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Part 2 book “Kidney transplantation” has contents: Approaches to the induction of tolerance, chronic allograft nephropathy, vascular complications after kidney transplantation, urological complications after kidney transplantation, cardiovascular complications after renal transplantation, neurological complications after renal transplantation, kidney transplantation in children,… and other contents.
X3343-Ch23 4/8/08 2:58 PM Page 361 Chapter 23 Approaches to the Induction of Tolerance Satish N Nadig • Gregor Warnecke • Kathryn J Wood Historical Perspective Definition of Tolerance Need for Tolerance in Clinical Transplantation Understanding the Immunological Mechanisms behind Tolerance Induction Overview of T Cell Activation Mechanisms of Tolerance to Donor Antigens Methodology of Tolerance Induction and Maintenance Information from Analyzing Tolerant Recipients Current Strategies Used to Induce Immunological Tolerance to an Allograft Mixed Chimerism Costimulation Blockade Targeting CD3 and Accessory Molecules Leukocyte Depletion at the Time of Transplantation Effect of Immunosuppression on Tolerance Induction HISTORICAL PERSPECTIVE In 1951, Billingham and Medawar18 published a landmark article entitled “The Technique of Free Skin Grafting in Mammals” in the Journal of Experimental Biology In it, Billingham and Medawar provided the foundation for what would become the field of transplant immunology Classic experimental observations, which included a noticeable acceleration in rejection responses after transplanting a second full-thickness allogeneic skin graft harvested from the same donor as the initial graft, set the standard for what eventually would become the groundwork for immunological memory.18,186 Further work that was based on earlier writings of Owen187 involved skin grafting dizygotic mammalian twin calves The observations that these grafts are accepted by both hosts led to the hypothesis that a phenomenon of tolerance to the grafts was achieved secondary to “foreign” blood cells persistent in each twin owing to placental fusion.18 These breakthroughs in research translated to the clinic in 1954, when Murray and colleagues performed the first successful kidney transplant between monozygotic twins at the Peter Bent Brigham Hospital in Boston, Massachusetts The success of this operation was partly due to the lack of immunosuppression needed in the transplant of monozygotic twins Allografts that were subsequently attempted failed initially because of uncontrolled acute rejection responses The quest to identify methods of immunosuppression and tolerance induction in transplantation began.290 The impact of all of this work is still felt today, as many of the experimental models and methods are reproduced in transplant immunology laboratories around the world DEFINITION OF TOLERANCE Generally, the concept of tolerance (operational) refers to the persistent survival of a transplanted allograft in the absence of continuing immunosuppressive therapy and an ongoing destructive immune response targeting the graft The functional and nonspecific nature of this definition may be appropriate in that multiple immunological mechanisms and donor-recipient conditions are required to induce and maintain tolerance to a defined set of donor antigens in vivo Achieving functional tolerance in transplant recipients mandates that specific allograft-destructive responses are “switched off,” while the global immune response to pathogens and carcinogens remains intact The most robust form of transplantation tolerance has to be donor-specific, as opposed to mere immunoincompetence, a requirement that can be tested experimentally by grafting third-party transplants and by challenging tolerant recipients to respond to virus infections and tumor loads The concept of graftspecific tolerance is essential to maintain long-term survival of the graft and host and to eliminate the adverse events associated with lifelong nonspecific immunosuppression NEED FOR TOLERANCE IN CLINICAL TRANSPLANTATION The human immune system broadly comprises a balance between the innate and adaptive responses.96,182 First, these responses recognize antigens from pathogens or foreign material, and then they mount a response against invading tissue or cells to destroy it and clear the body from potential harm The key difference between the two pathways relies on antigen specificity, that is, the innate response neither is specific nor is altered with multiple antigenic challenges; however, the adaptive response is specific for a particular antigen and “remembers” the infectious agent on each successive insult The adaptive response improves with each encounter of a particular foreign agent When the immune system encounters an antigen, it has to decide which type of response to make Multiple factors are taken into account in making this decision, 361 23 X3343-Ch23 4/8/08 2:58 PM Page 362 Table 23–1 Immunosuppressive Agents Used in Solid Organ Transplantation Class of Agent Agent Corticosteroid Prednisone Methylprednisolone Azathioprine Mycophenolate mofetil Mycophenolate sodium Cyclosporine Tacrolimus Sirolimus Everolimus ALG ATG ALS Muromonab (CD3) Basiliximab (IL-2a receptor–CD25) Daclizumab LEA 29Y (CTLA4Ig) Antiproliferative Calcineurin inhibitor mTOR inhibitor Polyclonal antilymphocyte antibodies Monoclonal antibodies (with target) Costimulation blockade Adapted from Taylor AL, Watson CJ, Bradley JA: Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy Crit Rev Oncol Hematol 56:23-46, 2005 including where the antigen is “seen” and the conditions at the time of presentation, in particular, the presence or absence of inflammation Components of the innate and adaptive arms of the immune system participate in this decision-making process.57 The ability to manipulate the outcome—either activation or unresponsiveness—of these immunological responses to foreign antigens on a molecular level may provide insight into therapeutics that mediate acceptance of a graft after transplantation Currently, a variety of immunosuppressive agents are available that are used to control unwanted immune responses against an allograft The improvements in short-term (1 year) graft survival seen since the 1970s in large part are due to the use of immunosuppressive pharmacotherapies in transplant recipients, and 1-year graft survival is now greater than 90% after kidney transplantation at most centers worldwide.169,246,248 In the context of solid organ transplantation, the drugs that currently are available for clinical use, including azathioprine, cyclosporine, tacrolimus, mycophenolate mofetil, rapamycin, antithymocyte globulin, anti-CD25 monoclonal antibodies, and steroids (Table 23-1), are effective at suppressing the processes that lead to early activation of the immune system Each immunosuppressive agent acts, however, on a specific area of the immune response to an allograft, and all are globally nonspecific Each agent has its own deleterious side effects These drugs can be used successfully to prevent or control acute allograft rejection; however, they are less effective at controlling the long-term response to injury and activation of the immune system, or chronic rejection They also seem to be unable to promote the development of unresponsiveness or tolerance to the donor antigens consistently in the way they are used clinically at present Experimental studies suggest that some of these agents may block the development of unresponsiveness under certain circumstances.135,276 For nearly all transplant recipients, the continued survival of the allograft depends on lifelong administration of several immunosuppressive drugs 362 X Nonspecific monoclonal and polyclonal antibodies X Cyclosporine, tacrolimus, pimecrolimus Resting T lymphocyte Early activation Azathioprine, mycophenolate mofetil, mycophenolate sodium IL2 Daclizumab, basiliximab X IL2R Sirolimus Everolimus X X Late activation Proliferation Figure 23–1 Schematic sites of action of common immunosuppressants Each immunosuppressive agent targets a specific step in the activation and proliferation of T lymphocytes (Adapted from Taylor AL, Watson CJ, Bradley JA: Immunosuppressive agents in solid organ transplantation: mechanisms of action and therapeutic efficacy Crit Rev Oncol Hematol 56:23-46, 2005.) The inability of current immunosuppressive drug regimens to induce tolerance to donor antigens may be partly due to the nonspecific nature of the immunosuppression achieved by using drug therapy Drugs, including those mentioned previously, are unable to distinguish between the potentially harmful immune response mounted against the organ graft and responses that could be beneficial, protecting the recipient from infectious pathogens and providing mechanisms to control the development of malignant cells Generally, the drugs act by interfering with lymphocyte activation or proliferation regardless of the antigen specificity of the lymphocyte targeted (Fig 23-1) This lack of immunological specificity means that the immune systems of patients treated with these medications are compromised not only in their ability to respond to the transplant but also in their ability to respond to any other antigenic stimuli that may be encountered after transplantation Patients are more susceptible to infections and are at a higher risk for developing cancer.90,195 It has been suggested that some of the drugs used to treat transplant patients, in particular cyclosporine and tacrolimus, may have additional properties that play a role in enhancing tumor growth in a manner that is unrelated to the drugs’ effects on the immune system.50,89,155 On the contrary, pharmacotherapies such as rapamycin and its analogues which inhibit the mammalian target of rapamycin (mTOR) that is necessary for cellular growth and proliferation, have shown antineoplastic properties.212 The promotion of CD25+CD4+ regulatory T cells by rapamycin along with interleukin (IL)-10, bolstering the suppression of allograftmediated rejection, also has been shown.12 The full potential of organ transplantation may not be realized until alternative approaches to nonspecific immunosuppression are identified Novel strategies that lead to the targeting of only the immune response directed against the transplant in the short-term or the long-term are needed If tolerance to donor antigens of the graft could be achieved X3343-Ch23 4/8/08 2:58 PM Page 363 UNDERSTANDING THE IMMUNOLOGICAL MECHANISMS BEHIND TOLERANCE INDUCTION (see Chapter 2) Overview of T Cell Activation Understanding the mechanisms of activation and regulation of the immune system is important in the development of novel approaches for tolerance induction in the context of transplantation The constant wealth of data on immunological activation appearing in the literature may be overwhelming at times; however, these findings are crucial if strategies for targeting the immune system are to be developed in the future This section sets the scene for discussing the different approaches to tolerance induction being explored most actively at present Developing thymocytes containing mature T cell receptors (TCRs) with low affinity for self-antigen are “neglected” in the thymus and not proliferate TCRs with a high affinity for self-antigen undergo programmed cell death and are “deleted,” leaving the T cells with receptors that have an intermediate affinity to enter the bloodstream and recirculate between blood and peripheral lymphoid tissue Naive T cells continue to circulate, receiving survival signals along the way via IL-7 receptors and in the form of self-peptide/self–major histocompatibilty complex (MHC) complexes; however, when these naive cells encounter a specific antigen, they can differentiate and proliferate into an effector population Naive T cells encounter antigen in the form of a peptide/MHC complex on the surface of antigen-presenting cells (APCs), of which there are many forms Antigen presentation to T cells occurs via macrophages, B cells, and dendritic cells (DCs) DCs are the most professional of the APCs and are highly specialized in ingesting and presenting antigen During the immediate postoperative phase of transplantation, innate immunological responses induce inflammatory reactions and the increased maturation of tissue-specific DCs, hastening antigen uptake and migration to lymphoid tissue for subsequent presentation to naive T cells.96 When activated, CD4+ T cells differentiate early on into T helper type (Th1) or Th2 cells, each with its own portfolio of cytokines Th1 cells secrete macrophage-activating cytokines, including interferon (IFN)-γ, and are responsible for eliciting cell-mediated immune responses In contrast, Th2 cells stimulate antibody production by B cells and secrete a variety of cytokines distinct from Th1 cells, including IL-4 and IL-10.96 There has been strong evidence to suggest a paradoxical influence of IFN-γ on cell and organ transplantation.247,288 On the one hand, IFN-γ is a key mediator in the dysregulated Th1 response that results in a variety of autoimmune diseases, including type diabetes and multiple sclerosis.288 On the other hand, IFN-γ has been identified to play a role in the induction and maintenance of immunological tolerance to alloantigens Experiments using costimulation blockade in wild-type versus IFN-γ−/− murine allograft models revealed the inability to prolong allograft survival in the absence of IFN-γ.85,127 Evidence from our laboratory and others corroborates data linking the suppressive effects of IFN-γ to immunoregulatory T cells.113,218,288 Specifically, our laboratory has shown that the rapid and transient nature of IFN-γ secreted early by alloantigen-induced regulatory T cells may inhibit the proliferation of effector lymphocytes and delay the effects of the adaptive immune response.288 APCs and T lymphocytes are pivotal to the adaptive arm of the immune response They can act as helper and effector cells and play a role in the destructive immune response that occurs after transplantation of a mismatched graft.161 T lymphocytes also may have immunoregulatory suppressive actions to induce tolerance in peripheral lymphoid tissues, controlling ongoing immune responses and suppressing unwanted actions.1,214,287 After transplantation, donor-derived passenger leukocytes are triggered to migrate out of the graft, partly by the proinflammatory environment created as a result of the transplantation procedure itself.133 The release of chemokines and cytokines and complement and endothelial cell activation influence the events leading to the initiation of the immune response In particular, secondary lymphoid tissue chemokine has been reported to play an important role in the migration of DCs in vivo to T cell compartments of the spleen and lymph node.43 As DCs home from the graft to host lymphoid tissue under conditions of inflammation (i.e., after transplantation), they undergo a maturation process that results in the upregulation of costimulatory and adhesion molecules and MHC/peptide complexes, which are essential to trigger the response of naive T cells In this way, immunostimulatory APCs expressing donor-type MHC/peptide complexes are brought into close proximity to naive T cells that may have TCRs capable of recognizing the donor antigens via the direct pathway of allorecognition The interaction of the MHC/peptide complex and TCR forms an immunological synapse, which depends on the successful dynamic rearrangement and polarization of the filamentous actin in the DC cytoskeletal membrane to bring the MHC/peptide complex in close relation to the TCR, initiating an activation response.48,132,156 Specific T cell membrane compartments termed lipid rafts serve as recruitment centers for costimulatory molecules to concentrate on the cytoskeleton, allowing for closer interactions with molecules on the APCs.92,156 T cell activation has been shown to be inhibited when this cytoskeletal arrangement does not occur (Fig 23-2).3 Damage to the graft as a result of removal from the donor and implantation into the recipient causes the release of donor antigen from the graft The proinflammatory environment within the graft attracts recipient-derived APCs to the graft site In this situation, donor alloantigens are taken up by recipient APCs Immature forms of the cells are well designed to capture antigen because they are phagocytic and 363 APPROACHES TO THE INDUCTION OF TOLERANCE reliably, it would ensure that only lymphocytes in the patient’s immune repertoire responding to donor antigens were suppressed, leaving most lymphocytes immunocompetent and able to perform their normal function of protecting the body from infection and cancer after transplantation The development of specific unresponsiveness to donor alloantigens in the short-term or the long-term after transplantation seems to offer the best possibility of achieving effectiveness and specificity in the control of the immune system after transplantation in either the absence or at least reduced loads of nonspecific immunosuppressive agents This chapter discusses the mechanisms underlying tolerance induction and strategies used to induce unresponsiveness in transplanted allografts 23 X3343-Ch23 4/8/08 2:58 PM Page 364 CD40L CD40 B7–1/B7–2 CD28/CTLA-4 MCH with Peptide CD3 ICAM-1 LFA-1 TCR CD4 CD2 LFA-3 Transplanted allograft SLC Passenger leukocytes Maturation Rearrangement DC T cell IS Lymph node Figure 23–2 Formation of the immunological synapse Passenger leukocytes from a transplanted allograft emigrate from the organ and under the influence of secondary lymphoid tissue chemokine (SLC) migrate to the lymph nodes and spleen En route, these dendritic cells (DC) undergo maturation and upregulation/rearrangement of their cell surface markers using mechanisms linked to lipid rafting When in the lymph node, T cell activation ensues on the formation of the immunological synapse (IS) T cell activation requires at least two signals Signal is delivered to the T cell when MHC class II peptide complexes on the antigen-presenting cells (APC) are recognized specifically by the T cell receptor/CD3 complex expressed by the T cell CD4 (T cell) interacts with the MHC class II molecule, fulfilling an adhesion and a signaling function Signal or costimulation is provided by additional cell surface interactions CD28 (T cell) can bind to B7.2 (CD86) and B7.1 (CD80) expressed by the APC This interaction delivers a signal to the T cell that lowers the threshold for T cell activation CD40 on the APC can bind to its ligand, CD40L (CD154) (T cell) This interaction provides additional signals to the T cell but, in contrast to the CD28 pathway, also delivers signals to the APC, resulting in an increase in expression of B7.1 and B7.2 To ensure that the T cell engages the APC for sufficient time for the signaling events to occur, adhesion molecules, including intercellular adhesion molecule (ICAM)-1 and lymphocyte function antigen (LFA)-1, also engage each other have the ability to take up material by micropinocytosis.209 Antigens taken up by one of these routes enter the endocytic pathway and are processed into peptides that can be expressed at the cell surface bound to recipient MHC class II molecules In addition, recipient DCs can take up apoptotic cells that may be generated as a result of ischemia-reperfusion injury after transplantation, and this can lead to antigen presentation in the context of MHC class I molecules More recent evidence suggests that another pathway may exist wherein antigen processed by apoptotic cells may be crosspresented by DCs to generate a MHC class I/peptide complex.4,19 Presentation of donor-derived allopeptides by recipient APCs triggers recipient T cells to respond to donor alloantigen through the indirect pathway of allorecognition.227 T cells responding through the direct and indirect pathway