Chapter 10 Transplantation
Principles of Surgery Companion Handbook
|Transplant Immunology and Immunosuppression|
|Overview of Immunity|
|Genetic and Structural Characteristics of Transplant Antigens|
|Biology of Transplant Antigen Recognition and Destruction|
|Clinical Rejection Syndromes|
|Lung and Heart-Lung Transplantation|
Transplantation is the process of taking a graftcells, tissues, or organsfrom one individualthe donorand placing it into another individualthe recipient or host. If the graft is placed into its normal anatomic location, the procedure is called orthotopic transplantation (e.g., heart transplants, liver transplants). Transplantation between genetically different members of the same species is referred to as allogeneic transplantation, such as transplantation of tissues or organs between two different strains of experimental animals (e.g., rat strain ACI to Lewis). In human beings, all transplants except those between identical twins are allotransplants. Failure of graft to take is the result of immunologic rejection, mediated by the recipient's lymphocytes.
An epitope is the molecular unit of specific immune recognition. It is a carbohydrate or peptide moiety with a defined stereochemical configuration. Antigen is used to describe an epitope containing molecules that can be bound by one of two types of lymphocyte receptors: the T-cell receptor (TCR) of T cells or the antibody (or immunoglobulin) of B cells. The degree to which an allograft shares regulatory molecules of the immune system with the recipient is referred to as the histocompatibility of the graft. This is a description of the similarity of a cluster of genes on chromosome 6 known as the major histocompatibility complex [MHC, known as human leukocyte antigen (HLA) in human beings]. Two different classes of MHC gene products are produced, class I and class II. The importance of MHC gene products stems from their polymorphism. Because MHC is polymorphic, it can serve as an antigen to another individual. Antigens derived from different MHC molecules within the same species are called alloantigens. Isografts are organs transplanted between identical twins and are immunologically inconsequential. Xenografts are organs transplanted from one species to another.
Immunity has two distinct but complementary branches to combat disease: innate and acquired immunity. The hallmark of acquired immunity is specific recognition and elimination of nonself. The pathogen is recognized as a specific entity, not just as nonself, and a record is retained for more rapid response to future encounters, a phenomenon known as immunologic memory. Antigen recognition is mediated by lymphocytes, T cells, and B cells. T cells protect the cells of the body against alterations by mutation or viral infection (cellular immunity) and bind peptide antigens that have been processed by the body's cells. B cells provide protection against extracellular infectious organisms and foreign material (humoral immunity) and recognize antigens in their native unprocessed state. Parenchymal cells express class I MHC molecules. Class I molecules display peptides from within, e.g., peptides from normal cellular processes or from viral replication, which are bound by T cells expressing an adhesion molecule with special affinity to class I, the CD8 molecule. Hematopoietic cells also express class II MHC molecules. These molecules display peptides that have been phagocytized from surrounding extracellular spaces and bind to T cells complemented by an adhesion molecule with affinity to class II, the CD4 molecule. B cells bind soluble antigens and secrete soluble forms of their receptor, known as antibodies, to bind these foreign molecules. Material that is bound by an antibody is opsonized (flagged) for destruction by cells of the innate arm of immunityphagocytic cells lacking the ability to distinguish self from nonselfprimarily macrophages, monocytes, and polymorphonuclear leukocytes (PMNs). Antibody-bound surfaces activate a destructive enzymatic cascade known as the complement system. This leads to destruction of the membrane to which the complement is bound and further opsonization. The entire immune process is facilitated by a means of amplifying the response of one cell to one antigen. Cytokines [known as interleukins (ILs)] are polypeptides that are released by many cell types and activate or suppress adjacent immune cells (Table 10-1). The immune response to an allograft is the result of incompatibility between the recipient's receptor repertoire and the donor's MHC polymorphisms. Effector mechanisms that have evolved to counteract viral, fungal, and bacterial infections, as well as those in place to prevent malignancy and autoimmunity, all come into play after transplantation. Rejection, like physiologic immunity, can be divided into humoral and cellular mechanisms. Humoral rejection of a graft can be the result of antibodies existing in circulation prior to exposure or antibodies acquired after exposure. Cellular rejection is the result of T-cell incompatibility between the donor and recipient.
TABLE 10-1 PROPERTIES OF SOME HUMAN CYTOKINES
The antigens primarily responsible for human allograft rejection are those encoded by the HLA region of chromosome 6. The polymorphic proteins encoded by this locus that directly affect transplant rejection are class I molecules (HLA-A, -B, and -C) and class II molecules (HLA-DR, -DP, and -DQ). The blood group antigens of the ABO system also must be considered polymorphic transplant antigens, and their biology is critical to humoral rejection. Class I is expressed as a single MHC-encoded transmembrane heterodimeric protein. The critical structural feature of class I molecules is the presence of a groove. Within this groove, a nine-amino-acid peptide, formed from fragments of proteins being synthesized in the cell's endoplasmic reticulum, is mounted for presentation to the body's T cells. Class I molecules are found on all nucleated cells except neurons. The structural features of class II molecules are strikingly similar to those of class I molecules. The groove of class II is filled with a peptide derived from endocytosed proteins (as opposed to proteins formed by the cell, as is the case for the groove of class I). Class II molecules are found primarily on cells of the innate immune system, particularly phagocytes, such as dendritic cells, macrophages, and monocytes, but can be upregulated to appear on other parenchymal cells by cytokines released during an immune response or injury. The TCR accessory molecule CD8 selectively binds to class I, whereas the accessory molecule CD4 binds to class II. In this way T cells geared toward the initial recognition of intruders and subsequent amplification of the immune response (CD4+ helper T cells) are targeted to bind the cells with the ability to capture and present these antigens. Similarly, T cells that survey the body's parenchyma for signs of entrenched intracellular pathogens and destroy infected cells (CD8+ cytotoxic T cells) are outfitted to perform this duty.
T-Cell Receptor (TCR) The formation of the TCR is fundamental to an understanding of alloreactivity and self nonreactivity. T cells are formed in the fetal liver and bone marrow and migrate to the thymus, where they accquire a single TCR with a single specificity through genetic rearrangement. Developing T cells also express CD4 and CD8, increasing the binding repertoire of the population to include either class I or class II MHC molecules. To avoid the release of self-reactive T cells, developing cells undergo a process after recombination known as thymic selection. Cells initially interact with the MHC-expressing cortical thymic epithelium. If binding does not occur to self MHC, the cells are useless to the individual because they would be unable to bind and function in the periphery. All nonbinding cells undergo apoptosis, or programmed self-destruction, a process called positive selection. Cells surviving positive selection then move to the thymic medulla and lose either CD4 or CD8. If binding to self MHC in the medulla occurs with an unacceptably high affinity and apoptosis results, this is called negative selection. Any foreign peptide encountered alters the affinity that has been preordained in the thymus, resulting in T-cell activation. MHC molecules that were not part of the T cell's thymic education will bind the TCR with unacceptable affinity and lead to activation. This phenomenon defines alloreactivity.
Antibody, also called immunoglobulin (Ig), is formed in B cells much the way TCR is in T cells, although maturation occurs in the bone marrow, not in the thymus, and continues in the periphery. Antibodies have a basic structure of four chains, two of which are identical heavy chains and two of which are identical light chains. The heavy-chain usage defines the Ig type as being either IgM, IgG, IgA, IgE, or IgD. The Fc portion is bound by Fc receptors on phagocytic cells of the innate immune system, facilitating phagocytosis, followed by destruction of the antigen and processing of antigenic peptides. The Fc portion of IgM and some classes of IgG also serves to activate complement. IgG becomes the most significant soluble mediator of opsonization and is the dominant antibody resulting from allostimulation. To avoid a vigorous humoral rejection of the graft, screening for these antibodies must be done before transplantation.
T-Cell Activation T cells can respond to transplant antigens directly, through TCR binding to foreign MHC molecules expressed on transplanted tissues, or indirectly, by encountering antigen-presenting cells (APCs) that have phagocytosed fragmented allograft tissues and processed the antigens for expression on self MHC. The TCR transmits its signal to the cell by initiating the activity of intracytoplasmic protein tyrosine kinases (PTKs) associated with the TCR-associated transmembrane protein complex called CD3 (Fig. 10-1). After calcium-dependent activation and nuclear transcription, interleukin-2 (IL-2) is then released and binds to the T cell in an autocrine loop. In addition to TCR engagement, a second confirmatory signal is required for T-cell activation. Costimulation can control whether a TCR signal results in activation or quiescence. This control has a role in self-tolerance.
