David J Reich

Late postoperative complications following abdominal organ transplantation are related to side effects of chronic immunosuppression, disease recurrence, chronic rejection, and technical problems. As the outcomes after transplantation improve and recipients live longer, the late complications are seen more frequently. Long-term recipient survival depends on careful screening and management of the medical complications that these patients develop.

18.1. COMPLICATIONS OF IMMUNOSUPPRESSION

Long-term immunosuppressive therapy is a significant risk factor for renal dysfunction, hypertension, diabetes mellitus, hyperlipidemia, obesity, osteoporosis, malignancy, and infection. Although the toxicity profiles of individual immunosuppressive regimens differ, all transplant recipients are prone to develop these problems. As more immunosuppressant agents come into use, various combination regimens are being used to reduce toxicity.

18.1.1. Renal Dysfunction

The glomerular filtration rate falls continuously in recipients with long-term follow-up. Creatinine is typically elevated, between 1.5 and 2.5 mg/dL. Calcineu-rin inhibitors increased resistance in afferent glomerular arterioles and reduce renal blood flow. This process is exacerbated in the presence of concomitant diabetes or hypertension. Recurrent diseases may also aggravate renal dysfunction, such as recurrent glomerulosclerosis or glomerulonephritis in renal recipients, or glomerulonephritis and cryoglobulinemia in liver recipients with recurrent hepatitis C. Several medications compete with cyclosporine A and tacrolimus for cytochrome P450 metabolism, producing nephrotoxic levels of calcineurin inhibitors. Such medications include fluconazole, diltiazem, and verapamil. A common mistake is to administer erythromycin, often in combination with a nonsteroidal anti-inflammatory drug, to transplant recipients with upper respiratory tract infections; both drugs increase calcineurin inhibitor nephrotoxicity. Drugs that increase cytochrome P450 metabolism, such as many anticonvulsants, can cause nep-hrotoxicity if they are discontinued abruptly. Management of calcineurin inhibitor nephrotoxicity may include dose reduction and addition of nonnephrotoxic, newer immunosuppressive agents, including mycophenolate mofetil (CellCept; Roche, Nutley, NJ) and sirolimus (Rapamune; Wyeth-Ayerst, Wayne, PA).

Cyclosporine and tacrolimus are also notorious for causing renal tubular acidosis, associated with hypomagnesemia and hyperkalemia. Hypomagnesemia must be corrected, because it acts synergistically with cyclosporine and tacrolimus to lower the seizure threshold. Many transplant recipients require magnesium supplementation as well as a low potassium diet.

18.1.2. Hypertension

Although hypertension is common in transplant recipients, it is often easy to control with antihypertensive medications. Calcineurin inhibitors and steroids are the most significant causative agents among the immunosuppressant drugs, and cyclosporine causes hypertension more frequently than tacrolimus. These agents cause renal vasoconstriction resulting in increased reabsorption of sodium, fluid overload, and thus arterial hypertension. Management of post transplant hypertension requires diuretics and reduction of sodium intake if there is fluid overload. Furosemide is the agent of choice, because potassium-sparing diuretics exacerbate calcineurin-inhibitor-induced hyperkalemia. The preferred antihypertensives for use after transplantation are calcium channel blockers, which inhibit endothelin-induced vasoconstriction. It should be noted that diltiazem and verapamil, but not nifedipine, increase calcineurin inhibitor levels. Addition of a beta-blocker is often required. It has been shown that many transplant recipients tolerate complete steroid withdrawal, which decreases hypertension.

18.1.3. Diabetes Mellitus

Steroids increase gluconeogenesis and insulin resistance, and calcineurin inhibitors inhibit insulin release. Tacrolimus is more prone to cause hyper-

glycemia than is cyclosporine. Treatment of posttransplant diabetes mellitus requires dietary prudence, reduction of steroids, and/or calcineurin inhibitors and use of oral hypoglycemics or insulin.

18.1.4. Hyperlipidemia

Hyperlipidemia is commonplace in transplant recipients but tends to improve over time as immunosuppression is reduced. Posttransplant hyperlipidemia is of a mixed pattern, involving elevated cholesterol and/or triglyceride levels. Steroids and calcineurin inhibitors are causative. It has been shown that cyclosporine is a worse offender than tacrolimus. A major cause of mortality in long-term survivors after transplantation is cardiovascular-related disease; therefore, screening for, and managing, hyperlipidemia is important in this population. Therapy involves managing coexistent diabetes, hypertension, obesity, and smoking. Pharmacologic therapy may involve 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, although these are rarely associated with myopathy and rhabdomyolysis, particularly in kidney recipients.

18.1.5. Obesity

Although many transplant recipients are malnourished before transplantation, excessive weight gain frequently occurs after transplantation. Risk factors include increased caloric intake, decreased physical activity, corticosteroid use, and coexistence of diabetes mellitus. Managing obesity is particularly important because this complication is itself a significant risk factor for development of the other complications of hypertension, diabetes mellitus, hyperlipidemia, and osteoporosis. Managing posttransplant obesity requires dietary restriction, exercise, and steroid reduction. Although there is interest in the use of medication to treat obesity, further studies are required to evaluate the safety of such therapy in this patient population.