of allorecognition contribute to allograft rejection.72 For a T cell to become activated fully, a threshold number of TCRs needs to be engaged.261 TCR recognition of a donor MHC/peptide complex present on an APC results in signal transduction through the CD3 proteins that associate with the TCR at the cell surface This signal transduction initiates a cascade of biochemical signaling pathways that are contributed to by interactions between accessory, costimulatory, and adhesion molecules and culminate ultimately in cytokine production and proliferation of the triggered T cell and its differentiation into an effector cell (Fig 23-3) 364 Accessory and costimulatory molecules that have been shown to be important in triggering T cell activation on the T cell side include CD4, CD11b/CD18 (leukocyte function associated antigen [LFA]-1), CD28, and CD154 (CD40 ligand) These molecules must engage their ligands on APCs, MHC class II, intercellular adhesion molecule (ICAM), CD86/80 (B7-1/B7-2), and CD40 to ensure that the threshold for activation of a naive T cell is overcome when antigen recognition has occurred It is well established that T cell activation occurs in the two-signal pathway described previously, wherein the MHC/peptide complex interacts with TCR constituting the first signal, and then various costimulatory molecules interact with each other to complete the induction of activation The process is much more complex, however When CD28 molecules on the T cell surface interact with B7 molecules on the APC, lipid rafts become rapidly polarized even in the absence of TCR/MHC complex formation Some downstream effects of TCR triggering, such as increases in intracellular calcium levels and translocation of nuclear factor κB to the nucleus, may occur with B7-CD28 interaction alone, questioning the actual sequence of the traditional signaling hypothesis.128 The cytokine and chemokine milieu present at the time these molecular engagements occur affects the differentiation pathway a T cell takes and the course of the response.180 Cytokines and chemokines can modulate the expression of 4/8/08 2:58 PM Page 365 CD4/8 CD28 CTLA-4 APPROACHES TO THE INDUCTION OF TOLERANCE TcR LFA-1 CTLA-4 CD3 Y P PI3K PY PIP3 PIP2 Y SHP-2 P PP2A PLC-γ1 SLP-76 LAT P YY P P YY P LCK PIP3 ZAP-70 X3343-Ch23 VAV NCK ADAP IP3 IP3-Receptor WASP DAG SKAP55 Calcineurin RAS or PKC Ca+ X ER NF-AT P Inhibition of ERK/JNK activation, inhibition of NF-AT, AP-1, NF-κB activation X X X Nucleus T-bet NF-AT IFN-γ NF-AT AP-1 NF-AT GATA3 IL-2 IL-4 NF-κB Figure 23–3 Model for T cell receptor (TCR) and costimulator signaling during T cell activation Engagement of the TCR leads to rapid activation of Src kinase Lck, which phosphorylates ITAM motifs in the CD3 and TCR chain, followed by the activation of ZAP-70, which contributes to the downstream phosphorylation of adapters, such as LAT, SLP-76, and ADAP These adapters form a signaling complex that includes NCK, VAV, PLCγ1, and other molecules The phosphorylated PLCγ is important for regulating calcium flux and activating PKC and MAPK/ERK, leading to activation of transcription factors (i.e., NF-AT, AP1, and NFκB) and cytokine production NF-AT proteins cooperate with T-bet in Th1 cells and GATA3 in Th2 cells to maintain and commit to T helper cell differentiation through the induction of IFN-γ or IL-4 Also, CD28 associates with PI3K and VAV to upregulate cytokine production through RAS/PKC or PI3K effector-involved signal pathways CTLA4 might interact with PP2A, PI3K, or SHP-2 Cross-linking of CTLA4 has been found to reduce TCR-dependent activation of MAPK, ERK, and JNK and of transcription factors (i.e., NF-AT, AP1, and NFκB) VAV-NCK-WASP contributes to actin polymerization, and SLP76-ADAP-SKAP55 regulates integrin-mediated T cell adhesion the cell surface molecules mentioned previously and the expression of cytokine and chemokine receptors themselves This modulation can result in differential signaling in the T cell and APC, tipping the balance of the response from full to partial activation or, in some circumstances, inactivation of the cells involved, dramatically modifying the downstream events (i.e., cell migration patterns and the generation of effector cells) Activation signals in the form of cytokines propagate the responses initiated by signals and and are often referred to as the third signal in T cell activation.138 Mechanisms of Tolerance to Donor Antigens The human immune system has evolved naturally to respond to challenges in a precise and controlled way A constant balance exists to ensure an effective, but not excessive, response to any unwanted stimuli It may be possible to take advantage of these mechanisms to induce or maintain tolerance to donor antigens Many mechanisms of tolerance are continuously used by the body to prevent reactions against self-antigens, which ultimately would lead to autoimmune pathologies.181 The self-tolerance of the immune system comprises a conglomeration of mechanistic pathways all working together to discriminate between self and nonself Many of these mechanisms may be applied to alloantigens The mechanisms identified as responsible for inducing or maintaining tolerance to donor antigens include the following59: Deletion of donor reactive cells centrally in the thymus and in the periphery T cell ignorance or a state of effector unresponsiveness that is relevant to grafts placed at “immunologically privileged” sites, such as the cornea or brain Exhaustion, in which the ability of donor reactive cells is eliminated as a result of overstimulation Anergy, defined as a state of unresponsiveness that is refractory to further stimulation More recently, a state of antiallograft/antibody persistence, termed accommodation, has appeared in the literature This term must not be confused with that of tolerance, in that allograft accommodation is a series of physiological 365 23 X3343-Ch23 4/8/08 2:58 PM Page 366 changes that allow a transplanted organ to function in the face of responses directed against the graft.126 The induction and maintenance of tolerance is a dynamic process and operates as multiple mechanisms in concert with one another, similar to that of self-tolerance and prevention of autoimmune diseases Each facet varies in its degree of function as the process develops Methodology of Tolerance Induction and Maintenance Persistence of Donor Antigen An overriding feature in all of the above-mentioned mechanisms of tolerance is the persistent presence of donor antigen throughout the period of tolerance in vivo Many experimental models have established that donor antigen must be present continuously to maintain a tolerant state, before or after transplantation, regardless of the precise nature of the mechanism that is operating.27,81,116,223 The source of the antigen can be donor-derived cells introduced before transplantation, as is the case in models of mixed chimerism,116 or the graft itself after transplantation.81,217,234 In the absence of antigen, tolerance is lost gradually because the mechanisms responsible for maintaining tolerance are no longer stimulated During the induction phase and the maintenance phase of tolerance, the presence of alloantigen is the key factor driving the outcome As is often the case with the immune system, the same element can influence the response positively and negatively In the case of donor antigen, presentation in the wrong context, as in a proinflammatory environment, as outlined earlier, could lead to activation with the potential of destroying the tolerant state and triggering graft rejection Deletion of Donor Reactive Leukocytes Tolerance to peripheral self-antigens is achieved routinely by processes that begin with selective propagation or deletion in the thymus These developing thymocytes undergo successive levels of TCR and cell surface molecule expression in their central development The stochastic mechanism of TCR development renders many formed TCRs useless Through thymic selection, a mature T cell repertoire is developed that not only is diverse but also can react to foreign antigen, while remaining tolerant to self-antigens The newly formed TCRs that the thymocytes express are challenged by self-MHC and are selected based on response Thymocytes that are positively selected express TCRs that relay a signal on activation; cells that have no response to self-MHC/peptide die through neglect Cells containing TCRs that transmit a robust signal in response to self-MHC/ peptide complexes are deleted via programmed cell death.112 Thymocytes expressing a functional αβ TCR develop into mature T cells in the thymus only if the constraints for positive and negative selection are met Central tolerance by clonal deletion of T cells in the thymus is the major mechanism by which tolerance to self-antigens is induced.64 This process is essential to ensure that a diverse T cell repertoire is produced and maintained Thymocyte selection is so meticulous that only 1% to 3% of thymocytes actually succeed in survival and export.244 Despite the stringency of selection, however, the process of deletion of T cells in the thymus may be incomplete 366 Although residual T cells have a TCR with only a lower affinity and avidity for the selecting ligand, they still are present and have the potential to react with the selecting antigen or by cross-reactivity with another antigen at a later stage.107 Central deletion of T cells in the thymus can be exploited as a mechanism for inducing tolerance to donor antigens This mechanism has been particularly successful in the context of therapeutic strategies using donor bone marrow in combination with nonmyeloablative therapy, such as T cell depletion or costimulation blockade, for the induction of tolerance.275 The clinical applicability of this strategy can be shown by kidney transplant recipients who have previously undergone bone marrow transplantation from the same donor because of hematologic indications Macrochimerism in these patients leads to long-term graft acceptance without immunosuppression.275 In mixed allogeneic chimeras in the mouse, donor-derived DCs have been shown to reside and persist in the recipient thymus.157,255 As a result, there is continuous deletion of donor reactive thymocytes, leading to the absence of donor reactive T cells in the periphery and tolerance The challenge of these approaches is to achieve a sufficient level of chimerism reliably without using a treatment regimen that is excessively toxic More recent shifts in paradigm have allowed the use of costimulation blockade as conditioning regimens in maintenance therapy rather than tolerance induction, eliminating long-term calcineurin inhibition and its harmful side effects.138 Intrathymic injection of donor antigen or allopeptides directly into the thymus results in the deletion of donor reactive cells.98,159,184,197 If this injection of antigen is combined with leukocyte or T cell depletion in the periphery, it can lead to the successful induction of operational donorspecific tolerance in rodents.97 In contrast to the situation that occurs in stable mixed chimeras, after intrathymic delivery of donor antigen, the antigen persists in the thymus for only a defined period after injection Intrathymic delivery of donor antigen provides a window of opportunity in which to transplant a solid organ graft, rather than producing persistent deletion of thymocytes in the long-term.98 Antigen-reactive T cells also may be deleted in the periphery.272 The introduction of high doses of defined antigens intravenously or orally has been shown to result in deletion of mature T cells in the peripheral lymphoid organs.14,111 CD4+ and CD8+ T cells can be eliminated by peripheral deletion, but in many cases deletion is incomplete even when high doses of antigen are used When analyzed, these residual antigen-reactive cells remaining in the periphery were shown to be hyperresponsive to further stimulation by the same antigen, showing that additional mechanisms of tolerance were in operation.190 The mechanisms by which T cells are deleted in the thymus and the periphery have been an area of active investigation To maintain the longevity of self-antigen and to protect against foreign invasion, autoreactive thymocytes are believed to undergo programmed cell death centrally These T cells continue to be pruned by apoptosis in the periphery as well Two distinct modes of apoptosis have been implicated as the mechanism essential for T cell death Activation-induced cell death (AICD) is a receptor-driven, caspase-8–dependent pathway wherein high doses of antigen or repetitive stimulation is necessary for cellular demise Activated T cell autonomous death, formerly known as passive cell death, X3343-Ch23 4/8/08 2:58 PM Page 367 In contrast to central mechanisms, the Fas pathway may play a greater role, in combination with other mechanisms, in deletion of T cells at particular sites in the periphery, so-called immune privileged sites.13 At these sites, transplantation of allogeneic tissues results in the prolonged survival of the transplanted tissue relative to the survival obtained after transplantation of the same tissue at other sites These sites include the anterior chamber of the eye and the testis.60,174 Fas ligand expression has been shown to be important for these sites to maintain their immune privileged status More recent studies have shown that islet allograft transplantation in the testis not only generated fewer CD8+ memory cells but also generated an increase in CD4+CD25+ regulatory T cells compared with islets that were transplanted conventionally under the kidney capsule When costimulatory pathways were blocked, there was an induction of tolerance in the testicular islet allografts, but not in those transplanted under the kidney capsule.174 Fas ligand–mediated apoptosis has been shown to be the mechanism by which inflammatory cells entering these sites are eliminated The Fas pathway also has been implicated in deletional tolerance after administration of allogeneic bone marrow.69 In the periphery, the Fas pathway may be more important in deletion of antigen-reactive cells when antigen is present at high concentration or at particular sites of the body where Fas ligand is expressed endogenously Many other attempts have been made to harness the immunological potential of these immune privileged sites and have had varying degrees of success.75,258 In the periphery, AICD maintains homeostasis in the lymphocyte compartment In addition to the Fas pathway, many other peripheral mechanisms have been implicated in clonal downsizing after the elimination of antigen, including upregulation of expression of CD152 (CTLA4) on T cells, a molecule that prevents further costimulation by competing for and binding to CD80 and CD86 (B7-1 and B7-2) on the APC and by delivering negative signals to the responding cell, shutting down further clonal expansion.36,262 Similar to CTLA4 are the CD28-related programmed cell death receptors (PD-1), which share a 23% homology with CTLA4 In contrast to CTLA4, however, PD-1 is not restricted to T cells alone but can be found on myeloid cells and B cells as well, suggesting a broader role in immunological regulation The binding of PD-1 to its ligands PD-L1 and PD-L2, which are upregulated on the surface of T cells, B cells, macrophages, and DCs on activation, leads to the inhibition of lymphocyte activation.185 Loss of antigen-reactive cells through AICD rapidly eliminates reactivity toward the stimulating antigen In normal circumstances (i.e., during responses to nominal antigens), this process is used to balance the response Antigen-reactive T cells no longer are activated when the antigen has been eliminated After transplantation, antigen stimulation potentially continues as long as the organ continues to function Expansion of donor reactive T cells could occur indefinitely, unless the response was actively controlled AICD may be one of the mechanisms that is used to ensure that the size of the population of leukocytes responding to donor antigen is kept at a manageable level Certain immunosuppressive drugs, such as rapamycin, may be able to facilitate this process.145,276 The reappearance of donor reactive cells at a functional level can be controlled or prevented by the continuing 367 APPROACHES TO THE INDUCTION OF TOLERANCE is a caspase-8–independent and death receptor–independent pathway wherein a downregulation of the T cell–protective, Bcl-2–related protein, Bcl-2 interacting mediator of cell death (Bim), causes signals that lead to apoptosis.87 AICD was a term originally coined to describe death of thymocytes after activation via their CD3 molecules,224 but AICD also can occur in the periphery.276 Subsequent reports proved, however, that in vitro thymocyte death occurs through pathways initiated by TCR and possibly tumor necrosis factor (TNF)-α receptor engagement.141 These receptors subsequently go on to propagate signals through the Fas pathway, which has been shown to play an essential role in the homeostasis of the peripheral lymphocyte compartment and in effector mechanisms used by cytotoxic T lymphocytes and natural killer cells to destroy target cells.172 The Fas receptor (CD95, APO-1) is a type membrane protein of the TNF receptor superfamily When it finds its natural ligand (CD95L, Fas-ligand), a complex signaling cascade is initiated, leading to caspase activation, which can result in the death of the Fas-expressing cell by apoptosis.87,172 High levels of FLIP, an inert homologue of caspase-8, are expressed in primary T cells and render these cells resistant to AICD It has been shown, however, that during the S phase of the cell cycle, IL-2 sensitizes T cells to AICD by downregulating levels of FLIP.5 Although there are conflicting data about the role of the Fas pathway in the thymus, the overall impression from many analyses suggests that the Fas pathway can play a role in antigen-specific deletion of thymocytes, but only at high concentrations or repetitive stimulation of antigen It is possible in these scenarios that increased antigenic exposure leads to upregulation of IL-2 expression, attenuating the levels of FLIP, creating a proapoptotic milieu.87 More relevant to negative selection in the thymus may be the role of activated T cell autonomous death During the first checkpoint of thymocyte development, or TCR-β selection, CD4−CD8−CD3− thymocytes transition to doublepositive cells and pass through a second checkpoint of positive selection where single-positive CD8+ or CD4+ T cells are chosen to develop in the thymic cortex based on signal delivery via MHC class I (CD8+) or MHC class II (CD4+).260 As mentioned previously, thymocytes with TCRs that express exceedingly intense signals to self-MHC/peptide complex are seen as autoreactive and destroyed Thymic deletion of these autoreactive cells is thought to be less dependent on the Fas pathways described earlier and more dependent on the dynamic process of activated T cell autonomous death During activated T cell autonomous death, Bim, a member of the Bcl-2 family of proteins, is thought to be essential for initiation of cytokine withdrawal, calcium flux, and ultimately Bcl-2–regulated apoptotic signaling.235 It has been well established by previous studies that autoreactive thymocytes harbor an increased level of intracellular calcium More recent evidence shows that signals of negative selection induce calcium-dependent Bim transcription via protein kinase C signaling pathways.31 This pathway differs from that of AICD in that it is triggered by growth factor (IL-2) withdrawal or various cytotoxic drugs and induces the mitochondrial release of cytochrome c, which forms an apoptosome with the adapter protein APAF-1, ultimately activating the proapoptotic aspartic acid–specific cysteine protease, caspase-9.236 23 X3343-Ch23 4/8/08 2:58 PM Page 368 presence of donor antigen in the form