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Principles Of Trauma Care


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Principles Of Trauma Care

  1. 1. TRANSPLANTATION Celso M. Fidel, MD,FPSGS,FPCS Diplomate Philippine Board of Surgery
  2. 2. INTRODUCTION <ul><li>References have existed in the scientific literature for centuries </li></ul><ul><li>  </li></ul><ul><li>Field of modern transplantation did not come into being until the latter half of the 12 th century. </li></ul><ul><li>Experimental procedure 50 years ago, it has evolved to become the treatment of choice for end-stage organ failure resulting from almost any of a wide variety of causes. </li></ul>
  3. 3. INTRODUCTION <ul><li>Transplantation of the kidney, liver, pancreas, intestine, heart, and lungs has now become commonplace in all parts of the world. </li></ul><ul><li>In fact, transplantation is now so widely accepted and successful </li></ul>
  4. 4. INTRODUCTION <ul><li>Main problem facing the field today is not </li></ul><ul><li>surgical technique, rejection, or management of complications, but rather supply of organs . </li></ul><ul><li>  An increasing number of diseases and patients are now potentially treatable with transplants; however, this increase, coupled with the decrease in contraindications to transplants, has meant an increasing number of patients are now awaiting organ replacement therapy . </li></ul>
  5. 5. Definitions <ul><li>Transplantation is the act of transferring an organ, tissue, or cell from one place to another. Transplants are divided into three categories based on the similarity between the donor and the recipient: </li></ul><ul><li>1. Autotransplants </li></ul><ul><li>2. Allotransplants </li></ul><ul><li>3. Xenotransplants </li></ul>
  6. 6. Definitions <ul><li>1 . Autotransplants Involve transfer of tissue or organs from one part of an individual to another part of the same individual. & include skin grafts, vein grafts for bypasses, bone and cartilage transplants, and nerve transplants. </li></ul><ul><li>Since donor & recipient are the same person no im munologic disparity exists, no i mmunosuppres sion </li></ul><ul><li>They are the most common type of transplants </li></ul>
  7. 7. Definitions <ul><li>2 . Allotransplants -transfer from one individual to a different individual of the same species— </li></ul><ul><li>Most common are solid organ transplants. Immunosuppression is required for allograft recipients in order to prevent rejection . </li></ul><ul><li>3. Xenotransplants -Involve transfer across species barriers. Currently, these are relegated to the laboratory, given the complex, potent immunologic barriers to success. </li></ul>
  8. 8. History <ul><li>Important events in the first half of the 20th century included </li></ul><ul><li>The development of the surgical techniques for vascular anastomosis by Alexis Carrel ; </li></ul><ul><li>The first human-to-human kidney transplants by Yu Yu Voronoy in the 1930s </li></ul><ul><li>The studies of skin transplantation in animal models by Sir Peter Medawar in the 1940s. </li></ul>
  9. 9. History <ul><li>Medawar's work was especially crucial: it provided scientific evidence for the role of the immune system in the failure of allografts to function long-term, through a process later termed rejection . His work and observations formed the basis for modern transplant immunobiology </li></ul>
  10. 10. History <ul><li>First human kidney transplant with long-term success was performed in Boston by Joseph Murray in 1954. A living-donor transplantion between identical twin brothers , recipient required no immunosuppressio n & lived more than 20 years, eventually dying of coronary artery disease. </li></ul><ul><li>Other centers performed similar transplants, w/c led to attempts at kidney transplants between nonidentical individuals, using total body radiation & agents 6-mercaptopurine for immunosuppression. </li></ul>
  11. 11. History <ul><li>By the late 1950s to early 1960s, the combination of azathioprine w/ corticosteroids allowed kidney allotransplantation to advance out of the realm of experimental therapy </li></ul><ul><li>Along with azathioprine and corticosteroids, the development of antilymphocyte serum (antibodies against human lymphoid tissue) gave clinicians reliable, ad equate immunosuppression , allowing the birth of extra renal transplants </li></ul>
  12. 12. History <ul><li>In 1963, the first liver transplant was performed by Thomas Starzl in Denver. </li></ul><ul><li>The first pancreas transplant was performed in 1966 in Minneapolis by William Kelly and Richard Lillehei . </li></ul><ul><li>Christiaan Barnard performed the first heart transplant in 1967 in Cape Town, South Africa. The 1970s saw other firsts with intestine, lung, and islet transplants. </li></ul>
  13. 13. History <ul><li>Kidney transplants flourished during the 1970s , but extrarenal transplants remained largely experimental. One major reason - rejection remained a major obstacle to the success </li></ul><ul><li>Dramatic change occurred, w/ the introduction in the early 1980 s of cyclosporine. </li></ul><ul><li>1.Most specific immunosuppressive agent available. </li></ul><ul><li>2. I mproved graft survival post kidney transplants by 30% </li></ul><ul><li>3.Allowed extrarenal transplants to develop as viable therapies </li></ul>
  14. 14. History <ul><li>In the 1990s, many new agents have been developed and approved for use in clinical transplantation. </li></ul><ul><li>These agents allowed more specific targeting of the immune system pathways of rejection process. As a result, rejection rates substantia lly declined for all types of transplants & graft survival rates have increased. </li></ul>
