1 Transplantation - Immunosuppression A Case-based Approach January 20, 2009 Paul D. Greig, MD, FRCS(C) Professor of Surgery University of Toronto.

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Transplantation - Immunosuppression

A Case-based ApproachJanuary 20, 2009

Paul D. Greig, MD, FRCS(C)Paul D. Greig, MD, FRCS(C)

Professor of SurgeryProfessor of Surgery

University of TorontoUniversity of Toronto

Saint Cosmas & Saint Damian

perform the first transplant

280 CE

Alexis Carrel (1875-1944)

“I have started research into the procedure of vascular

anastomoses in order to be able to transplant certain

organs…” 1901

Sir Peter Medawar (1915-1987)Recognized that lymphocytes were the “immunocompetent cells” that were responsible for rejection – Nobel prize, 1960

Joseph E. Murray, MD

First successful organ transplant: 1954, Brigham Hospital, Boston, Mass.

Kidney transplant between dizygotic twins (recipient

received sub-lethal dose of total body X-radiation)

The Pioneers of Liver Transplantation

Sir Roy Calne Thomas E. Starzl, MD

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Liver Transplant at the University of TorontoLiver Transplant at the University of Toronto1985 - 20081985 - 2008

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Case 1

• 52 y.o. male– Hepatitis C +ve cirrhosis, ascites (paracentesis q

2-3 weeks)– Liver transplant

• conventional vascular reconstruction• conventional biliary reconstruction: CBD-CBD

– ? Initial postoperative immunosuppression

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Question 1

• why is immunosuppression necessary?

• Corollary– what are the immunologic mechanisms of

allograft rejection?• what are the targets of the allo-immune response?• what are the “steps” of this response?

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Question 2a

• what are the immunosuppression options?

• Corollary– what points in the allo-immune response are the targets

of current immunosuppressive drugs?– What are the current (new) immunosuppressive drugs

available?– What is the mechanism of action of each of these

drugs?

Transplantation - Immunosuppression IMMUNOSUPPRESSIVE DRUGS

• Traditional DrugsTraditional Drugs– Steroids– Cyclosporine A– Azathioprine– Anti-lymphocyte

antibodies: • polyclonal or

monoclonal (OKT3)

• Newer DrugsNewer Drugs– Neoral– Tacrolimus– Mycophenolate

Mofetil– Sirolimus– anti- IL2R antibodies

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Question 2b

• what are the toxicities of these immuno-suppression drugs?

• Option– balance the immunosuppressive activity with toxicity

with different combinations– summary of each drug:

Transplantation - Immunosuppression CORTICOSTEROIDS

• Mechanism of action– inhibition of cytokine production by APCs

• Toxicity– infection, poor wound healing,osteoporosis, aseptic necrosis,

hypertension, DM, hyperlipidemia, obesity,cushinoid facies

• Currently– minimize dose, alternate day therapy– early steroid withdrawal

Transplantation - Immunosuppression MICROEMULSION CYCLOSPORINE A

NEORAL• Mechanism of Action

– inhibits calcineurin --> inhibits IL2 production– Microemulsion CsA (NEORAL)

• improved absorption, avoid IV dosing

• Toxicity– Nephotoxicity, hypertension– Neurotoxicity (tremor, headache, direct CNS)– DM, hyperlipidemia, hirsutism, gingival hyperplasia

• Currently– 10 agent

– ? Optimal monitoring using C2 (peak level) not C0 (trough levels)

Transplantation - Immunosuppression TACROLIMUS, formerly FK506 - PROGRAF

• Advantages– lower incidence of acute rejection than CsA?– useful for refractory or chronic rejection– less hyperlipidemia, hirsutism, gingival hypertorphy than CsA

• Toxicity– same as Cyclosporine A, possibly higher incidence– More DM,

• Currently– primary immunotherapy, esp. those at high risk– for steroid resistant or refractory rejection

Transplantation - Immunosuppression AZATHIOPRINE

• Mechanism of action– antimetabolite, inhibits PRPP amidotransterase

• Toxicity– marrow: esp. neutropenia, thrombocytopenia– liver: cholestasis

• Currently– routine “triple therapy”– added to reduce calcineurin inhibitor– added for rejection despite adequate calcineurin inhibitor levels

Transplantation - Immunosuppression MYCOPHENOLATE MOFETIL

CELLCEPT or MYFORTIC

• Advantages– no nephro- or neuro-toxicity– MoA more lymphocyte-specific than azathioprine – reduced acute rejection