FIGURE 10-1 T-cell receptor activation through its interaction with MHC and adhesion molecules and the mechanism of action of selected immunosuppressants. The TCR binds to an MHC molecule (class II is shown). This event is stabilized by an accessory molecule (CD4 or CD8, depending on the MHC class). The costimulatory molecule gp39 upregulates the expression of the APC costimulation molecules B7, shifting the balance of negative regulation by CTLa4 to positive regulation by CD28. This potentiates signal transduction and activation of NF-AT, which in turn induces IL-2 synthesis. IL-2 works in an autocrine loop to force the cell into a division cycle. Cyclosporine (CyA) and tacrolimus (FK506) both block this signal transduction by blocking the calcineurin/calmodulin-potentiating proteins cyclophilin and FK-binding protein, respectively. Rapamycin (RAP) blocks the IL-2 receptor signal transduction by blocking the interaction of RAFT and FK-binding protein.
T-Cell Amplification Once activation occurs, cytokines, particularly IL-2 and interferon-g (IFN-g), create a potent milieu, recruiting other T cells into the response and potentiating clonal expansion.
T-CellMediated Cytotoxicity T cells assume one of two roles: that of an amplifier or that of a cytotoxic effector. The amplification role generally is performed by CD4+ cells, because these cells are most suited for communication with class IIexpressing APCs. Cytotoxicity is best mediated by CD8+ cells, because they bind to the MHC of all nucleated cells. The mechanisms of direct T-cellmediated destruction of microorganisms or non-MHC-expressing tissue are poorly defined.
B-Cell Activation and Clonal Expansion B cells recognize antigen in its native form without the requirement for processing and presentation on MHC molecules. Surface antibody cross-linking by antigen leads to B-cell proliferation and differentiation into a plasma cell. Like the T cell, the threshold for B-cell activation is high. This can be lowered by costimulation signals received by the transmembrane complex CD19/CD21. B cells also can internalize antigens bound to surface antibody and process them for presentation to T cells. As such, B cells can bind antigen in circulation and initiate a T-cell response to deal with antigen incorporated into tissues of the body. Antigen exposure generally leads to B-cell affinity maturation and isotype switching and produces high-affinity IgG antibodies. Naturally occurring antibodies are low-affinity IgM antibodies and respond to a broad array of carbohydrate epitopes found on many common bacterial pathogens. Natural antibody is responsible for ABO antigen responses.
Antibody-Mediated Cytotoxicity Antibody facilitates the destruction and removal of antigenic cells. Once bound to an antigen, antibody serves as an anchoring site for the complement component C1q and subsequent activation of the classical complement activation cascade. Antibody also can serve as an opsonin directly. Most phagocytic cells have receptors for the Fc portion of IgG and actively engulf antibody-coated targets in a process known as antibody-dependent cellular cytotoxicity (ADCC). Antibody binding to the endothelium, and the subsequent activation of complement, also alters the activation status of the endothelial cell. This leads to cellular retraction and exposure of the underlying matrix, which in turn potentiates platelet activation and aggregation. Endothelial activation also alters its usually anticoagulant environment in favor of a procoagulant one. The result is microvascular thrombosis, a hallmark of the two antibody-mediated graft rejections: hyperacute rejection and acute vascular rejection.
Rejection has been classified as hyperacute, acute, and chronic. Only acute rejection can be reversed successfully. Although hyperacute rejection is mostly preventable, chronic rejection is a difficult problem.
Hyperacute Rejection Hyperacute rejection (HAR) is caused by presensitization of the recipient to an antigen expressed by the donor. It develops in the first minutes to hours after graft reperfusion. Antibodies bind to the donor tissue. This initiates complement-mediated lysis and induces a procoagulant state, resulting in immediate graft thrombosis. Exposure usually is in the form of prior transplant, transfusion, or pregnancy. Prevention is through preoperative screening via the lymphocytotoxic crossmatch and ABO typing. A delayed variant of HAR known as vascular rejection also is mediated by humoral factors.
Acute Rejection Acute rejection is caused primarily by T cells and evolves over a period of days to weeks. It can occur any time after the first 5 postoperative days but is most common in the first 6 months and is inevitable without immunosuppression directed against the T cell. T cells bind antigen via their TCR either directly or after phagocytosis of donor tissue and representation of MHC peptides by self APCs. This leads to cell activation, resulting in a massive infiltration of the graft by T cells, with destruction of the organ. Any mismatch puts the patient at risk for T-cellmediated graft destruction and mandates T-cellspecific immunosuppression. Treatment of rejection leads to successful restoration of graft function in 9095 percent of patients, and failure to treat results almost uniformly in graft loss.
Chronic Rejection Unlike acute and hyperacute rejection, chronic rejection (CR) is poorly understood. Onset is insidious over a period of months to years, and chronic rejection is untreatable. Heightened immunosuppression is not effective in reversing or retarding the progression of chronic rejection. Histologically, CR, regardless of the organ involved, is characterized by parenchymal replacement by fibrous tissue with a relatively sparse lymphocytic infiltrate. Those organs with epithelium show a dropout of the epithelial cells and endothelial destruction. Chronic rejection requires retransplantation.
Without some attenuation of the immune system, all allografts eventually would be destroyed. For all organs, the events occurring at the time of transplantation are the most critical in establishing the state of immune unresponsiveness necessary for long-term graft survival. Immunosuppression is extremely intense in the early postoperative period and subsequently tapers. Initial conditioning of the recipient's immune system is known as induction immunosuppression. Medications used to prevent acute rejection for the life of the patient are called maintenance immunosuppressants. All have side effects that increase the risk of infection and malignancy. Immunosuppressants used to reverse an acute rejection episode are called rescue agents. They are the same as the agents used for induction therapy.
Corticosteroids Corticosteroids remain a central tool in the prevention and treatment of allograft rejection. Higher doses of steroids also are used as a rescue agent to treat acute cellular rejection. Although steroids have a desirable immunosuppressive effect, they can contribute significantly to the morbidity of transplantation. Glucocorticosteroids bind to an intracellular receptor after nonspecific uptake into the cytoplasm and form a receptor-ligand complex that enters the nucleus and ultimately prevents the function of NF-kB, a key activator of proinflammatory cytokines. In doing so, steroids prevent the primary mechanism by which lymphocytes amplify their responsiveness. The adverse effects of steroid therapy are numerous and include a suppressed hypothalamic-pituitary-adrenal axis, impairment of glucose tolerance, delayed wound healing, salt and fluid retention that may exacerbate hypertension, and central nervous system (CNS) effects such as insomnia, depression, nervousness, and euphoria. Chronic side effects of corticosteroids include Cushing's syndrome (i.e., central obesity, acne, striae, hirsutism, and altered facies), cataracts, muscle wasting, and growth retardation in prepubertal children. Patients show an increased propensity toward peptic ulceration. Osteoporosis results from the combined effects of the inhibition of bone matrix formation and intestinal absorption of calcium.
Antiproliferative Agents Azathioprine The antimetabolite azathioprine is a part of many maintenance immunosuppressive protocols. The derivatives of azathioprine inhibit DNA synthesis by alkylating DNA precursors and inducing chromosomal breaks. They inhibit the enzymatic conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP) and guanosine monophosphate (GMP). The effects of azathioprine are relatively nonspecific; it acts not only on proliferating lymphocytes and PMNs but also on all rapidly dividing cells. Azathioprine effectively inhibits rejection when given as a maintenance agent but, unlike steroids, has no value as a rescue or induction agent.
Mycophenolate Mofetil Mycophenolate mofetil (MMF, RS-61443) is a potent immunosuppressive agent approved for use in adults; it is a noncompetitive, reversible inhibitor of IMP dehydrogenase. Physiologic purine metabolism requires that GMP be synthesized for subsequent synthesis of guanosine triphosphate (GTP) and deoxyguanosine monophosphate (dGTP). GTP is required for RNA synthesis and dGTP for DNA synthesis. GMP is formed from IMP by IMP dehydrogenase, and therefore, MMF prevents a critical step in RNA and DNA synthesis. Of major importance is the presence of a salvage pathway for GMP production in most cells except lymphocytes (hypoxanthine-guanine phosphoribosyl transferasecatalyzed GMP production directly from guanosine). MMF exploits a critical difference between lymphocytes and other body tissues, including PMNs, to produce relatively selective immunosuppressive effects.
