Cytomegalovirus infection in renal transplant recipients

INTRODUCTION

Cytomegalovirus (CMV) is one of the most important infections in renal transplant recipients [1-5]. Exposure to the virus, as indicated by the presence of detectable immunoglobulin G (IgG) anti-CMV antibodies in the plasma, increases with age in the general population and is present in more than two-thirds of donors and recipients prior to transplantation [1]. It is therefore common for the donor and/or recipient to be CMV-positive at the time of transplantation.

CMV can be transmitted from the donor either by blood transfusion or by the transplanted kidney; the concurrent administration of immunosuppressive drugs to prevent rejection further increases the risk of clinically relevant CMV disease, with induction therapy principally being associated with an increased risk of disease [6,7]. Thus, both the recipient and the donor are routinely tested for anti-CMV antibodies prior to transplantation. (See "Evaluation for infection before solid organ transplantation".)

CMV is also a significant underlying cause of morbidity and mortality in the renal transplant setting:

This was shown in a study using data from the United States Renal Data System in which donor and recipient CMV serostatus was available for over 17,000 deceased-donor renal transplant recipients [8]. Based upon a multivariate analysis, CMV-positive patients had significantly higher incidence of CMV disease, allograft loss, and overall costs, compared with CMV-negative recipients.

The impact of CMV on overall mortality was examined in a prospective, single-center study of almost 500 patients who did not receive induction therapy or CMV prophylaxis [9]. Patients were monitored by weekly CMV pp65 antigenemia for 100 days and followed for a median length of time of 66 months. Despite the absence of induction therapy and maintenance immunosuppressive therapy with cyclosporine, mycophenolate mofetil (MMF), and low-dose prednisone, CMV-antigenemia was detectable in over 60 percent of patients in the first 100 days after transplant. Compared with those without CMV, CMV disease was associated with a relative risk of overall mortality of 2.5, and, importantly, asymptomatic CMV infection was associated with a relative risk of overall mortality of 2.9.

                             