18.1.6. Osteoporosis

The most common presentation of posttransplant osteoporosis is an atrauma-tic fracture of trabecular bones, such as vertebrae and ribs. Avascular necrosis commonly affects the femoral heads or the knees. Immunosuppressive therapy is a risk factor for postoperative loss of bone mass. Corticosteroids cause increased bone reabsorption, decreased bone formation, and calcium malabsorption. Cal-cineurin inhibitors also cause high bone turnover. The most frequently used tool for determining the presence of significant osteoporosis is dual energy X-ray absorptiometry (DEXA) scanning. Magnetic resonance imaging (MRI) is the test of choice for determining the presence of avascular necrosis. Management options include weight loss, exercise, and pharmacotherapy, including vitamin D and calcium supplementation, and hormone therapy or use of biphosphonates. Osteonecrosis may require prosthetic hip or knee replacement, which can be performed safely in transplant recipients.

18.1.7. Posttransplant Malignancies

Immunosuppressive medications do not increase the frequency of most common malignancies but do significantly increase the risk of lymphoma, skin cancer, and some rare malignancies, including Kaposi's sarcoma and carcinoma of the cervix, external genitalia, and perineum.

18.1.7.1. Posttransplant Lymphoproliferative Disease

PTLD is related to infection with Epstein-Barr virus. Most PTLD arises from B lymphocytes. Patients at highest risk for developing PTLD are children, recipients who were seronegative for Epstein-Barr virus and received organs from donors that were seropositive, and patients who required the use of monoclonal antibody immunosuppressive therapy (OKT3). PTLD, in contrast to nontransplant-related lymphomas, is often extranodal, presenting in such places as the gastrointestinal tract, lung, or central nervous system. Therapy involves decreasing immunosuppressive medications, and use of antivirals and sometimes chemotherapy or radiotherapy.

18.1.7.2. Skin Cancer and Kaposi's Sarcoma

Skin cancer, including squamous cell carcinoma, melanoma, and basal cell carcinoma, occurs up to 20 times more frequently in transplant recipients than in the general population. In general, skin cancer is more aggressive in transplant recipients than in the general population. Transplant recipients should avoid sun exposure and undergo routine skin evaluations. Kaposi's sarcoma may present with bluish skin lesions or may affect the oropharynx, lung, or other viscera. Treatment involves decreasing immunosuppression and may also involve chemotherapy or radiotherapy.

18.1.8. Posttransplant Infections

Patients with long-term follow-up after organ transplantation are only at slightly increased risk for developing common bacterial or viral infections. How ever, they are at increased risk for opportunistic infections. The usual viral culprits are DNA herpes viruses, most importantly cytomegalovirus, and also Epstein-Barr virus, herpes simplex virus, and varicella. Cytomegalovirus may present with fever, malaise, leukopenia, hepatitis, esophagitis, enterocolitis, pneumonitis, or retinitis. Treatment involves immunosuppression reduction and gancyclovir, which is highly therapeutic. The most common fungal infections in transplant recipients include candida, aspergillus, cryptococcus, and histoplasmosis. Risk factors for these opportunistic infections include heavy immunosuppressive regimens, often in the face of allograft dysfunction, and use of broad-spectrum antibiotics. Aspergillosis most often presents with respiratory symptoms, and cryptococcus, most often with meningitis. These fungal infections are treated with fluconazole or amphotericin B, but mortality rates are high. Other opportunistic infections include Pneumocystis carinii, mycobacterium, and the bacteria Legionella, Nocardia, and Listeria. Patients with long-term follow-up who still require heavy immunosuppression should be maintained on chronic antifungal as well as antiviral prophylaxis, with agents such as oral mycelex, vaginal nystatin and acyclovir. Trimethoprim-sulfamethoxazole is used for Pneumocystis carinii pneumonia prophylaxis.

Transplant recipients should receive annual pneumococcal and influenza vaccines. The use of live attenuated viral vaccines is contraindicated in the face of high-level immunosuppression.

18.2. DISEASE RECURRENCE, CHRONIC REJECTION, AND TECHNICAL PROBLEMS

18.2.1. Disease Recurrence

Transplant recipients may be susceptible to recurrence of their original disease. Some recurrent diseases are mild, whereas others have a propensity to cause allograft failure. Liver transplant recipients may develop recurrence of hepatitis C, hepatitis B, hepatocellular carcinoma, alcoholic liver disease, or one of the autoimmune hepatitides (see Chapter 19). Kidney recipients may develop recurrence of diabetic nephropathy, focal segmental glomerulosclerosis, membranoprolifera-tive glomerulonephritis, immunoglobin A (IgA) nephropathy, hemolytic uremic syndrome, or systemic lupus erythematosus (see Chapters 19 and 21).

18.2.2. Chronic Rejection

Chronic rejection involves progressive deterioration of allograft function. The process is based on immune humoral reactivity leading to tissue fibrosis; it may be exacerbated by nonimmunologic factors such as ischemia reperfusion injury, cytomegalovirus infection, and immunosuppression induced hyperlipid-emia, diabetes, and hypertension. Heavy immunosuppression with tacrolimus, mycophenolate mofetil, and/or sirolimus may reverse chronic rejection in the early phases. Renal recipients are particularly prone to chronic rejection. They suffer decreased glomerulofiltration rates, proteinuria, and uremia. Histopathol-ogy reveals vascular intimal thickening and obliteration, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Liver recipients can also develop chronic rejection. They develop hepatic arteriolar thickening, loss of bile ductules and hepatic fibrosis, resulting in jaundice, loss of synthetic function, and portal hypertension (see Chapter 19 for a detailed discussion about chronic rejection in kidney and liver transplantation).

18.2.3. Technical Problems

Discussion of the technical problems that occur posttransplantation is found in Chapter 19.

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