Calcineurin Inhibitors Cyclosporine Borel demonstrated the T-cellspecific immunosuppressive properties of cyclosporin A, a cyclic endecapeptide isolated from the fungus Tolypocladium inflatum Gams. Cyclosporine's mechanism of action is mediated primarily through its ability to bind to cytoplasmic protein cyclophilin, blocking the calcium-dependent phosphorylation and activation of the transcription-regulating factor NF-AT. This prevents the transcription of the IL-2 gene critical for T-cell activation. Cyclosporine reversibly inhibits T-lymphocytemediated immune responses, but it does not prevent antigen recognition by T cells, and its effects can be overcome with exogenous (or in the case of an ongoing rejection episode, ambient) IL-2. Cyclosporine works as a maintenance agent and is ineffective as a rescue agent.
Cyclosporine causes dose-related nephrotoxicity, an idiosyncratic reaction producing hemolytic uremic syndrome; hyperkalemia also may result. Long-term use causes a 30 percent reduction in renal function; hypertension also is a common adverse effect but usually can be treated effectively. Cyclosporine frequently causes neurologic side effects consisting of tremors, paresthesias, headache, depression, confusion, somnolence, and rarely, seizures. Hypertrichosis of the face, arms, and back is seen in about 50 percent of patients. Gingival hyperplasia also may occur.
Tacrolimus Tacrolimus (FK506) is a macrolide produced by Streptomyces tsukubaenis. Tacrolimus, like cyclosporine, blocks the effects of NF-AT, prevents cytokine transcription, and arrests T-cell activation. Tacrolimus is 100 times more potent in blocking IL-2 and IFN-g production than cyclosporine. Like cyclosporine, the effects of tacrolimus are relatively T-cell specific, but in addition to its role as a maintenance agent, tacrolimus has shown promise as a rescue agent. The side effect profile of tacrolimus is similar to that of cyclosporine with regard to renal and hepatic toxicity. Neurotoxicity, in the form of tremors and mental status changes, is somewhat more pronounced, as is its diabetogenic effect. Cosmetic side effects are reduced substantially.
Antilymphocyte Globulin Antilymphocyte globulin (ALG) is a polyclonal serum against human lymphocytes. Thymocytes rather than lymphocytes are sometimes used, and this is designated as antithymocyte globulin (ATG); ATGAM is the most widely used preparation. ATGAM targets the T cell by coating multiple epitopes on this cell type and promoting their clearance through complement-mediated lysis, opsonin-induced phagocytosis, and internalization of key surface receptors. One side effect is severe thrombocytopenia, which may result from cross-reactivity with platelets and may limit the use of the drug. Major side effects are rare; the most common symptoms are the result of transient cytokine release after antibody binding. Chills and fevers occur in up to 20 percent of patients. Thrombocytopenia and leukopenia do require an alteration in treatment. Because antilymphocyte preparations profoundly inhibit T lymphocytes, they also suppress cell-mediated immunity. The use of ALG has been associated with an increase in the reactivation and development of primary cytomegalovirus (CMV) infections. In addition to CMV infections, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and varicella infections may occur more frequently after therapy with antilymphocyte preparations.
Monoclonal Antibodies Monoclonal antibodies have very specific targets. OKT3 is the murine monoclonal antibody to the signal-transduction subunit on human T cells (CD3). There are several ways in which OKT3 is thought to have its effect. Because OKT3 binds to the CD3 determinant, it prevents signal transduction of the TCR antigen-binding event and arrests amplification of a rejection episode. After the administration of OKT3, there is a rapid decrease in the number of circulating T lymphocytes. This is partially a result of opsonization and clearance by the reticuloendothelial system of the OKT3-lymphocyte complex. Another way in which OKT3 exerts its effect is by downregulation of the TCR complex, producing a blind T cell incapable of binding to antigen. In addition to interfering with the generation of cytotoxic T cells and the modulation of cell surface proteins, OKT3 blocks the cytotoxic activity of already activated T cells through inappropriate activation and degranulation. This is perhaps its most important function, but it leads to substantial side effects. Administration of OKT3 leads to a profound systemic cytokine release syndrome that can result in hypotension, pulmonary edema, and rarely, fatal cardiac myodepression. In approximately 2 percent of patients, the inflammatory response manifests itself as aseptic meningeal inflammation. Administration of high-dose methylprednisolone prior to OKT3 administration is required to blunt this adverse response, but rarely is the response averted altogether. The syndrome abates with subsequent dosage as the target cells available for degranulation are consumed or exhausted. The adequacy of dosage is determined by the percentage of CD3+ cells using flow cytometry. The presence of less than 10 percent CD3+ cells is associated with therapeutic efficacy. OKT3 was first used as a rescue agent to treat rejection. It is vastly superior to conventional steroid therapy in reversing rejection and improving allograft survival, but its side effects and the limiting nature of the antimurine antibody response have served to limit its use to the treatment of steroid-resistant rejection. OKT3, like other antilymphocyte preparations, causes a high reactivation rate of CMV. EBV infection leading to lymphoproliferative disorders is also associated with its use.
Diabetes is now the leading cause of renal failure in the United States and commonly contributes to blindness, debilitating neuropathies, and accelerated atherosclerosis. Numerous studies have demonstrated the beneficial effect of intensive glucose control on arresting the development and progression of end-organ complications. It might be possible to prevent or ameliorate systemic complications of diabetes by achieving more precise glucose control. Alternative methods of insulin replacement therapy are under investigation, but none has been successful enough to warrant more widespread application.
Indications Type I insulin-dependent diabetics younger than 45 years of age are potential candidates (Table 10-2). For major organ transplant necessitating long-term immunosuppression, contraindications include untreated malignancy, active infection, and human immunodeficiency virus (HIV) seropositivity. Pancreas transplantation is performed in three different sets of circumstances: pancreas transplantation alone (PTA) in the nonuremic diabetic with minimal or no evidence of diabetic nephropathy, pancreas transplantation after successful kidney allografting (PAK), and pancreas transplantation performed simultaneously with a kidney transplant (SPK) in the uremic patient. Approximately 90 percent of pancreas transplants performed in the United States are SPK transplants.
TABLE 10-2 CRITERIA FOR SELECTION OF CANDIDATES FOR SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANTATION AND SOLITARY PANCREAS TRANSPLANTATION
Operative Procedure The pancreatic duct carrying the exocrine secretions can be drained by two methods, into the bladder or directly into the small bowel. Advantages of bladder drainage include the ability to use urinary amylase determinations as a screening test for rejection, avoidance of an enteric anastomosis and spillage of bowel contents, and reduced potential for peripancreatic infections. Advantages of the enteric drainage technique include avoidance of the postoperative urologic complications that occur in up to 30 percent of patients, avoidance of chronic dehydration and the need for bicarbonate replacement, and early removal of the Foley catheter. The pancreatic graft harvested en bloc with the liver is first separated. The recipient operation begins with a midline transabdominal incision. The pancreas usually is placed into the right iliac fossa, and the kidney, if transplanted simultaneously, is implanted on the left side. The venous anastomosis is performed first. This can be achieved by anastomosing the portal vein of the pancreas graft to the distal inferior vena cava or to a completely mobilized iliac vein. The arterial anastomosis is then performed between the reconstructed donor iliac artery Y graft and the common iliac artery. If bladder drainage is chosen, a pancreatic duodenocystostomy is performed in a side-to-side anastomosis to the dome of the bladder with two layers of running absorbable sutures. If enteric drainage is performed, the duodenal segment is sutured to the ileum in a side-to-side manner.
Postoperative Management Rejection occurs with greater frequency after pancreas and simultaneous pancreas-kidney transplantation than after isolated renal transplantation. This difference requires management that balances aggressive immunosuppression against the risks of infection. Acute rejection is the rule rather than the exception after pancreas transplantation, occurring in 7080 percent of patients, and primarily. Pancreas rejection more commonly occurs with kidney rejection. There is no ideal screening test for rejection of the pancreas allograft.
