Transplantation Medicine: A Rehabilitation Perspective

Ross D. Zafonte

Michael Munin

INTRODUCTION

History

The modern field of transplantation traces its origins to a successful renal auto-transplant in a dog performed in 1902. The development of vascular anastomosis, which underlies organ transplantation, was developed by Carrel (1,2) who is known as the father of transplantation although he did not pursue this as a career. For this development, he was awarded the Nobel Prize in Physiology. The recognition that allograft rejection is an immunologic process was discovered by Medawar (3). This classic series of studies foreshadowed the future by including descriptions of tolerance, a goal of transplantation (3, 4, 5). Progress in the field was fostered by the development of an understanding of the major histocompatibility complex (MHC), which in humans is referred to as the HLA, and the recognition that the HLA is the immunological target of rejection (6). Developments in the understanding of cellular immunity and pharmacologic manipulation has allowed for the growth of the clinical field of transplantation medicine. Transplantation medicine is essentially only 30 years old, with the first successful trial in kidney transplantation in the 1970s and liver transplantation in 1980 by Starzl (7,8). These developments where supported by the development of immunosuppression agents such as cyclosporine and tacrolimus (FK-506) (7,9). In fact, small bowel transplantation has only been recently approved by the FDA as an acceptable treatment for short-gut syndrome. Nonetheless, the field has advanced to such an extent that transplant surgery is almost considered routine.

The Transplantation Process

The reception of a transplant allograft in many ways represents a complete medical renaissance of an individual. The transplant patient is likely an extremely deconditioned, malnourished, cachectic individual with one, if not more, end-stage organ disease, whether it is cirrhosis, lung disease, and/or cardiac disease. Having withstood the often long and unavoidably bloody operation with its attendant risks (i.e., prolonged anesthesia, prolonged paralysis, single positioning), these patients are further deconditioned and commit themselves to a lifetime of immunosuppression with their associated side effects, for example, infection, rejection, steroid-related problems. Such persons often have associated musculoskeletal and neuromotor impairments making rehabilitation an important part of their care.

Despite these seemingly insurmountable obstacles, the transplant patient is often able to return to be a highly functional, productive member of society. Transplant patients are running marathons, having babies, and returning to work as a state governor.

ISSUES RELATED TO TRANSPLANTATION

Of importance to the rehabilitation specialist is a series of medical issues that impact the outcome in persons with transplant.

Immunosuppression

Immunosuppression is a double-edged sword. While rescuing the transplant patient from the wave of rejection, these medications, in addition to exposing the patient to infection, have significant direct toxicities (Table 46-1). Most transplant centers that choose to treat long-term transplant survivors rely on the three-drug cocktail: cyclosporine, azathioprine, and prednisone. At many centers cyclosporine has been replaced with tacrolimus, and the use of prednisone has declined in most patients (1,2). Of interest, many patients at such centers require only monotherapy with tacrolimus and theories regarding the taper of immunosuppressive medications are being espoused (10). Other medications, including rapamycin (11) and mycophenolate mofetyl, are also utilized and may be seen in transplant patients undergoing rehabilitation. Whatever the “primary cocktail” combination, the crucial component to immunosuppression resides in the calcineurin inhibitors, cyclosporine, and tacrolimus. Cyclosporine and tacrolimus work by inhibiting calcineurin, a phosphatase that acts on nuclear regulatory factor, the end effect of which is the inhibition of interleukin-2 (IL-2), a cytokine critical in T-cell activation and thus rejection (11).

Cyclosporine

Cyclosporine, in combination with prednisone and azathioprine, in the early 1980s allowed for the high rate of graft acceptance seen today, and thus it is the mainstay of
immunosuppression in many transplant centers. Cyclosporine is a unique agent that upon introduction nearly doubled the 1-year graft survival among those receiving kidney transplants (12). Working via the inhibition of calcineurin, cyclosporine acts to freeze antigen-activated lymphocytes at an early phase and potentially allows for a deescalation of the cycle of response (11,12). Both the drug and its metabolites are eliminated via the liver as a primary step and the kidney as a secondary clearance step (13).