of the organ graft or active immunoregulation This process results in the long-term survival of the graft provided that the rate of deletion is maintained or that additional mechanisms that can promote tolerance to the graft are induced In some situations, this process is described as exhaustion because the response to a particular antigen can be effectively exhausted by chronic stimulation of the responding populations Such a situation occurs most commonly in chronic viral infection.297 Suppression and Regulation of Immune Responses Although the concept of antigen-specific suppression is not new, over the past decade there has been a resurgence of interest in the characterization and functional dissection of T cell–mediated suppression, now more often called immunoregulation.281 Suppression was described first in the 1970s after the demonstration that antigen-specific unresponsiveness could be transferred from one recipient to another.70 Antigen-reactive T cell balance, in this case, is controlled by suppression of homeostatic proliferation, rather than the mechanisms of deletion that occur during T cell development When transferred between recipients, populations of cells present among those transferred adoptively must be capable of regulating the response of naive cells to the same antigen The human immune system has developed to protect self-tissues from external pathogens and autoreactive cells Although many autoreactive cells are deleted centrally in the thymus, some manage to escape and are stymied further in the periphery via the previously discussed mechanisms of ignorance, peripheral deletion, and anergy Even so, although rare, autoimmune diseases occur when mature effector T cells are unable to distinguish between self and nonself, abandoning basic self-tolerance Peripheral prevention of autoimmunity has been described to be regulated with “active” mechanisms of tolerance by using a unique subset of T cells with regulatory function.150,281 Maintenance of tolerance and active regulation of self-reactive leukocytes is essential in the prevention of autoimmune diseases.200 Regulatory T cells also have been implicated as being a key factor in the active induction and maintenance of unresponsiveness to donor alloantigen in vivo, a characteristic that may prove to be crucial in the realm of transplant tolerance.287 Phenotypic Characterization of Regulatory T Cells Although many varieties of regulatory T cells have been reported (e.g., natural killer cells, γδ T cells, regulatory DCs, CD8+ regulatory cells), an enriched subset of CD4+ T cells have enjoyed much attention in the literature.9 These CD4+ regulatory T cells may be subdivided further into cells that are induced and secrete IL-10 and transforming growth factor (TGF)-β or T regulatory-1 cells and the so-called naturally occurring regulatory T cells In recent years, many laboratories have attempted to find markers that are exclusive to this natural regulatory population to isolate and manipulate immunoregulatory cells in vitro and in vivo for potential therapeutics Originally, CD4+ effector cells causing colitis were shown to be controlled by a population of naive CD4+ CD45RBhi cells in an adoptive transfer model.198 Later, these 368 CD4+CD45RBhi cells were found to express constitutively the alpha chain of the IL-2 receptor, CD25.154 Although CD25 is not solely expressed on regulatory cells and is upregulated on activation of T cells, it seems to be the most useful marker to sort this population Naturally occurring regulatory T cells have been reported to represent 5% to 10% of the human T lymphocyte population.181,287 Further studies on cord blood found that CD25+CD4+ regulatory T cells that were able to suppress proliferation by anti-CD3Ab expressed twofold higher levels of the gene FOXP3, which encodes the forkhead/winged-helix transcription factor scurfin.280 A deficiency in the FOXP3 gene has been shown to cause autoimmune and inflammatory disease in rodents and humans Humans lacking FOXP3 develop the X-linked recessive disease IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) or XLAAD (X-linked autoimmunity-allergic dysregulation syndrome).279 More recent evidence has revealed that FOXP3 is expressed predominantly in regulatory T cells and is essential for their development and function.62 Ectopic expression of FOXP3 has been shown to influence suppressive activity on peripheral effector populations.62 Expression of other markers to identify and isolate regulatory T cells also has been reported A host of surface markers on CD25high cells have been identified in murine models and span a wide spectrum of variability Examples include CTLA4 and CD122 and members of the TNF receptor superfamily, such as glucocorticoid-induced TNF receptor– related protein Many other markers, such as chemokine receptors, Toll-like receptors, and homing receptors, also have been described; however, many of these markers have not been confirmed in humans and are upregulated on nonregulatory CD25− cells as well, making their utility as isolation molecules difficult to discern.281 Mechanism of Regulation To exploit suppression and regulation of the immune response to an organ graft for therapeutic purposes, a clearer understanding of the mechanisms by which this phenomenon operates is required Although regulation could be operating exclusively through deletional mechanisms, at present there is little evidence to support this as the dominant mechanism for active immunoregulation or suppression The demonstration that immunoregulatory cells can be used to transfer unresponsiveness adoptively from a transplant recipient with a long-term surviving graft to a fresh naive recipient through many generations of cells, the process known as infectious tolerance, suggests that this population of regulatory or suppressor cells can generate further cohorts by influencing the differentiation patterns of naive cells in vivo.178,270 These cells seem to function not by eliminating donor reactive aggressive leukocytes but by silencing their functional activity in vivo Multiple mechanisms are employed by regulatory T cells to suppress effector populations The methods of suppression used by naturally occurring regulatory T cells and Tr1 type cells vary and include the induction of effector cell anergy,54,67 suppression of an effector phenotype by T cells,160 and conversion of potential effector cell populations into regulatory subsets.63,100,105 Finally, the suppressive abilities of regulatory T cells may extend beyond acting on T effector cells alone; there is evidence to suggest that CD25+CD4+ regulatory T cells may control the ability of APCs to trigger T cell activation.35 X3343-Ch23 4/8/08 2:58 PM Page 369 regulating allogeneic skin grafts long-term, suggesting that regulatory T cells may develop from CD25−CD4+ precursors in the periphery independent of any centralized thymic influence.105 Finally, an alternative but complementary hypothesis to explain the action of regulatory T cells suggests that regulatory T cells may manipulate the ability of an APC to activate T cells.144,243 APCs have been shown to become licensed to trigger effector cell activation when they have encountered an activated T helper (CD4) cell.17,131,210 This hypothesis eliminates the need for clusters of helper and cytotoxic T cells to be brought together in the vicinity of the APC at the same time to ensure that only effector cells with the appropriate antigen specificity are activated Rather, the hypothesis suggests that when an APC has presented an antigen and activated a T helper cell, the T helper cell changes the functional activity of the APC to enable activation of an effector T cell to be triggered in its absence A similar scenario has been envisaged for regulatory T cells When regulatory cells are mixed into cultures of APCs and helper T cells, they can inhibit proliferation of the responding T cells It has been shown that regulatory T cells can inhibit the upregulation of costimulatory molecules on APCs when they are present in these cultures.145,215,243 These and other data suggest that regulatory cells can change the function of APCs, preventing them from triggering T cell activation Evidence, from our laboratory and others, tracking the movement and proliferation of effector T cell populations in the presence of regulatory T cells shows that regulatory T cells delay T cell priming at the level of the lymph nodes.22,33 These regulatory T cells intensify their response and home to the localized site of the affected tissue in the event of inflammation.22,33 Linked Unresponsiveness The phenomenon of antigen-induced tolerance was originally thought to be specific to a sole antigen, which served as the initial tolerogen.9 A potential powerful effect of regulatory and suppressor cells is a process known as linked unresponsiveness, wherein the immune response is manipulated to accept a variety of different antigens by initially targeting just one.49,153,282 If a recipient’s immune system is exposed to a defined alloantigen before transplantation, alone or in combination with a T cell modulating agent, the response to that antigen can be blunted in vivo.153,213,283 This unresponsive state may spread beyond the scope of this sole antigen and may be linked to other molecules present on a graft provided that the initiating antigen is present (Fig 23-4).287 One hypothesis as to how regulatory T cells suppress the rejection response is via linked unresponsiveness Regulatory T cells that recognize MHC molecules via the indirect pathway develop when donor alloantigens interact with a recipient either before or after transplantation.287 These regulatory cells have been shown to use the mechanism of linked unresponsiveness as their mode of suppression In our studies using a mouse model of transplantation, we have shown that when recipients are pretreated with cells expressing a single donor class I molecule, such as H2Kb alone153 or in combination with anti-CD4 monoclonal antibody,213,282,283 specific unresponsiveness to H2Kb is induced before transplantation After transplantation, this state of unresponsiveness to H2Kb can be linked to MHC 369 APPROACHES TO THE INDUCTION OF TOLERANCE Naturally occurring CD25+CD4+ regulatory T cells undergo positive selection in the thymus and enter the periphery as committed cells.41 These thymically derived regulatory T cells exhibit a cell contact–dependent, cytokineindependent mechanism of action, in contrast to the Tr1 cells, which function via cytokine-dependent and contact independent–mechanisms.205 Cell contact–dependent mechanisms seem to be essential for induction of anergy, yet a shift to cytokine dependence and contact independence may occur when these T cells are anergized Although controversial, the cytokines IL-10 and TGF-β have been suggested as having significant roles in rendering T effector populations anergic Experiments done mainly in the murine inflammatory bowel disease model exhibit classic inflammatory bowel disease lesions when CD25−CD4+ T cells are transferred to immunodeficient mice These lesions are prevented when the effector cells are cotransferred with CD25+CD4+ T cells When an anti–IL-10 receptor–blocking monoclonal antibody is administered to the pretreated mice, the prevention of inflammatory bowel disease is neutralized.215 Roles for TGF-β and IL-10 alone or in combination have been proposed in many different models of immunoregulation and anergy, including the anterior chamber of the eye, after oral or nasal delivery of antigen and in models of tolerance to self-antigen or alloantigen.7,101,199,278 TGF-β has been reported to modulate the function of the APC promoting Th2 responses.25,118 TGF-β has been shown to influence naive T cells into a regulatory phenotype, expressing Foxp3, with suppressive activity ex vivo.93 The ability to convert naive T cells to cells with a regulatory phenotype and ability may prove to be beneficial in diseases of autoimmunity and transplantation tolerance.63 The relationship between TGF-β and IL-10 in the development of tolerance still is being characterized as different models show differential requirements for one or both of these mediators at particular stages in the response.163 From these data, it seems reasonable to propose that there are certain soluble mediators that can promote the development of unresponsiveness when present in the correct microenvironment, TGF-β and IL-10 being two examples Similar to many immunological mediators, the presence of TGF-β and IL-10 in the right place at a certain concentration is integral to the way in which they function When present in the wrong place at the wrong time with respect to tolerance induction, TGF-β can cause fibrosis, and IL-10 can trigger acute graft rejection.20,168,170,204,206,267 These and other soluble mediators not yet identified likely act in combination with cell surface structures to promote the development of tolerance Inhibition of allograft rejection also may be mediated by a process whereby potential effector cell populations may be converted into regulatory T cells themselves Additionally, it is now known that T cells capable of regulatory function are not dependent on the thymic emigrant population of naturally occurring regulators Models of thymectomized mice, which have undergone donor-specific transfusion pretreatments under the cover of anti-CD4 antibody, are able to accept skin allografts long-term To dispel the concern that the pretreatment protocol may expand preexisting populations of regulatory T cells, thymectomized mice rendered immunodeficient by CD8+ and CD4+ T cell–depleting antibodies were reconstituted with CD25−CD4+ effector cells and administered peripheral donor-specific transfusions along with anti-CD4 antibody These mice were found to generate cells capable of 23 X3343-Ch23 4/8/08 2:58 PM Recipient APC Page 370 MHC class II TCR CD80/CD86 CTLA4 CD4+ CD25+ TReg ? GITR Donor/recipient APC Contact dependent? IL-10 TGF-β Aggressive CD4+ T cell MHC class I Aggressive CD8+ T cell Figure 23–4 Linked unresponsiveness as a mechanism of immunoregulation in transplantation When donor alloantigens are encountered under certain conditions, either before or after transplantation, regulatory T (Treg) cells that recognize the donor antigen through the indirect pathway develop When the graft is completely mismatched with the recipient, such Treg cells can recognize the donor alloantigen as an allopeptide bound to a recipient MHC class II molecule after processing by recipient antigen-presenting cells (APCs) The Treg cells are triggered to manifest their regulatory potential, which can affect other donor-specific alloantigen T cells responding through either the direct or the indirect pathways of allorecognition The functional activity of Treg cells in this in vivo setting has been shown to depend on cell-associated molecules, including CTLA4 and GITR, and soluble mediators such as interleukin (IL)-10 and transforming growth factor (TGF)-β (From Wood KJ, Sakaguchi S: Regulatory T cells in transplantation tolerance Nat Rev Immunol 3:199-210, 2003 Copyright 2003 Macmillan Magazines Ltd.) and minor histocompatibility complex antigens expressed by the graft (Table 23-2) If one transplants an organ graft expressing the initial antigen and other alloantigens, unresponsiveness to the triggering antigen and the alloantigens expressed by the transplant develops in the long-term after transplantation Table 23–2 The mechanisms underlying linked unresponsiveness are under active investigation Data from the analysis of anergized T cell clones in vitro and regulatory cells in vivo show that the process is active and requires cell-to-cell contact.83,149 In many systems, the initiating antigen is seen indirectly by the recipient’s immune system,73,83 after processing of the donor molecule by recipient APCs The cells have been described as possessing the phenotype of regulatory cells because they can function in adoptive transfer systems This phenomenon has important clinical implications, particularly when alloantigen is administered before transplantation in the form of blood transfusions The mechanism implies that tolerance established to one set of antigens can spread to others if they are presented on the same graft or the same APCs It might be possible to expose a recipient to one or more defined human leukocyte antigens (HLAs) that they themselves not express When an organ donor is available, the graft might express at least one of the antigens to which unresponsiveness has been induced before transplantation In this way, the presentation of this same donor molecule on an allograft would allow linked unresponsiveness to develop to the mismatched antigens expressed by the organ donor Evidence from Ochando and colleagues183 suggests that alloantigens introduced into the host intravenously are acquired and processed by plasmacytoid DCs These plasmacytoid DCs have been shown to play a distinct role in inducing and maintaining tolerance to vascularized allografts by phagocytizing alloantigen and homing to peripheral lymph nodes ultimately to aid in the induction of CD4+CD25+Foxp3+ regulatory cells.183 The characterization and expansion of these regulatory T cells may be the way forward in the induction of tolerance in clinical transplantation Studies already have begun to try to isolate cells that suppress the rejection response in vivo and in vitro.66,189,216 Additionally, current immunosuppression protocols may be tailored to the individual based on the tracking of expansion or deletion of regulatory T cells that is specific to each transplant recipient.2 INFORMATION FROM ANALYZING TOLERANT RECIPIENTS Operational tolerance, whereby an allograft remains functional and rejection-free for more than year without the influence of immunosuppression, is the “holy grail” of transplantation and an extremely rare event in the clinical setting.211 Clinical reports of patients with spontaneously tolerant allografts not only are infrequent but also are usually limited Experiments Showing Linked Unresponsiveness in a Cardiac Allograft Mouse Model∗ Source of Antigens Used to Pretreat CBA (H2k) Recipients in Combination with Anti-CD4 Strain and MHC Haplotype of Heart Donor Initiating Antigens B10-H2b B10-H2b CBK-H2Kb + H2d CBK-H2Kb + H2k B10-H2b BALB-H2d B10-H2b (CBK x BALB)F1 H2Kb + H2d (CBK x BALB)F1 H2k + H2d B10-H2b None H2Kb H2Kb CBK-H2Kb + H2k ∗ 370 Graft Survival (Median Survival Time) (days) None The recipient is pretreated with antigen in the form of blood under an umbrella of anti-CD4 monoclonal antibody 100 25 100 100 25 X3343-idx 4/8/08 3:17 PM Page 747 Pancreatic islet beta cells in glycemia control, 578 transplantation of, 582, 706t metabolic studies of, 593-594 Pancreatitis chronic, diabetes related to, 582 from steroids, 226 in peritoneal dialysis, 44 Pancuronium, for anesthesia, 196t-197t, 197 Pancytopenia, polyclonal antibodies causing, 315 Pandemic, of type diabetes mellitus, 630 Panel reactive antibody (PRA) assay in HLA typing, 148, 153 in sensitization screening, 350, 351t, 352 Papaverine, for erectile dysfunction, 467 Paraffin sections, in biopsy specimen, 383, 384, 389 Paralysis, in Guillain-Barré syndrome, 539 Parasite infections epidemiological exposures to, 492-494, 493t in renal transplant recipient in developing countries, 645-646 pretransplant evaluation of, 498-500, 499t of skin, 551 Parathyroid cancer, in dialysis patients, 566 Parathyroid hormone (PTH) calcium homeostasis role of, 39 dysregulation of See also Hyperparathyroidism in end-stage renal disease, 38, 38t, 41, 612 Parenchymal cells, as destructive immunity target, 24, 433 Parenteral nutrition, for hemodialysis patients, 37 Paresthesias, after kidney transplantation, drugrelated, 250, 538 Partial pressure of arterial carbon dioxide (PaCO2), in brain death diagnosis, 83, 84f, 85-86 Passive cell death, 