Chapter 11: Transplantation

1. The field of transplantation has made tremendous advances in the last 50 years, mainly due to refinements in surgical technique and development of effective immunosuppressive medications.

2. Although immunosuppressive medications are essential for transplantation, they are associated with significant short- and long-term morbidity.

3. Opportunistic infections can be significantly lowered by the use of appropriate antimicrobial agents.

4. Kidney transplantation represents the treatment of choice for almost all patients with end-stage renal disease. The gap between demand (patients on the waiting list) and supply (available kidneys) continues to widen.

5. Pancreas transplantation represents the most reliable way to achieve euglycemia in patients with poorly controlled diabetes.

6. The results of islet transplantation continue to improve but still trail those of pancreas transplantation.

7. Liver transplantation has become the standard of care for many patients with end-stage liver failure and/or liver cancer.

Organ transplantation is a relatively novel field of medicine that has made significant progress since the second half of the twentieth century. Advances in surgical technique and a better understanding of immunology are the two main reasons that transplants have evolved from experimental procedures, just several decades ago, to a widely accepted treatment today for patients with end-stage organ failure. Throughout the world, for a variety of indications, kidney, liver, pancreas, intestine, heart, and lung transplants are now the current standard of care.

But the success of transplantation has created new challenges. A better understanding of the pathophysiology of end-stage organ failure as well as advances in critical care medicine and in the treatment of various diseases led to expanding the criteria for, and decreasing the contraindications to, transplants. As a result, the discrepancy between the ever-growing number of patients awaiting a transplant and the limited number of organs available is one of the biggest challenges (Fig. 11-1). In 2009 alone, according to the United Network for Organ Sharing (UNOS), about 105,000 patients in the United States were awaiting a transplant, yet the number of transplants performed was only about 28,000 (Fig. 11-2).

In addition to being the overall name of this relatively new field of medicine, transplantation is the process of transferring an organ, tissue, or cell from one place to another. An organ transplant is a surgical procedure in which a failing organ is replaced by a functioning one. The organ is transplanted either orthotopically (implanted in the same anatomic location in the recipient as it was in the donor) or heterotopically (implanted in another anatomic location). Orthotopic transplants require the removal of the diseased organ (heart, lungs, liver, or intestine); in heterotopic transplants, the diseased organ is kept in place (kidney, pancreas).

According to the degree of immunologic similarity between the donor and recipient, transplants are divided into three main categories: (a) An autotransplant is the transfer of cells, tissue, or an organ from one part of the body to another part in the same person, so no immunosuppression is required. This type of transplant includes skin and vein, bone, cartilage, nerve, and islet cell transplants. (b) An allotransplant is the transfer of cells, tissue, or an organ from one person to another of the same species. The immune system of the recipient recognizes the donated organ as a foreign body, so immunosuppression is required in order to avoid rejection. (c) A xenotransplant is the transfer of cells, tissue, or an organ from one organism to another from a different species. To date, animal-to-human transplants are still experimental procedures, given the very complex immunologic and infectious issues that have yet to be solved.

Over the centuries, multiple references to transplantation can be found in the literature. Yet transplantation as a recognized scientific and medical field began to emerge only in the middle of the twentieth century. Two major events preceded the rise of transplantation.

First, the surgical technique of the vascular anastomosis was developed by French surgeon Alexis Carrel.¹ This led to increased transplant activity, especially in animal models. Russian surgeon Yu Yu Voronoy was the first to report a series of human-to-human kidney transplants in the 1940s.² But the outcomes were dismal, mainly because of the lack of understanding of the underlying immunologic processes.

Second, the findings of British scientist Sir Peter B. Medawar in the 1940s were also key.³ In his work with skin grafts in animal models and in human burn patients, he learned that the immune system plays a crucial role in the failure of skin grafts. His research led to a better understanding of the immune system and is considered to be the birth of transplant immunobiology.

The first human transplant with long-term success was performed by Joseph Murray in Boston, Massachusetts, in 1954.⁴ Because it was a living related kidney transplant between identical twins, no immunosuppression was required; the recipient lived for another 8 years before he died of issues unrelated to the transplanted kidney. Other centers performed similar transplants and could reproduce the good results.

Ultimately, attempts were made to perform kidney transplants between nonidentical individuals. For immunosuppression, total-body radiation and an anticancer agent called 6-mercaptopurine were used; given the profound toxicity of both those methods of immunosuppression, results were discouraging. A breakthrough was achieved in the early 1960s with the introduction of maintenance immunosuppression through a combination of corticosteroids and a less toxic derivative of 6-mercaptopurine, azathioprine.^5,6

Increasing experience with kidney transplants and the better results achieved with maintenance immunosuppression paved the way for the era of extrarenal transplants (Table 11-1). In 1963, the first liver transplant was performed by Thomas Starzl in Denver, Colorado, and the first lung transplant was performed by James Hardy in Jackson, Mississippi. In 1966, the first pancreas transplant was performed by William Kelly and Richard Lillehei in Minneapolis, Minnesota. In 1967, the first successful heart transplant was performed by Christiaan Barnard in Cape Town, South Africa. The early years of transplantation were marked by high mortality, mainly because of irreversible rejection. Dramatic changes occurred with the further development of immunosuppression. The groundbreaking event was the introduction of the first anti-T lymphocyte (T cell) drug, cyclosporine, in the early 1980s.⁷ Since then, with an even better understanding of immunologic processes, many other drugs have been introduced that target specific pathways of rejection. As a result, rejection rates have decreased substantially, allowing a 1-year graft survival rate in excess of 80% in all types of transplants.

The gradual increase in the organ shortage led to innovative surgical techniques. For example, deceased donor split-liver transplants and living donor liver transplants have helped expand the liver donor pool. Similarly, living donor intestine and pancreas techniques have been developed. The evolution of donor nephrectomy from an open to a minimally invasive procedure (laparoscopic or robotic) has helped increase the pool of living kidney donors.

The outcomes of early transplants were unsatisfactory. The limiting factor was the lack of understanding of immunologic processes. Irreversible rejection was the reason for graft loss in the vast majority of recipients. A better understanding of transplant immunobiology led to significant improvements in patient and graft survival rates.^8,9 The immune system is designed as a defense system to protect the body from foreign pathogens, such as viruses, bacteria, and fungi, but it also acts to reject transplanted cells, tissues, and organs, recognizing them as foreign. It mediates other complex processes as well, such as the body’s response to trauma or to tumor growth. No matter what the pathogen is, the immune system recognizes it as a foreign antigen and triggers a response that eventually leads either to death or to rejection of the pathogen.

Transplants between genetically nonidentical persons lead to recognition and rejection of the organ by the recipient’s immune system, if no intervention is undertaken. The main antigens responsible for this process are part of the major histocompatibility complex (MHC). In humans, these antigens make up the human leukocyte antigen (HLA) system. The antigen-encoding genes are located on chromosome 6. Two major classes of HLA antigens are recognized. They differ in their structure, function, and tissue distribution. Class I antigens (HLA-A, HLA-B, and HLA-C) are expressed by all nucleated cells. Class II antigens (HLA-DR, HLA-DP, and HLA-DQ) are expressed by antigen-presenting cells (APCs) such as B lymphocytes, dendritic cells, macrophages, and other phagocytic cells.

The principal function of HLA antigens is to present the fragments of foreign proteins to T lymphocytes. This leads to recognition and elimination of the foreign antigen with great specificity. HLA molecules play a crucial role in transplant recipients as well. They can trigger rejection of a graft via two different mechanisms. The most common mechanism is cellular rejection, in which the damage is done by activated T lymphocytes. The process of activation and proliferation is triggered by exposure of T lymphocytes to the donor’s HLA molecules. The other mechanism is humoral rejection, in which the damage is done by circulating antibodies against the donor’s HLA molecules. The donor-specific antibodies can be present either pretransplant, due to previous exposure (because of a previous transplant, pregnancy, blood transfusion, or immunization), or posttransplant. After binding to the donor’s HLA molecules, the complement cascade is activated, leading to cellular lysis.

The immune system of each person is designed to discriminate between self and nonself cells and tissues. This process is called allorecognition, with T cells playing the crucial role. The recognition of foreign HLA antigens by the recipient’s T cells may occur by either a direct or an indirect pathway. Direct recognition occurs when the recipient’s T cells are activated by direct interaction with the donor’s HLA molecules. Indirect recognition occurs when the recipient’s T cells are activated by interaction with APCs that have processed and presented the foreign antigen. The foreign antigen can be shed from the graft into the circulation, or it can be identified by the APCs in the graft itself.

Independent of the pathway of foreign HLA antigen presentation, the ensuing activation of T cells is similar. A two-signal model, T-cell activation begins with the engagement of the T-cell receptor (TCR)/CD3 complex with the foreign molecule. This interaction causes transmission of the signal into the cell, named signal 1. However, this signal alone is not sufficient to activate the T cell. An additional costimulatory signal is required, named signal 2. Two well-characterized costimulatory interactions are the CD40/CD154 and B7/CD28 pathways. The “master switch” is turned on by the interaction of CD40 protein with APCs, along with the interaction of CD154 protein with T cells; this ligation induces the upregulation of other costimulatory molecules. Transmission of signal 1 and signal 2 into the cell nucleus leads to upregulation of the transcription of genes for several cytokines, including the T-cell growth factor interleukin-2 (IL-2). In turn, IL-2 activates a number of pathways, leading to proliferation and differentiation of T cells. Rejection is a result of an attack of activated T cells on the transplanted organ.

Although T-cell activation is the main culprit in rejection, B-cell activation and subsequent antibody production also play a role. After the foreign HLA antigen is processed by B cells, it interacts with activated helper T cells, leading to differentiation of B cells into plasma cells and subsequently to their proliferation and antibody production.

Graft rejection is due to a complex interaction of different parts of the immune system, including B and T lymphocytes, APCs, and cytokines. The end result is graft damage caused by inflammatory injury. According to its onset and pathogenesis, rejection is divided into three main types: hyperacute, acute, and chronic (each described in the following sections).

Hyperacute

Hyperacute rejection, a very rapid type of rejection, results in irreversible damage and graft loss within minutes to hours after organ reperfusion. It is triggered by preformed antibodies against the donor’s HLA or ABO blood group antigens. These antibodies activate a series of events that result in diffuse intravascular coagulation, causing ischemic necrosis of the graft. Fortunately, pretransplant blood group typing and cross-matching (in which the donor’s cells are mixed with the recipient’s serum, and then destruction of the cells is observed) have virtually eliminated the incidence of hyperacute rejection.

Acute

Acute rejection, the most common type of rejection, usually occurs within a few days or weeks posttransplant. According to the mechanism involved, it is further divided into cellular (T-cell–mediated) rejection, humoral (antibody-mediated) rejection, or a combination of both. The diagnosis is based on the results of biopsies of the transplanted organ, special immunologic stains, and laboratory tests (such as elevated creatinine levels in kidney transplant recipients, elevated liver function values in liver transplant recipients, and elevated levels of glucose, amylase, and lipase in pancreas transplant recipients).

Chronic

Chronic rejection is a slow type of rejection. It can manifest within the first year posttransplant, but most often progresses gradually over several years. The mechanism is not well understood, but the pathologic changes eventually lead to fibrosis and loss of graft function. With advances in immunosuppression, this relatively rare form of rejection is becoming more common.

A successful transplant is a balance between the recipient’s immune response, the donor’s allograft, and pharmacologic immunosuppression. Immunosuppressive regimens are very important to graft and patient survival posttransplant. Immunosuppression has evolved from the use of azathioprine and steroids in the 1960s and 1970s to the development, in the 1980s, of cyclosporine, which increased allograft survival.^10,11 The introduction of tacrolimus and mycophenolate mofetil (MMF) in the 1990s further changed the field of transplantation, enabling a variety of combinations to be used for immunosuppression (Table 11-2).

Immunosuppressants usually are used in multidrug regimens, aimed at increasing efficacy by targeting multiple pathways to lower the immune response and to decrease the toxicity of individual agents. Certain regimens may involve withdrawal, avoidance, or minimization of certain classes of drugs. Transplant centers generally institute their immunosuppressive protocols based on experience, risk profiles, cost considerations, and outcomes. Immunosuppression is delivered in two phases: induction (starting immediately posttransplant, when the risk of rejection is highest) and maintenance (usually starting within days posttransplant and continuing for the life of the recipient or graft). Thus, the level of immunosuppression is highest in the first 3 to 6 months posttransplant; during this time, prophylaxis against various bacterial, viral, or even antifungal opportunistic infections is also given.^12,13

A conventional immunosuppressive protocol might include (a) induction with anti-T-lymphocyte–depleting or nondepleting antibodies and (b) maintenance with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Characteristics of the most common immunosuppressive agents are listed in Table 11-3.

Induction includes the use of depleting (polyclonal) antibodies or nondepleting antibodies within the first month posttransplant. Studies have shown that induction with antibody regimens may prevent acute rejection, potentially leading to improved graft survival and the use of less maintenance immunosuppression.

Depleting Antibodies

Rabbit antithymocyte globulin (Thymoglobulin) is a purified gamma globulin obtained by immunizing rabbits with human thymocytes. Atgam, which has largely been replaced by Thymoglobulin, is a purified gamma globulin obtained by immunizing horses with human thymocytes. These agents contain antibodies to T cells and B lymphocytes (B cells), integrins, and other adhesion molecules, thereby resulting in rapid depletion of peripheral lymphocytes. Typically, the total dose of Thymoglobulin is roughly 6 mg/kg, a dose that has been shown to confer adequate lymphocyte depletion and better allograft survival. Doses of 3 mg/kg may not effectively prevent acute rejection, but more doses and prolonged duration increase the risk of infection and the potential occurrence of lymphoma. Thymoglobulin administration causes a cytokine release syndrome, so premedications (acetaminophen and diphenhydramine) are usually given. The principal side effects of Thymoglobulin include fever, chills, arthralgias, thrombocytopenia, leukopenia, and an increased incidence of a variety of infections.^14,15

Nondepleting Antibodies

Basiliximab (Simulect) is an anti-CD25 monoclonal antibody. The alpha subunit of the IL-2 receptor, also known as Tac or CD25, is found exclusively on activated T cells. Blockade of this component by monoclonal antibody selectively prevents IL-2–induced T-cell activation. No lymphocyte depletion occurs with basiliximab; it is not designed to be used to treat acute rejection. Its selectivity in blocking IL-2–mediated responses makes it a powerful induction agent without the added risks of infections, malignancies, or other major side effects. Currently, basiliximab is the only available anti-CD25 monoclonal antibody approved for clinical use. Usually, it is followed by the use of calcineurin inhibitors, corticosteroids, and MMF as maintenance immunosuppression.¹⁶

Alemtuzumab (Campath), another anti-CD52 monoclonal antibody, was initially used to treat chronic lymphocytic leukemia. The use of alemtuzumab has grown in the field of transplantation, given its profound lymphocyte-depleting effects. It causes cell death by complement-mediated cytolysis, antibody-mediated cytotoxicity, and apoptosis. One dose alone (30 mg) depletes 99% of lymphocytes. Monocyte recovery can be seen at 3 months posttransplant; B-cell recovery at 12 months; and T-cell recovery, albeit only to 50% of baseline, at 36 months. Alemtuzumab causes a significant cytokine release reaction and often requires premedications (steroids and antihistamines). Because of the long-lasting T-cell depletion, the risks of infection and posttransplant lymphoproliferative disorder remain. Currently, alemtuzumab is available only through a limited distribution program, not through commercial medication distributors.^17,18

Corticosteroids

Corticosteroids have had a role in immunosuppression since the beginning of the field of transplantation. Despite numerous attempts to limit or discontinue their use, they remain an integral component of most immunosuppressive protocols, for both induction and maintenance. Moreover, they are often the first-line agents in the treatment of acute rejection. Steroids bind to glucocorticoid-responsive elements in DNA that prevent the transcription of cytokine genes and cytokine receptors. In addition, steroids have an impact on lymphocyte depletion, on decreases in cell-mediated immunity, and on T-cell activation of many phases of rejection.

Nonetheless, the numerous adverse effects of steroid therapy contribute significantly to morbidity in transplant recipients.¹⁹ Common side effects include acne, increased appetite and associated weight gain, mood changes, diabetes, hypertension, and impaired wound healing.

One of the most common maintenance immunosuppressive regimens consists of triple-drug therapy: prednisone, a calcineurin inhibitor, and an antimetabolite. Large doses of steroids are usually given perioperatively and in the immediate postoperative period. Protocols vary by center, but the steroid dose is usually tapered to an adult dose of roughly 5 to 15 mg daily, or completely stopped at some point. Steroids are substrates for CYP3A4, CYP3A5, and P-glycoprotein pathways where drug interactions might need to be monitored.^20,21

Azathioprine

An antimetabolite, azathioprine (AZA) is converted to 6-mercaptopurine and inhibits both the de novo purine synthesis and salvage purine synthesis. AZA decreases T-lymphocyte activity and decreases antibody production. It has been used in transplant recipients for more than 40 years, but became an adjunctive agent after the introduction of cyclosporine. With the development of newer agents such as MMF, the use of AZA has decreased significantly. However, it is preferred in recipients who are considering conceiving a child, because MMF is teratogenic in females and can cause birth defects. AZA might be an option for recipients who cannot tolerate the gastrointestinal (GI) side effects of MMF.

