1 transplantation - immunosuppression a case-based approach january 20, 2009 paul d. greig, md,...
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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
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)
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20
40
60
80
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ChildrenAdult
Liver Transplant at the University of TorontoLiver Transplant at the University of Toronto1985 - 20081985 - 2008
Year
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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
Risk Factors for Early Toxicity
• 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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
Case 1
• DDx:– Hepatic artery thrombosis
• U/S liver & Doppler, CT & arterial phase, Angiogram
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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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
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Transplantation - Immunosuppression
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
10
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Cecka, Clinical Transplants 2002 (p.10)
HLA Matching Effect (1995-2001)
50 16%
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Transplantation - Immunosuppression
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 plus antiviral prophylaxis
– EBV naïve recipient • surveillance
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Transplantation - Immunosuppression
Risk Factors for Early Toxicity
• 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
Transplantation - Immunosuppression
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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Transplantation - ImmunosuppressionTreatment of Acute Rejection
• 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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Transplantation - ImmunosuppressionTreatment of Acute Rejection
• 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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
DDx:
1 Bacterial Infection– CXR, Urine C&S, Blood culture– U/S or CT scan abdomen– Treat on speculation?
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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
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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Transplantation - Immunosuppression
DDx:
3 Fungal Infection– candida, aspergillosis, cryptococcus,
mucormycosis– image and culture
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Transplantation - Immunosuppression
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