366-367 Patch anastomosis, of renal artery, during transplant surgery, 161, 161f, 442 Patch augmentation, of bladder, in ureteroneocystostomy, 166, 168 Patency of arterial blood flow, postoperative complications in, 445, 481 of arteriovenous fistula, 35, 68 of venous catheters, 64, 65, 65f definitions of, 66, 66t Patient education for pediatric compliance, 622 on kidney transplantation, 50-51, 51t on skin cancer risks, 557-558 Patient positioning for laparoscopic nephrectomy, 119, 119f, 201 for open nephrectomy, 111, 112f postoperative recovery and, 445 Patient sensitization profile, of HLA specificities transplanting strategies for, 153-154 unacceptable, 149 Patient survival compromised See Mortality rate graft survival vs See Graft survival hepatitis C virus impact on, 519-520 in child transplants, 599, 600f, 602, 650 bladder reconstruction impact on, 181182, 183t in developing countries, 641, 642t-643t, 643, 650 in living donor kidney transplantation, 123, 124f in pancreas-kidney transplantation, waiting time and, 591, 591f steroid withdrawal and, in cyclosporine era, 227-228, 228f-229f Patient-controlled analgesia (PCA) for laparoscopic donor nephrectomy, 119 morphine by for anesthesia, 194, 202 for postoperative analgesia, 203 Pattern recognition receptors, in innate immune response, 11 Pauci-immune granulomatosis, recurrent, in children, 609 Payment, for organs, 697, 699, 700, 701-702 PCA See Patient-controlled analgesia (PCA) PCR See Polymerase chain reaction (PCR) PCWP (pulmonary capillary wedge pressure), in brain-dead donor, 91f, 92, 94t, 95 PD See Peritoneal dialysis (PD) PD-1 (programmed cell death receptors), 367 Pediatric kidney transplantation See Children PEG See Polyethylene glycol (PEG) Pelvic floor, electromyography of, in pretransplant bladder assessment, 173 Pelvicaliceal dilation, urinary obstruction causing, 211, 212f Pelvis, peritoneal dialysis catheter positioning in, 74, 75f Penile prosthesis, for erectile dysfunction, 467-468, 468f Peptic ulcerations, 57, 226 Peptide complexes, in HLA system, 141, 142f, 143f Peptides in MHC class I and II proteins, 12-13, 12f, 14f allogeneic aspects of direct antigen presentation and, 15-16, 16f indirect antigen presentation and, 16, 16f semidirect antigen presentation and, 16-17, 16f graft tolerance and, 363-365, 364f, 367 vasoactive, in cyclosporine nephrotoxicity, 248 Percutaneous transluminal angioplasty (PTA) for arteriovenous fistula lesions, 68, 72 for transplant renal artery stenosis, 457, 458f Perforin in graft destruction, 23 in graft rejection, 21, 386, 387 Perfusion deficits, in arteriovenous fistulas, 35, 73 Perfusion fluids, for graft storage, Perfusion techniques extracorporeal, for in situ cooling of organs, 135 for harvested grafts cadaver donor, 114, 114f, 115 living donor, 111 machine See Machine perfusion in laparoscopic donor nephrectomy, 119 in multiple organ retrieval, 115 in pediatric kidney transplantation, 613 Pericardial effusion, as dialysis indication, 33, 34t Periodic acid–Schiff stain in acute cellular rejection, 386, 386f, 388, 389f in calcineurin inhibitors nephrotoxicity, 398, 399f in late graft diseases, 392f, 394 Peripheral edema, mTOR inhibitors associated with, 302, 302f Peripheral nerve disease/dysfunction after kidney transplantation, 535-537, 538-539 anesthesia and, 189 Peripheral vascular disease, 53, 470, 471, 473t, 475, 476t Peritoneal approach, to donor nephrectomy cadaver, 114-115, 114f laparoscopic, 118 living, 111, 112f, 117, 118 747 INDEX Pancreas after kidney (PAK) transplantation allocation scheme for, 581-582 description of, 580-581 diabetic nephropathy recurrence and, 595 for diabetic neuropathy outcomes of, 586-591, 586f-591f quality of life after, 592-593, 593t-594t living donor, 592, 592t tacrolimus for, 269, 270 Pancreas transplant alone (PTA) allocation scheme for, 581-582 description of, 580-581 diabetic nephropathy recurrence and, 595 for diabetic neuropathy outcomes of, 586-591, 586f-591f quality of life after, 592-593, 593t-594t living donor, 592, 592t Pancreas transplantation allocation schemes in, 581-582 for diabetic nephropathy, 578-595 history of, 579 immunosuppression in, 336, 338, 584-585 immunosuppression vs., 579-580 indications for, 579-580 metabolic studies of, 593-594 mortality rate of, 591, 591f, 595 multiple organ retrieval and, 115, 116f neuropathy and, 595 outcomes of, 586-591 by recipient and donor risk factors, 590-591, 590f changes over time in, 586-587, 586f-587f deceased donor and, 591 for contemporary U.S cases, 588-590, 588f-590f improvements in by era, 587-588, 587f-588f life-year gain factors in, 590-591, 591f living donor and, 592, 592t waiting impact on, 591, 591f quality-of-life with, 590 long-term, 593 study on, 592-593, 593t, 594t recipient categories of, 580-581 recurrence of, 595 retinopathy and, 594-595 retransplant data on, 591-592 secondary complications studies of, 594-595 segmental See Segmental pancreas transplantation specific risk factors in, 582 statistics on, 578, 579f annual U.S., 586, 586f surgical techniques of, 582-584, 583f-585f intraoperative care for, 585 postoperative care for, 585-586 technical failure rates, early graft losses with, 587-588, 589 waiting list for screening for, 581-582 survival probabilities based on, 591, 591f Pancreas-duodenum transplantation, whole historical aspects of, 579 multiple organ retrieval and, 115, 116f surgical technique for, 583, 583f-584f Pancreas-kidney transplantation, 57 anesthesia for, in diabetic patient, 205-206 categories of, 580-581 contraindications to, 205 surgical technique for, 159 tacrolimus for, 268-270 separate procedures and, 269, 270 simultaneous procedure and, 268-269 steroid withdrawal protocols in, 269-270 steroid-free protocols in, 270 Pancreatectomy, endocrine and exocrine deficiencies after, 578, 582, 593-594 X3343-idx 4/8/08 3:17 PM Page 748 Peritoneal cavity placing donor kidney into, 444 urine leak into, early postoperative, 212, 213 Peritoneal dialysis (PD), 41-44 access for, 73-78 anesthesia for, 204 catheter insertion, 74, 75f catheter removal indications, 76, 78 catheter selection, 41, 74, 74f complications of, 74-77, 76f, 76t, 77t adequacy of, 42 complications of, 42-44, 74-78, 74f contraindications to, 74, 75t, 78 delivery systems for, 73-74, 73f electrolytes and, 42 fluid status and, 41-42 forms of, 33, 73 goals of, 33 in children, pretransplantation evaluation of, 612-613 in developing countries, 632, 632f, 633 indications for, 33-34, 34t postoperative thromboses risk and, 447 process of, 41 renal transplant issues with, 78, 445 Peritoneal dialysis peritonitis microorganisms associated with, 42, 43, 74, 77-78 refractory, 43-44 renal transplant and, 78 Peritoneal equilibration test, 42 Peritoneal flush, for peritoneal dialysis infections, 77-78 Peritoneal sclerosis, encapsulating, 78 Peritoneum, exposure of, in renal transplant surgery, 160, 444 Peritonitis, in peritoneal dialysis microorganisms associated with, 42, 43, 74, 77-78 refractory, 43-44 renal transplant and, 78 Peritubular capillary (PTC) network biopsy of, 384 chronic allograft nephropathy and, 420-421 in transplant glomerulopathy, 428-429 in acute cellular rejection, 387, 389, 390, 391, 393, 393t in hyperacute rejection, 385 in late graft diseases, 394, 395, 396 Personal gain, in organ donation, 701 Personality changes, immediate postoperative, 679 Pertussis toxin, FTY720 response and, 337 Peru, end-stage renal disease in, 631 Pethidine (Meperidine), for anesthesia, 196 Pfannenstiel incision, in laparoscopic donor nephrectomy, 119, 121 Pharmacodynamics/pharmacokinetics of anesthetic agents, renal disease influence on, 190-200, 191t, 193f, 193t, 195f, 196t, 197t, 199t of calcineurin, tacrolimus and, 259, 260f of cyclosporine, in kidney transplantation, 246 drugs affecting, 242, 267 of mycophenolate mofetil, 279-281, 280f in dose monitoring, 284-285 of tacrolimus, in kidney transplantation, 259-260 absorption and distribution, 260, 260f metabolism and elimination, 260, 261t Pharyngeal reflexes, in brain death criteria, 85 Phenothiazines, for anesthesia premedication, 202 Phenotypes cell surface, of B cell subsets, in ABOincompatible transplants, 357-358, 357t 748 Phenotypes (Continued) of dendritic cells, T cells control of, 17 of regulatory T cells, 368 Phenylpiperidine drugs, for anesthesia, 194, 195-196, 195f Philippines end-stage renal disease in, 631 immunosuppressive regimens used in, 642t kidney transplantation in, 633f, 637f Phosphate binders, indications for, 38, 42 Phosphorus homeostasis maintenance of, 38 imbalance of continuous renal replacement therapies and, 45 hemodialysis and, 37t, 38, 38t mTOR inhibitors contributing to, 304 peritoneal dialysis and, 42 Phosphorus intake, for dialysis patients, 36, 36t Photodamage See Ultraviolet (UV) light exposure Photodynamic therapy, for skin cancer, 558 Photopheresis, extracorporeal, for immunosuppression, 342 Physical exercise for cardiovascular disease, 487 for new-onset diabetes mellitus, 486 Pig kidneys, as xenografts, 1, 7, 704 Pig transplants, graft tolerance in, 24, 341, 375 PIgR gene, in MMF adverse effects, 284 Pilosebaceous unit disorders, drugs associated with, 548 Pityriasis versicolor, 549, 549f PKD genes in polycystic liver disease, 509 screening for, in living donor, 104 Plasma cells in ABO-incompatible transplants, 357-358, 357t in acute cellular rejection, 386, 389, 390 Plasma exchange, total, in Guillain-Barré syndrome, 539 Plasma protein, in drug binding, anesthesia and, 190 Plasma, water composition of, 35, 36f Plasmapheresis for ABO-incompatibility, 357 for accelerated vascular rejection, 215 for antibody-mediated rejection, 261 for desensitization, 101, 106, 154, 352-354, 353t for humoral rejection, 355 for hyperacute rejection, 214 for immunosuppression, 342 for recurrent renal disease, in children, 606 for recurrent renal failure, early postoperative, 217 infection risks with, 495t Platelet inhibitors, thrombophilia and, 449 Platelet transfusion, uremic coagulopathy, 189 Platelet-derived growth factor, in allograft nephropathy, 23, 25, 419 Platelets allograft arteriosclerosis and, 25 biocompatibility of artificial membranes and, 34 management of, in brain-dead donor, 96 PML (progressive multifocal leukoencephalopathy), after kidney transplantation, 540-541 Pneumococcus spp infection, 504 Pneumocystis carinii/jirveci pneumonia diagnosis of, 505 epidemiological exposures to, 493t, 494, 494f mTOR inhibitors and, 296, 300, 301f mycophenolate mofetil and, 283 pathologic spectrum of, 505 postoperative prophylaxis for, 497, 497t, 505 Pneumocystis carinii/jirveci pneumonia (Continued) in children, 621 in pancreas-kidney transplantation, 586 postoperative timeline of, 217, 496f, 497 treatment of, 505 Pneumonia in developing countries, 644 P jirveci See Pneumocystis carinii/jirveci pneumonia streptococcal, 492, 493t, 504 Pneumonitis fever with, 500, 505 sirolimus-associated, 296, 300, 301f Pneumoperitoneum in laparoscopic donor nephrectomy, 119, 121 in laparoscopic nephrectomy, 201 Pneumosleeve flange, in laparoscopic donor nephrectomy, 121 Pneumothorax, in living donor nephrectomy, 111, 113t PNU156804, for immunosuppression, 339-340 Podocytes de novo pathology of, in congenital nephrosis, 405 in chronic allograft nephropathy, 405, 405f injury to, in transplant glomerulopathy, 394, 427, 430 Poikiloderma of Civatte, 552 Poisoning, brain death vs., 83, 84t Polyclonal antibody(ies) for graft rejection administration of, 315 adverse effects of, 315-316 general clinical considerations for, 311-313 historical perspectives on, 309-310 in multiple therapy regimens, 238t, 240 in sequential therapy regimen, 238t, 240 preparations of, 6, 313, 314f sites of action, 313, 314f specific clinical applications of, 314-316 tacrolimus vs., 261 for induction therapy, 314, 362, 362f, 362t in children, 605, 619f, 620 for rescue therapy, 314-315 Polycystic kidney disease cancers associated with, 565t, 566 evaluation of, in living donor, 102, 104 in renal transplant recipient, 53, 54, 59 surgical removal of, 159 Polycystic liver disease, 509, 509f Polyethylene glycol (PEG), in renal preservation solutions, 130-131, 130t limitations of, 135-136 Polymerase chain reaction (PCR) in chronic allograft nephropathy, 424, 435 in CMV infection, 501 in human herpes viruses, 528 in infectious disease screening, 499t in tuberculosis diagnosis, 644-645 in viral infections, 106, 518 of BK virus infection, 424, 425f, 625 Polyneuropathy chronic uremia causing, 535 proximal demyelinating, 539 Polyomavirus See BK virus infection Polysol solution, for renal preservation, 135 Polyuria bladder dysfunction and, 173, 180 evaluation of, in brain-dead donor, 95-96, 95t Porokeratosis, 555, 555f Portal drainage procedure, in pancreas transplantation, 579, 583, 584f outcomes of, 586-587 percentage of U.S., 583, 584f Portal hypertension, in children, 613 X3343-idx 4/8/08 3:17 PM Page 749 Post-transplant lymphoproliferative disorder (PTLD) (Continued) prevention of, 574 tacrolimus and, 272 in developing countries, 649 infections associated with, 389, 406, 498 mTOR inhibitors for, 299 pathology of, 406, 408, 408f Post-transplant malignancies, 567-574 See also Cancer(s), in renal transplant patient Potassium homeostasis of, in brain-dead donors, 133 imbalance of See also Hyperkalemia; Hypokalemia anesthesia and, 189, 203 continuous renal replacement therapies and, 45 hemodialysis and, 37-38, 37t, 38t in early allograft function, 201, 614 peritoneal dialysis and, 42 in renal preservation solutions, 130t, 131 serum, cyclosporine effect on, 250 Potassium chloride, in pediatric kidney transplantation, 614 Potassium intake, for dialysis patients, 36, 36t Povidone-iodine injection, for lymphocele sclerosis, 452 PPD (purified protein derivative) test, 53, 498, 499t, 500 PRA See Panel reactive antibody (PRA) assay “Precautionary principle,” in xenotransplantation, 703 Predialysis stage, psychological aspects of, 677-678 Predilution set, in hemofiltration, 45 Prednisolone, for graft rejection, acute, 224 cancer associated with, 570 cyclosporine vs., 243-244, 471 cyclosporine with, 236, 238, 238t, 241 dosage of, 223-224 in sequential therapy regimen, 238t, 240 in triple therapy regimen, 238t, 239, 264, 296 mechanism of action, 222 mTOR inhibitors with, 296, 297t resistance to, 222-223 side effects of, 224-227, 224t, 226f withdrawal of, 227-230 Prednisone for graft rejection, acute, 224 cancer associated with, 570 dosage of, 223-224 lymphoid irradiation with, 341 mechanism of action, 222 mycophenolate mofetil with, 287 clinical trials on, 281-282, 281t withdrawal of, 287 resistance to, 222-223 side effects of, 224-227, 224t, 226f tacrolimus vs., 264, 265, 266f, 267 withdrawal of, 227-230 for graft tolerance induction, 362, 362f, 362t in pancreas-kidney transplantation, outcomes of, 589-590, 590f pretreatment with, in children, 614 Predose concentration, in drug monitoring See Trough (C0) level Preeclampsia, kidney transplantation and, 649 Preemptive kidney transplantation, 49-50, 50f in children, 602, 613-614 outcomes of, 657-658, 664, 668f psychological aspects of, 684 Preemptive therapy, for CMV infection, 501-502 Pregnancy after kidney transplantation, 272 in developing countries, 649-650 Pregnancy (Continued) outcomes of, 669-670, 671f in living donor, 105t mycophenolate mofetil risks during, 283 tacrolimus risks during, 272 Prehypertension, 479, 480f Premalignant skin lesions, 554-555, 555f management of, 557-559 Premature births, kidney transplantation and, 649 Premedicant agents, for anesthesia, 190-191, 202 Preoperative assessment See also Medical evaluation for anesthesia, 189-190 in pancreas-kidney transplantation, 205 of diabetic patient, 204-205 for kidney transplantation, 210 in children, 610-614 of vascular systems, 440 psychological aspects of, 677-678 for laparoscopic donor nephrectomy, 118 for pancreas transplantation, 582 vaccination considerations in, 54, 493, 493t, 648 Preoxygenation, in brain death assessment, 85, 86 Prerenal azotemia, in early postoperative period, 216-217 Preservation, of donor kidney, 126-136 See also Renal preservation Pretransplant conditioning, for positivecrossmatch See Desensitization protocols Pretransplant meeting, for psychological issues, 678 Pretransplant testing donor crossmatching as, 153 historical perspectives of, 6, 6f of living donor, 99-109 See also Medical evaluation of recipient, 51t, 52-61 Prilocaine, for dialysis access surgery, 204, 204t Primary CNS lymphoma, after kidney transplantation, 541-543, 542f Primary hyperoxaluria type I in living donor, 105 in renal transplant recipient, 59, 609 renal transplant for, outcomes of, 669 Primate transplants baboon-to-human, 2, 6, 87, 341 graft tolerance in, monoclonal antibody therapy for, 374-375, 376 immunotoxins for, 325 monkey-to-human historical use of, 2, 3, new technology for, Procoagulant factors, thromboses complications related to, 446-447 Profibrotic factors, of chronic allograft nephropathy, 422-423, 424 Programmed cell death (PD-1) receptors, 367 Progressive multifocal leukoencephalopathy (PML), after kidney transplantation, 540-541 Proinflammatory mediators/state chronic allograft nephropathy and, 421-422, 422f steroid resistance and, 223 Proinsulin, hemipancreatectomy impact on, 594 Prokinetic drugs, for anesthesia premedication, 190 Prolactin, erectile dysfunction and, 467 Propofol, for anesthesia, 191, 191t, 200 sleep dose of, 202 Propoxyphene, for anesthesia, 194 Prostaglandin E1 injections, for erectile dysfunction, 467 Prostaglandin synthesis, NSAIDs effect on, 203 749 INDEX Portal vein abscesses of, 524 in multiple organ procurement, 115, 116f Portal vein catheter, in multiple organ procurement, 115, 116f Positive end-expiratory pressure, in brain-dead donor, 94-95, 94t Positive-crossmatch kidney transplant, 350, 357 ABO-incompatible vs., 356-357 antibody production in, 357, 357t antibody-mediated injury in, 357-358 clinical approaches to, 352-354 anti–class II alloantibody in, 354 high-level alloantibody in, 352-353, 353t low-level alloantibody in, 353-354, 354f immunological risk of, 351 clinical assessment of, 354-355, 355f late outcomes of, 356, 356t management of, 355-356 pretransplant conditioning for See Desensitization protocols Postdilution set, in hemofiltration, 45 Postmenopausal women, bone disease prevention for, 225-226 Postoperative care, in kidney transplantation analgesia for, 203 drain tube removal cautions, 445 in children, 614 monitoring guidelines for, 203 recovery phase of, 444-445, 445f Postoperative course/complications anesthesia and, 201 early, 210-218 in developing countries, 643-649 factors contributing to, 643-644 infections as, 644-648 malignancies as, 648-649, 649f infection risks during, 217-218 See also Infection(s) timeline for, 495-498, 496f medical problems, 210-211, 211t, 215-218 See also Medical complications neurological problems, 534-543 See also Neurological complications overview of, 210-211, 211t, 218 psychological aspects of, 678-679 rejection during, 214-215 See also Graft rejection surgical problems, 211-214, 211t See also Surgical complications urological problems, 462-468 See also Urological complications vascular problems, 439-460 See also Vascular complications wound-related See Wound complications Post-transplant meeting, for psychological issues, 679 Post-transplant diabetes mellitus (PTDM) assessment of, 57 cyclosporine and, 241, 263 1,25-dihydroxyvitamin D3 impact on, 338 hepatitis C virus associated with, 520 new-onset, 60, 484-486 steroids impact on, 225 tacrolimus associated with, 262, 263, 270t, 271-272 corticosteroids and, 264-265 Post-transplant lymphoproliferative disorder (PTLD) biologics and, 312-313, 314 Epstein-Barr virus–related, 568, 569, 572-573 diagnosis of, 502-503 in children, 625 incidence of, 669, 671t liver disease and, 509, 526 management of, 503, 574, 669 pathogenesis of, 502 X3343-idx 4/8/08 3:17 PM Page 750 Prostate cancer, 573 Prostate