• Toxicity– marrow, GI tract

• Currently– primary “triple immunotherapy”– add to CsA or FK monotherapy following rejection or to reduce

dose for CNI toxicity

Transplantation - Immunosuppression Toxicities - in - Common

• Infection– esp. viral and fungal

• Malignancy– all cancers with time

• importance of surveillance

– Lymphoproliferative Disease (LPD)• + Epstein Bar Virus (EBV-LPD)• --> monoclonal LPD --> lymphoma

IMMUNOSUPPRESSIONIMMUNOSUPPRESSIONIndividual ToxicitiesIndividual Toxicities

Obesity HBP Nepro Neuro DM Lipids Marrow GIT Inf’n

Steroids +++ +++ + +++ +++

Calcineurin Inhibitors

Cyclosporin A +++ +++ +++ + ++

Tacrolimus +++ +++ +++ ++ +

TOR Inhibitor

Sirolimus +++ ++

Antimetabolites

Azathioprine +++

Mycophenolate +++ +++

Antilymphocyte Ab

ALG ++

OKT3 ++

IL2R-Ab

Transplantation - Immunosuppression “Standard Combinations”

• Calcineurin-inhibitor based– Corticosteroids

• Solumedrol 500 mg pre-op, then taper form 200 mg/d to 20 mg/d during 1st week

– Cyclosporin A (NEORAL)• CsA 10 - 15 mg/kg/d divided BID, orally

OR

– Tacrolimus (PROGRAF)• FK 1 - 1.5 mg/kg/d divided BID, orally

– Third agent• MMF (Cellcept) 2 gm/d divided BID• Azathioprine 1-2 mg/kg/d

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Question 2c• Do all patients require the same degree and type of

immunosuppression?• Rephrased:

– what are the risk factors for acute rejection?• Who needs more immunosuppression, who needs less?

– What are the risk factors for toxicity?• Any alternates without Nephro/Neuro-toxicity?

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Risk Factors for Acute Rejection

• Increased Risk– ABO incompatibility (preformed anti- A or B antibodies)

– presensitized (+ve crossmatch)• From previous blood transfusions or pregnancy

– high PRA• Variable levels of preformed antibody

– previous immunologic graft loss (chronic rej’n)– underlying autoimmune disease

• PSC, Autoimmune CAH

– younger patients

• Lower risk– Uremia– Malnourished patient– older patient– critically ill

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Risk Factors for Early Toxicity

• Increased Risk– renal failure

• Rx: avoid CsA or FK by using antibody therapy * 5 - 10 days, introduce low dose CN-inhibitor with MMF or Azathioprine

– preop coma, postop depressed LOC• Rx same as above

– CMV -ve recipient of CMV +ve organ• Rx, lower immunosuppression or antiviral prophylaxis

– EBV naïve recipient • surveillance

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• Options for patients at Increased Risk– in general: it is the nephro- or neuro-toxicity– avoid (or minimize calcuneurin (IL2) inhibition

• i.e. avoid cyclosporin or tacrolimus

– use anti-lymphocyte antibodies• for 5 - 10 days • combine with MMF or Aza • introduce low dose CsA or Tac ~ POD 7

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Anti-Lymphocyte Antibodies

• Polyclonal Products: RATS, ATG, ALS– cocktail of anti-bodies to antigens on activated t-cells– Toxicity: 1. Fever 2. Cross-react with platelets (thrombocytopenia)

• Monoclonal Antibody: OKT3– murine antibody to the CD3 receptor– Toxicity: 1. Cytokine storm 2. Anti-murine antibodies

• Anti-IL2R Antibodies – anti-CD25 antibody to the -chain of IL2R– chimerized or humanized – toxicity: fever– ? Efficacy without CNI

IMMUNOSUPPRESSIVES BACKGROUND

What’s The Problem?• Toxicity

– major barrier to effective immunosuppression– variable spectrum of toxicities

• specific to each drug– objective

• juggle the toxicities of the available agents to achieve the lowest doses necessary for each patient

– problem• no objective measure of the net immunosuppressive effect in any one

individual

Transplantation - Immunosuppression Toxicities - in - Common

• Infection– esp. viral and fungal

• Malignancy– all cancers with time

• importance of surveillance

– Lymphoproliferative Disease (LPD)• + Epstein Bar Virus (EBV-LPD)• --> monoclonal LPD --> lymphoma