  15. 15. History <ul><li>Recent success of transplants is due to the developments in clinical immunosuppression . . More powerful immunosuppression has often meant more risk of infection with opportunistic viral, fungal, and bacterial pathogens. </li></ul><ul><li>T he development of powerful & ef fective antimicrobial , antifungal, and antiviral therapy (in parallel with immunosuppressive agents) has been crucial to successful solid organ transplantation. </li></ul>
  16. 16. History <ul><li>In the late 1980s and early 1990s , the development of cadaveric split-liver transplant techniques and of living-donor liver transplants have expanded the donor pool and helped alleviate the significant shortage of donors. </li></ul><ul><li>The development of laparoscopic donor nephrectomy enabled faster recovery of living kidney donors, thereby increasing their numbers. The 1990s ushered in innovations with thoracic, pancreatic, and cellular transplants. </li></ul>
  17. 17. Transplant Immunobiology <ul><li>Only after a basic understanding of transplant immunobiology was obtained could the obstacle of rejection be overcome, thus making clinical transplants possible. </li></ul><ul><li>The success of transplants today is due in large part to control of the rejection process , thanks to an ever-deepening understanding of the immune process triggered by a transplant </li></ul>
  18. 18. Transplant Immunobiology <ul><li>The immune system is important graft rejection, in the body's defense system against viral, bacterial, fungal, and other pathogens. Helps prevent tumor growth the body respond to shock and trauma. </li></ul><ul><li>As with the body's reaction to an infection, graft rejection is triggered when specific cells of the transplant recipient, namely T and B lymphocytes, recognize foreign antigens </li></ul>
  19. 19. Transplant Antigens <ul><li>Main antigens involved in triggering rejection are coded for by a group of genes known as the major histocompatibility complex (MHC) . In humans, the MHC complex is known as the human leukocyte antigen (HLA) system . It comprises a series of genes located on chromosome </li></ul>
  20. 20. Transplant Antigens <ul><li>Grouped into two classes, which differ in their structure and cellular distribution. </li></ul><ul><li>1. Class I molecules (named HLA-A, -B, and -C) are found on membrane of all nucleated cells. </li></ul><ul><li>2. 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. </li></ul><ul><li>. </li></ul>
  21. 21. Transplant Antigens <ul><li>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. </li></ul><ul><li>In the transplant setting, HLA molecules can initiate rejection and graft damage, via either humoral or cellular mechanisms. </li></ul>
  22. 22. Transplant Antigens <ul><li>Humoral rejection occurs if the recipient has circulating antibodies specific to the donor's HLA from prior exposure </li></ul><ul><li>1. blood transfusion </li></ul><ul><li>2. previous transplant </li></ul><ul><li>3. pregnancy </li></ul><ul><li>4. posttransplant, the recipient develops antibodies specific to the donor's HLA. </li></ul>
  23. 23. Transplant Antigens <ul><li>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 trigger this form of humoral rejection. </li></ul><ul><li>Cellular rejection is the more common type of rejection after organ transplants. Mediated by T lymphocytes, it results from activation proliferation after exposure to donor MHC molecules </li></ul>
  24. 24. Allorecognition and Destruction <ul><li>Allorecognition is the recognition of foreign HLA antigens by the recipient T cells .This process may occur by either a </li></ul><ul><li>1. Direct </li></ul><ul><li>2. Indirect pathway. </li></ul><ul><li>In the direct pathway , the recipient's T cells directly interact with donor HLA molecules, leading to the generation of activated cytotoxic T cells. </li></ul>
  25. 25. Allorecognition and Destruction <ul><li>In the indirect pathway , the recipient's own APCs first process the donor's antigens (which may be shed from the parenchymal cells of the graft into the recipient's circulation, or alternatively may be encountered by the recipient's APCs in the graft itself); then the recipient's APCs present the donor's antigens to the recipient T cells, leading to the activation of those T cells. </li></ul>
  26. 26. Allorecognition and Destruction <ul><li>Regardless of the method of presentation of foreign MHC, the subsequent steps are similar. </li></ul><ul><li>Binding of the T cell to the foreign molecule occurs at the T-cell receptor (TCR)-CD3 complex on the surface of the lymphocyte. </li></ul><ul><li>This binding leads to transduction of a signal to the cell, named signal 1. This signal by itself, however, is not sufficient to result in T-cell activation. </li></ul>
  27. 27. Allorecognition and Destruction <ul><li>Full activation requires transduction of a second signal that is not antigen-dependent. Signal 2 is provided by the binding of accessory molecules on the T cell to corresponding molecules (ligands) on the APC. </li></ul><ul><li>An example is CD25 on the T lymphocytes binding with its ligand B on the surface of the APC. </li></ul>
  28. 28. Allorecognition and Destruction <ul><li>Transmission of signal 1 and 2 to the cell nucleus leads to interleukin- 2 (IL-2) gene expression and to production of this important cytokine. </li></ul><ul><li>IL-2 then permits the entire cascade of T-cell activation to proceed, leading to proliferation and differentiation of these cells into cells capable of causing damage to the graft. </li></ul><ul><li>T-cell activation is key in initiating the rejection process, but B-cell activation and antibody production also play a role. </li></ul>
