Prevention of cytomegalovirus (CMV) is essential in organ transplantation. The two main strategies are pre-emptive therapy, in which one screens for and treats asymptomatic CMV viremia, and universal antiviral prophylaxis. We compared these strategies and examined long-term outcomes in a randomized, open-label, single-center trial. We randomly assigned 70 renal transplant recipients (CMV-seropositive recipient or donor) to 3-month prophylaxis with valacyclovir (n=34) or pre-emptive valganciclovir for significant CMV viremia detected at predefined assessments through month 12 (n=36). Among the 55 patients who had a protocol biopsy specimen available at 3 years to allow assessment of the primary outcome, 9 (38%) of 24 patients in the prophylaxis group and 6 (19%) of 31 patients in the pre-emptive therapy group had moderate to severe interstitial fibrosis and tubular atrophy (odds ratio, 2.50; 95% confidence interval, 0.74-8.43; P=0.22). The prophylaxis group had significantly higher intrarenal mRNA expression of genes involved in fibrogenesis. The occurrence of CMV disease was similar in both groups, but pre-emptive therapy improved 4-year graft survival (92% versus 74%; P=0.049) as a result of worse outcomes in patients with late-onset CMV viremia. In conclusion, compared with valacyclovir prophylaxis, pre-emptive valganciclovir therapy may lead to less severe interstitial fibrosis and tubular atrophy and to significantly better graft survival.

Department of Internal Medicine 1 Charles University Medical School and Teaching Hospital alej Svobody 80 304 60 Pilsen Czech Republic

J Am Soc Nephrol. 2012 Sep;23(9):1446-8. doi: 10.1681/ASN.2012070729. PubMed

Nat Rev Nephrol. 2012 Nov;8(11):614. doi: 10.1038/nrneph.2012.210. PubMed

Zobrazit více v PubMed

Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 357: 2601–2614, 2007 PubMed

Reischig T: Cytomegalovirus-associated renal allograft rejection: New challenges for antiviral preventive strategies. Expert Rev Anti Infect Ther 8: 903–910, 2010 PubMed

Sagedal S, Nordal KP, Hartmann A, Sund S, Scott H, Degré M, Foss A, Leivestad T, Osnes K, Fauchald P, Rollag H: The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2: 850–856, 2002 PubMed

Reischig T, Jindra P, Hes O, Bouda M, Kormunda S, Treska V: Effect of cytomegalovirus viremia on subclinical rejection or interstitial fibrosis and tubular atrophy in protocol biopsy at 3 months in renal allograft recipients managed by preemptive therapy or antiviral prophylaxis. Transplantation 87: 436–444, 2009 PubMed

Smith JM, Corey L, Bittner R, Finn LS, Healey PJ, Davis CL, McDonald RA: Subclinical viremia increases risk for chronic allograft injury in pediatric renal transplantation. J Am Soc Nephrol 21: 1579–1586, 2010 PubMed PMC

Sagedal S, Hartmann A, Nordal KP, Osnes K, Leivestad T, Foss A, Degré M, Fauchald P, Rollag H: Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 66: 329–337, 2004 PubMed

Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Snydman DR, Allen U, Humar A, Transplantation Society International CMV Consensus Group : International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 89: 779–795, 2010 PubMed

Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD, Valganciclovir Solid Organ Transplant Study Group : Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 4: 611–620, 2004 PubMed

Lowance D, Neumayer HH, Legendre CM, Squifflet JP, Kovarik J, Brennan PJ, Norman D, Mendez R, Keating MR, Coggon GL, Crisp A, Lee IC, International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group : Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. N Engl J Med 340: 1462–1470, 1999 PubMed

Reischig T, Jindra P, Mares J, Cechura M, Svecová M, Hes O, Opatrný K, Jr, Treska V: Valacyclovir for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection. Transplantation 79: 317–324, 2005 PubMed

Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K, Vimalachandra D, Craig JC: Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: A systematic review of randomised controlled trials. Lancet 365: 2105–2115, 2005 PubMed

Kalil AC, Levitsky J, Lyden E, Stoner J, Freifeld AG: Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 143: 870–880, 2005 PubMed

Khoury JA, Storch GA, Bohl DL, Schuessler RM, Torrence SM, Lockwood M, Gaudreault-Keener M, Koch MJ, Miller BW, Hardinger KL, Schnitzler MA, Brennan DC: Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 6: 2134–2143, 2006 PubMed

Reischig T, Jindra P, Hes O, Svecová M, Klaboch J, Treska V: Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant 8: 69–77, 2008 PubMed