IMMUNOSUPPRESSIONIMMUNOSUPPRESSIONIndividual ToxicitiesIndividual Toxicities

Obesity HBP DM Nephro Neuro Lipids Marrow GIT Inf’n

Steroids +++ +++ +++ + +++

Calcineurin Inhibitors

Cyclosporin A +++ + +++ +++ ++

Tacrolimus +++ ++ +++ +++ +

TOR Inhibitor

Sirolimus ++ +++ ++

Antimetabolites

Azathioprine +++

Mycophenolate +++ +++

Antilymphocyte Ab

ALG ++

OKT3 ++

IL2R-Ab

Transplantation - Immunosuppression Standard Combinations

• Corticosteroids– Solumedrol 500 mg pre-op, then taper form 200 mg/d to 20 mg/d

during 1st week

• Cyclosporin A (NEORAL)• CsA 10 - 15 mg/kg/d divided BID, orally

OR

• Tacrolimus (PROGRAF)• FK 1 - 1.5 mg/kg/d divided BID, orally

• Third agent• MMF (Cellcept) 2 gm/d divided BID• Azathioprine 1-2 mg/kg/d • Sirolimus (Rapammune)

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Case 1• 52 y.o. male, HCV+ve, Liver transplant

– Steroids: methylprednisilone or prednisone• 500, 100, 80, 60, 40, 20 -->7.5 mg/d by POM4

– Calcineurin (IL2) inhibition• Tacrolimus 5 mg bid, adjust to 10 - 15 ng/ml

• POD 20: – Bili: 13 --> 28, ALP 96 --> 170– AST 35 --> 125, ALT 40 --> 140

• DDx?

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Case 1

• DDx:– Hepatic artery thrombosis

• U/S liver & Doppler, CT & arterial phase, Angiogram

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Case 1

• DDx:– Hepatic artery thrombosisHepatic artery thrombosis

• U/S liver & Doppler, CT & arterial phase, AngiogramU/S liver & Doppler, CT & arterial phase, Angiogram

– Biliary Stenosis, Leak• U/S, MRCP, ERCP

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Case 1

• DDx:– Hepatic artery thrombosisHepatic artery thrombosis

• U/S liver & Doppler, CT & arterial phase, AngiogramU/S liver & Doppler, CT & arterial phase, Angiogram

– Biliary Stenosis, LeakBiliary Stenosis, Leak• U/S, ERCPU/S, ERCP

– Infection• CMV --> CMV antigenemia, Liver Bx• recurrent HCV --> Biopsy

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Case 1• DDx:

– Hepatic artery thrombosisHepatic artery thrombosis• U/S liver & Doppler, CT & arterial phase, AngiogramU/S liver & Doppler, CT & arterial phase, Angiogram

– Biliary Stenosis, LeakBiliary Stenosis, Leak• U/S, ERCPU/S, ERCP

– InfectionInfection• CMV --> CMV antigenemia, Liver BxCMV --> CMV antigenemia, Liver Bx• recurrent HCV --> Biopsyrecurrent HCV --> Biopsy

– Acute Rejection• Biopsy

•Rejection Activity Index:• infiltrate, phlebitis, ductitis

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Risk Factors for Acute Rejection

• Increased Risk– ABO incompatibility (preformed anti- A or B antibodies)

– presensitized (+ve crossmatch) - ** not with liver– high PRA - ** not with liver– previous immunologic graft loss (chronic rej’n)– underlying autoimmune disease

• PSC, Autoimmune CAH

– Younger, well nourished patients

• Lower risk– malnourished, older patient– critically ill

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HLA Matching Effect (1995-2001)

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• Increased Risk– renal failure

• Rx: avoid CsA or FK by using antibody therapy * 5 - 10 days, • introduce low dose CN-inhibitor with MMF or Azathioprine

– preop coma, postop depressed LOC• Rx same as above

– CMV -ve recipient of CMV +ve organ• Rx, lower immunosuppression plus antiviral prophylaxis

– EBV naïve recipient • surveillance

48



• Options for patients at Increased Risk– in general: it is the nephro- or neuro-toxicity– avoid (or minimize calcineurin (IL2) inhibition

• i.e. avoid cyclosporin or tacrolimus

– use anti-lymphocyte antibodies• for 5 - 10 days • combine with MMF or Aza • introduce low dose CsA or Tac ~ POD 7

49


Case 1

• 52 y.o. male, HCV+ve, Liver transplant

• POD 20: – Bili: 13 --> 28, ALP 96 --> 170– AST 35 --> 125, ALT 40 --> 140

• Bx = Acute Rejection – Grade 5-6 / 9

• Treatment?