The most significant side effect of AZA, often dose-related, is bone marrow suppression. Leukopenia is often reversible with dose reduction or temporary cessation of the drug. Other significant side effects include hepatotoxicity, pancreatitis, neoplasia, anemia, and pulmonary fibrosis. Its most significant drug interaction is with allopurinol, which blocks AZA’s metabolism, increasing the risk of pancytopenia. Recommendations are to not use AZA and allopurinol together, or if doing so is unavoidable, to decrease the dose of AZA by 75%.²²

Mycophenolate Mofetil

Approved in May 1995 by the U.S. Food and Drug Administration (FDA) for preventing acute rejection after kidney transplants, MMF has now been incorporated into routine maintenance regimens after many solid organ transplants. Mycophenolate is the prodrug of mycophenolate acid, derived from Penicillium fungi. Mycophenolate acid is an inhibitor of inosine monophosphate dehydrogenase (IMPDH) involved in the de novo pathway of purine synthesis.²³ MMF is available in capsules (250 and 500 mg); the starting dose is 1 g twice daily. In hopes of decreasing the GI side effects, an enteric-coated formulation called Myfortic was developed; its benefits have not been clearly demonstrated in studies, but in some conversion studies, patients did report less GI intolerance. The pharmacokinetics of MMF are complex; mycophenolic acid (MPA) levels are not routinely performed at most transplant centers. Studies have shown that MPA levels and the incidence of rejection are not significantly correlated.²⁴ The most common side effects of MMF are GI in nature, most commonly diarrhea, nausea, dyspepsia, and bloating. Esophagitis and gastritis occur in roughly 5% of recipients and may represent a cytomegalovirus (CMV) or herpesvirus family infection. The other important side effects are leukopenia, anemia, and thrombocytopenia (Table 11-4). Leukopenia can sometimes be reversed by lowering the MMF dose and discontinuing other agents like valganciclovir. MMF does not have any significant drug interactions, but clinicians should be careful to avoid additive toxicities with other medications that might lead to leukopenia and thrombocytopenia.

Sirolimus

The first mammalian target of rapamycin (mTOR) inhibitors to enter clinical use was sirolimus (Rapamune). A key regulatory kinase, mTOR changes cells from the G1 to S phase in the cell cycle, in response to proliferation signals provided by cytokines like IL-2. The mTOR inhibitors bind to FK506-binding protein (FKBP), and the sirolimus-FKBP complex binds to mTOR. Sirolimus also inhibits proliferation of vascular smooth muscle cells, possibly easing the vasculopathy and progressive fibrosis that can affect allografts. Sirolimus is a substrate for CYP3A4/4 and has many significant drug interactions (see Table 11-4).

To date, sirolimus has been used in a variety of combinations for maintenance immunosuppression, alone or in conjunction with one of the calcineurin inhibitors. In such combinations, sirolimus usually is used to help withdraw, or completely avoid the use of, steroids. It also has been used as an alternative to tacrolimus or cyclosporine, in a calcineurin-sparing protocol. One of the most significant side effects of sirolimus is hypertriglyceridemia, a condition that may be resistant to statins and fibrates. Impaired wound healing (immediately posttransplant in particular), thrombocytopenia, leukopenia, and anemia also are associated with sirolimus, and these problems are exacerbated when it is used in combination with MMF.^25,26

Cyclosporine

The introduction of cyclosporine in the early 1980s dramatically altered the field of transplantation by significantly improving outcomes after kidney transplantation. Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which subsequently inhibits the activity of calcineurin, thereby decreasing the expression of several critical T-cell activation genes, the most important being for IL-2. As a result, T-cell activation is suppressed.²⁷

Many formulations of cyclosporine exist, so it is important to know which one the transplant recipient is taking. Sandimmune, an older, oil-based formulation, has poor bioavailability and variable absorption. The newer formulations, Gengraf and Neoral, are microemulsified with improved bioavailability. Cyclosporine can be given intravenously or orally to maintain trough levels of 250 to 350 ng/mL for the first 3 months posttransplant; then it can be tapered to 150 to 250 ng/mL.²⁸

The metabolism of cyclosporine is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4). Calcineurin inhibitors are nephrotoxic and constrict the afferent arteriole in a dose-dependent, reversible manner (Table 11-5). They also can cause hyperkalemia and hypomagnesemia. Several neurologic complications, including headaches, tremor, and seizures, also have been reported.²⁹

Cyclosporine has several undesirable cosmetic effects, including hirsutism and gingival hyperplasia. It is associated with a higher incidence of hypertension and hyperlipidemia than is tacrolimus.

Tacrolimus

The calcineurin inhibitor tacrolimus (Prograf) is now the backbone of most immunosuppressive regimens. Tacrolimus acts by binding FKBPs, causing roughly 10 to 100 times more potent inhibition of IL-2 production than cyclosporine (which acts by binding cyclophilins). It can be given intravenously, orally, or sublingually to maintain trough levels of 8 to 12 ng/mL for the first 3 months posttransplant; then it can be tapered to 6 to 10 ng/mL.

The metabolism of tacrolimus is via the cytochrome P450 system, resulting in many significant drug interactions (see Table 11-4).

Tacrolimus causes a higher incidence of new-onset diabetes posttransplant than does cyclosporine. Other side effects include alopecia, nephrotoxicity, neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and an increased incidence of certain types of infection.³⁰

Belatacept

The best-characterized pathway of T-cell costimulation includes CD28; its homologue, the cytotoxic T-lymphocyte–associated protein 4 (CTLA4); and their ligands, CD80 and CD86. Belatacept (also known as LEA29Y) was developed through two amino acid substitutions to abatacept (also known as CTLA4-Ig), a fusion protein consisting of the extracellular domain of CTLA4 and the Fc domain of immunoglobulin G (IgG). It is a high-avidity molecule with slower dissociation rates.

Recent trials have compared the use of belatacept vs. a standard cyclosporine protocol in recipients of living donor, deceased donor, and extended-criteria donor kidneys. Belatacept was not inferior to cyclosporine in both patient and allograft survival rates, but was associated with a higher rate of biopsy-proven acute cellular rejection.

In terms of adverse effects, belatacept differs from standard calcineurin-based regimens because of an increased risk of posttransplant lymphoproliferative disorder (PTLD); the greatest risk is in recipients who are Epstein-Barr virus (EBV)-seronegative pretransplant. The FDA recommends the use of belatacept only in seropositive recipients. Studies in liver transplant recipients were halted early because of increased mortality rates.

However, belatacept does have a lower incidence of cardiovascular risk factors including metabolic lipid disorders, hypertension, neurotoxicity, glucose abnormalities, and adverse cosmetic effects. Except for the increased risk of malignancy, the more favorable adverse effect profile of belatacept and its convenient monthly dosing schedule may make it an attractive option for maintenance of immunosuppression, possibly improving compliance.^31,32

Rituximab

A chimeric anti-CD20 (anti-B cell) monoclonal antibody,rituximab is currently FDA approved for treating lymphoma. The CD20 antigen is expressed early in the B-cell cycle but is absent on mature plasma cells. The variable region binds to CD20 through three different mechanisms: (a) antibody-dependent cell cytotoxicity, (b) complement-dependent cell killing, and (c) induction of apoptotic cell death. The use of rituximab has grown to include the treatment of antibody-mediated rejection and use in desensitization protocols. Studies so far have been small, with rituximab usually used in conjunction with plasmapheresis, steroids, and intravenous immunoglobulin (IVIG).^33,34,35

Bortezomib

A proteasome inhibitor, bortezomib is FDA approved for treating multiple myeloma. It can directly target plasma cells. Traditional treatments have been successful in removing antibodies, inhibiting antibody activity, or lowering antibody production; however, targeting mature antibody production in plasma cells has not met with success. Bortezomib has been shown to cause apoptosis of normal plasma cells, thereby decreasing alloantibody production in sensitized patients. Several case reports and series have described the use of bortezomib for the treatment of antibody-mediated rejection and in desensitization protocols.^34,36,37

Eculizumab

A humanized monoclonal antibody with high affinity for C5, eculizumab is a first-in-class, FDA-approved agent for treating paroxysmal nocturnal hemoglobinuria and hemolytic uremic syndrome. It blocks the activation of the terminal complement cascade. Most antibody-mediated rejection episodes are associated with early complement activation as evidenced on renal transplant biopsies by the presence of C4d⁺ staining of the peritubular capillaries. Given its highly selective mechanism of action, this agent is predicted to be useful to treat antibody-mediated rejection and to desensitize patients pretransplant. However, its serious adverse effects include an increased risk of infections, especially due to encapsulated bacteria such as Neisseria meningitidis. Patients should be immunized with meningococcal vaccine at least 2 weeks before the administration of eculizumab.^34,38,39

Advances in immunosuppression have led to improved graft survival rates. However, the growing population of immunosuppressed patients, in turn, has led to an increased incidence of opportunistic infections and malignancies. Such posttransplant complications have become important barriers to long-term disease-free survival.

Infections

Transplant recipients are predisposed to a variety of infections. Immunosuppression is the obvious reason. Moreover, such patients have already endured end-stage organ disease pretransplant and then the stress of an invasive transplant operation. Posttransplant, they continue to have significant comorbid conditions.

Early

Early infections (i.e., infections occurring within 1 month posttransplant) can be due to a wide spectrum of pathogens (bacterial, viral, and fungal). In the immediate postoperative period, recipients are significantly compromised from the stress of the operation, from induction immunosuppression, and often from initially impaired graft function. Infections during this period can be devastating.

It is imperative to differentiate between medical and surgical infections. Surgical infections are the most common and require expedient surgical intervention. Typical examples include generalized peritonitis, intra-abdominal abscesses, and wound infections.

In liver and pancreas recipients, surgical infections are most severe. The incidence of intra-abdominal infections is decreasing, but they remain a significant problem: they are the second most common reason (after vascular thrombosis) for graft loss in pancreas recipients.

Lengthy operations with significant blood loss, prolonged warm and cold ischemic times, and spillage of contaminated fluid (bile, urine, or bowel contents) predispose patients to intra-abdominal infections. Other prominent risk factors are the high level of induction immunosuppression immediately posttransplant and anastomotic leaks. Furthermore, pretransplant infections can re-emerge or worsen.

The signs and symptoms of intra-abdominal infections are those of peritonitis: fever, hypotension, ileus, and abdominal pain, although the latter can be masked by immunosuppression. Treatment entails a prompt return to the operating room. Intra-abdominal infections are usually polymicrobial, involving several bacterial and fungal species. Common bacterial isolates include Escherichia coli, as well as Enterococcus, Klebsiella, and Pseudomonas species. Common fungal isolates are Candida albicans, Candida krusei, and Candida glabrata. Localized infections or abscesses can be treated with percutaneous drainage and antibiotics.

Medical infections include respiratory, urinary tract, and bloodstream infections. Medical treatment should also be aggressive, often including empiric antibiotics and antifungal medications even before culture results are available. Recipients of organs from infected donors should be treated per the results of donor culture speciation and the antibiotic sensitivity profile.

Late

Late infections primarily are due to chronic immunosuppression, specifically the depression of cell-mediated immunity that renders recipients susceptible to viruses, fungi, and parasites.

Members of the herpesvirus group are the most common etiologic agents of viral infections posttransplantation, with herpes simplex virus (HSV), CMV, and EBV being the most prominent. Pretransplant exposure to viruses may confer immunity. Recipients who are seronegative for HSV, CMV, and/or EBV have a higher incidence of posttransplant infections, especially if they receive donor allografts from seropositive donors.

CMV is a latent infection that can be transmitted to seronaive recipients by donor organs from seropositive individuals, can reactivate during immunosuppression, or both. Infections usually occur 3 to 6 months posttransplant or during treatment for rejection. The incidence of CMV has been greatly reduced with 12-week acyclovir prophylaxis.⁴⁰ CMV infections range from an asymptomatic or mild flu-like syndrome to tissue-invasive disease resulting in pneumonitis, hepatitis, and GI ulcerations. Symptomatic infections and all tissue-invasive CMV disease should be treated with intravenous (IV) ganciclovir, a reduction in immunosuppression, or both, although successful treatment of mild to moderate rejection and concurrent mild to moderate CMV disease has been described.

EBV infections range from a mild mononucleosis syndrome to severe hepatitis and highly morbid PTLD. PTLD ranges from a localized tumor to a progressive, diffuse infiltration of various organs including the brain. It results from the proliferation of EBV-positive B cells in immunosuppressed patients. The main risk factors are a high degree of immunosuppression and a predisposing EBV serostatus (seronaive recipient, seropositive donor). Among patients with early lesions, the first line of treatment is to reduce immunosuppression. For those with more advanced PTLD, rituximab is used.

After 6 months posttransplant, the risk of invasive fungal infections is closely associated with environmental exposures. Blastomyces dermatitidis grows in moist soil in the Midwest and Southeast regions of the United States. Diagnosis is confirmed by biopsy; the preferred treatment is IV amphotericin B.

Coccidioides immitis can cause invasive coccidioidomycosis after inhalation of aerosolized infectious particles. It is endemic in the Southwest, Northern Mexico, and various parts of Central and South America. This infection can be resilient and difficult to treat. The first line of treatment is high-dose amphotericin B.

Histoplasma capsulatum is found in chicken and bat droppings in the Ohio River and Mississippi River valleys. Dissemination is commonplace; up to a quarter of patients have central nervous system (CNS) involvement. Treatment consists of prolonged (3 to 13 months) administration of oral itraconazole.

Opportunistic infections with Aspergillus, Cryptococcus, Mucor, and Rhizopus species are rare but can cause serious infections. Patients with invasive Candida or Aspergillus infections have a 20% mortality rate. Prophylaxis with fluconazole has been shown to reduce invasive fungal infections in liver recipients.⁴¹

Pneumocystis jiroveci (also known as PCP) is ubiquitous and can cause pulmonary disease in immunocompromised patients. However, trimethoprim-sulfamethoxazole (TMP-SMX) is effective prophylaxis against PCP, and daily, lifelong administration has virtually eliminated this infection among transplant recipients.

Malignancies

Chronic immunosuppression increases the risk of developing certain types of malignancies. The most extensive data, from a cohort study involving more than 175,000 solid organ transplant recipients, showed that 10,656 of them developed malignancies. The standardized incidence ratio was 2.10 (as compared with the general population). Recipients had at least a fivefold increase (as compared with the general population) in these types of malignancies: Kaposi’s sarcoma, nonmelanoma skin cancer, non-Hodgkin’s lymphoma, and cancer of the liver, anus, vulva, and lip. In addition, recipients had a statistically significant increase (as compared with the general population) in melanoma, Hodgkin’s lymphoma, and cancer of the lung, kidney, colon, rectum, and pancreas.⁴²

Organ procurement is a key element in organ transplantation. Currently, 58 organ procurement organizations (OPOs) exist in the United States, all members of the Organ Procurement and Transplantation Network (OPTN), which is a federally mandated network created by and overseen by UNOS. Each OPO is responsible for evaluating and procuring deceased donor organs for transplantation in a specific geographic region. Hospitals receiving any type of federal reimbursement for their services (whether transplant-related or not) are required to report all deaths to their OPO in a timely manner. Each OPO then determines the medical suitability of the deceased for organ donation; requests consent for donation from family members; if consent is given, contacts the OPTN to analyze and identify potential recipients whose HLA antigens most closely match those of the donor; and arranges for the recovery and transport of any donated organs.

Strategies to increase organ donation and utilization have been successfully implemented in the last 10 years. The nationwide “Organ Donation Breakthrough Collaborative,” sponsored by the U.S. Department of Health and Human Services in 2003, brought the OPOs and transplant communities into a single concerted program to develop best practices guidelines. However, a severe donor shortage remains. The number of living organ donors peaked in 2007 and has declined since.

Alternative options include tissue engineering and stem cell research, but those fields are in their infancy in terms of producing fully functional and vascularized human organs. With the development of genetic knockout pigs, xenotransplantation still shows promise, but two problems in particular—immunologic barriers and xenosis (also known as zoonosis) of endogenous porcine retroviruses—have yet to be satisfactorily addressed.

Today, the gap between patients waiting for organ transplants and the number of organs available continues to widen. More than 110,000 patients are on the waiting list for solid organ transplants, but only 28,456 transplants were performed in 2011.

Deceased Donors

Most transplants today utilize organs from deceased donors. Formerly, death was determined by the cessation of both cardiac and respiratory function.

Donation after Brain Death

In 1968, the concept of “irreversible coma” was introduced by an ad hoc committee report at Harvard Medical School; that concept was pivotal to the final acceptance, in 1981, of “brain death” as a legal definition in the United States. The legal language states that the declaration of brain death should be in accordance with acceptable medical standards, but does not specify clinical methodology. It is customary for hospitals to establish their own policies to declare brain death, according to their standards of care and local regulations.

Typically, brain death is defined as the irreversible cessation of brain function, including the brainstem. The presence of medical conditions that mimic brain death—such as drug overdose, medication side effects, severe hypothermia, hypoglycemia, induced coma, and chronic vegetative state—need to be excluded. The latest evidence-based guideline on determining brain death in adults reaffirmed the validity of current clinical practice.⁴³ Briefly, the clinical diagnosis of brain death consists of four essential steps: (a) establishment of the proximate cause of the neurologic insult; (b) clinical examinations to determine coma, absence of brainstem reflexes, and apnea; (c) utilization of ancillary tests, such as electroencephalography (EEG), cerebral angiography, or nuclear scans, in patients who do not meet clinical criteria; and (d) appropriate documentation. A similar guideline on determining brain death in pediatric patients was recently developed.⁴⁴

Once the diagnosis of brain death has been established, the local OPO assumes the care of the potential donor and initiates the process of donor evaluation and organ donation, and the potential donor is screened for contraindications to donation. The medical history and social history are obtained from the available family members. A battery of tests, including serologic or molecular detection of human immunodeficiency virus (HIV) and viral hepatitis, are performed. The exact medical conditions that preclude donation vary; nonetheless, in the United States, infections and other medical conditions that determine eligibility are dictated by UNOS bylaws and routinely reviewed and updated.

The OPO focuses on preserving organ function and optimizing peripheral oxygen delivery until organ procurement commences.⁴⁵ In all deceased donors, core temperature, systemic arterial blood pressure, arterial oxygen saturation, and urine output must be determined routinely and frequently. Arterial blood gases, serum electrolytes, blood urea nitrogen, serum creatinine, liver enzyme, hemoglobin, and coagulation tests need to be monitored regularly. In all brain-dead donors, elevated intracranial pressure triggers a compensatory catecholamine response to maintain cerebral profusion pressure. Ischemic injury to the spinal cord and the sympathetic system may lead to a profound vasodilation. As a result, brain-dead donors frequently have severe hemodynamic and metabolic derangements, so aggressive monitoring and intervention are required to prevent loss of precious organs.