disorders, 59 Prosthetic grafts, for arteriovenous fistulas, 35, 64, 70-71, 71f Protamine, for heparin reversal, 119 Protease inhibitors, cyclosporine metabolism and, 247 Protein(s) See also Amino acids antigen-presenting See Antigen-presenting cell (APC)–T cell protein as tubular injury marker, in chronic allograft nephropathy, 434, 435 fusion, 320-325 See also Fusion proteins immune-related, HLA system role in, 141, 143, 143f in graft destruction, extracellular matrix, 23 in graft rejection antigen-specific immune response of, 12-17, 12f, 14f effector immune response of, 19f, 20-21 innate immune response of, 10f, 11 in graft tolerance, 366, 367 loss of, in peritoneal dialysis, 44 MHC class I and II ribbon diagram of, 12-13, 12f stick diagram of, 12-13, 12f synthesis of, mTOR inhibition of, 294-295, 294f Protein kinase C cold storage preservation and, 129 in graft tolerance, 367 Proteinuria cardiovascular disease and, 473, 473t-474t, 651 in chronic allograft nephropathy, 419, 430, 435 in congenital nephrotic syndrome, 608, 613 in early postoperative period, 217 in living donor, 103t mTOR inhibitors associated with, 298, 300-301, 401 nephrotic-range of, in dyslipidemia, 484 Proteoglycans, in chronic allograft nephropathy, 423 Proteomics, in chronic allograft nephropathy, 434, 435, 436 Prothrombin, G202210A mutations of, thromboses related to, 447 Protocol biopsy, for graft status, 397 Proton-pump inhibitors, for gastrointestinal disease, 57, 202 Protozoan infections, 645-646 Provider services, for kidney transplantation, in developing countries, 634-635 Prune-belly syndrome, 172, 173, 184 P-selectin brain death and for renal preservation, 134 immunological activation of, 133-134 in immunomodulation therapy, 323, 447 Pseudogenes, in HLA system, 141, 142f Pseudomonas aeruginosa infections catheter-related, 66 in peritoneal dialysis, 42-43, 77, 78 Pseudostenosis, postoperative, of renal artery, 213 PSGL1, as fusion protein, 323 Psoas hitch for ureteral leak, 464, 464f, 464t for urinary obstruction, early postoperative, 211-212 Psoriasis, 321, 552 Psychiatric disturbances assessment of, 55, 60, 678 in children, 610-611 from steroids, 227 immunosuppression and, 679-680 750 Psychological aspects, of kidney transplantation, 676-691 adherence and, 678, 680-681 pediatric, 622-623 cadaver donation and behavior patterns, 686 communicating with family, 687-689 further care in, 691 grief process in, 685-687 options of, 689-691 staff support for, 691 viewing body after death, 691 family interactions and, 681 graft function and, 681-682 hope as, 678 immediate postoperative issues, 678-679 immunosuppression and, 677, 678, 679-680 living donation and practice/program implications of, 684-685 related, 682-683 selection issues, 100, 102, 118 unrelated, 684 preemptive, 684 preoperative adjustment to disease, 677-678 quality of life and, 672, 676-677 Psychosis ICU, 536 steroids causing, 538 Psychosocial factors of living donor nephrectomy, 113, 117, 122 of living donor selection, 100, 101, 107 of organ allocation, 698-699 of organ donation, 699-702 of pediatric rehabilitation, 625-626 of renal transplant recipient, 60 quality of life outcomes and, 672-673, 673t of xenotransplantation, 703 PTA See Pancreas transplant alone (PTA); Percutaneous transluminal angioplasty (PTA) PTC See Peritubular capillary (PTC) network PTDM See Post-transplant diabetes mellitus (PTDM) PTFE (expanded polytetrafluoroethylene), for arteriovenous fistula grafts, 68, 71, 72 PTH See Parathyroid hormone (PTH) PTLD See Post-transplant lymphoproliferative disorder (PTLD) Puberty, kidney transplantation impact on, 624 Pubis, in multiple organ procurement, 115, 116f Public education, ethical issues of, 626-697 Publicity programs, ethical issues of, 626-697 Pulmonary artery catheter (PAC) for pancreas-kidney transplantation, 585 in brain-dead donor, 90, 91f, 92-93 Pulmonary artery, in multiple organ procurement, 115, 116f Pulmonary capillary wedge pressure (PCWP), in brain-dead donor, 91f, 92, 94t, 95 Pulmonary edema anesthesia and, 188 as dialysis indication, 33, 34t in brain-dead donor, 92, 94, 95 Pulmonary embolus, in living donor nephrectomy, 112, 113t Pulmonary fibrosis, mycophenolate mofetil associated with, 284 Pulmonary lesions, infections associated with, 53, 505 Pulmonary regurgitation, anesthesia and, 200 Pulmonary toilet, for brain-dead donor, 94, 94t, 95 Pulmonary venous congestion, anesthesia and, 188 Pulseless electrical activity, brain death vs., 86 “Punta Cana” group, 635 Pupillary response, in brain death criteria, 85 Purified protein derivative (PPD) test, 53, 498, 499t, 500 Purine synthetic pathways, inhibitory, of mycophenolic acid, 277, 278f Pyelography, antegrade, in urinary stenosis, 465, 466f Pyelonephritis acute differential diagnosis of, 388, 390 pathology, 403 emphysematous, in developing countries, 644 Pyelophlebitis, liver abscess related to, 524 Pyeloureterostomy, ureteroneocystostomy and, 166, 168, 168f Pyelovesicostomy, in renal transplant surgery, 168, 168f, 464t Pyogenic bacteria in liver abscess, 524 in skin infections, 549 Pyrazinamide, for infections, 78, 645 Pyridostigmine, for anesthesia, 199, 199t Pyrimidine inhibitors, for immunosuppression, 333-335 Pyrimidine salvage pathway, 333 Q QOL See Quality of life (QOL) Quadriparesis, drug-related, 538 Quadruple therapy regimen, 238t, 240, 241 Quality control, for urine collection, 434 Quality of life (QOL) after kidney transplantation donor organ management and, 90 in children, 626, 650 in living donor, 101-102, 101t in recipient, 48-49, 101 measurements of, 672-673, 673t after pancreas transplantation long-term, 593 one-year post-transplant scores with simultaneous kidney transplant, 593, 593t with solitary transplant, 593, 594t pretransplant baseline scores, 592-593, 593t study on, 590, 592-593 in living donor nephrectomy, 113, 122-123 psychological aspects of, 676-677 Quantity of life See also Life-year gains after kidney transplant, 49 advantage in U.S during 1990s, 49, 49t Quinolones, for peritoneal dialysis infections, 43 R Race See Ethnicity RAD001 See Everolimus (RAD001, SDZRAD, Certican) Radial artery, arteriovenous fistula anastomosis in, 67-68 Radiation, solar See Ultraviolet (UV) light exposure Radiation therapy cancers associated with, 564, 567, 573 delayed graft rejection with, for bone marrow transplant, for cancers, in renal transplant patient, 573 for graft tolerance, 4-5, 372-373 for immunosuppression thymic, 372-373 total lymphoid, 340-342 for primary CNS lymphoma, 543 Radiocephalic AVFs, 67-68, 69f surgical technique for, 69-70 Radiography, chest in brain-dead donor, 95 in infectious disease screening, 498 in P carinii/jirveci pneumonia, 505 X3343-idx 4/8/08 3:17 PM Page 751 Recipient, of kidney transplant (Continued) semidirect, 16-17, 16f T cell activation and, 10f, 17-19 CD4+ and CD8+ cells in, 12, 12f, 16, 18, 19, 20, 25 costimulatory signals and, 17f, 18-19, 365f immune synapse and, 17-18, 17f location of, 17 receptor signals and, 18 second signals and, 18-19 infections derived from, 493, 493t pretransplant evaluation of, 500 liver disease in, 508-528 See also Liver disease living donor kidney outcomes, 664 longest surviving, 672 medical assessment of, 51t, 52-61 preparation of, 61-62, 61t general, 61-62, 61t in children, 614 surgical, 158-159 psychological aspects of family interactions and, 681, 682-683 fears and emotions, 678, 679, 682, 685 feelings concerning donor, 679 immunosuppression and, 678, 679-680 informed consent and, 685 well-being as, 676-677 sensitized See Sensitization specific medical considerations for, 52-61 Recipient pool, U.S waiting list registrations of, 659, 659t Recombinant granulocyte colony-stimulating factor, for bone marrow suppression, 336 Recombinant growth hormone (rhGH), in pediatric transplantation, 622-623 Recombinant human erythropoietin (rEPO) See Erythropoietin (EPO) Recombinant tissue plasminogen activator, for vascular access thrombosis, 66, 72 Rectal pouch, in bladder reconstruction, 175 Red blood cells (RBCs) production of, erythropoietin regulation of, 39 renal preservation solutions effect on, 130, 136 transfusions of, in brain-dead donor management, 90, 96 Reflex(es) brainstem, in brain death criteria, 83, 84f, 84t, 85, 695 cardiovascular, in ischemic brain injuries, 88 Reflux, in renal transplant recipient gastroesophageal, 57 nephropathy, 59 urinary, early postoperative, 212 vesicoureteral, 172, 173, 177 Refractory rejection, 261, 621 Regenerative medicine, ethical issues of, 705, 706t Regional anesthesia for dialysis access, 204 for kidney transplantation, 200 Regret, in living donors, 683 Regulatory guidelines, for xenotransplantation, 704-705, 705t Regulatory T cells in graft tolerance, phenotypic characterization of, 368 in protocol biopsy, 397 Rehabilitation of transplanted children, 625-626 psychological aspects of, 679, 685 vocational, 673, 677, 681 Rehydration See Fluid loading Rejection encephalopathy, 536 Rejection, of kidney transplant See Graft rejection Relatives See Family entries Religion(s) cadaver organ donation and, 687, 691 kidney transplantation and, 582, 634, 637, 677, 703 Remifentanil, for anesthesia, 195-196, 200, 202, 205 Renal angiography early postoperative indications for, 213, 218 in chronic allograft nephropathy, 433 in transplant renal artery stenosis, 454f, 455, 456, 456f interventional, 457 pretransplant, in living donors, Renal artery anastomosis of, during transplant surgery, 160-161, 161f in children, 169 reperfusion and, 443-444, 443f technical complications of, 440 aneurysm of, 457, 459f in cadaver donor nephrectomy, 114-115, 114f in laparoscopic donor nephrectomy, 120-121, 120f short, consideration of, 118, 121, 123, 442 in living donor nephrectomy, 111, 112f, 123 kinking/twisting of, 453-454, 454f, 456, 457, 459f patency complications of, in postoperative recovery, 445, 481 stenosis of See Transplant renal artery stenosis (TRAS) thrombosis of cyclosporine associated with, 250 early postoperative, 213-214 factors contributing to, 443, 449 in acute cellular rejection, 390 in hyperacute rejection, 385 Renal blood flow cyclosporine effect on, 248, 262 Hume test for, 439 in chronic allograft nephropathy, 433 in laparoscopic donor nephrectomy pneumoperitoneum effect on, 119 preoperative evaluation of, 118 in transplant renal artery stenosis, 454-455, 457 interruption of during transplantation, effects of, 439 maintenance of in cadaver donor, 114, 114f, 115 in living donor, 111 NSAIDs effect on, 203 tacrolimus effect on, 262, 270, 271 trauma impact on, 95 Renal calculi See Nephrolithiasis Renal cell cancer in dialysis patients, 564, 565, 565t, 566 in living donor, 103t, 106 in renal transplant patient, 568 Renal disease after living donor nephrectomy, 101, 101t anesthetic agents pharmacokinetics and, 190-200, 191t, 193f, 193t, 195f, 196t, 197t, 199t autoimmune, mycophenolate mofetil effect on, 287 chronic See Chronic kidney disease (CKD) in renal transplant recipient assessment of, 57-59, 57t sensitized, late outcomes of, 356, 356t psychological adjustments to, 676, 677-678 recurrent diabetic, after pancreas transplant, 595 early postoperative, 216, 217 in children, 605-609 751 INDEX Radiology, interventional for arteriovenous fistula complications, 72 for central venous catheter complications, 66 Radionuclide scanning in brain death, 84, 86t renal See Renal scintigraphy Raffinose, in renal preservation solutions, 130, 130t Randomness, in organ allocation, 698 Ranitidine, for anesthesia premedication, 205 RANTES, in graft rejection, 21 Rapamune See Sirolimus (AY-22989, Rapamune) Rapamycin See Mammalian Target of Rapamycin (mTOR) inhibitors Rapid-sequence intubation, for anesthesia, 197, 205 Rash(es), skin mTOR inhibitors associated with, 298, 303, 303f polyclonal antibodies causing, 315 varicella-zoster virus, 527 Rat transplants graft rejection in, 15, 21 cyclosporine effect on, 234, 235, 235t graft tolerance in, privileged sites for, 24 historical experiments of, 2, immunosuppression modalities for, 234, 334, 335, 336, 340-341 Raynaud’s syndrome, cyclosporine associated with, 250 RBCs See Red blood cells (RBCs) RCRI (Revised Cardiac Risk Index), 478 Reactive oxygen species (ROS) chronic allograft nephropathy and, 419, 420 donor organ ischemia related to, 126, 129 ischemic brain injuries and, 88, 89 scavengers of, in renal preservation solutions, 130t, 131 Receptor signals, for recipient T cell activation, in graft rejection, 10f, 18 Receptor-based therapeutics, 309 Recipient, of kidney transplant age of, outcomes related to, 127, 127f, 146, 659-661, 661f anesthesia for, 158, 202 dialysis access and, 204, 204t monitoring during, 202-203 postoperative analgesia for, 203 postoperative care for, 203 cancer in, 567-574 See also Cancer(s) cardiovascular disease mortality in, 471, 472-473, 472t children as See Children chronic kidney disease patient as, 48 counseling for, 50-52, 51t desensitization of See Desensitization protocols duties owed by, 697-698 duty owed to, 696 expanded criteria kidney outcomes in, 663, 664t, 666 fitness advantage during 1990s vs., 48-49, 49t, 78 general concepts regarding, 48-50, 49t, 50f-51f HLA crossmatch between donor cells for, 149-153 clinical interpretation of, 152-153 historical perspectives of, 6, 149 pretransplant, 153 risk assessment in, 152, 152t survival improvement trends with, 145-146, 146f techniques for, 150-152, 151f in graft rejection dendritic cell presentations indirect, 16, 16f X3343-idx 4/8/08 3:17 PM Page 752 Renal disease (Continued) in chronic allograft nephropathy, 429-430, 430f in graft vessels, 4, 57-59 pathological classification of, 405-406, 406t, 407f recurrent, 405-406 risks of, 57, 58, 58t Renal failure acute, dialysis indications for, 33-34, 34t causes of, in dialysis and transplant patients, 57-59, 57t high-output, in children, 613 in early postoperative period, 217 Renal function cyclosporine effect on, 134, 247-249, 262-263 mTOR inhibitors vs., 296, 297t, 298 in brain-dead donor, 95, 95t, 133 in chronic allograft nephropathy, 430 in live donor allotransplantation, 123, 123f in living donor, evaluation of, 103t, 105t, 107, 118 post-transplant See Graft function/dysfunction residual, peritoneal dialysis and, 42 tacrolimus effect on, 262-263, 270, 270t, 271 in children, 267-268 urinary obstruction impact on, early postoperative, 212 Renal osteodystrophy in children, 612 uremia with, 189 Renal pelvis, in surgical revision, of ureteral leak, 462-465, 464t Renal preservation, 126-136 research outlook on, 135-136 solutions for, 6, cadaver donor, 115 composition of, 129-131, 130t in back table preparation, 441 machine perfusion of, 131-132, 132f outcomes related to, 662, 663f techniques for brain death and, 87 cadaver donor, 114, 115 cooling as See Cold storage preservation hypothermic machine perfusion for, 131132, 131f-132f in multiple organ retrieval, 115 living donor, 111 normothermic machine perfusion for, 135 perfusion fluids for, 6, starting in donor, 132-135, 132f, 134t transplantation cascade in, 126, 127f Renal protective strategies, for laparoscopic nephrectomy, 201 Renal replacement therapy for children, 34 statistical data on, 267, 272, 599, 600f in developing countries, 630-651 See also Developing countries nontransplant modalities of, 33-47 See also Nontransplant modalities psychological aspects of, 676 transplant as See Kidney transplantation Renal scintigraphy in delayed graft function, 216 isotopic, in chronic allograft nephropathy, 434 Tc 99m MAG-3 in ureteral leak, 463, 463f in ureteral stenosis, 465 Renal tubular dysfunction bladder capacity and, 177, 180 mTOR inhibitors associated with, 301-302, 304 Renal tubular injury from hydroxyethyl starch, 92 in brain-dead donors, 133 752 Renal tubular injury (Continued) in chronic allograft nephropathy biopsy findings with, 431, 431t, 433, 433t BK virus causing, 421, 422f, 424, 424f-425f calcineurin inhibitors causing, 425-427, 426f-427f early, 422-423 late, 424-425 prevention of, 435, 436, 436t urinary markers of, 434 necrosis acute See Acute tubular necrosis (ATN) in acute cellular rejection, 387, 391, 393t in chronic allograft nephropathy, 422-423 Renal vein anastomosis of, during transplant surgery, 161-162, 162f in children, 169 reperfusion and, 443-444 technical complications of, 440, 441-442, 442f in cadaver donor nephrectomy, 114-115, 114f in laparoscopic donor nephrectomy, 120, 120f, 121 exposure of, 120, 120f short, consideration of, 118, 121, 123 in living donor nephrectomy, 111, 112f preparation of, during renal transplant, 160 short, 161, 440, 442 in donor nephrectomy, 118, 121, 123 Renal vein thrombosis (RVT) early postoperative, 214, 214f factors contributing to, 442, 448-449, 448f pathology of, 403, 404, 404f short renal vessels and, 118 Renin-angiotensin system in chronic allograft nephropathy, 423, 427, 436t in cyclosporine nephrotoxicity, 248, 249 in transplant renal artery stenosis, 454-455 Reperfusion ischemia with See Ischemia-reperfusion injury phase of, in transplantation cascade, 126, 127f, 129 technical complications of, 443-444, 443f “Replacement” fluid, in hemofiltration, 45 Replicative senescence, in chronic allograft nephropathy, 420 Rescue principle, in organ allocation, 698 Rescue therapy antibody preparations as, 311, 313 monoclonal, 317-318, 320 polycolonal, 314-315 for transplant renal artery stenosis, 457 FTY720 as, 336 tacrolimus as, 261 Resection rib, in living donor nephrectomy laparoscopic, 121 open, 111, 112f, 118 surgical arterial anastomosis and, 442 for primary CNS lymphoma, 542 of cancers, in dialysis patients, 567 Residual reaction frequency, in HLA typing, 153 Residual urine, in pretransplant bladder assessment, 173 Resistance index (RI), of kidney transplant, 433 Resources, for kidney transplantation allocation of, 694 in developing countries, 634-635 Respiratory disease in renal transplant recipient, 53 infectious See Pneumonia; Pneumonitis sirolimus-associated, 296, 300, 301f Respiratory effort, in brain death criteria, 83, 85-86 Respiratory function in brain-dead donor management of, 93-95, 94t volume resuscitation and, 92 in living donor, 104t, 105t Respiratory system anesthesia and, 188, 200 mycophenolate mofetil toxicity in, 284 Resting membrane potential, hyperkalemia impact on, 37 Resuscitation continuation of, in NHB donor, 135, 696 historical perspectives of, volume, of brain-dead donor, 90-93, 92f, 95 Retinoic acid, topical, for skin cancer, 558 Retinoids, systemic, for skin cancer, 559 Retinopathy, diabetic, pancreas transplantation and, 594-595 Retractors, in renal transplant surgery, 160, 163, 164 Retransplantation, in renal transplant recipient, 60-61 Retroperitoneal space, postoperative hematoma in, 446, 446f Retroperitoneal tissue, in laparoscopic donor nephrectomy, 118 Retrovirus transmission, in xenotransplantation, 7, 703-704 Return to dialysis rates, after kidney transplantation, 665, 666, 668f Return to work after kidney transplantation, 672-673 in living donor nephrectomy, 113, 117, 122 Revascularization for cardiovascular disease, prophylactic, 477, 487 in kidney transplantation, 160, 161-162, 162f back table preparation for, 441 reperfusion and, 443-444, 443f technical complications of, 441-443 Reverse osmosis, in hemodialysis, 34 Revised Cardiac Risk Index (RCRI), 478 Rewarded gifting, for organ donation, 697, 699, 700 RFT5,dgA, as immunotoxin, 325 Rhabdomyolysis, renal injury susceptibility with, 95 Rheumatoid arthritis, 321, 334 rhGH (recombinant growth hormone), in pediatric transplantation, 622-523 RI (resistance index), of kidney transplant, 433 Rib resection, in living donor nephrectomy laparoscopic, 121 open, 111, 112f, 118 Ribavirin, for hepatitis C virus, pretransplant vs post-transplant, 520, 522t, 523 Ricin, antitumor effects of, 325 Rifampicin cyclosporine metabolism and, 247 for peritoneal dialysis infections, 43, 77, 78 for tuberculosis, 645 Right atrial pressure, as dry weight measure, 36 Right