141 RENAL TRANSPLANTATION
Harrison’s Manual of Medicine
With the advent of more potent and well-tolerated immunosuppressive regimens and further improvements in short-term graft survival, renal transplantation remains the treatment of choice for most pts with end-stage renal disease. Results are best with living-related transplantation, in part because of optimized tissue matching and in part because waiting time can be minimized. Many centers have recently begun to perform living-unrelated donor (e.g., spousal) transplants. Graft survival in these cases has been superior to that observed with cadaveric transplants, although less favorable than living-related transplants. Factors that influence graft survival are outlined in Table 141-1. Contraindications to renal transplantation are outlined in Table 141-2.
Table 141-1 Some Factors That Influence Graft Survival in Renal Transplantation
Table 141-2 Contraindications to Renal Transplantation
Immunologic rejection is the major hazard to the short-term success of renal transplantation. Rejection may be (1) hyperacute (immediate graft dysfunction due to presensitization) or (2) acute (sudden change in renal function occurring within weeks to months). Rejection is characterized by a rise in serum Cr, hypertension, fever, reduced urine output, and occasionally graft tenderness. A percutaneous renal transplant biopsy confirms the diagnosis. Treatment usually consists of a “pulse” of methylprednisolone (500–1000 mg/d for 3 days). In refractory or particularly severe cases, 7–10 days of a monoclonal antibody directed at human T lymphocytes may be given.
Maintenance immunosuppressive therapy usually consists of a two- or three- drug regimen, with each drug targeted at a different stage in the immune response. Cyclosporine is the cornerstone of immunosuppressive therapy. The most potent of orally available agents, its routine use has markedly improved short-term graft survival. Side effects of cyclosporine include hypertension, hyperkalemia, resting tremor, hirsutism, gingival hypertrophy, hyperlipidemia, hyperuricemia, and a slowly progressive loss of renal function with characteristic histopathologic patterns (also seen in exposed recipients of heart and liver transplants).
Prednisone is frequently used in conjunction with cyclosporine, at least for the first several years following successful graft function. Side effects of prednisone include hypertension, glucose intolerance, Cushingoid features, osteoporosis, hyperlipidemia, acne, and depression and other mood disturbances.
Until relatively recently, azathioprine was the most commonly used “third drug” in combination with cyclosporine and prednisone, although mycophenolate mofetil has become more popular than azathioprine in the past 2–3 years. Azathioprine is generally well tolerated; side effects include leukopenia (and occasionally anemia and thrombocytopenia), liver dysfunction, alopecia, and squamous cell carcinoma of the skin. The drug-drug interaction between azathioprine and allopurinol may complicate treatment of gout (a frequent complication of cyclosporine therapy). Mycophenolate mofetil has a similar mode of action as azathioprine but is more effective at preventing or reversing rejection. The major side effects of mycophenolate mofetil are gastrointestinal (i.e., abdominal discomfort, diarrhea).
Tacrolimus (FK-506) is similar in efficacy and side-effect profile to cyclosporine although it has been used more widely in liver than kidney transplantation. It is occasionally employed in pts with subacute or chronic rejection poorly controlled with cyclosporine. Sirolimus is gaining popularity in multidrug regimens or in refractory rejection. Treatment can be complicated by severe hyperlipidemia.
Infection and neoplasia are important complications of renal transplantation. Infection is common in the heavily immunosuppressed host (e.g., cadaveric transplant recipient with multiple episodes of rejection requiring steroid pulses or monoclonal antibody treatment). The culprit organism depends in part on characteristics of the donor and recipient and timing following transplantation. In the first month, bacterial organisms predominate. After 1 month, there is a significant risk of systemic infection with CMV, particularly in recipients without prior exposure whose donor was CMV positive. Prophylactic use of ganciclovir or valacyclovir can reduce the risk of disease. Later on, there is a substantial risk of fungal and related infections, especially in pts who are unable to taper prednisone to <20–30 mg/d. Daily low-dose trimethoprim-sulfamethoxazole is effective at reducing the risk of Pneumocystis carinii infection.
EBV-associated lymphoproliferative disease is the most important neoplastic complication of renal transplantation, especially in pts who receive polyclonal (antilymphocyte globulin, used at some centers for induction of immunosuppression) or monoclonal antibody therapy. Non-Hodgkin’s lymphoma and squamous cell carcinoma of the skin are also more common in this population.
For a more detailed discussion, see Carpenter CB, Milford EL, Sayegh MH: Transplantation in the Treatment of Renal Failure: Chap. 272, p. 1567, in HPIM-15.