Previous studies of deceased donor care focused on organ-specific resuscitation protocols that resulted in only marginal gains in the number of organs transplanted. The latest developments center on multisystem protocols to increase the number of organs transplanted per donor (OTPD).^46,47 The goals are to maintain a core temperature between 36.0 and 37.5°C, a mean arterial pressure >70 mmHg or a systolic pressure >100 mmHg, and a hemoglobin level between 7 and 10 g/dL; hormonal therapy and aggressive treatment of arrhythmias and metabolic derangements are also called for.⁴⁷

Surgical Technique

 Procurement of multiple organs (heart, lungs, kidney, liver, pancreas, and/or small bowel), or multivisceral procurement, was first described by the Pittsburgh group in 1987.⁴⁸ Since then, most centers have incorporated changes, especially with regard to the timing and location of dissection and flushing.^49,50 The basic steps involve a long incision to provide wide exposure of all thoracic and abdominal organs (Fig. 11-3). A Cattell-Braasch maneuver (complete mobilization of the distal small bowel, right colon, and duodenum) is performed to allow for identification of the distal aorta, iliac bifurcation, and distal inferior vena cava (IVC). The infrarenal aorta is the site for inserting the cannula that will allow for flushing of the organs with cold preservation solution. Sometimes, division of the inferior mesenteric artery is necessary to facilitate the exposure of the distal aorta. The third portion of the duodenum is retracted cephalad to expose the root of the superior mesenteric artery (SMA). Limited dissection is performed at the root of the SMA, which is encircled with a vessel loop to enable its temporary occlusion at the time of flushing, thus reducing the incidence of overperfusion injury to the pancreas.

A large anomalous or replaced right hepatic artery typically rises from the SMA, and this should be identified and preserved. Lateral to the SMA is the inferior mesenteric vein (IMV), which can be cannulated for portal flushing. Dissection of the hepatic hilum and the pancreas should be limited to the common hepatic artery (CHA), and branches of the CHA (e.g., splenic, left gastric, and gastroduodenal arteries) are exposed. The gastrohepatic ligament is carefully examined to preserve a large anomalous or replaced left hepatic artery, if present. The supraceliac aorta can be exposed by dividing the left triangular ligament of the liver and the gastrohepatic ligament.

The common bile duct is transected at the superior margin of the head of the pancreas. The gallbladder is incised and flushed with ice-cold saline to clear the bile and sludge. If the pancreas is to be procured, the duodenum is flushed with antimicrobial solution. Before the cannulation of the distal aorta, systemic heparinization (300 units/kg) is administered. The supraceliac aorta is clamped; cold preservation fluid is infused via the aortic (systemic) and IMV (portal) cannulas. The thoracic organs, liver, pancreas, and kidneys are then removed.

Donation after Cardiac Death

Given the severe shortage of donor organs, donation after cardiac death (DCD)—also known as donation by non–heart-beating donors (NHBDs)—was reintroduced to the transplant community in the 1990s.⁵¹ The category of DCD (Maastricht classification) was initially proposed at an international workshop and is now widely adopted for organ procurement.⁵² Currently, most NHBDs in the United States meet Maastricht classification III; that is, they have suffered a devastating injury with no chance of a meaningful recovery but do not meet the criteria for brain death. After consent for donation is obtained from the next of kin, the donor’s life support is removed. After the cessation of cardiac and respiratory function, organ procurement commences. DCD procurement protocols vary between states; religious and cultural differences need to be taken into consideration. The surgical team must be familiar with, and respect, the local protocol.

With cardiac death (as opposed to brain death), warm ischemic injury to organs can occur during the period between circulatory cessation and rapid core cooling through perfusion of preservation solution. However, the difference in long-term outcomes is negligible for recipients of organs from either type of donor. Still, a significant percentage of liver grafts procured after cardiac death, especially those with more than 25 minutes of warm ischemic time, develop devastating ischemic cholangiopathy and fail.⁵³

A new development to minimize ischemic injury to organs procured after cardiac death has been the application of extracorporeal membrane oxygenation (ECMO). With ECMO, DCD differs in two key ways: (a) cannulation occurs before withdrawal of life support and (b) organs are perfused via ECMO with warm oxygenated blood after declaration of cardiac death. The initial experience with organs procured using ECMO has been encouraging.

Surgical Technique

Surgeons who perform multiple organ retrieval should be familiar and experienced with the super-rapid technique described by the Pittsburgh group.⁵⁴ Preferably, NHBDs undergo withdrawal of life support in the operating room after the surgical site is prepped and draped, as soon as the surgical team is ready. Alternatively, the NHBD is transported to the operating room after declaration of cardiac death.

A midline incision is used to rapidly gain entry into the abdominal cavity. An assistant retracts the small bowel and the sigmoid colon laterally, so that the bifurcation of the aorta can be easily identified on the left side of the vertebral column. A short segment of the distal aorta is dissected out from the retroperitoneum. A moist umbilical tape is passed around the aorta, which is used to secure a cannula. The distal aorta is clamped. Next, a cannula is passed cephalad through an aortotomy and secured. Flushing with cold preservation solution is started at once, followed by cross-clamping the aorta proximally (thoracic aorta) and venting through the vena cava. The portal flush is then instituted.

The rest of the procedure is similar to procurement after brain death, with two noticeable differences. First, to avoid injury to a large anomalous or replaced left hepatic artery, the gastrohepatic ligament and the left gastric artery are separated from the stomach at the lesser curvature. Second, to avoid injury to a large anomalous or replaced right hepatic artery, the SMA is examined before it is divided. If the pancreas is not procured, a common aortic patch encompassing both the SMA and the celiac artery can be procured with the liver.

Living Donors

The maxim of medical ethics is “primum non nocere” (above all, do no harm), and for that reason, living organ donation presents unique ethical and legal challenges. Performing potentially harmful operations to remove organs from healthy individuals seems, at first glance, to contradict that maxim. But in fact, the ethical framework of living organ donation rests on three guiding principles respected in all discussions of medical practice: beneficence to the recipient, nonmaleficence to the donor, and the donor’s right to autonomy.⁵⁵ In order to achieve optimal outcomes (the common good), transplant professionals should focus on maximizing the benefits for the recipient and minimizing the damage to the donor. The Uniform Anatomical Gift Act adopted by all states in the United States (with slight variations) provides the legal framework for competent adult living donors to decide whether or not to donate. It is the fiduciary duty of transplant professionals to explain the risks of organ donation. Any decision to donate should be uncoerced, and no enticements should be offered.

The use of living donors offers numerous advantages for recipients in need. First and foremost is the availability of lifesaving organs for those who would otherwise succumb to the progression of their end-stage disease. In certain parts of the world, such as East Asia, the concept of brain death and the use of deceased donors conflict with the prevailing culture or religion. Even in countries where the use of deceased donors is accepted, the use of living donors may significantly shorten the waiting time for recipients. A shorter waiting time generally implies a healthier recipient—one whose body has not been ravaged by prolonged end-stage organ failure. Moreover, with the use of living donors, transplants are planned (rather than emergency) procedures, allowing for better preoperative preparation of the recipient. Receiving an organ from a closely matched relative may also have immunologic benefits. And long-term results may be superior with the use of living donors, as is certainly the case with kidney transplants.

The major disadvantage is the risk to the living donor. Medically, there is no possibility of benefit to the donor, only the potential for harm. The risk of death associated with donation depends on the organ being removed. For a nephrectomy, the estimated mortality risk is less than 0.05%; for a partial hepatectomy, about 0.2%. The risk of surgical and medical complications also depends on the procedure being performed. In addition, long-term complications may be associated with a partial loss of organ function after donation. The guiding principle should be minimization of risk to the donor. All potential risks must be carefully explained to the potential donor, and written informed consent must be obtained.⁵⁶

Surgical Technique

The kidney, the first organ to be transplanted from living donors, is still the most common organ donated by these individuals. The donor’s left kidney is usually preferable because of the long vascular pedicle. Use of living donor kidneys with multiple renal arteries should be avoided, in order to decrease the complexity of the vascular reconstruction and to help avoid graft thrombosis. Most donor nephrectomies are now performed via minimally invasive techniques, that is, laparoscopically, whether hand-assisted or not. With laparoscopic techniques, an intraperitoneal approach is most common: it involves mobilizing the colon, isolating the ureter and renal vessels, mobilizing the kidney, dividing the renal vessels and the distal ureter[C6], and removing the kidney (Fig. 11-4). Extensive dissection around the ureter should be avoided, and the surgeon should strive to preserve as much length of the renal artery and vein as possible.

Liver transplants with living donors are not as commonly performed, given the significantly higher rates of donor mortality and morbidity. Initially, only adult donors for pediatric recipients were selected, but now, living donor liver transplants also involve adult donors for adult recipients. In dual graft living donor liver transplants, segmental grafts from two living donors augment the recipient’s graft size.⁵⁷ The donor hepatectomy is similar to a major lobar hepatectomy, except that it is important to preserve the integrity of the vascular structure until graft resection (Fig. 11-5).

Living donor transplants of organs other than the kidney and liver are fairly uncommon, but certain centers do perform such transplants. Living donor pancreas transplants involve performing a distal pancreatectomy, with the graft consisting of the body and tail of the pancreas; vascular inflow and outflow are provided by the splenic artery and splenic vein. Living donor intestinal transplants usually involve removal of about 200 cm of the donor’s ileum, with inflow and outflow provided by the ileocolic vessels. Living donor lung transplants involve removal of one lobe of one lung from each of two donors; both grafts are then transplanted into the recipient.

Organ Preservation

The development and continuing refinement of organ preservation methods have completely revolutionized the transplant field. Extending the time that organs can be safely stored after procurement has enabled better organ utilization and better recipient outcomes.^58,59 Hypothermia and pharmacologic inhibition are the two most frequent methods. Both slow—yet cannot completely shut down—the removed organ’s metabolic activity, so both have adverse effects, such as cellular swelling and degradation. Cold storage solutions were introduced to mitigate some of the adverse effects of hypothermia or pharmacologic inhibition alone. Such solutions help prevent cellular swelling and the loss of cellular potassium.

One, and perhaps the most effective, preservation solution was developed at the University of Wisconsin and remains in wide use.⁶⁰ Its ingredients include lactobionate (which helps prevent cellular swelling and reperfusion injury), raffinose, and hydroxyethyl starch (which helps reduce swelling of endothelial cells, thereby decreasing edema). Histidine-tryptophan-ketoglutarate solution is also currently in wide use.⁶¹

Despite enhancements in preservation methods, the amount of time that an organ can be safely stored remains relatively short (hours, not days), particularly with organs from marginal donors. Among kidney recipients, delayed graft function becomes significantly more frequent after cold ischemic times of more than 24 hours, necessitating temporary dialysis, which is associated with increased risks of graft loss and higher costs.⁶² Among liver recipients, primary nonfunction and biliary complications ensue after prolonged cold ischemic times. In the case of heart and lung recipients, ischemic times should be under 6 hours. All of those times assume the use of normal donors.

There is revived interest in the use of the pulsatile perfusion pump, a kidney graft preservation method that has been available for more than 40 years.⁶³ With the increasing shortage of available donor organs and the rise in the use of organs after cardiac death, the pulsatile perfusion pump is garnering renewed enthusiasm as an adjunct method of preservation, even for donor organs other than kidneys.^64,65

Introduction

Ullman reported the first attempted human kidney transplant in 1902.⁶⁶ For the next 50 years, sporadic attempts all ended in either technical failure or in graft failure from rejection. Joseph Murray performed the first successful kidney transplant in 1954, an epochal event in the history of organ transplantation. In that first case, the immunologic barrier was circumvented by transplanting a kidney between identical twins.⁶⁷ For his pivotal contribution, Murray shared the Nobel Prize in Physiology or Medicine in 1990 with E. Donnall Thomas for their discoveries concerning “organ and cell transplantation in the treatment of human disease.”

The introduction of AZA (Imuran) in 1960 marked the beginning of a new era in kidney transplantation. With the combination of steroids and AZA for maintenance immunosuppression, the 1-year graft survival rate with a living related donor kidney approached 80%; with a deceased donor kidney, the rate was 65%.⁶⁸ In the ensuing years, major milestones included the introduction of more effective immunosuppressive medications with lower toxicity profiles, such as polyclonal antilymphocyte globulin in the 1970s, cyclosporine in the 1980s, tacrolimus in the 1990s, and biologics in the first decade of the twenty-first century, as previously mentioned.

Parallel to the developments in medical science were the transplant community’s concerted efforts to improve use of healthcare resources. In the United States, the Social Security amendments of 1972 provided Medicare coverage for patients with end-stage renal disease (ESRD). The National Organ Transplant Act of 1984 initiated the process of creating what later became UNOS, an umbrella organization to ensure access to organs by patients in need, to enhance organ procurement and allocation, and to improve posttransplant outcomes. This infrastructure later became the blueprint for other countries to follow. As a result, organ transplantation is the most transparent field of medicine. Data such as transplant center performance are readily available on public websites; penalties for violation of regulations and for underperformance often result in transplant programs being shut down.

Today, a kidney transplant remains the most definitive and durable renal replacement therapy for patients with ESRD. It offers better survival and improved quality of life and is considerably more cost-effective than dialysis.^69,70 According to the 2010 Scientific Registry of Transplant Recipients (SRTR) annual report, a total of 84,614 adult patients were on the kidney transplant waiting list, including 33,215 added just that year.⁷¹ Yet in 2009, only 15,964 adult kidney transplants were performed in the United States (9912 with a deceased donor and 6052 with a living donor). Of note, the number of patients added to the kidney transplant waiting list has increased every year, but the number of kidney transplants performed has been declining since 2006. On the positive side, posttransplant outcomes have continued to improve: in 2009, the 1-year graft survival rate with a living donor kidney was 96.5%; with a deceased donor kidney, the rate was 92.0%.

The advantages of a living donor kidney transplant include better posttransplant outcomes, avoidance of prolonged waiting time and dialysis, and the ability to coordinate the donor and recipient procedures in a timely fashion. Living donor kidney recipients enjoy better long-term outcomes, a low incidence of delayed graft function, and reduced risks of posttransplant complications. Furthermore, the elective nature of living donor kidney transplants provides unique opportunities for recipient desensitization treatment if the donor and recipient are ABO- incompatible or if the HLA cross-match results are positive.

Some of the challenges transplant professionals face today are closing the growing gap between supply and demand and thereby reducing the current prolonged waiting times; refining immunosuppressive medications to achieve better outcomes with reduced toxicity; and caring for patients who develop rejection, especially antibody-mediated rejection.

Pretransplant Evaluation

Active infection or the presence of a malignancy, active substance abuse, and poorly controlled psychiatric illness are the few absolute contraindications to a kidney transplant. Studies have demonstrated the overwhelming benefits of kidney transplants in terms of patient survival, quality of life, and cost-effectiveness, so most patients with ESRD are referred for consideration of a kidney transplant. However, to achieve optimal transplant outcomes, the many risks (such as the surgical stress to the cardiovascular system, the development of infections or malignancies with long-term immunosuppression, and the psychosocial and financial impacts on compliance) must be carefully balanced.

Any problems detected during the evaluation of transplant candidates are communicated to their referring physician and/or to a specialist if advanced evaluation and treatment are needed, ultimately improving overall care. Essentially, the pretransplant evaluation is a multifaceted approach to patient education and disease management.

Before the pretransplant medical evaluation begins, kidney transplant candidates are encouraged to attend a group meeting focused on patient education. The meeting is coordinated by a transplant physician or surgeon. The intent is to familiarize patients with the pretransplant evaluation process and with pertinent medical concepts and terms. In an open forum format, important decisions such as type of donor (living vs. deceased) are discussed. The group meeting empowers patients to fully participate in their care and serves as an impetus for a meaningful dialogue with healthcare professionals.

Medical Evaluation

Cardiovascular Disease

Diabetes and hypertension are the leading causes of chronic renal disease. Concomitant cardiovascular disease (CVD) is a common finding in this population. An estimated 30% to 42% of deaths with a functioning kidney graft are due to CVD.^72,73 Therefore, assessment of the potential kidney transplant candidate’s cardiovascular status is an important part of the pretransplant evaluation.

In fact, the American Heart Association and the American College of Cardiology Foundation recently published their expert consensus on CVD evaluation and management for solid organ transplant candidates.⁷⁴ The process should focus on careful screening for the presence of significant cardiac conditions (e.g., angina, valvular disease, and arrhythmias) and for a prior history of congestive heart failure, coronary interventions, or valvular surgery. The perioperative risk assessment is based on patient symptoms and exercise tolerance. For all kidney transplant candidates, a resting 12-lead electrocardiogram (ECG) should be obtained. In addition, in this population, the use of echocardiography to analyze left ventricular function and to assess for pulmonary hypertension is useful.

Stress testing may be considered in patients with no active cardiac condition but with risk factors such as diabetes, hemodialysis for more than 1 year, left ventricular hypertrophy, age greater than 60 years, smoking, hypertension, and dyslipidemia. The utility of noninvasive stress testing (as compared with angiographic studies) for evaluating coronary artery disease is controversial; an additional prognostic marker is the troponin T (cTnT) level.

