Principles Of Trauma Care

TRANSPLANTATIONTRANSPLANTATION

Celso M. Fidel, Celso M. Fidel, MD,FPSGS,FPCSMD,FPSGS,FPCS

Diplomate Philippine Diplomate Philippine Board of SurgeryBoard of Surgery

INTRODUCTIONINTRODUCTION

References have existed in the scientific References have existed in the scientific literature for centuriesliterature for centuries

Field of modern transplantation did not come Field of modern transplantation did not come into being until the latter half of the 12into being until the latter half of the 12thth century. century.

Experimental procedure 50 years ago, it has Experimental procedure 50 years ago, it has evolved to become the treatment of choice for evolved to become the treatment of choice for end-stage organ failure end-stage organ failure resulting from almost resulting from almost any of a wide variety of causes.any of a wide variety of causes.


Transplantation of the Transplantation of the kidney, liver, pancreas, kidney, liver, pancreas, intestine, heart, and lungs intestine, heart, and lungs has now become has now become commonplace in all parts of the world.commonplace in all parts of the world.

In fact, transplantation is now so widely In fact, transplantation is now so widely accepted and successful accepted and successful


Main problem Main problem facing the field today is notfacing the field today is not

surgical technique, rejection, or management surgical technique, rejection, or management of complications, but of complications, but rather supply of organsrather supply of organs. .

An increasing number An increasing number of of diseasesdiseases and patients and patients are now potentially treatable with transplants; are now potentially treatable with transplants; however, this increase, coupled with the however, this increase, coupled with the decrease in contraindications to transplants, decrease in contraindications to transplants, has meant has meant an increasing number of patients are an increasing number of patients are now awaiting organ replacement therapynow awaiting organ replacement therapy..

DefinitionsDefinitions

TransplantationTransplantation is is the act of transferring an the act of transferring an organ, tissue, or cellorgan, tissue, or cell from one place to another. from one place to another. Transplants are divided into Transplants are divided into three categories three categories based on the similarity between the donor and based on the similarity between the donor and the recipient:the recipient:

1. Autotransplants1. Autotransplants

2. Allotransplants 2. Allotransplants

3. 3. Xenotransplants Xenotransplants


11. . AutotransplantsAutotransplants Involve Involve transfer of tissue transfer of tissue or organs from one part of an individual to or organs from one part of an individual to another part of the same individual.another part of the same individual. & & include include

skin skin grafts, vein grafts for bypasses, bone and grafts, vein grafts for bypasses, bone and cartilage transplants, and nerve transplants.cartilage transplants, and nerve transplants.

Since donor & recipient are the same person Since donor & recipient are the same person no no imimmunologicmunologic disparity exists,disparity exists, no no iimmunosuppresmmunosuppression sion

They are the most common type of transplantsThey are the most common type of transplants


22. . AllotransplantsAllotransplants -transfer from one individual -transfer from one individual to a different individual of the same species—to a different individual of the same species—

Most common are solid organ transplants. Most common are solid organ transplants. Immunosuppression is required for allograft Immunosuppression is required for allograft recipients in order to prevent rejection . recipients in order to prevent rejection .

3. 3. XenotransplantsXenotransplants -Involve transfer across -Involve transfer across species barriers. Currently, these are relegated species barriers. Currently, these are relegated to the laboratory, given the complex, potent to the laboratory, given the complex, potent immunologic barriers to success.immunologic barriers to success.

HistoryHistory

Important events in the first half of the 20th Important events in the first half of the 20th century includedcentury included

The development of the surgical techniques for The development of the surgical techniques for vascular anastomosis by vascular anastomosis by Alexis CarrelAlexis Carrel;;

The first human-to-human kidney transplants by The first human-to-human kidney transplants by Yu Yu Voronoy Yu Yu Voronoy in the 1930sin the 1930s

The studies of skin transplantation in animal The studies of skin transplantation in animal models by models by Sir Sir Peter Medawar Peter Medawar in the 1940s.in the 1940s.

HistoryHistory

Medawar's work was especially crucial: it Medawar's work was especially crucial: it provided scientific evidence for the role of the provided scientific evidence for the role of the immune system in the failure of allografts to immune system in the failure of allografts to function long-term, through a process later function long-term, through a process later termed termed rejectionrejection.. His work and observations His work and observations formed the basis for modern transplant formed the basis for modern transplant immunobiologyimmunobiology

HistoryHistory

First human kidney transplant with long-term First human kidney transplant with long-term success was performed in Boston by success was performed in Boston by Joseph Joseph Murray Murray in 1954. in 1954. A living-donor A living-donor transplantion transplantion between between identical twin brothersidentical twin brothers, recipient required , recipient required no no immunosuppressioimmunosuppression & n & lived more than lived more than 20 years, 20 years, eventually dying of coronary artery disease. eventually dying of coronary artery disease.

Other centers performed similar transplants, w/c Other centers performed similar transplants, w/c led to attempts at kidney transplants between led to attempts at kidney transplants between nonidentical individuals, using nonidentical individuals, using total body total body radiation radiation & & agents agents 6-mercaptopurine 6-mercaptopurine for for immunosuppression.immunosuppression.

HistoryHistory

By the late 1950s to early 1960s, the By the late 1950s to early 1960s, the combination of combination of azathioprineazathioprine w/ w/ corticosteroidscorticosteroids allowed kidney allowed kidney allotransplantation to advance out of the realm allotransplantation to advance out of the realm of experimental therapyof experimental therapy

Along with Along with azathioprineazathioprine and and corticosteroids,corticosteroids, the development of the development of antilymphocyte serum antilymphocyte serum (antibodies against human lymphoid tissue) (antibodies against human lymphoid tissue) gave clinicians reliable, gave clinicians reliable, adadequate immunosuppressionequate immunosuppression, , allowing the birth of allowing the birth of extra renal transplants extra renal transplants

HistoryHistory

In 1963, the first liver transplant was performed In 1963, the first liver transplant was performed by by Thomas StarzlThomas Starzl in Denver. in Denver.

The first pancreas transplant was performed in The first pancreas transplant was performed in 1966 in Minneapolis by 1966 in Minneapolis by William Kelly William Kelly and and Richard LilleheiRichard Lillehei..

Christiaan Barnard Christiaan Barnard performed the first heart performed the first heart transplant in 1967 in Cape Town, South Africa. transplant in 1967 in Cape Town, South Africa. The 1970s saw other firsts with intestine, lung, The 1970s saw other firsts with intestine, lung, and islet transplants.and islet transplants.

HistoryHistory

Kidney transplants flourished during the Kidney transplants flourished during the 1970s1970s, , but extrarenal transplants remained largely but extrarenal transplants remained largely experimental. One major reason -experimental. One major reason -rejection rejection remained a major obstacle to the successremained a major obstacle to the success

Dramatic change occurred, w/ the introduction Dramatic change occurred, w/ the introduction in the early in the early 19801980s of s of cyclosporine.cyclosporine.

1.Most specific 1.Most specific immunosuppressive agent immunosuppressive agent available. available.

2.2.IImprovedmproved graft survival post kidney transplants by graft survival post kidney transplants by 30%30%

3.Allowed extrarenal transplants to develop as 3.Allowed extrarenal transplants to develop as viable therapiesviable therapies

HistoryHistory

In the In the 1990s,1990s, many new agents have been many new agents have been developed and approved for use in clinical developed and approved for use in clinical transplantation. transplantation.

These agents allowed more specific targeting of These agents allowed more specific targeting of the immune the immune system pathways of rejection system pathways of rejection process. process. As a result, rejection As a result, rejection rates substantiarates substantially declined lly declined for all types of transplants & graft survival rates havefor all types of transplants & graft survival rates have increased.increased.

HistoryHistory

Recent success of transplants is due to the Recent success of transplants is due to the developments in developments in clinical clinical immunosuppressionimmunosuppression. . More powerful . . More powerful immunosuppression has often meant more risk immunosuppression has often meant more risk of infection with opportunistic viral, fungal, and of infection with opportunistic viral, fungal, and bacterial pathogens.bacterial pathogens.

