Chapter 45: Organ Transplantation

The ability to transplant human organs successfully has developed in the span of a single generation of physicians and surgeons. This remarkable achievement is an excellent example of how animal models may be used to understand and develop treatments for human disease. Organ transplantation is now the preferred treatment modality for a variety of different types of organ failure. Transplantation offers not only improved long-term survival but also improved quality of life for many patients afflicted by renal, hepatic, cardiac, and pulmonary failure.

Enormous effort is currently being expended to develop methods of artificially replacing vital organ functions. Despite these efforts, the ability to replace organ function with mechanical or biomechanical devices remains elusive. While hemodialysis can replace renal function effectively, it offers neither a normal quality of life nor a normal life span. Despite major advances in artificial heart technology, current systems have not reached the point where they can be used routinely to restore normal cardiac function. To date, there are no effective replacements for hepatic or pulmonary function that are suitable for long-term use. Organ transplantation is frequently the only treatment modality that offers a normal lifestyle for patients with advanced organ failure. Recently, successful composite tissue allografts of limbs, face, and larynx have been reported. While these grafts are not lifesaving, it can be argued that for selected patients they reduce misery. This chapter discusses the indications for organ transplantation as well as the limitations to the current state of the art.

With the exception of organs from a genetically identical twin (isografts), all organs from genetically dissimilar individuals (allografts) will naturally be subjected to immunologic rejection. This fundamental biologic limitation has largely been overcome by the development of targeted immunosuppression therapies. These therapies are able to suppress the immunological reactivity that produces graft rejection while leaving intact sufficient immune competency to allow recovery from most infectious diseases. The same degree of success has not been reached when transplanting organs between species (xenografts).

Once it was realized that allografts failed due to an active immunologic attack of the recipient’s immune system on the donor organ, methods of suppressing the immune system were investigated. Early attempts at immunosuppression with substances such as nitrogen mustard and total lymphoid irradiation were unsuccessful because of the toxicity of the therapy. The first practical immunosuppressant was azathioprine, an antimetabolite inhibitor of DNA synthesis. When used in combination with corticosteroids, the first successful combination of immunosuppressants was born and the first boom in the number of transplants occurred. This combination remained the state of the art until it was realized that the cell type that exerts primary control over allograft rejection is the T lymphocyte. This led to the later development of agents able to specifically inhibit activation and proliferation of T cells. The result was immunosuppressants that were both more effective and much less toxic than the azathioprine/corticosteroids combination. These agents ushered in a further acceleration in the number of transplants occurring, because now it was possible to transplant organs between individuals who did not share human leukocyte antigens.

Almost all renal diseases responsible for renal failure can be treated by transplantation. Diabetes is the most common cause of chronic renal failure in adults and accounts for 45% of all renal failure in the United States. The second most common cause is hypertensive nephropathy (27%), followed by chronic glomerulonephritis (11%). The causes of renal failure in children are somewhat different, with congenital causes, including both nonobstructive and obstructive uropathies, predominating.

IMMUNOLOGIC RESPONSES

HLA Histocompatibility Antigens

The major histocompatibility (MHC) antigens are the most antigenic proteins on donor organs, meaning that they cause the most intense immune responses when the donor and recipient do not share the same antigens. The MHC genes are coded by a single chromosomal complex of closely linked genes on the short arm of the sixth chromosome. This complex consists of at least seven loci that code for genes involved with histocompatibility: human lymphocyte antigen (HLA)-A, HLA-B, HLA-C, HLA-D, HLA-DR, HLA-DQ, and HLA-DP. Each HLA gene locus is highly polymorphic, so that as many as 50 or more discrete antigens are controlled by each locus. The collection of HLA genes in an MHC complex is termed a haplotype.

Histocompatibility antigens are grouped into class I (A, B, C) and class II (DR, DQ, DP) antigens. Class I antigens are composed of a 45-kDa heavy chain with three globular extracellular domains (α1, α2, α3) that confers HLA specificity, a transmembrane portion, and an intracellular domain. Class I antigens are stabilized by β₂-microglobulin, a 12-kDa protein that is not encoded in the MHC complex. Class I antigens are expressed on all nucleated cells and interact primarily with CD8+ T cells. Class II antigens are composed of two noncovalently linked chains: a 33-kDa α chain and a 28-kDa β chain. Each chain has two extracellular domains that confer HLA specificities. Class II antigens are only constitutively expressed on B cells and antigen-presenting cells (macrophages, monocytes, dendritic cells) but can be induced on activated T cells and endothelial cells. Class II antigens interact primarily with CD4+ T cells. The three most important antigens clinically in solid organ transplantation are A, B, and DR. Since each person has two MHC complexes, one on each copy of chromosome 6, everyone has a total of six HLA antigens that are of primary importance to organ transplantation.

The 3D structures of both class I and II molecules are similar. The extracellular domains form a β-pleated sheet with two looping α-helices that creates a groove facing away from the cell. Following ribosomal synthesis, during assembly of the HLA antigens, peptides are added to this groove. Intracellularly derived peptides are added to class I antigens in the endoplasmic reticulum, while extracellularly derived proteins are added to class II antigens. The end of the groove on class II antigens is open, allowing class II antigens to accommodate longer peptides. Antigenic determinants are found predominantly on the α1 and α2 chains of the class I molecule and on the β chain of the class II molecule. Some antigenic determinants are shared by many different HLA allotypes. These common determinants are called public specificities. Antigenic determinants that are only found on a unique HLA antigen are termed private specificities.

Lymphocytes are categorized as either B or T cells. B cells are responsible for antibody production. T cells are categorized into two functional subsets: helper cells that are CD4+ and cytotoxic T cells that are CD8+. Helper T cells preferentially recognize peptides displayed in the groove of class II antigens, while cytotoxic T cells preferentially recognize peptides displayed by class I antigens. A third type of T cell, called regulatory T cells, is now well-established and may be either CD4+ or CD8+. Helper T cells direct both the formation of cytotoxic T cells, which are able to cause graft destruction directly, and the maturation of B cells. Helper T cells can be further subdivided based on their cytokine secretion profile into type 1 and type 2 cells. Type 1 helper T cells secrete interleukin (IL)-2, interferon (IFN)-γ, IL-12, and TNF-α. These cytokines stimulate delayed-type hypersensitivity, cytolytic activity, and the development of complement-fixing IgG antibodies. Type 2 helper T cells secrete IL-4, IL-5, IL-10, and IL-13. These cytokines activate eosinophils and cause the production of IgE antibodies. Additionally, Th17 cells are a distinct subset of helper T cells that produce the proinflammatory cytokine IL-17 and are implicated in diseases of autoimmunity and inflammatory states.

Allograft rejection begins when foreign antigen is taken up by an antigen-presenting cell, processed, and presented to helper T cells. The T cell is activated in response to properly presented antigen and secretes cytokines that in turn recruit and activate additional lymphocytes and cause them to begin to clonally proliferate. Cytokines released in the allograft milieu by other cells, including macrophages, contribute to the generation of the immune response as well. Helper T cells also stimulate the differentiation and proliferation of cytotoxic T cells and B cells.

B-cell activation induces the production of specific antibodies directed against donor antigens. This response is important, especially for class I antigens. Recipients who develop a primary immunological response to a particular antigen and produce cytotoxic antibodies directed against the donor HLA will often retain memory B cells and maintain the ability to produce antibodies that are directed against that particular HLA allotype. Upon reexposure to the same antigens, an immediate destructive reaction to the graft—called hyperacute rejection—occurs. Antibody directed against the donor vascular endothelium triggers fixation of complement, direct cellular damage, and the formation of platelet and fibrin plugs, leading to microvascular thrombosis and ischemic necrosis of the organ. Transplantation in the presence of cytotoxic anti-HLA antibody directed against a donor organ is prevented in practice by performing a complement-mediated cytotoxic crossmatch with pretransplant recipient sera against lymphocytes from the potential donor.

Histocompatibility Testing, Crossmatching, & Blood Group Compatibility

Grafts between identical twins are rare but very successful because immunosuppressive therapy is not required when there is no antigenic difference between the donor and recipient. Grafts between HLA-identical siblings who share two HLA haplotypes give the next best results. One-fourth of any given sibling pair will share both HLA haplotypes and thus share all of the same HLA antigens. Despite sharing HLA, immunosuppression is still required because of incompatibilities at minor histocompatibility loci. Parents, offspring, and half of siblings share one HLA haplotype. One-fourth of siblings will not share an HLA haplotype and will therefore share antigens only by chance. The same is true for genetically unrelated donor/recipient pairs such as spouses and friends. At one time, HLA compatibility was considered to be crucial because there were large differences between graft survivals depending on the degree of histocompatibility. Transplants between individuals who shared many HLA antigens were much more likely to avoid graft loss compared to donor/recipient pairs who did not share HLA antigens. This has changed due to the ability of modern immunosuppression to provide for excellent immunological outcome even in the setting of complete HLA mismatch. HLA testing is now of much lesser value than it once was. HLA histocompatibility testing is now primarily of value in determining which of several donors has the best histologic match to the intended recipient. Kidney allocation from deceased donors was once heavily influenced by HLA matching. This has now changed because of the realization that the degree of HLA match has a relatively unimportant effect on the odds of successful outcome. The newest allocation strategy relies more on waiting time and less on the degree of HLA match. Kidneys from donors who share all six HLA antigens with a recipient on the waiting list are still allocated first to any recipient who happens to be a “perfect match.” This situation is uncommon, affecting fewer than 10% of the kidneys from deceased donors.