  29. 29. Allorecognition and Destruction <ul><li>Foreign antigens are acquired by immunoglobulin receptors on the surface of B cells. These antigens are then processed similarly to the way that APCs process the donor's antigens. </li></ul><ul><li>The antigen-presenting B cells can then interact with activated T-helper cells. </li></ul><ul><li>This interaction leads to B-cell proliferation, differentiation into plasma cells, and to antibody production. </li></ul>
  30. 30. Clinical Rejection <ul><li>Graft rejection is a complex process involving several components, including </li></ul><ul><li>1. T lymphocytes, </li></ul><ul><li>2. B lymphocytes, </li></ul><ul><li>3. Macrophages </li></ul><ul><li>4. Cytokines, with resultant local inflammatory injury and graft damage </li></ul>
  31. 31. Clinical Rejection <ul><li>Rejection can be classified into four types, based on timing and pathogenesis: </li></ul><ul><li>1. Hyperacute </li></ul><ul><li>2. Accelerated acute </li></ul><ul><li>3. Acute </li></ul><ul><li>4. Chronic </li></ul>
  32. 32. Hyperacute Clinical Rejection <ul><li>Usually occurs within minutes after the transplanted organ is reperfused, </li></ul><ul><li>Due to the presence of preformed antibodies in the recipient, antibodies that are specific to the donor. </li></ul><ul><li>These antibodies may be directed against the donor's HLA antigens or they may be anti-ABO blood group antibodies. </li></ul>
  33. 33. Hyperacute Clinical Rejection <ul><li>Either way, they bind to the vascular endothelium in the graft and activate the complement cascade, leading to platelet activation and to diffuse intravascular coagulation. </li></ul><ul><li>The result is a swollen, darkened graft, which undergoes ischemic necrosis . </li></ul><ul><li>This type of rejection is generally not reversible, so prevention is key. </li></ul>
  34. 34. Hyperacute Clinical Rejection <ul><li>Prevention is best done by making sure the graft is ABO-compatible and by performing a pretransplant cross-match . An in vitro test that involves mixing the donor's cells with the recipient's serum = look for evidence of donor cell destruction by recipient antibodies. A positive cross-match indicates the presence of preformed antibodies in the recipient that are specific to the donor, thus a high risk of hyperacute rejection if the transplant is performed. </li></ul>
  35. 35. Clinical Rejection <ul><li>Accelerated Acute </li></ul><ul><li>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. </li></ul>
  36. 36. Acute Clinical Rejection <ul><li>This used to be the most common type of rejection </li></ul><ul><li>With modern immunosuppression it is becoming less and less common. </li></ul><ul><li>Usually seen within days to a few months posttransplant. </li></ul><ul><li>It is predominantly a cell-mediated process, with lymphocytes being the main cells involved. </li></ul><ul><li>Biopsy of the affected organ demonstrates a cellular infiltrate, with membrane damage and apoptosis of graft cells. </li></ul>
  37. 37. Acute Clinical Rejection <ul><li>The process may be associated with systemic symptoms such as fever, chills, malaise, and arthralgias. </li></ul><ul><li>With current immunosuppressive drugs, most acute rejection episodes are generally asymptomatic. </li></ul><ul><li>They usually manifest with abnormal laboratory values (e.g., elevated creatinine in kidney transplant recipients, and elevated transaminase levels in liver transplant recipients). </li></ul>
  38. 38. Acute Clinical Rejection <ul><li>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. Establishing the diagnosis may be difficult, as biopsy may not demonstrate a significant cellular infiltrate; special immunologic stains may be necessary. </li></ul>
  39. 39. Chronic Clinical Rejection <ul><li>Rejection occurs months to years posttransplant. </li></ul><ul><li>Now that short-term graft survival rates have improved so markedly, chronic rejection is an increasingly common problem. </li></ul><ul><li>Histologically, the process is characterized by atrophy, fibrosis, and arteriosclerosis. Both immune and nonimmune mechanisms are likely involved. </li></ul><ul><li>Clinically, graft function slowly deteriorates over months to years </li></ul>
  40. 40. Immunosuppressive Drugs <ul><li>  </li></ul><ul><li>FKBPs = FK506-binding proteins; IL-2 = interleukin-2; LDL = low-density lipoproteins. </li></ul><ul><li>Drugs generally used in combination w/ others rather than alone. </li></ul><ul><li>Induction immunosuppression drugs administered immediately posttransplant to induce immunosuppression . </li></ul><ul><li>Maintenance immunosuppression refers to the drugs administered to maintain immunosuppression once recipients have recovered from the operative procedure </li></ul>
  41. 41. Immunosuppressive Drugs <ul><li>  Individual drugs can be categorized as either biologic or nonbiologic agents. </li></ul><ul><li>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. </li></ul><ul><li>Nonbiologic agents form the mainstay of maintenance protocols. </li></ul> 
  42. 42. Immunosuppressive Drugs <ul><li>  Nonbiologic Agents </li></ul><ul><li>1. Corticosteroids </li></ul><ul><li>2. Azathioprine </li></ul><ul><li>3. Cyclosporine </li></ul><ul><li>4. Tacrolimus </li></ul><ul><li>5. Sirolimus </li></ul><ul><li>6. Mycophenolate Mofetil </li></ul>
  43. 43. Immunosuppressive Drugs <ul><li>  Biologic Agents </li></ul><ul><li>1 . Polyclonal antibodies against lymphocytes used in clinical transplantation since the 1960s. </li></ul><ul><li>2. Monoclonal antibody developed later, allowed in turn for the development of biologic agents (such as OKT3) targeted to specific subsets of cells. A number of different monoclonal antibodies (MABs) are under development or have been recently approved for use in clinical transplantation </li></ul>
