Department of Nephrology, University Hospital, Essen, Germany
Introduction
Over the last decades, kidney transplantation has developed into a standard treatment for end-stage renal failure. This was made possible by a variety of medical achievements such as marked improvements in immunosuppressive regimens. Unfortunately, immunosuppressive drugs always bear the risk of infectious diseases.
One of the most frequent infectious agents in the wake of transplantation is cytomegalovirus (CMV). CMV belongs to the group of herpes viruses and about 80% of adults are carriers. Whether or not CMV disease develops after transplantation depends on a variety of factors, particularly whether or not the donor and/or recipient are carriers of the virus [1].
Pathophysiology
CMV disease occurs most frequently if CMV-positive organs are transplanted into a CMV negative recipient. If the recipient is already CMV positive at the time of transplantation and the donor is negative, the recipient may develop a relapse/re-infection or, due to strain variations, a new infection with a different virus strain. While most of these episodes are clinically inapparent and, thus, do not require treatment [1] they may affect allograft survival [2].
CMV replication can be activated in many ways. The most important mechanism is mediated by TNF. High concentrations of TNF trigger the promoter of CMV and may thereby induce the disease. TNF release is mediated by cell destruction. Thus, the administration of depleting antibodies such as ATG, ALG, or OKT3, or acute rejection may provoke CMV replication [3]. As CMV itself can trigger acute rejection, the simultaneous presence of CMV and acute rejection is a difficult situation and treatment may consist of steroids as well as antiviral drugs. In some cases, especially if CMV activation occurs late after transplantation, the treatment of CMV alone may be sufficient to treat the rejection as well [4].
Depending on virus strain and immunosuppression, CMV may present with mild or severe symptoms about 812 weeks after transplantation. Mild symptoms include fever, appearance of atypical lymphocytes, leucocytopenia, thrombocytopenia, myalgias, arthralgias, and a rise in serum creatinine. Severe symptoms include interstitial pneumonia, hepatitis, colitis, gastritis, oesophagitis, retinitis, and encephalitis [5]. While retinitis is very frequent in HIV patients, it is rare in transplant recipients. If CMV presents with these symptoms it is called CMV disease. However, currently there is no clear definition of CMV disease as a guide in clinical practice. Most authors equate tissue invasive disease with histological evidence of CMV in the tissue. Bearing this in mind, it is easier to understand why studies on immunosuppressive drugs differ remarkably with respect to the incidence of CMV disease [6,7]. The situation is further complicated as the diagnosis of CMV as the sole cause of the symptoms is not easy to verify.
Assays for detection
In order to predict and/or verify CMV disease, several markers have been tested. The ideal marker has a high specificity, is cheap, standardized, and predictive. As in other fields of medicine, this ideal marker does not exist.
Serological markers, IgG and IgM against CMV, are reasonable as a base line before transplantation in order to adjust for the risk of CMV disease. However, after transplantation they have only confirmatory value. If serological markers appear de novo in recipients who had been negative before transplantation, they prove an infection. Unfortunately, while IgM antibodies may correlate with graft survival, they do not predict or correlate with the severity of the disease. Furthermore, in case of CMV disease, antibodies may not develop due to immunosuppression, or develop after the disease is already cured, or may persist for years [8].
The most frequently performed tests are immunohistological assays for the detection of early antigens such as pp65 or pp67. While there is a commercial kit for pp67, there are only in-house methods for pp65. In this assay, leukocyte populations are isolated from peripheral blood, stained for the antigen and the number of positive cells is related to the negative ones. pp65 is predictive for the severity of the disease. However, numbers differ between the various in-house methods and results suffer from transport and storage. This may explain missing correlations between disease and test results in some cases [9].
The virus may be cultured from tissue. This takes a long time and is expensive.
Molecular approaches consist of qualitative PCR, quantitative PCR, and Taqman. While the quantitative tests may predict the severity of the disease, qualitative PCR gives a yes or no answer to the question whether or not the virus is present in the recipient. It is specific and reliable, but only useful if the recipient was negative before transplantation.
Quantitative PCR and Taqman detect the number of virus copies in the blood. Although these assays have considerable potential, at present they are no better than pp65 [10].
With the growing importance of viral diseases a number of antiviral agents have been developed. As a result CMV disease has lost much of its former danger. Now, at least in the transplant community, almost all forms of CMV disease can be cured. However, not all agents are equally suited.
Drugs for treatment and prevention
Acyclovir is a comparatively cheap drug for the treatment and prophylaxis of herpes virus infections. However, in order to treat CMV high serum levels are essential. These levels carry the risk of toxicity and can hardly be achieved by oral administration. Thanks to pharmacological modifications valacyclovir has entered the market. This drug is a thioesther and has a high oral bioavailability. Thus, it is superior to oral acyclovir and may be successful in prophylactic treatment [11,12]. Currently it is primarily used as general antiviral prophylaxis.
Gancyclovir is the drug most frequently used against CMV. Gancyclovir has a high potency against CMV and allows an effective treatment of CMV disease. Gancyclovir is eliminated by the kidneys, so that the dose has to be adjusted to renal function. However, in its oral form, bioavailability is poor (6%) and a high number of pills are needed per day. Either as a result of low compliance or low trough levels, the number of cases of resistance is increased following prophylactic treatment [13,14].
Foscavir is another drug with a high activity against CMV. It is available as an i.v. preparation only and should be reserved for cases of gancyclovir resistance as side effects such as nephrotoxicity, and penile and vaginal ulcers limit its use in kidney transplantation. Doses have to be carefully adjusted to renal function and use in dialysis patients is strongly discouraged [15].
Nephrotoxicity is also the major problem of cidofovir, which is primarily used in the prophylaxis of CMV retinitis in AIDS patients. It is currently applied in stem cell and tested for prophylaxis in heart and liver transplantation [16].
Immunoglobulins have been frequently used in transplantation, both for prophylaxis and treatment. With the advent of gancyclovir, immunoglobulins are reserved in therapeutic indications for those cases only, where antibody production was insufficient. Gancyclovir was also favoured for prophylactic treatment. However, immunoglobulins are re-evaluated as a result of gancyclovir resistance and side effects [13]. Whether high-titre immunoglobulins, so-called hyperimmunoglobulins, are more effective than normal immunoglobulins remains a matter of debate as prospective randomized trials in large numbers are missing.
Therapeutic options
Whether or not prophylactic treatment is preferable to pre-emptive treatment remains a matter of debate. Pre-emptive treatment is started once early activation markers are detected and before clinical symptoms occur, while treatment is based on clinical symptoms of the disease.
Prophylactic treatment may be of value in high-risk patients (positive donor, negative recipient) and/or immunosuppression based cytotoxic antibodies [17]. In case of prophylaxis, it should be applied for about 3 months as CMV disease most frequently occurs 812 weeks after transplantation. However, in most cases pre-emptive treatment is the therapy of choice as it is more cost effective than prophylactic therapy. Furthermore, most studies indicate that pre-emptive therapy is at least as effective as prophylactic therapy [18,19]. On the other hand, some authors argue that even treatment is sufficient and no pre-emptive or prophylactic regimens are necessary [9].
The different results of and conclusions from these studies are probably based on differences in populations, in-house methods, duration of follow-up, and definition of disease. Furthermore, although the risk for disease is clearly associated with the serological status of donor and recipient, most published studies have not been matched with respect to the situation of positive donor and negative recipient.
If treatment is necessary, gancyclovir should be applied i.v. at least for as long as pp65 positive cells remain. In some cases, particularly if the situation of the patient does not improve or the number of pp65 positive cells or viral copies is not reduced, drug resistance and a switch to foscavir should be considered.
Whether or not the treatment should be continued after markers and clinical symptoms have disappeared is an open question. Currently, most centres tend to treat for 1014 days after symptoms have vanished. Secondary prophylaxis may be useful in early relapse or severe disease.
Summary
In summary, CMV should be considered in all cases of diarrhoea, creatinine increase, and/or leucopenia. In these cases and/or on a regular basis early markers for CMV should be tested and pre-emptive therapy initiated if tests give a positive result for as long as tests are positive.
Notes
Correspondence and offprint requests to: Uwe Heemann, Department of Nephrology, Essen University Hospital, Hufelandstr. 55, D-45122 Essen, Germany. Email: uwe.heemann{at}uni\|[hyphen]\|essen.de
References