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Principles of organ transplant and Renal transplant

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basic principles involved in organ transplantation and detail renal transplant

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Principles of organ transplant and Renal transplant

  2. 2. CONTENTS  INTRODUCTION  Definition of terms  Transplant immunology  Graft rejection PRINCIPLES  Pre-operatives  Intra-operatives  Post-operative  COMPLICATIONS  RENAL TRANSPLATATION ETHICAL CONSIDERATIONS CONCLUSION
  3. 3. INTRODUCTION DEFINITION OF TERMS An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one from a donor with a compatible tissue type. Autograft - Transfer of organ from one part to another in the same individual. E.g skin graft, vuscular graft. Allograft - from one individual to another of the same species Isograft - transfer of organ from one individual to his or her monozygotic twins Xenograft - transfer of organ from one individual to another of different species
  4. 4. INTRODUCTION DEFINITION OF TERMS Orthotopic graft- graft placed in it normal anatomical position Heterotopic graft - graft placed at a site different from the organ is normally located
  5. 5. Organs that can be transplanted are:  Heart  Kidneys  Liver Thymus  Pancreas Lungs  Intestine
  6. 6. Tissues that can be transplanted are:  Bones  Tendons  Cornea  Vein Heart valves  Skin of leg
  7. 7. TRANSPLANT IMMUNOLOGY The immune system recognizes graft from someone else as foreign body and triggers response via immune cells and substances they produce - cytokines and antibodies (Responses are via; recognition, amplification and memory) Immunity IMMUNE CELLS Lymphocytes : T-lymphocyte, B-lymphocyte, N-killer cells Antigen presenting cells(APC) : macrophages, dendritic cells The Effector Cells : Neutrophils , macrophages and T-lymphocytes Humoral (Antibody mediated) Cell mediated
  8. 8. LYMPHOCYTES  T-LYMPHOCYTES o Mediator of cell mediated immunity o They recognizes MHC antigen on transplant tissues o Cytotoxic T-cells produces cytotoxic factors (perforins, granzymes) implicated in transplant rejection  B-LYMPHOCYTES o Mediators of humoral immunity by antibody production. o There activation is aided by cytokine and the T-helper cells o Clonal selection generates plasma cells secreting antibodies. o There are 5 major classes of antibodies or immunoglobulin; IgG, IgM, IgA, IgE and IgD the 1st 3 are involve in graft rejection  N-KILLER CELLS o Cells of innate immunity, capable of killing foreign targets without prior sensitization
  9. 9. Cell-mediated immune response Defend against intracellular pathogens/rejection Active Cytotoxic T cells Memory Cytotoxic T cells Memory Helper T cells Antigen- presenting cell Antigen (2nd exposure) Helper T cell Engulfed by Antigen (1st exposure) Cytotoxic T cell Key Stimulates Gives rise to + + + + + + + T-CELLS - Helper T cells - Cytotoxic T cells - Memory T cells
  10. 10. Cytotoxic T cell Perforin Granzymes TCRCD8 Class I MHC molecule Target cell Peptide antigen Pore Released cytotoxic T cell Dying target cell
  11. 11. Key Stimulates Gives rise to + Memory Helper T cells Antigen- presenting cell Helper T cell Engulfed by Antigen (1st exposure) + + + + + + Defend against extracellular pathogens/Transplant rejection Memory B cells Antigen (2nd exposure) Plasma cells B cell Secreted antibodies Humoral (antibody-mediated) immune response 10/22/2015bbinyunus2002@gmail.com 11
  12. 12.  ANTIGEN PRESENTING CELLS(APC) o They capture antigens and display to lymphocytes e.g. Macrophages, dendritic cells and follicular dendritic cells. • Dendritic cells : initiate T-cells response • Macrophages : Initiate effector phase of cell mediated immunity • Follicular dendritic cells : display antigens to B-lymphocytes in humeral response.  EFFECTOR CELLS o They eliminate antigens by phagocytosis E.g neutrophils, macrophage and T-lymphocytes
  13. 13. TRANSPLANT ANTIGENS Human leucocytes antigen (HLA) ; a group of highly polymorphic cell surface molecules They act as antigen recognition unit on T-lymphocytes and are the major trigger for graft rejection Types : class1 – HLA- A,B,C present in all nucleated cells, CD8+ recognizes class 1 HLA class2 – HLA- DR, DP, DQ present only on APC Class 2- HLA-DR are most important in rejection CD4+ recognize class 2 HLA
