Transplantation – Immunosuppression January 25, 2011 Markus Selzner, MD Multi Organ Transplant Program University of Toronto.
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Transplantation – Immunosuppression January 25, 2011 Markus Selzner, MD Multi Organ Transplant Program University 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 Liver Transplantation The only chance of cure for patients with liver cirrhosis or advanced liver cancer Cirrhosis Normal Liver HCC Results Liver Transplantation Starzl TE et al. N Engl J Med 1989 Liver Transplantation in Toronto 1985 – 2009 180 Adults: 1905 Peds: 346 160 140 19 26 15 120 9 80 10 10 13 12 Pediatric Adult 15 11 6 145 15 15 14 20 21 20 60 116 16 40 96 15 10 59 20 30 34 65 59 67 64 73 77 74 83 86 73 85 138 123 123 109 81 41 Year 20 09 20 07 20 05 20 03 20 01 19 99 19 97 19 95 19 93 19 91 19 89 3 4 19 87 2 19 85 0 19 12 100 No. 20 UHN 2000-2009 91.5% 80% DD LD 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 Transplantation - Immunosuppression Question 1 • why is immunosuppression necessary? – what are the immunologic mechanisms of allograft rejection? – what are the targets of the allo-immune response? – what are the “steps” of this response? Transplantation - Immunosuppression Question 2a • what are the immunosuppression options? – 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? DEVELOPMENTS IN IMMUNOSUPPRESSION Anti-thymocyte globulin OKT3 Biologic agents LEA29Y Anti-lymphocyte Antisera 1950 1960 1970 Campath 1H Anti-IL2 Ra 1990 1980 2000 TAC AZA, Steroids (Prograf) CsA (Sandimmune) Chemical agents RAPA SDZ FTY720 MMF RAD FK778 CsA-ME (Neoral) 2010 Transplantation - Immunosuppression Question 2b • what are the toxicities of these immunosuppression drugs? • Option – balance the immunosuppressive activity with toxicity with different combinations – summary of each drug: 23 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 – Calcineurin inhibition: standard – Optimal monitoring using C2 (peak level) not C0 (trough levels) Transplantation - Immunosuppression TACROLIMUS, formerly FK506 - PROGRAF • Advantages – – – – Calcineurin inhibition, similar to CsA 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 lymphocyte proliferation (purin synthesis) • Toxicity – marrow: esp. neutropenia, thrombocytopenia – liver: cholestasis • Currently – rarely used – added to reduce calcineurin inhibitor – added for rejection despite adequate calcineurin inhibitor levels Transplantation - Immunosuppression MYCOPHENOLATE MOFETIL CELLCEPT or MYFORTIC • Advantages – – – – Inhibits lymphocyte proliferation More lymphocyte-specific than azathioprine no nephro- or neuro-toxicity 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 Drugs with similar pharmacology • IL-2 receptor ‘mabs’ – Basiliximab – Daclizumab • Anti-metabolites – Azathioprine – Mycophenolates • Calcineurin inhibitors – Ciclosporin A – Tacrolimus • m-TOR inhibitors – Sirolimus – Everolimus (not UK) Transplant Early Acute Rejection Late Rejection Chronic Rejection Maintenance Immunosuppression Induction Therapy Early Intense Immunosuppression Lower Dose Immunosuppression Transplantation - Immunosuppression Toxicities - in - Common • Infection – esp. viral and fungal • Malignancy – all cancers with time (skin) • importance of surveillance – Lymphoproliferative Disease (LPD) • + Epstein Bar Virus (EBV-LPD) • --> monoclonal LPD --> lymphoma IMMUNOSUPPRESSION Individual Toxicities Obes. HTN Nephro Neuro DM Steroids +++ +++ Lipids Marrow GIT + +++ +++ Inf. Calcineurin Inhibitors Cyclosporin A +++ +++ +++ + ++ Tacrolimus +++ +++ +++ ++ + TOR Inhibitor Sirolimus +++ ++ Antimetabolites Azathioprine Mycophenolate +++ +++ +++ Antilymphocyte Ab ATG ++ ++ OKT3 ++ IL2R-Ab + Maintenance Immunosuppression First Year after Transplantation Antibody Induction Agent Usage 40 Atgam/NRATG/NRATS Thymoglobulin 35 Simulect 30 OKT3 % Transplants Zenapax 25 Campath 20 15 10 5 0 1995 1996 1997 1998 1999 2000 Year 2001 2002 2003 2004 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 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? 