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Literature review current through: Nov 2014. | This topic last updated: Apr 3, 2014.
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References
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  1. Rubin RH. Infectious disease complications of renal transplantation. Kidney Int 1993; 44:221.
  2. Farrugia E, Schwab TR. Management and prevention of cytomegalovirus infection after renal transplantation. Mayo Clin Proc 1992; 67:879.
  3. Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc Nephrol 2001; 12:848.
  4. Smith SR, Butterly DW, Alexander BD, Greenberg A. Viral infections after renal transplantation. Am J Kidney Dis 2001; 37:659.
  5. Kotton CN, Fishman JA. Viral infection in the renal transplant recipient. J Am Soc Nephrol 2005; 16:1758.
  6. Büchler M, Hurault de Ligny B, Madec C, et al. Induction therapy by anti-thymocyte globulin (rabbit) in renal transplantation: a 1-yr follow-up of safety and efficacy. Clin Transplant 2003; 17:539.
  7. Burke GW 3rd, Kaufman DB, Millis JM, et al. Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results. Transplantation 2004; 77:1269.
  8. Schnitzler MA, Lowell JA, Hardinger KL, et al. The association of cytomegalovirus sero-pairing with outcomes and costs following cadaveric renal transplantation prior to the introduction of oral ganciclovir CMV prophylaxis. Am J Transplant 2003; 3:445.
  9. Sagedal S, Hartmann A, Nordal KP, et al. Impact of early cytomegalovirus infection and disease on long-term recipient and kidney graft survival. Kidney Int 2004; 66:329.
  10. 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 2005; 5:218.
  11. Toyoda M, Carlos JB, Galera OA, et al. Correlation of cytomegalovirus DNA levels with response to antiviral therapy in cardiac and renal allograft recipients. Transplantation 1997; 63:957.
  12. Roberts TC, Brennan DC, Buller RS, et al. Quantitative polymerase chain reaction to predict occurrence of symptomatic cytomegalovirus infection and assess response to ganciclovir therapy in renal transplant recipients. J Infect Dis 1998; 178:626.
  13. Ferreira-Gonzalez A, Fisher RA, Weymouth LA, et al. Clinical utility of a quantitative polymerase chain reaction for diagnosis of cytomegalovirus disease in solid organ transplant patients. Transplantation 1999; 68:991.
  14. Emery VC, Sabin CA, Cope AV, et al. Application of viral-load kinetics to identify patients who develop cytomegalovirus disease after transplantation. Lancet 2000; 355:2032.
  15. Reischig T, Jindra P, Hes O, et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant 2008; 8:69.
  16. Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant 2006; 6:2134.
  17. The American Society of Transplantation Infectious Disease Guidelines. Am J Transplant 2009; 9(Suppl 4):S8.
  18. Strippoli GF, Hodson EM, Jones C, Craig JC. Preemptive treatment for cytomegalovirus viremia to prevent cytomegalovirus disease in solid organ transplant recipients. Transplantation 2006; 81:139.
  19. Kalil AC, Levitsky J, Lyden E, et al. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med 2005; 143:870.
  20. Hodson EM, Jones CA, Webster AC, et al. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet 2005; 365:2105.
  21. Florescu DF, Qiu F, Schmidt CM, Kalil AC. A direct and indirect comparison meta-analysis on the efficacy of cytomegalovirus preventive strategies in solid organ transplant. Clin Infect Dis 2014; 58:785.
  22. Jung C, Engelmann E, Borner K, Offermann G. Preemptive oral ganciclovir therapy versus prophylaxis to prevent symptomatic cytomegalovirus infection after kidney transplantation. Transplant Proc 2001; 33:3621.
  23. Pescovitz MD, Rabkin J, Merion RM, et al. Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients. Antimicrob Agents Chemother 2000; 44:2811.
  24. Chamberlain CE, Penzak SR, Alfaro RM, et al. Pharmacokinetics of low and maintenance dose valganciclovir in kidney transplant recipients. Am J Transplant 2008; 8:1297.
  25. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2004; 4:611.
  26. Brennan DC, Garlock KA, Singer GG, et al. Prophylactic oral ganciclovir compared with deferred therapy for control of cytomegalovirus in renal transplant recipients. Transplantation 1997; 64:1843.
  27. Sun HY, Wagener MM, Singh N. Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review. Am J Transplant 2008; 8:2111.
  28. Humar A, Lebranchu Y, Vincenti F, et al. The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 2010; 10:1228.
  29. Limaye AP, Corey L, Koelle DM, et al. Emergence of ganciclovir-resistant cytomegalovirus disease among recipients of solid-organ transplants. Lancet 2000; 356:645.
  30. Snydman DR, Rubin RH, Werner BG. New developments in cytomegalovirus prevention and management. Am J Kidney Dis 1993; 21:217.
  31. Snydman DR, Werner BG, Heinze-Lacey B, et al. Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med 1987; 317:1049.