  14. 14.  Major histocompatibility complex MHC; o They are clusters of genes on the short arm of chromosome 6 expressed on the cell surface as HLA i.e. genes that encode HLA.  ABO o These blood group antigen are expressed not only on red blood cells but by most cell types as well. o Incompatibility leads to hyperacute rejection
  15. 15. Rejection of transplanted organs is a bigger challenge than the technical expertise required to perform the surgery. It results mainly from HLA and ABO incompatibility. Types of Graft Rejection  Hyperacute : o Immediate graft destruction due to ABO or preformed anti- HLA antibodies. o Characterized by intravenous thrombosis and interstitial hemorrhage. o Risk factors are previous failed transplant and blood transfusions o Kidney transplant is vulnerable to hyperacute rejection . Hyperacutly rejecting kidney rapidly becomes cyanotic, mottled, and flaccid and may excrete few drops of bloody urine. GRAFT REJECTION
  16. 16. Steps in the hyperacute rejection of a kidney graft. Hyperacute Rejection
  17. 17.  Acute : o Usually occurs during the first 6 months. o May be cell mediated (T-cell), antibody mediated or both. o Characterized by cellular infiltration of the graft (cytotoxic, B- cells, NK cells and macrophages). o Histologically, humoral rejection is associated with vasculitis, whereas cellular rejection is marked by an interstitial mononuclear cell infiltrate, edema, and tissue injury as well as mild interstitial haemorrhage.  Chronic : o It occurs after 6 month . o Most common cause of graft failure. o Non- immunological factors contribute to the pathogenesis characterized by myo-intimal proliferation in graft arteries leading to ischemia and fibrosis
  18. 18. PRINCIPLES PRE-OPERATIVE  Patient selection and Evaluation  Counseling  Informed consent  Optimization
  19. 19. PATIENT SELECTION AND EVALUATION 1. RECIPIENT  Patient who met the indication for transplant – ORGAN FAILURE  Clinical evaluation; history and physical examination to rule out other diseases and co-morbidities  Immunological evaluation  Blood group  Tissue typing & cross matching  Serology; HIV, Hepatitis, CMV, VDRL  Infection screening – septic work-up  Others ; CBC, clotting profile, FBS, ECG, LFT, RFT, tumour markers.
  20. 20. 2. DONOR I. Living donor : Donor remains alive and donates a renewable tissue/cell, or donates an organ or part of an organ in which the remaining organ can regenerate or take on the workload of the rest of the organ (single kidney donation, partial donation of liver). A living donor should be healthy • Living unrelated donor (LURD) • Living related donor. (LRD) Advantages of living donor  Improved graft survival  Less recipient morbidity  Early function and easier to manage  Avoidance long waiting time for transplant  Less aggressive immunosuppressive regimen
  21. 21. Contra-indications for living donor o Mental disease o Disease organ o Morbidity and mortality risk o ABO incompatibility o Crossmatching incompatibility o Transmissible disease Evaluation : to assess for suitability o CLINCAL - history of risk factors for infection, malignancy in the past 5 years. Presence of co-morbidities o ABO typing, Serology tests. o Infection and malignant screening o CT-Angiogram, Intravenous urography. o HLA typing.
  22. 22. II. Deceased donor - Brain dead donors: Donors who have been declared brain-dead and whose organs are kept viable by ventilators or other mechanical mechanisms until they can be excised for transplantation. o Normothermic patient. o No respiratory effort by the patient. o The heart is still beating. o No depressant drugs intake should be there while evaluating the patient. o Individual should not have any sepsis, cancer (except brain tumour). o Not a HIV or hepatitis individual. - Cardiac Death Donors (formerly non-heart beating donors) to increase the potential pool of donors as demand for transplants continues to grow. These organs have inferior outcomes to organs from a brain-dead donor.