  44. 44. Immunosuppressive Drugs <ul><li>Corticosteroids </li></ul><ul><li>1. Historically, corticosteroids represent the first family of drugs used for clinical immunosuppression . </li></ul><ul><li>2. Today steroids remain an integral component of most immunosuppressive protocols,often the first-line agents in treatment of acute rejection. </li></ul><ul><li>3. Despite proven benefit, it have significant side effects, especially with long-term use. </li></ul><ul><li>4 Interest in withdrawing steroids from long-term maintenance protocols recently considered </li></ul>
  45. 45. Immunosuppressive Drugs <ul><li>Steroids </li></ul><ul><li>Have both anti-inflammatory & immunosuppressive properties as the two are closely related. </li></ul><ul><li>Effects on the immune system are complex. </li></ul><ul><li>Have been used clinically for years, their exact mechanism of action is not fully understood. </li></ul><ul><li>Primarily, they inhibit the production of T-cell lymphokines, which are needed to amplify macrophage and lymphocyte responses. </li></ul>
  46. 46. Immunosuppressive Drugs <ul><li>Steroids </li></ul><ul><li>Have a number of other immunosuppressive effects that are not as specific. For example, </li></ul><ul><li>1. Cause lymphopenia secondary to redistribution of lymphocytes from vascular compartment back to lymphoid tissue </li></ul><ul><li>2. Inhibit migration of monocytes , and function as anti-inflammatory agents by blocking various permeability-increasing agents & vasodilators. </li></ul>
  47. 47. Immunosuppressive Drugs <ul><li>. Steroids in high doses are first-line choice of many clinicians for initial treatment of acute cellular rejection. </li></ul><ul><li>Steroids also are an integral part of most maintenance immunosuppressive regimens. </li></ul><ul><li>High-dose (IV) steroids are administe red immediately posttransplant as induction therapy, followed by high-dose oral steroids (e.g., prednisone at 30 mg/d in adults), tapering to maintenance dose of 5 to 15 mg/d over 3 to 6 months. </li></ul><ul><li>Adverse effects of steroid are contribute significantly to morbidity in transplant recipients. Side effects are dose-dependent . </li></ul>
  48. 48. Immunosuppressive Drugs <ul><li>Common side effects of Steroids </li></ul><ul><li>mild cushingoid facies and habitus, </li></ul><ul><li>acne, </li></ul><ul><li>increased appetite, </li></ul><ul><li>mood changes, </li></ul><ul><li>hypertension, </li></ul><ul><li>proximal muscle weakness, </li></ul><ul><li>glucose intolerance, </li></ul><ul><li>impaired wound healing. </li></ul>
  49. 49. Immunosuppressive Drugs <ul><li>Less common side effects of Steroids </li></ul><ul><li>posterior subcapsular cataracts </li></ul><ul><li>glaucoma </li></ul><ul><li>aseptic necrosis of the femoral heads. </li></ul>
  50. 50. Immunosuppressive Drugs <ul><li>. Azathioprine </li></ul><ul><li>An antimetabolite, it (AZA) is a derivative of 6-mercaptopurine, the active agent. </li></ul><ul><li>First introduced for clinical immunosuppression 1962; </li></ul><ul><li>In combination with corticosteroids, it became standard agent worldwide for the next two decades. </li></ul><ul><li>Until the introduction of cyclosporine, it was the most widely used immunosuppressive drug, but now has become an adjunctive component of immunosuppressive drug regimens </li></ul>
  51. 51. Immunosuppressive Drugs <ul><li>. Azathioprine </li></ul><ul><li>Acts late in the immune process, affecting the cell cycle by interfering with DNA synthesis, thus suppressing proliferation of activated B and T lymphocytes. </li></ul><ul><li>Preventing the onset of acute rejection, but is not effective in the treatment of rejection episodes themselves. </li></ul>
  52. 52. Immunosuppressive Drugs <ul><li>The most significant side effect of AZA is bone marrow suppression. All three hematopoietic cell lines can be affected, leading to leukopenia, thrombocytopenia, and anemia. </li></ul><ul><li>Suppression is often dose-related; it is usually reversible with dose reduction or temporary cessation of the drug. </li></ul><ul><li>. </li></ul>
  53. 53. Immunosuppressive Drugs <ul><li>Other significant side effects of Azathioprine </li></ul><ul><li>hepatotoxicity, </li></ul><ul><li>GI disturbances (nausea and vomiting) </li></ul><ul><li>Pancreatitis, and alopecia. </li></ul><ul><li>Of note is its reaction with allopurinol. It inhibits the breakdown of AZA and its metabolites, resulting in excessive accumulation of AZA and toxicity. </li></ul><ul><li>Severe, prolonged neutropenia, reported with both drugs at standard doses. Those who require allopurinol should receive half the standard dose of AZA and undergo careful hematologic monitoring. </li></ul>
  54. 54. Immunosuppressive Drugs <ul><li>Cyclosporine </li></ul><ul><li>Introduced in the early 1980s dramatically altered the field of transplantation. </li></ul><ul><li>S ignificantly improved results after kidney transplants, but its greatest impact was on extrarenal transplants . </li></ul><ul><li>It was introduced, as the most specific immunosuppressive agent available. </li></ul><ul><li>Compared with steroids or AZA, it much more selectively inhibits the immune response . </li></ul><ul><li>Currently, cyclosporine plays a central role in maintenance immunosuppression in almost all types of organ transplants . </li></ul>
  55. 55. Immunosuppressive Drugs <ul><li>Mode of Action </li></ul><ul><li>Cyclosporine binds w/ its cytoplasmic receptor protein, cyclophilin, w/c subsequently inhibits activity of calcineurin . </li></ul><ul><li>Doing so impairs expression of several critical T-cell activation genes, the most important being IL-2. </li></ul><ul><li>As a result, T-cell activation is suppressed . </li></ul><ul><li>Its metabolism is via the cytochrome P450 system , so several drug interactions are possible. Inducers of P450 such as phenytoin decrease blood levels ; drugs such as erythromycin, cimetidine, ketoconazole, and fluconazole increase them. </li></ul>
  56. 56. Immunosuppressive Drugs <ul><li>Adverse effects of cyclosporine can be classified as renal or nonrenal. </li></ul><ul><li>Renal Complications </li></ul><ul><li>1. Nephrotoxicity is the most important and troubling adverse effect of cyclosporine. </li></ul><ul><li>2.It has a vasoconstrictor effect on the renal vasculature. This effect (likely a transient, reversible, and dose-dependent phenomenon) may cause early posttransplant graft dysfunction or may exaggerate existing poor graft function. </li></ul>
  57. 57. Immunosuppressive Drugs <ul><li>Renal Complications </li></ul><ul><li>. </li></ul><ul><li>3. Also, long-term cyclosporine use may result in interstitial fibrosis of the renal parenchyma , coupled with arteriolar lesions. The exact mechanism is unknown, but renal failure may eventually result. </li></ul>
  58. 58. Immunosuppressive Drugs <ul><li>Non renal Complication </li></ul><ul><li>1.Cosmetic complications , hirsutism and gingival hyperplasia, may result in considerable distress, possibly leading to noncompliant behavior, especially in adolescents and women. </li></ul><ul><li>2.Several neurologic complications , including headaches, tremor, and seizures, also have been reported. Other nonrenal side effects include hyperlipidemia, hepatotoxicity, and hyperuricemia </li></ul>
  59. 59. Immunosuppressive Drugs <ul><li>Tacrolimus </li></ul><ul><li>A metabolite of soil fungus Streptomyces tsukubaensi , found in Japan. Released in the US in April 1994 for use in liver transplantation, it is currently used in a fashion similar to cyclosporine. </li></ul><ul><li>Like cyclosporine, is a calcineurin inhibitor & has a very similar mechanism of action. Cyclosporine acts by binding cyclophilins , while tacrolimus acts by binding FK506-binding proteins (FKBPs). </li></ul>
  60. 60. Immunosuppressive Drugs <ul><li>The tacrolimus-FKBP complex inhibits the enzyme calcineurin, which is essential for activating transcription factors in response to the rise in intracellular calcium seen with stimulation of the TCR. </li></ul><ul><li>The net effect of tacrolimus is to inhibit T-cell function by preventing synthesis of IL-2 and other important cytokines. . </li></ul>
  61. 61. Immunosuppressive Drugs <ul><li>Adverse effects of tacrolimus and cyclosporine are similar . </li></ul><ul><li>Most common problems include </li></ul><ul><li>1. Nephrotoxicity </li></ul><ul><li>2. Neurotoxicity </li></ul><ul><li>3. Impaired glucose metabolism </li></ul><ul><li>4. Hypertension </li></ul><ul><li>5. Infection </li></ul><ul><li>6. Gastrointestinal (GI) disturbances </li></ul>
  62. 62. Immunosuppressive Drugs <ul><li>Sirolimus </li></ul><ul><li>A macrolide antibiotic derived from a soil actinomycete originally found on Easter Island (Rapa Nui), </li></ul><ul><li>Sirolimus (previously known as rapamycin) is structurally similar to tacrolimus and binds to the same immunophilin (FKBP). </li></ul><ul><li>Unlike tacrolimus, it does not affect calcineurin activity, and therefore does not block the calcium-dependent activation of cytokine genes. </li></ul>
  63. 63. Immunosuppressive Drugs <ul><li>Sirolimus </li></ul><ul><li>Binds so-called target of rapamycin (TOR) proteins resulting in inhibition of P7056 kinase ( enzyme linked to cell division). </li></ul><ul><li>Net result is prevent progression from G 1 to the S phase of cell cycle , halting cell division. </li></ul><ul><li>Commonly used in conjunction with one of the calcineurin inhibitors. In such combinations, sirolimus is usually used to help withdraw or avoid the use of steroids completely in maintenance immunosuppressive regimens </li></ul>
  64. 64. Immunosuppressive Drugs <ul><li>It has also been used as an alternative to tacrolimus or cyclosporine, as part of a calcineurin-sparing protocol. The advantage of this type of protocol is that it is not associated with long-term nephrotoxicity (as may be seen with the calcineurin agents). </li></ul><ul><li>Hence, sirolimus may prove to be better for long-term preservation of renal function in transplant recipients. </li></ul>
  65. 65. Immunosuppressive Drugs <ul><li>The major side effects of sirolimus include </li></ul><ul><li>1. Neutropenia </li></ul><ul><li>2. Thrombocytopenia, </li></ul><ul><li>2. Significant elevation of the serum triglyceride and cholesterol levels. </li></ul><ul><li>3. Has also been associated with impaired wound healing, leading to a higher incidence of wound-related complications. </li></ul>
  66. 66. Immunosuppressive Drugs <ul><li>Mycophenolate Mofetil </li></ul><ul><li>Mycophenolate mofetil (MMF) was approved in May 1995 by the FDA for use in the prevention of acute rejection after kidney transplants. </li></ul><ul><li>It has since been rapidly incorporated into routine clinical practice at many centers as part of maintenance regimens. </li></ul><ul><li>A semisynthetic derivative of mycophenolate acid (MPA), it is isolated from the mold Penicillium glaucum . </li></ul>
  67. 67. Immunosuppressive Drugs <ul><li>It works by inhibiting inosine monophosphate dehydrogenase , which is a crucial, rate-limiting enzyme in de novo synthesis of purines. </li></ul><ul><li>Specifically, this enzyme catalyzes the formation of guanosine nucleotides from inosine. Many cells have a salvage pathway and therefore can bypass this need for guanosine nucleotide synthesis by the de novo pathway. </li></ul>
  68. 68. Immunosuppressive Drugs <ul><li>Activated lymphocytes, do not possess this salvage pathway & require de novo synthesis for clonal expansion. The net result is a selective , reversible antiproliferative effect on T and B lymphocytes. </li></ul><ul><li>MMF differs from cyclosporine, tacrolimus, and sirolimus in that it does not affect cytokine production or the events immediately after antigen recognition. </li></ul><ul><li>Rather, MMF works further distally in chain of activation events to prevent proliferation of the stimulated T cell. </li></ul>