Malignancies

Because of the long-term use of immunosuppressive medications, transplant recipients are at increased risk for development of malignancies. Untreated and/or active malignancies are absolute contraindications to a transplant (with two exceptions: nonmelanocytic skin cancer and incidental renal cell cancer identified at the time of concurrent nephrectomy [i.e., for polycystic kidney disease] and renal transplantation). For most patients who have undergone treatment of low-grade tumors with a low risk of recurrence (e.g., completely locally excised low-grade squamous cell cancer of the skin, colon cancer in a polyp absent stalk invasion), a wait of at least 2 years after successful treatment is recommended before a kidney transplant can be considered. However, for certain types of tumors, especially at advanced stages or those with a high risk of recurrence (e.g., melanoma, lymphoma, renal cell cancer, breast cancer, colon cancer), a delay of at least 5 years is advisable. According to the Israel Penn International Transplant Tumor Registry, tumor recurrence posttransplant is not infrequent: the recurrence rate is 67% in patients with multiple myeloma, 53% in nonmelanocytic skin cancer, 29% in bladder cancer, and 23% in breast cancer.⁷⁵

Infections

A thorough history of infections and immunizations should be obtained from transplant candidates, who need all recommended age-appropriate vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines. Ideally, vaccinations should be completed at least 4 to 6 weeks before the kidney transplant takes place. Immunosuppressive medications blunt the immune response and reduce the effectiveness of vaccinations; even more important, with attenuated vaccines, vaccine-derived infections could occur. If a splenectomy is anticipated (e.g., in recipients whose donor is ABO-incompatible or whose HLA cross-match results are positive), then they should be immunized against encapsulated organisms (such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae) well in advance of the splenectomy.

Transplant candidates should undergo routine tuberculosis (TB) screening. According to the latest CDC report, in 2011, 3929 TB cases were diagnosed in persons born in the United States and 6546 were diagnosed in foreign-born persons.⁷⁶ Serologic screening combined with a chest roentgenogram for fungal infections such as coccidioidomycosis or histoplasmosis, in patients who either have a history of those infections or are from an endemic area, are recommended. Chronic infections such as osteomyelitis or endocarditis must be fully treated; a suitable waiting period after successful treatment must occur, in order to ensure that relapse does not occur.

Hepatitis can be caused by five different type of viruses, hepatitis virus A, B, C, D, and E, with the first three being the most common. Acute viral hepatitis is a contraindication to a kidney transplant; however, chronic viral hepatitis (most commonly caused by hepatitis B [HBV] or C [HCV]) does not preclude a recipient from undergoing a kidney transplant. In such candidates, obtaining a liver biopsy is essential to assess the disease severity. Recipients infected with HBV should undergo antiviral treatment (e.g., lamivudine) to prevent reactivation and progression of liver disease. Note that HBV is a noncytopathic virus; the liver damage is the result of an immune-mediated process.⁷⁷ Moreover, the presence of normal liver enzymes in patients with HBV antigenemia does not predict the severity of parenchymal damage.

Transplant candidates with chronic HCV infection often have HCV-related glomerulonephritis. As with HBV infection, the clinical presentation and biochemical findings with HCV infection are often unreliable in predicting liver damage. In patients with evidence of cirrhosis, a combined liver-kidney transplant should be considered. In appropriate candidates, pretransplant antiviral treatment with interferon-α may be considered. However, after a kidney transplant, interferon treatment is not recommended, because it may precipitate graft rejection.

Thanks to the excellent outcomes of highly active antiretroviral therapy (HAART), infection with HIV is no longer considered a contraindication to a kidney transplant. Kidney transplant candidates with HIV must have an undetectable HIV viral load and a CD4 lymphocyte count greater than 200/mm³; in addition, they must not have had any opportunistic infection in the previous year.⁷⁸

Latent viral infections such as CMV and EBV are of particular interest, given the risks of reactivation posttransplant and the detrimental effects on graft and patient survival. Knowing the serologic status of CMV and EBV infections helps transplant professionals gauge the risk of immunosuppressive regimens and the impact of the donor’s viral status, thereby guiding plans for posttransplant antiviral prophylaxis treatment or, as noted earlier, avoiding transplants between a seropositive donor and a seronaive recipient.

Kidney Disease

The third most common cause of graft loss in kidney transplant recipients is recurrence of glomerular diseases such as focal segmental glomerulosclerosis (FSGS), immunoglobulin A (IgA) nephropathy, hemolytic uremic syndrome, systemic lupus erythematosus, and membranoproliferative glomerulonephritis. FSGS deserves special mention for its frequent occurrence and dramatic presentation of early graft loss. An estimated 30% to 40% of FSGS patients develop recurrent disease posttransplant; of those, up to half eventually lose their graft.⁷⁹ In recipients with a history of FSGS, posttransplant nephrotic proteinuria should be promptly investigated; if diagnosis is confirmed by kidney biopsy, rescue plasmapheresis should be instituted at once. Adjuvant therapy with rituximab recently has been proposed.⁸⁰

Hypercoagulopathy

Kidney transplant candidates with a history of thrombotic events, repeated miscarriages, or a family history of thrombophilia should be screened for the following coagulopathic disorders: activated protein C resistance ratio, factor V Leiden mutation, factor II 20210 gene mutation, antiphospholipid antibody, lupus anticoagulation, protein C or S deficiency, antithrombin III deficiency, and hyperhomocysteinemia. In recipients at risk for hypercoagulopathy, pediatric kidney grafts should be avoided; so should any kidney allografts with a complex vascular anatomy.⁸¹ A perioperative anticoagulation protocol is recommended in this population.

Surgical Evaluation

Urologic Evaluation

Kidney transplant candidates (pediatric patients, in particular) with chronic kidney disease as a result of congenital or genitourinary abnormalities should undergo a thorough urologic evaluation. A voiding cystourethrogram and a complete lower urinary tract evaluation to rule out outlet obstruction are essential. Indications for a native nephrectomy include chronic pyelonephritis, large polycystic kidneys with loss of intra-abdominal domain, significant vesicoureteral reflux, or uncontrollable renovascular hypertension.

Vascular Evaluation

The potential implant sites for a kidney graft include the recipient’s aorta, vena cava, and iliac vessels. Careful physical examination often reveals significant central and/or peripheral vascular disease. Findings such as a pulsatile intra-abdominal mass, diminished or absent peripheral pulse, claudication, rest pain, and tissue loss in lower extremities should be further evaluated by abdominal computed tomography scan or ultrasound, Doppler studies, and/or angiography. With the popularity of endovascular interventions, transplant surgeons should also be familiar with such technology and have detailed anatomic studies of patients with vascular stents.

Immunologic Evaluation

ABO blood typing and HLA typing (HLA-A, -B, and -DR) are required before a kidney transplant. The method of screening for preformed antibodies against HLA antigens (because of prior transplants, blood transfusions, or pregnancies) is evolving. The panel-reactive antibody (PRA) assay is a screening test that examines the ability of serum from a kidney transplant candidate to lyse lymphocytes from a panel of HLA-typed donors. A numeric value, expressed as a percentage, indicates the likelihood of a positive cross-match with a donor. A higher PRA level identifies patients at high risk for a positive cross-match and therefore serves as a surrogate marker to measure the difficulty of finding a suitable donor and the risk of graft rejection.

The latest development in anti-HLA antibody screening is Luminex technology, using HLA-coated fluorescent microbeads and flow cytometry. In theory, this technology pinpoints donor-specific antibodies (DSAs) in the serum of a kidney transplant candidate with a high PRA level. Since all organ donors must undergo HLA typing, a negative cross-match for recipients with a high PRA level can be ensured by avoiding the selection of donors carrying unacceptable antigens (i.e., a virtual cross-match).⁸² Kidney transplant candidate data (including ABO blood types, HLA types, and DSAs) are now entered into a nationwide central database to facilitate deceased donor kidney allocation, as described earlier.

Psychosocial Evaluation

Psychiatric disorders have been recognized as important contributing factors to poor outcomes posttransplant. Patients with uncontrolled psychiatric disorders are at high risk for noncompliance with treatment, impaired cognitive function, and the development of substance abuse. The psychosocial evaluation is essential to ensure that transplant candidates understand the risks and benefits of the procedure and that they adhere to the lifetime immunosuppressive medication regimen.

Recipient Operation

Kidney allografts usually are transplanted heterotopically. The iliac fossa is recognized as the ideal position because of its proximity to the recipient’s bladder and iliac vessels.^83,84

Retroperitoneal allograft placement also allows easy access for percutaneous biopsies and interventions for ureteral complications. The right iliac fossa is the preferred site because of its easy access to the recipient’s iliac vessels. However, if a pancreas transplant is anticipated in the future or if now failed kidney grafts have been placed at the right iliac fossa, then the left iliac fossa is used for implantation. The current surgical technique for kidney transplants was developed and popularized in the 1950s and 1960s and has changed little since.⁸⁵

A large-bore three-lumen urinary catheter is inserted after the recipient is anesthetized, and it is occluded with a clamp beneath the surgical drapes. Recipients whose native kidneys produce urine will naturally fill up the urinary bladder; those individuals whose kidneys do not will require insufflation of saline prior to creation of the ureteral anastomosis.

Exposure of the operative field starts with a curvilinear skin incision, one to two finger widths above the midline pubic bone and the lateral edge of the rectus sheath. Superiorly, the extension of the incision depends on the recipient’s body habitus and the size of the donor kidney. The anterior rectus sheath is incised, medially to laterally, until the lateral edge of the rectus sheath is exposed. The posterior rectus sheath is missing below the arcuate line, thus providing direct access to the extraperitoneal space. The rectus muscle can be easily mobilized medially without being divided. The remainder of the fascial incision is along the lateral edge of the rectus sheath until the desired exposure is achieved (Fig. 11-6).

The retroperitoneal space of the iliac fossa is entered by mobilizing the peritoneum medially. The inferior epigastric vessels, the round ligament (in females), and the spermatic cord and its vasculature (in males) are encountered in this space; the former two structures are divided, while the latter is retracted with a vascular loop. A self-retained retractor is used to expose the surgical field. The iliac vessels should be dissected with great care. To minimize the risk of lymphocele development postoperatively, dissection of the iliac artery should be limited; the intertwining lymphatics around the iliac vessels should be ligated. In general, the donor’s renal artery and vein are anastomosed to the recipient’s external iliac vessels in an end-to-side fashion (Fig. 11-7). In recipients with a severely calcified iliac artery, the internal iliac artery can be used as an alternative, and in select cases, an endarterectomy must be performed.

After restoring the circulation to the donor’s kidney, urinary continuity can be established via several approaches. The approach chosen depends on such factors as the length of the donor ureter and a recipient history of bladder surgery, native nephrectomy, or pelvic radiation. The two most common procedures to restore urinary continuity are the Leadbetter-Politano and a modification of the Lich (e.g., extravesical) ureteroneocystostomy, which actually was designed to avoid ureteral reimplantation.

During the former procedure, a large cystotomy is created in the dome of the bladder, and the donor ureter is brought through a lateral and somewhat inferior 1-cm submucosal tunnel into the bladder, the end of which is spatulated and then sewn in place without tension with interrupted absorbable sutures placed through the mucosa and submucosa on the inside of the bladder.

An extravesical ureteroneocystostomy is performed by careful dissection of a 1-cm portion of the muscular layers on the anterolateral portion of the bladder until a “bubble” of mucosa is exposed. The donor ureter is spatulated in a diamond-shaped fashion, the bladder mucosa is incised, absorbable interrupted sutures are placed in four quadrants, and a mucosa-to-mucosa anastomosis is created using running absorbable sutures with a temporary ureteral stent in place of the first three-quarters of the anastomosis. The muscular layers of the bladder are then carefully approximated over the anastomosis to prevent reflux.

The decision to place a ureteral stent depends on the surgeon, who must try to balance the risk of infectious complications with the possible technical complications of a ureteral anastomosis, but in general, this is not required except during the rarely performed donor ureter to recipient ureter anastomosis or in the case of a pediatric kidney transplant. Fixation of the donor’s kidneys is not necessary, except in the case of small kidneys (usually from a pediatric donor) or en bloc kidneys.

Grafts with Multiple Renal Arteries

In 10% to 30% of donor kidneys, multiple renal arteries are encountered. Unless kidney transplant candidates have hypercoagulopathy, grafts with multiple renal arteries fare as well as those with single vessels.⁸⁶ Vascular reconstruction options include implanting the donor’s arteries separately, reconstructing the multiple arteries into a common channel, or combining multiple arteries into a common Carrel patch (Fig. 11-8).

En Bloc Grafts

Debate persists about whether to implant kidneys obtained from young donors (<5 years or whose body weight is under 20 kg) as a single en bloc unit into one recipient or separately into two recipients. The underlying issues are the shortage of donor organs, the complexity of the surgical procedure, the risks of graft thrombosis, ureteral complications, and long-term outcomes.

In en bloc kidney transplants, the donor aorta and vena cava are used as the vascular inflow and outflow conduits. Therefore, reconstruction of the en bloc graft pretransplant is key to a successful transplant. The donor’s suprarenal vena cava and aorta are oversewn. The lumbar branches of the cava and aorta are ligated. Dissection around the renal hilum should be avoided. The orientation of the cava and aorta should be clearly marked, in order to avoid torsion of the anastomosis. If the color of the two kidneys looks different after reperfusion, repositioning should be attempted to rule out vascular torsion; fixation of the en bloc kidneys to the retroperitoneum is often necessary. The donor’s ureters are implanted to the recipient’s bladder, either as two separate anastomoses or as a common patch (Fig. 11-9). Only a handful of centers have performed en bloc kidney transplants, but the long-term outcomes are encouraging.^87,88

Perioperative Care

Preoperatively, a thorough history and physical examination should be performed. Any changes in transplant candidates’ recent medical history should be investigated in great detail. In those recipients with a historically negative PRA level who have recently undergone blood transfusions, a prospective tissue cross-match is necessary to avoid graft rejection. Electrolyte panels should be checked. Emergency dialysis may be necessary for transplant candidates experiencing hyperkalemia or fluid overload.

For dialysis-dependent transplant candidates, the catheter sites should be examined preoperatively to rule out infections. Vascular access for hemodialysis is essential to avoid complications related to posttransplant acute tubular necrosis (ATN). Vascular evaluation is mandatory; any changes in results should be investigated by appropriate imaging studies.

As is routine for other major surgical procedures, transplant candidates should preoperatively undergo a chest x-ray, a 12-lead ECG, blood typing, cross-match tests, and prophylaxis against surgical site infection (by administration of a nonnephrotoxic antibiotic with activity against both common skin microflora and gram-negative pathogens); candidates should receive nothing to eat or drink.

Intraoperatively, transplant recipients should be kept well-hydrated to avoid ATN and should receive heparin prior to vascular occlusion. Before reperfusion of the transplanted kidney, the desired central venous pressure should be maintained at around 10 mmHg, and the systolic blood pressure should be above 120 mmHg. In pediatric recipients of an adult graft, a superphysiologic condition may be necessary to avoid ATN or graft thrombosis. Mannitol often is administered before reperfusion as a radical scavenger and diuretic agent, and a diuretic such as furosemide is administered as well.

Postoperatively, the guiding principles for the care of kidney transplant recipients are the same as for other surgical patients. The crucial elements include hemodynamic stability and fluid and electrolyte balance. To achieve a euvolemic state, the recipient’s urine output is replaced with either an equal or a reduced volume of IV fluid on an hourly basis, depending on the medical status. In recipients undergoing brisk dieresis, aggressive replacement of electrolytes (including calcium, magnesium, and potassium) may be necessary. In recipients experiencing ATN, fluid overload, or hyperkalemia, however, fluid restriction, treatment for hyperkalemia, and even hemodialysis may be necessary.

Hypotension is an unusual event immediately posttransplant. The differential diagnoses include hypovolemia, vasodilation, and myocardial infarction with cardiac failure. Immediate action should be taken to avoid life-threatening complications. Posttransplant hypertension can be mediated by catecholamines, fluid overload, or immunosuppressive agents.

Postoperatively, urine output is used as a surrogate marker to monitor graft function. Among recipients whose native kidneys produce significant amounts of urine, normal or increased urine output can be misleading; for them, serum blood urea nitrogen and creatinine levels are more reliable indicators of kidney graft function.

Suddenly decreased or minimal urine output requires immediate attention. A change in volume status is the most common cause, but other culprits include blockage of the urinary catheter, urinary leak, vascular thrombosis, hypotension, drug-related nephrotoxicity, ATN, and rejection (all of which must be thoroughly investigated). Diagnostic studies such as Doppler ultrasound, nuclear renograms, or biopsies should be considered.

Postoperative bleeding is an uncommon event after a kidney transplant. Recipients on anticoagulation or antiplatelet treatments are at increased risk. Signs and symptoms (such as an expanding hematoma over the surgical site, increased pain over the graft, a falling hemoglobin level, hypotension, and tachycardia) should arouse suspicion of hemorrhage. Doppler ultrasound is useful to establish the underlying cause. Surgical exploration seldom is required, because the accumulated hematoma tamponades the bleed. Indications for surgical exploration include ongoing transfusion requirement, hemodynamic instability, and graft dysfunction from hematoma compression. For recipients on anticoagulation or antiplatelet treatments, the threshold for surgical exploration is lower. Small unligated vessels at the donor’s renal hilum or recipient’s retroperitoneum are likely sources of bleeding.

One of the most devastating postoperative complications in kidney recipients is graft thrombosis. It is rare, occurring in fewer than 1% of recipients. The recipient risk factors include a history of recipient hypercoagulopathy and severe peripheral vascular disease; donor-related risk factors include the use of en bloc or pediatric donor kidneys, procurement damage, technical factors such as intimal dissection or torsion of vessels, and hyperacute rejection. Graft thrombosis usually occurs within the first several days posttransplant. Acute cessation of urine output in recipients with brittle posttransplant diuresis and the sudden onset of hematuria or graft pain should arouse suspicion of graft thrombosis. Doppler ultrasound may help confirm the diagnosis. In cases of graft thrombosis, an urgent thrombectomy is indicated; however, it rarely results in graft salvage.

Urologic complications are seen in up to 5% of recipients. The cause is often related to ureteral ischemia, damage during procurement of the donor’s distal ureter, or technical errors. Symptoms of urine leak include fever, pain, swelling at the graft site, increased creatinine level, decreased urine output, and cutaneous urinary drainage. Diagnosis can be confirmed by a combination of ultrasound, nuclear renography, drainage of perinephric fluid collection, and comparison of serum and fluid creatinine levels. Depending on the location and volume of the urine leak, satisfactory results can be achieved by surgical exploration and repair or by percutaneous placement of a nephrostomy and ureteral stenting.

