Transplantation Immunosuppression January 25, 2011

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Transplantation Immunosuppression January 25, 2011

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1. Transplantation ? Immunosuppression January 25, 2011 Markus Selzner, MD Multi Organ Transplant Program University of Toronto

2. Saint Cosmas & Saint Damian perform the first transplant 280 CE

3. Alexis Carrel (1875-1944) ?I have started research into the procedure of vascular anastomoses in order to be able to transplant certain organs?? 1901

4. 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)

5. The Pioneers of Liver Transplantation Sir Roy Calne Thomas E. Starzl

6. Liver Transplantation The only chance of cure for patients with liver cirrhosis or advanced liver cancer

9. Results Liver Transplantation

10.

13. 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

14. 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?

20. 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?

23. 23 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:

24. 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

25. 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)

26. 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

27. 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

28. 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

29. Transplantation - Immunosuppression RAPAMYCIN SIROLIMUS or EVEROLIMUS Advantages No neuro-toxicity Less nephro-toxicity synergistic with CsA and with FK (despite competition for FKBP) ? effective without calcineurin inhibitor Toxicity Hyperlipidemia Impaired wound healing Currently ?BLACK BOX WARNING? regarding HAT following liver transplantation

30. Drugs with similar pharmacology IL-2 receptor ?mabs? Basiliximab Daclizumab Calcineurin inhibitors Ciclosporin A Tacrolimus Anti-metabolites Azathioprine Mycophenolates m-TOR inhibitors Sirolimus Everolimus (not UK)

32. 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

33. IMMUNOSUPPRESSION Individual Toxicities

34. Maintenance Immunosuppression First Year after Transplantation

36. 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

37. 37 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?

38. 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

39. 39 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 na?ve recipient surveillance

40. 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

41. 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

42. 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

43. 43 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, ALP 96 --> 170 AST 35 --> 125, ALT 40 --> 140 DDx?

44. 44 Transplantation - Immunosuppression Case 1 DDx: Hepatic artery thrombosis U/S liver & Doppler, CT & arterial phase, Angiogram

45. 45 Transplantation - Immunosuppression Case 1 DDx: Hepatic artery thrombosis U/S liver & Doppler, CT & arterial phase, Angiogram Biliary Stenosis, Leak U/S, MRCP, ERCP

46. 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

47. 47 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

49. 49 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

51. 51 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 na?ve recipient surveillance

52. 52 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

53. 53 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?

54. Transplantation - Immunosuppression Treatment of Acute Rejection Treat Rejection Increase CNI If mild (RAI < 4) Corticosteroids methylprednisilone 500 mg/d * 3 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

56. 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

57. 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

58. 58 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?

59. 59 Transplantation - Immunosuppression DDx: Bacterial Infection CXR, Urine C&S, Blood culture U/S or CT scan abdomen Treat on speculation?

60. 60 Transplantation - Immunosuppression DDx: Viral Infection ) 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)

61. 61 Transplantation - Immunosuppression DDx: Viral Infection ) 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

62. 62 Transplantation - Immunosuppression DDx: Fungal Infection candida, aspergillosis, cryptococcus, mucormycosis image and culture

63. 63 Transplantation - Immunosuppression DDx: Other Infection TB cat-scratch fever Herpes simplex

64. 64 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?

65. 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

67. 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

69. 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)

70. 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

71. IMMUNOSUPPRESSION Individual Toxicities

72. 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


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