TABLE 46.1 Immunosuppressive Agents

Immunosuppressive	Mechanism	Role	Side Effects
Cyclosporine	Inhibits IL-2	Primary	Neurotoxicity Nephrotoxicity Electrolyte imbalance
Tacrolimus	Inhibits IL-2	Primary	Neurotoxicity Nephrotoxicity Electrolyte imbalance
Sirolimus	Inhibits IL-2	Primary/adjunct	Neutropenia Hyperlipidemia Concerns regarding bronchial anastomosis
Steroids	Cytokine inhibitor	Adjunct	Muscle wasting Poor wound healing Osteoporosis
Azathioprine	Purine synthesis inhibitor	Adjunct	Pancytopenia GI distress
Mycophenolic acid	Purine synthesis inhibitor	Adjunct	Pancytopenia Diarrhea

Concerns

Several medications interact with cyclosporine, especially those that act at the cytochrome P450 system. Anticonvulsant therapy leads to decreased levels, while several antibiotics and ketoconazole markedly increase levels of cyclosporine. Of importance is the fact that St. John’s Wort interacts with cyclosporine to cause a decrease in cyclosporine blood levels. In several cases this has lead to transplant rejection.

The main toxicity of cyclosporine is nephrotoxicity, occurring in approximately 18% of patients (14,15). Cyclosporine appears to inhibit renal function via multiple mechanisms, including vasoconstriction via endothelins and thromboxane stimulation, direct toxicity of vascular endothelium causing acute microvascular disease and inducing a chronic interstitial fibrosis (15,16). The two former mechanisms may be reversible, with reduction or cessation of cyclosporine, whereas the latter may progress to renal failure or, fortunately in many cases, stabilize. Loss of renal function remains significant with 9.5% requiring dialysis at 13 years post liver transplant (15,16). There is great variation in patient susceptibility to cyclosporine-based nephrotoxicity, although those with underlying renal impairment appear predisposed to renal failure from cyclosporine. Urine output and creatinine remains the first line of nephrotoxicity detection. Elevation of creatinine should prompt a nephrology or transplantation consultation with a plan to lower cyclosporine if possible and if rejection is not a problem.

Neurotoxicity remains the other major side effect of cyclosporine, ranging from peripheral neuropathy, tremors, and dysethesias, which are very common, to less commonly, seizures and full-blown encephalopathy (17, 18, 19, 20). The fine motor tremor associated with cyclosporine therapy can often be diminished by adjustment of the medication and/or accommodation by the patient. Headaches secondary to cyclosporine therapy have been reported, and a demyelinating neuropathy can also occur (21).

Hypertension is associated with the use of cyclosporine therapy. It appears to be secondary to sodium and water retention, and as well as increased intracellular calcium (22,23). Other complications include electrolyte abnormalities such as mild hyperkalemia, which sometimes requires treatment (24,25). Lipid profile dysfunction is also noted with cyclosporine therapy. Hypomagnesemia is also common and may need oral replacement as it predisposes the transplant patient to seizures. Hypertrichosis and gingival hyperplasia are not medically severe, but can be cosmetically troublesome (26).

Tacrolimus

Tacrolimus (FK-506) was introduced in the 1990s and is considered more potent than cyclosporine. This agent has been reported to be as much as 100 times more potent than cyclosporine (27). Tacrolimus is a metabolite of the fungus Streptomycin tskubaensis. It is a macrolide, highly plasma bound, and processed in a variable fashion via the liver in the cytochrome
P450 system (28,29). Tacrolimus immunosuppressive action is similar to that of cyclosporine, working via the calcineurin system. Tacrolimus has allowed for steroid-free therapy, and has permitted small bowel transplantation to be more acceptable (30). Several large trials have examined the efficacy of tacrolimus in preventing rejection after liver transplantation (31). The incidence of acute and chronic rejection appeared to be lowered by the use of tacrolimus. There also appeared to be more retransplantations required in the non-tacrolimustreated group (32,33). In a study of over 1,000 liver transplant patients by Jain et al., they concluded that chronic rejection occurred rarely among patients maintained long term on tacrolimus-based immunosuppressive therapy (33). In addition, the Multicenter Tacrolimus Rescue Trial has shown that among transplant patients receiving cyclosporine who are experiencing chronic rejection, many can be salvaged by transfer to tacrolimus (34). An additional potential benefit of tacrolimus is that it has been shown to demonstrate a reduction in serum cholesterol when compared to cyclosporine (35,36).