Early urinary obstruction can be due to edema, blood clots, torsion of the ureter, or compression from a hematoma. Late urinary obstruction is often related to ischemia. The appearance of hydronephrosis on ultrasound is a good initial indicator. Treatment includes percutaneous placement of a nephrostomy and ureteral stenting. If transluminal intervention fails, surgical intervention (such as ureteral reimplantation or a ureteropyelostomy) can be undertaken.

Results

A kidney transplant remains the most common solid organ transplant in the world today. With the introduction of induction immunosuppressive therapy and ever-improving, less toxic immunosuppressive medications, posttransplant outcomes have become better and better. According to a recent analysis of more than 250,000 U.S. adult kidney transplant recipients, the actual half-life (50% graft survival) of a deceased donor kidney was 6.6 years in 1989, 8 years in 1995, and 8.8 years in 2005. Interestingly, during that same period—though with a much better overall outcome—the half-life of a living donor kidney has essentially remained the same: 11.4 years in 1989 and 11.9 years in 2005.⁸⁹

The biggest improvements have been in the reduction of 1-year graft failure. With a deceased donor kidney, the 1-year graft failure rate dropped from 20% in 1989 to less than 7% in 2009; with a living donor kidney, the rate dropped from 8.5% in 1989 to less than 3% in 2009.⁸⁹ Furthermore, steroid-free protocols⁹⁰ and calcineurin-free protocols⁹¹ have been validated and implemented in the last two decades, further reducing medication-related side effects and vastly improving the quality of life for tens of thousands of recipients.

Currently, the most common cause of graft loss is recipient death (usually from cardiovascular causes) with a functioning graft. The second most common cause is chronic allograft nephropathy; characterized by a slow, unrelenting deterioration of graft function, it likely has multiple causes (both immunologic and nonimmunologic).^92,93 The graft failure rate due to complications related to surgical technique has remained at about 2%.

A successful pancreas transplant is currently the only definitive long-term treatment for patients with insulin-dependent diabetes mellitus (IDDM) that (a) restores normal glucose hemostasis without exposing patients to the risk of severe hypoglycemia and (b) prevents, halts, or reverses the development or progression of secondary complications of diabetes.⁹⁴

Given its vast medical, social, and financial implications, diabetes mellitus is a huge burden to patients and to society as a whole. An estimated 10% to 15% of the U.S. population is affected by it; of all diabetic patients, 10% have early-onset disease. In the United States, diabetes mellitus is the most common cause of end-stage kidney disease, blindness, impotence, major limb amputations, and coronary or peripheral vascular bypass procedures. It is one of the most common causes of death, along with myocardial infarction and stroke. Diabetes significantly decreases not only the quality of life but also life expectancy.

Despite improvements in exogenous insulin administration (including the use of devices such as insulin pumps), wide fluctuations in glucose levels and the risk of hypoglycemic episodes are common. The Diabetes Control and Complications Trial (DCCT) demonstrated in the late 1990s that intensive insulin therapy may slow the rate of secondary complications of diabetes—yet at the expense of (life-threatening) iatrogenic hypoglycemia. The annual mortality rate of patients with insulin-induced inadvertent hypoglycemia is estimated to be as high as 2% to 3%.

Since the first pancreas transplant in December 1966, performed by William Kelly and Richard Lillehei at the University of Minnesota, more than 25,000 pancreas transplants in the United States and more than 10,000 pancreas transplants from all over the world have been reported to the International Pancreas Transplant Registry (IPTR), which is maintained at the University of Arizona.^94,95

Pancreas transplants are performed in three recipient categories:

• Simultaneous pancreas and kidney (SPK) transplant in diabetic and uremic patients. Almost 80% of pancreas transplants are performed in this category. The recipient is already obligated to lifelong immunosuppressive therapy, due to the need for a kidney transplant, so only the surgical risk of a pancreas transplant is added. A successful SPK transplant renders the recipient dialysis-free and insulin-independent.

• Pancreas after kidney (PAK) transplant in diabetic and posturemic patients. Approximately 15% of all pancreas transplants fall into this category. These patients previously underwent a kidney transplant with either a living or deceased donor, but are candidates for a subsequent pancreas transplant because of poor glucose control or because of progression of secondary diabetic complications (which may include the development of diabetic nephropathy in the transplanted kidney).

• Pancreas transplant alone (PTA) in nonuremic patients with brittle diabetes mellitus. Only about 8% of all pancreas transplants are in this category. These patients have not yet developed advanced diabetic nephropathy, but their glucose levels are extremely labile despite best efforts to control it. Because of the lifelong need for immunosuppressive therapy, the surgical risk has to be balanced with the medical risks of brittle diabetes (e.g., frequent episodes of hypoglycemia and hypoglycemic unawareness).

In SPK recipients, a plethora of literature exists that demonstrates significant improvements in secondary diabetic complications (across all organ systems) posttransplant. Improvements have been reported in diabetic nephropathy, neuropathy (autonomic and peripheral), micro- and macrovascular disease, retinopathy, gastroparesis, and other secondary complications.⁹⁶ Currently, more than 1000 pancreas transplants are performed annually in the United States, with the goal of conferring the following benefits: excellent glucose control (similar to that of a functioning native pancreas), prevention or improvement of secondary diabetic complications, and increased quality of life and life expectancy. In addition, pancreas transplants can be successfully performed in patients who have undergone a total pancreatectomy for benign disease (such as chronic pancreatitis) to treat both endocrine and exocrine deficiency after surgery.⁹⁷

Donor Operation

The general criteria for selecting deceased donors for pancreas procurement are similar to those for other solid organs; a history of type 1 diabetes mellitus obviously is a contraindication. Relative contraindications include previous pancreatic procedure(s), as well as pancreatic disorders, such as chronic pancreatitis and intraductal papillary mucinous neoplasm. Hyperglycemia in itself is not a contraindication to pancreas procurement, because its cause in brain-dead donors usually is severe insulin resistance, which is rarely observed in recipients.

In light of better anatomic understanding and improved surgical skills, all three abdominal organs that share a common blood supply (pancreas, liver, and intestine) can be procured at the same time and transplanted into three different recipients (Fig. 11-10). During pancreas procurement, a “no-touch” technique of the gland is preferred; dissection of the pancreas is carried out in a way that avoids direct manipulation of the organ such that simultaneous procurement of the spleen, duodenum, and surrounding connective tissues occurs.

In contrast to the liver and kidneys, the pancreas should not be extensively flushed at the end of the procurement. To minimize the amount of preservation fluid that reaches the pancreas, the splenic artery and SMA can be temporarily clamped at their origin from the aorta. Usually, the celiac axis with an aortic Carrel patch is retained with the liver. The splenic artery is divided close to its origin and is retained with the pancreas. The SMA is also procured with an aortic Carrel patch and is retained with the pancreas.

In case of a replaced or aberrant right hepatic artery, this first branch off of the SMA is carefully dissected out from the posterior surface of the pancreas. A replaced or aberrant right hepatic artery does not transverse the pancreas and is not a contraindication to combined pancreas and liver procurement. But with this anatomic variant, an aortic Carrel patch with the proximal SMA and replaced or aberrant right hepatic artery remains with the liver; the distal SMA with the inferior pancreaticoduodenal artery remains with the pancreas.

In the relatively rare event that the liver is not procured, then neither the splenic nor the gastroduodenal arteries need to be divided at their respective takeoff; the donor’s celiac axis and the SMA are included on a common Carrel patch. This technique allows a single arterial anastomosis to be performed in the recipient without reconstruction. At the end of the procurement, the pancreas is attached to the spleen, duodenum, and proximal jejunum, which is stapled at both ends.⁹⁸

Back Table Preparation of the Pancreas Graft

Back table preparation of the pancreas graft consists of four steps: (a) removal of the spleen; (b) shortening, restapling, and/or suture reinforcement of the mesenteric root; (c) trimming of any excess distal and proximal duodenum, along with reinforcement of the proximal staple line; and (d) arterial reconstruction.

Back table preparation is carried out in a basin filled with chilled preservation solution. The most common technique to create a single arterial inflow to the pancreas graft is the “Y-graft” reconstruction, using a resected segment of the donor iliac artery bifurcation. In this technique, the donor external iliac artery is anastomosed end-to-end to the donor SMA, and the donor internal iliac artery is anastomosed end-to-end to the splenic artery (Fig. 11-11). This procedure allows the donor common iliac artery to be anastomosed as a single vessel to the recipient’s common iliac artery. For venous outflow, the portal vein is kept relatively short, in order to avoid the risk of venous thrombosis by kinking or impingement.⁹⁸

Recipient Operation

Over the years, different surgical techniques have been described for (a) the management of exocrine pancreatic secretions and (b) the type of venous drainage. For the secretions, the two most common techniques are drainage of the duodenal segment to the bladder (bladder drainage) or to the small bowel (enteric drainage) (Figs. 11-12 and 11-13). For venous drainage, systemic venous drainage is preferred over portal venous drainage.

The pancreas graft is usually placed intra-abdominally and preferably on the right side, because the iliac vessels are in a more shallow position on the right than on the left side; moreover, the vessels are already appropriately aligned for the vascular anastomoses (i.e., a lateral position for the common iliac vein, a medial position for the common iliac artery). Venous and arterial anastomoses are performed end-to-side. After restoration of blood flow to the graft, hemostasis must be meticulously maintained. Because the donor portal vein purposely is kept short, ligation and transection of all of the recipient’s internal iliac vein branches are frequently performed, in order to prevent tension on the venous anastomosis. The pancreas usually is placed with the pancreatic head and duodenum pointing caudally.

Bladder drainage is performed using either a hand-sewn or a stapled anastomosis in which the antimesenteric side of the donor duodenum is sewn to the superior portion of the dome of the bladder. The stapled technique requires that a circular cutting stapler be inserted through the open distal end of the donor duodenum, which is subsequently closed. Bladder drainage has two main advantages. First, rejection of the exocrine pancreas precedes rejection of the endocrine pancreas by 5 to 7 days. Amylase levels are measured routinely in the recipient’s urine. With bladder drainage, antirejection treatment can successfully be implemented when the recipient is still normoglycemic and only hypoamylasuric. In the absence of hyperglycemia, more than 90% of pancreas rejection episodes are reversible. Second, bladder drainage avoids the bacterial contamination that occurs with enteric drainage. If an anastomotic leak occurs, it is easier to treat, because the infection usually remains localized to the right lower quadrant.

Enteric drainage is more physiologic and has advantages as well. The antimesenteric side of the donor’s duodenum is anastomosed to the antimesenteric portion of the recipient’s jejunum in a side-to-side fashion. The enteric anastomosis can also involve a defunctionalized Roux-en-Y loop, which minimizes the potential complications if an enteric leak occurs.⁹⁸ Currently, in the United States, more than 80% of all pancreas transplants are performed with enteric drainage for the exocrine pancreatic secretions, and more than 90% employ systemic venous drainage.⁹⁵

Complications

The technical complication rate for pancreas transplants is higher than for any other solid organ transplant. Four factors contribute to the high surgical complication rate⁹⁹: (a) the nature of the organ itself with inherent organ-specific surgical complications (e.g., pancreatitis, abscesses, necrosis, fistulas, and pseudocysts) and its low blood flow (which significantly increases the risk of thrombosis, as compared with a kidney or liver transplant); (b) the risk of a leak or infection after connecting two hollow viscera (the duodenum and either the bladder or small intestine); (c) the increased incidence of rejection episodes, because the pancreas is one of the most immunogenic solid organs; and (d) the underlying disease of diabetes mellitus, predisposing patients not only to infections but also to cardiovascular and other complications.

The most common surgical complications are thrombosis (an incidence of 5%–15%), intra-abdominal abscesses (5%–10%), and bleeding (6%–8%). Other pancreas-specific complications include graft pancreatitis (frequently due to procurement or reperfusion injury), pancreatic fistulas, and pancreatic pseudocysts. Anastomotic leaks do not always require a graft pancreatectomy, but arterial pseudoaneurysms, arteriovenous fistulas, and wound dehiscence may. Bleeding frequently requires relaparotomy.

Thrombosis usually occurs within the first week posttransplant. It manifests as a sudden increase in insulin requirements or as a sharp drop in urinary amylase levels. Venous thrombosis, which is more common than arterial thrombosis, is associated with distinct clinical symptoms, including a swollen and tender graft, hematuria, lower extremity edema, and deep vein thrombosis, the latter two occurring ipsilaterally. Arterial thrombosis is less symptomatic and may not initially cause pain; its diagnosis is usually confirmed by Doppler ultrasonography. Surgical exploration in recipients with thrombosis usually requires a graft pancreatectomy.

With the advent of advanced interventional radiologic procedures to drain intra-abdominal abscesses, the reoperation rate has markedly decreased. Pancreas transplant recipients are usually kept on broad-spectrum antimicrobial agents for the first 7 days posttransplant.

The most common nonsurgical complication posttransplant is rejection. The incidence of rejection is about 30% within the first year. The diagnosis is usually based on an increase in serum amylase and lipase levels and, in bladder-drained recipients, a decrease in urinary amylase levels. A sustained drop in urinary amylase levels greater than 25% from baseline should prompt a pancreas graft biopsy to rule out rejection. In enteric-drained recipients, one must rely on serum amylase and lipase levels only. Other signs and symptoms of rejection include tenderness over the graft, unexplained fever, and hyperglycemia, which usually is a late finding; fewer than 5% of all rejection episodes can be reversed in its presence. The diagnosis of rejection should be confirmed by a percutaneous pancreas graft biopsy.

Other nonsurgical complications include infections with CMV, HCV, or extra-abdominal bacteria or fungi; malignancies, such as PTLD; and, rarely, graft-versus-host disease. For such complications, the diagnosis and treatment are similar to what is recommended after other solid organ transplants.

Bladder-drained pancreas recipients may experience an array of unique urologic complications. Usually the result of the irritating nature of pancreatic enzymes on the urothelium in the bladder and urethra, these urologic complications can lead to cystitis, hematuria, and dysuria. With the loss of bicarbonate from pancreatic secretions, dehydration and metabolic acidosis are not uncommon. Many of these complications are chronic, such that approximately 20% to 30% of all bladder-drained recipients require conversion to enteric drainage within the first 5 years posttransplant.¹⁰⁰

Living Donor Pancreas Transplants

Pancreas transplants using living donors also can be performed safely and successfully in select donors and recipients. Since 1979, about 150 such transplants have been performed worldwide, with 1-year graft survival rates in excess of 85% over the last decade. A meticulous donor evaluation using standard criteria remains key to a low donor metabolic and surgical complication rate. The concept of procuring the distal pancreas from a living donor is based on the observation that patients with benign or malignant pancreatic disorders can undergo a distal hemipancreatectomy without any serious change in endocrine function.

Living donor pancreas transplants are ideal for patients with an identical twin, but other relatives can be suitable donors as well. In particular, patients with high PRA levels should be considered for a living donor transplant.

Living donor pancreas transplants decrease the number of deaths of diabetic patients on the waiting list, help overcome the organ shortage, reduce mortality and morbidity, and improve the quality of life for patients with debilitating side effects of diabetes. The use of living donors also reduces the risk of graft rejection, as compared with the use of deceased donors. Yet living donor pancreas transplants remain relatively rare, performed under very selective circumstances. In terms of surgical technique, the donor splenic artery and vein are anastomosed to the recipient’s external iliac artery and vein in an end-to-side fashion, and exocrine drainage can occur via an anastomosis of the pancreatic duct and transected end of the pancreas to the bladder or bowel¹⁰¹ (Fig. 11-14).

Results

As of December 2010, more than 35,000 pancreas transplants had been reported to the IPTR: more than 25,000 transplants in the United States and more than 10,000 in other countries According to IPTR data, recipient age at the time of the transplant has increased significantly, and so has the number of transplants for patients with type 2 diabetes. The trend over time has been toward stricter donor criteria, with a concentration on younger donors, preferably trauma victims, and on short pancreas graft preservation time.

Drainage techniques have changed over time, too: enteric drainage of exocrine pancreatic secretions is now predominant, in combination with systemic drainage of the venous effluent of the pancreas graft. Immunosuppressive protocols have developed toward antibody induction therapy, followed by administration of tacrolimus and MMF for maintenance. Steroid avoidance has increased over time in all three recipient categories.

These changes have led to improved patient and graft survival rates. In all three recipient categories, early technical graft loss rates have decreased significantly to about 8%. Likewise, the 1-year immunologic graft loss rate has also decreased, ranging from 2% to 6%. The 1-year patient survival rates now exceed 90% in all three recipient categories. The highest 1-year pancreas graft survival rate is in SPK recipients: 86% for the pancreas and 93% for the kidney. The 1-year pancreas graft survival rate is 80% in PAK recipients and 78% in PTA recipients.

Significant improvements have been noted not only in 1-year pancreas graft function but also in long-term success rates. The most recent 5-, 10-, and 20-year pancreas graft function rates are 80%, 68%, and 45% for SPK recipients; 62%, 46%, and 16% for PAK recipients; and 59%, 39%, and 12% for PTA recipients, respectively. The quality of the deceased donor graft is of paramount importance. The use of anti–T-cell induction therapy has had a significant impact on long-term graft survival, specifically in PTA recipients.

IPTR data show significant improvements in patient survival and pancreas graft function rates since the inception of UNOS, over a course of 24 years.^92,95,99,102 Clearly, pancreas transplants now offer excellent outcomes for patients with IDDM.