Kliem V, Fricke L, Wollbrink T, Burg M, Radermacher J, Rohde F: Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: Results of a randomized clinical trial. Am J Transplant 8: 975–983, 2008 PubMed

Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR: The natural history of chronic allograft nephropathy. N Engl J Med 349: 2326–2333, 2003 PubMed

Cosio FG, Grande JP, Wadei H, Larson TS, Griffin MD, Stegall MD: Predicting subsequent decline in kidney allograft function from early surveillance biopsies. Am J Transplant 5: 2464–2472, 2005 PubMed

Mannon RB, Matas AJ, Grande J, Leduc R, Connett J, Kasiske B, Cecka JM, Gaston RS, Cosio F, Gourishankar S, Halloran PF, Hunsicker L, Rush D, DeKAF Investigators : Inflammation in areas of tubular atrophy in kidney allograft biopsies: A potent predictor of allograft failure. Am J Transplant 10: 2066–2073, 2010 PubMed PMC

Stegall MD, Park WD, Larson TS, Gloor JM, Cornell LD, Sethi S, Dean PG, Prieto M, Amer H, Textor S, Schwab T, Cosio FG: The histology of solitary renal allografts at 1 and 5 years after transplantation. Am J Transplant 11: 698–707, 2011 PubMed

Halloran PF, de Freitas DG, Einecke G, Famulski KS, Hidalgo LG, MengeL M, Reeve J, Sellares J, Sis B: An integrated view of molecular changes, histopathology and outcomes in kidney transplants. Am J Transplant 10: 2223–2230, 2010 PubMed

Pribylova-Hribova P, Kotsch K, Lodererova A, Viklicky O, Vitko S, Volk HD, Lacha J: TGF-beta1 mRNA upregulation influences chronic renal allograft dysfunction. Kidney Int 69: 1872–1879, 2006 PubMed

Benmarzouk-Hidalgo OJ, Cisneros JM, Cordero E, Martín-Peña A, Sanchez B, Martin-Gandul C, Gentil MA, Gomez-Bravo MA, Lage E, Perez-Romero P: Therapeutic effect of the acquisition of cytomegalovirus-specific immune response during preemptive treatment. Transplantation 91: 927–933, 2011 PubMed

Nickel P, Bold G, Presber F, Biti D, Babel N, Kreutzer S, Pratschke J, Schönemann C, Kern F, Volk HD, Reinke P: High levels of CMV-IE-1-specific memory T cells are associated with less alloimmunity and improved renal allograft function. Transpl Immunol 20: 238–242, 2009 PubMed

Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M, VIPP Study Group : Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation 93: 61–68, 2012 PubMed

Spinner ML, Saab G, Casabar E, Bowman LJ, Storch GA, Brennan DC: Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 90: 412–418, 2010 PubMed PMC

Couzi L, Helou S, Bachelet T, Moreau K, Martin S, Morel D, Lafon ME, Boyer B, Alain S, Garrigue I, Merville P: High incidence of anticytomegalovirus drug resistance among D+R- kidney transplant recipients receiving preemptive therapy. Am J Transplant 12: 202–209, 2012 PubMed

Humar A, Lebranchu Y, Vincenti F, Blumberg EA, Punch JD, Limaye AP, Abramowicz D, Jardine AG, Voulgari AT, Ives J, Hauser IA, Peeters P: The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 10: 1228–1237, 2010 PubMed

Lisboa LF, Preiksaitis JK, Humar A, Kumar D: Clinical utility of molecular surveillance for cytomegalovirus after antiviral prophylaxis in high-risk solid organ transplant recipients. Transplantation 92: 1063–1068, 2011 PubMed

Preiksaitis JK, Brennan DC, Fishman J, Allen U: Canadian society of transplantation consensus workshop on cytomegalovirus management in solid organ transplantation final report. Am J Transplant 5: 218–227, 2005 PubMed

Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff M, Weening JJ: Banff ’05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’). Am J Transplant 7: 518–526, 2007 PubMed

A Randomized Trial of Valganciclovir Prophylaxis Versus Preemptive Therapy in Kidney Transplant Recipients

Heterologous Cytomegalovirus and Allo-Reactivity by Shared T Cell Receptor Repertoire in Kidney Transplantation

Less renal allograft fibrosis with valganciclovir prophylaxis for cytomegalovirus compared to high-dose valacyclovir: a parallel group, open-label, randomized controlled trial

Randomized trial of valganciclovir versus valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation