Transplantion (Graft) by 4Cf80ne

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									Transplantion (Graft)

Done by Ossama Fanek & Safwan Rawabdeh

   Supervised by : Dr. Nawaf Shatnawi



                                         1
Definition

   Is transferring of tissue, to replace the
    recipient's damaged or absent tissue .




                                                2
Classification
      Transplantation can be for cell, tissue or organ(s).
      Can be in the same person, from person to other of the same
       species or different.

1. Autograft :
   transfering of tissue to the same person (ex : Skin grafts, vein
       extraction for CABG, bone and cartilage transplants, and nerve
       transplants ).
2. Allograft :
   transplant of an organ or tissue between two genetically non-identical
       members of the same species.
3. Isograft :
      A subset of allografts in which organs or tissues are transplanted
       from a donor to a genetically identical recipient (such as an
       identical twins) , so they don’t trigger an immune response.
4. Xenograft :
      transplant of organs or tissue from one species to another. An
       example are porcine heart valve transplants, which are quite
       common and successful .

    Note: Xenotransplantion is often an extremely dangerous type of
       transplant because of the increased risk of non-compatibility,         3
       rejection, and disease carried in the tissue. This is a very serious
    According to the implanting site :
1.   Orthotopic Transplantation: Donor organ is
     placed in the normal anatomical position
     (ex: heart, lung, liver).
2.    Heterotopic Transplantation: Donor organ
     is placed in a different site than the normal
     anatomical position (ex: kidney, pancreas).
3.    Paratopic Transplantation : Donor organ is
     placed close to the original organ.
                                                     4
Basic Immunology
   The main antigens involved in triggering
    rejection are coded for by a group of
    genes known as :

                    MHC
      (Major histocompatibility complex)


                                           5
                  MHC
    (Major Histocompatibility Complex)

   These antigens are the product of
    genes, which defines the "foreign"
    nature of a donors tissue to the
    recipient immune mechanism.
   In humans, the MHC complex antigens
    is known as the human leukocyte
    antigen (HLA) system.
   It comprises a series of genes located
    on chromosome 6.                         6
    Grouped into 3 classes :
    Class I molecules (named HLA-A, -B, and -C)
    are found on the membrane of all nucleated
    cells
   Class II molecules (named HLA-DR, -DP, and
    -DQ) are generally expressed by antigen-
    presenting cells (APCs) such as B
    lymphocytes, monocytes, and dendritic cells
   Class III molecules : encoded for other
    immune component ( complement system,
    cytokine                                     7
   In a nontransplant setting, the function of the
    HLA gene product is to present antigens as
    fragments of foreign proteins that can be
    recognized by T lymphocytes. In the transplant
    setting, HLA molecules can initiate rejection
    and graft damage, via either humoral or
    cellular mechanisms. Humoral rejection occurs
    if the recipient has circulating antibodies
    specific to the donor's HLA from prior exposure
    (i.e., blood transfusion, previous transplant, or
    pregnancy), or if posttransplant, the recipient
    develops antibodies specific to the donor's
    HLA. The antibodies then bind to the donor's
    recognized foreign antigens, activating the
    complement cascade and leading to cell lysis.
    The blood group antigens of the ABO system,
    though not part of the HLA system, may also         8
    trigger this form of humoral rejection.
T- Lymphocytes
   Thymus is the principal organ responsible for
    the T cell's maturation.
   Distinguished from other lymphocyte types,
    such as B-Cells and natural killer cells (NK
    cells) by the presence of a special receptor on
    their cell surface called T-Cell receptors.
   They can recognized foreign antigen
    presented by APC(antigen presenting cell).
   Once presented with an antigen they will
    produce ILs, and proliferate (cloning).
                                                  9
   Types of T-Cells :
    Helper : These cells are also known as CD4+ T cells because they
    express the CD4 protein on their surface. Helper T cells become
    activated when they are presented with peptide antigens by MHC class
    II molecules that are expressed on the surface of Antigen Presenting
    Cells (APCs)
   Cytotoxic :These cells are also known as CD8+ T cells since they
    express the CD8 glycoprotein at their surface. These cells recognize
    their targets by binding to antigen associated with MHC class I, which
    is present on the surface of nearly every cell of the body
   Memory T cells are a subset of antigen-specific T cells that persist long-
    term after an infection has resolved. They quickly expand to large
    numbers of effector T cells upon re-exposure to their cognate antigen,
    thus providing the immune system with "memory" against past
    infections
   Regulatory T cells formerly known as suppressor T cells, are crucial for
    the maintenance of immunological tolerance. Their major role is to shut
    down T cell-mediated immunity toward the end of an immune reaction
    and to suppress auto-reactive T cells that escaped the process of
    negative selection in the thymus
                                                                             10
   Natural killer cells.
Problems with transplantation

   REJECTION

   AVALAIBILITY OF THE TRANSPLANTED
    TISSUE



                                   11
Why do rejection occurs?

   Transferred tissue carries antigens

    Ag presentation to CD8 or CD4 T cell

     clonal expansion, IL2 production and Ab production
    by B lymphocyte

    Activation of all immune component        cell lysis
    and vascular occlusion

                                                           12
   Graft rejection is a complex process
    involving several components, including
    T lymphocytes, B lymphocytes,
    macrophages, and cytokines, with
    resultant local inflammatory injury and
    graft damage. Rejection can be
    classified into four types, based on
    timing and pathogenesis: hyperacute,
    accelerated acute, acute, and chronic.
                                          13
Clinical Rejection
   Hyperacute:
•   occurs within minutes after the transplanted organ is
    reperfused, is due to the presence of preformed
    antibodies in the recipient, antibodies that are specific
    to the donor
•   These antibodies may be directed against the donor's
    HLA antigens or they may be anti-ABO blood group
    antibodies
•   they bind to the vascular endothelium in the graft and
    activate the complement cascade, leading to platelet
    activation and to diffuse intravascular coagulation result
    in swollen, darkened graft, which undergoes ischemic
    necrosis.
•   This type of rejection is generally not reversible, so
    prevention is key.
•   Prevention is best done by making sure the graft is ABO-
    compatible and by performing a pretransplant cross- 14
    match
   Accelerated Acute :

   This type of rejection, seen within the
    first few days posttransplant, involves
    both cellular and antibody-mediated
    injury. It is likely when a recipient has
    been sensitized by previous exposure to
    antigens present in the donor, resulting
    in an immunologic memory response.
                                            15
    Acute :
•    seen within days to a few months posttransplant
•   It is predominantly a cell-mediated process, with
    lymphocytes being the main cells involved. Biopsy of the
    affected organ demonstrates a cellular infiltrate, with
    membrane damage and apoptosis of graft cells
•   Type IV Hypersensitivity Rxn
•   may be associated with systemic symptoms such as
    fever, chills, malaise, and arthralgias unless good
    immunosupressents are used
•   Acute rejection episodes may also be mediated by a
    humoral, rather than cellular, immune response. B cells
    may generate antidonor antibodies, which can damage
    the graft


                                                          16
    Chronic :
•   This form of rejection occurs months to
    years posttransplant
•   Histologically, the process is
    characterized by atrophy, fibrosis, and
    arteriosclerosis
•   Both immune and nonimmune
    mechanisms are likely involved
•   Clinically, graft function slowly
    deteriorates over months to years       17
   Cellular rejection is the more common
    type of rejection after organ
    transplants. Mediated by T
    lymphocytes, it results from their
    activation and proliferation after
    exposure to donor MHC molecules.



                                            18
Successful transplantation
requires:
   ABO and HLA cross matching
   Reduce the immune response. By :
    * Inducing a specific tolerance to the transplanted
    tissue only (best).
    * Radiation of all immune components.
    * Chemo reduction.
    * Immunosuppressive drugs.



