Long-Term Complications in Renal Transplantation

The preferred modality for renal replacement is renal transplantation, and its superiority in prolonging the longevity of patients with end-stage renal disease is well established (1). In the United States, more than 12,000 kidney transplants were performed in 1998 and the waiting list for transplants has increased threefold, from approximately 13,000 in 1988 to 43,000 in 1999 (2). Economically, transplant is a more feasible method of replacement therapy, an important factor when considering the increasing health care costs and the government's continued commitment to providing coverage of endstage renal disease therapies. In many countries, nephrologists and technicians trained in dialytic techniques are relatively scarce and transplantation remains the only feasible option. In terms of quality of life, patient surveys have consistently indicated a clear preference for transplantation over other replacement therapies. The series of cadaveric renal transplants performed in the early 1950s by Hume in Boston, as well as similar operations in Paris, marked the first successes in the field (3). In the mid-1950s, expertise in the science of cell-mediated immunity provided a foundation for the understanding of the immune response. Around this time, transplants using identical twins served to propel the field forward from a technical standpoint and fueled hope that transplants from nonidentical donors would someday become feasible. Where radiation-induced bone marrow suppression had been used for some of the early transplants in Boston and Paris, the introduction of 6-mercaptopurine (6-MP) in 1953 spawned one of the mainstays in the immunosuppressive regimen. Azathioprine, a less toxic derivative of 6-MP introduced in 1960, and corticosteroids remained the primary immunosuppressive drug regimen over the next two decades. During this time, technical expertise in the transplant procedure as well as proficiency in the care of the transplant recipient rapidly grew, and the advent of dialysis provided an option for individuals awaiting transplantation and for those in whom transplantation was unsuccessful. The field of transplantation was revolutionized by the introduction of cyclosporine in the early 1980s, and this agent remains the mainstay of immunosuppression at most centers. Cyclosporine is derived from fungi and works by inhibiting the transcription of interleukin-2 (IL-2) mRNA, leading to decreased production of IL-2 and other cytokines critical to T cell activation and proliferation. Cyclosporine and other immunosuppressive drugs have lowered the incidence of acute rejection and have improved long-term survival. The median cadaveric graft survival improved from 5.2 years in 1986-1987 to 10.2 years in 1994-1995. This twofold increase is largely attributable to cyclosporine, since a dramatic decrease in first-year allograft loss rate occurred after the introduction of the drug in 1983. Median living donor graft survival also improved over the same periods from 10 years to 16.2 years, and steady increases in both cadaveric and living donor graft survival also occurred (4). Patient survival has also improved, but has been associated with medical complications that both impair the quality of life of transplant recipients and substantially add to societal health care costs. Long-term complications of renal transplantation can arbitrarily be thought of as those occurring more than 3 months from the time of surgery. Certainly there are a number of complications in the early perioperative period, including delayed graft function due to tubular necrosis, acute allograft dysfunction from a variety of causes (acute rejection, ischemic tubular necrosis, nephrotoxic drugs, infection), untoward side effects from drugs at higher doses, and a variety of infections more common early in the transplant course. However, long-term medical complications of renal transplantation have become increasingly important. The most important of these include infection, malignancy, bone disease, and cardiovascular disease. Additionally, hypertension, posttransplant diabetes mellitus, cataracts, posttransplant erythrocytosis, chronic rejection, and recurrent disease all account for increased morbidity in the transplant recipients and deserve special consideration. Infection Infection has long been one of the most important medical complications of transplantation of all types. Over time, however, the pattern and severity of the various infections has changed, with a general trend toward a reduction in severity. In fact, the incidence of infection has dropped from 70% in the early days of renal transplantation to 15 to 44% more recently. Mortality due to infection in these same series ranged from 11 to 40% in the former to less than 5% in the latter (5). This trend is probably attributable to a number of factors, including refinement of the actual surgical technique, better and more appropriately tailored immunosuppressive regimens, the use of prophylactic antimicrobial agents, improved