintenance immunosuppression may be markedly diminished owing to a nearly tolerant state. Lancet 1998;351:1701-2 INTAC Study findings show favorable results with Alemtuzumab specially in low risk patients. However the long term acute rejection rates are higher.

32. Evidence of Alemtuzumab as induction agent

33. MUROMONAB- CD3(OKT3) OKT3 is a murine monoclonal antibody directed against the CD3 receptor. When OKT3 is bound to CD3, the TCR undergoes endocytosis resulting in an inert T-cell. T cells are then removed via opsonization and ultimately, phagocytosis. A substantial T-cell loss could occur within the first few hours after an initial dose. As the T-cell counts begin to fall, several T-cell-derived cytokines (eg,TNF, IL-2, and IFN-γ) are released into the circulation.

34. MUROMONAB- CD3(OKT3) Dosage: 5mg iv bolus, daily for 10 days Side Effects: “Cytokine release syndrome”, typically 45 minutes after the injection. Non-cardiogenic pulmonary edema Neurologic complications (mild headache, aseptic meningitis to severe encephalopathy) Infections and lymphoma Develpoment of neutralizing antibodies (anti-OKT3 response) seen in 50% of treatments.

35. Rituxumab Most of the induction therapeutics focused on role of T-cell–mediated processes. However, there is increasing evidence that B cells may have a role by their ability to act as antigen-presenting cells and T-cell activators Because all mature B-cells express CD20, one such potential therapy would be to use the chimeric monoclonal anti-CD20 antibody rituximab as an induction therapy in renal transplant patients.

36. Rituxumab-mechanism of action

37. Rituxumab Dosage is 375mg/m2 The possibility of use of Rituxumab was postulated by Genberg et al after they found that patients with ABO incompatibilty did better than those with compatibility with the difference in Rx being the use of Rituxumab. However, when they performed a RCT with 140 patients (rituxumabvs placebo), there was no significant difference in the rejection rates. Thus, its use as an induction agent warrants further investigation.

38. Immune tolerance-new strategies Use of hematopoietic cells (donor). Chimerism (macrochimerism and mixed chimerism). Total Lymphoid Irradiation. Lymphocyte Depletion and prope tolerance. Co-stimulation Blockade.

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

40. TAKE HOME message Induction therapy in renal transplantation improves short-term outcomes in terms of improvement in acute cellular rejection after transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. There is no standard immunosuppression regimen that is considered the most effective; therefore, the agent of choice must be determined by individual clinicians and institutions. The possible benefits of Alemtuzumab needs to be verified with further trials

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