Regardless of the results of tissue typing and antigen matching, it is essential to determine whether a recipient has preformed antibodies against donor antigens, since their presence would result in a hyperacute rejection of the graft as described previously. Preexisting antibodies may develop because of prior exposure to foreign histocompatibility antigens in the form of blood transfusion, pregnancy, or previous organ transplants.

These antibodies are identified by performing a crossmatch between the patient’s serum against the donor’s lymphocytes. Multiple methods of performing the crossmatch are available with varying degrees of sensitivity and specificity. It is difficult to find an appropriate donor with a negative crossmatch for patients who have antibodies directed against multiple HLA specificities. Some of these patients can be treated with desensitization strategies to reduce their burden of circulating antibodies. Methods currently utilized include plasmapheresis, infusion of random intravenous donor immune globulin, and anti–B-cell monoclonal antibodies. Experience is accumulating with desensitization protocols suggesting that donor/recipient pairs with positive crossmatches can sometimes be successfully transplanted. The long-term outcome for these kidneys is unclear.

The ABO blood group antigens behave as strong histocompatibility antigens for kidney transplantation; therefore, ABO-incompatible kidney transplants have generally been considered an absolute impossibility. It is certainly true that ABO-incompatible kidneys will fail rapidly if nothing is done to reduce the amount of antibody directed against the incompatible antigen in the recipient’s serum. Success is now being reported for ABO-incompatible kidney transplants using combinations of anti–B-cell therapy and plasmapheresis.

Immunosuppressive Drug Therapy

Multiple immunosuppressive strategies are effective at preventing acute allograft rejection. Most strategies involve the use of more than one agent. Conceptually, using multiple immunosuppressive agents has the effect of blocking multiple targets in the immune response cascade, which allows relatively low doses of each drug to be used, thus avoiding toxicity associated with high doses of these powerful drugs. Thus, many patients are treated with “triple therapy” using corticosteroids, a calcineurin inhibitor, and either an antimetabolite or a mammalian target of rapamycin (mTOR) inhibitor. A variant of this strategy, termed “quadruple therapy,” involves the initial use of a very potent antilymphocyte agent and chronic administration of the same drugs used for triple therapy. The antibody treatment has two effects: it decreases the likelihood of rejection in the critical first few months after the transplant, and it allows there to be a delay before the introduction of the calcineurin inhibitor. This is advantageous because of the associated nephrotoxicity of calcineurin inhibitors. Since the risk of rejection is highest immediately after the transplant, it is typical to begin with relatively high doses of each agent and gradually taper down to a maintenance level over several weeks to months.

Rejection is diagnosed by biopsy. Patients are followed up with serial measurements of renal function in the form of serum creatinine. When a transplanted kidney begins to function, the serum creatinine will fall gradually over several days to reach a nadir level that becomes a new baseline for the patient. Any significant elevation above the baseline should prompt evaluation as to the cause, and once obstruction, dehydration, and infection have been ruled out, it is usually appropriate to biopsy the kidney graft. Rejection may be treated with high-dose “pulse” corticosteroid therapy over several days or with antilymphocyte antibodies. Rejection therapy is effective in more than 90% of cases.

Many drugs are available today for immunosuppression. All of these drugs share the common side effect of increasing susceptibility to infectious diseases. This is an intrinsic feature of currently available therapy, which aims to suppress natural immune responses against all foreign antigens. When the transplant recipient develops an infection, it is vital that a physician with experience prescribing immunosuppression is involved with the patient’s care. In many cases, it is appropriate to temporarily reduce the degree of immunosuppression in order to allow recovery from the infection. Precisely, how this is accomplished varies widely among practitioners, but it generally involves lowering the dosage or withholding one or more of the agents being used for maintenance immunosuppression. When the infection has resolved, immunosuppression is restored to an acceptable maintenance regimen. It is appropriate to individualize therapy because different individuals have different propensities to develop both rejection and infection.

Many long-term immunosuppressive therapies are associated with the development of malignancy, especially skin cancer and lymphomas. Patients receiving chronic immunosuppression should pay particular attention to minimizing direct exposure to ultraviolet radiation. Since many skin cancers are treatable with simple resection, it is also important that transplant physicians are careful to monitor for and treat skin lesions that develop in transplant recipients.

In the future, it may be possible either to modify the graft so that it is not viewed as foreign to the recipient’s immune system or to modify the recipient’s immune system so that it will not reject the graft without altering the immune response to other foreign antigens.

A. Antimetabolites

The antimetabolite drugs include azathioprine, cyclophosphamide, mycophenolate, and leflunomide. These drugs inhibit nucleic acid synthesis, which in turn limits the ability of activated lymphocytes to rapidly clonally expand. In general, these drugs are used to prevent rejection but are not effective at reversing active acute rejection.

Azathioprine, a purine analog, is the original member of this family. The effects of this drug are not specific to lymphocytes; therefore, the drug also frequently causes decreased levels of circulating neutrophils and platelets. This side effect is dose dependent. This drug is of only historical importance currently.

Cyclophosphamide is an alkylating agent that is a common component of chemotherapy protocols. It is an effective immunosuppressant when given in high doses, but it has been used only very infrequently in clinical transplantation.

Mycophenolate is an inhibitor of inosine monophosphate dehydrogenase, a critical enzyme in the de novo synthesis pathway of purines. Lymphocytes uniquely depend on the de novo pathway to synthesize purines, while other cells are able to utilize a salvage pathway for synthesis. Mycophenolate is therefore more specific for lymphocytes than the other antimetabolites. It has largely replaced azathioprine for use in combination with a calcineurin inhibitor and corticosteroids since well-designed studies have shown it to have a superior ability to prevent rejection. Side effects are primarily gastrointestinal in nature. Enterically coated formulations are available for patients who are unable to tolerate mycophenolate mofetil.

Leflunomide is a selective inhibitor of de novo pyrimidine synthesis. It is thought to work by inhibiting the enzyme dihydroorotate dehydrogenase. It is used widely for treatment of rheumatoid arthritis. Clinical trials have demonstrated it to be efficacious in terms of preventing rejection, but it is difficult to use clinically because of its long half-life (15-18 days).

B. Corticosteroids

Corticosteroids used in combination with azathioprine was the first combination of immunosuppressants with the ability to prevent the development of allograft rejection, and high doses of corticosteroids was the first practical and effective means of reversing established rejection. Hence, over the past 40 years, corticosteroids have been a component of most successful immunosuppressive protocols. Typically, a high dose of intravenous corticosteroids is given at the time of engraftment, and the dose is tapered over weeks to months down to a maintenance dosage of 0.1-0.2 mg/kg of oral prednisone. In the recent past, there has been strong interest in discontinuation of corticosteroids—and even more recently, in developing protocols that do not require the administration of any corticosteroids. The evidence is accumulating that this treatment is appropriate and effective for some low-risk renal transplant recipients, but the use of corticosteroid-free protocols for higher-risk candidates—including those with known sensitization to HLA and patients undergoing second renal transplants—is more controversial.

Corticosteroid therapy is associated with many different side effects, including infection, weight gain, cushingoid features, hypertension, increased bruisability, hyperlipidemia, hyperglycemia, and acne. Daily corticosteroid therapy in children may inhibit somatic growth. This may be circumvented to some degree by alternate-day treatment, administering the drug once in the morning every other day.

Corticosteroids are standard therapy for a rejection episode, typically consisting of three or more daily doses of between 100 and 500 mg of intravenous methylprednisolone (“steroid pulses”). Depending on the severity of the rejection, steroid pulses will resolve 50%-80% of allograft rejection episodes.

C. Calcineurin Inhibitors

Transplantation was revolutionized by the introduction of the first calcineurin inhibitor, cyclosporine, into clinical practice in the early 1980s. Cyclosporine is a cyclic undecapeptide isolated from a fungus. It is a potent immunosuppressant and the first compound identified that can inhibit immunocompetent lymphocytes specifically and reversibly. Cyclosporine was followed by the introduction of tacrolimus, another compound derived from a fungus that also inhibits calcineurin. The primary mechanism of these agents appears to be inhibition of the production and release of IL-2 by helper T cells. They also interfere with the release of IL-1 by macrophages as well as with proliferation of B lymphocytes. Blood levels must be carefully monitored because both drugs are nephrotoxic and neurotoxic at higher levels. They also both have chronic effects on renal function and lead to significant long-term renal dysfunction in many patients who take them chronically. Both cyclosporine and tacrolimus are also associated with an increased incidence of neoplasms, particularly lymphomas.

D. Inhibitors of Mammalian Target of Rapamycin

Sirolimus is a macrocyclic triene antibiotic produced by a species of Streptomyces. It was originally developed as an antifungal and antitumor agent but was found to have significant immunosuppressive properties. The effect of sirolimus is believed to relate to inhibition of lymphocyte transduction pathways through binding to the mTOR. It functions as an antiproliferative and prevents not only expansion of lymphocyte clones but also smooth muscle proliferation. It is known to effectively prevent rejection in combination with a calcineurin inhibitor. The major advantages of this drug are that it does not cause renal dysfunction and its antiproliferative properties suggest that it will not be associated with the same risk of developing long-term malignancy. Side effects, in addition to the infections associated with immunosuppression, include oral ulcerations, wound healing problems associated with its ability to inhibit smooth muscle proliferation, and significant hyperlipidemias. An association with hepatic artery thrombosis has also been noted in patients receiving sirolimus therapy as part of their initial immunosuppression regimen following liver transplantation.

Everolimus is a derivative of sirolimus that also acts as an mTOR inhibitor. It has a side-effect profile similar to that of sirolimus but a shorter serum half-life.

E. Polyclonal Antithymoblast or Antilymphocyte Globulin and Antithymocyte Globulin

Antilymphoblast globulin and antithymocyte globulin are polyclonal antibody preparations derived by immunizing animals against human lymphocytes and collecting and purifying the antibodies that animals develop in response to the foreign antigenic proteins. They are potent drugs that deplete circulating lymphocytes, an effect that can be measured and followed by flow cytometry or by simply following the complete blood count with differential. Because they are polyclonal, they not only are effective against T cells but also may have important effects against circulating B cells and natural killer cells.

These agents are particularly effective in induction of immunosuppressive therapy and in the treatment of established rejection that is either severe or resistant to pulse corticosteroid therapy. Therapy is typically given daily for 5-7 days. The effect of these agents is profound immunosuppression that lasts for weeks to months. They are associated with increased incidence of viral infections because of their effects on cellular immunity and also with a higher lifetime risk of developing malignancy, particularly B-cell lymphoma.

Side effects are many and include fevers and chills, neutropenia, and thrombocytopenia. Fever, chills, and malaise occur because of mediator release by T cells and circulating mononuclear cells, especially TNF-α, IL-1, and IL-6, that occurs when the antibody is bound to certain cell surface receptors. The symptoms are very similar to those associated with an acute viral infection. These effects are usually transient, often lasting less than 12 hours. They occur primarily following the first or second dose of the treatment and can be attenuated markedly by pretreatment with corticosteroids, acetaminophen, and diphenhydramine. Neutropenia and thrombocytopenia occur because of direct antibody binding to these cell types, causing depletion. This effect is also transient and tends to resolve in 24-48 hours. It is necessary to monitor neutrophil and platelet counts during therapy and withhold doses of the treatment if the counts drop to dangerously low levels.

F. Monoclonal Antibody Therapy

The knowledge that the T cell is central to the development of allograft rejection led to the development of agents that selectively inhibit or deplete T cells, or both. The first example of such an agent is the monoclonal antibody OKT3 (muromonab-CD3), which is secreted by a hybridoma in culture. This agent may have some advantages over antilymphoblast globulin and antithymocyte globulin preparations in management of rejection because it specifically blocks T-cell generation and function. Because it is a monoclonal antibody and reacts with a defined antigen, it can be consistently produced with a defined activity and without unwanted reactivities against other cells like neutrophils and platelets. OKT3 is most effective in the treatment of steroid-resistant rejection, where more than 90% of rejection episodes are reversed, thus obviating further high-dose steroids. The downside of this antibody treatment is that since it is a murine monoclonal antibody, it may induce recipient antibody directed against the murine antibody molecule. This effect occurs in 5%-10% of patients treated with OKT3 and may decrease the efficacy of the treatment if given a second or third time. Like the polyclonal antilymphocyte preparations, treatment is usually given daily for 5-7 days. Side effects due to cytokine release are typically more severe than those seen with polyclonal agents but may also be attenuated with appropriate pretreatment. Since the antibody does not bind to epitopes other than the CD3 molecule, which is found only on T cells, it does not cause cytopenias.

The success of OKT3 led to the development of a new generation of monoclonal antibodies that are “humanized.” The monoclonal antibody molecule has been modified by genetic engineering to avoid the side effects seen with OKT3. The genetic code directing the production of the antibody molecule by the hybridoma has been altered by replacing most of the murine portion of the sequence with human antibody sequence. The antibody is thus chimeric, or “humanized” since only the highly variable portion of the antibody that binds to the antigenic epitope is foreign to the human recipient. Cytokine release therefore does not occur when the antibody is administered, nor is it likely that the recipient will develop neutralizing antibodies against the monoclonal preparation. Because the antibodies so closely resemble human immunoglobulin, they also have a long circulating half-life.

The first of these agents, daclizumab and basiliximab, binds to CD25, the high-affinity subunit of the T-cell receptor for IL-2. Since IL-2 is necessary for T-cell activation and proliferation, these agents have the ability to selectively inhibit the expansion of T-cell clones that are activated at the time of transplantation, without affecting existing T-cell immunity to other antigens. Existing cellular immunity to viruses, for example, is left intact. Induction treatment with anti-CD25 antibodies at the time of engraftment has been shown to reduce the incidence of future rejection episodes.

A more recent agent, alemtuzumab (Campath-1H), is a depleting humanized monoclonal antibody that binds to CD52, an antigen found on all peripheral blood mononuclear cells. Alemtuzumab administration causes a profound and sustained depletion of T cells from peripheral blood that lasts for many months. It similarly depletes B cells, natural killer cells, and monocyte, but to a lesser degree. Alemtuzumab is currently approved for treatment of patients with some forms of chronic lymphocytic leukemia. It is being used by some transplant centers for initial induction immunosuppression and for treatment of rejection.

G. Costimulation Blockade

Another emerging avenue for immunosuppression is that of signal two costimulation blockade. Once the T-cell receptor is engaged (signal 1), lipid rafts carry costimulation molecules to the immunologic synapse and allow for second messenger signaling to carry messages to the cell nucleus. Cytotoxic T lymphocyte antigen 4—immunoglobulin (CTLA4-Ig) or belatacept is a second-generation intravenous fusion protein designed to bind CD80/86 (B7 molecules) on antigen-presenting cells with high avidity, thereby inhibiting B7-CD28 complexes and T-cell activation. When compared to CNIs, phase II and III clinical trials have revealed that belatacept portends superior renal function and exhibits similar patient and graft survival with a decrease in the side-effect profile of renal toxicity and donor specific antibody formation. It has been recently approved for use as maintenance therapy. Due to an increased risk of patients developing posttransplant lymphoproliferative disorder, its use is restricted to Epstein–Barr virus (EBV) + recipients. Further studies attempting to design more selective targeting of alloreactive lymphocytes are ongoing. Specifically, pathways involving CD40/40L, LFA-1/ICAM, and CD2/LFA-3 are targets of newer, more potent monoclonal antibodies and fusion proteins.

SOURCES OF DONOR KIDNEYS

The two sources of kidneys for renal transplantation are living donors and deceased donors. Approximately one-third of patients who are acceptable candidates for transplantation will have a willing and medically suitable living donor. ABO-compatible donors are not absolutely required today because of the availability of treatments that can reduce the amount of antidonor antibody in the recipient. However, ABO-compatible donors are greatly preferred, because antibody reduction treatments are expensive and associated with infectious risk due to the depletion of protective antibodies.

At one time, only related living donors were acceptable because it was necessary to have closely matched HLA antigens between the donor and recipient in order to achieve acceptable graft survival rates. The graft survival rate for donor/recipient pairs who do not share any HLA antigens is now greater than 90%, leading transplant programs to accept increasing numbers of donors who are not genetically related to the recipients. It is now common practice to accept volunteer donors who are spouses, in-laws, friends, coworkers, and even members of the same community who may be only acquaintances. More controversial is a recent trend for patients and donors to meet through Internet web sites. Despite initial hesitancy to condone this method of finding a living donor, it has been difficult for the transplant community to make value judgments about the relationship between living donors and recipients as long as both parties are fully informed and committed.

Recently, programs have begun arranging transplants between two or more pairs of living donors and recipients who participate in a paired exchange. Recipients with willing but incompatible donors are paired with another donor/recipient pair who have the same problem. The outcome from paired donation transplants has been similar to that seen with other living donor transplants.

Living donors should be in good health both physically and psychologically. Above all, the living donor should be a volunteer and must clearly understand the nature of the procedure so that informed consent to the operation can be given. Donors should generally be of legal age, but reasonable exceptions have been made in extenuating circumstances, particularly when an identical twin donor is available. In these circumstances, it is wise for the program to assign to the donor an outside advocate who has no relationship with either the recipient or the remainder of the family to ensure that the minor is not coerced into proceeding.

Living Donors

Live kidney donors are now as common as deceased donors, although since each deceased donor can donate two kidneys, the total number of kidneys from deceased donors still far exceeds that obtained from living donors. Because of the biological ability of the body to compensate for the loss of one kidney, renal function tends to stabilize at approximately 75%-80% of the original renal function a few months following donation. Follow-up studies on donors show that they have good renal function and do not appear to suffer ill effects from the procedure, either physically or psychologically. Women with one kidney do not have an increased incidence of urinary infections during pregnancy.

There are at least two methods of performing donor nephrectomy in common practice: open nephrectomy and laparoscopic nephrectomy. Open nephrectomy, long the standard method, involves a flank incision about 15 cm long below the 12th rib. The peritoneum is retracted medially, and the kidney is removed along with its vessels and ureter without disturbing the intra-abdominal contents. More recently, laparoscopic techniques have been developed to allow the removal of a kidney for transplantation. The donor is placed under general anesthesia, and the abdomen is insufflated with carbon dioxide to allow visualization of the abdominal structures. Some surgeons use a large port in the midline, just above the umbilicus, to insert their hand into the abdomen. The kidney is then withdrawn through the hand port once it has been dissected free from surrounding tissues and the vessels and ureter have been divided. It is also possible to remove the kidney using purely laparoscopic techniques without inserting a hand port. The kidney is removed by placing it in a bag inside the abdomen and withdrawing the bag through a low transverse incision. Laparoscopic nephrectomy tends to take longer than a nephrectomy through an open approach, but it is associated with somewhat less postoperative pain and a briefer period of convalescence. Prospective donors should be informed about the options for nephrectomy and the advantages and disadvantages of each technique as well as the associated risk and the known complications.