                                                          19
Conditions with suppressed
immunity
   Uremia
   Profound jaundice
   Advanced malignancy
   AIDS
   Controlled reduction



                             20
Immunosuppressent agents
   The success of modern transplantation
    is in large part due to the successful
    development of effective
    immunosuppressive agents. Without
    these agents, only transplants between
    genetically identical individuals would
    be possible

                                          21
   Immunosuppressive drugs are generally used
    in combination with others rather than alone.
   All of these drug carry the risk of infection
    and developing some tumors (lymphoid
    tumor).
    Induction immunosuppression refers to the
    drugs administered immediately
    posttransplant to induce immunosuppression.
    Maintenance immunosuppression refers to
    the drugs administered to maintain
    immunosuppression once recipients have
    recovered from the operative procedure.
                                                22
   Individual drugs can be categorized as
    either biologic or nonbiologic agents.
   Biologic agents consist of antibody
    preparations directed at various cells or
    receptors involved in the rejection
    process; they are generally used in
    induction (rather than maintenance)
    protocols.
    Nonbiologic agents form the mainstay
    of maintenance protocols.                23
CORTICOSTEROIDS
   The most commonly used in transplant is
    Prednisone.
   It primarily blocks production of IL-1 by
    macrophage and stabilizes lysosomal
    membrane of macrophage.
   Side effects : Cushinoid status, alopecia,
    striae, HTN, DM, pancreatitis, ulcer diseases,
    osteomalacia, avascular necrosis esp in the
    femoral head,…

                                                     24
AZATHIOPRINE
   It is a prodrug that is cleaved into
    mercaptopurine; inhibits synthesis of DNA
    and RNA, leading to decreased cellular (T/B
    cells) production
    Side effects: bone marrow toxicity(
    leukopenia and thrombocytopenia),
    hepatotoxicity, associated with pancreatitis
   Allopurinol Azathioprine interaction: decrease
    dose if patient on allopurinol because it
    inhibits Xanthine oxidase. Which is necessary
    for break down of azathioprine
                                                 25
CYCLOSPORINE (A)
   Inhibits production of IL-2 by TH cells
   Side effects :

    11 Hs : Hepatitis – Hypertrichosis – gingival
    Hyperplasia – Hyperlipidemia – Hyperglycemia –
    Hypertention – Hemolytic uremic syndrome –
    Hyperkalemia – Hypercalcemia – Hypomagnesemia –
    Hyperuricemia

    3 Ns : Nephrotoxicity – Neurotoxicity – Neoplasia
    (lymphoma, Kaposi sarcoma and squamous cell skin
    cancers)
                                                        26
Antithymocyte Globulin
   Antibody against thymocytes,
    lymphocytes (polyclonal).
   Used maily for induction.
   Side effects : Thrombocytopenia –
    leukopenia – serum sickness syndrome
    – fever – rigors – anaphylaxis –
    arthralgia – increase risk of viral
    infection.
                                           27
OKT3
   Monoclonal antibody that binds CD3
    receptor (on T-Cells).
   There is major problem with multiple
    doses of OKT3 that it blocks antibodies
    develop, also it is less effective each
    time it is used.


                                              28
TACROLIMUS (Prograf)
   It works similar to CSA by blocking IL-2
    receptor and inhibits T-Cells.
   It is much more potent than CSA by
    100 times.
   Side effects : Nephrotoxicity –
    Hyperkalemia – alopecia – DM – CNS
    toxicity( tremor, seizure, parasthesia,
    coma).
                                           29
SIROLIMUS (Rapamycin)

   It works like CSA and Tacrolimus.

   Side effects : Hypertrigleceridemia,
    thrombocytopenia, wound healing
    problems,anemia and oral ulcers.


                                           30
MYCOPHENOLATE MOFETIL
(CellCept)
   Inhibits inosine monophosphate
    dehydogenase required for de novo
    purine synthesis which expanding T and
    B cells depend on; also inhibits
    adhesion molecule and antibody
    production.



