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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2007  |  Volume : 18  |  Issue : 4  |  Page : 505-511
Review of the CMV in Renal Transplantation


Department of Surgery and Microbiology/Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA

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Keywords: Cytomegalovirus infection, Kidney transplantation, Treatment

How to cite this article:
Pescovitz MD. Review of the CMV in Renal Transplantation. Saudi J Kidney Dis Transpl 2007;18:505-11

How to cite this URL:
Pescovitz MD. Review of the CMV in Renal Transplantation. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2020 Oct 30];18:505-11. Available from: https://www.sjkdt.org/text.asp?2007/18/4/505/36470

   Introduction Top


Cytomegalovirus (CMV), the most important infectious complication to affect recipients of kidney transplants, is a significant cause of morbidity and mortality. [1] In the absence of any preventative therapy, CMV infection occurs in approximately 30-75% of transplant recipients, with an incidence of CMV disease of between 8 and 80%, depending on the type of transplantation, immunosuppression and, most importantly, the donor/recipient (D/R) CMV serostatus. [2] Additionally, pediatric patients are at increased risk of developing CMV infection as they are more likely to be seronegative at the time of transplantation and therefore immunologically native with respect to CMV. [3] With the current agents available for prevention of CMV, it is rare to see CMV while on therapy. [4] Instead, a new phenomenon of delayed CMV has appeared that requires increased vigilance.

There are two general patterns of CMV infection in transplant patients. [5] Primary infection occurs when a CMV-naive recipient is first exposed to virus. This most often occurs at the time of transplant by a virus contained within an organ obtained from a donor previously infected with CMV. Alternatively, transfusion of blood from a CMV-positive donor can result in disease. Rarely, primary infection can still occur through nosocomial infection. More frequently, virus already present in the recipient in a latent state can reactivate, leading to disease. This is typically less severe than primary disease as the recipient's immune system is more able to contain the infection. A major factor in CMV reactivation is tumor necrosis factor-alpha, [6] which is released by agents known to increase CMV disease such as anti-CD3. [7]

Initial infection with, or reactivation of, CMV can cause direct effects, including an acute viral syndrome with fever and other constitutional symptoms; and various end≠organ syndromes such as pneumonitis, entero≠colitis, nephritis, and hepatitis. [1] In the early days of transplant with older immuno≠suppressive agents and in the absence of effective prophylaxis, CMV infection and disease typically presented with high fever in the first 40 days post-transplant. [8],[9] More recently, CMV is more insidious, occurring later after prophylaxis has been discontinued, and with reduced systemic symptoms, particularly the absence of significant fever. [4],[10] In addition to these primary effects, CMV infection may cause indirect effects, including allograft injury and acute and chronic rejection, increased risk of cardiac complications, diabetes, post transplant lymphoproliferative disorder (PTLD), and even death. [11],[12],[13] Ultimately, it is these secondary effects that may have a greater impact on kidney survival.

Because of the substantial morbidity in solid organ transplant recipients, several drugs have been developed and used for CMV prophylaxis after kidney transplantation. These include CMV immunoglobulin, [14] acyclovir, [15] valacyclovir, [16] ganciclovir, [13] and, most recently, valganciclovir.[4] Furthermore, these drugs have been used in different therapeutic options. Prophylaxis refers to providing drug to a patient who has no detectable viremia. This can be universal prophylaxis, where a drug is administered to every patient; or more commonly, selective prophylaxis, where the drug of choice is provided only to patients considered at increased risk of CMV disease. The practice of monitoring for the presence of CMV viremia and treating only those with evidence of circulating virus is referred to as preemptive treatment. [17] Lastly, there is the option of only treating patients with active CMV disease. Until recently, this required intravenous dosing. A recently completed study, presented at the American Transplant Congress 2007, demons≠trated that valganciclovir could be effective for oral treatment. [18]

Ganciclovir, the first antiviral drug to be approved for the treatment of human CMV infection, has an established record of efficacy for both prevention and treatment of CMV infection and disease. Ganciclovir should be phosphorylated by the virally encoded kinase UL97 in order to exert its antiviral activity. Following this, cellular enzymes complete production of the active metabolite ganciclovir triphosphate (GCV-TP). GCV-TP then inhibits CMV viral DNA polymerase (UL54). [19],[20] Ganciclovir is active against all known human herpes viruses. Viral resistance to ganciclovir occurs primarily through mutations in the UL97 gene despite the appearance of UL54. [21],[22]