37 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 rejection) – underlying autoimmune disease • PSC, Autoimmune Hepatitis – younger patients • Lower risk – – – – Uremia Malnourished patient older patient critically ill 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 39 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 Transplantation - Immunosuppression Anti-Lymphocyte Antibodies • Polyclonal Products: , ATG, RATS, 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 a-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 Case 1 • 52 y.o. male, HCV+ve, Liver transplant – Steroids: methylprednisilone or prednisone • 500, 100, 80, 60, 40, 20 – Calcineurin inhibition • Tacrolimus 5 mg bid, adjust to 10 - 15 ng/ml • POD 20: – Bili: 13 --> 28, – AST 35 --> 125, • DDx? ALP 96 --> 170 ALT 40 --> 140 43 Transplantation - Immunosuppression Case 1 • DDx: – Hepatic artery thrombosis • U/S liver & Doppler, CT & arterial phase, Angiogram 44 Transplantation - Immunosuppression Case 1 • DDx: – Hepatic artery thrombosis • U/S liver & Doppler, CT & arterial phase, Angiogram – Biliary Stenosis, Leak • U/S, MRCP, ERCP 45 Transplantation - Immunosuppression Case 1 • DDx: – Hepatic artery thrombosis • U/S liver & Doppler, CT & arterial phase, Angiogram – Biliary Stenosis, Leak • U/S, ERCP – Infection • CMV --> CMV antigenemia, Liver Bx • recurrent HCV --> Biopsy 46 Transplantation - Immunosuppression Case 1 • DDx: – Hepatic artery thrombosis • U/S liver & Doppler, CT & arterial phase, Angiogram – Biliary Stenosis, Leak • U/S, ERCP – Infection • CMV --> CMV antigenemia, Liver Bx • recurrent HCV --> Biopsy – Acute Rejection • Biopsy 47 •Rejection Activity Index: • infiltrate, phlebitis, ductitis 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 rejection) underlying autoimmune disease • PSC, Autoimmune CAH – Younger, well nourished patients • Lower risk – malnourished, older patient – critically ill 49 Percent Graft Survival (log) HLA Matching Effect Kidney (1995-2001) 100 63 58 52 47 50 10 HLA mm n 0 8,196 1-2 7,835 3-4 23,776 5-6 13,173 0 1 2 16% t1/2 16.0 13.2 11.1 9.8 3 4 5 6 7 8 Years Posttransplant 9 10 Cecka, Clinical Transplants 2002 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 51 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 52 Transplantation - Immunosuppression Case 1 • 52 y.o. male, HCV+ve, Liver transplant • POD 20: – Bili: 13 --> 28, – AST 35 --> 125, ALP 96 --> 170 ALT 40 --> 140 • Bx = Acute Rejection – Grade 5-6 / 9 • Treatment? 53 Transplantation - Immunosuppression Treatment of Acute Rejection 1 Treat Rejection – Increase CNI • If mild (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 Transplantation - Immunosuppression Treatment 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 Transplantation - Immunosuppression Treatment 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 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 d 25% – PE: unremarkable • DDX? 58 Transplantation - Immunosuppression DDx: 1 Bacterial Infection – CXR, Urine C&S, Blood culture – U/S or CT scan abdomen – Treat on speculation? 59 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) 60 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 61 Transplantation - Immunosuppression DDx: 3 Fungal Infection – candida, aspergillosis, cryptococcus, mucormycosis – image and culture 62 Transplantation - Immunosuppression DDx: 4 Other Infection – TB – cat-scratch fever – Herpes simplex 63 Transplantation - Immunosuppression Chronic 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… 64 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 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) 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 IMMUNOSUPPRESSION Individual Toxicities Obesity HBP DM +++ +++ +++ Cyclosporin A +++ + Tacrolimus +++ ++ Steroids Nephro Neuro Lipids + +++ +++ +++ ++ +++ +++ + Marrow GIT Inf’n Calcineurin Inhibitors TOR Inhibitor Sirolimus ++ +++ ++ Antimetabolites Azathioprine Mycophenolate +++ +++ +++ Antilymphocyte Ab ALG ++ OKT3 ++ IL2R-Ab Transplantation - Immunosuppression IMMUNOSUPPRESSIVE DRUGS • Traditional Drugs – Steroids – Cyclosporine A – Azathioprine – Anti-lymphocyte antibodies: • polyclonal or monoclonal (OKT3) • Newer Drugs – Neoral – Tacrolimus – Mycophenolate Mofetil – Sirolimus – anti- IL2R antibodies Liver Transplant at the University of Toronto 1985 - 2009 180 160 140 120 100 Children Adult 80 60 40 20 Year 20 07 20 05 20 03 20 01 19 99 19 97 19 95 19 93 19 91 19 89 19 87 19 85 0