atrium, temporary vascular catheter insertions and, 64, 65 Right ventricular function, as dry weight measure, 36 Rigors, monoclonal antibodies causing, 318 Risk/benefit ratio, in kidney transplantation, 685, 694 Ritonavir, cyclosporine metabolism and, 247 Rituximab (humanized anti-CD20) for ABO-incompatibility, 358 for acute rejection, 215, 621 for desensitization, 352, 353t, 354 for graft tolerance, 22 X3343-idx 4/8/08 3:17 PM Page 753 S Sadness, immediate postoperative, 679 Safe lock devices, in peritoneal dialysis delivery systems, 73-74, 73f “Safety first option,” for reperfusion complications, 443 Saline infusions See also Normal saline infusion for hyponatremia, neurological considerations of, 536 in brain-dead donor management, 90 Saline slush, iced, in back table preparation, 441 Salmonella spp infection, epidemiological exposures to, 492, 493, 493t, 494 Salvage pathway of inhibition by mycophenolic acid, 277, 278f of pyrimidine, 333 Salvage procedures for arteriovenous fistula complications, 35, 72-73 for vascular thrombosis, 446 Saphenous vein graft for arteriovenous fistula, 71 for renal artery anastomosis, 160 Sarcomas See Kaposi’s sarcoma SARS (severe acute respiratory syndrome), pretransplant evaluation of, 498, 499-500, 499t Satinsky clamp, 123, 160 Saudi Arabia dialysis options in, 632, 632f immunosuppressive regimens used in, 643t kidney transplantation in, 633f, 634, 637f, 638, 638f Scabies, 551 SCC See Squamous cell carcinoma (SCC) Schistosomiasis, 106, 646 School attendance, after pediatric transplantation, 625-626 Scientific Registry of Transplant Recipients (SRTR) outcome data of, 657, 660, 660t pediatric data of, 599, 601, 601f on graft survival, 602, 603f, 604t Scintigraphy renal See Renal scintigraphy transcranial Doppler, for brain death confirmation, 84, 86t Scissors curved, in laparoscopic donor nephrectomy, 119, 119f-120f Thorek, in renal transplant surgery, 163 Sclerosants, injection of, for lymphoceles, 452 Sclerosis arterial See Arteriosclerosis; Atherosclerosis diffuse mesangial, in children, 608 glomerular See Glomerulosclerosis lymphocele, 452 peritoneal, encapsulating, 78 tuberous, 59 SCR See Subclinical rejection (SCR) Scribner shunt, 67, 67f SDZCHH380, in immunomodulation therapy, 324 SDZRAD See Everolimus (RAD001, SDZRAD, Certican) Seborrheic dermatitis, 552 Seborrheic keratoses, 552 Second signals, for recipient T cell activation, in graft rejection, 10f, 18-19 Segmental pancreas transplantation anticoagulation recommendations for, 586 historical aspects of, 579 living donor, 592 metabolic studies of, 594 surgical techniques for, 583-584, 585f Seizures after kidney transplantation, 535, 536 drug-related, 250, 538 in children, pretransplantation evaluation of, 610 Selectins See also specific type, e.g., P-selectin in graft rejection, 21 Selective serotonin reuptake inhibitors, calcineurin inhibitor nephrotoxicity and, 217 Self-catheterization See Clean intermittent self-catheterization Self-esteem immunosuppression and, 680 living donation and, 682-683 Self-image, immediate postoperative, 679 Selling, of organs, 697, 699, 700, 701 Semidirect antigen presentation, in antigenspecific immunity, 16-17, 16f Semipermeable membranes, in hemodialysis, 33, 34 Senescent cells, in chronic allograft nephropathy, 420 Sensitization, 350-358 during prolonged dialysis, 100 in children, 604-605 in renal transplant recipient, 60, 101, 241 antibody detection and specificity in, 146-149 assays for, 350-351, 351t comparison of, 354-355, 355f anti–class II DSA and, 354 cadaver donors and, 351-352 chronic allograft nephropathy related to, 423 clinical approaches to, 351-354 cyclosporine for, 241 high-level DSA and, 352-353, 353t humoral rejection and, 350, 353-354, 354f, 356, 390 treatment of, 355-356 immunological risk of, 350, 351 clinical assessment of, 354-355, 355f immunosuppression for, 336 late outcomes of, 356, 356t living donors and, 352-354, 353t, 354f low-level DSA and, 353-354, 354f outcomes related to, 661-662, 662f paired donation and, 352 Sensitization (Continued) patient profile of, 149 plasmapheresis for, 342 post-transplant monitoring of, 155-156, 352, 353t, 356 routes of, 60, 146 screening for, 149 transplant strategies with, 153-154 treatment of, 355-356 unacceptable specificities in, 149 Sensory indices, pancreas transplantation impact on, 595 Sepsis/septicemia dialysis and, 44 access-related, 65, 66-67 death rate from, 35 urinary, in renal transplant recipient, 59 Sequential therapy regimen, 216, 238t, 240 Sequestrants, bile acid, for dyslipidemia, 483-484, 484t Serology, in infectious disease screening, 499t, 501 Sevelamer hydrochloride (Renagel), for hyperphosphatemia, 38 Severe acute respiratory syndrome (SARS), pretransplant evaluation of, 498, 499-500, 499t Sevoflurane, for anesthesia, 199-200 Sexual dysfunction, after transplantation, 673, 673t, 681, 682 Sexual maturation, after kidney transplantation, 624 Shivering, hemodialysis causing, 40 Shock, as grief reaction, 688, 689 Shunts insertion of, anesthesia for, 204 Scribner, 67, 67f Sibling-to-sibling transplants, 4, See also Twin-to-twin transplants cyclosporine for, 241 HLA-idential vs non–HLA-identical, 140-141, 592, 604, 610, 614 psychological aspects of, 683, 684, 685 Sick role, relinquishing of, after transplantation, 681 Sickle cell anemia, recurrent, 610 Sigmoidocystoplasty, for bladder augmentation, 177, 178f-179f, 180 Silicone (Silastic) catheters, for renal replacement therapy, 64, 65, 74 Silicone (Silastic) vessel slings, for arteriovenous fistula, 70 Simultaneous pancreas-kidney (SPK) transplantation allocation scheme for, 581-582 description of, 580-581 diabetic nephropathy recurrence and, 595 for diabetes, kidney-alone transplant vs., 668 for diabetic neuropathy outcomes of, 586-591, 586f-591f quality of life after, 592-593, 593t history of, 578 immunosuppression for, 268-269 in Europe, 269, 448 living donor, 592, 592t surgical technique for, 583, 583f Singapore immunosuppressive regimens used in, 643t kidney transplantation in, 633f, 634, 636 Single–HLA antigen assays, in sensitization screening, 351, 351t, 352 SIP1 (sphingosine 1-phosphate 1) receptors, FTY720 response and, 337 Siplizumab (MEDI-507), 321 753 INDEX Rituximab (humanized anti-CD20) (Continued) for induction therapy, 240, 320 for rescue therapy, 320 pharmacodynamics of, 320 RNA testing See also mRNA translation for hepatitis C, 54, 106 RNA viruses, 518, 672 Rocuronium, for anesthesia, 99, 196t-197t, 198 Rodents histocompatibility research on, 24, 140 transplants in See Mouse transplants; Rat transplants Role models, for coping with renal disease, 678 Romania, kidney transplantation in, 640-641, 640f Ropivacaine, for dialysis access surgery, 204, 204t ROS See Reactive oxygen species (ROS) Roux-en-Y loop, in pancreas transplantation, 583, 584f, 589 Russia end-stage renal disease in, 631 kidney transplantation in, 640-641, 640f Rutherford Morison incision, for kidney transplantation, 159-160, 159f RVT See Renal vein thrombosis (RVT) X3343-idx 4/8/08 3:17 PM Page 754 Sirolimus (AY-22989, Rapamune), 293-305 adverse effects of, 296, 297t chronic allograft nephropathy related to, 422, 423 cyclosporine vs., 244 discovery of, 7, 293 drug interactions with, 295 for children, 615, 619 for induction immunosuppression, 288, 288t for maintenance immunosuppression, 244, 288, 288t, 298-299 hepatotoxicity of, 511 in de novo therapy with calcineurin inhibitors, 296 phase III studies of, 296, 297t, 298 without calcineurin inhibitors, 296 in double therapy regimen, 263-264 de novo combination, 296-298, 297t in kidney transplantation cancer associated with, 570 clinical trials on, 295-299 evaluation of, 293, 304-305 in pancreas-kidney transplantation, 269, 270, 585 outcomes of, 590 in triple therapy regimen, 238t, 296, 297t malignancy and, 299 mechanism of action, 293-295, 294f molecular mechanisms of, 236 mycophenolate mofetil with, 281, 285-286, 287, 295, 296 myelosuppression from, 283 outcomes related to, 664, 665f pharmacokinetics of, 295 prednisolone interaction with, 222 safety of, 299 side effects of, 299-304, 301f-303f, 305f skin lesions as, 548 steroid withdrawal and, 229-230 in children, 615 structure of, 293, 294f tacrolimus vs., 267 tacrolimus with, 263-264 in children, 268 Site selection, for kidney transplantation, 159 Skeletal system See Bone entries Skin cancer in dialysis patients, 564, 565t, 566 in renal transplant recipient, 572, 574 anatomical distribution of, 554f common, 555-556, 555f-556f de novo development of, 568-569 epidemiology of, 553-554, 554f in developing countries, 648-649, 649f management of, 557-559 mTOR inhibitors for, 299 pathogenesis of, 556-557 recurrence of, 574 risk factors for, 556-557, 669 transmission from donor, 568 Skin disorders immunosuppressives associated with cyclosporine and, 250, 262 mTOR inhibitors and, 298, 303, 303f steroids and, 226 tacrolimus and, 262, 270t, 271, 272 malignancies as, 272 post-transplant, mTOR inhibitors for, 299 pyrimidine inhibitors associated with, 334, 335 Skin infections, 549-551 bacterial, 549 fungal, 549-550, 549f-550f microorganisms associated with, 548, 549 parasite, 551 viral, 550-551, 551f 754 Skin lesions, 546-559 frequency of, 546, 547f, 559 from drug side effects, 546-548, 547f-548f management of, 548-549 infectious, 549-551, 549f-551f inflammatory vs noninflammatory, 551-553, 552f-553f malignant, 554t, 555-557, 555f-556f epidemiology of, 553-554, 554f management of, 557-559 premalignant, 554-555, 555f management of, 557-559 Skin tags, 552-553, 553f Skin tests for tuberculosis, 53, 498, 499t, 500, 524 preemptive, for polyclonal antibody therapy, 315 Sleep disruption, steroids causing, 679-680 Sling, urethral, for urinary incontinence, 174, 176f Small intestines in bladder reconstruction, 172, 175-177, 178f-179f, 180 in cadaver donor nephrectomy, for kidney removal only, 114, 114f in multiple organ retrieval, 115, 116f obstruction of See Ileus transplantation of, T lymphocyte activation after, 17 Smoking cessation post-transplant, indications for, 478-479, 574 pre-transplant, in living donor, 104t Smoking/smoking history cardiovascular disease and, 473, 473t-474t, 475, 476t, 487 chronic allograft nephropathy and, 435, 436t of brain-dead donor, 94 of renal transplant recipient, 52, 53, 60 Smooth muscle cells in chronic allograft nephropathy, 425, 425f in epithelial-mesenchymal transition–induced fibrosis, 420, 420f vascular, mycophenolate mofetil and, 279 Social factors See Psychosocial factors Social worth, in organ allocation, 699 Sodium homeostasis of, in brain-dead donors, 133 imbalance of hemodialysis and, 36-37, 37t in brain-dead donor, 84t, 85, 92, 95t, 96 in cold storage preservation, 129, 129f, 131 in early allograft function, 201 neurological complications related to, 536 peritoneal dialysis and, 42 in renal preservation solutions, 130t, 131 retention of, in end-stage renal disease, 35 Sodium intake for dialysis patients, 36, 36t, 37 restriction of for cyclosporine nephrotoxicity, 249 for end-stage renal disease, 36, 37 for peritoneal dialysis patients, 42 Sodium modeling, 40 Solar keratosis, 553, 554-555, 554f Solid phase assays, in sensitization screening, 351, 351t, 352 Solutes, plasma in continuous renal replacement therapies, 44-45 in hemodialysis, 34, 36 in peritoneal dialysis, 41 tonicity of, 36-37 Somatostatin analogues, allograft arteriosclerosis and, 25 South Africa dialysis options in, 632-633, 632f, 693 end-stage renal disease in, 631, 650 immunosuppressive regimens used in, 643t South America dialysis options in, 632 immunosuppressive regimens used in, 642t-643t kidney transplantation in, 633f, 634, 635 Soviet bloc countries end-stage renal disease in, 631, 632 kidney transplantation in, 639-641, 640f Spain, DCD donor use in, 135 Sparing protocols, in kidney transplantation immunosuppression for azathioprine, 243-244 for cyclosporine nephrotoxicity and, 243-244 with or without steroids, 223, 266-267 for tacrolimus, 266-267 Spasm See Vascular spasm Specialist journals, origin of, Spergualin, for immunosuppression, 335-336 Spermatic cord, division of, in renal transplant surgery, 160 Sphingosine 1-phosphate (SIP1) receptors, FTY720 response and, 337 Spinal cord, ischemia of, in brain death, 88, 88f-89f Spinal lipomatosis, epidural, 538 SPK See Simultaneous pancreas-kidney (SPK) transplantation Splanchnic vasodilation, hemodialysis causing, 40 Spleen in organ rejection, 2, specimens of, in cadaver donor nephrectomy, 115, 117 transplantation of, multiple organ retrieval and, 115, 116f Splenectomy for ABO-incompatibility, 357 for humoral rejection, 356 for immunosuppression, 342, 372 in desensitization, of transplant recipient, 106, 356 Splenic arteries in multiple organ procurement, 115, 116f in pancreas-kidney transplantation, 583, 583f, 585f Splenic vein, in multiple organ procurement, 115, 116f Sputum production, mycophenolate mofetil causing, 284 Squamous cell carcinoma (SCC), 555, 556f epidemiology of, 553-554 genetic factors of, 557 HPV associated with, 557 management of, 558-559 SRTR See Scientific Registry of Transplant Recipients (SRTR) Staphylococcus spp infection catheter-related, 66, 72, 496 epidemiological exposures to, 492, 493t, 494 in peritoneal dialysis, 42-43, 76, 77 of skin, 549 postoperative timeline of, 496, 496f Stasis, thromboses complications related to, 446-447 prevention of, 449 STAT6 proteins, leflunomide impact on, 334 Statins, for dyslipidemia, 482-483, 484, 484t, 625 Stay sutures, for vascular anastomoses, 161, 162f Steal syndrome, of arteriovenous fistula, 35, 73 Steatohepatitis, nonalcoholic, in renal transplant recipient, 508 Stem cell infusion/transplantation, 7, 372 as regenerative medicine, 705, 706t in children, 620 Stenoses of arteriovenous fistula, 35, 64, 73 X3343-idx 4/8/08 3:17 PM Page 755 Steroids (Continued) withdrawal of, 227-230 early, 265 in azathioprine era, 227 in children, 615 in cyclosporine era, 227-228, 228f-229f regimens for, 239, 269 with newer immunosuppressives, 228-230, 287 in pancreas-kidney transplantation, 268, 269, 585 outcomes of, 589-590, 590f infection risks with, 495, 495t low-dose azathioprine dose and, 221 high-dose vs., 221, 679 medical complications of, 56, 57 outcomes related to, 664, 665f skin lesions associated with, 546-547, 547f Stomach cancer, in dialysis patients, 565t, 566 Stomatitis, mycophenolate mofetil causing, 283 Stone disease See Calculi Stool tests, in infectious disease screening, 499t Streptococcus pneumoniae, 504 epidemiological exposures to, 492, 493t Streptococcus spp infection in peritonitis, 43, 77 of skin, 549 Streptokinase, for vascular access thrombosis, 66, 72, 75 Stress tests, for renal transplant recipient, 52, 477 Stressors pathophysiological, in chronic allograft nephropathy, 419 replicative senescence and, 420 psychological See Psychological aspects Strictures, ureteral endoscopic management of, 465-466 in early postoperative period, 211-212, 212f “Stripped” ureter, 462 Stroke See Cerebrovascular events Strongyloides stercoralis infection epidemiological exposures to, 493t, 494, 494f in renal transplant recipient, 55, 646 pretransplant evaluation of, 498, 499t, 500 Subclavian vein arteriovenous fistula considerations of, 67, 68 for temporary vascular access, 64 Subclinical rejection (SCR), of allografts, 417, 418, 423-424, 423f biopsy findings with, 431, 431t, 432t, 433 management of, 436 Subendothelial fibrillary material, in chronic allograft nephropathy, 428, 428f Sudden death hemodialysis and, 39 organ donation with, 113-114, 126 Sufentanil, for anesthesia, 194-195, 195f Sulfamethoxazole/trimethoprim, prophylactic, in pancreas-kidney transplantation, 586 Sun exposures See Ultraviolet (UV) light exposure Sun protection, measures for, 557-558 Superior vena cava (SVC) in multiple organ procurement, 115, 116f mural thrombus in, 66 temporary vascular catheter insertions and, 64, 65 Superoxides, cold storage preservation and, 129 Supply and demand, of kidney transplants, 7, 50, 99, 100, 100f, 117, 126, 132f, 699 Supportive care, of brain-dead donor, 95-96 Supraorbital nerve, in brain death assessment, 85 Suprapubic port, in laparoscopic donor nephrectomy, 121 Supraumbilical port, in laparoscopic donor nephrectomy, 121 Surgical complications, of kidney transplantation, 211-214, 211t bleeding as, 214 urinary problems, 211-212, 212f-213f vascular problems, 212-213, 214f “Surgical escape,” for kidney positioning, 444 Surgical management/techniques for arteriovenous fistulas, in hemodialysis, 68-70 for kidney transplantation, 158-170 closure in, 169 incision in, 159-160, 159f kidney preparation in, 160-161, 161f operative bed preparation in, 160 pediatric donors, 169-170 pediatric recipient, 159, 159f, 169, 169f, 605 recipient preparation in, 158-159 revascularization in, 160, 161-162, 162f site selection in, 159 transplant nephrectomy in, 170 urinary tract reconstruction in, 163-166, 163f-168f, 168-169 ureteral complications and, 462, 463f of cancers in dialysis patients, 567 in renal transplant patient, 574 of transplant renal artery stenosis, 457, 459f Survival loss of See Graft loss; Mortality rate of kidney transplant See Graft survival of patients See Patient survival Sutures/suturing for donor kidney fixation, 444 for renal transplant wound closure, 169 for transplant nephrectomy, 170 for urinary tract reconstruction, 163, 164-165, 165f for vascular anastomoses, 1, 161, 162f, 442, 444 Suxamethonium, for anesthesia, 196-197, 196t, 202 in diabetic patient, 205 SVC See Superior vena cava (SVC) Sympathetic nervous system, ischemic brain injuries and, 88 SYMPHONY trial, on mTOR inhibitors, 296 Syndrome X, 189 Syngeneic transplant, 10t Synthetic grafts, for arteriovenous fistulas, 35, 64, 70-71, 71f Synthetic polymer membranes, in hemodialysis, 34 Syphilis, 55 Systemic diseases, neurological disturbances associated with, 534 Systemic lupus erythematosus, 534, 609, 669 Systemic vascular resistance (SVR), in braindead donor, 91f Systolic blood velocity in chronic allograft nephropathy, 433 in transplant renal artery stenosis, 455-456, 456f T T cell AHG crossmatch, 350-351, 351t T cell receptor (TCR) fusion proteins targeting, 325 in developing thymocytes, 363 in graft rejection, 12f CD3 complex necessity for, 17-18, 17f mTOR inhibitors and, 294-295, 294f signaling pathways of, 18 second (costimulatory), 17f , 18-19, 365f in graft tolerance, 363-364, 364f analysis of recipient, 371 755 INDEX Stenoses (Continued) of vascular anastomosis, 442, 442f, 453 in growing children, 169 of venous catheter, in hemodialysis, 64, 65f renal artery See Transplant renal artery stenosis (TRAS) ureteral, after kidney transplantation, 465-466, 466f prophylaxis for, 466, 466f-467f, 466t Stents/stenting for central vein thrombosis, 66 for renal artery stenosis, 481 transplant, 457, 458f of arteriovenous fistula, 35, 73 ureteral, 166, 168 management of, 168-169 therapeutic retrograde, 463, 465 urinary obstruction and, 211, 212f Steroid resistance, in acute rejection, 222-223 plasmapheresis for, 342 polyclonal antibodies for, 314-315 Steroids chronic allograft nephropathy related to, 423, 424 for congenital nephrotic syndrome, 608 high-dose indications for, 224 low-dose vs., 221 in brain-dead donor management, 91f, 93, 95, 96 for renal preservation, 134 in kidney transplantation, 222-230 adverse effects of, 287, 673, 679 alternate-day, for maintenance therapy, 224, 227, 335 azathioprine with, 223-224 cancer associated with, 570 cyclosporine conversion from, 238t, 241-242 cyclosporine vs., 236-237, 237f sparing protocols, 243-244 cyclosporine with or without, 223, 237-239, 238f early clinical trials on, 236-237, 237f sparing regimens for, 266-267 dosage of, 223-224 low- vs high-, 221, 224 for acute rejection, 215, 224, 621 for children, 267, 621 avoidance of, 616, 623 dosing guidelines for, 618t growth impact of, 623 protocols for, 614, 615 for induction immunosuppression, 362, 362f, 362t biologics vs., 312, 314 