  69. 69. Immunosuppressive Drugs <ul><li>Like AZA, it is an antimetabolite; unlike AZA, its impact is selective: it only affects lymphocytes, not neutrophils or platelets. In several clinical trials, it has proven to be more effective than AZA, and has largely replaced it. </li></ul>
  70. 70. Immunosuppressive Drugs <ul><li>Biologic Agents </li></ul><ul><li>Polyclonal antibodies directed against lymphocytes used in clinical transplantation since the 1960s. </li></ul><ul><li>Monoclonal antibody techniques, developed later, allowed for the development of biologic agents ( such as OKT3 ) targeted to specific subsets of cells. </li></ul><ul><li>Different monoclonal antibodies (MABs) are currently developed or have been recently approved for use in clinical transplantation. </li></ul><ul><li>Many are directed against functional secreted molecules of the immune system or their receptors, </li></ul>
  71. 71. Immunosuppressive Drugs <ul><li>Polyclonal Antibodies </li></ul><ul><li>Polyclonal antibodies are produced by immunizing animals (such as horses, goats, or rabbits) with human lymphoid tissue, allowing for an immune response, removing the resultant immune sera, and purifying the sera in an effort to remove unwanted antibodies. What remain are antibodies that will recognize human lymphocytes. </li></ul>
  72. 72. Immunosuppressive Drugs <ul><li>Monoclonal Antibodies </li></ul><ul><li>MABs are produced by the hybridization of murine antibody-secreting B lymphocytes with a nonantibody-secreting myeloma cell line. </li></ul><ul><li>OKT3 remains the most commonly used MAB, but in the last few years introduction of a number of &quot;humanized&quot; MABs (genetically engineered, possess large domains of human antibody while retaining the murine antigen binding site), have a significantly lower potential for toxicity than OKT3. </li></ul>
  73. 73. Immunosuppressive Drugs <ul><li>Monoclonal Antibodies </li></ul><ul><li>OKT3 is directed against the CD3 antigen complex found on all mature human T cells. The CD3 complex is an integral part of the TCR. </li></ul><ul><li>Inactivation of CD3 by OKT3 causes the TCR to be lost from the cell surface. </li></ul><ul><li>The T cells are then ineffective and are rapidly cleared from the circulation and deposited into the reticuloendothelial system </li></ul>
  74. 74. Immunosuppressive Drugs <ul><li>Efficacy of OKT3 can be measured by monitoring levels of CD3-positive cells in the circulation. </li></ul><ul><li>If it is effective, the percentage of CD3-positive cells should fall to and stay below 5%. </li></ul><ul><li>Failure to reach this level indicates an inadequate OKT3 dose or the presence of recipient antibodies directed against OKT3, the latter scenario being more common after repeated administration of the drug. </li></ul>
  75. 75. Immunosuppressive Drugs <ul><li>. </li></ul><ul><li>OKT3 is highly effective and versatile. Most commonly, it is used to treat severe acute rejection episodes (i.e., those resistant to steroids). </li></ul><ul><li>OKT3 also has been used as prophylaxis against rejection, as induction therapy, and as primary rejection treatment. </li></ul>
  76. 76. Immunosuppressive Drugs <ul><li>Significant, even life-threatening adverse effects may be seen after OKT3 administration, . The most common symptoms are </li></ul><ul><li>1. Fever </li></ul><ul><li>2. Chills </li></ul><ul><li>3. headaches. </li></ul>
  77. 77. Immunosuppressive Drugs <ul><li>Most serious side effect of OKT3 is </li></ul><ul><li>1. a rapidly developing, noncardiogenic pulmonary edema; the risk of this side effect significantly increases if the patient is fluid-overloaded at the time of OKT3 treatment. </li></ul><ul><li>Other serious side effects include 1.encephalopathy </li></ul><ul><li>2. aseptic meningitis </li></ul><ul><li>3. nephrotoxicity. </li></ul>
  78. 78. Organ Donation <ul><li>The clinical diagnosis of brain death rests on three criteria: </li></ul><ul><li>(1) irreversibility of the neurologic insult; </li></ul><ul><li>(2) absence of clinical evidence of cerebral </li></ul><ul><li>function; and most important, </li></ul><ul><li>(3) absence of clinical evidence of brain stem </li></ul><ul><li>function. </li></ul>
  79. 79. Organ Donation <ul><li>When testing for brain death exclude , </li></ul><ul><li>1. hypothermia </li></ul><ul><li>2. medication side effects </li></ul><ul><li>3. drug overdose </li></ul><ul><li>4. intoxication </li></ul><ul><li>Brain death can be diagnosed by: </li></ul><ul><li>1. routine neurologic examinations (including cold caloric and apnea testing on two separate occasions at least 6 hours apart), </li></ul>
  80. 80. Organ Donation <ul><li>2. coupled with prior establishment of the underlying diagnosis. Confirmatory tests must verify the absence of intracranial blood flow on brain flow studies or the presence of an isoelectric electroencephalogram (EEG) reading. </li></ul>
  81. 81. Organ Donation <ul><li>Once the diagnosis of brain death has been established, the process of organ donation can be initiated. </li></ul><ul><li>1. Focus switches from treatment of elevated intracranial pressure to preserving organ function and optimizing peripheral oxygen delivery </li></ul><ul><li>2. It is important that management of the deceased organ donor is an active process, requiring aggressive monitoring and intervention to ensure that perfusion to the organs of interest is not compromised. </li></ul>