Complications Despite improvements in technique, preservation, and patient selection, surgical complications are not uncommon and threaten the survival of the graft and the patient. Proper management of complications is critical to a successful outcome. The development of a urologic complication is most frequent after SPK transplantation performed with bladder drainage. A metabolic acidosis is present postoperatively in approximately 80 percent of patients after pancreas transplantation with bladder drainage and usually is a result of excessive urinary loss of bicarbonate-containing exocrine fluids. Oral replacement should be initiated to maintain a serum bicarbonate level of at least 2225 mg/dL. This problem usually stabilizes and diminishes over time and only infrequently requires conversion from bladder to enteric drainage. Enteric conversion is used for treatment of persistent urologic and electrolyte problems.
Results Between 1987 and 1995, over 4500 cadaver donor pancreas transplants were performed in the United States and reported to the International Pancreas Transplant Registry. The 1-year patient survival rate is more than 90 percent, and the 1-year pancreas graft survival rate (as measured by insulin independence) is more than 75 percent. The addition of a pancreas to a kidney transplant does not adversely affect patient or kidney graft survival rates in uremic diabetic patients. Long-term kidney function is not negatively affected by a simultaneous pancreas transplant.
Effect of Pancreas Transplantation on Secondary Complications of Diabetes The major benefit of a pancreas transplant over a kidney transplant alone is enhanced quality of life.
Potential Candidates Most potential candidates for intestinal transplantation are patients with short-bowel syndrome. Different disease processes can lead to short-bowel syndrome, but adults and children generally develop this syndrome after extensive intestinal resections. Common indications for intestinal transplantation in adults are Crohn's disease, mesenteric thrombosis, and trauma. Necrotizing enterocolitis, intestinal pseudo-obstruction, gastroschisis, volvulus, and intestinal atresia are indications in children.
Operative Procedures There are three methods of intestinal transplantation, the choice depending on the disease and sequelae that occur in combination with the short-bowel syndrome. For patients without liver failure, isolated intestinal grafting is preferred; patients with liver failure receive a combined liver-intestine transplant. In a small number of patients, a multivisceral procedure is performed that includes grafting of the liver, stomach, pancreas, duodenum, and small intestine with or without the colon.
Immunology The two major immunologic problems after intestinal transplantation have been graft-versus-host disease (GVHD) and host-versus-graft disease (rejection). To prevent GVHD, sufficient immunosuppressive therapy must be administered. Clinically, there has been a low incidence of GVHD. The prevention of rejection after intestinal transplantation is more difficult. The introduction of tacrolimus significantly improved the outcome after intestinal transplantation.
Diagnosis of Rejection The earlier rejection is detected, the more effective might treatment be in reversing the rejection process and minimizing damage to the grafted organ. Rejection is detected primarily by clinical symptoms and graft histology. These symptoms include fever, abdominal pain, elevated white blood cell count, ileus, increased stomal output, gastrointestinal bleeding, and positive blood cultures. Intestinal biopsies may show evidence of cryptitis, shortening of villi, mononuclear infiltrate, or even mucosal sloughing.
Results The International Intestinal Transplant Registry reported results on 178 intestinal transplants performed worldwide since 1985. The results of tacrolimus-based immunosuppression were superior to those of cyclosporine-based immunosuppression. The 1-and 3-year actuarial graft survivals were 65 and 29 percent for isolated intestine, 64 and 38 percent for liver-intestine, and 51 and 37 percent for multivisceral transplants, respectively.
Indications Liver transplantation is indicated for the treatment of irreversible liver failure from acute or fulminant disease or, more commonly, chronic liver disease. Fulminant hepatic failure frequently has an unknown cause but may be secondary to viral hepatitis, Wilson's disease, hepatotoxins, or alcoholic hepatitis. Outcomes for liver transplantation in patients with fulminant hepatic failure have a worse prognosis than in patients with chronic liver disease because the former are generally more unstable and have more comorbid conditions. Survival rates of 70 percent at 1 year are expected for patients transplanted for fulminant disease (Table 10-3). Posthepatitic cirrhosis resulting from hepatitis B or C is associated with the risk of recurrence of viral hepatitis and cirrhosis in the transplanted liver. Strategies to prevent recurrence of hepatitis B have included administration of hepatitis B hyperimmune globulin, interferon, and lamivudine. Hepatitis C also has been associated with frequent recurrence of disease in the transplanted liver and often is unresponsive to interferon therapy. Liver transplantation for primary biliary cirrhosis is associated with a high success rate, but the primary disease may recur and is difficult to distinguish from chronic rejection. Primary sclerosing cholangitis should be treated with liver transplantation before cholangiocarcinoma develops. Patients with alcoholic liver disease account for 75 percent of liver failure in the United States, comprising the largest group of patients who could potentially benefit from liver transplantation. A period of abstinence and evidence of family and social support are required before the candidate can be eligible for transplantation. Comorbid features, such as alcoholic cardiomyopathy, also must be excluded. Numerous metabolic defects and many inborn errors of metabolism, with their primary defect in the liver, also can be corrected by liver transplantation (Table 10-4). Liver transplantation for cancer is controversial, and the results are poor. Five-year patient survival rates around 40 percent are reported, which is better than the outcome without transplantation.
TABLE 10-3 CAUSE OF LIVER FAILURE IN ADULT RECIPIENTS AT UNIVERSITY OF WISCONSIN
TABLE 10-4 CAUSES OF LIVER FAILURE IN CHILDREN
Preoperative Evaluation The signs and symptoms of liver failure should be evaluated in detail in patients being considered for liver transplantation. Hepatic encephalopathy is determined by clinical examination and often is paralleled by serum ammonium levels. Patients with stage IV coma must be managed aggressively to prevent cerebral edema or hemorrhage, common causes of death in patients with end-stage liver failure. Coagulopathy associated with liver failure is associated with an elevated international normalized ratio (INR) unresponsive to vitamin K replacement. Thrombocytopenia is common and usually is caused by hypersplenism related to underlying portal hypertension. Patients with bleeding should be treated with administration of fresh frozen plasma and platelet transfusions. Gastrointestinal bleeding related to underlying portal hypertension, if associated with Child's class B or C liver failure and liver fibrosis or cirrhosis, constitutes an indication for liver transplantation. Variceal bleeding before transplantation should be controlled with a combination of medical, radiologic, and, if necessary, surgical therapy. Ascites resulting from portal hypertension may be severe and require medical treatment with diuretics and paracentesis. Hepatorenal failure, a fatal condition before the advent of liver transplantation, is reversible after liver transplantation. Other correctable causes of underlying kidney dysfunction must be excluded before hepatorenal failure is diagnosed. If hepatorenal failure has caused renal function to deteriorate acutely over a period of days or weeks, renal function can be expected to return to normal after liver transplantation. Biliary obstruction in patients with primary biliary cirrhosis is associated with fatigue, and severe itching should prompt liver transplantation. Patients with primary sclerosing cholangitis who develop recurrent bouts of cholangitis requiring hospitalization should be considered for early liver transplantation to avoid the septic complications of cholangitis. Patients with liver failure are immunocompromised. Spontaneous bacterial peritonitis may present with evidence of generalized sepsis and peritonitis and can be treated with antibiotics. Other causes of peritonitis, such as a perforated viscus, must be excluded. Patients with liver failure develop a hyperdynamic state, with elevated cardiac output and low systemic vascular resistance.
Contraindications Contraindications to liver transplantation are summarized in Table 10-5.
TABLE 10-5 CONTRAINDICATIONS TO LIVER TRANSPLANTATION
Immunologic Considerations Graft failure in liver transplantation usually is not because of immunologic rejection in compliant patients but more frequently is because of primary nonfunction, recurrence of original disease (hepatitis or primary biliary cirrhosis), or biliary and vascular complications.
Donor Procedure, Procurement, and Preservation The liver can be procured from a brain-dead donor as part of an en bloc procurement with the pancreas (Fig. 10-2) or as an isolated liver procurement. Care must be taken to preserve anomalous arteries, such as a right hepatic artery arising from the superior mesenteric artery or an accessory left hepatic artery arising from the left gastric artery.
FIGURE 10-2 Procurement of the donor liver involves arterial perfusion of UW solution via an aortic cannula with cross-clamping of the supraceliac aorta and concomitant perfusion of the portal vein via a separate cannula. En block procurement with the pancreas, duodenum, and spleen is performed routinely, and the pancreas and liver are then separated on the back table.