                                         31
32
33
Organ preservation
   The storage tempreture of an organ is 4
    degrees, keep on ice in a cooler.
   Cold decreases the rate of chemical reactions;
    decreased energy use minimizes effects of
    hypoxia and ischemia.
   The most commonly used fluid worldwide is
    the University of Wisconsin (UW) solution for
    lengthening organ preservation time.
     It contains:
    potassium sulfate, buffers, starch, steroids,
    insulin, electrolytes and adenosine.
                                                34
Maximum Time between harvest
and transplant of organ
     Heart          6 hours

     Lungs          6 hours

    Pancreas       24 hours

     Liver         24 hours

     Kidney      Up to 72 hours

                                  35
        Timeline of successful
        transplants
   1905: First successful cornea transplant by Eduard Zirm[6]
   1954: First successful kidney transplant by Joseph Murray (Boston, U.S.A.)
   1966: First successful pancreas transplant by Richard Lillehei and William Kelly (Minnesota,
    U.S.A.)
   1967: First successful liver transplant by Thomas Starzl (Denver, U.S.A.)
   1967: First successful heart transplant by Christiaan Barnard (Cape Town, South Africa)
   1981: First successful heart/lung transplant by Bruce Reitz (Stanford, U.S.A.)
   1983: First successful lung lobe transplant by Joel Cooper (Toronto, Canada)
   1986: First successful double-lung transplant (Ann Harrison) by Joel Cooper (Toronto, Canada)
   1995: First successful laparoscopic live-donor nephrectomy by Lloyd Ratner and Louis Kavoussi
    (Baltimore, U.S.A.)
   1998: First successful live-donor partial pancreas transplant by David Sutherland (Minnesota,
    U.S.A.)
   1998: First successful hand transplant (France)
   1999: First successful Tissue Engineered Bladder transplanted by Anthony Atala (Boston
    Children's Hospital, U.S.A.)[7]
   2005: First successful partial face transplant (France)
   2006: First jaw transplant to combine donor jaw with bone marrow from the patient, by Eric M.
    Genden (Mount Sinai Hospital, New York)[8]
   2008: First successful complete full double arm transplant by Edgar Biemer, Christoph Höhnke
    and Manfred Stangl (Technical University of Munich, Germany)[9]
   2008: First baby born from transplanted ovary.[10]
   2008: First transplant of a human windpipe using a patient’s own stem cells, by Paolo Macchiarini
    (Barcelona, Spain)[11]
   2010: First full facial transplant, by Dr Joan Pere Barret and team (Hospital Universitari Vall
    d'Hebron on July 26, 2010 in Barcelona, Spain.)[12]
                                                                                                        36
Recepient Qualification
   Most cases <60 yr old
   Disqualified if:
       Recent MI
       Active infection
       Malignancy
       Substance abuse
       Limited life expectancy from unrelated
        disease
                                                 37
Kidney transplant
   There are 2 sources of donor kidneys :
    Cadaveric (70%) and living related
    donor (30%).
   ABO and HLA typing are the tests for
    compatibility.
   The left donor kidney is preferred over
    the right because it has longer renal
    vein that allows for easier anastomosis.
                                           38
   The placement of the kidney should be
    heterotopic – Retroperitoneal in the
    right lower quadrant or left lower
    quadrant above the inguinal ligament.
   It is placed heterotopic to preserve
    native kidneys, allow easy access to
    iliac vessels, places ureter close to the
    bladder, easy to biopsy kidney.
                                                39
   Anastomoses of heterotopic kidney transplant
    are :

   Renal artery to iliac artery.
   Renal vein to iliac vein.
   Ureter to bladder

Note: the ureter should be placed
 submucosally through the bladder wall to
 decrease reflux.                              40
41
   Always should keep the native kidneys
    in site unless there are indications for
    removal like uncontrolled HTN and
    ongoing renal sepsis.