  82. 82. Organ Donation <ul><li>For all organ donors determined routinely and frequently: </li></ul><ul><li>1. Core temperature </li></ul><ul><li>2. Systemic arterial blood pressure </li></ul><ul><li>3. Arterial oxygen saturation </li></ul><ul><li>4. Urine output must be Arterial blood gases, serum electrolytes, blood urea nitrogen, serum creatinine, liver enzymes, hemoglobin, and coagulation tests also need to be monitored regularly. </li></ul>
  83. 83. Organ Donation <ul><li>Tests monitored regularly: </li></ul><ul><li>1. Arterial blood gases </li></ul><ul><li>2. Serum electrolytes </li></ul><ul><li>3. Blood urea nitrogen </li></ul><ul><li>4. Serum creatinine </li></ul><ul><li>5. Liver enzymes </li></ul><ul><li>6. Hemoglobin </li></ul><ul><li>7. Coagulation </li></ul>
  84. 84. Organ Donation <ul><li>Other Points to remember </li></ul><ul><li>1. Respiratory maintenance with vigorous tracheobronchial toilet is important </li></ul><ul><li>2. Maintaining adequate systemic arterial perfusion pressure and brisk urine output (>1 to 2 mL/kg per hour), while minimizing the use of vasopressors, contributes to good kidney allograft function and reduces the rate of acute tubular necrosis (ATN) posttransplant. </li></ul>
  85. 85. Organ Donation <ul><li>Other Points to remember </li></ul><ul><li>3. Polyuria is frequent in brain-dead donors, usually secondary to diabetes insipidus. </li></ul><ul><li>a. Urine volumes exceed 300 mL/h </li></ul><ul><li>b. Hypernatremia </li></ul><ul><li>c. Elevated serum osmolality </li></ul><ul><li>d. Low urinary Na+ concentration & osmolality. </li></ul><ul><li>4.Once urine output due to diabetes insipidus exceeds 300 mL/h , desmopressin (a synthetic analogue of vasopressin) should be administered. </li></ul>
  86. 86. Organ Donation <ul><li>Other Points to remember </li></ul><ul><li>5. After brain death, hypothermia usually ensues. Adverse effects of hypothermia include: </li></ul><ul><li>a. Decreased myocardial contractility </li></ul><ul><li>b. Hypotension </li></ul><ul><li>c. Cardiac dysrhythmias </li></ul><ul><li>d. Cardiac arrest </li></ul><ul><li>e. Hepatic and renal dysfunction </li></ul><ul><li>d. Acidosis, and coagulopathy. Therefore donor core temperature must be maintained in the normal range </li></ul>
  87. 87. Organ Donation <ul><li>Living Donors </li></ul><ul><li>1. The use of living donors is an integral and important part of the field of transplantation today. </li></ul><ul><li>2. The first transplants ever performed used living donors. </li></ul><ul><li>3. Today living donors are commonly used for every type of transplant except heart transplants. dealt with by the transplant team. </li></ul>
  88. 88. Organ Donation <ul><li>Living Donors </li></ul><ul><li>4. The use of living donors offers numerous advantages. </li></ul><ul><li>a. Primary is the availability of a life-saving organ. b. A shorter waiting time generally implies a healthier candidate—one whose body has not been ravaged by prolonged end-stage organ failure. </li></ul><ul><li>c. Moreover, living-donor transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the potential recipient. </li></ul>
  89. 89. Organ Donation <ul><li>Living Donors </li></ul><ul><li>d. Receiving an organ from a closely matched relative may also have immunologic benefits. </li></ul><ul><li>e. Lastly, long-term results may be superior with living-donor transplants, which is certainly the case with kidney transplants. </li></ul><ul><li>The major disadvantage of living-donor transplants is to the donor. </li></ul>
  90. 90. Organ Donation <ul><li>Living Donors </li></ul><ul><li>5. Medically, there is no possibility of benefit for the donor, only potential for harm. . </li></ul><ul><li>6. The kidney, first organ to be used for living-donor transplants, is the most common type of organ donated by living donors today. . If both kidneys are the same, the left kidney is preferred because of the longer left renal vein of the kidney, division of the renal vessels, and removal of the kidney </li></ul>
  91. 91. Organ Preservation <ul><li>1. Organ preservation methods have played an important role in the success of cadaver donor transplants </li></ul><ul><li>2.The use of hypothermia and pharmacologic inhibition to slow down metabolic processes in the organ once removed from the deceased donor. . </li></ul><ul><li>3. The most commonly used fluid worldwide is the University of Wisconsin (UW) solution. It contains lactobionate, raffinose, and hydroxyethyl starch. </li></ul>
  92. 92. Kidney Transplantation <ul><li>A kidney transplant now represents the treatment of choice for patients with end-stage renal disease (ESRD). It offers the greatest potential for restoring a healthy, productive life in most such patients. Compared with dialysis, it is associated with better patient survival and superior quality of life, and is more cost-effective </li></ul>
  93. 93. Kidney Transplantation <ul><li>The preoperative evaluation can be divided into four parts: </li></ul><ul><li>1. Medical </li></ul><ul><li>2. Surgical </li></ul><ul><li>3.Immunologic </li></ul><ul><li>4.Psychosocial. </li></ul>
  94. 94. Kidney Transplantation <ul><li>The immediate postoperative care of all recipients involves </li></ul><ul><li>1. Stabilizing the major organ systems (e.g., cardiovascular, pulmonary, and renal); </li></ul><ul><li>2. Evaluating graft function </li></ul><ul><li>3. Achieving adequate immunosuppression </li></ul><ul><li>4. Monitoring and treating complications directly and indirectly related to the transplant. . </li></ul>
  95. 95. Kidney Transplantation <ul><li>1. Careful attention to fluid and electrolyte management is crucial. </li></ul><ul><li>2. Recipients should be kept euvolemic or slightly hypervolemic. </li></ul><ul><li>3. Fluid replacement regulated by hourly replacement of urine. Half-normal saline is a good solution to use for urine replacement. </li></ul><ul><li>4. Aggressive replacement of electrolytes, including calcium, magnesium, and potassium, may be necessary, especially for recipients undergoing brisk diuresis . </li></ul>