Recipient Operative Procedure Orthotopic liver transplantation begins with native hepatectomy (including removal of a segment of the intraabdominal inferior vena cava), followed by implantation of the donor liver (Fig. 10-3). Because this technique requires occlusion of the inferior vena cava and portal vein simultaneously during the entire anhepatic phase, this method was found to result in hemodynamic instability in a significant proportion of adult patients. Venovenous bypass was developed to return blood from the inferior vena caval and portal venous circuits to the superior vena cava. A donor liver procured from an adult may be reduced in size as necessary for transplantation to a pediatric recipient. An additional modification is the split-liver technique, which uses the entire liver for two recipients; the right and left lobes are used for different patients. Application of these surgical techniques to the left lateral segment of a live donor has resulted in successful living-related liver transplantation, typically from a parent to a child with liver failure. Reconstruction of the common bile duct in liver transplantation involves an end-to-end anastomosis of donor-to-recipient bile ducts. This has been performed over a T tube, although using an internal stent or no stent at all has become popular. If the recipient common bile duct is inadequate or unsuitable for any reason, a Roux-en-Y choledochojejunostomy is performed. The donor hepatic artery is reconstructed by anastomosing the donor celiac axis to the recipient hepatic artery. If the recipient hepatic artery is compromised (including intrinsic or extrinsic stenosis of the celiac axis), a donor iliac artery graft is placed on the aorta in the supraceliac or infrarenal position and used as a conduit to the donor celiac artery.
FIGURE 10-3 Conventional orthotopic liver transplantation includes division of the donor hepatic artery, portal vein, common bile duct, and infrahepatic and suprahepatic inferior vena cava with subsequent anastomosis of these from the donor, as shown here. The bile duct anastomosis shown is performed over a T-tube stent. The donor celiac axis is anastomosed end-to-end to the proper hepatic artery or to an arterial graft anastomosed to the recipient aorta.
Postoperative Management The immediate postoperative management of liver transplant patients includes optimizing the patient's physiology and conditions that favor good liver function. Maintenance immunosuppression in liver transplant recipients relies principally on cyclosporine or tacrolimus. Tapering doses of steroids also are used. Azathioprine or mycophenolate mofetil also have been used as maintenance agents. Acute rejection episodes after liver transplantation are common, but graft loss from rejection is rare. An elevation in liver enzyme levels, particularly canalicular enzymes [gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin], that is not explained by bile duct obstruction or hepatic artery thrombosis should prompt percutaneous liver biopsy because the diagnosis of rejection is best made histologically.
Complications Primary nonfunction of the liver is manifested by a high INR, low fibrinogen level, and high ammonia level in the first several days posttransplant. Primary nonfunction must be treated with urgent retransplantation, but livers that demonstrate initial poor function typically recover after a period of days. Portal vein thrombosis is a rare complication of liver transplantation but requires immediate diagnosis and operative intervention. Hepatic artery thrombosis has an incidence of approximately 5 percent in adult liver transplantation and a higher incidence in pediatric liver transplantation. Because the biliary tree depends on hepatic artery blood flow, hepatic artery thrombosis results in ischemic changes of the bile ducts, resulting grossly in sloughing of the biliary epithelium and leading to plugging and obstruction of the bile ducts. If uncorrected, this leads to biloma formation and eventually liver abscess and sepsis. The management of hepatic artery thrombosis includes retransplantation or observation (because some patients tolerate this complication without ill effects). Bile leaks after liver transplantation must be corrected immediately because they lead to peritonitis, sepsis, and graft loss. Recurrence of original disease may be a problem after liver transplantation in particular groups of patients. These include patients with primary biliary cirrhosis, which is difficult to differentiate from chronic rejection. Hepatitis B and C are likely to recur after liver transplantation but will not necessarily lead to cirrhosis of the transplanted liver. If alcoholism recurs after liver transplantation, it is considered a contraindication to retransplantation. Posttransplant lymphoproliferative disorder (PTLD) may arise in liver transplant recipients as a side effect of overimmunosuppression. Particularly at risk are pediatric recipients, especially those treated with high-dose immunosuppression for recalcitrant rejection. The primary treatment of PTLD is reduction of immunosuppressive therapy.
Results Patients in better medical condition at the time of liver transplantation have better outcomes, which has prompted earlier referral of patients with liver failure. Combined patient and graft survival rates for U.S. centers are shown in Figure 10-4. Certain indications, such as primary biliary cirrhosis in adults and biliary atresia in children, are associated with higher-than-average success rates.
FIGURE 10-4 Combined data for U.S. liver transplant centers for the period 19871993 on current patient and graft survival rates for adults.
Preoperative Considerations Recipient Selection Rigid adherence to recipient selection criteria is important in achieving the excellent results observed in cardiac transplantation. The United Network for Organ Sharing (UNOS) heart transplant waiting list contains over 2800 patients, with about 300 new patients added to the list each month. Donor organ availability permits only 150160 cardiac transplants each month. The average length of time on the waiting list has increased to over 300 days for outpatients, contributing to the 1520 percent mortality rate among patients on the waiting list.
Indications Generally accepted indications for cardiac transplant evaluation are listed in Table 10-6. Patients who suffer from severe cardiac disability despite maximal medical therapy but who are otherwise healthy are considered for cardiac transplantation. Most cardiac transplant recipients suffer from end-stage, inoperable coronary artery disease or idiopathic cardiomyopathy and often require multiple hospitalizations. Other diagnoses include defined cardiomyopathy (e.g., viral, postpartum, familial), congenital anomalies, and valvular disease. Disabling symptoms typically include those associated with congestive heart failure (e.g., dyspnea, orthopnea, generalized edema, and weakness), although recurrent symptomatic ventricular arrhythmias and severe ischemic symptoms (i.e., unstable angina) are observed frequently. Cardiac transplant candidates generally fall into the New York Heart Association's (NYHA) functional classes III and IV. Formerly, a left ventricular ejection fraction (LVEF) of less than 20 percent was relied on as a key indicator of severe cardiac dysfunction requiring transplantation, but refinements in medical management, particularly aggressive vasodilator therapy, have rendered this parameter less representative of severe patient disability or predictive of imminent death. Peak oxygen consumption, a function of peak cardiac output and peripheral oxygen extraction, correlates well with functional class and is an independent predictor of outcome in heart failure patients. Prospective studies have shown that patients with severely reduced peak oxygen consumption (< 15 mL/kg/min, approximately 50 percent of normal) have a 1-year mortality rate exceeding 50 percent.
TABLE 10-6 GENERAL INDICATIONS WARRANTING CONSIDERATION FOR ADULT CARDIAC TRANSPLANTATION
Contraindications (Table 10-7) Active infection and malignancy are absolute contraindications to transplantation in view of the lifelong immunosuppression required. Acute transient infections must be thoroughly cleared before transplantation; chronic infective agents, including chronic hepatitis B, hepatitis C, and human immunodeficiency virus (HIV), preclude transplantation. Chronic conditions predisposing to serious infection, including symptomatic cholelithiasis, severe diverticulitis, active peptic ulcer disease, and cerebral/pulmonary embolization, should be evaluated and treated before transplantation. With the exception of fully resected squamous cell carcinoma of the skin, patients with previous malignancies should not be listed for cardiac transplantation less than 5 years after the malignancy has been considered cured. Severe, fixed pulmonary hypertension has been confirmed as a significant independent risk factor for early mortality after orthotopic cardiac transplantation because of a heightened incidence of acute posttransplant right ventricular failure.
TABLE 10-7 CONTRAINDICATIONS TO ADULT CARDIAC TRANSPLANTATION
Evaluation and Management of Patients Awaiting Cardiac Transplantation Candidate Evaluation and Listing Patients suitable for cardiac transplantation are categorized and listed on the basis of clinical status, time on the waiting list, body size, and ABO blood group. Heart failure and clinical deterioration refractory to parenteral support necessitate mechanical intervention in the form of intraaortic balloon pump (IABP) counterpulsation or ventricular assist system (VAS) placement. Complications observed in left VAS-supported patients include bleeding (40 percent), infection (2075 percent), and right ventricular failure (1030 percent).