  23. 23. FACTORS DETERMING ORGAN FUNCTION AFTER TRANSPLANT  DONOR CHARACTERISTICS ■ Extremes of age ■ Presence of pre-existing disease in the transplanted organ ■ Haemodynamic and metabolic instability  PROCUREMENT-RELATED FACTORS ■ Warm ischaemic time ■ Type of preservation solution ■ Cold ischaemic time  RECIPIENT-RELATED FACTORS ■ Technical factors relating to implantation ■ Haemodynamic and metabolic stability ■ Immunological factors ■ Presence of drugs that impair transplant function
  24. 24. Tissue typing The tissue typing laboratory carries out 3 tasks :  To determine the HLA type of blood for both donor and recipient by PCR.  Lymphocyte cross-matching to exclude circulating antibodies in recipient against HLA expressed by donor.  HLA antibody screening and specificity in recipient before and after transplant to guide immunosuppressive therapy
  25. 25.  Positive cross matching; o Recipient antibodies attacks donor’s. o Not suitable for transplant  Negative cross matching; o Recipient antibodies donot attack donor o Suitable for transplant  Methods; o Micro-cytotoxic assay, mixed lymphocytes, flow cytometry, DNA analysis. Lymphocyte cross-matching
  26. 26. Typing procedures for HLA antigens. (a) HLA typing by microcytotoxicity. (b) Because cells express numerous HLA antigens, they are tested separately with a battery of antibodies specific for various HLA-A antigens. Here, donor 1 shares HLA-A antigens recognized by antisera in wells 1 and 7 with the recipient, whereas donor 2 has none of HLA-A antigens in common with the recipient Graft Donors and Recipients Are Typed for RBC and MHC Antigens
  27. 27. O May involve professional counselors/ psychotherapist O Aimed at preventing / minimizing possible complication O Need for adherence to post-op maintenance medications O Regular follow-up thorough evaluation O Life style modification; smoking, alcohol, sedentary life style, junks, excessive salt ingestion. COUNSELING
  28. 28. INFORMED CONSENT  Living Donor ;  Education  Willingly not for any financial reason or under stress  Most undergo extensive screening – medical, psychological  Surgery and anesthetic complications outline to patients
  29. 29. DECEASED DONOR Some Factors influencing refusal to consent by relatives;  non-acceptance of brain death.  A delay in funeral  Lack of consensus within family members  Fear of social criticism  Dissatisfaction with the hospital staff  Various Superstitions & Religious beliefs
  30. 30. INFORMED CONSENT  RECIPIENT  Nature of disease and the need for transplant  Outcome and complications  Need for compliance to immunosuppressive therapy  Other available options
  31. 31. OPTIMIZATION OF RECIPIENT  Correction of derangements, getting patient ready for surgery  Correction of anemia  Uremia  Dehydration  Treatment of infection  Central line  Urethral catheter  Loading dose immunosuppression 12hr pre-op  Prophylactic antibiotics
  32. 32. PRINCIPLES INTRA-OPERATIVE Organ procurement and preservation LIVING DONORs a. Strict asepsis and hemostasis b. Adequate exposure c. Removal of the organ d. Preservation
  33. 33. Preservation After removal, the organ is flushed with chilled organ preservation solution e.g. University of Wisconsin(UW), Eurocolins, HTK, Celsior, Custodiol, Citrate/Marshall solutions
  34. 34. g. Organ packaging
  35. 35. NONHEART-BEATING KIDNEY DONATION Initiation of preservation in situ- for DCD donors- donation after circulatory death donors
  36. 36. h. Transplantation/vascular reconstruction Warm ischemic time ; time an organ remains at body temperature between which the blood supply is cut off before cold perfusion. (within 30min) Cold ischemic time ; the time between the chilling of the organ, after blood supply has been cut off and the time it is warmed by reconnection Maximum and optimal cold storage times (approximate) Organ Optimal (hours ) Safe maximum(hours) Kidney < 24 48 Liver < 12 24 Pancreas < 10 24 Small intestine < 4 8 Heart < 3 6 Lung < 3 8
  37. 37. PRINCIPLES Post-operative Post-operative assessment Clinical – vital signs; fever, tachychardia, hypertension, pain at site of transplant, pedal edema (compression of external iliac vein), decrease urine volume- features of hyperacute rejection Investigations ; U/Scr USG- increase in size, pelvicalyceal dilation Biopsy; mononuclear infiltrates, fibrinoid necrosis, interstitial haemorrhage. Others Maintenance immunosuppression, DVT prophylaxis Treatment of infection , Regular follow up
  38. 38. IMMUNOSUPPRESSION  The principles are the same for all type of organ transplant; maximize graft protection and minimize side effect.  The agents used to prevent rejection act predominantly on T cells.  The need for immunosuppression is highest in the first 3 month but indefinite treatment is needed  It increase the risk of infection and malignancy.