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Transplantation - ImmunosuppressionTreatment of Acute Rejection

1 Treat Rejection– Increase CNI

• If RAI < 4

– Corticosteroids • methylprednisilone 500 mg/d * 3

2 Prevent Recurrence– depends on reason for AcR– if Tac or CsA levels sub-therapeutic

• increase Tac or CsA

– if Tac or CsA levels adequate• add a third agent: MMF or Rapamycin

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• Outcome– normalization of liver biochemistry– + liver Bx confirmation

• For high RAI

• Steroid - Resistant Rejection– antilymphocyte anti-body therapy:– Polyclonal anti-lymphocyte antibodies

• RATS, ATG, ALS

– Monoclonal ALG• OKT3

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• Sequelae of an episode of AcR– treatment increases risks of all immunotherapy related complications

• viral infections– CMV, EBV

• DM, psychosis,

– Renal Tx• reduced graft 1/2 life• Also Lung & Heart• “Cumulative graft injury”

– Liver• Increase recurrence of Hepatitis C• fewer long term sequelae• ? Induce tolerance

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Case 1

• 52 y.o. male, HCV+ve, Liver transplant

• POD 20: – Acute Rejection , Grade 5-6 / 9– Treatment: corticosteroid (2 cycles)

• POD 90:– fever (39O), generally unwell– WBC = 2.8, Liver enzymes 25%– PE: unremarkable

• DDX?

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DDx:

1 Bacterial Infection– CXR, Urine C&S, Blood culture– U/S or CT scan abdomen– Treat on speculation?

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DDx:2 Viral Infection

a ) Cytomegalovirus (CMV)• risk in CMV +ve recipients = 25%

• risk in -ve recipients of +ve organ = 50 - 100% (should receive prophylaxis)

• CMV syndrome (antigenemia)

• CMV disease (Bx confirmation)– liver (Bx), lung (BAL), brain (CT or MRI)

– Treatment• reduce immunosuppression

• Gancyclovir (IV --> PO)

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DDx:2 Viral Infection

b ) Epstein Barr Virus (EBV)• presents as lymphoproliferative disease (LPD) • lympadenopathy • CT: head, chest, abdomen• Biopsy• graded: LPD --> monoconal B-cell lymphoma

– Treatment• reduce (stop) immunosuppression• antiviral therapy (Gancyclovir)• chemotherapy for lymphoma

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DDx:

3 Fungal Infection– candida, aspergillosis, cryptococcus,

mucormycosis– image and culture

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DDx:

4 Other Infection– TB– cat-scratch fever– Herpes simplex

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Transplantation - ImmunosuppressionChronic Rejection

• Advanced graft injury• Secondary to repeated episodes of acute rejection and/or persistent low

grade immunologic injury• Additive to previous injury

• In donor• Preservation/ischemia/reperfusion

• Liver: duct loss: “ductopenic rejection”• Target = duct or small arterioles

• Lung: bronchiolar loss: “Brochiolitis obliterans”• Cumulative injury

• Heart: accelerated atherosclerotic change: “graft vasculopathy”• Kidney: “chronic graft nephropathy”• Probably multifactorial

• Including donor injury, preservation injury, postop injury…

Transplantation - Immunosuppression TOWARDS TOLERANCE

• Partial Tolerance– “adaptation” allows reduction in total immunosuppression during

first 3 months– = microchimerism?

• Tolerizing Strategies– objective

• drug-free, donor-specific hyporesponsiveness

– needs:• stem or dendritic cell• induction therapy with tolerizing antibodies• continuous antigen exposure

Transplantation - Immunosuppression FUTURE

• Multi-drug Regimens– variety of “protocol” therapies– increased patient-specific individualization

• New Drugs– less toxicity

• or non-overlapping toxicities

– increased efficacy• reduced chronic rejection

– more “patient-friendly”• for improved long-term compliance

1 Transplantation - Immunosuppression A Case-based Approach January 20, 2009 Paul D. Greig, MD, FRCS(C) Professor of Surgery University of Toronto.

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