Although initially available only as an intra≠venous formulation, an oral form of ganciclovir was approved for prevention of CMV disease in transplant recipients based on the efficacy of 100 days' therapy in liver transplant recipients. [13] However, its usefulness for pro≠phylaxis is limited by its poor oral absorption such that frequent large daily doses are needed and resistance and breakthrough CMV disease can occur. [13],[23],[24] Valganciclovir was designed to overcome some of these limitations. [25] Valganciclovir, the L-valine ester of ganci≠clovir, is rapidly converted to ganciclovir. Once converted to ganciclovir, the mechanism of antiviral activity is the same. [19],[20] The bio≠-availability of ganciclovir from valganciclovir is approximately 60% in comparison to oral GCV, where it is only about 6%. [26] An international multicenter randomized double≠blind, double-dummy trial of 364 CMV≠seronegative recipients of hearts, livers, or kidneys from seropositive donors (D+/R-) compared 100 days of valganciclovir (900 mg once daily) with oral ganciclovir (1 g three times daily) for the prevention of CMV disease, with primary end point at six months and secondary end point at one year. [4] The results demonstrated that valganciclovir was equal to oral ganciclovir at both six (12.1% vs. 15.2%) and 12 months (17.2% vs. 18.4%). These efficacy results have been reproduced elsewhere. [27] In many centers, valganciclovir has become the standard of care for CMV prophylaxis.

There are two main issues with the use of valganciclovir for CMV prophylaxis: how long should the prophylaxis be, and what dose should be used? The standard duration for valganciclovir prophylaxis, 100 days, [4] is based on the placebo-controlled trial in which Balfour et al. used 12 weeks of acyclovir to prevent CMV post-transplant. [15] They stated, "Three months is a logical duration of prophylaxis, because cytomegalo≠virus disease usually occurs during that period." As prophylaxis has become more common, the peak incidence of CMV has moved away from the early post-transplant period-now occurring after prophylaxis has stopped. [4],[28] In an attempt to reduce the incidence of this delayed CMV, some clinicians have recently suggested that perhaps pro≠phylaxis should be extended past 100 days. For example, Zamora et al. found that the recurrence rate for post-'lung transplant' CMV was greater than 36% for patients who received less than six months' course of valganciclovir prophylaxis as opposed to less than 10% for patients who received a course longer than six months. [29] Doyle et al. reported a similar advantage when they used oral ganciclovir for six rather than three months in kidney transplant recipients. [30] An international double blind trial in high-risk, donor+/recipient- kidney transplant recipients sponsored by Roche is currently underway to formally test the advantages of extended prophylaxis. In an effort to reduce leukopenia, which was somewhat more common with valganciclovir 900 mg than oral ganciclovir, [4] and with a desire to reduce drug costs and pill burden, many sites have now started low≠dose valganciclovir, 450 mg once a day, in patients with normal renal function. It is believed that the reduced dose of valganci≠clovir provides the same drug exposure as 1000 mg three times a day of oral ganci≠clovir and therefore should provide equal efficacy. While lower doses do appear to be equally effective, most studies are retro≠spective; none are adequately powered for non-inferiority of 450 mg versus 900 mg, [31],[32],[33] and the actual renal function of the patients in the studies is not reported. [30],[32],[34] For a patient with a clearance of less than 60 ml/min, 450 mg might be the appropriate dose as per the label. Population pharmaco≠kinetics suggests that the drug exposure from 450 mg once a day of valganciclovir would in fact be less than that achieved with 1000 mg t.i.d. of oral ganciclovir. [35] In addition, while valganciclovir is frequently blamed, neutropenia is multifactorial and could result from depleting antibodies, mycophenolate mofetil, sirolimus, and the reduced use of corticosteroids, which normally would increase the neutrophil count. It is however unlikely that this question of dosing would be tested in an appropriately powered study.

Increasingly, the indirect effects of CMV are being addressed. A number of studies have investigated the potential relationship between CMV infection and acute allograft rejection. [36] In a study of 451 renal transplant recipients, both CMV infection (RR = 1.6; 95% CI = 1.1-2.5; p = 0.02) and CMV disease (RR = 2.5; 95% CI = 1.2-5.1; p = 0.01) were significant independent risk factors for the development of clinical acute allograft rejection following transplantation. [37] In a double-blind placebo-controlled study evaluating the effect of valacyclovir prophylaxis in preventing CMV disease in 616 renal transplant recipients (208 D+/R- and 408 R+ patients), the risk of acute graft rejection was reduced by half (p = 0.001) among CMV-seronegative recipients who received valacyclovir. [16] While it is suggested that the reduction in CMV was the primary cause of the reduced rejection, anti≠viral drugs have antiproliferative activity in allogeneic mixed lymphocyte culture and the reduced rejection might be a direct benefit of the drugs. [38]

In another study, there was evidence of CMV infection association with chronic graft rejection in kidney transplant recipients. [39] In a trial of 144 renal transplant recipients who had a protocol biopsy performed two years after transplantation, CMV infection (either viremia or tissue-invasive disease) in the first year after transplantation occurred significantly more frequently in patients who later developed chronic allograft nephropathy (i.e., chronic rejection) (p = 0.038).