The main risk to a donor is the anesthesia and the operation itself. The mortality rate is estimated to be 0.03%, and most deaths are not judged to be preventable but appear to be intrinsic risks of having a major operation. The most common significant complications following nephrectomy are wound related, including infection and hernia formation. These complications occur in less than 1%-3% of cases. Wound infections typically respond to dressing changes, and hernias require operative repair.

The evaluation of a living donor must be thorough and complete. It is first necessary to make sure that the donor is truly a volunteer and is not being coerced or unfairly influenced by the recipient or other family members. This often involves a careful evaluation by an individual with excellent understanding of the transplant process as well as excellent communication skills. It is advisable that this portion of the interview be conducted in private so that donors can be honest about their feelings. Transplant social workers, psychologists, and psychiatrists are typically involved with this aspect of donor selection. Once it is clear that the donor is genuinely seeking to donate of his or her own accord, a detailed history is taken, and a physical examination is performed. Factors that may affect operative risk as well as future risk of renal failure are carefully sought out. The routine workup includes chest x-ray, electrocardiography, urinalysis, complete blood count, fasting blood glucose, serum bilirubin, hepatic transaminases, serum creatinine, and blood urea nitrogen. If these are normal, the kidneys are imaged radiographically to make sure that two kidneys are present, to rule out intrinsic or structural renal disease, and to evaluate the vasculature of the kidneys. Angiography, CT, and MRI are all methods that can be used. Kidneys with multiple renal arteries may be transplanted, but care must be taken in the anastomosis of small accessory vessels, particularly when they come from the lower pole and may therefore provide the sole vascular supply to the ureter. When there are multiple renal veins, the smaller veins can often be ligated, since there is free communication of the veins within the kidney.

Deceased Donors

Two-thirds of eligible kidney recipients do not have a suitable living donor. These patients are placed on a waiting list for a kidney from a deceased donor. Since more patients are added to the list each year, the number of patients waiting for a kidney from a deceased donor grows longer each year.

Kidneys can be successfully transplanted from donors who are declared dead on the basis of brain death or from donors who die of cessation of spontaneous cardiovascular activity.

Brain death is now widely accepted, in principle, in the United States, and all hospitals have protocols to be followed to ensure that the diagnosis of brain death is confirmed without any doubt.

Consent for donation should always be obtained by individuals with training in how to approach the family of the donors. In this way, the family can be given time to grieve and express the inevitable sorrow and anger that accompanies the death of a loved one. Individuals who are not part of the team caring for the patient are best able to provide the emotional support that families need during this time. The discussion regarding donation can then occur separate from the discussion in which the family learns that their loved one has died.

Kidneys from brain-dead donors are removed operatively. The excision of the kidneys occurs operatively following in situ cold perfusion and exsanguination of the kidneys, often in concert with the removal of other transplantable abdominal and thoracic organs. The kidneys are perfused with specially designed preservative solutions and kept cold. Successful transplantation has been reported following cold storage of more than 72 hours, but optimal results are achieved if the kidney is transplanted as soon as possible following removal from the donor, preferable within 24 hours.

Kidneys may also be transplanted from deceased donors following cardiopulmonary death, a practice termed “donation following cardiac death.” The most common circumstance under which this occurs in the United States is when medical therapy that is judged to be futile is withdrawn from an individual. Typically, patients have suffered profound, irreversible brain injury and have essentially no conscious awareness and no potential for meaningful recovery. Standard medical practice in this circumstance is to recommend withdrawal of life-sustaining support such as mechanical respiration and intravenous infusions, since the vast majority of people state that they would not want to be kept alive in such a hopeless state. Withdrawal of support always occurs with the consent and understanding of the family. The decision to donate organs should be made separate from the decision to withdraw medical therapy. Once consent is obtained and preparation for donation is completed, support is withdrawn by the primary care team. When cardiopulmonary activity ceases, the primary physician team declares death, and the organs are then excised as with brain-dead donors.

SELECTION OF RECIPIENTS

Patients with chronic renal failure should be considered for transplantation. Acute renal failure on the basis of acute tubular necrosis can usually be managed with temporary dialysis, and therefore kidney transplantation is not appropriate in this setting. It is not necessary for patients to be on dialysis at the time of transplantation. In fact, results for patients who receive kidney transplants prior to beginning dialysis have the best chance of graft survival, while patients who had long-term dialysis prior to transplantation have poorer success rates. It is therefore important to begin consideration for renal transplantation as soon as dialysis appears to be inevitable and imminent within the next year.

During the early years of renal transplantation, most of the patients accepted for transplantation were between 15 and 45 years old. In recent years, the age range has been extended in both directions—children younger than age 1 and adults who are over 70 years old have received transplants. For many years, the success rates for transplanting in young children was inferior to that achieved with adults, but this problem has now been corrected. Even children younger than 1 year of age at the time of transplantation can be expected to have an excellent chance of graft survival.

Historically, there has been reluctance to perform renal transplants in the elderly. However, as the practice of renal transplantation continues to improve, with less toxic and more effective immunosuppression and more effective methods of preventing posttransplant infections, this unwillingness appears less justified. Elderly individuals naturally have a shorter life span, but to date, patients over 60 years old who receive transplants appear to enjoy approximately the same degree of improvement in life expectancy as do younger patients.

This benefit has been quantified by comparing the mortality rate of suitable candidates awaiting kidney transplantation with the mortality rate following transplantation. Life expectancy appears to be approximately doubled by kidney transplantation in all age ranges that have been studied to date. The improved life expectancy following kidney transplantation is particularly dramatic for diabetic patients. Today, patients tend to be judged on the basis of their physiologic functional status rather than on their chronological age. It is nevertheless true that elderly patients are more commonly found to be poor candidates for transplantation because of either coexisting disease or poor functional status.

Candidates must be free of active infections at the time of transplantation. Chronically infected tissues such as chronic pyelonephritis or chronic osteomyelitis should be definitively treated prior to consideration for transplantation. Patients with active viral or bacterial infection at the time, an organ is available for transplantation should usually be deferred until the infection has resolved. This is because it is unwise to initiate immunosuppression during an active infection, particularly given that the highest doses of immunosuppression are given around the time of the procedure.

Recipients with almost all types of primary renal disease have been successfully transplanted: glomerulonephritis, hypertensive nephropathy, chronic pyelonephritis, polycystic kidney disease, reflux pyelonephritis, Goodpasture syndrome, congenital renal hypoplasia, renal cortical necrosis, Fabry syndrome, and Alport syndrome. Successful transplants have been achieved in patients with certain systemic diseases in which the kidney is one of the end organs affected (cystinosis, systemic lupus erythematosus, and diabetic nephropathy). Renal transplantation is generally inadvisable in patients with oxalosis if high serum levels of oxalate are present because the disease recurs in the transplant quickly. However, liver transplantation corrects the enzymatic defect that leads to excessive oxalate accumulation. Therefore, combined liver-kidney transplantation may be an acceptable treatment option for these patients.

Patients who do not have normal bladder function may be acceptable kidney transplant candidates, but a plan for ureteral drainage should be made before transplantation occurs. Many patients with long-term defunctionalized bladders can still undergo ureteral reimplantation and then be treated with intermittent catheterization if necessary posttransplant. If the bladder is congenitally or surgically absent, a defunctionalized loop of small bowel can be created, brought out as a stoma, and used for a urinary conduit. Care must be taken in planning the positioning of the conduit so that the ureter from a transplanted kidney will reach it.

Transplant patients must be compliant with posttransplant care to achieve successful outcome. Patients with a history of poor compliance may be candidates for transplantation if they are regretful of past behavior and have established a compliant pattern. In some cases, especially in the adolescent age group, it is wise for the patient to experience dialysis prior to receiving a kidney transplant in order to foster a complete understanding of the differences in lifestyle that are afforded by a successful kidney transplant. It is also necessary that patients have a support network to help them manage following the transplant. They will need a way to reliably obtain immunosuppressive therapy as well as transportation to and from the transplant center that is continuously and reliably available. Fortunately, support services are often available to patients who lack social support, and it is rare to deny transplantation solely on the basis of inadequate social support.

In the early years of kidney transplantation, it was common to perform bilateral nephrectomy prior to transplantation, but this has recently become very uncommon. Most patients who have native nephrectomy have polycystic kidney disease with profound pain, recurrent infections, or recurrent hemorrhage. Other indications for native nephrectomy include recurrent infection, especially when associated with ureteral reflux, and occasionally profound hypertension attributable to an ischemic native kidney.

OPERATIVE TECHNIQUES

The surgical technique of renal transplantation involves anastomoses of the renal artery and vein and ureter (Figure 45–1). The transplant kidney is placed in the iliac fossa through an oblique lower abdominal incision. The dissection is carried out by retracting the peritoneum medially so the kidney will lie in an extraperitoneal position. The iliac arteries and veins are mobilized as indicated for the proposed specific anastomoses. An end-to-side anastomosis is performed between renal vein and iliac vein; an end-to-side anastomosis is then performed between the renal artery and the external iliac artery. An alternative technique is to connect the renal artery end-to-end to the internal iliac artery, but this technique is more difficult in most patients. When multiple arteries are present, there are several options. If the artery is very small (< 2 mm), it can often be ligated, especially if it is an upper pole branch. If the kidney is from a deceased donor, it is often possible to use a large Carrell patch of donor aorta that encompasses all of the arteries. Other options include reimplanting multiple renal arteries into the iliac artery using multiple anastomoses; reimplanting a smaller artery into the side of the dominant renal artery and then using the larger artery for anastomoses to the iliac; and spatulating the ends of the two arteries together to form a single lumen for anastomosis.