  96. 96. Kidney Transplantation <ul><li>5. Hypotension is unusual early after a kidney transplant. When it occurs, it is usually related to hypovolemia. The treatment is to optimize preload and afterload kidney function, dialysis may be necessary. </li></ul><ul><li>6. A critical aspect of postoperative care is the repeated evaluation of graft function, w/c begins intraoperatively, soon after kidney is reperfused. </li></ul><ul><li>7. Postoperatively, urine output is most readily available & easily measured indicator of graft function. </li></ul>
  97. 97. Kidney Transplantation <ul><li>Recipients divided into three groups : </li></ul><ul><li>1. Immediate graft function (IGF)= brisk diuresis posttransplant & rapid fall in serum creatinine </li></ul><ul><li>2.Slow graft function (SGF)=moderate degree of kidney dysfunction posttransplant, with modest amounts of urine and a slowly falling creatinine level, no need for dialysis at any time posttransplant; </li></ul><ul><li>Delayed graft function (DGF), which represents the far end of the spectrum of posttransplant graft dysfunction and is defined by the need for dialysis </li></ul>
  98. 98. Kidney Transplantation <ul><li>Other causes include </li></ul><ul><li>1. A blocked urinary catheter </li></ul><ul><li>2. vascular thrombosis </li></ul><ul><li>3. Urinary leak or obstruction </li></ul><ul><li>4. Early acute rejection </li></ul><ul><li>5. Drug toxicity, or DGF </li></ul>
  99. 99. Kidney Transplantation <ul><li>Potential complications that may occur early after surgery </li></ul><ul><li>1. Hemorrhage </li></ul><ul><li>from unligated vessels in the graft hilum or from the retroperitoneum of the recipient. </li></ul><ul><li>2. Vascular complications can involve the donor vessels (renal artery thrombosis or stenosis, renal vein thrombosis), the recipient vessels (iliac artery thrombosis, pseudoaneurysms, and deep venous thrombosis), or both. Renal artery thrombosis usually occurs early posttransplant </li></ul>
  100. 100. Kidney Transplantation <ul><li>Potential complications that may occur early after surgery </li></ul><ul><li>3. Urologic Complications </li></ul><ul><li>Manifesting as leakage or obstruction, generally occur in 2 to 10% of kidney recipients. The underlying cause is often related to poor blood supply and ischemia of the transplant ureter. </li></ul><ul><li>Leakage most commonly occurs from the anastomotic site. </li></ul>
  101. 101. Kidney Transplantation <ul><li>Potential complications that may occur early after surgery </li></ul><ul><li>3. Urologic Complications </li></ul><ul><li>Manifesting as leakage or obstruction, generally occur in 2 to 10% of kidney recipients. The underlying cause is often related to poor blood supply and ischemia of the transplant ureter. </li></ul><ul><li>Leakage most commonly occurs from anastomotic site. </li></ul><ul><li>Causes: </li></ul><ul><li>ischemia </li></ul><ul><li>undue tension created by a short ureter, and </li></ul><ul><li>direct surgical injury </li></ul>
  102. 102. Urologic Complication <ul><li>Symptoms include of Anastomotic leak </li></ul><ul><li>fever, </li></ul><ul><li>pain, </li></ul><ul><li>swelling at the graft site, </li></ul><ul><li>increased creatinine level, </li></ul><ul><li>decreased urine output </li></ul><ul><li>cutaneous urinary drainage </li></ul>
  103. 103. Urologic Complication <ul><li>Anastomotic leak </li></ul><ul><li>Diagnosis can be confirmed initially with a hippurate renal scan , percutaneous nephrostogram is required for precise definition. </li></ul><ul><li>Early surgical exploration with ureteral re-implantation is usually indicated, although small leaks may be managed by percutaneous nephrostomy and stent placement with good results. </li></ul>
  104. 104. Urologic Complication <ul><li>Anastomotic leak </li></ul><ul><li>Diagnosis can be confirmed initially with a hippurate renal scan , percutaneous nephrostogram is required for precise definition. </li></ul><ul><li>Early surgical exploration with ureteral re-implantation is usually indicated, although small leaks may be managed by percutaneous nephrostomy and stent placement with good results. </li></ul>
  105. 105. Urologic Complication <ul><li>Early Ureteral obstruction may be due to: </li></ul><ul><li>1. Edema </li></ul><ul><li>2. Blood clots </li></ul><ul><li>3. Hematomas, or torsion of the ureter. </li></ul><ul><li>4. Late obstruction generally is due to scarring and fibrosis from chronic ischemia </li></ul>
  106. 106. Other Complications <ul><li>A wide variety of medical complications can be seen after a kidney transplant. Infections are probably the most common . Common sites for infection include the urinary tract, the pulmonary system, and the wound. </li></ul><ul><li>Noninfectious medical complications affecting the cardiac, gastrointestinal, and neurologic systems have also been well described posttransplant </li></ul>
  107. 107. Kidney Transplantation <ul><li>Posttransplant outcomes have steadily improved over the past three decades due to improvements in </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Antirejection therapy </li></ul><ul><li>Organ retrieval techniques </li></ul><ul><li>Perioperative care </li></ul><ul><li>Treatment of infectious posttransplant complications. </li></ul>
  108. 108. Pancreas Transplantation <ul><li>Posttransplant outcomes have steadily improved over the past three decades due to improvements in </li></ul><ul><li>Immunosuppression </li></ul><ul><li>Antirejection therapy </li></ul><ul><li>Organ retrieval techniques </li></ul><ul><li>Perioperative care </li></ul><ul><li>Treatment of infectious posttransplant complications. </li></ul>
  109. 109. THANK YOU!!!