methods for diagnosis, and more effective therapies. In the early postoperative period, the most common infections are bacterial and involve the urinary tract, the wound, the respiratory tract, and intravenous lines. These problems are not unique to the transplant patient and many can be avoided by common-sense measures such as prompt removal of the bladder catheter, prophylactic intraoperative antibiotics with meticulous wound management, and avoidance of prolonged intravenous lines. Urinary tract infection is the most common infection in the transplant recipient with an incidence of more than 30% in the first 3 months following transplantation (6). The clinical presentation is variable, from asymptomatic bacteriuria or pyuria to pyelonephritis and septicemia. Graft dysfunction is not uncommon as the major presenting feature. Because an anatomically and functionally intact kidney is important as a primary host defense against infection, it is not surprising that urinary tract infections would be more common in patients who must undergo implantation of a donor ureter into their own bladder. Many centers encourage the use of trimethoprimsulfamethoxazole as prophylaxis against urinary tract infections as well as Pneumocystis carinii, Listeria, and Nocardia. Community-acquired infections such as the common cold, influenza, pneumococcal pneumonia, diarrheal syndromes, and sexually transmitted diseases can all affect the transplant recipient. It is necessary that these routine infections be considered carefully, because there is a temptation to focus on some of the more unusual opportunistic infections, sometimes to the exclusion of those that are more common. When prescribing antibiotics, it is important to be aware of the drug interactions that may result with other drugs of the immunosuppressive regimen, particularly cyclosporine. Erythromycin and other macrolide antibiotics inhibit cytochrome P450-IIIA, resulting in elevated levels of cyclosporine and a tendency toward nephrotoxicity. When treating an organism such as Legionella with azithromycin, for example, cyclosporine dose adjustments may become necessary. Opportunistic infections can occur at any time following transplantation but tend to occur after the first month when the immunosuppressive effect is at its peak. The degree of immunosuppression is clearly linked to the development of opportunistic infections, and patients who have been treated for multiple rejection episodes or who have received a more aggressive regimen are definitely at higher risk. A recent study dividing patients into three groups based on the presence of acute rejection and subsequent therapy showed a significant increase in the number of infections during the first 6 months posttransplant in patients treated with high-dose corticosteroids for acute rejection compared to those without rejection (71% versus 52%). The addition of cytolytic therapy, either OKT3, an anti-CD3 monoclonal antilymphocyte preparation, or a polyclonal antilymphocyte preparation resulted in a further increase in the incidence of infections that rose to 86%. Not all infections were opportunistic, however; urinary tract infection was the most common in all groups (7). Additional studies will be necessary to establish the risk in the use of some of the newer agents, including the humanized monoclonal antibody daclizumab and the chimeric monoclonal antibody basiliximab. Cytomegalovirus (CMV) is one of the most common infections encountered in the renal transplant patient population with an incidence of 34 to 55% (6). The typical onset of disease is within the first 1 to 4 months after transplant. Transmission can occur through transplantation of an infected organ or through transfusion of blood products from a seropositive donor. Clinically significant disease with CMV can evolve in three ways: (1) Primary infection can occur when a seronegative recipient receives an organ from a seropositive donor. This group of patients represents those at highest risk and it is this group for which prophylaxis is deemed most important. (2) Seropositive individuals can reactivate latent virus and develop clinically significant disease. (3) Reactivation of donor virus can occur in a seropositive recipient and has been labeled superinfection. Prophylaxis with acyclovir has been used historically, although the efficacy of this therapy in the prevention of disease is questionable. Some transplant physicians believe that it does attenuate disease severity and that its use is justified for that reason as well as its prophylactic effect on herpes simplex virus. Many centers now, however, favor the use of oral ganciclovir as prophylaxis, and evidence supports the fact that it is superior to acyclovir in providing effective CMV prophylaxis for recipients of seropositive donor kidneys (8). A recent study demonstrated the effectiveness of valacyclovir, a prodrug of acyclovir, in the prevention of CMV disease compared to placebo. Interestingly, the use of valacyclovir was associated with a reduction in the number