maintenance immunosuppression vs., 288, 288t for rescue therapy, polyclonal antibodies vs., 314-315 historical use of, 5, 140, 220 in triple therapy regimen, 221, 238t, 239240, 239f, 264, 266, 285, 296 lymphoid irradiation with, 341 mechanism of action, 222 mycophenolate mofetil with, 222, 286, 287 clinical trials on, 281-282, 281t resistance to, 222-223, 314-315, 342 side effects of, 224-227, 224t, 226f neurological, 538-539, 679 tacrolimus with or without, 263-264 avoidance regimen for, 267 in kidney transplantation, 265-266, 266f in pancreas-kidney transplantation, 269-270, 585, 589-590 side effects of, 264-265, 272 sparing regimens for, 266-267 X3343-idx 4/8/08 3:17 PM Page 756 T cell receptor (TCR) (Continued) engagement model for, 364, 365f reactive leukocyte deletion and, 366-367, 376 MHC class I and II recognition by, 13, 363 T cell–antigen-presenting cell synapse, in graft rejection, 17-18, 17f HLA system and, 141, 142, 144f in children, 621 T cells/lymphocytes antibodies of cancer risk associated with, 569, 570, 572 for kidney-pancreas transplantation, 268269, 584, 587 outcomes of, 589-590, 589f in immunomodulation therapy, 321-325 therapeutic preparations of See Antibodybased therapies crossmatch assays of comparison to other crossmatches, 354-355, 355f in desensitization assessment, 352-353, 353t in humoral rejection, channel shift correlation to, 354-355, 355f in sensitization screening, 350-351, 351t, 352-354 cytotoxic See Cytotoxic T lymphocytes (CTLs) dendritic cell phenotype control by, 17 depletion of, in transplantations, 268, 269 dysfunction of, infection risk and, 492 in graft destruction, 23, 24 in graft rejection activation of recipient, 10f, 17-19 CD4+ and CD8+ cells in, 12, 12f, 16, 18, 19, 20, 25 costimulatory signals and, 17f, 18-19, 365f immune synapse and, 17-18, 17f location of, 17 receptor signals and, 18 second signals and, 18-19 Banff recognition of, 393 chronic, 25, 395-396, 395f cyclosporine effect on, 235-236, 251 effector immune response in, 19-21, 19f histocompatibility reactions, 385, 386t HLA system in, 141, 142, 144f, 151, 152 innate immune response in, 10f, 11, 133 MHC protein antigens and, 12f, 13, 15-17, 16f, 21 mycophenolate mofetil and, 277, 278f, 279 steroids impact on, 222 tacrolimus effect on, 259, 260f true interstitial features of, 425 in graft tolerance induction activation of, 363-365, 364f-365f regulation of, 362, 368-369 phenotypic characterizations, 368 in newborns, immunosuppressives impact on, 669-670 infiltrating, in tubulointerstitial rejection, 385-387, 386f naive, graft tolerance and, 17, 363, 368, 375 Notch signaling pathway influence on, 20 proliferation of after small bowel transplantation, 17 immunosuppressives impact on, 222, 251, 259, 277, 333, 335, 337, 338, 340 total lymphoid irradiation impact on, 340-342 T1-driven immunity in graft rejection, 10f, 19-20, 19f in graft tolerance, 363 T2-driven immunity in graft destruction, 24 756 T2-driven immunity (Continued) in graft rejection, 10f, 19-20, 19f in graft tolerance, 363, 365f T10B9 (Medi-500), in immunomodulation therapy, 325 Tacrolimus (FK506, Prograf), 259-273 acute rejection and, 215 alemtuzumab vs., 265-266, 266f, 267 as maintenance immunosuppression, 261, 262 as rescue therapy, 261 avoidance regimens for, 267 azathioprine with, 222, 263 blood level of, value of monitoring, 259-260, 272 clinical studies of, 259, 261-268 corticosteroid-free regimens for, 265-266, 266f corticosteroids and, 263-264 early withdrawal regimens for, 265 sparing regimens for, 266-267 cyclosporine conversion from, 242, 261 cyclosporine vs., 234, 243, 262-263, 267 developing countries use of, 636, 637, 641, 642t-643t development of, 7, 234, 259 drug interactions with, 260, 261t ethnicity and, 260, 262, 266 for children, 260-261, 267-268, 272, 621, 623 dosing guidelines for, 618t protocols for, 605, 614, 615-617, 615f, 616 for graft rejection, 7, 621 antibody-mediated, 261-262 for graft tolerance induction, 362, 362f, 362t for recurrent renal disease, in children, 606 hepatotoxicity of, 261, 511, 520 hyperglycemia and, 263-264 hypertension and, 261, 263 in double therapy regimen, 263-264 in pancreas-kidney transplantation, 268-270, 585 clinical studies of, 268-270 mycophenolate mofetil vs., 267 outcomes of, 587, 589-590 separate procedures and, 270 simultaneous procedure and, 268-269 steroid withdrawal protocols in, 269-270 steroid-free protocols in, 270, 585 in special patient populations, 260-261, 272 in triple therapy regimen, 229, 264, 266 mechanism of action, 235, 259, 260f mycophenolate mofetil with, 263-264, 265266, 266t, 280, 282, 285 for exposure reduction, 286 nephrotoxicity of, 243, 247, 270t, 271 in chronic allograft nephropathy, 425-427, 426f-427f in early postoperative period, 216 outcomes related to, 664, 665, 665f pharmacokinetics of, 259-260 absorption and distribution, 260, 260f metabolism and elimination, 260, 261t pregnancy and, 272 side effects of, 270-272, 680 cardiovascular, 262, 263, 271 dermatologic, 270t, 271, 272, 548 diabetes mellitus as, 262, 263, 271-272, 520 gastrointestinal, 270t, 271, 272 hematologic, 270-271, 448 in special patient populations, 272 malignant, 272 metabolic, 263, 270t, 271-272 neurologic, 270t, 272, 538 profile of, 270-271, 270t renal, 262-263, 270t, 271 sirolimus vs., 267 sirolimus with, 263-264 steroid withdrawal and, 228-230 structure of, 293, 294f Tacrolimus (FK506, Prograf) (Continued) thromboses related to, 448 thrombotic microangiopathy caused by, in children, 607-608 Tail procedures, in pancreas transplantation, 579, 583-584, 585f Tamm-Horsfall protein, 386, 396 TAP (transporters associated with antigen processing) transporter genes, in MHC class I and II proteins, 13, 14f Target cells, in graft destruction, 23, 24 Tc 99m MAG-3 renal scan for ureteral leak, 463, 463f for ureteral stenosis, 465 Tc 99m-HMPAO flow scan, in brain death, 84, 86t TCR See T cell receptor (TCR) TdT-uridine-nick end label See TUNEL technique Telangiectasias, drugs associated with, 552, 552f Temazepam, for anesthesia premedication, 202, 205 Temperature See Body temperature Temsirolimus (CCI-779), 299 Tenckhoff catheter, for peritoneal dialysis, 73f, 74 Tenofovir, for hepatitis B virus, 518 Teratogens, immunosuppressive agents as, 272, 283 Terazosin, for bladder dysfunction, early postoperative, 211 Testosterone, erectile dysfunction and, 467 Tetanus vaccine, 611 Tetracycline injection, for lymphocele sclerosis, 452 TGF-β See Transforming growth factor-β (TGF-β) Th2-driven immunity 1,25-dihydroxyvitamin D3 and, 338, 339 lymphoid irradiation and, 340 Th17-driven immunity, in graft rejection, 10f, 19, 19f, 20 Therapeutic monitoring of azathioprine, 221 of cyclosporine assays for, 246, 246t drugs affecting, 242, 247, 247t in children, 616 maintenance doses, 238 target values for, 245, 246t value of, 244-246, 245f of mycophenolate mofetil, 279, 280f, 284 in children, 618 pharmacokinetic vs pharmacodynamic, 284-285 research directions for, 288-289 of tacrolimus, 259-260, 272 in children, 617 Thermoregulation, dysfunction of, ischemic brain injury and, 88, 96 Thiazolidinediones, for new-onset diabetes mellitus, 486 Thiopental, for anesthesia induction, 191t, 192 Thiopurines, as immunosuppressives, 220-221 Thirst, stimulation of, in end-stage renal disease, 36 Thoracic approach to living donor nephrectomy, 111, 112f, 118 to multiple organ procurement, 115 Three-point anastomosis, arterial, during renal transplant surgery, 161, 162f Throat swab, in brain death assessment, 85 Thrombectomy, for arteriovenous fistula thrombosis, 72 Thrombocytopenia immunosuppression causing, 221, 303, 335 polyclonal antibodies causing, 315 X3343-idx 4/8/08 3:17 PM Page 757 Tissue engineering, in regenerative medicine, 705, 706t Tissue factor, in graft destruction, 22 Tissue inhibitor of metalloproteinases (TIMP), in chronic allograft nephropathy, 422, 423 Tissue specimen, optimal, for allograft biopsy, 383 Tissue typing historical perspectives of, 6, 6f organ preservation and, 126 TLI (total lymphoid irradiation), 340-342 TMA See Thrombotic microangiopathy (TMA) TMP-SMX See Trimethoprim/sulfamethoxazole (TMP-SMX) TNF See Tumor necrosis factor (TNF) entries TNX355, in immunomodulation therapy, 322 Tobacco use See Smoking entries Tolerance, of kidney transplants See Graft tolerance Toll-like receptors, in graft tolerance, 11, 368 Tonicity dialysate-to-plasma gradient of, 37 of plasma solutes, 36-37 Topical treatment of HPV-associated warts, 551 of skin cancer, 558-559 TORC1 complex, in mTOR inhibitor action, 294-295 TORC2 complex, in mTOR inhibitor action, 294-295 Total body water, composition of, 35, 36f Total lymphoid irradiation (TLI), for immunosuppression, 340-342 Toxins, Mab fusion to specific, 320-321 Toxoplasmosis, in renal transplant recipient, 55 TP-10 (complement receptor type 3), in immunomodulation therapy, 325 Tracheal reflexes, in brain death criteria, 85 Train of four stimuli, 85 Transcription factors cyclosporine effect on, 235-236 in chronic allograft nephropathy, profiling of, 434 in protocol biopsy, 397 nuclear, steroid resistance and, 223 Transcriptome gene chips, in chronic allograft nephropathy, 435 Transforming growth factor-β (TGF-β) allograft arteriosclerosis and, 25 chronic allograft nephropathy and, 419, 422, 423 as urinary marker, 434 in cyclosporine nephrotoxicity, 249 in graft destruction, 23 cyclosporine effect on, 236 in graft tolerance, 368, 369, 370f mycophenolate mofetil and, 279 Transfusion(s) blood See Blood transfusions platelet, uremic coagulopathy and, 189 Transient ischemic attacks, 53 Transitional cell carcinoma, in living donor, 103t, 106 Transmembrane proteins, fusion proteins targeting, 324 Transmission routes See Disease transmission Transperitoneal approach to living donor nephrectomy, 111, 112f disincentives to, 117, 118 to pediatric kidney transplantation, 169 Transplant biopsy See Kidney biopsy Transplant glomerulitis, 388 Transplant glomerulopathy acute, 388 chronic, 394, 425, 428-429, 428f-429f “Transplant hand,” 553, 554f Transplant nephrectomy, 60-61 for graft loss, 215 surgical technique for, 170 Transplant renal artery stenosis (TRAS), 453-457 definition of, 453 diagnostic approaches to, 455-456 imaging of, 455-456, 455f-456f in early postoperative period, 212-213, 214f, 218 incidence of, 453, 455 natural history of, 453 pathogenesis of, 404, 453-454, 454f pathophysiology of, 454-455 progressive graft dysfunction with, 396, 457 recurrence of, 457 treatment of, 481 conservative, 456-457 invasive, 213, 214f, 457, 458f, 481 surgical, 457, 459f Transplant tourism, in developing countries, 631, 635, 704 Transplantation(s) See also specific organ or type history of See also Historical perspectives early experiments on, 1, 2f-3f landmarks in, 1, 2t hospitals’ interest in, previous, in renal transplant recipient, 60-61 rescue vs utility principles of, 695, 698 terminology for, 9, 10t trauma of, 9, 10f, 11 Transplantation of Human Organs Act of India (1994), 634 Transplantation societies, origin of, 5, Transversalis fascia, exposure of, in renal transplant surgery, 160 Transvesical ureteroneocystostomy, 163, 164f TRAS See Transplant renal artery stenosis (TRAS) Trauma intraoperative, in living donor nephrectomy, 122 liver abscess related to, 524 renal injury susceptibility with, 95 to head See Brain injury to transplant grafts, during harvesting and storage, 4, 9, 10f, 11 brain death and, 87 cascade of events, 126, 127f immunology of, 11-24 Traumatic death, communicating to family members, 687, 689 Travel, epidemiological exposures during, 493, 493t Treg cells, in graft tolerance, 370f Tremor, after kidney transplantation, drugrelated, 250, 538 Trendelenburg position, for laparoscopic nephrectomy, 201 Tri-Continental Study, mycophenolate mofetil data from, 281-282, 281t Tricyclic antidepressants, intoxication with, brain death vs., 83, 84t, 85 Triglycerides, elevated See Hyperlipidemia Tri-iodothyronine (T3), in brain-dead donor management, 91f, 93 Trimethoprim/sulfamethoxazole (TMP-SMX) for P carinii/jirveci pneumonia, 505 prophylactic indications for, postoperative, 497, 497t, 498, 505 Triple therapy regimen azathioprine in, 221, 239 cyclosporine in, 238t, 239-240, 239f in developing countries, 636 mTOR inhibitors in, 296, 297t mycophenolate mofetil in, 285-286 photopheresis with, 342 tacrolimus in, 229, 264, 266 757 INDEX Thrombolysis therapy for renal vein thrombosis, 448-449 for vascular access thrombosis, 66, 72, 75 Thrombophilia, postoperative, 447 prevention of, 449 Thrombophlebitis, in living donor nephrectomy, 112, 113t Thromboses arterial See Renal artery, thrombosis of central vein, angioplasty for, 66 cyclosporine associated with, 250 during anesthesia, in diabetic patient, 205, 206 graft, biologics and, 312 in graft rejection acute cellular, 389, 389f, 390 hyperacute, 140, 385 mTOR inhibitors associated with, 304 mural, in superior vena cava, 66 of dialyzer, in hemodialysis, 34 of vascular access in hemodialysis, 35, 46, 65, 66, 72 in peritoneal dialysis, 75, 76t postoperative deep vein, 442, 449-450, 449f-450f, 451 early, arterial vs venous, 213-214, 214f, 442, 443, 448-449 factors contributing to, 446-447, 446f in pancreas-kidney transplantation, 586, 589 prevention strategies for, 449 risk screening for, in renal transplant recipient, 59-60, 59t venous See Renal vein thrombosis (RVT) Thrombotic microangiopathy (TMA) calcineurin inhibitors nephrotoxicity and, 398-399, 399f in acute cellular rejection, 390, 391 in cadaver donor kidney, 385 in chronic allograft nephropathy, 429 in cyclosporine nephrotoxicity, 248, 250, 448 in early postoperative period, 211, 217, 218 mTOR inhibitors and, 300 recurrent, 405, 406t in children, 607-608 tacrolimus associated with, 270-271, 448 Thromboxane, in cyclosporine nephrotoxicity, 248 Thymocytes developing, T cell receptors in, 363, 367 in graft tolerance, 363, 366 Thymoglobulin See Antithymocyte globulin Thymus in graft rejection, 13, 15 in graft tolerance removal indications for, 376 T cell deletion in, 366-367 T cell regulation in, 369, 375 Thyroid cancer, in dialysis patients, 564, 565, 565t, 566, 567 Thyroid hormone, ischemic brain injuries and, 89, 90 Thyroid hormone replacement, in brain-dead donor, 89, 91f, 93, 95 Thyroxine (T4), in brain-dead donor management, 91f, 93 Time to transplant, recent U.S trends of, 659, 659t Time-dependent insults, in chronic allograft nephropathy, 418, 421, 422f Timing of transplantation as live donation justification, 99-100 disease-free time intervals for cancers, 55, 56t in children, 601-602 TIMP (tissue inhibitor of metalloproteinases), in chronic allograft nephropathy, 422, 423 Tip migration, of peritoneal dialysis catheters, 75 Tissue donation, 689 X3343-idx 4/8/08 3:17 PM Page 758 Triple-lumen catheter, for anesthesia monitoring, 203 Troponin, release of, in brain-dead donor, 90 Trough (C0) level of cyclosporine, 245, 245f drugs affecting, 242 in children, 616 nephrotoxicity associated with, 247-248 target ranges for, 245, 246t of mycophenolate mofetil in children, 618 target ranges for, 279, 284 toxicities associated with, 283 Trypanosoma cruzi infection, 55, 492, 493t, 498 American See Chagas’ disease Tryptophan, in renal preservation solutions, 130, 130t, 131 Tuberculosis in renal transplant recipient donor-derived, 492 in developing countries, 644-645, 644t pulmonary vs extrapulmonary, 53 liver disease and, 524 peritoneal dialysis and, 78 pretransplant screening for, 53, 498, 499t, 500 Tuberous sclerosis, 59 Tubocurarine, for anesthesia, 196, 196t-197t, 197 Tubular atrophy calcineurin inhibitors nephrotoxicity and, 401 chronic graft, 416, 419 See also Chronic allograft nephropathy Tubular injury See Renal tubular injury Tubular necrosis See Acute tubular necrosis (ATN) Tubulitis in humoral rejection, 388-389, 389f, 390, 393t post-transplant lymphoproliferative disorder associated with, 406, 408f Tubulointerstitial fibrosis, chronic allograft, 416, 419, 421 See also Chronic allograft nephropathy acute cellular rejection vs., 391, 393t biopsy findings with, 424, 431, 431t, 433, 433t early phase of, 421, 422-423 epithelial-mesenchymal transition–induced, 419-420, 420f late phase of, 392f, 394 management of, 435, 436, 436t true rejection and, 425, 425f Tubulointerstitial nephritis, drug-induced acute, 402 Tubulointerstitial rejection acute, 385-387, 386f, 386t chronic, 392f, 394 Tubulopathy, toxic, calcineurin inhibitors nephrotoxicity and, 398 Tumor necrosis factor (TNF) chronic allograft nephropathy and, 419 receptor superfamilies of, in graft tolerance, 373 Tumor necrosis factor (TNF)-α allograft arteriosclerosis and, 25 fusion protein specific approach to, 323 HLA system role in, 141, 142, 145 immunosuppression impact on, 334, 337 in graft destruction, 23-24 in graft rejection, 12f, 15 in graft tolerance, 367, 368 in tubulointerstitial rejection, 386-387 Tumor necrosis factor (TNF)-β, in graft rejection, 15, 19f Tumors See Neoplasms TUNEL technique for renal preservation, 136 in tubulointerstitial rejection detection, 386, 387 758 Tunisia dialysis options in, 632, 632f kidney transplantation in, 633f, 643t Tunneled catheters for hemodialysis, 65 insertion techniques for, 65, 65t for peritoneal dialysis, 42, 43, 76 infections of, 42, 43, 67, 76-77 Turkey, end-stage renal disease in, 631 Twin-to-twin transplants, 4, graft tolerance in, 361 identical (monozygotic), 99, 106, 107 graft survival with, 666 HLA matching of, 140-141, 241, 592 Two-hour (C2) monitoring, of cyclosporine, 245-246, 245f drugs affecting, 242 target ranges for, 245, 246t Type diabetes mellitus, 57, 578 pancreas transplant for, 578-595 See also Pancreas transplantation Type diabetes mellitus, 57, 630 Type I allergy, to immunosuppression, 552 Tyrosine kinases, pyrimidine inhibitors effect on, 333-334, 335 Tyrphostin AG-490, for immunosuppression, 339 U Ulcers aphthous, 548 oral, mTOR inhibitors and, 298, 300, 302, 302f peptic, 57, 226 Ullmann, Emerich, 1, 2f Ulnar artery, arteriovenous fistula considerations of, 68 Ulnar neuropathy, after kidney transplantation, 537 Ultrafiltration hemofiltration vs., 45 in hemodialysis, 35-36, 40 in peritoneal dialysis, 33, 41-42 Ultrasound Doppler See Doppler ultrasound duplex for perioperative management, 210, 445 for thromboses, 446, 446f, 448, 448f in graft function/dysfunction, 216, 218 in lymphocele diagnosis, 451, 451f, 452 in surgical complications, 211, 213, 214, 214f vascular imaging of, 455, 455f-456f, 457, 460f in ureteral complications, 463, 465 transonic, of arteriovenous fistula, 35 two-dimensional, in chronic allograft nephropathy, 433 Ultraviolet (UV) light exposure skin cancer associated with, 566, 569, 572, 573 contributing risk factors, 556-557 pathogenesis of, 556 premalignant conditions and, 553, 554f preventive education on, 557-558 protection from, 574 telangiectasias associated with, 552, 552f Umbilical cord blood, in regenerative medicine, 706t Umbilical hernia, peritoneal dialysis and, 74, 74f, 76 Umbilical stoma, for urinary catheterization, 173-174, 174f-175f Unger, Ernst, 1, 3f United Kingdom brain death criteria in, 83 DCD donor use in, 135, 650 HLA matching trends in, 146, 146f, 153-154 xenotransplantation in, 704-705, 705t United Network for Organ Sharing (UNOS), 99, 107, 123 immunosuppression data of, 262 pancreas transplant data of, 578, 591 renal preservation data of, 127-128, 457 sensitization data of, 351, 352, 663 transplant outcome data of, 216, 241, 657, 659 in children, 602 United States brain death criteria in, 82-83 DCD donor use in, 135 kidney donation rates in, 658 kidney transplantation in, 633-634, 633f for children, 600, 600t outcome data on, 657, 672 laparoscopic donor nephrectomy in, 118, 118f nontransplantable kidney trends in, 127-128, 127f pancreas transplantation in annual statistics on, 586, 586f outcomes of contemporary cases, 588-590, 588f-590f percentage per procedure, 583, 584f preservation solutions used in, 128, 128f United States Renal