Donor Selection and Management Criteria Donors must have sustained irreversible brain death, usually as a result of blunt or penetrating head trauma or intracranial hemorrhage. Suggested criteria for cardiac donors and guidelines for recipient matching developed by the American Heart Association in 1992 are listed in Table 10-8.
TABLE 10-8 SUGGESTED CRITERIA FOR CARDIAC DONORS AND GUIDELINES FOR RECIPIENT MATCHING
Absolute contraindications for donation include severe coronary or structural disease, prolonged cardiac arrest, prior myocardial infarction, a carbon monoxide hemoglobin level greater than 20 percent, arterial oxygen saturation of less than 80 percent, metastatic malignancy (sometimes excluding primary brain and skin cancers), and positive HIV status.
Donor-Recipient Matching Donor-recipient matching parameters include ABO compatibility and body size.
Operative Procedures Procurement The chest is entered through a median sternotomy (Fig. 10-5). The superior and inferior vena cavae are divided, then the heart is cooled, and cardioplegia solution is infused. When the heart is fully arrested, cooled, and perfused with cardioplegia solution, it is elevated from the pericardial well, and each of the pulmonary veins is divided at its pericardial reflection. The pulmonary artery is divided at the level of the bifurcation, and the aorta is divided at the level of the innominate artery. The explanted heart is placed into cold sterile saline and stored until implantation.
FIGURE 10-5 Donor cardiac procurement. A. Anticipated lines of transection of the vena cavae, aorta, and pulmonary veins. B. Donor heart excision, beginning with transection of the inferior vena cava (IVC) and pulmonary veins (PV; R = right, L = left, I = inferior, S = superior) and proceeding superiorly before transecting the pulmonary arteries and aorta. RPA = right pulmonary artery; RV = right ventricle; LV = left ventricle; PDA = posterior descending artery. (From: Smith JA, McCarthy PM, et al: The Stanford Manual of Cardiopulmonary Transplantation. Armonk, NY, Futura Publishing, 1996, with permission.)
Orthotopic Transplantation The recipient operation is performed via a median sternotomy under cardiopulmonary bypass and moderate hypothermia.
Heterotopic Transplantation This is rarely performed.
Postoperative Management Early Postoperative Period Precautions are taken to minimize patient contact with objects or persons harboring active infectious agents. A primary objective in the immediate postoperative period is to maintain adequate perfusion in the recipient while minimizing cardiac work. Approximately 1020 percent of transplant recipients have some degree of transient sinus node dysfunction, often manifested as sinus bradycardia that usually resolves within a week. Because cardiac output is primarily rate dependent after transplantation, the heart rate should be maintained between 90 and 110 beats/min during the first few postoperative days using temporary pacing or isoproterenol. The systolic blood pressure should be maintained between 90 and 110 mmHg using afterload reduction in the form of nitroglycerin or nitroprusside if necessary. Cardiac function generally normalizes within 34 days. Optimizing pulmonary function is another critical objective in the acute postoperative period. An initial endomyocardial biopsy is taken several days postoperatively, and a second endomyocardial biopsy and baseline coronary arteriogram are obtained approximately 2 weeks postoperatively.
Graft Physiology The grafted heart presents several unique physiologic characteristics. The denervated heart graft is isolated from normal autonomic regulatory mechanisms. The resting heart rate is higher because vagal tone, sinus arrhythmia, and carotid reflex bradycardia are absent. The denervated heart graft develops an increased sensitivity to catecholamines, possibly from an increase in beta-adrenergic receptor density and a loss of norepinephrine uptake in postganglionic sympathetic neurons. This augmented sensitivity has an important role in maintaining an adequate cardiac response to exercise and stress. The output of cardiac allografts is at the low end of the normal range and the measured cardiac response to exercise or stress is below normal, but the response of the cardiac allograft is adequate for most activities. The atrial cuff anastomoses also result in abnormal cardiac physiology. The normal atrial contribution to ventricular end-diastolic filling is impaired by the dissociation between recipient and donor atrial contractions.
Immunosuppression Conventional immunosuppression in cardiac transplant recipients consists of the triple-drug combination of cyclosporine, azathioprine, and glucocorticoids.
Postoperative Complications Acute Rejection Acute graft rejection is a major cause of death after cardiac transplantation. The incidence of acute graft rejection is highest during the first 3 months after transplantation. After this initial 3-month period, the incidence of acute rejection averages about one episode per patient per year. Despite attempts at developing noninvasive means to detect acute rejection in a timely manner, the endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection. Surveillance endomyocardial biopsies allow rejection to be diagnosed before significant organ damage and dysfunction occur. Endomyocardial biopsies are repeated 1014 days after antirejection therapy to assess efficacy.
Chronic Rejection Accelerated graft coronary artery disease (CAD) or atherosclerosis is a major limiting factor for long-term survival in cardiac transplant recipients. Significant graft CAD resulting in diminished coronary blood flow may lead to arrhythmias, myocardial infarction, sudden death, or impaired left ventricular function with congestive graft failure. Typical angina from myocardial ischemia usually is not noted in transplant patients because the cardiac graft essentially is denervated. In a retrospective analysis of cardiac transplants from 1980 through 1993, the actuarial freedom from graft CAD at 1, 5, and 10 years was 95, 73, and 65 percent, respectively. The definitive therapy for diffuse disease is retransplantation. Effective prevention of graft CAD relies on developments in improved immunosuppression, recipient tolerance induction, improved CMV prophylaxis, and inhibition of vascular intimal proliferation.
Infection Infection is the leading cause of morbidity and mortality in post-cardiac transplantation patients. The risk of infection and infection-related death peaks during the first few months after transplantation and rapidly declines to a low persistent rate. Early infections, those occurring during the first month after transplantation, are commonly bacterial (especially gram-negative bacilli) and are manifested as pneumonia, mediastinitis, catheter sepsis, and urinary tract and skin infections. Treatment of these infections involves identification of the infective agent (e.g., cultures, antibiotic sensitivity tests), source control (e.g., catheter removal, debridement), and appropriate antibiotic regimens. In the late posttransplant period, opportunistic viral, fungal, and protozoan pathogens are more prevalent. The lungs, CNS, gastrointestinal tract, and skin are the usual sites of invasion. CMV infection is widely recognized as the most common and important viral infection in transplant patients, with an incidence of 73100 percent in cardiac transplant recipients. It presents as a primary infection or reactivation of a latent infection, most commonly 14 months after transplantation. CMV infection has protean manifestations, including leukopenia with fever, pneumonia, gastroenteritis, hepatitis, and retinitis. CMV pneumonitis is the most lethal of these, with a 13 percent mortality rate, whereas retinitis is the most refractory to treatment, requiring indefinite treatment. Fungal infections are less common than bacterial or viral infections. Long-term prophylaxis typically includes nystatin mouthwash for thrush, sulfamethoxazole-trimethoprim for opportunistic bacterial and Pneumocystis carinii infections, and antiviral agents such as acyclovir or ganciclovir.
Neoplasm Organ transplant recipients are at significantly higher risk for developing cancer, undoubtedly because of chronic immunosuppression. Recipients are predisposed to skin cancer, B-cell lymphoproliferative disorders, carcinoma in situ of the cervix, carcinoma of the vulva and anus, and Kaposi's sarcoma.
Retransplantation The primary indications for cardiac retransplantation are graft failure from accelerated graft atherosclerosis or recurrent acute rejection. Patients in need of retransplantation are held to the same standard criteria as initial candidates. Survival rates after retransplantation are significantly less than those achieved in primary transplant patients.
Results Actuarial 1-, 5-, and 10-year survivals are 82, 61, and 41 percent, respectively. Most patients are fully rehabilitated to New York Heart Association functional class I status.
PEDIATRIC CARDIAC TRANSPLANTATION
Cardiac transplantation is now an accepted therapeutic option for infants and children with end-stage heart disease. The leading indications in children are acquired dilated cardiomyopathy and congenital heart disease. Contraindications for transplantation in this group are similar to those in adults, with the addition of some complex venous drainage anomalies. Blood type and donor size are the most important considerations in donor-recipient matching. Actuarial 1-, 5-, and 10-year survival estimates are 75, 60, and 50 percent, respectively, with most survivors achieving the New York Heart Association functional class I. Normal somatic growth rate can be maintained in these patients, and normal cardiac chamber dimensional growth also occurs.