of acute rejection episodes, a finding that supports the association of CMV with acute rejection (9). Additional studies will be necessary to compare valacyclovir to ganciclovir and other agents. The most common clinical presentation for CMV is fever, malaise, and leukopenia. Other manifestations include chorioretinitis, pneumonitis, and gastrointestinal involvement (esophageal discomfort, abdominal cramping, diarrhea, and hepatitis). As mentioned, those at highest risk include CMV seronegative recipients of CMV seropositive donor kidneys. Reactivation disease in a seropositive recipient is generally less severe clinically, and superinfection is generally rare. Disease can range from asymptomatic to severe, the latter characterized by sight-threatening retinitis or life-threatening systemic involvement (pulmonary, gastrointestinal, or hematologic). In this group, therapy with intravenous ganciclovir is initiated and immunosuppression is occasionally reduced. Because CMV infection can lead to an intensified immunosuppression of host defenses, concomitant superinfection with other opportunistic pathogens (Pneumocystis, Aspergillus, and Listeria) should be considered (5). Epstein-Barr virus (EBV) plays a central role in the development of posttransplant lymphoproliferative disorder (PTLD), although milder manifestations of infection include a mononucleosis syndrome consisting of fever, malaise, leukopenia, and atypical lymphocytosis. Because EBV is responsive to acyclovir, many centers have continued to use this drug as a prophylactic medication. Reactivation of herpes simplex virus is frequently seen in transplant recipients during the first several months. The incidence is markedly reduced when prophylactic acyclovir is used. Ganciclovir also has activity against herpetic lesions. Orolabial, esophageal, and genital involvement can be seen, and treatment consists of acyclovir or famciclovir. More severe disease may be manifested by pneumonitis or hepatitis. Varicella-Zoster virus (VZV) can cause a reactivation infection characterized by zoster lesions in a localized dermatomal pattern, as well as a more disseminated cutaneous presentation. Primary disease in a seronegative transplant recipient exposed to VZV can be especially severe, with life-threatening pneumonia, encephalitis, hepatitis, and disseminated intravascular coagulation possible. Prompt administration of varicella-zoster immune globulin early in the postexposure period can prevent serious illness (5). The major causes of liver disease in the renal transplant population are hepatitis B (HBV) and hepatitis C (HCV) viruses. Due to the dependence on blood transfusions prior to the availability of recombinant erythropoietin, HBV has long been an important pathogen in transplant patients. and rate of disease are markedly increased with the use of posttransplant immunosuppressive drugs, and of will develop end-stage liver disease or within 10 years most centers HBV infection a to prior to transplantation is for individuals without to and is a routine for patients with end-stage renal disease on the availability of a better infection and transplantation HBV for only a of renal transplant recipients with chronic liver disease. In for all of the 10 to of transplant recipients who develop chronic liver disease. The clinical of in the transplant population is more with generally major on years after transplant. that however, liver and are with has been and allograft rejection is a major through of cytokines some have the of therapy prior to transplant when an allograft is not at risk and reduction of immunosuppression for significant disease after In most infection in a is considered a to some patients have many develop and of infections after the transplant surgery. the newer an in longevity after transplantation is diseases include and In transplant from and must be by antibody transplantation, as life-threatening disseminated infection can occur in the are generally not for the of the organism to in the gastrointestinal tract for Pneumocystis is uncommon in patients who prophylaxis with In a of and or can be When a from a transplant on and may some the diagnosis, especially with and Infection with systemic such as and should be considered in a transplant recipient with a of to Because studies may not be in the of an of the organism through or of may be necessary. The most common infection in the renal transplant recipient is with the most frequently such as suppression of by antibiotics, and and of host with intravenous and bladder all to of Other that a similar pattern of opportunistic disease in patients include Aspergillus, and remains a significant in the transplant recipient and either through primary infection or reactivation of disease. Many centers for prophylaxis for 6 to months in individuals with a in the group by the and for Disease and for liver in this group to be and should not prevent therapy transplant patients should against hepatitis A and and pneumococcal disease. 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