CMV infection has been associated with increased risk of death resulting from cardio≠vascular causes. [40] Among 158 patients who died with a functioning allograft, 50 had cardio≠vascular causes. (As many as 94% of them were seropositive for CMV at the time of transplant or within 90 days post-transplant.) Of the 108 patients who died of other causes, only 74% were seropositive for CMV (p < 0.003). A similar increased risk of cardiac complications was noted in 1,859 kidney transplantations performed between 1984 and 1997 at a single institution. [12]

Significant risk factors for cardiac compli≠cations, identified by multivariate analysis, were patient age older than 50 years (OR = 2.5; p = 0.0001), diabetes (OR = 1.99; p = 0.0001), a history of cardiac disease pre≠transplant (OR = 1.34; p = 0.04), and CMV disease (OR = 1.5; p = 0.01). These findings suggest a role for CMV in the pathogenesis of coronary heart disease.

CMV prophylaxis also may be beneficial in preventing diseases other than CMV, such as Epstein-Barr virus (EBV)-associated PTLD. [41] Although there is no widely accepted consensus on the best preventive treatment for PTLD, antiviral drugs such as ganciclovir and acy-clovir are often used to inhibit EBV replication and prevent expansion of the EBV≠infected B-cell pool that results in PTLD. [41] In a recent case-controlled study, ganciclovir prophylaxis was associated with an 18% hazard ratio, or an 82% reduction in the risk of PTLD. For every 30 days of ganciclovir treatment, the risk of PTLD was reduced by 30% (OR = 0.70; 95% CI = 0.50-0.99). [42]

Although valganciclovir is effective and now widely used for CMV prophylaxis in transplant patients, late CMV particularly continues to be a problem. The search for newer and better agents continues. A vaccine using DNA tech≠nology (Vical, Inc.) is entering phase 2 clinical trials attempting to immunize patients prior to transplant. [43] Other oral agents such as maribavir (Viropharma, Inc.) have been proposed as possible replacements for ganciclovir or for use against resistant strains. [44] These latter two technologies/drugs, if successful in the various clinical stages, are at least five years away from regulatory approval.

 
   References Top

1.Fishman JA, Rubin RH. Infection in organ transplant recipients. N Engl J Med 1998;338(24):1741-51.  Back to cited text no. 1    
2.Preiksaitis JK, Brennan DC, Fishman J, Allen U. Canadian Society of Trans≠plantation consensus workshop on cyto≠megalovirus management in solid organ transplantation final report. Am J Trans≠plant 2005;5(2):218-27.  Back to cited text no. 2    
3.Burd RS, Gillingham KJ, Farber MS, et al. Diagnosis and treatment of cytomegalo≠virus disease in pediatric renal transplant recipients. J Pediatr Surg 1994;29(3): 1049-54.  Back to cited text no. 3    
4.Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cyto≠megalovirus disease in solid organ trans≠plant recipients. Am J Transplant 2004;4 (4):611-20.  Back to cited text no. 4    
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30.Doyle Am, Warburton KM, Goral S, Blumberg E, Grossman RA, Bloom RD. 24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course. Transplantation 2006;81(8):1106-11.  Back to cited text no. 30    
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35.Wiltshire H, Hirankarn S, Farrell C, et al. Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients. Clin Pharmacokinet 2005;44(5):495-507.  Back to cited text no. 35    
36.Humar A, Gillingham KJ, Payne WD, Dunn DL, Sutherland DE, Matas AJ. Association between cytomegalovirus disease and chronic rejection in kidney transplant recipients. Transplantation 1999; 68(12):1879-83.  Back to cited text no. 36    
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39.Solez K, Vincenti F, Filo RS. Histo≠pathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: A report of the FK506 Kidney Transplant Study Group. Trans≠plantation 1998;66:1736-40.  Back to cited text no. 39    
40.Kalil RS, Hudson SL, Gaston RS. Deter≠minants of cardiovascular mortality after renal transplantation: a role for cytomegalo≠virus? Am J Transplant 2003;3 (1):79-81.  Back to cited text no. 40    
41.Razonable RR, Paya CV. Herpesvirus infections in transplant recipients: current challenges in the clinical management of cytomegalovirus and Epstein-Barr virus infections. Herpes 2003;10(3):60-5.  Back to cited text no. 41    
42.Funch DP, Walker AM, Schneider G, Ziyadeh NJ, Pescovitz MD. Ganciclovir and acyclovir reduce the risk of post≠transplant lymphoproliferative disorder in renal transplant recipients. Am J Transplant 2005;5(12):2894-900.  Back to cited text no. 42    
43.Schleiss MR, Heineman TC. Progress toward an elusive goal: current status of cytomegalovirus vaccines. Expert Rev Vaccines 2005;4:381-406.  Back to cited text no. 43  [PUBMED]  [FULLTEXT]
44.Ma JD, Nafziger AN, Villano SA, Gaedigk A, Bertino JS Jr. Maribavir pharmacokinetics and the effects of multiple-dose maribavir on cytochrome P450 (CYP) 1A2, CYP 2C9, CYP 2C19, CYP 2D6, CYP 3A, N-acetyltransferase-2, and xanthine oxidase activities in healthy adults. Antimicrob Agents Chemother 2006;50(4):1130-5.  Back to cited text no. 44    

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Correspondence Address:
Mark D Pescovitz
Indiana University, RM MS-2031, 635 Barnhill Dr, Indianapolis, Indiana 46202
USA
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PMID: 17951935

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