                                               42
   Indication for renal transplant :

Irreversible renal failure from :
 Glomerulonephritis (leading cause).

 Pyelonephritis.
 Polycystic kidney disease.
 Malignant HTN.

 Reflux pyelonephritis.
 Goodpasture’s syndrome.
 Congenital renal hyperplasia.

 Fabry’s disease.
 Alport syndrome.

 Renal cortical necrosis.

 Damage caused bay type 1 DM.

                                        43
   Rejection :
the red flag that indicate rejection is increased
    creatinine.

 Differential diagnosis:
1.   Obstruction.
2.   Dehydration.
3.   Infection.
4.   Intoxication.
5.   Lymhocele.
6.   ATN.
Symptoms : fever- malaise- HTN – ipsilateral leg edema
     – pain at the transplant site- oligouria.       44
   Work up :
o   U/S with doppler : look for fluid
    collection around the kidney,
    hydonephrosis, flow in vessels.
o   Radionuclide scan : look at the flow and
    the function.
o   Biopsy : to distinguish between
    rejection and cyclosporine toxicity.
                                           45
   The time course for return of normal renal
    function after renal transplant is :

    3-5 days in living related donor.
    7-15 days in cadaveric donor.

   Survival rate associated with cadaveric source
    is 90 % at 1 year if HLA matched; 80 % at 1
    year if not HLA matched; 75 % graft survival
    at 3 years.                                  46
Liver Transplant
    Indication :
 liver failure from :
    Cirrhosis (leading indication in adult).
    Budd chiari.
    Biliary atresia (leading indication in children).
    Neonatal hepatitis.
    Chronic active hepatitis.
    Fulminant hepatitis with drug toxicity.
    Sclerosing cholangitis.
    Caroli’s disease.
    Subacute hepatic necrosis.
    Congenital hepatic fibrosis.
    Inborn errors of metabolism.
    Fibrolamellar hepatocellular carcinoma.
    Hepatorenal syndrome.

                                                         47
   The proper placement of liver transplant is
    Orthotopic.

   ABO test for compatibility.

    An adult donates a left lateral segment to a child or
    an adult donates a right lobe to another adult.




                                                             48
49
   Split liver transplant :

     A cadaveric liver is harvested and
    divided into two halves for two
    recipients usually the left lateral lobe
    segment for a child and a right lobe for
    an adult.

                                               50
51
   Rejection :
    Red flags :
o   Decreased bile drainage.
o   Increased serum bilirubin.
o   Increased LFTs.

Note : Rejection usually involves the biliary epithelium
  first and later the vascular endothelium.

   “Vanishing bile duct syndrome” is called for chronic
    liver rejection.
                                                           52
Work up :
 U/S with doppler : look at flow of portal
  vein, hepatic artery; rule out
  thrombosis, leaky anastomosis,
  infection (abcess).
 Cholangiogram : look at the bile ducts.

 Biopsy : important especially 3-6 wks
  postop (CMV).
                                          53
 First year survival rate is approximately 80%
  to 85%.
 About 20% require retransplant. The reasons
  behind that are :
1- Primary graft dysfunction
2- Rejection
3- Infection
4- Vascular thrombosis
5- Recurrence of primary disease.
                                              54
Pancreas Transplant
   Indications :
    Type I (juvenile) diabetes mellitus
    associated with sever complications
    (renal failure, blindness, neuropathy) or
    very poor glycemic control.
    ABO, DR matching (class II) are the
    tests for compatibility.
   Should be placed heterotopic in the iliac
    fossa or paratopic.
                                            55
   The anastomoses of the exocrine duct
    in heterotopic replacement is to the
    bladder in order to measure the
    ammount of amylase in the urine and
    gives an indication of pancreatic
    function (high urine amylase indicate
    good pancreatic function).
   Possible complication ---- loss of
    bicabonate.
                                            56
   The anastomoses of the exocrine duct
    in paratopic placement is to the
    jujenum.
   There is advantage here that endocrine
    function drains to the portal vein
    directly to the liver, and pancreatic
    contents stay within the GI tract ( no
    need to replace bicarbonate).
                                         57
58
   Kidney-pancreas transplantation:

kidney function is a better indicator of
 rejection; also better survival of graft is
 associated with kidney-pancreas
 transplant than pancreas alone !!!!