Data System (USRDS), 35, 222, 271, 282, 471 pediatric trends in, 599, 601 United States Renal Transplant Study, mycophenolate mofetil data from, 281-282, 281t United States Scientific Registry of Transplant Recipients, 591 University of Wisconsin Cold Storage Solution (UW-CSS), for renal preservation composition of, 130, 130t EC solution vs., 130, 131 new solutions vs., 135-136 usage data on, 128, 662, 663f UNOS See United Network for Organ Sharing (UNOS) UO See Urine output (UO) Urate, serum, cyclosporine effect on, 250 Urea kinetic model, for dialysis dosing, 39 Urea, serum See Blood urea nitrogen (BUN) Uremia as dialysis complication, 36 as dialysis indication, 33, 34t cancers associated with, in dialysis patients, 566 carbohydrate metabolism and, 204 endogenous immunosuppression of, graft rejection related to, in developing countries, 632, 633 in diabetic patients, pancreas-kidney transplantation for, 580-581 neurological disturbances associated with, 534-535 pregnancy complications with, 649 Uremic lung, 188 Ureterocystoneostomy, 444 in pancreas-kidney transplantation, 583, 584f-585f Ureterocystoplasty, for bladder augmentation, 180, 181 Ureteroductostomy, in pancreas transplantation, 579 Ureteroenterostomy, 168 Ureteroneocystostomy, 163-165 augmented bladder and, 166 bladder management during, 163, 163f complications of, 212 double ureters and, 165-166, 167f extravesical, 163-165 See also Extravesical ureteroneocystostomy pyeloureterostomy and, 166, 168, 168f sutures for, 163, 164-165, 165f transvesical, 163, 164f X3343-idx 4/8/08 3:17 PM Page 759 Urinary system/tract (Continued) reconstruction procedures for, 174, 175, 176f complications of, 180-181 malignancies of, in dialysis patients, 564, 565, 565t, 566 obstruction of in children, 612 in early postoperative period, 211-212, 212f-213f ureteral stenosis causing, 465-466, 466f reconstruction of, in kidney transplantation, 163-166, 163f-168f, 168-169 before vs after, 172, 175 in children, 169-170, 172 upper, in pretransplant bladder assessment, 173-175, 174f-176f Urinary tract infection (UTI) in living donor evaluation of, 103t, 105 postoperative, 113t, 122 in renal transplant recipient, 59, 504, 644 abnormal bladder and, 172, 184 early postoperative, 217-218 pretransplant evaluation of, 498, 499t, 500 Urine collection of, quality control for, 434 concentration of in children, 614 in chronic allograft nephropathy, 421 cytology of, for infectious disease, 499t, 503 glucose in, cyclosporine effect on, 250 leakage of after kidney transplantation, 462-463, 463f surgical management of, 463-465, 464f-465f, 464t in early postoperative period, 212, 213 retention of, after kidney transplantation, 467 Urine dipstick of peritoneal dialysate, for catheter leak, 44 of postoperative wound drainage, 445 Urine output (UO) decrease in sudden early postoperative, 213, 214 ureteral leak causing, 463 donor organ management goals for, 90, 91f, 92f, 93 polyuria and, 95-96, 95t in brain-dead donor, physiologic, 91, 92f, 95 in delayed graft function diagnosis, 216 in postoperative recovery phase, 444-445 maintenance of during anesthesia, 201, 202, 203 in living donor nephrectomy, 111, 119 in pediatric kidney transplantation, 614 perioperative management of, 210-211 stimulus for, in early allograft function, 201, 202, 210 Urodynamics, invasive vs noninvasive, in bladder assessment, 173, 176, 177f, 184 Urogenital system/tract abnormalities of, 59 causes in children, 172, 173 malignancies of in dialysis patients, 564, 565t, 566 in renal transplant recipient, 572, 573, 574 Urokinase, for vascular access thrombosis, 66, 72, 75, 78 Urolithiasis after kidney transplantation, 466-467 bladder reconstruction causing, 180 Urological complications, after kidney transplantation, 462-468 erectile dysfunction as, 467-468, 468f incidence of, 462 ureteral leak as, 462-463, 463f Urological complications, after kidney transplantation (Continued) surgical management of, 463-465, 464f-465f, 464t ureteral stenosis as, 465-466, 466f ureteral stents for prophylactic, 466, 466f-467f, 466t therapeutic retrograde, 463, 465 urinary calculi as, 180, 466-467 urinary retention as, 467 Urticaria, immunosuppression and, 315, 552 USRDS See United States Renal Data System (USRDS) UTI See Urinary tract infection (UTI) Utilitarianism, 695, 698 UV exposure See Ultraviolet (UV) light exposure UW-CSS See University of Wisconsin Cold Storage Solution (UW-CSS) V Vaccinations, for renal transplant recipient, 53, 527 before transplantation, 493, 493t, 648 childhood, 54, 611, 624 hepatitis B virus, 513, 514 Vacuolation, tubular, in chronic allograft nephropathy, 425, 426f Vaginal cancer, in dialysis patients, 564, 565t, 566 Vagolytic agents, for anesthesia premedication, 202 Vagus nerve, disruption of, in ischemic brain injury, 88, 93 Valganciclovir for CMV infection, 502 prophylactic, in pancreas-kidney transplantation, 586 Valvular heart disease, in renal transplant recipient, 52, 470, 472 Vancomycin, for peritoneal dialysis infections, 43, 77, 78 Vancomycin-resistant Enterococcus, 217, 493t Variceal hemorrhage, hepatitis B virus infection and, 513 Varicella zoster immunoglobulin, 624 Varicella-zoster virus (VZV) central nervous system and, 504, 540 disseminated infection of, 527-528 epidemiological exposures to, 493, 493t, 494 in children, 611, 624-625 liver disease and, 524, 526-528, 527f pretransplant evaluation of, 499, 499t, 611 Vascular access catheters as, 35, 64-73 fistulas as, 35, 64, 67-73 for renal replacement therapy, 33, 34 continuous modalities and, 45, 46 hemodialysis and, 35, 64-73, 204 in elderly patients, 64 synthetic grafts as, 35, 64, 70-71, 71f Vascular access catheters for hemodialysis, 64-73 anesthesia for, 204 complications of, 64, 65f, 66-67 functional definitions of, 66, 66t insertion techniques for, 65, 65t long-term use, 66 temporary, 64-65 tunneled, 65, 65t types of, 35, 46, 65, 66 in renal transplant recipient for fluid monitoring, 158 protection during anesthesia, 190 infections associated with See Catheterrelated infections 759 INDEX Ureteropyelostomy, for urinary complications, 211, 214 Ureteroureterostomy for ureteral leak, 464t, 465, 465f for urinary obstruction, 211, 213f Ureters anastomoses of, in pancreas-kidney transplantation, 583, 584f-585f bridging gap between bladder and, surgical techniques for, 463-465, 464f, 464t cancer of, in dialysis patients, 565t, 566 double, in renal transplant surgery, 165-166, 167f in donor nephrectomy cadaver, 114f, 115 laparoscopic, 120, 120f living, 111, 112f, 123 in lymphocele localization, 451-452 ischemia of necrotic, early postoperative, 212, 213-214 surgical placement and, 462 leak of, after kidney transplantation, 462-463, 463f early postoperative, 212 surgical management of, 463-465, 464f-465f, 464t misdirected, discovery during reperfusion, 444 necrosis of in living donor nephrectomy, 111, 112 ischemic, early postoperative, 212, 213-214 surgical management of, 465, 465f obstruction of early postoperative, 211, 212f surgical management of, 211-212, 213f pediatric in renal transplant surgery, 169, 170 pretransplantation evaluation of, 612 stenosis of, after kidney transplantation, 465-466, 466f prophylaxis for, 466, 466f-467f, 466t stents for, 166, 168 indications for prophylactic, 466, 466f-467f, 466t therapeutic retrograde, 463, 465 urinary obstruction and, 211, 212f Urethral sling, for urinary incontinence, 174, 176f Urethral valves, posterior, in children, 172, 173, 177 kidney transplantation and, 182, 184 Uric acid, cyclosporine effect on, 250 Uridine diphosphate–glucuronosyl transferase, mycophenolate mofetil and, 279, 280-281 Uridine, in pyrimidine inhibition, 333, 334, 335 Urinalysis, in living donor, 103t, 105, 105t Urinary bladder See Bladder entries Urinary catheters balloon See Foley catheter straight See Clean intermittent selfcatheterization Urinary diversion, for abnormal bladder, 174-175 complications of, 180-181 pediatric series results of, 181-182, 183t safety of, in kidney transplantation, 172 Urinary sphincter, artificial, for urinary incontinence, 174, 176f Urinary system/tract bleeding into, in early postoperative period, 212 complications of, 462-468 See also Urological complications diagnostics of, in chronic allograft nephropathy, 434-435 disease of, in children, 612 lower in pretransplant bladder assessment, 173 X3343-idx 4/8/08 3:17 PM Page 760 Vascular anastomoses for arteriovenous fistula insertion, 67-68 in kidney transplantation in children, 169, 605 of hypogastric artery, 159f, 161, 161f-162f of iliac artery, 161, 161f, 162 of iliac vein, 161, 161f, 162 of renal artery, 160-161, 161f-162f, 169 of renal vein, 161-162, 162f, 169 technical complications of arterial, 442-443 venous, 441-442, 442f in pancreas-kidney transplantation, 583, 583f-585f stenosis of, 169, 442, 442f, 453 Vascular cell adhesion molecule (VCAM)-1 brain death and, immunological activation of, 133-134 in endarteritis, 388 in graft rejection, 21, 133 in late graft diseases, 395 in tubulointerstitial rejection, 386-387 Vascular clamps for arteriovenous fistula insertion, 70 in laparoscopic donor nephrectomy, 121 in renal transplant surgery, 123, 160, 161, 163, 169 reperfusion and, 443-444 technical complications of, 440, 442, 442f, 445 Vascular complications, after kidney transplantation biopsy-related, 457, 460f early, 212-213, 214f hematoma as, 445-446, 446f lymphocele as, 450-453 rejection as See Vascular rejection technical problems, 439-446 arterial anastomosis and, 442-443 back table preparation and, 440-441, 441f compartment syndrome and, 445, 445f description of, 439-440 drain tube removal and, 445 positioning the kidney and, 442, 444 postoperative recovery and, 444-445 preoperative assessment for, 440 reperfusion and, 443-444, 443f right or left donor kidney and, 440 right-sided or left-sided surgery and, 440, 441-442 venous anastomosis and, 441-442, 442f wound closure and, 444 thrombophilia as, 447-448 thrombosis as, 446-447, 446f deep vein, 442, 449-450, 449f-450f, 451 prevention strategies for, 449 renal artery, 443, 449 renal vein, 442, 448-449, 448f transplant renal artery stenosis as, 453-457, 454f-456f, 458f-459f Vascular disease cardiac See Cardiovascular disease (CVD) graft Banff scores and, 393 immunosuppression and, 300, 337 in sensitized recipient, late outcomes of, 356, 356t major, pathology of, 403-404, 404f in kidney donor, pretransplant assessment of, in renal transplant recipient assessment of cardiac, 52-53, 469, 470 peripheral, 53, 470, 471 renal, 261 pathogenesis of, 472 760 Vascular endothelial growth factor, cyclosporine effect on, 250 Vascular endothelium, in graft rejection activated cells migration into, 20-21 brain death and, 89 chronic, 25 chronic allograft nephropathy and, 425, 425f, 427 destructive immune response in, 24 hyperacute pathology, 385 Vascular rejection, in kidney transplantation calcineurin inhibitors causing, 425-427, 426f-427f early accelerated, 214-215 rescue therapy for, 261 true interstitial features of, 425, 425f Vascular resistance in brain-dead donor arterial, 90, 92f systemic, 91f renal, in chronic allograft nephropathy, 433 Vascular spasm, prevention of, in organ procurement, 111, 444 Vascular steal syndrome, 440 of arteriovenous fistulas, 35, 73 Vascular surgery, kidney transplantation as, 158, 160-162, 161f-162f preoperative assessment for, 210 Vascularity, ensuring in living donor nephrectomy, 111, 112, 113t in multiple organ procurement, 115, 116f Vasculitis mTOR inhibitors associated with, 293 recurrent, in renal transplant recipient, 59 Vasculopathy See Vascular disease Vasoactive peptides, in cyclosporine nephrotoxicity, 248 Vasoactive support, for brain-dead donor, 90, 91f, 93, 96 Vasoconstriction, ischemic brain injuries and, 88-89 Vasodilation in brain-dead donor, 88-89, 92f, 93, 96 splanchnic, hemodialysis causing, 40 Vasodilators, direct, for hypertension, 483t Vasomotor tone, in brain-dead donor, 91, 92f Vasopressors, in brain-dead donor management, 90, 91f, 93 VCAM-1 See Vascular cell adhesion molecule (VCAM)-1 Vecuronium, for anesthesia, 196t-197t, 198, 199 Vegetative state, persistent, brain death vs., 84t, 85, 695 Vein(s) See also specific artery, e.g., Renal vein fistulas of, for hemodialysis See Arteriovenous (AV) fistula(s) in kidney transplantation, technical complications of anastomosis-related, 441-442, 442f preoperative assessment for, 440 Vein grafts for arteriovenous fistula, 71 for renal artery anastomosis, 160, 440 in laparoscopic donor nephrectomy, 121 Vein transposition, brachiobasilic arteriovenous fistula with, for hemodialysis, 70, 70f-71f Vena cava inferior See Inferior vena cava superior See Superior vena cava (SVC) Venipuncture, of arteriovenous fistulas, 69, 71 Venogram, of iliac vein, 442, 442f Venous catheters central See Central venous catheters for hemodialysis, 35, 46 complications of, 66-67, 66t indications for, 65, 65t, 66 Venous drainage impaired renal, consequences of, 439 in pancreas transplantation metabolic studies of, 593-594 options for, 579, 582, 583 outcomes of, 589 percentage in U.S., 583, 584f techniques for, 583-584, 583f-585f Venous hypertension, in arteriovenous fistulas, 69, 69f Venous thromboses See Renal vein thrombosis (RVT) Venous volume reservoir (capacitance), in brain-dead donor, 90, 92f, 94 Ventilatory support See Mechanical ventilation Verapamil, cyclosporine metabolism and, 242 Verbal cues, in family communication, 688 Veress needle, for pneumoperitoneum, in laparoscopic donor nephrectomy, 119 Verotoxin-producint Escherichia coli (VTEC), 607 Vesicoureteral reflux, 172, 173, 177 Viaspan solution, for renal preservation, use in U.S vs ET region, 128, 128f Videourodynamics, in pretransplant bladder assessment, 173 Viral infections brainstem encephalitis caused by, 540 cancers associated with in dialysis patients, 566 in renal transplant patient, 568, 569 prevention of, 574 chronic allograft nephropathy related to, 421, 422f, 424, 424f-425f management of, 435, 436, 436t epidemiological exposures to, 492-494, 493t hemolytic-uremic syndrome associated with, 608 in renal transplant recipient, 54, 492, 504 biologics and, 313 important specific, 500-504 in children, 611, 621, 624-625 in developing countries, 647-648 liver disease and, 524-528, 527f postoperative timeline of, 495-498, 496f pretransplant evaluation of, 498-500, 499t in xenotransplantation, 704 mTOR inhibitors for, 299 mycophenolate mofetil associated with, 282, 288, 300, 302f of skin, 550-551, 551f pancreas-kidney transplant risks with, 269, 582, 586 post-transplant lymphoproliferative disorder associated with, 406, 408f Visilizumab (HuM291), 321 Vitamin A analogues, for skin cancer, 559 Vitamin C supplementation, cyclosporine metabolism and, 247 Vitamin D supplementation for bone health, in renal transplant recipient, 225-226, 612 for hypocalcemia, 39 Vitamin D3 for immunosuppression, 338-339 in calcium homeostasis, 39 Vitamin E supplementation cyclosporine metabolism and, 247 for cardiovascular disease, 487 Vitamin K, for anticoagulation reversal, 53, 60 Vitamins, antioxidant, for cardiovascular disease, 487 Volume contraction, in early postoperative period, 216-217 graft dysfunction and, 218 Volume status See Fluid status X3343-idx 4/8/08 3:17 PM Page 761 W Waiting list for donor kidney ABO-incompatible candidates on, 357 cardiovascular disease mortality and, 471, 472-473, 472t children on, 601, 601f current trends of, 7, 50, 99, 100, 100f duties owed to patients on, 696-697 in developing countries, 650 joining and remaining on, 61 new registrations for in U.S., 659, 659t psychological aspects of being on, 677-678 remaining on dialysis during, 49, 49t screening tests for, 61-62, 61t sensitized patients on, 351-352, 357 vascular assessment for, 440 for pancreas-kidney transplants screening for, 581-582 survival probabilities related to, 591, 591f Waiting time, graft survival related to in kidney transplantation, 117, 126, 657-658, 659 in pancreas-kidney transplantation, 591, 591f Warfarin (Coumadin) for central venous catheter, 66 for vascular disease, in renal transplant recipient, 53 postoperative, in pancreas-kidney transplantation, 586 thrombophilia and, 449 Warm ischemia, and renal injury, 126, 444 prevention strategies for, 135, 449 Warts, HPV associated with, 550-551, 551f Water composition, of body, 35, 36f Water purification, in hemodialysis, 34 Wegener’s granulomatosis, 609 Weight gain intradialytic, prevention of, 40, 44 potential for, in pancreas transplantation, 594 Weight loss before kidney transplantation, 60 for new-onset diabetes mellitus, 486 Well-being, psychological, for renal transplant recipient, 676-677 West Nile virus, 492, 493t, 498, 499, 504 Westmead Transplant Unit, 448 WHI-P131 compounds, for immunosuppression, 339 White Americans, end-stage renal disease in, 650, 650t White blood cells (WBCs), in peritoneal dialysis infections, 43, 77 WHO See World Health Organization (WHO) Whole-blood hybrid capture assay, in CMV infection, 501 Whole-cell immunization, 313 Wilm’s tumor, in children, 610, 613 Withdrawal, as grief reaction, 688 Working space, for laparoscopic donor nephrectomy, 118-119 World Health Organization (WHO) HLA nomenclature of, 144-145 on diabetes criteria, 484-485 Wound closure in kidney transplantation, 169, 444 in transplant nephrectomy, 170 Wound complications after kidney transplantation, 462-463 in living donor nephrectomy, 112, 113t, 122 Wound healing, steroids impact on, 225 Wound infections after arteriovenous access procedure, 72 bacterial, 549 mTOR inhibitors associated with, 296, 298, 302 Wrists, arteriovenous fistulas in, radiocephalic, 67-68, 69f surgical technique for, 69-70 X X chromosome, in Alport’s syndrome, 606 Xanthine oxidase cold storage preservation and, 129 ischemic brain injuries and, 88 thiopurine metabolism and, 221 Xenoantibody(ies), T cell–independent IgM formation of, 334 Xenobiotic metabolism, of drugs, anesthesia and, 190 Xenogeneic transplant, 10t, 334 Xenograft kidney transplantation historical perspectives of, 1, 2, 3, HLA system class I antigens and, 141 immunosuppression for, 334, 335, 336, 341, 342 new technology for, 7, 341, 704 waiting for, Xenograft transplant See Xenotransplantation Xenotourism, regulation of, 704 Xenotransplantation breeding animals for, 702-703 description of, 10t, 695 ethical debate concerning, 702-704, 702t graft rejection in, pyrimidine inhibitors for, 334, 335 graft tolerance in, induction therapies for, 374-375 guidelines for, 704-705, 705t historical perspectives of, 1, physiological issues with, 341, 705 recent developments in, 702 Xenozoonosis, 695, 703-704 XLAAD syndrome, in graft tolerance, 368 XomaZyme-CD5 Plus, in immunomodulation therapy, 324 Y Y delivery system, for peritoneal dialysis, 73-74, 73f, 633 Yeast infection See Candida spp infection Y-graft, in pancreas-kidney transplantation, 583, 583f-584f Y-tube system, for bladder management, during renal transplant surgery, 163, 163f Z Zoonosis, in xenotransplantation, 7, 695, 703-704 761 INDEX Vomiting anesthesia/analgesia and, 189, 202 as hemodialysis complication, 40 monoclonal antibodies causing, 318 von Decastello, Alfred, von Willebrand factor, 447, 607, 608 Voronoy, Yu Yu, 3, 3f VTEC (verotoxin-producint Escherichia coli), 607 Vulvar cancer, in dialysis patients, 564, 565t, 566 VZV See Varicella-zoster virus (VZV) ... selection Immunol Rev 193: 82- 92, 20 03 23 6 Strasser A: The role of BH3-only proteins in the immune system Nat Rev Immunol 5:189 -20 0, 20 05 23 X3343-Ch23 4/8/08 2: 58 PM Page 3 82 2 62 Van Parijs L, Abbas... Transplantation 62: 1 725 -1730, 1996 24 1 Swanson SJ, Hale DA, Mannon RB, et al: Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy Lancet 360:16 62- 1664, 20 02 2 42 Sykes... immunosuppression Transplantation 82: 13 42- 1351, 20 06 25 8 Turvey SE, Gonzalez-Nicolini V, Kingsley CI, et al: Fas ligand-transfected myoblasts and islet cell transplantation Transplantation 69:19 721 976, 20 00 25 9