Islet vs. Pancreas Transplants

Pancreas transplants are frequently compared with islet transplants, which are less invasive and, therefore, more appealing. It is important to emphasize that these two types of transplants are not mutually exclusive but rather complementary. The results of islet transplants have improved over the past decade, but overall islet graft function, specifically long-term function, still significantly trails overall pancreas graft function.¹⁰³ Islet transplants involve pancreas procurement (as described earlier) and then separation of islets from the exocrine pancreatic tissues using proteolytic enzymes (as described later). The human pancreas contains about one million islets, of which half are lost during the isolation process. About 10,000 islets per kilogram of body weight are needed to achieve insulin independence when transplanted into the liver. Frequently, one donor pancreas does not suffice; in fact, up to four donor pancreases have been used for one islet recipient.

Because of the relatively disappointing long-term outcomes, insurance providers in the United States do not provide reimbursement for islet transplants. Transplant centers with both pancreas and islet transplant programs follow an algorithm that favors islet transplants in patients with a high surgical risk and pancreas transplants in patients with a low surgical risk. Although solitary donor pancreases are not in short supply, only one donor pancreas is required for a successful pancreas transplant; in contrast, two to four donor pancreases are commonly used for one islet recipient with less favorable long-term outcomes.

Of note, the primary goal of current islet transplant trials is not insulin independence but rather a reduction in the incidence and severity of hypoglycemic events, a reduction in exogenous insulin requirements, and an amelioration of hemoglobin A1c levels. Islet transplants rarely maintain long-term insulin independence. A recent study showed a higher rate of insulin independence in PTA recipients than in recipients of an islet transplant alone, despite the use of up to three donor pancreases in each of the islet recipients.¹⁰⁴ Until islet transplant results significantly improve and include long-term insulin independence, a pancreas transplant remains the treatment of choice for β-cell replacement therapy in patients with IDDM.

Transplanting islets of Langerhans isolated from deceased donor pancreases is an appealing option for patients with type 1 diabetes. An islet transplant involves the procurement of a donor pancreas and its transportation to a specialized islet isolation facility, where the pancreas is enzymatically digested; then, the islets are purified from the rest of the digested pancreas using density gradients. The purified islets are then cultured and evaluated for their identity, viability, and potency, before being infused into the portal vein of a diabetic recipient. When the procedure is successful, these islet cells engraft into the recipient and secrete insulin, providing excellent moment-to-moment control of blood glucose, as is seen with a whole-pancreas transplant.

A successful islet transplant offers advantages over exogenous insulin injections—advantages that are similar to those of a whole-pancreas transplant. These advantages include restoring β-cell secretory capacity, improving glucose counterregulation, restoring hypoglycemia awareness, providing perfect or near-perfect glucose homeostasis, and, potentially, preventing secondary diabetic complications.

Unlike a whole-pancreas transplant, an islet transplant does not involve a major surgical procedure with its associated mortality and morbidity. Instead, it can generally be performed as an outpatient procedure using percutaneous catheter-based therapy to cannulate a branch of the portal vein, with minimal recovery time for the recipient. Potential complications associated with islet injection include portal hypertension, portal vein thrombosis, hepatic abscesses, and bacteremia. Theoretically, islet transplants could have wider application (as compared with current practice and with whole-pancreas transplants), given the significantly lower surgical risk, the relatively small tissue volume transplanted, and the potential for islet immunomodulation or immunoisolation, which could minimize or eliminate the need for immunosuppression.

The first reported attempt at an islet transplant was in 1893 by Watson-Williams and Harsant: they transplanted a sheep’s minced pancreas into the subcutaneous tissue of a young boy with ketoacidosis.¹⁰⁵ The discovery of insulin may have reduced interest in islet transplants as a treatment for diabetes, at least until the realization that insulin could not provide perfect glycemic control and that, therefore, patients ultimately suffered devastating secondary complications. Several milestones ensued: the first whole-pancreas transplants,¹⁰⁶ early success with rodent islet transplants,¹⁰⁷ and then, in the 1970s, human islet autotransplants after pancreatectomy, in order to address the intractable pain associated with chronic pancreatitis, by Sutherland, Najarian, and colleagues in Minnesota.¹⁰⁸

Until recently, attempts to extend those trailblazing findings of clinical islet autotransplants to clinical islet allotransplants in patients with type 1 diabetes met with generally very poor success. For example, in 1995, a report of the International Islet Transplant Registry indicated that of 270 recipients, only 5% were insulin-independent at 1 year posttransplant.

In 2000, Shapiro and colleagues reported the results of the Edmonton protocol, which enabled consistent diabetes reversal and short-term (<1 year) insulin independence.^109,110,111 The Edmonton protocol prescribed transplanting a large number of freshly isolated islets (>10,000 islet equivalents per kilogram body weight, typically requiring the use of two to four pancreases) with a specialized “islet-sparing,” steroid-free immunosuppressive protocol consisting of low-dose tacrolimus, sirolimus, and IL-2 receptor antibody induction. Those results were replicated at other experienced transplant centers,^112,113 but the rates of long-term (>5 year) insulin independence remained poor, well below those of whole-pancreas transplants.¹¹⁴ Still, despite the low rates of long-term insulin independence, most islet recipients were C-peptide positive and retained hypoglycemia awareness, indicating residual islet function and benefit. In fact, at 9 years posttransplant, 15% remained insulin-independent, and 73% had hypoglycemia awareness and corrected hemoglobin A_1c levels.¹¹⁵

In the mid-2000s, new trials began with the goal of establishing protocols that enable insulin independence, using islets from a single donor pancreas; the results were good, especially with strict donor and recipient selection.^116,117 In the most experienced centers, long-term rates of diabetes reversal are now about 50% at 5 years posttransplant. The reasons include refinements in pancreas preservation, islet isolation, and culture protocols, as well as the use of newer induction immunosuppressive agent combinations, such as a T-cell–depleting antibody (anti-CD3 antibody, alemtuzumab, or antithymocyte globulin) and a tumor necrosis factor-alpha (TNF-α) inhibitor (etanercept or infliximab). Presumably, viable β-cell mass is now preserved, both pre and posttransplant.^{116,117,118,119,120} Thus, islet transplant results are approaching those of whole-pancreas transplants; however, because islets from more than one pancreas are typically needed, those results cannot be directly compared with the results of whole-pancreas transplants.^121,122

In the United States, an islet transplant is still officially deemed an experimental procedure. In contrast, since 2001, it has been considered a standard of care and is fully reimbursed in Canada and, more recently, in the United Kingdom, Sweden, Switzerland, France, and Italy as well. Worldwide, since 2000, more than 750 patients with diabetes have undergone an islet transplant, and 80 ongoing trials have enrolled up to 1500 islet recipients.¹¹⁸ One of the U.S. trials (a multicenter phase 3 registration trial sponsored by the National Institutes of Health) aims to collect the necessary data for submitting a biological license application (BLA) to the FDA. A successful BLA would open the road for islet transplants to become a standard of care and thus reimbursable by the Centers for Medicare and Medicaid Services.

The full potential of islet transplants remains to be realized, but the future is exciting. As the latest improvements in pancreas preservation, islet isolation and purification, islet culture, and islet immunoisolation are implemented clinically, the hope is that sustained insulin independence will become consistently possible with a single pancreas donor and without the need for systemic immunosuppression.

The first attempts at liver transplants in the late 1960s through the 1980s were largely experimental endeavors, with a 1-year survival rate of only 30%. But breakthroughs in immunosuppression, surgical technique, organ preservation, anesthesia, and critical care have improved that rate to approximately 85% today. Liver transplants remain daunting, especially in the face of an organ shortage that results in sicker potential candidates. Unfortunately, the perioperative mortality rate and the 1-year mortality rate are among the highest of any surgical operation currently performed.

History

The first experimental liver transplants in dogs are often attributed to C. Stuart Welch in 1955 and then Jack Cannon in 1956. However, current scholarship reveals that Vittorio Staudacher first described the technique in 1952.¹²³ A series of canine experiments followed, which refined the surgical technique to ensure perioperative survival.

The next obstacle—immunologic rejection—was addressed by drug immunosuppression with AZA and prednisone. The first human liver transplant trials started in 1963 with Thomas Starzl, but a series of deaths led to a voluntary moratorium for 3.5 years. With the resumption of clinical transplants in 1967, Starzl performed the first successful liver transplant. Still, for the next decade, survival rates were dismal: only 20% of the 170 liver transplant recipients in Starzl’s program at the University of Colorado survived more than 5 years.¹²⁴

Several innovations dramatically improved outcomes. The advent of better immunosuppressive drugs was instrumental. In 1978, cyclosporine was introduced clinically in England. It was soon combined with prednisone to great effect. The arrival of tacrolimus in the 1990s further improved graft survival.

Technical advances were also significant. Donor procurement techniques and cold organ preservation protocols were standardized, and the recipient operation was also refined. Choledochocholedochostomy or choledochojejunostomy to a Roux-en-Y limb became standard and significantly decreased the frequency of biliary complications. Innovations, including living donor liver transplants and deceased donor split-liver transplants, enabled more pediatric recipients to be transplanted. Improvements in portosystemic shunting and perioperative critical care also were contributory.

Indications

In general, any form of irreversible liver disease is an indication for a liver transplant. Chronic alcoholic disease and HCV are the most common indications in the United States. An extensive list of acute and chronic diseases of the liver that are treatable by a liver transplant is provided in Table 11-6.

Offering transplants to alcoholic patients has always drawn some opposition, because of the perception of it being a self-inflicted illness, as well as concerns about recidivism and the recipient’s possible inability to maintain postoperative immunosuppression and care. Yet studies have shown that such patients have excellent outcomes and that liver transplants for them are cost-effective.^125,126,127 Because patients who drink 4 to 8 ounces of liquor daily for 10 to 15 years have an increased risk of developing cirrhosis, the general requirement for acceptance as a transplant candidate is 6 months of abstinence. Furthermore, most transplant centers recommend rehabilitation and Alcoholics Anonymous programs.

Transplants for HCV have yielded worse outcomes than transplants for other diseases.¹²⁸ The reason is the universal recurrence of the virus posttransplant. Viral levels reach pretransplant levels as early as 72 hours posttransplant.¹²⁹ The course of the viral infection is often accelerated posttransplant: 10% to 20% of recipients develop cirrhosis after just 5 years.¹³⁰ Studies have suggested that use of older donors may increase the chance of aggressive recurrence.¹³¹ The best method to prevent recurrence would be to eradicate the infection pretransplant, but doing so is not always possible because patients with decompensated cirrhosis often cannot tolerate treatment. Once recurrence occurs, treatment methods are limited. One study found that pegylated interferon and ribavirin therapy achieved a sustained viral response in 44% of patients.¹³²

A substantial number of patients undergo liver transplants for cholestatic disorders. Primary biliary cirrhosis, an autoimmune disease, is characterized by damage to the intralobular bile ducts that progresses to liver cirrhosis. Trends toward earlier treatment may explain the slight decrease in liver transplants for this disorder.¹³³ Posttransplant outcomes in patients with this disorder have been excellent, with many centers achieving 1-year survival rates of 90% to 95%. Recurrence is relatively uncommon: a large series reported a 30% recurrence rate at 10 years posttransplant.¹³⁴

The second most common cholestatic disorder among liver transplant candidates is primary sclerosing cholangitis. It is characterized by inflammation and fibrosis of large intra- and extrahepatic biliary ducts; 70% of such patients also have inflammatory bowel disease. Recurrent cholangitis is common and increases mortality rates beyond what would be expected on the basis of laboratory values. On behalf of such patients, appeals can often be made for priority in allocation to the UNOS regional review boards. Posttransplant outcomes for such patients have been excellent. Primary sclerosing cholangitis is a significant risk factor for cholangiocarcinoma, so annual screenings (including imaging and measurement of serum CA 19-9 levels) should be carried out. Recurrence is fairly uncommon: studies have reported a recurrence rate of up to 20% at 10 years posttransplant.¹³⁵

Progressive metabolic disorders also are treatable with liver transplants. Hemochromatosis, an inherited disorder, results in excessive intestinal iron absorption. Iron deposition can cause cirrhosis and severe cardiomyopathy. Careful cardiac evaluation is necessary pretransplant.

Another metabolic disorder, α₁-antitrypsin deficiency, is characterized by insufficient levels of a protease inhibitor, resulting in early-onset emphysema and cirrhosis. Careful pulmonary evaluation is necessary pretransplant.

Wilson’s disease, an autosomal recessive disorder characterized by impaired cellular copper transport, leads to copper accumulation in the liver, brain, and cornea. Patients can develop significant neurologic complications and cirrhosis. Several reports suggest improvement of neurologic deficiencies posttransplant.^136,137

Transplants can also be performed in patients with hepatic malignancies, but only in accordance with strict criteria. Hepatocellular carcinoma (HCC), a complication of cirrhosis, is the most common type of hepatic malignancy. Resection is the first line of treatment if possible, but often, cirrhosis is too advanced. If the tumor meets the Milan criteria, a liver transplant can be performed. These criteria were established by a landmark paper in 1996 showing that patients with a single tumor under 5 cm in diameter, or with three tumors under 3 cm in diameter, in the absence of vascular invasion, had a 4-year survival rate of 85%.¹³⁸ Patients with such tumors receive exception points, based on their UNOS region, allowing for a timely transplant before their tumors spread.

Transplants for cholangiocarcinoma are still in the experimental stages but may be performed if the center has an experimental protocol in place. The Mayo Clinic protocol, which uses neoadjuvant therapy and strict exclusion criteria, has resulted in a 5-year survival rate of 82%.¹³⁹

Acute fulminant hepatic failure also is an indication for a liver transplant; in fact, such patients are the highest priority for the next available liver in their UNOS region. This devastating illness is defined by acute and severe liver injury with impaired synthetic function and encephalopathy in a person who had normal liver function. It is often caused by acetaminophen overdose; acute fulminant viral hepatitis A, B, and E; other viral infections; drug toxicity; ingestion of Amanita mushrooms; acute fatty liver of pregnancy; or Wilson’s disease. A significant number of patients will recover with supportive care. The difficulty lies in predicting who will not recover and therefore would benefit from a liver transplant. The King’s College criteria were developed for this purpose: patients with acetaminophen-induced disease, a pH <7.3 or grade III/IV encephalopathy, a prothrombin time >100 seconds, and serum creatinine >3.4 mg/dL meet those criteria.¹⁴⁰ Management of acute liver failure is very intensive. Such patients suffer from severe coagulopathy, hypoglycemia, lactic acidosis, and renal dysfunction. They are susceptible to infections, which are frequently overwhelming. Cerebral edema, a serious complication of acute liver failure, is a leading cause of death from brain herniation. Intracranial pressure monitoring and serial imaging are often necessary; if a patient develops irreversible brain damage, a transplant is not performed.

Recipient Selection

The diagnosis of cirrhosis itself is not an indication for a transplant. Patients may have compensated cirrhosis for years such that the traditional indication for a transplant is decompensated cirrhosis, manifested by hepatic encephalopathy, ascites, spontaneous bacterial peritonitis, portal hypertensive bleeding, and hepatorenal syndrome (each described below).

Hepatic encephalopathy is an altered neuropsychiatric state caused by metabolic abnormalities resulting from liver failure. The early stages result in sleep disturbances and depression. As the liver disease progresses, patients can become somnolent and confused and, in the end stages, comatose. Ammonia is produced by enterocytes from glutamine and from colonic bacterial catabolism, and the use of serum ammonia levels as a marker of encephalopathy is controversial because a variety of factors can influence levels. Hyperammonemia suggests worsening liver function and bypass of portal blood flow around the liver. GI bleeding and infection can exacerbate hepatic encephalopathy.

Ascites (the accumulation of fluid in the abdominal cavity) that is caused by cirrhosis is a transudate with a high serum-ascites gradient (>1.1 g/dL). Associated with portal hypertension, it is treated initially with sodium restriction and diuretics. Refractory ascites necessitates large-volume paracentesis and eventually a transjugular intrahepatic portosystemic shunt (TIPS). Contraindications to TIPS placement include significant hepatic encephalopathy, advanced liver disease, congestive heart failure, renal insufficiency, and severe pulmonary hypertension.¹⁴¹

Spontaneous bacterial peritonitis, an infection of the ascitic fluid without an evident intra-abdominal source, is characterized by fever, abdominal pain, and an ascitic fluid polymorphonuclear count ≥250 cell/mm³ on paracentesis. The first line of empiric treatment is with a third-generation cephalosporin because the majority of cases are caused by aerobic gram-negative microbes such as E. coli, although Gram stain and culture results should be used to guide therapy.

Portal hypertensive bleeding can be a devastating event for patients with cirrhosis. Each bleeding event carries a 30% mortality rate and accounts for a third of all deaths related to cirrhosis. Only 50% of bleeding events cease spontaneously, so treatment must be expedient. The initial medical treatment is with vasopressin and octreotide. The initial intervention is endoscopy with sclerotherapy and band ligation of bleeding varices. If those initial attempts fail, more aggressive treatment is necessary with a balloon tamponade (using a Sengstaken-Blakemore tube) and with emergent TIPS placement. The last line of treatment is emergency surgery to place a portosystemic shunt, transect the esophagus, or devascularize the gastroesophageal junction (Sugiura procedure). Preventing variceal bleeding is essential and can be achieved, with some success, using β-blockers.

Hepatorenal syndrome is a form of acute renal failure that develops as liver disease worsens. The etiology is unclear, but splanchnic vasodilation from portal hypertension and increased production of circulating vasodilators result in a decline in renal perfusion. Characterized by oliguria (<500 mL of urine/day) and low urine sodium levels (<10 mEq/L), hepatorenal syndrome is often reversed by a liver transplant, even after dialysis dependence. Pretransplant, other causes of renal failure need to be excluded, including ATN, drug nephrotoxicity, and chronic renal disease. The initial medical therapy includes octreotide, midodrine, and vasopressin analogs, but the syndrome often progresses to dialysis dependence.

The Model for End-Stage Liver Disease (MELD) was originally developed to assess risk for TIPS placement.¹⁴² Later analysis revealed it to be an excellent model to predict survival among patients with cirrhosis, especially those on the waiting list for a liver transplant.¹⁴³ In 2002, liver graft allocation was restructured to be based on the MELD score.