  39. 39. AGENT MODE OF ACTION SIDE FFECT CALCINEURINE INHIBITORS Cyclosporine Tacrolimus Block IL-2 gene transcription Nephrotoxicity, hypertension, dyslipidaemia, hirsutism, gingival hyperplasia, neurotoxicity and diabetes AZATHIOPRINE Prevents lymphocyte proliferation Leucopenia, thrombocytopenia, hepatotoxicity, gastrointestinal symptoms MYCOPHENOLIC ACID DERIVATIVES eg MMF – Mycofenolate mofetil Prevents lymphocyte proliferation Leucopenia, thrombocytopenia, gastrointestinal symptoms CORTICOSTEROIDS Widespread anti- inflammatory effects Hypertension, dyslipidaemia, diabetes, osteoporosis, avascular necrosis, cushingoid appearance mTOR-inhibitors Sirolimus, Everolimus Blocks IL-2 receptor signal transduction Thrombocytopenia, dyslipidaemia,
  40. 40. AGENT MODE OF ACTION SIDE EFFECT ANTIBODY THERAPIES a. OKT3 monoclonal antibody b. Anti-CD25 monoclonal antibody c. Polyclonal antibody [antilymphocyte globulin (ALG) or anti- lymphocyte serum (ALS)] Depletion and blockade of T Cells Targets activated T cells Depletion and blockade of lymphocytes a. Cytokine release syndrome, pulmonary oedema, leucopenia b. None described c. Leucopenia, thrombocytopenia
  41. 41. REGIMENS Immunosuppressive agents are given as  Induction; early post-op period  Maintenance ; given for life  Rescue agents ; to reverse acute rejection  Induction regimen (most currently used )  CNI + anti CD 25 monoclonal antibody  Triple therapy ; CNI, anti-proliferative agent (MMF) and steroids  Dual therapy ; CNI + MMF or steroids  Polyclonal antibody (ALG/ALS)
  42. 42. Maintenance ;  mTOR- inhibitors (specially in kidney transplant because they provide a non-nephrotoxic alternative to CNI)  Multidrug therapy ; steroids, anti-proliferatives, CNIs. Acute Rejection;  Polyclonal antibody combine with induction regimen- quadruple therapy.
  43. 43. COMPLICATIONS OF IMMUNOSUPPRESSION  INFECTIONS; high risk of opportunistic infections o Bacterial : common during first month after transplantation Community acquired infections Wound infection UTI (catheter related) Tuberculosis
  44. 44. COMPLICATIONS OF IMMUNOSUPPRESSION o Viral ; highest in the first six month • CMV infection; may presents as pneumonia, gastrointestinal disease, hepatitis, retinitis, encephalitis • Herpes simplex virus (HSV) ; muco-cuteneous lesions sometimes around the genitalia • BK-virus; graft dysfunction • Herpes zoster infection; chicken pox o Fungal ; pneumocystis jiroveci (carinii), candidiasis, aspergillosis o Parasitic; strongiloides, leishmaniasis, toxoplasmosis
  45. 45. COMPLICATIONS OF IMMUNOSUPPRESSION  MALIGNANCY o Post transplant lymphoprolipherative disease (PTLPD); seen 1-3% of kidney transplant with 50% mortality o Squamous cell ca of the skin o Basal cell ca and malignant melanoma are higher in transplant patient than the general population o 50% of transplant patient would develop skin malignancy in 20years o Kaposi sarcoma; 300 fold increased risk
  46. 46. KIDNEY TRANSPLANT  Indications o End-stage renal disease Causes :  Glomerulonephritis;  Diabetic Nephropathy;  Hypertensive Nephrosclerosis;  Renal Vascular Disease;  Polycystic Disease;  Pyelonephritis;  Obstructive Uropathy;  Systemic Lupus Erythematosus;  Analgesic Nephropathy;  Metabolic disease (oxalosis, amyloid). Irreversible GFR of less than 10 mL/min serum creatinine level of greater than 8 mg/dl
  47. 47. O Exclusion criteria for living donor
  48. 48. Exclusion Criteria for Recipient  Drug abuse.  Morbid obesity. BMI >/= 35  Compliance • S. phosphorus </= 6mg/dl • Inter-dialysis wt gain (<5% dry wt for period of 3 month)  High risk of heart disease.  Cause of ESRD • Focal segmental glomerulosclerosis • Hemolytic uremic syndrome. • 10 Oxalosis  Active Infection  Active malignancy
  50. 50.  Donor Nephrectomy  Open or Laparoscopic or Robotic.  Laparoscopic donor nephrectomy is the gold standard.  Open donor nephrectomy is via the 11th/12th rib cutting incision, and in fat patient 10th rib cutting incision.  Extraperitoneal : avoid de-vascularizing ureter, sharp dissection, avoid diathermy near vessels  Renal vasculature dissect flush to IVC/Aorta  Ligate lumbar veins posteriorly ± gonadal vein