TThehe development development of powerful & efof powerful & effective antimicrobialfective antimicrobial, , antifungal, and antiviral therapy antifungal, and antiviral therapy (in parallel with (in parallel with immunosuppressive agents)immunosuppressive agents) has been crucial to has been crucial to successful solid organ transplantation.successful solid organ transplantation.

HistoryHistory

In the In the late 1980s and early 1990slate 1980s and early 1990s, the , the development of development of cadaveric split-liver transplant cadaveric split-liver transplant techniques and of living-donor liver transplants techniques and of living-donor liver transplants have expanded the donor pool have expanded the donor pool and helped and helped alleviate the significant shortage of donors. alleviate the significant shortage of donors.

The development of The development of laparoscopic donor laparoscopic donor nephrectomynephrectomy enabled faster recovery of living enabled faster recovery of living kidney donors, thereby increasing their numbers. kidney donors, thereby increasing their numbers. The 1990s ushered in innovations with thoracic, The 1990s ushered in innovations with thoracic, pancreatic, and cellular transplants.pancreatic, and cellular transplants.

Transplant ImmunobiologyTransplant Immunobiology

Only after a basic understanding of transplant Only after a basic understanding of transplant immunobiology was obtained could the immunobiology was obtained could the obstacle of rejection be overcome, thus making obstacle of rejection be overcome, thus making clinical transplants possible.clinical transplants possible.

The success of transplants today is due in The success of transplants today is due in large part to large part to control of the rejection processcontrol of the rejection process, , thanks to an ever-deepening understanding of thanks to an ever-deepening understanding of the immune process triggered by a transplant the immune process triggered by a transplant

Transplant ImmunobiologyTransplant Immunobiology

The immune system is important graft rejection, The immune system is important graft rejection, in the body's defense system against viral, in the body's defense system against viral, bacterial, fungal, and other pathogens. Helps bacterial, fungal, and other pathogens. Helps prevent tumor growth the body respond to prevent tumor growth the body respond to shock and trauma. shock and trauma.

As with the body's reaction to an infection, graft As with the body's reaction to an infection, graft rejection is triggered when specific cells of the rejection is triggered when specific cells of the transplant recipient, namely T and B transplant recipient, namely T and B lymphocytes, recognize foreign antigenslymphocytes, recognize foreign antigens

Transplant AntigensTransplant Antigens

Main antigens involved in triggering rejection Main antigens involved in triggering rejection are coded for by a group of genes known as the are coded for by a group of genes known as the major histocompatibility complex major histocompatibility complex (MHC) . In (MHC) . In humans, the MHC complex is known as the humans, the MHC complex is known as the human leukocyte antigen (HLA) systemhuman leukocyte antigen (HLA) system. It . It comprises a series of genes located on comprises a series of genes located on chromosome chromosome


Grouped into two classes, which differ in their Grouped into two classes, which differ in their structure and cellular distribution. structure and cellular distribution.

1. 1. Class I molecules Class I molecules (named HLA-A, -B, and -C) (named HLA-A, -B, and -C) are found on membrane of all nucleated cells.are found on membrane of all nucleated cells.

2. 2. Class II molecules Class II molecules (named HLA-DR, -DP, and (named HLA-DR, -DP, and -DQ) are generally expressed by -DQ) are generally expressed by antigen-antigen-presenting cells presenting cells (APCs) such as B (APCs) such as B lymphocytes, monocytes, and dendritic cells.lymphocytes, monocytes, and dendritic cells.

..


In a nontransplant setting, the function of the HLA In a nontransplant setting, the function of the HLA gene product is to present antigens as gene product is to present antigens as fragments of foreign proteins that can be fragments of foreign proteins that can be recognized by T lymphocytes.recognized by T lymphocytes.

In the transplant setting, HLA molecules can In the transplant setting, HLA molecules can initiate rejection and graft damage, via either initiate rejection and graft damage, via either humoral or cellular mechanisms. humoral or cellular mechanisms.


Humoral rejection occurs if the recipient has Humoral rejection occurs if the recipient has circulating antibodies specific to the donor's circulating antibodies specific to the donor's HLA from prior exposure HLA from prior exposure

1. blood transfusion1. blood transfusion

2. previous transplant2. previous transplant

3. pregnancy3. pregnancy

4. posttransplant, the recipient develops 4. posttransplant, the recipient develops antibodies specific to the donor's HLA.antibodies specific to the donor's HLA.


The antibodies then bind to the donor's recognized The antibodies then bind to the donor's recognized foreign antigens, activating the complement foreign antigens, activating the complement cascade and leading to cell lysis. The cascade and leading to cell lysis. The blood blood group antigens group antigens of the ABO system, though not of the ABO system, though not part of the HLA system, may also trigger this part of the HLA system, may also trigger this form of humoral rejection.form of humoral rejection.

Cellular rejection is the more common type of Cellular rejection is the more common type of rejection after organ transplants. Mediated by T rejection after organ transplants. Mediated by T lymphocytes, it results from activation lymphocytes, it results from activation proliferation proliferation after exposure to donor MHC moleculesafter exposure to donor MHC molecules

Allorecognition and Allorecognition and DestructionDestruction

AllorecognitionAllorecognition is the recognition of foreign HLA is the recognition of foreign HLA antigens by the recipient T cells .This process may antigens by the recipient T cells .This process may occur by either a occur by either a

1. Direct 1. Direct

2. Indirect pathway.2. Indirect pathway.

In In the direct pathwaythe direct pathway, the recipient's T cells directly , the recipient's T cells directly interact with donor HLA molecules, leading to the interact with donor HLA molecules, leading to the generation of activated cytotoxic T cells.generation of activated cytotoxic T cells.


In the In the indirect pathwayindirect pathway, the recipient's own , the recipient's own APCs first process the donor's antigens (which APCs first process the donor's antigens (which may be shed from the parenchymal cells of the may be shed from the parenchymal cells of the graft into the recipient's circulation, or graft into the recipient's circulation, or alternatively may be encountered by the alternatively may be encountered by the recipient's APCs in the graft itself); then the recipient's APCs in the graft itself); then the recipient's APCs present the donor's antigens recipient's APCs present the donor's antigens to the recipient T cells, leading to the activation to the recipient T cells, leading to the activation of those T cells.of those T cells.


Regardless of the method of presentation of Regardless of the method of presentation of foreign MHC, the subsequent steps are similar.foreign MHC, the subsequent steps are similar.

Binding of the T cell to the foreign molecule Binding of the T cell to the foreign molecule occurs at the occurs at the T-cell receptor T-cell receptor (TCR)-CD3 (TCR)-CD3 complex on the surface of the lymphocyte. complex on the surface of the lymphocyte.

This binding leads to transduction of a signal to This binding leads to transduction of a signal to the cell, named signal 1. This signal by itself, the cell, named signal 1. This signal by itself, however, is not sufficient to result in T-cell however, is not sufficient to result in T-cell activation. activation.


Full activation requires transduction of a second Full activation requires transduction of a second signal that is not antigen-dependent. Signal 2 is signal that is not antigen-dependent. Signal 2 is provided by the binding of accessory molecules provided by the binding of accessory molecules on the T cell to corresponding molecules on the T cell to corresponding molecules (ligands) on the APC.(ligands) on the APC.

An example is CD25 on the T lymphocytes An example is CD25 on the T lymphocytes binding with its ligand B on the surface of the binding with its ligand B on the surface of the APC.APC.


Transmission of signal 1 and 2 to the cell nucleus Transmission of signal 1 and 2 to the cell nucleus leads to leads to interleukin-interleukin-2 (IL-2) gene expression and 2 (IL-2) gene expression and to production of this important cytokine. to production of this important cytokine.

IL-2 then permits the entire cascade of T-cell IL-2 then permits the entire cascade of T-cell activation to proceed, leading to proliferation and activation to proceed, leading to proliferation and differentiation of these cells into cells capable of differentiation of these cells into cells capable of causing damage to the graft.causing damage to the graft.