In small children and infants, the kidney transplant can be performed either through a midline abdominal incision or by making a very large flank-type incision extending from the pubic symphysis to the costal margin and exposing the aorta and vena cava by reflecting the peritoneal contents medially and superiorly. End-to-side anastomoses of the renal vessels may be made to the iliac vessels if they are large enough, but often it is necessary to use the infrarenal vena cava and aorta for the anastomotic site.

Kidneys from small pediatric deceased kidneys function poorly when transplanted into small pediatric recipients. However, many pediatric kidneys have often been transplanted en bloc with the donor aorta and vena cava anastomosed to the recipient’s iliac vessels along with double ureteral anastomoses. The exact age at which it is best to transplant kidneys as a single unit is unclear, but certainly kidneys from children as young as 6 will function well and last a long time when transplanted into adults.

Urinary tract continuity can be established by pyeloureterostomy, ureteroureterostomy, or ureteroneocystostomy. The most common technique is ureteroneocystostomy. This technique can be performed by bringing the ureter into the bladder through a submucosal tunnel and suturing the mucosa of the ureter to the mucosa of the bladder from the inside of the bladder through a large cystotomy (Politano-Leadbetter method). Other techniques include an external neocystostomy, which avoids the need for a large cystotomy and is more common, and the “one stitch” technique, whereby the mucosa of the ureter is not directly sutured to the bladder mucosa, but rather the ureter is fixed into place in the interior of the bladder with a suture that traverses the full thickness of the bladder wall. A ureteral stent may be placed with any of the techniques discussed above. A 6Fr pediatric ureteral stent with a J shape at each end fits nicely across the anastomosis and goes from the interior of the renal pelvis into the bladder or other urinary conduit. The stent should be removed in the first month or two following the transplant to prevent stone formation and bladder infection.

POSTOPERATIVE MANAGEMENT & COMPLICATIONS

Recipients who have received a kidney transplant usually produce urine immediately, and the serum creatinine falls over the next 3-7 days. The magnitude of urine output is related to how hydrated the patient was before transplantation and to how much fluid is administered during the procedure. It is important that the patient is fully hydrated at the time the kidney is revascularized in order to achieve the best chance of immediate transplant kidney function. Transplanted kidneys frequently will have an obligate diuresis for a period of hours to days after they begin to function. During this phase, it may be necessary to replace urinary output in order to prevent the development of hypovolemia as a result of excess urinary output. Once this phase has passed, intravenous fluid can be discontinued. However, patients are encouraged to maintain generous fluid intake to prevent dehydration in the future, as transplanted kidneys appear to have a greater susceptibility to hypovolemia than native kidneys. Patients are usually able to eat the morning following the transplant procedure and should be encouraged to get out of bed with assistance. The urinary catheter can be removed as early as 2 days following the procedure, depending on the technique used for ureteral anastomosis. Some programs prefer to leave the urinary catheter in place for a longer period of time to allow sufficient healing of the anastomosis. Most recipients are able to be discharged from the hospital on the second or third postoperative day if there are no complications in their postoperative course once they are able to maintain oral hydration, have learned how to properly take their medications, and have received training about what to do, what not to do, and what to watch out for in the next few weeks.

Kidney transplantation can be followed by a variety of postoperative complications that must be recognized and treated early for optimal results. The most frequent complications are infection and rejection, reflecting the natural tension between too much and too little immunosuppression. Urinary infection is one of the most common complications and usually responds to antibiotic therapy. Bacterial pneumonia is the most common pulmonary complication and may be very serious if not promptly diagnosed and treated. Current immunosuppression protocols that focus on the T lymphocyte are associated with unusual, opportunistic types of infections including herpesviruses, the parasite Pneumocystis carinii, and fungal infections. These infections are seen much less often than previously because it is standard to prescribe prophylactic anti-infective therapy aimed at preventing the common types of infection. In particular, the availability of agents that are effective against cytomegalovirus (CMV) infection has almost eliminated clinical CMV infections. At one time, CMV infections were a frequent, expensive, and exceedingly unpleasant occurrence after many transplants.

In approximately 20% of kidney transplants from deceased donors, the kidney will fail to function immediately. This complication is termed delayed graft function and is due to acute tubular necrosis of the kidney. In some cases, there is a modest urinary output, but the serum creatinine does not fall. In other cases, there is profound oliguria. Delayed graft function can also occur following living donor transplantation, but it is much less common (< 3%). Delayed graft function is associated with older donors and donors who had a rising creatinine at the time of donation. Long ischemic times are also known to increase the chance of delayed graft function. In most cases, the acute tubular necrosis will resolve and the renal function will recover. Most recovery happens within a week, but in some cases, the kidney will require several weeks before renal function is sufficient to support the patient without dialysis. Treatment is supportive with dialysis as necessary. If recovery takes more than a week, it may be wise to biopsy the kidney to rule out silent rejection.

Vascular complications of kidney transplants are uncommon, affecting 1%-2% of renal transplants. Either renal artery or venous thrombosis of the kidney is devastating and almost uniformly results in graft loss. The incidence of acute graft thrombosis is higher in patients with high levels of circulating anti-HLA antibodies, suggesting that some of these cases are related to accelerated acute rejection. The incidence of graft thrombosis is also higher in patients with factor V Leiden and other physiologic derangements that cause a hypercoagulable state. Patients should be screened for factor V Leiden if they have a history of unusual thrombotic events and receive anticoagulation perioperatively when it or other known hypercoagulable states are known. Renal artery stenosis, which may be associated with rejection involving the renal artery, is also a rare complication. It can present with severe hypertension. It may be treated surgically or in some cases by percutaneous transluminal balloon angioplasty.

Urologic complications occur in about 4% of patients, most often urinary extravasation from the cystotomy closure or ureteral obstruction. These complications can almost always be managed with percutaneous placement of a nephrostomy tube by an interventional radiologist and are not associated with a higher risk of graft loss.

A complication relatively unique to kidney transplantation is formation of a pelvic lymphocele in the transplant bed. Lymphatic fluid may come from either lymphatics in the hilum of the kidney or from lymphatics disrupted during exposure of the iliac vessels. Careful ligation of the adjacent lymphatics during preparation of the recipient blood vessels may decrease the incidence of this complication. Large lymphoceles may obstruct the ureter or the vasculature of the transplanted kidney, and they occasionally become infected. Sterile lymphoceles may be drained into the peritoneal cavity, while infected lymphoceles need to be drained externally.

Gastrointestinal complications may affect all levels of the intestine, but upper gastrointestinal symptoms, including nausea and abdominal pain, are most common. In many cases, the culprit is the large number of medications that the patient must take. Peptic ulceration was once a major problem for transplant recipients, but this complication has virtually disappeared because of routine use of medications like H₂-blockers and proton pump inhibitors to inhibit the production of gastric acid.

GRAFT REJECTION

Despite advances in immunosuppressive management, rejection is still a major hazard for the postoperative allograft recipient. Most episodes of rejection occur within the first 3 months. There are three basic kinds of rejection:

1. Hyperacute rejection is due to preformed cytotoxic antibodies against donor antigens. Pretransplant crossmatch testing is designed to prevent this type of rejection. This reaction begins soon after completion of the anastomosis, and complete graft destruction occurs in 24-48 hours. Initially, the graft is pink and firm, but it then becomes blue and soft, with evidence of diminished blood flow. There is often no effective method of treating hyperacute rejection, but treatment with plasmapheresis and immunoglobulin infusion may be effective if the diagnosis is made immediately.

2. Acute rejection is the most common type of rejection episode during the first 3 months after transplantation. It is primarily an immune cellular reaction against foreign antigens. The reaction may be predominantly cellular, or there may be a component of antibody-mediated inflammation. Typically, the patient is asymptomatic and the diagnosis of rejection is suspected on the basis of serial measurement of serum creatinine levels. In severe cases, symptoms may include oliguria, weight gain, and worsened hypertension. Fever and tenderness and enlargement of the graft are uncommon with modern immunosuppressive protocols but used to be seen when only azathioprine and corticosteroids were available. This type of rejection process is usually treated with pulse steroid therapy. If this is unsuccessful, or in very severe cases of acute rejection, either a polyclonal or monoclonal depleting antilymphocyte preparation is used. The vast majority of acute rejection episodes are successfully reversed. Currently, grafts are only lost to rejection when patients are noncompliant or when rejection occurs together with a life-threatening infection, since it is unsafe to enhance the degree of immunosuppression in this setting.

3. Chronic rejection is a late cause of renal deterioration. It is unclear precisely what causes chronic rejection, but the absence of cellular elements on biopsy and the association of antidonor antibodies with chronic graft loss have led to the assumption that it is mediated by humoral factors. It is most often diagnosed on the basis of slowly decreasing renal function in association with proteinuria and hypertension. Chronic rejection is resistant to all known methods of therapy and graft loss will eventually occur, though perhaps not for several years after renal function begins to deteriorate. It is unclear what the relationship is between this pathologic process and the damage produced by chronic calcineurin inhibitor use, which is seen in nonrenal transplant recipients as well. It has recently been uncovered that chronic graft loss is accelerated in patients who experienced rejection in the first year after a transplant, in patients who had delayed graft function, and in patients who received kidneys from marginal donors.