  51. 51.  Donor Kidney Bench Surgery o The kidney is perfused with ice-cold preservative o Iced saline is mashed into a slush and kidney immersed o Extra veins ligated, accessory artery(ies) anastomosed together o Kidney now ready for transplanting
  52. 52. PRESERVATIVES Ischemia Na pump is impaired NaCl and water passively diffuse into the cell Cellular swelling & NO-REFLOW phenomenon  Cellular K & Mg lost.  Ca + gained  Anaerobic glycolysis and Acidosis  Lysosomal enzymes activated  On reperfusion, Hypoxanthine a product of ATP degradation is oxidized to xanthine and free radicals causes further injury ATP and Oxygen depletion Patho-physiology  ATP-MgCl2  Ca+ channel blocker  Vaso-protective agents  Free radical scavenger  Lysosome stabilizer (Methylprednisolone)
  53. 53.  THE TRANSPLANT o Right donor kidney to left recipient site and vice versa o Gibson’s incision; Curvilinear incision 2 cm above the inguinal ligament, from midline to just above the anterior Sup. Iliac Spine o End to side venous anastomosis 5/0 prolene o End to end arterial anastomosis 5/0 prolene o Implant ureter to bladder
  54. 54. Recipient Preparation o Antibiotic administered just before surgery. o Immunosuppression started just before or during surgery. o Before temporary vascular occlusion HEPARIN is given I/V to recipient.
  55. 55. Indication for pre-transplant Nephrectomy o Renal stone not cleared. o Polycystic symptomatic (infected) kidney. o Persistent anti glomerular basement membrane antibody. o Significant protienuria. o Recurrent pyelonephritis. o Grade 4/5 Hydronephrosis
  56. 56. Extra-peritoneal approach in either iliac fossa. Renal artery is anastomosed end-to-end to the internal iliac artery or end-to-side to the external iliac artery. Renal vein is sutured end to side to external iliac vein. After revascularization, the ureter is implanted into the side wall of the bladder
  57. 57. COMPLICATIONS  TECHNICAL  Vascular hemorrhage; Vascular thrombosis 10-20%, within 2-3 days→ technical, 2/12→rejection, most are lost: ↓urine output, ↑creatine  Urological ; infection, fistula, obstruction  Wound infection  RENAL  Acute tubula necrosis  Cortical necrosis  Lymphocele  Graft rupture  Recurrent glomerulo-nephritis
  58. 58. Outcome  Patient survival after deceased donor renal transplantation is >90% at 1 year and > 80% at 5 years.  Graft survival is around90% at 1 year and 75% at 5 years. Graft survival after a second transplant is only marginally worse than after a first graft.  After living-related kidney transplantation, overall graft survival is around 95% at 1 year and 85% at 5 years.  The half-life of grafts obtained from living donors is longer than that of cadaveric grafts: • deceased donor grafts : 13 years; • living unrelated grafts : 14 years; • living haplo-identical grafts : 15 years; • living identical sibling grafts : 27 years
  59. 59. ETHICAL CONSIDERATION INTERNATIONAL PERSPECTIVES ON THE ETHICS AND REGULATION OF HUMAN CELL AND TISSUE TRANSPLANTATION o Consent for removal of human cells and tissues o Confidentiality of donor data o Unpaid donation o Fair procurement of cells and tissues o Stewardship for donated cells and tissues o Quality and safety of HC/HT procurement and processing o Fair distribution of processed cells and tissues o Consent for HC/HT transplantation
  60. 60. Future trend  Genetic engineering – Cloning  Newer specific Immuno-suppresive therapy
  61. 61. CONCLUSION Organ transplant is a successive therapeutic option for treatment of end-stage organ disease. Success depends on improved surgical technique, immunosuppression, organ preservation and follow-up .
  62. 62. REFERENCES O Bailey and Love’s “Short Practice of Surgery” 26th edition CRC press Taylor and Francis group. 2013 O E.A Badoe et al, “Principles and Practice of surgery including pathology in the tropics” 4th edition, Assembly of God Literature Center ltd, 2009 O M.A.R Al-Fallouji; “Postgraduate Surgery the candidate guide”. 2nd Edition. Rced Educational and Professional Pub. Ltd 1998 O Sabiston texbook of surgery. 18th edition.2007 O Andrew C et al “Operative urology at the cleveland clinic” 2nd edition. 2006. O Campbell-walsh urology.