T-cell activation is key in initiating the rejection T-cell activation is key in initiating the rejection process, but B-cell activation and antibody process, but B-cell activation and antibody production also play a role. production also play a role.


Foreign antigens are acquired by Foreign antigens are acquired by immunoglobulin receptors on the surface of B immunoglobulin receptors on the surface of B cells. These antigens are then processed cells. These antigens are then processed similarly to the way that APCs process the similarly to the way that APCs process the donor's antigens. donor's antigens.

The antigen-presenting B cells can then interact The antigen-presenting B cells can then interact with activated T-helper cells. with activated T-helper cells.

This interaction leads to B-cell proliferation, This interaction leads to B-cell proliferation, differentiation into plasma cells, and to antibody differentiation into plasma cells, and to antibody production.production.

Clinical RejectionClinical Rejection

Graft rejection is a complex process involving Graft rejection is a complex process involving several components, includingseveral components, including

1. T lymphocytes, 1. T lymphocytes,

2. B lymphocytes,2. B lymphocytes,

3. Macrophages 3. Macrophages

4. Cytokines, with resultant local inflammatory 4. Cytokines, with resultant local inflammatory injury and graft damage injury and graft damage


Rejection can be classified into four types, Rejection can be classified into four types, based on timing and pathogenesis: based on timing and pathogenesis:

1. Hyperacute1. Hyperacute

2. Accelerated acute 2. Accelerated acute

3. Acute 3. Acute

4. Chronic 4. Chronic

Hyperacute Clinical RejectionHyperacute Clinical Rejection

Usually occurs Usually occurs within minutes within minutes after the after the transplanted organ is reperfused, transplanted organ is reperfused,

Due to the presence of Due to the presence of preformed antibodies preformed antibodies in in the recipient, antibodies that are specific to the the recipient, antibodies that are specific to the donor. donor.

These antibodies may be These antibodies may be directed against directed against the the donor's HLA antigens donor's HLA antigens or they may be anti-ABO or they may be anti-ABO blood group antibodies. blood group antibodies.


Either way, they bind to the Either way, they bind to the vascular vascular endotheliumendothelium in the graft and activate the in the graft and activate the complement cascade, leading to platelet complement cascade, leading to platelet activation and to diffuse activation and to diffuse intravascular intravascular coagulation. coagulation.

The result is a The result is a swollen, darkened graft, which swollen, darkened graft, which undergoes ischemic necrosisundergoes ischemic necrosis..

This type of rejection is generally not This type of rejection is generally not reversible, so prevention is key.reversible, so prevention is key.


Prevention is best done by making sure the Prevention is best done by making sure the graft is ABO-compatible and by performing a graft is ABO-compatible and by performing a pretransplant cross-matchpretransplant cross-match. An in vitro test that . An in vitro test that involves involves mixing the donor's cells mixing the donor's cells with the with the recipient's serum recipient's serum = look for evidence of = look for evidence of donor donor cell destructioncell destruction by recipient antibodies. A by recipient antibodies. A positive cross-match indicates the presence of positive cross-match indicates the presence of preformed antibodies in the recipient that are preformed antibodies in the recipient that are specific to the donor, thus a high risk of specific to the donor, thus a high risk of hyperacute rejection if the transplant is hyperacute rejection if the transplant is performed.performed.


Accelerated AcuteAccelerated Acute

This type of rejection, seen within This type of rejection, seen within the first few the first few days posttransplant,days posttransplant, involves both cellular and involves both cellular and antibody-mediated injury. It is likely when a antibody-mediated injury. It is likely when a recipient has been sensitized by previous recipient has been sensitized by previous exposure to antigens present in the donor, exposure to antigens present in the donor, resulting in an resulting in an immunologic memory response.immunologic memory response.

Acute Clinical RejectionAcute Clinical RejectionThis used to be the most common type of rejection This used to be the most common type of rejection

With modern immunosuppression it is becoming With modern immunosuppression it is becoming less and less common. less and less common.

Usually seen Usually seen within days within days to a few months to a few months posttransplant. posttransplant.

It is predominantly a cell-mediated process, with It is predominantly a cell-mediated process, with lymphocytes being the main cells involved. lymphocytes being the main cells involved.

Biopsy of the affected organ demonstrates a Biopsy of the affected organ demonstrates a cellular infiltrate, with membrane damage and cellular infiltrate, with membrane damage and apoptosis of graft cells.apoptosis of graft cells.

Acute Clinical RejectionAcute Clinical RejectionThe process may be associated with systemic The process may be associated with systemic symptoms such as fever, chills, malaise, and symptoms such as fever, chills, malaise, and arthralgias. arthralgias.

With current immunosuppressive drugs, most With current immunosuppressive drugs, most acute rejection episodes are generally acute rejection episodes are generally asymptomatic. asymptomatic.

They usually manifest with abnormal laboratory They usually manifest with abnormal laboratory values (e.g., elevated creatinine in kidney values (e.g., elevated creatinine in kidney transplant recipients, and elevated transaminase transplant recipients, and elevated transaminase levels in liver transplant recipients).levels in liver transplant recipients).

Acute Clinical RejectionAcute Clinical Rejection

Acute rejection episodes may also be mediated Acute rejection episodes may also be mediated by a humoral, rather than cellular, immune by a humoral, rather than cellular, immune response. B cells may generate antidonor response. B cells may generate antidonor antibodies, which can damage the graft. antibodies, which can damage the graft. Establishing the diagnosis may be difficult, as Establishing the diagnosis may be difficult, as biopsy may not demonstrate a significant biopsy may not demonstrate a significant cellular infiltrate; special immunologic stains cellular infiltrate; special immunologic stains may be necessary.may be necessary.

Chronic Clinical RejectionChronic Clinical RejectionRejection occurs months to years posttransplant.Rejection occurs months to years posttransplant.

Now that short-term graft survival rates have Now that short-term graft survival rates have improved so markedly, chronic rejection is an improved so markedly, chronic rejection is an increasingly common problem. increasingly common problem.

Histologically, the process is characterized by Histologically, the process is characterized by atrophy, fibrosis, and arteriosclerosis. Both atrophy, fibrosis, and arteriosclerosis. Both immune and nonimmune mechanisms are likely immune and nonimmune mechanisms are likely involved. involved.

Clinically, graft function slowly deteriorates over Clinically, graft function slowly deteriorates over months to yearsmonths to years

Immunosuppressive DrugsImmunosuppressive Drugs

FKBPs = FK506-binding proteins; IL-2 = FKBPs = FK506-binding proteins; IL-2 = interleukin-2; LDL = low-density lipoproteins.interleukin-2; LDL = low-density lipoproteins.

Drugs generally used in combination w/ others Drugs generally used in combination w/ others rather than alone. rather than alone.

Induction immunosuppressionInduction immunosuppression drugs drugs administered administered immediately posttransplant to induce immediately posttransplant to induce immunosuppressionimmunosuppression. . Maintenance immunosuppressionMaintenance immunosuppression refers to the drugs refers to the drugs administered to maintain immunosuppression once administered to maintain immunosuppression once recipients have recovered from the operative procedurerecipients have recovered from the operative procedure


Individual drugs can be categorized as either Individual drugs can be categorized as either biologic or nonbiologic agents.biologic or nonbiologic agents.

Biologic agents Biologic agents consist of antibody consist of antibody preparations directed at various cells or preparations directed at various cells or receptors involved in the rejection process; they receptors involved in the rejection process; they are generally used in induction (rather than are generally used in induction (rather than maintenance) protocols. maintenance) protocols.

Nonbiologic agents Nonbiologic agents form the mainstay of form the mainstay of maintenance protocols.maintenance protocols.


Nonbiologic AgentsNonbiologic Agents

1. Corticosteroids1. Corticosteroids

2. Azathioprine2. Azathioprine

3. Cyclosporine3. Cyclosporine

4. Tacrolimus4. Tacrolimus

5. Sirolimus5. Sirolimus

6.6. Mycophenolate MofetilMycophenolate Mofetil


Biologic AgentsBiologic Agents

11. Polyclonal antibodies against lymphocytes . Polyclonal antibodies against lymphocytes used in clinical transplantation since the 1960s. used in clinical transplantation since the 1960s.