Differential Diagnosis of Renal Allograft Dysfunction

An unexpected elevation in serum creatinine above baseline levels in a renal transplant recipient has a broad differential diagnosis list. Dehydration should be ruled out by history and physical examination. The medication the patient is taking should be reviewed, paying attention to over-the-counter medications, especially nonsteroidal anti-inflammatory drugs and herbal remedies. These drugs can cause renal dysfunction or can alter the metabolism of immunosuppressant medications and result in blood levels that are either too high or too low. Urinary infection should be ruled out with a urinalysis. If these simple evaluations do not disclose the cause of renal dysfunction, the next step is usually a renal ultrasound to rule out ureteral obstruction, followed by a renal allograft biopsy. This last step is crucial to arriving at the correct diagnosis. A biopsy may disclose acute rejection, or it may show calcineurin inhibitor toxicity. Since the treatment for these conditions is opposite, a biopsy is very important to guide appropriate therapy.

The first successful human heart allograft was performed in 1967 by Christiaan Barnard. At that time, however, the only available immunosuppressive therapy was azathioprine and steroids. This regimen was inadequate to safely prevent rejection in these patients. As a result, the procedure remained experimental and was limited to a small number of institutions worldwide. The introduction of cyclosporine in 1981 resulted in dramatically improved survival. As a result, heart transplantation was federally designated as no longer experimental in 1985. In 2003, there were about 2000 heart transplants performed in the United States at more than 100 centers. The 1-year survival rate is now over 85%, and the 3-year survival rate is over 75%.

SELECTION OF DONORS

At one time, deceased donors were considered suitable for cardiac donation only if they were men aged 40 years or younger or women 45 or younger. The large waiting list and the increasing number of patients who die on the waiting list has led surgeons to accept hearts from donors as old as 60, and more than one-third of current donors are older than 40. Cardiac donors must be ABO-compatible with the recipient and should be within 20% of the recipient’s ideal body weight. Ideally, there should be no history of preexistent or intercurrent cardiac disease. It is routine to obtain echocardiography to determine cardiac function, even in young donors. At many programs, it is routine to obtain cardiac catheterization in older donors to rule out silent coronary artery disease. Ideally, there should be no history of cardiac arrest, but if cardiac function is good, this factor alone does not usually rule out a cardiac donor. The donor should be receiving only moderate doses of pressor drugs.

At the donor operation, the chest is opened and the heart is inspected for evidence of contusion and observed to determine its overall function. If the heart is suitable, this information is relayed to the recipient operating team so that the timing of the recipient operation can be carefully coordinated. The heart is removed following cross-clamping of the aorta and infusion of cold cardioplegia, which results in cessation of electrical and mechanical cardiac activity. The heart is typically removed first, prior to the excision of kidney, liver, or pancreas. It is flushed with a preservative solution and stored aseptically at 4°C. Optimal function is obtained when the heart is implanted within 4 hours of procurement. For recipients who have previously had cardiac procedures through a sternotomy, it is sometimes necessary to delay the procurement of the donor heart to make sure that the recipient will be ready to receive the heart when it arrives back at the transplant hospital. The same is true when recipients have left ventricular assist devices implanted and extra time is necessary to prepare the recipient to receive the donor heart.

SELECTION OF RECIPIENTS

Patients for cardiac transplantation should have end-stage cardiac disease for which there is no other surgical option and should have received maximal medical treatment. Most heart transplant candidates have idiopathic dilated cardiomyopathy or ischemic cardiomyopathy. Most patients are younger than 55 years of age, but successful transplantation has been reported on more elderly patients. Patients should not have systemic disease that will be worsened by the immunosuppressive regimen (infection, type 1 diabetes, severe peripheral vascular disease, poorly controlled hypertension), nor should they have underlying renal insufficiency that cannot be attributed to low cardiac output.

Patients should have pulmonary vascular resistance of less than 5 Wood units, since levels above this or a pulmonary artery systolic pressure of greater than 50 mm Hg or a transpulmonary gradient (mean pulmonary artery pressure–pulmonary capillary wedge pressure) of greater than 15 mm Hg are associated with inadequate donor heart function. As with other organs, a history of compliance with a complex medical regimen and a strong social support system are necessary for long-term success.

If the recipient has circulating antibodies directed against HLA antigens, it is necessary to perform a crossmatch between the recipient’s serum and the donor lymphocytes to make sure that hyperacute rejection of the cardiac graft does not occur. Patients who have left ventricular assist devices in place may be particularly difficult to obtain hearts for because of the sensitizing effect that the device has on the immune system.

OPERATIVE TECHNIQUE

The operative technique originally developed by Lower and Shumway continues to be used and is shown in Figure 45–2. A median sternotomy is performed and the patient is placed on cardiopulmonary bypass. The recipient heart is removed, and the atrial cuffs trimmed. The left atrial anastomosis is performed first and then the right, each with one continuous suture. Before the left atrium is closed, it is filled with saline to avoid air embolism. The aortic and then pulmonary artery anastomoses are then performed. Topical cooling may be continued, and the addition of blood cardioplegia after the atrial anastomoses may be done in order to improve graft function. The implant time is generally 45-60 minutes. It is frequently necessary to provide chronotropic support for the denervated heart in the form of atrial pacing or isoproterenol.

IMMUNOSUPPRESSION

Triple immunosuppression with a calcineurin inhibitor, antimetabolite, and corticosteroids is typical of the standard immunosuppressive protocol at most heart transplant programs. Perioperative induction immunosuppressive therapy with either polyclonal or monoclonal antibody therapy directed at lymphocytes is sometimes used in order to avoid the renal toxicity associated with early high-dose calcineurin inhibition and to reduce the risk of later rejection. Rejection is diagnosed on endomyocardial biopsy, which is performed regularly, since rejection may occur in the absence of clinical symptoms. Rejection is treated with 3 days of pulse steroids and resistant rejection with antilymphocyte therapy.

FOLLOW-UP CARE

Transplant recipients must be carefully monitored for infection and rejection. Protocols for endomyocardial biopsies vary by center but are typically performed every other month for the first year, then every 3 months. The incidence of rejection episodes is 0.5-1.5 per patient for the first year. The major infection rate is 1.5 episodes per patient for the first year and then declines. Accelerated coronary atherosclerosis, believed to be a manifestation of chronic graft rejection, occurs in 30%-40% of patients within 5 years after transplantation. There is no effective therapy for this condition except for retransplantation in highly selected, usually younger, patients. Progressive renal dysfunction may occur over time due to the cumulative effect of calcineurin inhibitor therapy.

Combined heart-lung transplantation was first performed in 1981. Initially, it was felt that rejection of both organs would be evident in the myocardial biopsy. However, experience has shown that rejection is dissimilar in the two organs, with heart rejection occurring infrequently and lung rejection, evidenced by obliterative bronchiolitis and arteritis, being a more severe problem. Heart-lung transplantation is currently performed with gradually decreasing frequently. In 1994, there were 71 heart-lung transplants in the United States. This number had declined to 28 in 2003. The main indication for heart-lung transplantation is end-stage disease in both organs or end-stage disease in one with poor function in the other prohibiting single-organ transplantation. Examples are primary pulmonary hypertension, congenital heart disease with Eisenmenger physiology, fibrotic lung disease and cor pulmonale, and cystic fibrosis.

The operation consists of en bloc heart-lung transplantation with anastomosis of the trachea, right atrium, and aorta of the donor.

Immunosuppression parallels that of heart transplantation with the exception that steroids are avoided initially in order to promote tracheal wound healing. Heart-lung transplantation currently results in a 70% 1-year survival rate.

Single-lung transplantation became clinically successful through a systematic approach by the Toronto Lung Transplant Group to the problem of bronchial disruption, which had made previous attempts unsuccessful. The addition of an omental wrap to the bronchial anastomosis and the avoidance of steroids during the first 3 weeks allowed bronchial healing and clinical success. Lung transplantation is currently performed for a myriad of indications, including emphysema, cystic fibrosis, idiopathic pulmonary fibrosis, α₁-antitrypsin deficiency, primary pulmonary hypertension, and congenital diseases. Candidates for lung transplantation have irreversible end-stage disease for which there is no other therapy, are oxygen dependent, and are likely to die of their disease within 12-18 months. Lung donors are scarce, but the use of one lung for transplantation does not preclude using the heart for another recipient. Long-distance procurement of lungs has been possible since institution of a regimen consisting of pulmonary artery flush with cold preservative solution following alprostadil (PGE₁) via the central venous line to promote pulmonary vasodilatation.

Patients with bilateral pulmonary sepsis, such as cystic fibrosis or bronchiectasis, or patients with emphysema and normal heart function may sometimes be eligible for double-lung transplantation. The advantage is that the patient does not have the potential complications of heart transplant and rejection. Another innovative approach to the lung transplant patient with a normal heart is the operation whereby a heart-lung block is placed in a patient with end-stage lung disease and a normal heart, and the recipient’s heart is extracted and donated to a patient in need of an isolated heart transplantation.

Immunosuppressive management of lung transplant recipients is very similar to that of heart recipients in that the cornerstone of therapy is a calcineurin inhibitor. The major difference is that steroids are omitted for several weeks in order to promote healing of the bronchial anastomosis. Postoperative management focuses on prevention of sepsis and detection and treatment of rejection. Bronchoscopy is performed liberally and transbronchial lung biopsy is used to diagnose lung transplant rejection. Acute rejection may be effectively treated with corticosteroid pulse therapy, or by enhancing the existing immunosuppressive regimen. The major long-term complication in lung transplant recipients is the development of bronchiolitis obliterans syndrome (BOS). BOS is felt to be the lung manifestation of chronic rejection. Episodes of acute rejection are risk factors for the development of BOS in the future. There is currently no effective therapy for BOS. A promising development that is currently experimental is aerosolized delivery of immunosuppression. It is hoped that directing immunosuppression preferentially to the lung itself may allow enhanced protection from rejection without increasing the risk of infection.