Chronic obstructive lung disease has been treated effectively with single-lung transplantation and currently constitutes a major indication for this procedure.
Preoperative Considerations The indications are shown on Table 10-9.
TABLE 10-9 INDICATIONS FOR ADULT SINGLE-LUNG, BILATERAL SINGLE-LUNG, AND HEART-LUNG TRANSPLANTATION
Postoperative Complications Early morbidity and mortality after lung and heart-lung transplantation are most commonly caused by infection, graft failure, and heart failure. Mortality after 1 year is caused most commonly by obliterative bronchiolitis, infection, and malignancy. The majority of acute rejection episodes occur during the first 3 months after transplant (6070 percent of patients in the first month). Signs of rejection include fever, dyspnea, impaired gas exchange manifested by a decrease in PaO2, a diminished forced expiratory volume in 1 s (FEV1, a measure of airway flow), and the development of an interstitial infiltrate on chest x-ray. Fiberoptic bronchoscopy with transbronchial parenchymal lung biopsy and bronchoalveolar lavage is used routinely to diagnose acute rejection or rule out infection.
Immunosuppression Immunosuppression protocols for lung and heart-lung transplant recipients are similar to those used in cardiac transplantation. Triple-drug therapy begins immediately after operation and is tapered according to standard protocols. Episodes of acute rejection are treated with a short course of intravenous steroid boluses. After steroid therapy, improvement often is rapid and dramatic and is considered confirmatory of rejection. Persistent rejection is treated with ATG or OKT3 monoclonal antibodies. Chronic lung allograft rejection is the greatest limitation to the long-term benefits of lung and heart-lung transplantation. Chronic lung rejection most commonly presents as obliterative bronchiolitis (OB), a pulmonary corollary to cardiac graft atherosclerosis.
Infection Bacterial, viral, and fungal infections are the leading causes of morbidity and mortality in lung and heart-lung transplant recipients. Most common are pulmonary bacterial infections involving the allograft. Absence of the cough reflex in the denervated lung, abnormal mucociliary clearance mechanisms, and deficiencies in lymphatic drainage predispose grafted lungs to infection. CMV is the most common and most clinically significant viral pathogen. The diagnosis of CMV pneumonitis, usually the most severe manifestation of CMV infection, is made from a positive viral culture or cytologic evidence obtained from bronchoalveolar lavage or transbronchial biopsy, respectively. Ganciclovir is the treatment of choice. CMV prophylaxis includes ganciclovir, acyclovir, and polyvalent immune globulin. Lung and heart-lung transplant patients also are at a higher risk for developing lymphoproliferative disease, particularly in association with EBV infection. Treatment consists of lowering immunosuppression and administering acyclovir. Fungal infections are the most infrequent and most deadly of infectious complications. P. carinii pneumonia has been effectively prevented in lung transplant patients since the institution of prophylaxis in the form of oral trimethoprim-sulfamethoxasole or, for sulfa-allergic patients, inhalational pentamidine. Improvements in surgical technique and posttransplant management have resulted in a relatively low incidence of airway complications after lung and heart-lung transplantation. The rates of lethal airway complications and late stricture have been reported at 3 and 10 percent, respectively. The most common airway complications are partial anastomotic dehiscence and stricture. The most common causes of death after retransplantation are infection and OB.
Results According to the International Heart-Lung Registry, the 6-year actuarial survival rate for single-lung and bilateral single-lung transplants performed worldwide from 1982 to 1995 is about 40 percent (Fig. 10-6). Most recipients are able to resume an active lifestyle without supplemental oxygen. Pulmonary function measured by spirometry and arterial blood gases is improved significantly in patients after transplantation, with a normalization of ventilation and gas exchange after 12 years.
FIGURE 10-6 Actuarial survival rates of adult lung transplant recipients (19821995). (From: Hosenpud JD, Novick RJ, et al: The registry of the International Society for Heart and Lung Transplantation: Thirteenth official report1996. J Heart Lung Transplant 15:655674, 1996, with permission from MosbyYear Book.)
Renal transplants are the most common solid organ allografts performed, and transplantation has become the preferred treatment of chronic renal failure for many patients.
Preoperative Management Transplant Recipient Evaluation Evaluation should include a careful and complete history and physical examination, with attention directed to the history of renal disease, prior surgery, and comorbid conditions, such as heart disease, peripheral vascular disease, and diabetes. Any history of cancer or recent infection should be documented. Laboratory studies should include standard chemistries, complete blood counts, urinalysis, and serologic studies for hepatitis B and C, cytomegalovirus, and HIV. A chest x-ray and electrocardiogram also are included for adult candidates. Evidence of risk factors for surgery should prompt more thorough investigations. Specific tests for associated conditions may include noninvasive cardiac studies such as an echocardiogram or a stress test, evaluation for peripheral vascular disease with noninvasive vascular studies, and pulmonary function tests for patients with a significant history of chronic pulmonary disease. Cardiac catheterization may be required for assessment of coronary disease. Urine cultures should be obtained and a urologic evaluation performed if there is evidence of urologic anatomic abnormalities or prior urologic surgeries.
Indications and Contraindications The contraindications are shown in Table 10-10.
TABLE 10-10 CONTRAINDICATIONS TO RENAL TRANSPLANTATION
Histocompatibility Testing The workup begins with blood group typing and HLA typing. Blood group typing is essential because renal endothelial cells express major blood group antigens, and the preformed natural antibodies to these antigens can result in hyperacute rejection. In cadaveric transplantation, absolute blood type matching is required, but type O donors are universal donors. The standard typing procedure is a lymphocytotoxic serologic test in which the potential recipient's cells are tested against a battery of sera or as monoclonal antibody preparations. These sera have been selected because of reactivity against specific HLA antigens. All cadaveric and potential living donors are HLA typed as well. Standard tests include typing for the class I antigens HLA-A, -B, and -C and the class II antigens HLA-DR, -DP, and -DQ. HLA typing can be of significant importance in living donor transplantation by allowing identification of the best match from multiple potential donors. For cadaver donor allocation, matching also has an important role. In living donor transplantation, an HLA match is correlated with short- and long-term graft survival. In cadaveric transplantation, matching is used to facilitate organ allocation. There is a correlation between the degree of HLA matching; the 1-year survival advantage for six-antigen matches over completely mismatched cadaveric transplants is about 5 percent. Serum screening is another important histocompatibility test in renal transplantation. As a result of sensitizing events, such as blood transfusions, pregnancies, and previously failed transplants, patients may produce anti-HLA antibodies. The consequences of sensitization are the production of antibodies against specific HLA antigens. Serum screening is performed by testing a patient's serum against a panel of lymphocytes selected to represent the known HLA antigens. Sensitization is designated by the patient's panel-reactive antibodies (PRA) level, which is a reflection of the percentage of cells on the panel against which the sera react. The most important histocompatibility test in renal transplantation is the final crossmatch. This is similar to the crossmatch test performed for blood transfusions. Cells from a potential donor and serum from a recipient are incubated together. Crossmatching is performed just before proceeding with transplantation. The use of sensitive crossmatch techniques has essentially eliminated hyperacute rejection as a problem in renal transplantation.
Renal Donor Evaluation of the Living Donor According to recent statistics from the United Network of Organ Sharing (UNOS), there are over 30,000 patients awaiting renal transplants in the United States. The cadaveric donor pool has remained static over the past 5 years, with only 40005000 donors realized each year. Because of the shortage of cadaveric donors, live donors, related and unrelated, have a larger role in many renal transplant programs. The advantages of live donation are excellent immediate graft function and avoidance of posttransplant dialysis, better short- and long-term results, preemptive transplantation (i.e., avoidance of dialytic support), avoidance of waiting time for a cadaveric kidney, and in the case of HLA-identical transplants, a reduction in immunosuppressive therapy. The risks to the donor are relatively low, but there is a 1 in 10,000 risk of death and a 10 percent or less risk of morbidity. No definitive long-term morbidity has been demonstrated for live donors. The presence of diabetes, hypertension, malignancy, significant cardiopulmonary disease, a history of renal disease, and age over 65 years are the primary reasons not to proceed with live donation.