2. 2. Monoclonal antibodyMonoclonal antibody developed later, allowed developed later, allowed in turn for the development of biologic agents in turn for the development of biologic agents (such as OKT3) targeted to specific subsets of (such as OKT3) targeted to specific subsets of cells. A number of different cells. A number of different monoclonal monoclonal antibodiesantibodies (MABs) are under development or (MABs) are under development or have been recently approved for use in clinical have been recently approved for use in clinical transplantationtransplantation


CorticosteroidsCorticosteroids

1. Historically, corticosteroids represent the first 1. Historically, corticosteroids represent the first family of drugs used for clinical immunosuppressionfamily of drugs used for clinical immunosuppression..

2. Today steroids remain an integral component 2. Today steroids remain an integral component of most immunosuppressive protocols,often the of most immunosuppressive protocols,often the first-line agents in treatment of acute rejection.first-line agents in treatment of acute rejection.

3. Despite proven benefit, it have significant side 3. Despite proven benefit, it have significant side effects, especially with long-term use. effects, especially with long-term use.

4 Interest in withdrawing steroids from long-term 4 Interest in withdrawing steroids from long-term maintenance protocols recently considered maintenance protocols recently considered


Steroids Steroids

Have Have both anti-inflammatory & immunosuppressiveboth anti-inflammatory & immunosuppressive properties as the two are closely related.properties as the two are closely related.

Effects on the immune system are complex. Effects on the immune system are complex.

Have been used clinically for years, their exact Have been used clinically for years, their exact mechanism of action is not fully understood. mechanism of action is not fully understood.

Primarily, they inhibit the production of T-cell Primarily, they inhibit the production of T-cell lymphokines, which are needed to amplify lymphokines, which are needed to amplify macrophage and lymphocyte responses. macrophage and lymphocyte responses.


Steroids Steroids

Have a number of other immunosuppressive Have a number of other immunosuppressive effects that are not as specific. For example, effects that are not as specific. For example,

1. 1. Cause lymphopenia secondary to Cause lymphopenia secondary to redistribution of redistribution of lymphocytes lymphocytes from vascular compartment back from vascular compartment back to lymphoid tissueto lymphoid tissue

2. 2. Inhibit migration of monocytesInhibit migration of monocytes, and function , and function as anti-inflammatory agents by blocking various as anti-inflammatory agents by blocking various permeability-increasing agents & vasodilators.permeability-increasing agents & vasodilators.

Immunosuppressive DrugsImmunosuppressive Drugs. . Steroids in high doses are first-line choice Steroids in high doses are first-line choice of many of many clinicians for initial treatment of acute cellular rejection. clinicians for initial treatment of acute cellular rejection.

Steroids also are an integral part of most Steroids also are an integral part of most maintenance immunosuppressive regimens.maintenance immunosuppressive regimens.

High-dose (IV) steroids are administeHigh-dose (IV) steroids are administered red immediatelyimmediately posttransplant as induction therapy, followed by high-posttransplant as induction therapy, followed by high-dose oral steroids (e.g., prednisone at 30 mg/d in adults), 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 tapering to maintenance dose of 5 to 15 mg/d over 3 to 6 months.months.

Adverse Adverse effects of steroid are contributeeffects of steroid are contribute significantly to morbidity significantly to morbidity

in transplant recipients. in transplant recipients. Side effects are dose-dependentSide effects are dose-dependent..


Common side effects of SteroidsCommon side effects of Steroids

mild cushingoid facies and habitus,mild cushingoid facies and habitus,

acne,acne,

increased appetite, increased appetite,

mood changes, mood changes,

hypertension, hypertension,

proximal muscle weakness, proximal muscle weakness,

glucose intolerance, glucose intolerance,

impaired wound healing. impaired wound healing.


Less common side effects of SteroidsLess common side effects of Steroids

posterior subcapsular cataractsposterior subcapsular cataracts

glaucomaglaucoma

aseptic necrosis of the femoral heads. aseptic necrosis of the femoral heads.

Immunosuppressive DrugsImmunosuppressive Drugs. . AzathioprineAzathioprine

An antimetabolite, it (AZA) is a derivative of 6-An antimetabolite, it (AZA) is a derivative of 6-mercaptopurine, the active agent. mercaptopurine, the active agent. First introduced for clinical immunosuppression 1962;First introduced for clinical immunosuppression 1962;

In combination with corticosteroids, it became In combination with corticosteroids, it became standard agent worldwide for the next two standard agent worldwide for the next two decades. decades.

Until the introduction of cyclosporine, it was the most Until the introduction of cyclosporine, it was the most widely used immunosuppressive drug, but now has widely used immunosuppressive drug, but now has become an adjunctive component of become an adjunctive component of immunosuppressive drug regimensimmunosuppressive drug regimens

Immunosuppressive DrugsImmunosuppressive Drugs. . AzathioprineAzathioprine

Acts late in the immune process, affecting the Acts late in the immune process, affecting the cell cycle by interfering with DNA synthesis, thus cell cycle by interfering with DNA synthesis, thus suppressing proliferation of activated B and T suppressing proliferation of activated B and T lymphocytes. lymphocytes.

Preventing the onset of acute rejection, but is Preventing the onset of acute rejection, but is not effective in the treatment of rejection not effective in the treatment of rejection episodes themselves.episodes themselves.


The most significant side effect of AZA is bone The most significant side effect of AZA is bone marrow suppression. All three hematopoietic cell marrow suppression. All three hematopoietic cell lines can be affected, leading to leukopenia, lines can be affected, leading to leukopenia, thrombocytopenia, and anemia. thrombocytopenia, and anemia.

Suppression is often dose-related; it is usually Suppression is often dose-related; it is usually reversible with dose reduction or temporary reversible with dose reduction or temporary cessation of the drug. cessation of the drug.

. .

Immunosuppressive DrugsImmunosuppressive Drugs Other significant side effects of AzathioprineOther significant side effects of Azathioprine

hepatotoxicity, hepatotoxicity,

GI disturbances (nausea and vomiting)GI disturbances (nausea and vomiting)

Pancreatitis, and alopecia. Pancreatitis, and alopecia.

Of note is its reaction with allopurinol. It inhibits Of note is its reaction with allopurinol. It inhibits the the

breakdown of AZA and its metabolites, breakdown of AZA and its metabolites, resulting in resulting in excessive accumulation of AZA and toxicity. excessive accumulation of AZA and toxicity.

Severe, prolonged neutropenia, reported with Severe, prolonged neutropenia, reported with both both drugs at standard doses. Those drugs at standard doses. Those who who require allopurinol require allopurinol should receive half the standard dose of AZA and undergo should receive half the standard dose of AZA and undergo careful hematologic monitoring.careful hematologic monitoring.

Immunosuppressive DrugsImmunosuppressive Drugs CyclosporineCyclosporine

Introduced in the Introduced in the early 1980s dramatically altered early 1980s dramatically altered the field of transplantation. the field of transplantation.

SSignificantly improved results after kidney transplants, but ignificantly improved results after kidney transplants, but

its greatest impact was on its greatest impact was on extrarenal transplantsextrarenal transplants. . It was introduced, as the most specific immunosuppressive It was introduced, as the most specific immunosuppressive agent available. agent available.

Compared with steroids or AZA, it much more Compared with steroids or AZA, it much more selectively selectively inhibits the immune responseinhibits the immune response. .

Currently, cyclosporine plays a central role in Currently, cyclosporine plays a central role in maintenance maintenance immunosuppression in almost all types of organ transplantsimmunosuppression in almost all types of organ transplants..

Immunosuppressive DrugsImmunosuppressive DrugsMode of ActionMode of ActionCyclosporine binds w/ its cytoplasmic receptor protein, Cyclosporine binds w/ its cytoplasmic receptor protein, cyclophilin, cyclophilin, w/c subsequently inhibits activity w/c subsequently inhibits activity of calcineurinof calcineurin. .

