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بسم الله الرحمن الرحيم

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بسم الله الرحمن الرحيم

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  1. بسم الله الرحمن الرحيم

  2. Kidney Transplantation Dr. Anmar Nassir, FRCS(C) Canadian board in General Urology Fellowship in Andrology (U of Ottawa) Fellowship in EndoUrology and Laparoscopy (McMaster Univ) Assisstent Prof Umm Al-Qura Consultant Urology King Faisal Specialist Hospital

  3. Kidney Transplantation: Objectives • Why transplantation? • Types of transplantations • Assessment of transplant recipient and donor • Transplant immunology • Immunosuppressants • Complications • New advances in transplantation • Challenges

  4. ESRD: Incidence PMP

  5. Incidence of ESRD: KSA PMP Fourth Urology Course KAUH, 2004

  6. ESRD: Modality of Treatment in USA

  7. Modality of Renal Replacement Therapy in KSA 2001

  8. Performed Cadaveric Renal Transplant in KSA

  9. Kidney Transplantation: Why? • Better quality of life • Restoring healthy productive life • May restore sexuality and fertility • Dialysis-associated morbidity • Access problems and other infections • Bone disease and dialysis-associated amyloidosis • Lower mortality

  10. ESRD: Mortality

  11. ESRD: Risk of Death

  12. Kidney Transplantation: Why?Special Reasons in KSA • Increasing number of ESRD patients. • Negative image of dialysis. • High Incidence and prevalence of HCV infection. • Poor dialysis therapy “inadequacy”. • Improper treatment of anaemia and bone disease.

  13. Hemodialysis Access problems Blood Stream Infection HCV Bone disease Dialysis-associated amyloidosis Acquired cystic diseases & RCC IHD Peritoneal Dialysis CAPD peritonitis Loss of Peritoneal membrane Hyperglycaemia Hyperlipidemia Acquired cystic diseases & RCC IHD Causes of Morbidity and Mortality

  14. ESRD: HCV-Ab Status in HD Patients in KSA

  15. HCV in HD Population in KSA

  16. Kidney Transplantation: Types • Living-related • Cadaveric • Emotionally-related • Living-non-related

  17. Allograft (homograft) Genetically disparate individuals of the same species Hx Background: • In 1933: the 1st Renal allograft by Voronoy in Ukraine

  18. Transplant Immunology:Components of Immune System • Antigen presenting cells (APC) • Macrophages & dendritic cells, Langarhan’s cells & vascular cells • T lymphocytes • CD4+ (helper T cells) • CD8+ (suppressor or Cytotoxic T cells) • B lymphocytes (antibody-forming)

  19. What can happen ?

  20. Graft destruction: Ag specific & graft-destructive T-cell Complement-dependent cell-mediated cytotoxicity • Effector T-cell & NK cell stimulated by granzyme B & perforin • IL-2 & IL-10 plays important role • IFN-g & TNF-a: • up-regulating HLA molecules & co-stim (B7) upon graft & APCs Ab-dependent cell-mediated cytotoxicity

  21. In 1954: the 1st long term renal transplant in Boston HOW ?

  22. Isograft

  23. Then…. 1958: 1st histocompatibility Ag was described 1969: radiation was used

  24. What is this coming drug?

  25. Azathioprine(Imuran) Became available for human use in 1951 ?

  26. Immunosuppressants:Azathioprine • Imidazole analogue • Purine antagonist thus inhibiting cellualr proliferation • Poorly selective (suppress all cells population) • Dose 1-2mg/kg/day • Allopurinol blocks its catabolism Fourth Urology Course KAUH, 2004

  27. Immunosuppressants:Azathioprine, Complications • Bone marrow suppression : usually one cell line (especially with allopurinol) • Granulocytopenia • Red cell aplasia • Isolated thrombocytopenia Fourth Urology Course KAUH, 2004

  28. Prednisone Became part of therapy w AZA in 1962 ?

  29. Immunosuppressants:Corticosteroids • Maximal effect on macrophages & lymphocytes • Inhibits cytokines gene transcription • Inhibit IL-1, IL-2, IL-6 • Inhibits INF-gamma & TNF • This will lead to inhibition of T cell proliferation • Used as maintenance therapy (PO) and as a treatment for acute rejection (IV) Fourth Urology Course KAUH, 2004

  30. 1962: tissue matching 1966: direct cross match Then ….

  31. The strongest of the Tx Ag is the expression of a single chromosomal region called MHC: • large gene that control traits which influence the entire immune response • located on chromosome 6 • the gene products of MHC were first investigated on leukocyte & named HLA • Many Ag can serve as histocompatibility Ag: • ABO • Xenografts

  32. Can be detected on the cell surface of almost all nucleated cells • The best trigger of the proliferation of allogenic lymphocytes • Only on the cells of immune system: mac. dend. B, & activated T • Not as strong • On each chromosome 6 there are 6 genetic loci , and on each pair there are 12 loci

  33. HLA: Major Histocompatibility Complex (MHC) Chromosome 6 A B C Class I DP DQ DR Class II A B C Class I DP DQ DR Class II

  34. HLA: Mendelian Transmission Father Mother A31 B22 C10 DR01 DP43 DQ7 A03 B14 C28 DR20 DP19 DQ31 A14 B8 C24 DR05 DP12 DQ 03 A18 B53 C11 DR22 DP18 DQ20 1 2 3 4 5 A31,B22,C10 DR5, DP12,DQ3 A14, B8, C24 DR1,DP43,DQ7 A03, B14, C28 DR5, DP12, DQ3 A18, B53, C11 DR20, DP19, DQ31 A14, B8, C24 DR1,DP43,DQ7

  35. MHC/Ag B7 CD28 IL-2R TCR/CD3 CD T-cell Activation APC IL-2 T Cell Nucleus

  36. MHC/Ag Simulect G1 B7 CyA FK CD28 TCR/CD3 Rap S Imuran MMF OKT3 M M IL2 gene Steroid APC IL-2 T Cell IL-2R Nucleus Calcineurin G0

  37. B-cell stimulation: T-cell derived IL-2, IL-4 Physical contact w T-cell

  38. Immunosupression protocol Repeated transplant First transplant • -Cadaver • -LRD (non-identical) • Living related (HLA identical)

  39. Intra-op Methylprednisolone CyA Post-op CyA--> Neoral MMF Prednisone First Cadaveric & LRD (non-identical)

  40. Out pt Neoral Prednisone Taper gradually MMF: Maintain for 1 yr, then D/C Switch to Azatioprine if concern about rejection First Cadaveric & LRD (non-identical)

  41. Repeated Tx (Same protocol as 1st Tx) + Polyclonal Ab (ALG) should be started in RR Few days then start Neoral Most pts will remain on CyA, MMF, Pred.

  42. First Living related (HLA identical) Same protocol as above w/o MMF (or Azathioprine)

  43. Therapy of rejection Prednisone pulse therapy 500 mg--10 mg / 9 days Sever or Steroid resistant Monoclocal OKT3 for 14 days Polyclonal ATG, ALG

  44. There are 4 key needs which, if not met, could marginalize Tx as a form of therapy: 1-Achieving optimal immunosuppression 2-Overcoming chronic rejection 3-New therapeutic targets 4-Increasing the # of organ donation

  45. Immune factors Non-immune factors 2-Overcoming chronic rejection