Donor Nephrectomy The donor operation is carried out through a flank incision and retroperitoneal approach. The most common complications after live donation include urinary tract infections, wound infections, and pneumothorax. More serious complications are rare. In the case of cadaveric donation, with the exception of older donors, whose liver and pancreas may not be used for transplantation, retrieval of kidneys usually is part of a multiorgan procurement that includes the heart, lung, liver, pancreas, and most recently, the intestine. Figure 10-7 illustrates intraabdominal multiorgan procurement of the liver, pancreas, and kidneys.
FIGURE 10-7 Multiorgan procurement of the liver, pancreas, and kidneys. Note intraaortic and portal vein cannulas for in vivo flushout.
Surgical Technique A right curvilinear incision is made, extending from the pubic tubercle to a point just medial to the iliac crest and to the tip of the eleventh rib. In the event of a second transplant, the opposite side is used. If three or more transplants are necessary, a transabdominal approach is used. The donor renal artery may be anastomosed end-to-side to the common or external iliac artery or end-to-end to the hypogastric artery. Occasionally in children the donor renal artery is sewn to the distal aorta. The renal vein is sutured to the common or external iliac vein or the distal vena cava. The ureteral anastomosis is performed most commonly on the recipient's bladder.
Postoperative Care Immediate Care Because early delayed graft function occurs in approximately 25 percent of cadaveric transplants, fluid replacement linked to urinary output helps to prevent fluid overload and the need for urgent hemodialysis. Diabetic patients need to have blood glucose level monitored closely, and insulin may be given via a sliding scale or an insulin drip. Patients also need to have their blood pressure monitored closely because moderate hypertension is common in the postoperative period. This results from preexisting hypertension from long-standing renal disease, postoperative pain, fluid administration, and medications that are known to cause hypertension, such as prednisone, cyclosporine, and tacrolimus (FK506).
Technical Complications Early technical complications include graft thrombosis, urine leaks, bleeding, and wound infections; late complications include lymphoceles, ureteral strictures, and renal artery stenosis. Graft thrombosis is from an arterial or venous thrombosis and in the early postoperative period is technical in origin. Urine leaks occur most commonly at the ureterovesical junction but may occur anywhere along the length of the ureter or from the renal pelvis. Technical failure results from a ureteral anastomosis that is too loose or too tight or from a bladder closure that is less than watertight. Urine leaks also occur because of distal ureteral slough from inadequate blood supply. Lymphoceles may present with swelling over the transplant, unilateral leg edema caused by iliac vein compression, and an increased creatinine level as a result of ureteral compression. Small asymptomatic lymphoceles do not require treatment, but lymphoceles that cause obstruction or venous compression must be drained.
Immunosuppression New immunosuppressive agents have permitted immunosuppression to be tailored to the type of transplant and according to specific recipient needs. The immunosuppressive agents in use include antithymocyte globulin (ATG), OKT3, cyclosporine, tacrolimus (FK506), azathioprine, mycophenolate mofetil, and prednisone.
Treatment of Rejection High-dose steroids, usually methylprednisolone, are the first line of treatment for first rejection episodes. With the exception of HLA-identical transplant recipients, first rejection occurs in 4050 percent of renal transplant recipients. When a rejection episode is resistant to high-dose steroids, which usually is evident after 12 days, OKT3 is effective in reversing 90 percent of these rejection episodes. Chronic rejection, which must be differentiated from other forms of late graft dysfunction, has no specific treatment. Prevention of acute rejection episodes and earlier treatment of acute rejection episodes with OKT3 may reduce the incidence of chronic rejection.
Long-Term Complications The three most common causes of death after renal transplantation are cardiovascular disease, infectious disease, and malignancy, which are known to be increased significantly in transplant recipients and reflect chronic long-term immunosuppression, particularly the infectious and malignancy-related deaths. The two most common causes of graft loss are death with a functioning graft and chronic rejection. Noncompliance, particularly in adolescent transplant recipients, may be responsible for 1015 percent of late graft losses. Recurrent disease, especially recurrent glomerulonephritis, may result in late graft loss. After transplantation, bone and mineral metabolism can be adversely affected. Early manifestations include hypophosphatemia and hypercalcemia, which may be from persistent secondary hyperparathyroidism. Asymptomatic patients with serum calcium levels in the range of 10.512.5 mg/dL should not undergo subtotal parathyroidectomy within the first year because the majority of patients will have resolution of their hypercalcemia. Long-term bone disease usually is manifested as severe osteopenia or osteonecrosis. Osteonecrosis, particularly of the femoral head, is a significant long-term complication after renal transplantation related primarily to steroid therapy. Another common problem after renal transplantation is hyperglycemia, which requires treatment with oral hypoglycemic agents or insulin. Transplant-associated malignancies related to long-term immunosuppression, particularly lymphomas, are a long-term concern for renal transplant recipients. Skin cancer, particularly squamous cell carcinoma, has an incidence up to 20 times higher in immunosuppressed patients. Transplant recipients also have a higher incidence of Kaposi's sarcoma and genital neoplasms, such as vulvar, vaginal, and cervical carcinomas. Posttransplant lymphoproliferative disease (PTLD) is a spectrum of B-cell abnormalities that are driven by EBV. The development of posttransplant lymphomas occurs more frequently in heavily immunosuppressed patients. Polyclonal lymphomas also may respond to antiviral treatment with acyclovir or ganciclovir, but monoclonal lymphomas respond less favorably.
Results Figure 10-8 illustrates the current 5-year survival rates of patients receiving living-related, living-unrelated, and cadaveric renal transplants.
FIGURE 10-8 Five-year survival rates of patients receiving living-related, living-unrelated, and cadaveric renal transplants. (From: Cecka JM: Living donor transplants, in Cecka JM, Terasaki PI (eds): Clinical Transplants 1995. Los Angeles, UCLA Tissue Typing Laboratory, 1996, pp 363377, with permission.)
Because the majority of organs transplanted are from a cadaveric source, the organ inevitably must be stored for some time after removal from the organ donor until the recipient is prepared for the transplant procedure. The organ donor and the recipient often are not in the same location, and time is needed for transport of the donor organ to the hospital where the recipient is being prepared for transplantation. This requires the use of effective, safe, and reliable methods to preserve the organ ex vivo until the transplant procedure can be performed. Acceptable preservation times vary with the organ. Most surgeons prefer to transplant the heart within 5 h after donor cardiectomy; the kidney can be stored safely for 4050 h, but earlier transplantation is preferable. Most pancreas transplants are performed after 1020 h of preservation time. Liver transplants usually are performed within 612 h after donor hepatectomy. Preservation of the organ begins at the time a donor is identified, and the donor must be adequately maintained hemodynamically so that the organ is not injured before procurement and preservation. Hypothermia and the composition of the organ preservation solution are key factors in successful organ preservation. In cold storage of organs, the organ is rapidly cooled to approximately 4°C by flushout of the vascular system with an appropriate organ preservation solution. Hypothermia is beneficial because it slows metabolism. Organs exposed to normothermic ischemia remain viable for relatively short periods (for most organs, 1 h or less). In warm ischemia, the absence of oxygen leads to a rapid decline in the energy content [adenosine triphosphate (ATP)] of the organ, a redistribution of electrolytes across the cell membrane, and a decrease in biosynthetic reactions. However, biodegradable reactions continue, including a decrease in intracellular pH, proteolysis, and lipolysis. These events contribute to changes in the concentration of intracellular metabolites, and structural alterations in cellular membranes contribute to loss of viability on restoration of blood reperfusion of the organ. Hypothermia alone is not sufficient for adequate preservation for the time necessary for optimal use of cadaveric organs; the organ also must be flushed with an appropriate preservation solution. Two requirements of any ideal preservation solution are (1) the presence of impermeant molecules that suppress hypothermically induced cell swelling and (2) an appropriate biochemical environment. The University of Wisconsin (UW) solution contains lactobionic acid as the primary impermeant. The UW solution also contains raffinose (a trisaccharide), hydroxyethyl starch as a colloid, and adenosine to stimulate ATP synthesis during reperfusion of the organ.
For a more detailed discussion, see Sollinger HW, D'Alessandro AM, Deierhoi MH, Kalayoglu M, Kirk AD, Knechtle SJ, Odorico JS, Reitz BA, Yuh DD: Transplantation, chap. 10 in Principles of Surgery, 7th ed.
Copyright © 1998 McGraw-Hill
Seymour I. Schwartz
Principles of Surgery Companion Handbook