Doing so impairs expression of several critical Doing so impairs expression of several critical T-cell T-cell activation genes, the most important being IL-2. activation genes, the most important being IL-2.

As a result, T-cell activation is suppressedAs a result, T-cell activation is suppressed. .

Its metabolism is via the cytochrome P450 systemIts metabolism is via the cytochrome P450 system, so , so several drug interactions are possible. Inducers of P450 several drug interactions are possible. Inducers of P450 such as phenytoin decrease blood levelssuch as phenytoin decrease blood levels; drugs such as ; drugs such as erythromycin, cimetidine, ketoconazole, and erythromycin, cimetidine, ketoconazole, and fluconazole increase them.fluconazole increase them.

Immunosuppressive DrugsImmunosuppressive DrugsAdverse effects of cyclosporine can be classified as Adverse effects of cyclosporine can be classified as renal or nonrenal.renal or nonrenal.

Renal ComplicationsRenal Complications

1. 1. NephrotoxicityNephrotoxicity is the most important and troubling is the most important and troubling adverse effect of cyclosporine.adverse effect of cyclosporine.

2.It has a vasoconstrictor effect on the renal 2.It has a vasoconstrictor effect on the renal vasculature. vasculature. This effect (likely a transient, reversible,This effect (likely a transient, reversible, and and dose-dependent phenomenon) may cause early dose-dependent phenomenon) may cause early posttransplant graft dysfunction or may exaggerate posttransplant graft dysfunction or may exaggerate existing poor graft function.existing poor graft function.


Renal ComplicationsRenal Complications

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3. Also, long-term cyclosporine use may result 3. Also, long-term cyclosporine use may result in in interstitial fibrosis of the renal parenchymainterstitial fibrosis of the renal parenchyma, , coupled with arteriolar lesions. The exact coupled with arteriolar lesions. The exact mechanism is unknown, but renal failure may mechanism is unknown, but renal failure may eventually result.eventually result.


Non renal ComplicationNon renal Complication

1.Cosmetic complications1.Cosmetic complications, hirsutism and gingival , hirsutism and gingival hyperplasia, may result in considerable hyperplasia, may result in considerable distress, possibly leading to noncompliant distress, possibly leading to noncompliant behavior, especially in adolescents and women. behavior, especially in adolescents and women.

2.Several neurologic complications2.Several neurologic complications, including , including headaches, tremor, and seizures, also have headaches, tremor, and seizures, also have been reported. Other nonrenal side effects been reported. Other nonrenal side effects include hyperlipidemia, hepatotoxicity, and include hyperlipidemia, hepatotoxicity, and hyperuricemiahyperuricemia

Immunosuppressive DrugsImmunosuppressive DrugsTacrolimusTacrolimus

A metabolite of soil fungus A metabolite of soil fungus Streptomyces Streptomyces tsukubaensitsukubaensi,, found in Japan. Released in the US found in Japan. Released in the US in April 1994 for use in liver transplantation, it is in April 1994 for use in liver transplantation, it is currently used in a fashion similar to cyclosporine.currently used in a fashion similar to cyclosporine.

Like cyclosporine, is a Like cyclosporine, is a calcineurin inhibitorcalcineurin inhibitor & & has a very similar mechanism of action. has a very similar mechanism of action. Cyclosporine acts by Cyclosporine acts by binding cyclophilinsbinding cyclophilins, while , while tacrolimus acts by binding FK506-binding proteins tacrolimus acts by binding FK506-binding proteins (FKBPs). (FKBPs).


The tacrolimus-FKBP complex inhibits the The tacrolimus-FKBP complex inhibits the enzyme calcineurin, which is essential for enzyme calcineurin, which is essential for activating transcription factors in response to activating transcription factors in response to the rise in intracellular calcium seen with the rise in intracellular calcium seen with stimulation of the TCR. stimulation of the TCR.

The net effect of tacrolimus is to inhibit T-cell The net effect of tacrolimus is to inhibit T-cell function by preventing synthesis of IL-2 and function by preventing synthesis of IL-2 and other important cytokines. .other important cytokines. .


Adverse effects of tacrolimus and Adverse effects of tacrolimus and cyclosporine are similarcyclosporine are similar..

Most common problems include Most common problems include

1. Nephrotoxicity 1. Nephrotoxicity

2. Neurotoxicity 2. Neurotoxicity

3. Impaired glucose metabolism 3. Impaired glucose metabolism

4. Hypertension 4. Hypertension

5. Infection 5. Infection

6. Gastrointestinal (GI) disturbances6. Gastrointestinal (GI) disturbances

Immunosuppressive DrugsImmunosuppressive DrugsSirolimusSirolimus

A macrolide antibiotic derived from a soil A macrolide antibiotic derived from a soil actinomycete originally found on Easter Island actinomycete originally found on Easter Island (Rapa Nui),(Rapa Nui),

Sirolimus (previously known as rapamycin) is Sirolimus (previously known as rapamycin) is structurally similar to tacrolimus and binds to the structurally similar to tacrolimus and binds to the same immunophilin (FKBP). same immunophilin (FKBP).

Unlike tacrolimus, it does not affect calcineurin Unlike tacrolimus, it does not affect calcineurin activity, and therefore does not block the activity, and therefore does not block the calcium-dependent activation of cytokine genes. calcium-dependent activation of cytokine genes.

Immunosuppressive DrugsImmunosuppressive DrugsSirolimusSirolimus

Binds so-called target of rapamycin (TOR) proteins Binds so-called target of rapamycin (TOR) proteins resulting in inhibition of resulting in inhibition of P7056P7056 kinase ( enzyme kinase ( enzyme linked to cell division).linked to cell division).

Net result is prevent progression from GNet result is prevent progression from G11 to the to the S S

phase of cell cyclephase of cell cycle, halting cell division., halting cell division.

Commonly used in conjunction with one of the Commonly used in conjunction with one of the calcineurin inhibitors. In such combinations, calcineurin inhibitors. In such combinations, sirolimus is usually sirolimus is usually used to help withdraw or avoid used to help withdraw or avoid the use of steroidsthe use of steroids completely in maintenance completely in maintenance immunosuppressive regimensimmunosuppressive regimens


It has also been used as an alternative to It has also been used as an alternative to tacrolimus or cyclosporine, as part of a tacrolimus or cyclosporine, as part of a calcineurin-sparing protocol. The advantage of calcineurin-sparing protocol. The advantage of this type of protocol is that it is not associated this type of protocol is that it is not associated with long-term nephrotoxicity (as may be seen with long-term nephrotoxicity (as may be seen with the calcineurin agents).with the calcineurin agents).

Hence, sirolimus may prove to be Hence, sirolimus may prove to be better for better for long-term preservation of renal function in long-term preservation of renal function in transplant recipients.transplant recipients.


The major side effects of sirolimus includeThe major side effects of sirolimus include

1. Neutropenia 1. Neutropenia

2. Thrombocytopenia, 2. Thrombocytopenia,

2. Significant elevation of the serum triglyceride 2. Significant elevation of the serum triglyceride and cholesterol levels. and cholesterol levels.

3. Has also been associated with impaired 3. Has also been associated with impaired wound healing, leading to a higher incidence of wound healing, leading to a higher incidence of wound-related complications.wound-related complications.


Mycophenolate MofetilMycophenolate Mofetil

Mycophenolate mofetil (MMF) was approved in Mycophenolate mofetil (MMF) was approved in May 1995 by the FDA for use in the prevention May 1995 by the FDA for use in the prevention of acute rejection after kidney transplants. of acute rejection after kidney transplants.

It has since been rapidly incorporated into It has since been rapidly incorporated into routine clinical practice at many centers as part routine clinical practice at many centers as part of maintenance regimens. of maintenance regimens.

A semisynthetic derivative of mycophenolate A semisynthetic derivative of mycophenolate acid (MPA), it is isolated from the mold acid (MPA), it is isolated from the mold Penicillium glaucumPenicillium glaucum. .


