André Castro Lyra Prof. Adjunto Doutor do Departamento de Medicina da Universidade Federal da Bahia Médico - Pesquisador do Hospital São Rafael

Transcrição

1 XVI Workshop Internacional de Hepatites Virais de Pernambuco V Simpósio de Transplante Hepático e Hipertensão Porta Brasil/ Inglaterra 03/05/12 a 05/05/12 André Castro Lyra Prof. Adjunto Doutor do Departamento de Medicina da Universidade Federal da Bahia Médico - Pesquisador do Hospital São Rafael

2 Rejeição : perda de enxerto e morte Risco de rejeição x toxicidade das drogas Imunobiologia da rejeição aguda 1. Reconhecimento de antígenos 2. Ativação de linfócitos 3. Expansão clonal 4. Inflamação

3 lymphocyte activation T cell receptor (TCR; CD3 complex) signal 1 Dendritic cells costimulation signal 2 activate Signal transduction pathways the calcium/ calcineurin RAS mitogenactivated protein (MAP) kinase Nuclear factor kappa B (NF-jB) activate expression of interleukin-2 (IL-2) and other cytokines activate

4 signal 3 or the trigger for cell proliferation. Production of effector T and B cells. hepatic allograft infiltration and an inflammatory response

5 Steroids Signal 3 Signal 2 Signal 1 Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

6 The graft is infiltrated by: effector T cells activated macrophages secretory B cells plasma cells Secretion of: Tumor necrosis factor a Tumor necrosis factor b Cytotoxins perforin and granzyme F Expression of Fas ligand

7 Pathology - invasion of the liver by: Mononuclear cells, which target: Small arteries Veins Bile duct epithelium

8 Induction Maintenance Treatment of acute cellular rejection Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

9 Induction Initial immunosuppressive regimen - First 30 days after transplantation Alloreactivity is at its peak Induction regimen varies Triple-drug therapy (most common) CNI Corticosteroids Mycophenolic acid (MPA)].

10 Maintenance After 30 days post-transplant and used indefinitely thereafter. Attempt to reduce the number and doses of agents. After the first year monotherapy with just a CNI.

11 Treatment of acute cellular rejection High-dose, intravenous-bolus corticosteroid therapy In steroid-resistant rejection anti-lymphocyte antibody Increase CNI and antimetabolite before steroids

12 Pharmacological Immunosuppressive Agents Biological Immunosuppressive Agents

13 Corticosteroids CNIs CSA TAC Azathioprine MPA CellCept Myfortic Rapamycin (mtor inhibitors) Sirolimus Everolimus

14 T cell depleting agents Anti-CD3 (monoclonal): OKT3 ATG: horse and rabbit ATG and ALG Anti-CD52 (monoclonal): Campath 1H (alemtuzumab) Non T cell depleting agents Anti IL-2 receptors Basiliximab Daclilumumab Belatacept Daclizumab

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16 1ª linha na imunossupressão Inibe fase de reconhecimento de antígenos Não existem protocolos padrões Desmame entre 3 e 6 meses

17 Steroids Signal 3 Signal 2 Signal 1 Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

18 Efeitos colaterais: metabólicos HCV x corticóide

19 Meta-analysis of 2590 patients enrolled into 21 randomized controlled trials (RCTs) steroid-free cohorts appeared to benefit: de novo diabetes mellitus development Cytomegalovirus (CMV) infection) severe acute rejection and overall acute rejection

20 Meta-analysis of 2590 patients enrolled into 21 randomized controlled trials (RCTs) steroid-free cohorts appeared to benefit: de novo diabetes mellitus development Cytomegalovirus (CMV) infection) severe acute rejection and overall acute rejection transplanted HCV patients significant advantage of steroid-free protocols: HCV recurrence Acute graft hepatitis Treatment failure

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22 (Arm 1; n 80) Tacrolimus and corticosteroids (Arm 2; n 79) Tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 3; n 153). Daclizumab induction, tacrolimus, and MMF

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30 Ciclosporina Peptídeo derivado do fungo Cylindrocarpon lucidum Inibe a ativação dos linfócitos T Liga-se dentro da célula à ciclofilina ativação da calcineurina >> IL-2 resposta dos linfócitos T à antígenos

31 Ciclosporina Toxicidade renal ; neurológica HAS Hipercalemia ; hipomagnesemia Hiperplasia gengival; hirsutismo ; dislipidemia

32 Tacrolimus Macrolídeo derivado de Streptomyces tsukubaensis Inibe produção de IL-2 e interferon 100 vezes mais potente do que ciclosporina Metabolização hepática via CYP 3A4

33 Tacrolimus Nefrotoxicidade Hipercalemia ; hipomagnesemia Neurotoxicidade Diabetes

34 Steroids Signal 3 Signal 2 Signal 1 CSA,TAC Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

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41 retrospectively analyzed data from the UNOS on 8809 chronic HCV liver transplant recipients

42 Hazard CSA-ME treated patients are at increased risk of patient death graft failure biopsy-confirmed AR CsA Tacrolimus

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45 Steroids Signal 3 Signal 2 Signal 1 MPA, MMF CSA,TAC Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

46 Inibidores das purinas MMF Micofenolato mofetil ( Cellcept ) Micofenolato sódico ( Myfortic ) Objetivo: dose de CNI e de corticóide Efeitos colaterais: - Mielotoxicidade - Sintomas GI

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48 Standard-Dose Tacrolimus Reduced-Dose Tacrolimus with Mycophenolate Mofetil

49 (A) Kaplan Meier distributions of occurrence of acute graft rejection (risk)

50 (B) Kaplan Meier distributions of occurrence of renal dysfunction or arterial hypertension or diabetes (benefit).

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52 Inibidores do alvo da rapamicina em mamíferos (MTOR) Sirolimus Everolimus Drogas de 2ª linha : efeitos colaterais

53 Steroids Everolimus, Sirolimus Signal 3 Signal 2 Signal 1 MPA, MMF CSA,TAC Russell H. Wiesner1 and John J. Fung. LIVER TRANSPLANTATION 17:S1-S9, 2011

54 Sirolimus/Everolimus Alternativa em pacientes com nefrotoxicidade/neurotoxicidade associado aos CNI Reduz risco de HCC? Efeitos colaterais: - Trombose da artéria hepática? - Mielotoxicidade - Edema - Diarréia

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56 Não são usados rotineiramente no pós transplante Rejeição resistente à esteróide Poupadores de CNI no PO imediato - ex: nefropatia prévia

57 Knowledge of the principles of mechanisms of action Knowledge of the main adverse events Steroids: metabolic complications CNI: renal toxicity and metabolic complications MPA: myelotoxicity and GI disorders Infection Lower possible dose to keep normal liver enzymes Common-sense consider age, co-morbidities, etiology of liver disease

58 Salvador-Bahia- Brazil