Concerns

Tacrolimus, being also a calcineurin inhibitor, has a toxic profile remarkably similar to that of cyclosporine, although neurotoxicity is more prevalent (37,38). Susceptibility to neurotoxicity may have a genetic relationship. In a study by Yamauchi (39), the genotype of six patients who had experienced neurotoxicity after liver transplantation was examined. The authors found a relationship between neurotoxicity associated with polymorphism in the ABCB1gene (39). Resting tremor is the most common neurologic adverse reaction although more serious effects such as peripheral neuropathy and encephalopathy have been reported. Debate exists as to how often this profile of side effects occurs among those taking tacrolimus when compared to the population utilizing cyclosporine for immunosuppression (37). Shimono (40) utilized diffusion weighted MRI to evaluate those that developed neurotoxicity following organ transplantation. He noted that 35.7% had white matter abnormalities, 7.1% had putaminal hemorrhage, and 57.1% had normal findings on MRI (40). Bartynski (41) evaluated 22 patients with a neurotoxic reaction. He also noted the significance of white matter lesions in this population. Patients often have tremors initially, although personal observation suggests that there may be an acclimation to the drug. For persistent tremor that affects activities of daily living, low-dose clonazepam may be helpful.

Drug interactions are common, especially when using itraconazole or ketoconazole since hepatic metabolism is inhibited, risking toxicity. Because of profound hypomagnesemia, frequent monitoring of magnesium levels should be done and often both oral and intravenous (IV) supplementation is required.

Sirolimus

Sirolimus (Rapamycin) is an immunosuppressive that inhibits the cell cycle and the activation of IL-2 (42,43). This agent is produced by Streptomyces hygroscopicus. Sirolimus is still finding its place in immunosuppression as either a primary drug or adjunct with tacrolimus or cyclosporine. Its mechanism of action is different from either cyclosporine or tacrolimus in that it does not inhibit calcineurin (44). Sirolimus appears to prevent the translation of mRNA impacting cell cycle regulation (45, 46, 47). Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (42,48, 49, 50). In a retrospective review, patients who were more than 3 years posttransplantation were selected to evaluate the role of sirilomus. Patients who had proteinuria, those administered any other nephrotoxic agents, and those with a creatinine clearance less than 20 mL/min were excluded. Renal insufficiency was defined as mild, moderate, or severe. In the 16 patients studied, there was significant improvement in serum blood urea nitrogen and serum creatinine levels 6 months after switching to sirolimus therapy. No patient developed cellular rejection or other graftrelated complications (51). Among liver transplant recipients with chronic renal insufficiency, conversion to sirolimusbased immunosuppression may allow complete withdrawal of other agents, leading to some improvement in renal function. Another recent study evaluated the safety and efficacy of sirolimus plus steroids as a maintenance regimen with or without small-dose cyclosporine adjunctive therapy in renal transplantation (52). A total of 133 recipients of kidney allograft transplantations recruited in the United Kingdom and Ireland were enrolled into the study. Patient and graft survival were 97.7% and 95.5%, respectively, whereas the biopsy proven acute rejection rate in the first 6 months was 19.5%; incidents of acute rejection rates comprised 22 episodes (16.5%) during the first 3 months of the study and four episodes (3%) after randomization. These data demonstrate that withdrawal of cyclosporine from a small-dose sirolimus maintenance regimen is safe and is associated with an improvement in renal function (52). The study also suggests that the addition of small-dose cyclosporine to a sirolimus maintenance regimen does not increase the immunosuppressive efficacy. A recent study of 26 subjects receiving liver transplantation who experience nephrotoxicity owing to calineurin inhibitors, suggests successful transfer to sirolumus monotherapy is possible and results in improved renal function (53).

Concerns

Sirolimus causes neutropenia and hyperlipidemia and may predispose patients to more infection. Its antiproliferative properties can also delay healing (54). It is also noted to cause thrombocytopenia, and has also been suggested to have prothrombotic activity. Sirolimus increases the levels of cyclosporine, when used in combination. Even though sirolimus is not primarily nephrotoxic, dual treatment groups have noted an increased incidence of nephrotoxicity (55). Combination sirolimus-tacrolimus may cause nephrotoxicity in some patients by mechanisms that are presently unexplained. Sirolimus appears to prolong delayed graft function (DGF), therefore, it may not be the optimal immunosuppressive choice in the DGF setting (56). A report of delayed wound healing in a person treated
with sirolimus who received a liver transplant has been noted, and late wound dehiscence can occur as well (57).

Corticosteroids

Corticosteroids have been used in transplantation medicine since the early days of solid organ transplantation. These agents impact the functional capacity and the concentration of active leukocytes (58). This tends to occur via the regulation of cytokine gene transcription. These agents have value as adjuvant therapy, at times of stress, and in the treatment of mild-moderate acute rejection. Several attempts have been made at discontinuing steroid therapy. The most successful of these have been programs with tacrolimus-based paradigms (59,60).

Corticosteroids have long been a cornerstone of orthotopic liver transplant immunosuppression. Newer, more potent agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in liver transplant recipients. Washburn (60) hypothesized that corticosteroids can be safely avoided after the first postoperative day using these newer agents. Thirty adult orthotopic liver transplant recipients were prospectively enrolled in a randomized open-label protocol. The incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both the steroid and the “no steroid” groups. Serum cholesterol levels were significantly lower in the “no steroids group” at 6 months after transplantation. Serum triglycerides were also lower, but the difference was not significant. Boots (61) evaluated the role of steroids in renal transplantation, by comparing tapering in 3 to 6 months, with stopping steroids 1 week posttransplantation. Results were noted to be comparable in patients and graft survival, with a similar incidence of acute rejections. The incidence of new-onset diabetes may be reduced among those receiving early taper from steroids (61). The immunosuppressive benefit of adding enteral prednisone to tacrolimus seems to be limited. In a prospective, randomized, double blind, placebo controlled, multicenter study of early steroid withdrawal versus chronic steroid therapy for those with renal transplantation, Woodle et al. (62) noted that early steroid withdrawal is associated with an increase in biopsy-associated rejection (usually mild) yet results in similar allograft survival and function.

The side effects of long-term steroid use are well described and are significant in transplant patients. These include poor wound healing, glucose intolerance, osteoporosis, anasarca, muscle wasting and myopathy, and emotional liability. Lipid abnormalities have also been described. Genotypic testing noted that the presence of an Apolipoprotein E4 allele worsened high-density lipoproteins (HDL), triglycerides, and cholesterol (63). Thus, Apolipoprotein E4 has a larger impact than Apolipoprotein E2 on fasting-lipid profile in transplant candidates. There have been occasional reports of acute respiratory and skeletal muscle weakness in intensive care unit patients treated with massive doses of corticosteroids for rejection prophylaxis or treatment. Compared to the pretreatment condition, approximately 45% of patients showed acute generalized muscle weakness that recovered after approximately 2 months (64). If given a “risk-free” choice, the majority of recipients prefer withdrawal of steroids (65).

Alternative Agents

Azathioprine and mycophenolic acid are adjunctive immunosuppressive agents that inhibit purine synthesis; thereby generally inhibiting immune cells, particularly lymphocytes. These agents have been noted to block de novo purine synthesis by blocking key enzymes. This process is required by T and B lymphocytes for proliferation (66). The role of mycophenolic acid as adjunct therapy in preventing rejection has been established among those with renal and heart transplantation (67). Mycophenolate combined with cyclosporine and prednisone significantly lowers acute rejection frequency in the early post-renal transplantation phase (67). A comparative retrospective analysis of the 5-year results with mycophenolate was performed by Offerman (69). Both the total population and subgroups showed a nonsignificant trend toward better graft survival with mycophenolate, evident at 2 years and persisting for 5 years. Extrapolation indicates that combination therapy with mycophenolate versus azathioprine, results in approximately 10% more patients being alive at 10 years with a functional graft. These agents are also employed in the treatment of acute rejection in such populations (68). Side effects include diarrhea that can mimic Clostridium difficile infection, neutropenia, and pancytopenia. Thymoglobulin was effective as induction therapy in high-risk pancreatic transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population (70).

Monoclonal Antibody Agents

A major thrust of transplantation research is to find more effective and less broadly toxic immunosuppressive agents. One potential way is the use of monoclonal antibodies directed to IL-2 receptors. Several monoclonal antibodies have been introduced that target the IL-2 receptor. Daclizumab and Basiliximab focus on the α-2 chains of the IL-2 receptor (71,72). Pediatric patients appear to be among those that benefit the most from anti-IL-2 receptor therapy (73). Immunoprophylaxis with daclizumab has been shown to be effective in the prevention of acute rejection in kidney transplant patients. Niemeyer initiated a pilot study in 28 liver transplant patients. Daclizumab was administered intravenously. At 4 years posttransplant, no lymphoproliferative disease was observed (74). Immunoprophylaxis with a two-dose daclizumab regimen appears safe, effective and well tolerated, and does not lead to increased opportunistic infections. Such agents are utilized in combination with the agents previously described (74, 75, 76, 77). A two-dose regimen appears to be as effective as the five-dose regimen in preventing acute rejection and is associated with the lowest acute rejection rates and the highest rate of eventfree survival (no rejection or graft loss). However, the benefits
of daclizumab compared with no antibody induction await larger sample size accrual (78).

FIGURE 46-1. Complications of transplantation.

Gene Therapy

One major complication facing organ transplant recipients is the requirement for life-long systemic immunosuppression to prevent rejection, which is associated with an increased incidence of malignancy and susceptibility to opportunistic infections. Presently, exciting investigations into the role of gene therapy for immunosuppression are underway. A further understanding of genetic polymorphisms may also assist in defining those who are at risk for complications such as graft versus host disease (79). Gene therapy has the potential to eliminate problems associated with immunosuppression by allowing the production of immunomodulatory proteins in the donor grafts, resulting in local rather than systemic immunosuppression (80,81). The use of gene therapy may also make xenografts more practical. Alternatively, gene therapy approaches could eliminate the requirement for general immunosuppression by allowing the induction of donor-specific tolerance. Gene therapy interventions may also be able to prevent graft damage owing to non-immune-mediated graft loss or injury and prevent chronic rejection (80,82; Fig. 46-1).

INFECTION

Immunosuppression places these patients at extreme risk for opportunistic infections, which has probably remained the most significant cause of morbidity and mortality in the transplant recipient. Since the immunosuppressive regimen includes medications that suppress both T and B cell action, these patients are vulnerable to many types of infections: bacterial, viral, fungal, tuberculosis, and pneumocystis. Several of these infectious agents are not typically seen in immunocompetent individuals. Despite the fact that aggressive pretransplantation infectious evaluation is part of every protocol, infections are common. Moreover, immunosuppressives, especially prednisone, may mask infectious etiologies making the diagnosis of infection difficult in transplant patients (83). Fever and leukocytosis are still the most common signs of infection, although their absence does not rule it out. Systemic infection may present with a low-grade temperature or no fever at all. It is not uncommon for a transplant patient to have two simultaneous opportunistic infections. Again because of the immunosuppression, once a patient begins to show signs of infection, the course to fulminate sepsis and potentially death can be brief and dramatic (84, 85, 86). Vigilance and a high index of suspicion is the rule in detecting infections in transplant patients. During the past decade, ever-increasing numbers of patients have undergone renal, pancreatic, small bowel, hepatic, cardiac, or lung transplantation. Significant improvements in patient and allograft survival have been observed in all categories. Unfortunately, despite such improved results, the risks of infection related to immunosuppression continue to be substantial. Dunn performed a review of transplant-related nosocomial infections. These authors noted that suppression of host defenses by exogenous immunosuppressive agents renders patients susceptible to invasion by either resident or environmental bacterial, fungal, viral, and protozoal microbes or parasites (87). Invasion of organisms that typically produce mild infection in nonimmunosuppressed individuals can produce severe, lethal disease in those receiving immunosuppressive agents. Thus in an ideal world, immunosuppression could be decreased or eliminated in such patients.

