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.
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.
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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.
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).
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.
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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.
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.
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.
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.
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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.
Technique of renal transplantation.
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.
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:
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.
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.
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.