After many years of experimental effort, Dr Thomas Starzl performed the first successful human liver transplantation in 1967. Over the next decade and a half, the procedure was done only in low volumes, and outcomes were generally poor. As with other organs, the introduction of cyclosporine in the 1980s resulted in marked improvement in survival rates. Today, more than 5000 liver transplants are performed annually in the United States, and 1-year patient survival rates are more than 85%.

Since the introduction of clinical liver transplantation, the list of indications has rapidly expanded and the list of contraindications has diminished. The most common indication for liver transplantation is currently cirrhosis due to chronic hepatitis C infection. Other diseases for which liver transplant is indicated include cirrhosis due to hepatitis B, alcoholic cirrhosis, primary biliary cirrhosis, sclerosing cholangitis, autoimmune hepatitis, and cirrhosis secondary to nonalcoholic fatty liver disease. Less common indications are Wilson disease, α₁-antitrypsin deficiency, Budd-Chiari syndrome, and hemochromatosis. In children, the most common indication is biliary atresia. Other common diagnoses include α₁-antitrypsin deficiency, tyrosinemia, and other inborn errors of metabolism.

Alcoholic cirrhosis was once a subject of considerable controversy because of the self-induced nature of the disease. The world community rejected the notion that lifesaving therapy should be withheld from patients who could benefit from it merely because their disease is self-induced. It was pointed out that many, if not most, diseases are to some degree self-induced, whether it is diabetes and high blood pressure due to obesity or cancer and heart disease due to smoking. It is now recognized that alcoholic cirrhosis is an accepted indication for liver transplant if the patient has demonstrated the ability to abstain from alcohol and is clearly committed to continued abstinence. Overall results in alcoholic recipients have shown that patients transplanted for alcoholic cirrhosis fare at least as well as patients transplanted for most other diagnoses.

Chronic active hepatitis B was formerly considered to be a controversial indication for liver transplantation because recurrence was quite frequent and tended to result in rapid graft failure. This changed when effective strategies to prevent recurrence of hepatitis B using high-dose hepatitis B hyperimmune globulin infusions posttransplant were reported. Now hepatitis B is considered to be a standard indication, and results are equal to those obtained for other diagnoses. In contrast, the outcome for patients transplanted for hepatitis C was once considered to be equal to that of other diagnoses. Recent data, however, suggest that recurrence of hepatitis C in the new liver graft is virtually universal following transplantation, and 25% of patients will have developed cirrhosis in the graft within 5 years. It is not surprising that longer-term data are now appearing showing that the 10-year survival for patients transplanted for hepatitis C is significantly worse than for other diagnoses.

As with transplantation for hepatitis B and C, the consensus opinion has gone back and forth in recent years regarding whether liver transplantation should be used for the treatment of hepatocellular carcinoma in adults. Patients with cirrhosis are at risk for development of primary hepatocellular cancer. Since these patients usually die of liver failure, unlike patients with other forms of malignancy who usually succumb to widespread metastatic disease, it was reasoned that transplantation would be a curative therapy. Unfortunately, the initial results with transplantation for hepatoma were disappointing due to a high rate of tumor recurrence. These poor results prompted many programs to stop doing transplants for hepatoma. The group from Barcelona, Spain, then reported that survival rates are good if the tumor is small (< 5 cm in diameter) but poor if the tumor is large or shows evidence of large vessel invasion. Numerous reports have confirmed this finding, and currently liver transplantation is considered to be a standard treatment for patients with small hepatomas. Results for liver transplantation for other malignancies remain poor, with the exception of several encouraging reports of reasonable survival rates for highly selected patients with cholangiocarcinoma who receive adjuvant radiation and chemotherapy.

Current contraindications are few and are primarily related to evidence of cardiopulmonary disease that prohibits safe liver transplantation. Examples are significant, uncorrected coronary artery disease; pulmonary hypertension with pulmonary artery systolic pressures greater than 70 mm Hg; and FEV₁ of less than 1 L on pulmonary function testing. Active substance abuse is also an absolute contraindication to transplantation. Diabetes increases the risks associated with transplantation and the incidence of posttransplant complications, but it is not an absolute contraindication to liver transplantation. Even infection with HIV, long considered a contraindication to transplantation, is no longer an absolute contraindication at some centers that are reporting good results in small numbers of carefully selected HIV-positive patients. Portal vein thrombosis, which at one time was a contraindication to transplant, is now managed by performing thrombectomy on the portal vein, by using vein grafts to bypass thrombosed vessels, or by using the infrahepatic cava for portal inflow.

Donor Selection

The number of patients listed for liver transplantation increases each year. This has led to a gradual increase in the number of patients who die while waiting and consequently to a relaxation of past standards for liver graft suitability. Livers are currently being transplanted from donors more than 80 years old with acceptable outcomes. It is important that the liver is a rough size match for the donor, but there is much leeway in this regard. Blood-type compatibility is preferred but not an absolute requirement. Matching of tissue antigens does not appear to be relevant for liver transplantation, and a positive crossmatch is not a contraindication to proceeding with transplantation because it is not associated with a worse outcome posttransplant.

The technique of preserving the liver grafts after removal from the donor is based on decreasing metabolic requirements by keeping the graft cold. Blood is flushed from the organ to prevent vascular occlusion; preservation solution is infused; and the organ is kept on ice at 4°C. Multiple preservative solutions are in common use worldwide. Most contain inert high-molecular-weight molecules that do not diffuse into the cell to prevent cellular swelling. Also, free oxygen radical scavengers, which are thought to prevent injury upon reperfusion of the graft, are frequently included. The introduction of Viaspan solution in the late 1980s revolutionized liver transplantation by extending the period of safe in vitro liver preservation from 10 hours to more than 24 hours. Despite this advance, it is clear that prolonged cold ischemia is bad for the liver graft, particularly if the graft contains a large amount of intracellular fat or is from an older donor. Transplant programs therefore continue to strive to minimize the cold ischemic time to whatever degree is feasible.

Operative Technique

In general, liver transplantation is an orthotopic procedure: The host liver is removed and the donor organ placed in an orthotopic position. The operation is performed in three phases: the dissection phase, during which the attachments of the diseased liver are dissected and the vascular structures are prepared for resection; the anhepatic phase, which extends from the time the host liver is removed until the time the donor liver is revascularized; and the reperfusion phase, during which blood is circulating through the new organ and the biliary tree is reconstructed.

Several techniques are available for handling the retrohepatic vena cava. Historically, the liver was removed en bloc with the vena cava and hemodynamic instability was avoided by using venovenous bypass to overcome decreased venous return when vena caval and portal vein flow was interrupted. The new liver was then sutured into place using a bicaval technique with end-to-end caval anastomoses being performed from donor to recipient both above and below the new liver. With careful anesthetic technique and preloading with fluid, venovenous bypass may be avoided in many cases. An alternative method of handling the retrohepatic cava is to dissect the liver off the cava and sequentially ligate the hepatic venous branches that enter the cava directly from the right and caudate lobes. This allows the liver to be removed by clamping the main hepatic veins without occluding the vena cava. The new liver is then sutured into place by connecting the suprahepatic cava of the donor to a common orifice created by connecting the right, middle, and left hepatic veins. This technique is called the piggyback technique because the donor cava sits directly on top of the recipient cava. The infrahepatic cava of the donor is occluded with either sutures or a vascular stapler. This method may preclude the need for venovenous bypass because caval flow is usually not completely interrupted. A third option for caval reconstruction is to connect the donor cava to the recipient cava using a side-to-side technique by making longitudinal incisions from the hepatic veins caudally, creating a very wide anastomosis. This technique is difficult when the donor liver is large relative to the size of the recipient’s hepatic fossa.

The current methods of biliary reconstruction include primary choledochocholedochostomy (when the recipient duct is intact) or Roux-en-Y choledochojejunostomy if the recipient bile duct is not intact or if anatomically the donor and recipient duct cannot be approximated without creating tension on the anastomosis. It was once standard to place a T tube or another type of biliary stent across the biliary anastomosis, but many programs have now discontinued this practice because it is not clear that the presence of a stent influences the rate of biliary complications.

Although the liver can function normally with only portal venous flow, the bile duct is dependent on hepatic arterial flow. For this reason, the hepatic arterial anastomosis is crucial to postoperative graft survival. The arterial supply of the liver is quite variable, with nearly half of the patients having some form of aberrant circulation. The most common aberrancies are replacement of the right hepatic artery to the superior mesenteric artery and the presence of an accessory left hepatic artery that derives from the left gastric artery. When aberrant arterial vessels are identified on a deceased donor, it is important that they are carefully preserved so that reconstruction can occur when the liver has been perfused and cooled and is sitting in sterile ice slush. Multiple methods of reconstruction of aberrant vessels are available and, if necessary, a conduit of donor iliac artery may be used in the reconstruction.