                                           59
60
   Rejection :
    Red flags :
o   Hyperamylasemia.
o   Hyperglycemia (late).
o   Hypoamylasuria.
o   Graft tenderness.

                            61
Heart Transplant
 Indications :
  Age birth to 65 years with terminal acquired
  heart disease– class IV of New York Heart
  Association classification (inability to do any
  physical activity without discomfort = 10%
  chance of surviving 6 months).
 Contraindications:
 Active infection.

 Poor pulmonary function.

 Increased pulmonary artery resistance.
                                                    62
   ABO Test required for compatibility.

   The placement should be orthotopic.

   The donor heart atriums, pulmonary
    artery and aorta are sewn to the
    recipient heart atriums, pumonary
    artery and aorta.
                                           63
   Rejection :

    Red flags:
    fever, HTN & Hypotention.

The test for rejection is endomyocardial biopsy
  which is much more important than clinical
  signs and symptoms so patient should
  undergo routine biopsy.

                                                  64
   Survival rates for 1 year is 85%, and for
    5 years is 65%.




                                            65
Intestinal Transplant
 Transplantation of small bowel
 Transplant anastomoses are :

   1. Donor SMA to recipient aorta.
   2. Donor SMV to recipient portal vein.
 Indications:
  1. Short gut syndrome.
  2. inability to sustain TPN(liver failure,
  lack of venous access,…).
                                               66
   >90% of intestinal transplant recipients
    have an episode of rejection in the first
    6 months.
   Post op problems :
   Rejection.
   Graft versus host disease from large
    lymphoid tissue in transplanted
    intestines.
   Sepsis (most common cause of death
    post op).                                67
   Graft survival rate for the 1st year is
    65%, for 3 years is 50% and for 5 years
    is only 15%.




                                         68
Lung transplant
    Indications :
    Any disease that substantially limits activities of daily living
     and is likely to result in death within 12-18 months :
    Pulmonary fibrosis.
    COPD.
    Eosinophilic granuloma.
    Primary pulmonary HTN.
    Cystic fibrosis.

 Contraindications:
   Current smoking
   Active infection.
                                                                   69
Donor Requirments:
 55 years of age or younger.

 Clear chest film.

 PA oxygen tention of 300 on 100%
  oxygen and 5 cm PEEP.
 No purulent secretions on

  bronchoscopy.

                                     70
   The anastomoses are Bronchi,
    Pulmonary aretry and pulmonary veins.
   Post op complications include :
   Bronchial necrosis/stricture.
   Reperfusion.
   Pulmonary edema.
   Rejection.
                                        71
   The survival rate for the 1st year is 71%
    and for the 5 years is 45%.




                                            72
Transplant Complications
1) Infection:
   DNA viruses specially CMV, HSV and VZV.
  CMV virus is suspected after 21 days post-
   transplant, and the peak incidence of CMV
   infections 4-6 weeks post transplant.
  Signs and symptoms of CMV infection : fever,
   neutropenia, signs of rejection, viral pneumonitis,
   hepatitis and colitis. Treated by Ganciclovir with
   immunoglobulins.
  HSV signs and symptoms : herpetic lesions,
   shingles, fever, neutropenia and rejection of
   transplant. Treated by Acyclovir.
                                                         73
2) Malignancy esp (basal cell and
   squamous cell skin/lip cancer)
3) Rejection
4) Post transplant lymphoproliferative
   disease
5) Complications of steroids


                                         74
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