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
Kidney Transplantation: Objectives • Why transplantation? • Types of transplantations • Assessment of transplant recipient and donor • Transplant immunology • Immunosuppressants • Complications • New advances in transplantation • Challenges
Incidence of ESRD: KSA PMP Fourth Urology Course KAUH, 2004
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
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.
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
Kidney Transplantation: Types • Living-related • Cadaveric • Emotionally-related • Living-non-related
Allograft (homograft) Genetically disparate individuals of the same species Hx Background: • In 1933: the 1st Renal allograft by Voronoy in Ukraine
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)
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
Then…. 1958: 1st histocompatibility Ag was described 1969: radiation was used
Azathioprine(Imuran) Became available for human use in 1951 ?
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
Immunosuppressants:Azathioprine, Complications • Bone marrow suppression : usually one cell line (especially with allopurinol) • Granulocytopenia • Red cell aplasia • Isolated thrombocytopenia Fourth Urology Course KAUH, 2004
Prednisone Became part of therapy w AZA in 1962 ?
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
1962: tissue matching 1966: direct cross match Then ….
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
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
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
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
MHC/Ag B7 CD28 IL-2R TCR/CD3 CD T-cell Activation APC IL-2 T Cell Nucleus
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
B-cell stimulation: T-cell derived IL-2, IL-4 Physical contact w T-cell
Immunosupression protocol Repeated transplant First transplant • -Cadaver • -LRD (non-identical) • Living related (HLA identical)
Intra-op Methylprednisolone CyA Post-op CyA--> Neoral MMF Prednisone First Cadaveric & LRD (non-identical)
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)
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.
First Living related (HLA identical) Same protocol as above w/o MMF (or Azathioprine)
Therapy of rejection Prednisone pulse therapy 500 mg--10 mg / 9 days Sever or Steroid resistant Monoclocal OKT3 for 14 days Polyclonal ATG, ALG
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
Immune factors Non-immune factors 2-Overcoming chronic rejection