Posttransplantation infections can be divided into three main etiological categories based on time after surgery: During the first 3 to 4 weeks infections are related to technical and mechanical problems (i.e., line infections, abscess, cholangitis from biliary stenosis, bowel obstruction, and wound infections). In a second phase, the first through sixth months posttransplant, cytomegalovirus (CMV) accounts for two thirds of infections, and beyond 6 months, infections are similar to that seen in a general population (88,89). The typical transplant patient receiving acute inpatient rehabilitation is in the first category, although now with long-term transplant survivors, physiatrists are also treating posttransplant patients with other medical problems, such as hip replacement in a patient with an allograft.

Along with factors related to immunosuppression, those receiving transplant may have prolonged hospitalization and thus secondary infection. Common pathogens include Aspergillus, Staphylococcus, Clostridium difficile, Pseudomonas aeruginosa, and Legionella. Viral infections are also quite possible and include: CMV, Epstein Barr virus, Herpes Simplex, Varicella Zoster, Hepatitis B and C (90).

Pulmonary infections are the most common cause of morbidity in the lung transplant population. Prompt recognition and treatment is necessary to prevent poor outcomes. An understanding of the temporal relationship between
immunosuppression and the risk for developing infection can assist the clinician with appropriate treatment. Bacterial pneumonia is common within the first 4 months after transplantation whereas CMV infection becomes more prevalent after the discontinuation of prophylaxis in at-risk patients (91,92). Fungal infections, especially aspergillosis, can be fatal if not treated early and the risk for infection is present throughout the transplant period. Community-acquired viral infections present with upper respiratory symptoms and wheezing that may lead to a persistent decline in lung function. Suspicion of a pulmonary infection in these immunosuppressed individuals should lead to an urgent diagnostic bronchoscopy and empiric antimicrobial therapy (90).

CMV is the most common infection in transplant patients and deserves significant attention. CMV is usually found latent in either recipient or donor and becomes active in a milieu of immune inhibition (91,92). The most virulent CMV infection is seen when a CMV naïve recipient succumbs to CMV carried within the donor allograft. CMV can be widely disseminated and infection can occur anywhere in the body. Fever, leukopenia, and generalized malaise are the most common symptom; although, pneumonitis, hepatitis, cholecystitis, and colitis with occasional GI bleed are not uncommon (92). Posttransplant CMV infection has been associated with posttransplant arteriopathy and can signify invasive infection (93). In many transplant centers, a fever work-up includes CMV culture and antigen detection. In our center, all transplant patients receive prophylaxis with acyclovir (200 mg PO bid), and active treatment is initially with IV ganciclovir (5 mg/kg for 3 to 4 weeks followed by maintenance dose orally for a specified period of time, usually months) (94). Treatment is continued until the patient has three consecutive CMV antigen negative tests. CMV antigen detection is done weekly at many institutions for all patients within the first month of their operation.