It works by inhibiting It works by inhibiting inosine monophosphate inosine monophosphate dehydrogenasedehydrogenase, which is a crucial, rate-limiting , which is a crucial, rate-limiting enzyme in de novo synthesis of purines. enzyme in de novo synthesis of purines.

Specifically, this enzyme catalyzes the Specifically, this enzyme catalyzes the formation of guanosine nucleotides from formation of guanosine nucleotides from inosine. Many cells have a salvage pathway inosine. Many cells have a salvage pathway and therefore can bypass this need for and therefore can bypass this need for guanosine nucleotide synthesis by the de novo guanosine nucleotide synthesis by the de novo pathway. pathway.


Activated lymphocytes, do not possess Activated lymphocytes, do not possess this salvage this salvage pathway & require de novo synthesis for clonal pathway & require de novo synthesis for clonal expansion. expansion. The net result is a selectiveThe net result is a selective, reversible , reversible antiproliferative effect on T and B lymphocytes.antiproliferative effect on T and B lymphocytes.

MMF differs from cyclosporine, tacrolimus, and MMF differs from cyclosporine, tacrolimus, and sirolimus in that it does not affect cytokine sirolimus in that it does not affect cytokine production production or the events immediately after antigen or the events immediately after antigen recognition.recognition.

Rather, MMF works further distally in chain of Rather, MMF works further distally in chain of activation events to prevent proliferation of the activation events to prevent proliferation of the stimulated T cell. stimulated T cell.


Like AZA, it is an antimetabolite; unlike AZA, its Like AZA, it is an antimetabolite; unlike AZA, its impact is selective: it only affects lymphocytes, impact is selective: it only affects lymphocytes, not neutrophils or platelets. In several clinical not neutrophils or platelets. In several clinical trials, it has proven to be more effective than trials, it has proven to be more effective than AZA, and has largely replaced it.AZA, and has largely replaced it.

Immunosuppressive DrugsImmunosuppressive DrugsBiologic AgentsBiologic Agents

Polyclonal antibodies directed against Polyclonal antibodies directed against lymphocytes used lymphocytes used in clinical transplantation since the 1960s. in clinical transplantation since the 1960s.

Monoclonal antibody techniques, developed Monoclonal antibody techniques, developed later, allowed later, allowed for the development of biologic agents (for the development of biologic agents (such as OKT3such as OKT3) ) targeted to specific subsets of targeted to specific subsets of cells. cells.

Different monoclonal antibodies (MABs) are currently Different monoclonal antibodies (MABs) are currently developed or have been recently approved for use developed or have been recently approved for use in clinical transplantation. in clinical transplantation.

Many are directed against functional secreted Many are directed against functional secreted molecules of the immune system or their molecules of the immune system or their receptors, receptors,


Polyclonal AntibodiesPolyclonal Antibodies

Polyclonal antibodies are produced by Polyclonal antibodies are produced by immunizing animals (such as horses, goats, or immunizing animals (such as horses, goats, or rabbits) with human lymphoid tissue, allowing rabbits) with human lymphoid tissue, allowing for an immune response, removing the for an immune response, removing the resultant immune sera, and purifying the sera in resultant immune sera, and purifying the sera in an effort to remove unwanted antibodies. What an effort to remove unwanted antibodies. What remain are antibodies that will recognize human remain are antibodies that will recognize human lymphocytes.lymphocytes.

Immunosuppressive DrugsImmunosuppressive DrugsMonoclonal AntibodiesMonoclonal Antibodies

MABs are produced by the hybridization of murine MABs are produced by the hybridization of murine antibody-secreting B lymphocytes with a antibody-secreting B lymphocytes with a nonantibody-secreting myeloma cell line. nonantibody-secreting myeloma cell line.

OKT3 remains the most commonly used MAB, but OKT3 remains the most commonly used MAB, but in the last few years introduction of a number of in the last few years introduction of a number of "humanized" MABs (genetically engineered, "humanized" MABs (genetically engineered, possess large domains of human antibody while possess large domains of human antibody while retaining the murine antigen binding site), have a retaining the murine antigen binding site), have a significantly lower potential for toxicity than OKT3.significantly lower potential for toxicity than OKT3.

Immunosuppressive DrugsImmunosuppressive DrugsMonoclonal AntibodiesMonoclonal Antibodies

OKT3 is directed against the CD3 antigen OKT3 is directed against the CD3 antigen complex found on all mature human T cells. complex found on all mature human T cells. The The

CD3 complex is an integral part of the CD3 complex is an integral part of the TCR.TCR.

Inactivation of CD3 by OKT3 causes the TCR Inactivation of CD3 by OKT3 causes the TCR to be lost from the cell surface. to be lost from the cell surface.

The T cells are then ineffective and are rapidly The T cells are then ineffective and are rapidly cleared from the circulation and deposited into cleared from the circulation and deposited into the reticuloendothelial systemthe reticuloendothelial system


Efficacy of OKT3 can be measured by Efficacy of OKT3 can be measured by monitoring monitoring levels of CD3-positive cells in the circulation. levels of CD3-positive cells in the circulation.

If it is effective, the percentage of CD3-positive If it is effective, the percentage of CD3-positive cells should fall to and stay below 5%. cells should fall to and stay below 5%.

Failure to reach this level indicates an Failure to reach this level indicates an inadequate OKT3 dose or the presence of inadequate OKT3 dose or the presence of recipient antibodies directed against OKT3, the recipient antibodies directed against OKT3, the latter scenario being more common after latter scenario being more common after repeated administration of the drug.repeated administration of the drug.


..

OKT3 is highly effective and versatile. Most OKT3 is highly effective and versatile. Most commonly, it is used to treat severe acute commonly, it is used to treat severe acute rejection episodes (i.e., those resistant to rejection episodes (i.e., those resistant to steroids). steroids).

OKT3 also has been used as prophylaxis OKT3 also has been used as prophylaxis against rejection, as induction therapy, and as against rejection, as induction therapy, and as primary rejection treatment.primary rejection treatment.


Significant, even life-threatening adverse Significant, even life-threatening adverse effects may be seen after OKT3 administration, effects may be seen after OKT3 administration, . The most common symptoms are . The most common symptoms are

1. Fever1. Fever

2. Chills2. Chills

3. headaches. 3. headaches.


Most serious side effect of OKT3 is Most serious side effect of OKT3 is

1. a rapidly developing, noncardiogenic 1. a rapidly developing, noncardiogenic pulmonary edema; the risk of this side effect pulmonary edema; the risk of this side effect significantly increases if the patient is fluid-significantly increases if the patient is fluid-overloaded at the time of OKT3 treatment.overloaded at the time of OKT3 treatment.

Other serious side effects include Other serious side effects include 1.encephalopathy1.encephalopathy

2. aseptic meningitis2. aseptic meningitis

3. nephrotoxicity.3. nephrotoxicity.

Organ DonationOrgan Donation

The clinical diagnosis of brain death rests on The clinical diagnosis of brain death rests on three criteria: three criteria:

(1) irreversibility of the neurologic insult; (1) irreversibility of the neurologic insult;

(2) absence of clinical evidence of cerebral (2) absence of clinical evidence of cerebral

function; and most important, function; and most important,

(3) absence of clinical evidence of brain stem (3) absence of clinical evidence of brain stem

function. function.

Organ DonationOrgan DonationWhen testing for brain death exclude ,When testing for brain death exclude ,

1. hypothermia1. hypothermia

2. medication side effects 2. medication side effects

3. drug overdose 3. drug overdose

4. intoxication 4. intoxication

Brain death can be diagnosed by:Brain death can be diagnosed by:

1. routine neurologic examinations (including cold 1. routine neurologic examinations (including cold caloric and apnea testing on two separate caloric and apnea testing on two separate occasions at least 6 hours apart), occasions at least 6 hours apart),


2. coupled with prior establishment of the 2. coupled with prior establishment of the underlying diagnosis. Confirmatory tests must underlying diagnosis. Confirmatory tests must verify the absence of intracranial blood flow on verify the absence of intracranial blood flow on brain flow studies or the presence of an brain flow studies or the presence of an isoelectric electroencephalogram (EEG) isoelectric electroencephalogram (EEG) reading.reading.