Living Donor Liver Transplantation & Split Liver Transplantation

The shortage of organs for small children in the late 1980s prompted the development of techniques to reduce the size of an adult liver graft by performing an anatomic resection of one or more lobes and transplanting the reduced graft. In this way, it was possible to transplant the left lobe or the left lateral segment from an adult liver into a child. This technique was successful and rapidly became a standard method of obtaining grafts for small children. The natural evolution of this technique was to apply the method used to reduce the size of a deceased donor liver graft to adult living donors. Broelsch at the University of Chicago popularized the transplantation of the left lateral segment from an adult into a child and showed that this technique could be at least as effective as using full-sized grafts from small children. It was hoped that living-related liver transplantation would offer an immunologic advantage as it does with kidney transplantation, but this did not turn out to be the case. The major advantage of living donor liver transplantation appears to be the ability to allow transplant to occur prior to the deterioration of the recipient’s condition into a poor state of health that is associated with a higher risk for transplantation.

The success of living donor liver transplantation from adult donors into children, together with the shortage of suitable adult donors, led to the development by Marcos and Tanaka of techniques to utilize the right lobe from a living donor to transplant into another adult. The donor operation is a major undertaking and is associated with appreciable morbidity as well as a mortality rate of approximately 0.5%. Nevertheless, living donor liver transplants have become a standard option when timely deceased donor liver transplantation is not possible.

By applying the living donor technique to deceased donors, two transplants can be obtained from a single adult liver from a deceased donor. This has been termed a split liver transplant. Typically, the lateral segment of the left lobe is used for a child or very small adult, while the remainder of the liver consisting of the right lobe plus the medial segment of the left lobe is used for an adult. Less commonly, the liver from an adult deceased donor can also be split into a right lobe graft and a left lobe graft and used for two adults. In fact, improvements in operative technique in the last decade have allowed for an increased use of living donor left lobe grafts in adults with improvements in outcomes.

Immunosuppressive Therapy

The mainstay of immunosuppression for liver transplant recipients is a calcineurin inhibitor. An antimetabolite or corticosteroids, or both, may also be included but are not absolutely necessary. Induction therapy with antilymphocyte preparations was once considered standard but has now been abandoned by many liver transplant programs because it appears unnecessary.

Despite being one of the largest organs transplanted in terms of mass, the liver seems to require less immunosuppression for maintenance therapy compared to other organs. Corticosteroids can frequently be safely discontinued. Typically, monotherapy with a low dose of a calcineurin inhibitor is all that is required to suppress rejection long term. Spontaneous tolerance with normal graft function despite complete discontinuation of all immunosuppressants occurs in approximately 10%-20% of liver transplant recipients. The liver is unique in this regard, since rejection is almost universal if immunosuppression is discontinued in recipients of renal, cardiac, pulmonary, and pancreatic grafts.

Complications

Complications following liver transplantation are common, but most can be treated effectively. Coagulopathy is routinely present during liver transplant procedures, particularly during the anhepatic phase. For this reason, bleeding is common following the procedure, and 5%-10% of liver transplant recipients will require reoperation because of continued bleeding following the procedure.

One of the most devastating complications is primary nonfunction of the liver. Primary nonfunction is a condition in which the new liver does not function and death results unless a second transplant is performed. Patients with primary nonfunction typically have profoundly elevated serum transaminases together with severe coagulopathy and acidosis. The incidence of this complication is between 5% and 10%. The cause of primary nonfunction is poorly understood, but multiple donor factors are known to be associated. Long cold ischemic times, poor perfusion of the graft with preservative solution, severe hepatic steatosis, and elevation of the donor serum sodium level above 165 mEq/L are all known risk factors for primary nonfunction.

Vascular complications occur in 5%-10% of transplant recipients. The hepatic artery is particularly prone to thrombosis, especially in children. If this is detected early, it is frequently possible to perform thrombectomy and restore hepatic arterial flow. If flow cannot be reestablished, necrosis of the intrahepatic and extrahepatic biliary tree usually occurs, resulting in death from sepsis if retransplantation is not performed.

The bile duct has been called the Achilles heel of the liver transplant because it is so prone to anastomotic leakage or stricture. Fortunately, while as many as 20% of liver transplant recipients will experience a bile duct complication, it is uncommon for this complication to be lethal. Leaks tend to occur early and can often be managed by placing a biliary stent using endoscopic retrograde cholangiopancreatography (ERCP). If a large collection of bile develops because of a bile leak, it is usually necessary to drain the area either operatively or by placing a percutaneous suction drain. Biliary stenosis can occur early or late. Unlike the native liver, the transplanted liver will not always develop intrahepatic biliary dilatation when the bile duct is obstructed. It is therefore necessary to have a high index of suspicion. Patients with elevated bilirubin or elevated serum alkaline phosphatase levels (or both) should be evaluated with either ERCP or magnetic resonance cholangiography. Strictures can often be managed noninvasively with biliary stents and balloon cholangioplasty, but in some cases, operative correction is required. Patients who develop multiple intrahepatic strictures usually require retransplantation.

Rejection is a frequent complication of liver transplantation—it occurs in about 20%-50% of patients. Rejection should be suspected whenever serum transaminases or bilirubin levels, or both, worsen or fail to gradually normalize following a liver transplant. The diagnosis of rejection is made histologically by the finding of a mixed portal cellular infiltrate together with injury to bile duct epithelium and inflammation of the central vein endothelium (endotheliitis). When the condition is diagnosed early and treated aggressively, rejection rarely culminates in a need for retransplantation. Because the principal rejection target is the bile duct epithelium, severe, unrelenting rejection is often manifested by destruction and disappearance of bile ducts (vanishing bile duct syndrome). The treatment for rejection depends on its severity. Mild rejection is treated either with corticosteroid pulse therapy or by increasing the dosage of maintenance immunosuppressive therapy. Rejection that does not respond to these measures may require treatment with an antilymphocyte preparation.

CMV is a member of the herpes family of viruses. Prior to the availability of prophylaxis against this virus, as many as half of liver transplant recipients developed clinical CMV infection. Symptoms of this infection typically include fever, leukopenia, and malaise, but a more serious clinical syndrome with pneumonitis or hepatitis is possible. Patients at greatest risk for severe CMV disease are those without previous CMV exposure who receive a liver from a CMV-positive donor, but reactivation of CMV infection is possible in any patient with prior exposure to the virus. In order to prevent CMV infection, most liver transplant programs prescribe either ganciclovir or valganciclovir for a period of months following liver transplantation to all patients at risk for CMV infection.

EBV is another common viral pathogen in these patients. Although the systemic illness with Epstein-Barr virus infection is usually mild, it may be associated with development of a lymphoproliferative disorder known as posttransplant lymphoma. This disorder can progress to frank malignancy, and the mortality rate is high. In many cases, the lymphoproliferation resolves merely be reducing immunosuppression. If the lymphoproliferative tissue expresses CD20, treatment with the monoclonal antibody rituximab may be helpful. Patients with lymphoproliferation that does not respond to these measures may require chemotherapy.

Immunosuppression predisposes to fungal infections, especially esophageal Candida albicans (“thrush”). The incidence of this infection is reduced by the use of prophylactic nystatin to decrease gastrointestinal fungal colonization.

Although pancreatic transplantation involves transplantation of a nonessential organ as compared with the liver, heart, or kidney, it has enormous potential in the management of patients with insulin-dependent diabetes. In many patients with type 1 diabetes—even though insulin and diet are carefully controlled—the complications of the disease progress relentlessly. Many patients develop severe retinopathy at an early age, leading to blindness and renal disease as well as severe neuropathy and peripheral vascular disease that ultimately results in limb loss. The goal of pancreas transplantation is primarily to prevent or delay end-organ damage by the complications of diabetes. Another important indication for pancreas transplantation is hypoglycemic unawareness. Diabetic nephropathy can cause loss of the autonomic nervous pathways that allow patients to sense hypoglycemia. These patients can lapse into a coma at any moment. For patients with severe hypoglycemic unawareness, pancreas transplantation can truly be a lifesaving procedure.

Currently, most pancreas transplants are whole-organ grafts from deceased donors. The pancreas is procured along with a cuff of the first, second, and third portion of the duodenum attached. The graft can be placed into the pelvis with the iliac artery supplying arterial supply to the pancreas and the iliac vein used for portal venous drainage of the graft. Alternatively, the graft can be placed in the mid-abdomen and connected to the infrarenal aorta and the superior mesenteric vein. This allows insulin secreted by the pancreas to enter the portal circulation rather than the systemic circulation, which is more physiologic. The pancreatic exocrine secretions may be managed by anastomosing the duodenum to the bladder or to a loop of small bowel.

If the pancreas graft is successful, the patient will quickly become normoglycemic. As long as the graft functions normally, the patient will no longer require exogenous insulin because the pancreas graft responds normally by secreting insulin in response to rising blood glucose levels that occur following eating and ceasing insulin secretion when blood glucose levels fall to normal.

Much research has dealt with the transplantation of isolated pancreatic islet cells, which make up only about 2% of the pancreatic mass. This procedure is intuitively very attractive because it does not require an abdominal incision or general anesthesia. A team from Edmonton has reported successful transplantation of islets into the liver using a transhepatic injection into the portal vein. The patients in the original report all achieved insulin independence, although this often required more than one infusion of islets from more than one deceased donor pancreas. Immunosuppression consisted of rapamycin, tacrolimus, and induction treatment basiliximab, an inhibitor of IL-2R. The success at Edmonton has led to increased enthusiasm worldwide for islet transplantation, but to date, no other center has achieved the same degree of success. The critical factor appears to be the isolation procedure of the islets themselves. Nevertheless, it seems likely that in the long run, islet transplantation will eventually replace whole-organ pancreas transplantation.