Fungal infections are also more common in the immunosuppressed transplant patients than the general population. The clinician has to be vigilant because fungal infections can be devastating. Feltis (95) has noted mycotic aneurysms after transplantation. Fungal infections are associated with high morbidity and mortality, and make up a significant proportion of infectious complications. Unfortunately, the diagnosis is usually made late, and symptoms may be mild and nonspecific, even with dissemination. Mortality associated with disseminated fungal infections is high, while those associated with more local fungal infections is low (96). Although the risk factors for invasive fungal infections in liver transplant patients are well identified, early diagnosis is challenging, and commonly used diagnostic methods lack sensitivity and specificity (96). The incidence of fungal infections following liver transplantation appears to be falling. Future developments should focus on enhancing earlier diagnosis, implementing more effective and less toxic antifungal therapy recipients (97,98). Early fungal infections are related to surgical complications, while the period of 1 to 6 months after transplant reflects opportunistic, relapsed, or residual infections; fungal infections greater than 6 months after transplant and thereafter are usually associated with treatments for chronic rejection or bronchial airway mechanical abnormalities (99). The majority of fungal infections in lung transplant recipients involve Aspergillus species, followed by Candida, Pneumocystis, Cryptococcus, geographically restricted agents, and newly emerging fungal pathogens. Virulent infections such as Aspergillus or Mucormycosis are usually fatal. Aspergillus can be widely disseminated and may not grow in culture despite systemic infection (100).

Of note, persons receiving lung transplants for cystic fibrosis appear to be at particular risk for Aspergillus infection (100). The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients appears to be highly predictive of invasive aspergillosis (101). The presence of Aspergillus “fungus balls” lesions in the brain usually means death, and lung involvement requires resection for any chance of survival. Mucormycosis spreads by the nasal sinuses into the brain where their infection portents death; cure, if caught early enough, requires aggressive debridement and resection of facial tissues.

REJECTION

Rejection exists as a continuum of responses that are important to understand. Transplant rejection has been classified as hyperacute, acute, subacute, and chronic. Hyperacute rejection occurs when the recipient has antibodies to antigens present on the transplanted organs. This elicits an aggressive immune response resulting in organ failure. This response type has generally been limited by extensive routine cross matching. Acute rejection is a relatively intense inflammatory response to the new organ. The inflammation that occurs has been described as being similar to that seen in a hypersentivity type of reaction (102). The result of this reaction is the deposition of a large number of inflammatory cells within the graft. The clinical syndrome manifests itself as rubor, edema, fever, and pain. The transplanted organ’s function-related laboratories may also become acutely impaired. Despite potent immunosuppression, more chronic forms of rejection are still a common event usually within the first 3 months after transplantation. Symptoms such as fever and leukocytosis are sometimes present although rejection often occurs in the absence of these symptoms. Usually subacute and chronic rejection is heralded by a rise in an allograft laboratory value, such as increased creatinine in persons with renal transplant, increase in bilirubin or liver function enzymes in persons with liver transplantation, and elevation in amylase and lipase among those with pancreas transplants. Tissue biopsy, usually obtained percutaneously, with histologic examination remains the gold standard for the diagnosis of rejection. The incidence of chronic rejection varies by type of solid organ transplantation. The incidence of chronic rejection has been reported as high as 50% in the lung transplantation population and as low as 5% among those receiving liver transplantation (103,104).

Chronic allograft nephropathy (CAN) is, besides death of the recipient, the most common cause of renal transplant loss.
It is characterized by loss of function and replacement of tissue by fibrotic material (103). The pathogenesis is not clear, but seems to be multifactorial and involves events both early and late after transplantation.

TABLE 46.2 Rejection Symptoms

Type	Symptom	Treatment
Hyperacute	Occurs in OR during initial transplantation surgery. Secondary to preformed antibodies. Graft is lost.	Graft replacement/retransplantation
Acute chronic	T-cell-mediated antigraft inflammatory infiltrate ↑ LFT in liver transplants. ↑ Glucose in pancreas transplants. ↑ Blood urea nitrogen (BUN) with creatinine in kidney transplants. ↑ Heart/lung biopsy may reveal ↑ inflammation. There may be ↑ inflammation. ↑ Shortness of breath. ↑ Edema	Solumedrol; if steroid resistant, thymoglobulin or OKT3 Organ replacement is the treatment of choice. Possibly ↑ FK-506 or give steroid bolus.