Organ DonationOrgan DonationOnce the diagnosis of brain death has been Once the diagnosis of brain death has been established, the process of organ donation can be established, the process of organ donation can be initiated. initiated.

1. 1. Focus Focus switches from treatmentswitches from treatment of elevated of elevated intracranialintracranial pressure to preserving organ function and optimizing pressure to preserving organ function and optimizing peripheral oxygen deliveryperipheral oxygen delivery

2. 2. It is important that management of the It is important that management of the deceased organ deceased organ donor is an active process, requiring aggressive donor is an active process, requiring aggressive monitoring and intervention to ensure that perfusion monitoring and intervention to ensure that perfusion to the organs of interest is not compromised.to the organs of interest is not compromised.

Organ DonationOrgan DonationFor all organ donors determined routinely and For all organ donors determined routinely and frequently:frequently:

1. Core temperature1. Core temperature

2. Systemic arterial blood pressure2. Systemic arterial blood pressure

3. Arterial oxygen saturation3. Arterial oxygen saturation

4. Urine output must be Arterial blood gases, 4. Urine output must be Arterial blood gases, serum electrolytes, blood urea nitrogen, serum serum electrolytes, blood urea nitrogen, serum creatinine, liver enzymes, hemoglobin, and creatinine, liver enzymes, hemoglobin, and coagulation tests also need to be monitored coagulation tests also need to be monitored regularly.regularly.


Tests monitored regularly:Tests monitored regularly:

1. Arterial blood gases1. Arterial blood gases

2. Serum electrolytes2. Serum electrolytes

3. Blood urea nitrogen3. Blood urea nitrogen

4. Serum creatinine4. Serum creatinine

5. Liver enzymes5. Liver enzymes

6. Hemoglobin6. Hemoglobin

7. Coagulation7. Coagulation


Other Points to rememberOther Points to remember

1. Respiratory maintenance with vigorous 1. Respiratory maintenance with vigorous tracheobronchial toilet is importanttracheobronchial toilet is important

2. Maintaining adequate systemic arterial 2. Maintaining adequate systemic arterial perfusion pressure and brisk urine output (>1 to perfusion pressure and brisk urine output (>1 to 2 mL/kg per hour), while minimizing the use of 2 mL/kg per hour), while minimizing the use of vasopressors, contributes to good kidney vasopressors, contributes to good kidney allograft function and reduces the rate of acute allograft function and reduces the rate of acute tubular necrosis (ATN) posttransplant. tubular necrosis (ATN) posttransplant.

Organ DonationOrgan DonationOther Points to rememberOther Points to remember

3. Polyuria is frequent in brain-dead donors, usually 3. Polyuria is frequent in brain-dead donors, usually secondary to diabetes insipidus. secondary to diabetes insipidus.

a. Urine volumes exceed 300 mL/h a. Urine volumes exceed 300 mL/h

b. Hypernatremiab. Hypernatremia

c. Elevated serum osmolality c. Elevated serum osmolality

d. Low urinary Na+ concentration & osmolality.d. Low urinary Na+ concentration & osmolality.

4.Once urine output due to diabetes insipidus exceeds 4.Once urine output due to diabetes insipidus exceeds 300 mL/h300 mL/h, , desmopressindesmopressin (a synthetic (a synthetic analogue of analogue of

vasopressin) should be vasopressin) should be administered.administered.

Organ DonationOrgan DonationOther Points to rememberOther Points to remember

5. After brain death, hypothermia usually ensues. 5. After brain death, hypothermia usually ensues. Adverse effects of hypothermia Adverse effects of hypothermia include: include:

a. Decreased myocardial contractility a. Decreased myocardial contractility

b. Hypotension b. Hypotension

c. Cardiac dysrhythmias c. Cardiac dysrhythmias

d. Cardiac arrest d. Cardiac arrest

e. Hepatic and renal dysfunction e. Hepatic and renal dysfunction

d. Acidosis, and coagulopathy. d. Acidosis, and coagulopathy. Therefore donor core Therefore donor core temperature must be maintained in the normal rangetemperature must be maintained in the normal range


Living DonorsLiving Donors

1. The use of living donors is an integral and 1. The use of living donors is an integral and important part of the field of transplantation important part of the field of transplantation today.today.

2. The first transplants ever performed used 2. The first transplants ever performed used living donors. living donors.

3. Today living donors are commonly used for 3. Today living donors are commonly used for every type of transplant except heart every type of transplant except heart transplants. dealt with by the transplant team.transplants. dealt with by the transplant team.

Organ DonationOrgan Donation Living DonorsLiving Donors

4. The use of living donors offers numerous 4. The use of living donors offers numerous advantages.advantages.

a. Primary is a. Primary is the availability of a life-saving the availability of a life-saving organ. b. A organ. b. A shorter waiting time generally implies a shorter waiting time generally implies a healthier healthier

candidate—one whose body has not candidate—one whose body has not been ravaged by been ravaged by prolonged end-stage organ failure. prolonged end-stage organ failure.

c. Moreover, living-donor transplants are planned c. Moreover, living-donor transplants are planned (rather than emergency) procedures, allowing for (rather than emergency) procedures, allowing for better preoperative preparation of the potential better preoperative preparation of the potential recipient.recipient.



d. Receiving an organ from a closely matched d. Receiving an organ from a closely matched relative may also have immunologic benefits. relative may also have immunologic benefits.

e. Lastly, long-term results may be superior e. Lastly, long-term results may be superior with living-donor transplants, which is certainly with living-donor transplants, which is certainly the case with kidney transplants.the case with kidney transplants.

The major disadvantage of living-donor The major disadvantage of living-donor transplants is to the donor.transplants is to the donor.



5. Medically, there is no possibility of benefit for 5. Medically, there is no possibility of benefit for the donor, only potential for harm. .the donor, only potential for harm. .

6. The kidney, first organ to be used for living-6. The kidney, first organ to be used for living-donor transplants, is the most common type of donor transplants, is the most common type of organ donated by living donors today. . If both organ donated by living donors today. . If both kidneys are the same, the left kidney is kidneys are the same, the left kidney is preferred because of the longer left renal vein preferred because of the longer left renal vein of the kidney, division of the renal vessels, and of the kidney, division of the renal vessels, and removal of the kidney removal of the kidney

Organ PreservationOrgan Preservation

1. Organ preservation methods have played an 1. Organ preservation methods have played an important role in the success of cadaver donor important role in the success of cadaver donor transplantstransplants

2.The use of hypothermia and pharmacologic 2.The use of hypothermia and pharmacologic inhibition to slow down metabolic processes in inhibition to slow down metabolic processes in the organ once removed from the deceased the organ once removed from the deceased donor. .donor. .

3. The most commonly used fluid worldwide is 3. The most commonly used fluid worldwide is the the University of Wisconsin (UW) solution. University of Wisconsin (UW) solution. It It contains lactobionate, raffinose, and contains lactobionate, raffinose, and hydroxyethyl starch.hydroxyethyl starch.

Kidney TransplantationKidney Transplantation

A kidney transplant now represents the A kidney transplant now represents the treatment of choice for patients with end-stage treatment of choice for patients with end-stage renal disease (ESRD). It offers the greatest renal disease (ESRD). It offers the greatest potential for restoring a healthy, productive life potential for restoring a healthy, productive life in most such patients. Compared with dialysis, in most such patients. Compared with dialysis, it is associated with better patient survival and it is associated with better patient survival and superior quality of life, and is more cost-superior quality of life, and is more cost-effectiveeffective


The preoperative evaluation can be divided The preoperative evaluation can be divided into four parts: into four parts:

1. Medical 1. Medical

2. Surgical 2. Surgical

3.Immunologic3.Immunologic

4.Psychosocial. 4.Psychosocial.


The immediate postoperative care of all The immediate postoperative care of all recipients involves recipients involves

1. Stabilizing the major organ systems (e.g., 1. Stabilizing the major organ systems (e.g., cardiovascular, pulmonary, and renal);cardiovascular, pulmonary, and renal);

2. Evaluating graft function 2. Evaluating graft function

3. Achieving adequate immunosuppression 3. Achieving adequate immunosuppression

4. Monitoring and treating complications directly 4. Monitoring and treating complications directly and indirectly related to the transplant. .and indirectly related to the transplant. .