Although the historic indication for a liver transplant is decompensated cirrhosis, a landmark analysis comparing waiting list mortality with posttransplant mortality established that a minimum MELD score of 18 is necessary to have a survival benefit posttransplant. A MELD score between 15 and 18 does not confer a survival advantage, but a transplant may be justified if the patient has significant morbidity from cirrhosis.¹⁴⁴

Acute liver failure itself is an indication for a liver transplant. To qualify for Status 1 (first priority for a donor liver within the UNOS region), the transplant candidate must meet the following criteria: (a) onset of hepatic encephalopathy within 8 weeks after the first symptoms of liver disease; (b) absence of pre-existing liver disease; and (c) ventilator dependence, dialysis, or an international normalized ratio (INR) >2.0.

Contraindications

In general terms, contraindications to a liver transplant include insufficient cardiopulmonary reserve, uncontrolled malignancy or infection, and refractory noncompliance. Older age is only a relative contraindication: carefully selected recipients over the age of 70 years can achieve satisfactory outcomes.¹⁴⁵

Patients with reduced cardiopulmonary reserve are unlikely to survive a liver transplant. Candidates should have a normal ejection fraction. If coronary arterial disease is present, they should undergo revascularization pretransplant. Severe chronic obstructive pulmonary disease (COPD) with oxygen dependence is a contraindication. Severe pulmonary hypertension with a mean pulmonary artery pressure greater than 35 mmHg that is refractory to medical therapy is also a contraindication. Candidates with pulmonary hypertension should be evaluated with a right heart catheterization.

For candidates with alcoholic liver disease, few reliable predictors of posttransplant relapse exist.¹⁴⁶ Most centers require 6 months of abstinence from drugs and alcohol. Insurance companies often make more stringent demands, including random drug screening and 1 year of abstinence.

Uncontrolled infections pretransplant are a substantial risk posttransplant when the patient becomes significantly immunosuppressed. Fungal and multidrug-resistant bacterial infections are relative contraindications. Some centers require an extended period of treatment and documented eradication pretransplant. HIV infection is a relative contraindication; some centers have strict protocols that exclude patients with a history of acquired immunodeficiency syndrome (AIDS)-related illnesses as well as those who are coinfected with HCV.

Ideally, patients with a history of malignancy (with the exception of HCC) should be cured of the cancer pretransplant. In most cases, this means eradication, completion of curative therapy, and absence of recurrence over a certain period of time, which varies by the tumor type, but can be up to 5 years or longer for aggressive tumors (see earlier Malignancy section).

Surgical Procedure

A liver transplant is among the most extensive operations performed, and it can be associated with considerable blood loss. A bilateral subcostal incision with midline extension is used. Mechanical retraction spreads the rib cage to allow access. The ligamentous attachments of the liver are dissected free. The vascular structures are isolated, including the suprahepatic and infrahepatic vena cava, the portal vein, and hepatic artery (Fig. 11-15). The bile duct, portal structures, and vena cava are divided, completing the hepatectomy (Fig. 11-16)—often the bloodiest and most difficult part of the operation, particularly in the presence of extensive varices and severe coagulopathy.

After the liver is removed, the anhepatic phase begins. This phase is characterized by the absence of inferior vena caval return to the heart and by portal congestion due to clamping of the portal vein. Significant hemodynamic instability and increased variceal bleeding can occur. Patients who are unable to tolerate this phase can be placed on venovenous bypass, with cannulas drawing blood from the IVC via the femoral vein and via the portal vein, returning it to the systemic circulation via the subclavian vein. Venovenous bypass itself can cause complications, including air embolism, thromboembolism, and trauma to the cannulated vessels.

The donor liver is placed in the orthotopic position. The suprahepatic vena caval anastomosis is performed first in an end-to-end fashion, followed by the infrahepatic vena caval and portal anastomosis, both also end-to-end. The liver is then reperfused, often leading to a period of hemodynamic instability and cardiac arrhythmias due to the release of byproducts of ischemia from the donor liver. Coagulopathy also can worsen because of these byproducts as well as fibrinolysis.

The arterial anastomosis between the donor common hepatic or celiac trunk is most often performed with the recipient CHA in an end-to-end fashion. Of course, many variations are possible. After arterial reperfusion, the bile duct anastomosis is performed between the donor and recipient common ducts, also in an end-to-end fashion. If necessary for technical reasons, the recipient common duct can be joined to a Roux-en-Y limb. Some surgeons choose to insert a T-tube or place internal stents in the common bile duct to protect the anastomosis.

The piggyback technique is a common variation of the standard technique. The recipient’s IVC is preserved by carefully dissecting off the posterior aspect of the liver. This added dissection is a disadvantage of this variation, often increasing hepatectomy time and blood loss. The recipient’s liver is removed by dividing it at the confluence of the hepatic veins. The preserved IVC is an advantage of this variation, allowing venous return from the lower body to the heart during the anhepatic phase and improving renal perfusion. No randomized studies, however, have demonstrated the superiority of the piggyback technique over the standard technique.

Pediatric Transplants

Outcomes after pediatric liver transplants are among the best after any type of transplant, with a 1-year survival rate of 90%. The most common indication is biliary atresia. After diagnosis is confirmed, a Kasai procedure is promptly carried out: a Roux-en-Y loop of bowel is directly anastomosed to the hilum of the liver. The Kasai procedure often allows time for the children to grow in size, reducing the risk of a transplant when it is required, as it eventually is in 75% of such children.

The other common indication for a pediatric liver transplant is a metabolic disorder, such as α₁-antitrypsin deficiency, tyrosine metabolism deficiencies, and primary oxalosis. Since the MELD score was developed for adults, pediatric liver allocation is based on an analogous model, the Pediatric End-Stage Liver Disease (PELD) score, which incorporates bilirubin levels, INR, albumin levels, age, and growth failure.

The surgical procedure is similar to the adult procedure. Graft implantation is more challenging, given the pediatric recipient’s smaller vascular structures. As a result, surgical complications are much more common in pediatric recipients. Hepatic artery thrombosis is about three times more common. Donor size matching is very important in the pediatric population and often limits the donor pool for pediatric recipients. To address this issue, deceased donor split-liver transplants and living donor transplants (both described in the following sections) have been developed.

Deceased Donor Split-Liver Transplants

A deceased donor allograft can be split into two grafts, most frequently into a left lateral segment for a child and an extended right segment for an adult (Fig. 11-17). It can be done in vivo (during the donor operation) or ex vivo (on the back table after the donor liver is removed). Both techniques have similar outcomes. Increased morbidity is associated with splitting allografts, whether for adult or pediatric recipients; however, the technique is justified given the donor shortage and has been important for improving access to transplants for pediatric recipients.¹⁴⁷

Living Donor Transplants

Donation by an adult living donor to an adult recipient requires either the right or left lobe of the liver (Fig. 11-18). Donation by an adult living donor to a pediatric recipient requires the left lateral lobe (Fig. 11-19). Donor safety is paramount. The donor operation has a 0.2% mortality rate and significant morbidity rates, including rehospitalization (8.5%), bile leak or stricture (6.0%), reoperation (4.5%), and major postoperative infections (1.1%).¹⁴⁸ Careful donor selection is vital. Potential donors should be medically and psychologically healthy, their hepatic anatomy should be amenable to donation, and absolutely no coercion can occur. A separate donor team should serve as the donor advocate and thoroughly explain all risks.

Careful recipient selection is essential. Transplant candidates also must qualify for a deceased donor liver transplant, because a significant number of living donor transplant recipients will eventually require a retransplant. Transplant candidates should be medically fit enough to withstand the rigors of the operation and of the postoperative course with a partial graft. An absolute contraindication is a critical illness: the limited success of such transplants does not justify the risks to the living donor. The obvious advantages of a living donor transplant are that it can be done expediently (avoiding the waiting list mortality associated with candidates for a deceased donor transplant) and that it can be planned.

Postoperative Care

A liver transplant imposes significant trauma on the major organ systems. Immediately posttransplant, the first goal is to stabilize those systems. Acid-base equilibrium and hemodynamic stability are often difficult to maintain but are essential. Periods of hypotension can increase the risk of hepatic artery thrombosis. Careful attention needs to be paid to ongoing bleeding. Appropriate hemoglobin levels should be maintained. Ongoing bleeding mandates a return trip to the operating room; the rate of reoperation can be as high as 25% among high-risk patients. Transfusion of platelets and fresh frozen plaza must be done prudently, because theoretically their administration can increase the risk of hepatic artery thrombosis. Graft function should be evaluated frequently; if it is impaired, an ultrasound is urgently required to assess for the presence of vascular complications.

Evaluation of Graft Function

Evaluation of the graft begins in the operating room. Its appearance overall, any swelling, and the quantity and quality of bile production after reperfusion can help assess function. In the intensive care unit, hemodynamic stability, correction of coagulopathy, euglycemia, successful temperature regulation, clearance of lactic acid, and restoration of neurologic status are all signs of a functioning graft, even before the first set of liver function test results are obtained. Transaminases usually peak by postoperative day 2. An aspartate transaminase (AST) level greater than 2500 IU/L is suggestive of significant injury. Cholestasis usually peaks from postoperative day 7 to 12. The INR should improve shortly after reperfusion.

In 3% to 4% of patients undergoing a liver transplant, the graft does not function for any identifiable reason, a condition termed primary nonfunction; in such cases, a retransplant is the only option. Some studies suggest that a peak AST level of 5000 IU/L may be predictive of primary nonfunction.^149,150,151 Factors associated with primary nonfunction include donor macrosteatosis, prolonged cold and warm ischemic times, and prolonged donor hospital stay.¹⁵¹

Complications

Vascular complications occur in about 8% to 12% of recipients and include thrombosis, stenosis, and pseudoaneurysm formation.

The most common vascular complication is hepatic artery thrombosis. Recent reviews suggest that its incidence is between 1.6% and 4%¹⁵²; the mortality rate is 50%, even after definitive therapy.¹⁵³ Early presentation can be quite dramatic, with fulminant hepatic necrosis, primary nonfunction, transaminitis, or fever. Late presentation, however, can be asymptomatic or subtle, with cholangitis, bile leak, mild transaminitis, hepatic abscesses, or failure to thrive. Diagnostic imaging with ultrasound has more than 90% sensitivity and specificity. If hepatic artery thrombosis is identified, urgent re-exploration is needed. A thrombectomy or revision of an anastomosis may be successful, but with significant hepatic necrosis, a retransplant is necessary.

Thrombosis of the portal vein is very uncommon. Signs of early thrombosis include liver dysfunction, ascites, and variceal bleeding. Upon diagnosis, an operative thrombectomy should be attempted.

Biliary complications remain the Achilles’ heel of liver transplantation, affecting 10% to 35% of these organ recipients. Signs include fever and abdominal pain, with bilious drainage from surgical drains. Diagnosis is made with cholangiography.

Complications manifest themselves as leaks or strictures. Leaks require a reoperation and surgical correction, whereas strictures can most often be managed with radiologic or endoscopic interventions. Two common reconstructions are choledochostomy and choledochojejunostomy. Some centers also routinely use T-tube stents or internal stents. Consensus has not been reached as to which reconstruction technique is superior. Early infectious complications are often associated with initial graft function and pretransplant risk factors. Intra-abdominal infections should raise concerns of a possible bile leak. Fungal infections are often associated with poor graft function. Given the immunosuppressed and compromised state of liver recipients, early infectious complications can be devastating.

The types of opportunistic infections that occur in liver transplant recipients are similar to those that occur in other types of solid organ transplant recipients and are due to suppression of cell-mediated immunity by chronic immunosuppressive drug administration.

Acute rejection occurs in approximately 20% of liver recipients. The first line of treatment is with a high dose of a corticosteroid, which is usually effective; if not, antilymphocyte therapy is initiated. Rejection of the liver (unlike other transplanted organs) does not adversely affect patient or graft survival rates. Maintenance immunosuppression consists of a corticosteroid, tacrolimus, and mycophenolate.

After the introduction of long-term total parenteral nutrition (TPN) in the late 1970s and the early success of liver, kidney, and heart transplants, the first attempts at intestine transplants were made. Over the first two decades, the results were dismal. But the introduction of the immunosuppressive drug tacrolimus in the late 1980s led to significant improvement in graft and patient survival rates. Nonetheless, intestine transplants remain the least frequently performed of all transplants, with the lowest graft survival rates.

The main obstacle is the high immunogenicity of the intestine, caused by its abundant lymphoid tissue. High levels of immunosuppression are needed, yet the rejection rate is still high. The microbial colonization of the intestine confers the risk of translocation of pathogenic microorganisms into the recipient’s circulation, causing severe systemic infections. Through the first decade of the twenty-first century, the survival of patients on long-term TPN was superior to the survival of intestine transplant recipients, so a transplant was considered only as rescue therapy for patients with life-threatening TPN-related complications.

Over the last several years, improvements in surgical techniques, in perioperative and postoperative care, and particularly in immunosuppressive protocols have led to significantly better patient and graft survival rates posttransplant.¹⁵⁴ Recent data indicate that survival rates after an intestine transplant often are better than, or at least similar to, survival rates among patients receiving chronic TPN in the home setting.¹⁵⁵ Today, an intestine or multivisceral transplant is recognized as a feasible treatment.

Indications and Recipient Selection

An intestine transplant is indicated for patients with irreversible intestine failure in combination with TPN failure. The definition of intestine failure does not specify the exact length of the remaining intestine. Intestine failure is typically multifactorial. Variables include what part of the small intestine is absent, whether or not the ileocecal valve is present, whether or not the patient underwent an ostomy, and how long the remaining colon is. TPN failure is defined as significant biochemical or pathologic evidence of liver injury, loss of central vein access with thrombosis of at least two central veins, frequent indwelling catheter infection or a single episode of fungal infection, and recurrent episodes of severe dehydration despite IV fluid supplementation.

Indications for a transplant differ between the adult and pediatric population. The leading causes of intestine failure are summarized in Table 11-7. The disease involvement of organs other than the intestine dictates the extent of the operation required. Liver failure is often seen in patients on long-term TPN. If pathologic or biochemical evidence of severe liver damage is combined with signs of portal hypertension, then a combined liver-intestine transplant is the treatment of choice. However, a multivisceral transplant (liver, pancreas, stomach, duodenum, and/or small intestine) might be necessary among children who suffer diffuse intestinal dysmotility syndromes and adults who develop diffuse portomesenteric thrombosis, extensive intra-abdominal desmoid disease encasing the main visceral vascular structures with concurrent short gut syndrome, or massive abdominal trauma.

Surgical Procedure

For both the donor and recipient surgery, the key decision is which organs will be transplanted.¹⁵⁶ For an isolated intestine transplant, the blood supply is based on the arterial inflow from the SMA and on the venous outflow from the superior mesenteric vein (SMV). Both vessels are isolated at the root of the mesentery.

For a combined liver-intestine transplant, the blood supply is based on the arterial inflow from the celiac axis and SMA, which are procured en bloc with an aortic patch. The liver, duodenum, pancreas, and small intestine—because of their close anatomic relationship—are procured en bloc. If the hepatoduodenal ligament is left intact, no biliary reconstruction is necessary, which virtually eliminates the risk of postoperative biliary complications.¹⁵⁷ Because the entire splanchnic system drains into the liver, venous drainage is achieved by anastomosis of the hepatic veins to the recipient’s vena cava.

For both an isolated intestine transplant and a combined liver-intestine transplant, the proximal transection of the GI tract occurs at the first portion of the duodenum. For a multivisceral transplant, the stomach is part of the graft; hence, the transection of the GI tract occurs at the distal esophagus. Figs. 11-20 to 11-22 show these three main types of transplants.

The vast majority of intestine transplants use a deceased donor organ. However, advances in surgical techniques have made the use of living donors a feasible alternative for either an isolated intestine transplant or a combined liver-intestine transplant. With a living donor, the donor operation is slightly different: for an isolated intestine transplant, 150 to 200 cm of the donor’s ileum, on a vascular pedicle comprising the ileocolic artery and vein, are used¹⁵⁸ (Fig. 11-23); for a combined liver-intestine transplant, performed almost exclusively for pediatric recipients, segments II and III of the donor’s liver are used, in addition to the intestine (Fig. 11-24).

Similarly, the recipient operation also varies by the organs transplanted. Generally, the recipient’s infrarenal aorta is used to achieve the arterial inflow to the graft. For an isolated intestine transplant, venous drainage is achieved via systemic or portomesenteric drainage; for a combined liver-intestine transplant or a multivisceral transplant, venous drainage is achieved via the hepatic veins. Systemic venous drainage, given its lesser technical difficulty, is preferred over portomesenteric drainage. The diversion of splanchnic flow into the systemic venous circulation can cause several metabolic abnormalities, but no hard evidence shows any negative impact clinically on the recipient.

After the organs are perfused, the continuity of the recipient’s GI tract is restored, which includes the placement of a gastrostomy or jejunostomy feeding tube and an ileostomy. In the early postoperative period, the ileostomy enables regular endoscopic surveillance and biopsy of the intestinal mucosa. Once the recipient recovers, the ileostomy can be taken down.

The last, but often the most difficult, part of the recipient operation is abdominal wall closure. It is especially challenging in intestine transplant recipients because they have usually undergone multiple previous procedures, resulting in many scars, ostomies, feeding tubes, and the loss of abdominal domain. To provide sufficient coverage of the transplanted organs, the use of prosthetic mesh often is necessary.

Postoperative Care

Initial postoperative care for intestine transplant recipients does not significantly differ from that for other organ transplant recipients. In the intensive care unit, each recipient’s cardiovascular, pulmonary, and renal function is closely monitored; aggressive resuscitation with fluid, electrolytes, and blood products is performed. Broad-spectrum antibiotics are an integral component of care.

