Induction agents in renal transplantation

DM SEMINAR

INDUCTION AGENTS IN RENAL

TRANSPLANTATIONDr. Vishal Golay

24/06/2011

THREE SIGNAL MODEL

TOPIC OVERVIEW Need for induction agents.

Various agents used in transplantation.

Trials of various agents used for induction.

Newer agents and future therapies.

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

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

Reduce acute rejection

Reduction in other components of

immunosuppressive regimen

? Improvement in long term graft

function

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.

INDUCTION AGENTS Monoclonal (Daclizumab, Basiliximab,

Alemtuzumab, OKT3)

Polyclonal (Thymoglobulin, atgam)

Depleting agents (Thymoglobulin, Alemtuzumab,

OKT3)

Non-depleting agents (Daclizumab, Basiliximab)

INDUCTION AGENTS Monoclonal agents are produced using murine

hybridoma 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.

MONOCLONAL ANTIBODIES-NOMENCLATURE

Random Target class

Prefix - Substem A - Substem B - Suffix

Species on which mab

Ig sequence is based

DAC-LI-ZU-MAB

immunomodulatory humanized

PREFIX SUBSTEM A SUBSTEM B SUFFIX

immunomodulatory chimeric

BASI-LI-XI-MAB

TRENDS IN USE OF INDUCTION AGENTS

DEPLETING AGENTSEg. 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

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.

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.

Evidence on ATG use as induction agentNo. of patients

Reference Trial Maintenance Rx

Outcome P value

1. Brennan et al 72 Transplantation. 1999; 67:1011–8

Thymoglobulin vs Atgam

Cycl, MMF, steroids

Acute rejection:-4% thymoglob, --25% atgam

0.014

2.Hardinger et al

“ Transplantation. 2008; 86:947–52.

10 yr follow up of (1)

“ Event free survial:48% with thymoglob vs 29% with atgamAcute rejection:42% with thymoglob vs11% with atgam

0.011

0.004

3. Agha et al 40+48 Transplantation 2002; 73: 473-5

Short course(3 days) ATG vs 7 day ATG Rx

Acute rejection:5% vs 4%Graft Survivial:95% vs 98%

Not significant

ANTI CD25 ANTIBODIES

ANTI CD25 ANTIBODIES DOSINGDaclizumab: 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

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.

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

Evidence of anti CD25 antibodies as induction agents

No of patients

Reference Trial Maintenance Rx

Outcome P value

1. Nashan et al (CHIB 201 International Study Group)

380 Lancet 350:1193-1198, 1997

Basiliximab vs placebo

Ciclosporin, steroids

Acute rejection:29.8% vs44%

0.012

2. Ponticelli et al 340 Transplantation72:1261-1267, 2001

“ Cyclosporine, azathioprine,steroids

Acute Rejection:20.8% vs34.9%

0.05

3. Nashan et al 275 Transplantation 67:110-115,1999

Daclizumab vs placebo

Cyclosporine, stroids

Acute Rejection:28% vs 47%

0.001

4. Vincenti et al 260 N Engl J Med 338:161-165, 1998

“ Cyclosporine, azathioprine,steroid

Acute Rejection:22 % vs 35%

0.03

Evidence of anti CD25 antibodies as induction agents

No of patients

Reference Trial Maintenance Rx

Outcome P value

5. Lebranchu et al

100 Am J Transplant 2:48-56, 2002

Basiliximab vs Thymoglobulin

Cyclo, MMF, Steroids

Acute rejection:8% in each group

Not significant

6. Mourad et al

105 Transplantation. 2004; 78:584–90

“ “ Similar results in both groups

Not significant

7. Brennan et al

141 vs137(patients having at least 1 high risk factor)

N Engl J Med. 2006; 355:1967–77.

ATG vs Basiliximab

“ Composite end points:Similar in both.Acute Rejection:15.6% vs. 25.5%

0.34

0.02

Evidence of anti CD25 antibodies as induction agents

No of patients

Reference Trial Maintenance Rx

Outcome P value

8. Webster et al

4670 (30 trials)

Transplantation. 77(2):166-176

MetanalysisIL2Ra vs placebo

IL2Ra reduces acute rejection, graft loss and is cost effective

9. Gralla et al 28,686Retrospective study)

Transplantation. 27: 639-644

IL2Ra vs placebo

Tac/MMF/Steroids

Acute Rejection:11.6 %vs 13%1 & 3 yr graft & patient survival:Similar in 2 groups

0.001

10. Grego et al

127 Transplant Proc. 2007 Dec;39(10):3093-7

Basiliximab vs Daclizumab

CsA, MMF, Steroids

BPAR, patient & graft survival

Not significant

11. Kandus et al

200 Transplantation. 2010 Apr 27;89(8):1022-7

Basiliximab vs Daclizumab

CsA, MMF, Steroids

“ “

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.

ALEMTUZUMABDosing: 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%).

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.

Evidence of Alemtuzumab as induction agent

No of patients Reference Trial Maintenance Rx

Outcome P value

1. Ciancio et al

90 (30 each) Transplantation80:457-465, 2005

Thymoglobulin valemtuzumab vdaclizumab

Tac, MMF ±steroids

Acute Rejection:16.6 % in each group

Not significant

2. Hanaway et alINTAC Study

1.139 high risk pts randomized to Campath vs ATG2.335 low risk pts randomized to Campath vs Basiliximab

N Engl J Med 2011;364:1909-19.

“ according to the randomization

Tac+ MMF with early steroid taper in 5 days

3 yrs BPAR:(Campath vs Basiliximab)10% vs. 22%(Campath vs ATG)18% vs. 15%Adverse events; similar in all groups

0.003

0.63

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.

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.

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.

RITUXUMAB-MECHANISM OF ACTION

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 (rituxumab vs placebo), there was no significant difference in the rejection rates.

Thus, its use as an induction agent warrants further investigation.

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.

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)

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

THANK YOU