Kidney TransplantationKidney Transplantation 1. Careful attention to fluid and electrolyte 1. Careful attention to fluid and electrolyte

management is crucial. management is crucial.

2. Recipients should be kept euvolemic or slightly 2. Recipients should be kept euvolemic or slightly hypervolemic. hypervolemic.

3. Fluid replacement regulated by hourly replacement 3. Fluid replacement regulated by hourly replacement of urine. Half-normal saline is a good solution to use of urine. Half-normal saline is a good solution to use for urine replacement. for urine replacement.

4. Aggressive replacement of electrolytes, including 4. Aggressive replacement of electrolytes, including calcium, magnesium, and potassium, may be calcium, magnesium, and potassium, may be necessary, especially for recipients undergoing brisk necessary, especially for recipients undergoing brisk diuresis .diuresis .

Kidney TransplantationKidney Transplantation 5. Hypotension is unusual early after a kidney 5. Hypotension is unusual early after a kidney

transplant. When it occurs, it is usually related to transplant. When it occurs, it is usually related to hypovolemia. The treatment is to optimize preload hypovolemia. The treatment is to optimize preload and afterload kidney function, dialysis may be and afterload kidney function, dialysis may be necessary.necessary.

6. A critical aspect of postoperative care is the 6. A critical aspect of postoperative care is the repeated evaluation of graft function, w/c begins repeated evaluation of graft function, w/c begins intraoperatively, soon after kidney is intraoperatively, soon after kidney is reperfused. reperfused.

7. Postoperatively, urine output is most readily 7. Postoperatively, urine output is most readily available & easily measured indicator of graft available & easily measured indicator of graft function. function.

Kidney TransplantationKidney TransplantationRecipients divided into three groups :Recipients divided into three groups :

1. Immediate graft function (IGF)= brisk diuresis 1. Immediate graft function (IGF)= brisk diuresis posttransplant & rapid fall in serum creatinineposttransplant & rapid fall in serum creatinine

2.Slow graft function (SGF)=moderate degree of 2.Slow graft function (SGF)=moderate degree of kidney dysfunction posttransplant, with modest kidney dysfunction posttransplant, with modest amounts of urine and a slowly falling creatinine amounts of urine and a slowly falling creatinine level, no need for dialysis at any time level, no need for dialysis at any time posttransplant; posttransplant;

Delayed graft function (DGF), which represents Delayed graft function (DGF), which represents the far end of the spectrum of posttransplant graft the far end of the spectrum of posttransplant graft dysfunction and is defined by the need for dialysis dysfunction and is defined by the need for dialysis


Other causes include Other causes include

1. A blocked urinary catheter1. A blocked urinary catheter

2. vascular thrombosis2. vascular thrombosis

3. Urinary leak or obstruction 3. Urinary leak or obstruction

4. Early acute rejection4. Early acute rejection

5. Drug toxicity, or DGF 5. Drug toxicity, or DGF

Kidney TransplantationKidney TransplantationPotential complications that may occur early after Potential complications that may occur early after surgerysurgery

1. Hemorrhage1. Hemorrhage

from unligated vessels in the graft hilum or from the from unligated vessels in the graft hilum or from the retroperitoneum of the recipient.retroperitoneum of the recipient.

2. Vascular complications can involve the 2. Vascular complications can involve the donor donor vesselsvessels (renal artery thrombosis or stenosis, renal (renal artery thrombosis or stenosis, renal vein thrombosis), vein thrombosis), the recipient vessels the recipient vessels (iliac artery (iliac artery thrombosis, pseudoaneurysms, and deep venous thrombosis, pseudoaneurysms, and deep venous thrombosis), or both. Renal artery thrombosis thrombosis), or both. Renal artery thrombosis usually occurs early posttransplantusually occurs early posttransplant


Potential complications that may occur early Potential complications that may occur early after surgeryafter surgery

3. Urologic Complications3. Urologic Complications

Manifesting as leakage or obstruction, generally Manifesting as leakage or obstruction, generally occur in 2 to 10% of kidney recipients. The occur in 2 to 10% of kidney recipients. The underlying cause is often related to poor blood underlying cause is often related to poor blood supply and ischemia of the transplant ureter. supply and ischemia of the transplant ureter.

Leakage most commonly occurs from the Leakage most commonly occurs from the anastomotic site. anastomotic site.

Kidney TransplantationKidney TransplantationPotential complications that may occur early after Potential complications that may occur early after surgerysurgery

3. Urologic Complications3. Urologic Complications

Manifesting as leakage or obstruction, generally Manifesting as leakage or obstruction, generally occur in 2 to 10% of kidney recipients. The occur in 2 to 10% of kidney recipients. The underlying cause is often related to poor blood underlying cause is often related to poor blood supply and ischemia of the transplant ureter. supply and ischemia of the transplant ureter.

Leakage most commonly occurs from anastomotic site.Leakage most commonly occurs from anastomotic site.

Causes: Causes: ischemia ischemia

undue tension created by a short ureter, and undue tension created by a short ureter, and

direct surgical injurydirect surgical injury

Urologic ComplicationUrologic Complication

Symptoms include of Anastomotic leakSymptoms include of Anastomotic leak

fever,fever,

pain,pain,

swelling at the graft site,swelling at the graft site,

increased creatinine level, increased creatinine level,

decreased urine output decreased urine output

cutaneous urinary drainagecutaneous urinary drainage


Anastomotic leakAnastomotic leak

Diagnosis can be confirmed initially with a Diagnosis can be confirmed initially with a hippurate renal scanhippurate renal scan, , percutaneous percutaneous nephrostogramnephrostogram is required for precise is required for precise definition.definition.

Early surgical exploration with ureteral re-Early surgical exploration with ureteral re-implantation is usually indicated, although implantation is usually indicated, although small leaks may be managed by percutaneous small leaks may be managed by percutaneous nephrostomy and stent placement with good nephrostomy and stent placement with good results.results.


Early Ureteral obstruction may be due to:Early Ureteral obstruction may be due to:

1. Edema 1. Edema

2. Blood clots2. Blood clots

3. Hematomas, or torsion of the ureter. 3. Hematomas, or torsion of the ureter.

4. Late obstruction generally is due to scarring 4. Late obstruction generally is due to scarring and fibrosis from chronic ischemiaand fibrosis from chronic ischemia

Other ComplicationsOther Complications

A wide variety of medical complications can be A wide variety of medical complications can be seen after a kidney transplant. Infections are seen after a kidney transplant. Infections are probably the most common . Common sites for probably the most common . Common sites for infection include the urinary tract, the infection include the urinary tract, the pulmonary system, and the wound.pulmonary system, and the wound.

Noninfectious medical complications affecting Noninfectious medical complications affecting the cardiac, gastrointestinal, and neurologic the cardiac, gastrointestinal, and neurologic systems have also been well described systems have also been well described posttransplant posttransplant


Posttransplant outcomes have steadily Posttransplant outcomes have steadily improved over the past three decades due to improved over the past three decades due to improvements in improvements in

ImmunosuppressionImmunosuppression

Antirejection therapyAntirejection therapy

Organ retrieval techniquesOrgan retrieval techniques

Perioperative care Perioperative care

Treatment of infectious posttransplant Treatment of infectious posttransplant complications. complications.

Pancreas TransplantationPancreas Transplantation

Posttransplant outcomes have steadily Posttransplant outcomes have steadily improved over the past three decades due to improved over the past three decades due to improvements in improvements in

ImmunosuppressionImmunosuppression

Antirejection therapyAntirejection therapy

Organ retrieval techniquesOrgan retrieval techniques

Perioperative care Perioperative care

Treatment of infectious posttransplant Treatment of infectious posttransplant complications. complications.

Principles Of Trauma Care

Health & Medicine

Transcript of Principles Of Trauma Care