Of all solid organ transplants, intestine transplants have the highest rate of rejection. With intestine transplants, no serologic marker of rejection is available, so frequent biopsies and histologic evaluation of the intestinal mucosa are of utmost importance. Rejection leads to structural damage of the intestinal mucosa. Translocation of endoluminal pathogens into the circulation can cause systemic infections.

Thanks to the introduction of new immunosuppressive protocols, the rejection rates and the overall patient and graft survival rates have improved significantly. Variations between the protocols exist, but the general concept is to induce immunosuppression with polyclonal T-cell antibody and high doses of a corticosteroid, followed by maintenance doses of corticosteroids and the calcineurin inhibitor tacrolimus.

Immediately posttransplant, recipients are maintained on TPN. Enteral nutrition is initiated as early as possible, but is advanced very cautiously. It can take several weeks for the transplanted intestine to achieve structural integrity and functionality and for the recipient to tolerate the full strength of tube feeds.

Despite all the recent advances, the complication rate posttransplant remains high. The most common complications include intra-abdominal abscesses, enteric leaks, intra-abdominal sepsis, the need for a reoperation, graft thrombosis, life-threatening bleeding, and central line problems. Immunosuppression-specific complications include rejection, PTLD, graft-versus-host disease (GVHD), infections, and malignancies. Tailoring the recipient’s immunosuppression plays a critical role in preventing these complications: a low level of immunosuppression leads to graft rejection, but too much confers a high risk of infectious complications, PTLD, and, less commonly, GVHD—all of which are associated with a significantly increased risk of graft failure and mortality.

The long-term results of intestine transplants have improved significantly, even though they still remain inferior to the results of other abdominal organ transplants.^159,160

History

The first successful heterotopic heart transplant, in an animal model, was performed by Carrel and Guthrie in 1905.¹⁶¹ Subsequent progress with cardiopulmonary bypass and immunologic modulation facilitated the first successful adult human heart transplant, performed by Christiaan Barnard in 1967 in Cape Town, South Africa.¹⁶² However, it was Norman Shumway at Stanford who persisted with heart transplants, in the face of disappointing patient outcomes at a number of early centers. Thanks to the diligence of Shumway and colleagues in perfecting heart transplant techniques, along with the development, by Caves, of endomyocardial biopsy as a method of allograft rejection surveillance, human heart transplants began to reappear in the 1980s as a viable solution to end-stage heart failure. By 1981, the introduction of cyclosporin A finally created the necessary clinical immunologic modulation necessary to make long-term survival of heart recipients a reality.¹⁶¹

Lung transplants have a similar history. In the 1950s, Metras in France and Hardin and Kittle in the United States performed canine lung transplants, demonstrating that meticulous anastomotic technique could produce normal pulmonary pressures. Hardy performed the first human lung transplant in 1963, although the patient lived only 18 days. The first successful long-term lung transplant was performed in 1983 in Toronto. These early lung recipients, however, were plagued by infection, rejection, and, most significantly, bronchial anastomotic dehiscence. Cooper and colleagues soon determined that the high-dose corticosteroids used for immunosuppression were responsible for the frequent occurrence of dehiscence. The combination of high-dose corticosteroids and ischemic donor bronchi was deadly to lung recipients. Cooper, Morgan, and colleagues showed that the bronchial anastomosis could be protected by wrapping it with a vascular omental pedicle, which not only provided neovascularity but also offered a buttress against any partial dehiscence.¹⁶³

Once cyclosporine became available for lung recipients, corticosteroid doses could be quickly tapered and stopped; cyclosporine poses no danger to the integrity of the bronchial anastomosis. In fact, the introduction of cyclosporine allowed the success of the first combined heart-lung transplant at Stanford in 1981 (after unsuccessful attempts by Cooley in 1969, Lillehei in 1970, and Barnard in 1981, all of whom used only high-dose corticosteroids for immunosuppression). The 1980s marked the start of the modern age of thoracic transplants.

Heart Transplants

Indications

The most common diagnosis leading to a heart transplant is ischemic dilated cardiomyopathy, which stems from coronary artery disease, followed by idiopathic dilated myopathy and congenital heart disease. About 3000 patients are added to the waiting list each year.

Evaluation

Pretransplant, both candidates and potential donors are evaluated to ensure their suitability for the procedure. Transplant candidates undergo echocardiography, right and left heart catheterization, evaluation for any undiagnosed malignancies, laboratory testing to assess the function of other organs (such as the liver, kidneys, and endocrine system), a dental examination, psychosocial evaluation, and appropriate screening (such as mammography, colonoscopy, and prostate-specific antigen testing). Once the evaluation is complete, the selection committee determines, at a multidisciplinary conference, whether or not a heart transplant is needed and is likely to be successful. Transplant candidates who meet all of the center’s criteria are added to the waiting list, according to the UNOS criteria, which are based on health status.

Once a potential deceased donor is identified, the surgeon reviews the status report and screening examination results. The donor is initially matched to the recipient per the recipient’s status on the UNOS waiting list, the size match, and the blood type. Results of the donor’s serologic testing, echocardiography, chest x-ray, hemodynamic testing, and possibly coronary artery evaluation are assessed, in order to determine whether or not the donor’s heart can withstand up to 4 hours of cold ischemic time during procurement, transport, and surgery.

Procedure

Heart transplants are most often performed orthotopically (Fig. 11-25). The recipient’s native heart is removed, leaving the superior vena cava, the IVC, the left atrial cuff, the aorta, and the pulmonary artery in situ, in order to allow for anastomosis of the donor’s heart. Usually the left atrial cuff is anastomosed first, providing left heart inflow. Right heart inflow is achieved using a bicaval technique, by directly sewing the donor’s superior vena cava and IVC to the recipient’s venae cavae or by creating an anastomosis of the right atrium to a right atrial cuff. The donor’s main pulmonary artery is connected to the recipient’s pulmonary artery, and finally, the aortic anastomosis is completed (Fig. 11-26).

Once the cross-clamp is removed, the heart is allowed to receive circulation from the recipient and begins to function normally. Inotropic support with isoproterenol, dobutamine, or epinephrine is often required for 3 to 5 days, in order to support recovery from the cold ischemia.¹⁶⁴

On rare occasions, a heterotopic or “piggyback” heart can be transplanted, leaving the native heart in place. But this scenario is becoming very uncommon with the increasing use of mechanical circulatory support for single-ventricle failure.

Posttransplant Care

Patient survival rates for heart recipients differ slightly after primary transplants vs. retransplants. After primary transplants, the patient survival rates at 1, 3, and 5 years are 87%, 79%, and 72%, respectively; after retransplants, the rates are 82%, 67%, and 58%.¹⁶⁵ An increasing number of heart recipients have now survived more than 15 to 20 years with their first graft, especially those with no significant history of either cellular or antibody-mediated rejection.

Heart recipients must be monitored for both early and late complications. Early complications include primary graft dysfunction, acute cellular or antibody-mediated rejection, right heart failure secondary to pulmonary hypertension, and infection. Hemodynamic values are monitored to assess early graft function; pharmacologic and sometimes mechanical support is instituted if needed.

The goal of immunosuppression is to prevent rejection, which is assessed by immunosuppressive levels and, early on, by endomyocardial biopsy. Both T-cell–mediated (cellular) and B-cell–mediated (antibody-mediated) rejection are monitored. Most of the immunosuppression used is aimed at T cells; however, if the recipient has many preformed antibodies or develops donor-specific antibodies, other strategies (such as plasmapheresis or rituximab) are used to reduce the antibody load. Immunosuppressive regimens can vary by center, but most often consist of three categories of medications: a calcineurin inhibitor (usually tacrolimus or cyclosporine), an antiproliferative agent (MMF or AZA), and a corticosteroid (prednisone). Other immunosuppressive agents can be used, depending on the needs of individual recipients.

Recipients are also assessed for any infections, with visual inspection of wound healing and with monitoring of the complete blood count and cultures as needed. Other common early sequelae include drug-induced nephrotoxicity, glucose intolerance, hypertension, hyperlipidemia, osteoporosis, malignancies, and biliary disease.

Late complications include acquired transplant vasculopathy, progressive renal failure, and, most commonly, malignancies, especially skin cancer and PTLD. Accelerated coronary artery disease is the third most common cause of death posttransplant (after infections and acute rejection) and the most common cause after the first year. Coronary artery disease can begin to develop as early as 1 year posttransplant. Its pathogenesis is unknown, but it is believed to be immunologic. Because of these late complications, most transplant centers continue to perform screening tests and recipient examinations at least annually after the first year.

Lung Transplants

Indications

The indications for a lung transplant include congenital disease, emphysema, COPD, cystic fibrosis, idiopathic pulmonary fibrosis, primary pulmonary hypertension, α₁-antitrypsin deficiency, and the need for a retransplant after primary graft failure. Each year in the United States, about 1600 patients are added to the waiting list; nearly a third of them have COPD and/or emphysema. The next most common diagnosis among patients on the waiting list is cystic fibrosis. A lung allocation score (LAS) was instituted in 2005. The average lung transplant candidate requires oxygen (often 4 L/min or more at rest) and has an extensively compromised quality of life, as documented by the results of pulmonary function and 6-minute walk tests.

Evaluation

Evaluation for a lung transplant is very similar to evaluation for a heart transplant, except that lung transplant candidates undergo more extensive pulmonary function testing, a 6-minute walk test, chest computed tomography, ventilation-perfusion (V-Q) scanning, and arterial blood gas assessment. In addition, all lung transplant candidates must have adequate cardiac function and must meet psychosocial requirements.

Potential lung donors are also screened for blood type and size match. Larger lungs are accepted for COPD patients; smaller lungs are chosen for the restricted chest cavity of fibrotic patients. Donors should have a partial pressure of oxygen in arterial blood (Pao₂) value >300 mmHg on a fraction of inspired oxygen (Fio₂) of 100% and a positive end-expiratory pressure (PEEP) value of 5. Ideally, donors will have normal chest x-ray results, but exceptions for isolated abnormalities that will not affect subsequent graft function can be made. Living donors can donate a single lobe to a smaller recipient, such as a child. Single-lung transplants are common in many centers and can serve to increase the availability of lungs for multiple recipients. Newer concepts, such as “lung in the box” extracorporeal lung perfusion and stem cell technologies, may further improve the availability of donor lungs by optimizing the use of otherwise marginal grafts.

Procedure

Lung transplants can be done either as (a) single-lung transplants (to either side via thoracotomy) or as (b) sequential bilateral-lung transplants (via bilateral thoracotomies or via a single clamshell incision that divides the sternum; Fig. 11-27). They can be done absent extracorporeal mechanical cardiopulmonary perfusion (bypass), with the lung with the worst function (as predicted by preoperative ventilation and perfusion scanning) transplanted first. Despite careful surgical technique and excellent anesthesia, the poor pulmonary reserve of some lung recipients may require the institution of cardiopulmonary bypass to complete the transplant. Bypass is initiated through the chest by direct cardiac cannulation or peripherally via the femoral vessels.

Once the thoracotomy is made, a recipient pneumonectomy is performed with care, in order to avoid injury to the phrenic or recurrent laryngeal nerves. The pulmonary veins and main pulmonary artery are encircled outside the pericardium. At this point, once the main pulmonary vessels are occluded, the need for cardiopulmonary bypass can be assessed. The vessels and bronchus are ligated; the donor’s lung is prepared and brought to the table wrapped in cold iced gauze, in order to extend the cold preservation time. The bronchial anastomosis (Fig. 11-28) is performed first and then covered with peribronchial tissue or pericardium. The pulmonary artery and, finally, the vein are anastomosed. The lung is then deaired before the final anastomotic suture is tightened, with gentle lung insufflation. All clamps are removed, and the lung is aerated. At least two chest tubes are left in place. After the transplant is complete, a bronchoscopy is performed to clear the airway of blood and secretions.

Posttransplant Care

Patient survival rates for lung recipients vary significantly after primary vs. redo transplants. After primary transplants, the patient survival rates at 1, 3, and 5 years are 83%, 62%, and 46%, respectively; after retransplants, the rates are 64%, 38%, and 28%.

Postoperative care of lung recipients can be very labor- intensive. These patients require meticulous ventilator management, in order to maintain Fio₂ at a minimum and to keep Pao₂ at 70 mmHg. Most patients are extubated within the first 24 to 48 hours. Recipients can require multiple bronchoscopies for both airway management and surveillance biopsies. Diuretics are used generously to counteract any positive fluid balance from the operation and to help with pulmonary recovery.

Early complications include technical complications, graft dysfunction, infections, and rejection. Technical complications often involve stenosis of one or more anastomoses leading to graft dysfunction. Bronchoscopy, V-Q scanning, echocardiography, and radiologic imaging are useful in identifying the causes of graft dysfunction. In up to 20% of recipients, primary early graft dysfunction can occur with no obvious cause. Such dysfunction may be due to some pathology from the donor, perhaps an unknown aspiration, infection, or contusion; or it could result from poor graft preservation at the time of organ procurement. In the intensive care unit, aggressive ventilator and pharmacologic management can help, but recipients can nonetheless progress to the need for mechanical support in the form of ECMO. Infections are treated with appropriate antibiotics, which can be challenging in patients with cystic fibrosis and a history of multidrug-resistant organisms. Rejection is monitored by biopsies and treated as needed.

Late complications include airway complications, such as strictures and, rarely, dehiscence, bronchiolitis obliterans, and malignancies. Strictures are treated with bronchoscopic dilation and intervention. Bronchiolitis obliterans often is a sequela of chronic rejection, but can be due to aspiration, chronic infections, or various other causes. In recipients with a progressive fall in their forced expiratory volume in 1 second (FEV₁), bronchiolitis obliterans is suspected. All recipients should be taught to perform microspirometry at home as a screening tool posttransplant. Biopsies are performed to confirm the diagnosis of any complication and, if possible, the cause. Despite aggressive screening and treatment, more than 50% of recipients will develop graft dysfunction. Most if not all of the sequelae of chronic immunosuppression that occur in lung transplant recipients are similar to those occurring in other groups of solid organ transplants.

Heart-Lung Transplants

Every year in the United States, 30 to 50 patients are added to the list of patients waiting to receive a simultaneous heart-lung transplant. The most common diagnosis is idiopathic pulmonary fibrosis, followed by primary pulmonary hypertension. Heart-lung candidates are often younger than their single-organ counterparts. The patient survival rates at 1, 3, and 5 years are 66%, 48%, and 39%, respectively. Often, lung complications ultimately lead to graft failure. The immunosuppression is the same as that for single thoracic organ recipients, with emphasis on weaning the patient off corticosteroids as early as possible.

Xenotransplants (i.e., cross-species transplants of organs, tissues, or cells) have immense, yet untapped, potential to solve the critical shortage of available grafts. A primary hurdle is the formidable immunologic barrier between species, especially with vascularized whole organs.^{166,166,167,168,169,170} Other problems include the potential risk of transmitting infections (known as zoonoses or xenoses) and the ethical problems of using animals for widespread human transplants, even though great progress has been made in the past few years in efforts to overcome these problems.^{166,166,167,168,169,170,171,172}

Pigs are generally accepted as the most likely donor species for xenotransplants into human beings.¹⁷³ Pigs would also be easier to raise on a large-scale basis. Guidelines for raising pigs in specialized facilities designated as pathogen-free have been established; in anticipation of clinical trials, such facilities have already been created and populated.^171,172

The immunologic barrier in pig-to-human xenotransplants is highly complex, but generally involves four subtypes of rejection.¹⁶⁶ The first is hyperacute rejection (HAR), which is mediated by the presence of natural (preformed) xenoantibodies in humans. These antibodies bind to antigens found mainly on the vascular endothelial cells of porcine donor organs, leading to complement activation, intravascular coagulation, and rapid graft ischemia soon after the transplant. The second subtype is acute humoral xenograft rejection (AHXR), a delayed form of antibody-mediated rejection seen in pig-to-nonhuman-primate transplants after steps to prevent HAR—steps such as depletion of anti-pig antibodies or complement from nonhuman primates’ serum. Alternative names for AHXR include acute vascular rejection or delayed xenograft rejection. The third subtype is an acute cellular rejection process (similar to the classic T-cell–mediated acute rejection seen in allograft recipients). The fourth subtype is chronic rejection in grafts that survive for more than a few weeks (similar to the chronic rejection seen in long-surviving allograft recipients, with features of chronic vasculopathy).

Many different options are being tested to overcome this immunologic barrier, including the genetic engineering of pigs, the use of agents to inhibit platelet aggregation and complement activation, and the administration of powerful immunosuppressive drugs.^{166,166,167,168,169,170,171,172,173}

During the first decade of the twenty-first century, the field of whole-organ xenotransplantation progressed significantly, thanks to the increasing availability of genetically engineered pigs and new immunosuppressive protocols. At a recent symposium organized by the International Xenotransplantation Association, data presented demonstrated extended survival time of porcine solid organs in nonhuman primates: from about 30 days to an average of 60 days and even up to 250 days (depending on the model).^{166,169,174,175} However, clinical application is still limited by thrombotic microangiopathy and consumptive coagulopathy; novel methods to prevent those complications will be required for further progress.

Cellular xenotransplants have made great strides and are currently in the early stages of clinical trials. Porcine islet xenotransplants are the most advanced form; five independent groups have now demonstrated survival and function of porcine islets in nonhuman primates for more than 100 days.^{166,175,176,177,178,179,180,181} For the clinical trials, cost-benefit models have been developed, and the regulatory framework has been established.^{170,171,172,178} One trial of particular interest involves transplanting encapsulated porcine islets without immunosuppression.¹⁷⁹ Early results are encouraging. But the efficacy of that approach may be limited until further genetic engineering enables proper oxygenation and nourishment of islet grafts, thereby supporting their viability and function.

The future of xenotransplantation is exciting. Continued active research will focus on further genetic engineering of pigs, newer immunosuppressive drugs, and tissue engineering approaches that will minimize or eliminate the need for immunosuppression. Given recent progress, routine clinical application of cellular xenotransplants is likely within the next decade.