  32. Kuypers DR, Vanrenterghem YF. Prophylaxis of cytomegalovirus infection in renal transplantation: new data for an old problem. Nephrol Dial Transplant 1999; 14:2304.
  33. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group. N Engl J Med 1999; 340:1462.
  34. Reischig T, Hribova P, Jindra P, et al. Long-term outcomes of pre-emptive valganciclovir compared with valacyclovir prophylaxis for prevention of cytomegalovirus in renal transplantation. J Am Soc Nephrol 2012; 23:1588.
  35. Santos RD, Brennan DC. Randomized trial of pre-emptive or prophylactic valganciclovir therapy for prevention of cytomegalovirus infection in renal transplantation. J Am Soc Nephrol 2012; 23:1446.
  36. Kliem V, Fricke L, Wollbrink T, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized clinical trial. Am J Transplant 2008; 8:975.
  37. Spinner ML, Saab G, Casabar E, et al. Impact of prophylactic versus preemptive valganciclovir on long-term renal allograft outcomes. Transplantation 2010; 90:412.
  38. Valacyclovir: Package Insert.
  39. Knight DA, Hejmanowski AQ, Dierksheide JE, et al. Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide. Transplantation 2001; 71:170.
  40. Waldman WJ, Knight DA, Blinder L, et al. Inhibition of cytomegalovirus in vitro and in vivo by the experimental immunosuppressive agent leflunomide. Intervirology 1999; 42:412.
  41. Waldman WJ, Knight DA, Lurain NS, et al. Novel mechanism of inhibition of cytomegalovirus by the experimental immunosuppressive agent leflunomide. Transplantation 1999; 68:814.
  42. John GT, Manivannan J, Chandy S, et al. Leflunomide therapy for cytomegalovirus disease in renal allograft recepients. Transplantation 2004; 77:1460.
  43. Chong AS, Zeng H, Knight DA, et al. Concurrent antiviral and immunosuppressive activities of leflunomide in vivo. Am J Transplant 2006; 6:69.
  44. Balfour HH Jr, Chace BA, Stapleton JT, et al. A randomized, placebo-controlled trial of oral acyclovir for the prevention of cytomegalovirus disease in recipients of renal allografts. N Engl J Med 1989; 320:1381.
  45. Kletzmayr J, Kotzmann H, Popow-Kraupp T, et al. Impact of high-dose oral acyclovir prophylaxis on cytomegalovirus (CMV) disease in CMV high-risk renal transplant recipients. J Am Soc Nephrol 1996; 7:325.
  46. Jassal SV, Roscoe JM, Zaltzman JS, et al. Clinical practice guidelines: prevention of cytomegalovirus disease after renal transplantation. J Am Soc Nephrol 1998; 9:1697.
  47. Kudlacz E, Perry B, Sawyer P, et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004; 4:51.
  48. Winston DJ, Wirin D, Shaked A, Busuttil RW. Randomised comparison of ganciclovir and high-dose acyclovir for long-term cytomegalovirus prophylaxis in liver-transplant recipients. Lancet 1995; 346:69.
  49. Schnitzler MA, Lowell JA, Hmiel SP, et al. Cytomegalovirus disease after prophylaxis with oral ganciclovir in renal transplantation: the importance of HLA-DR matching. J Am Soc Nephrol 2003; 14:780.
  50. Goodrich JM, Bowden RA, Fisher L, et al. Ganciclovir prophylaxis to prevent cytomegalovirus disease after allogeneic marrow transplant. Ann Intern Med 1993; 118:173.
  51. Schnitzler MA, Woodward RS, Brennan DC, et al. The effects of cytomegalovirus serology on graft and recipient survival in cadaveric renal transplantation: implications for organ allocation. Am J Kidney Dis 1997; 29:428.
  52. Schnitzler MA, Woodward RS, Brennan DC, et al. Impact of cytomegalovirus serology on graft survival in living related kidney transplantation: implications for donor selection. Surgery 1997; 121:563.
  53. Hibberd PL, Tolkoff-Rubin NE, Cosimi AB, et al. Symptomatic cytomegalovirus disease in the cytomegalovirus antibody seropositive renal transplant recipient treated with OKT3. Transplantation 1992; 53:68.
  54. Oh CS, Stratta RJ, Fox BC, et al. Increased infections associated with the use of OKT3 for treatment of steroid-resistant rejection in renal transplantation. Transplantation 1988; 45:68.
  55. Doyle AM, Warburton KM, Goral S, et al. 24-week oral ganciclovir prophylaxis in kidney recipients is associated with reduced symptomatic cytomegalovirus disease compared to a 12-week course. Transplantation 2006; 81:1106.
  56. Akalin E, Bromberg JS, Sehgal V, et al. Decreased incidence of cytomegalovirus infection in thymoglobulin-treated transplant patients with 6 months of valganciclovir prophylaxis. Am J Transplant 2004; 4:148.
  57. Helanterä I, Lautenschlager I, Koskinen P. Prospective follow-up of primary CMV infections after 6 months of valganciclovir prophylaxis in renal transplant recipients. Nephrol Dial Transplant 2009; 24:316.
  58. Geddes CC, Church CC, Collidge T, et al. Management of cytomegalovirus infection by weekly surveillance after renal transplant: analysis of cost, rejection and renal function. Nephrol Dial Transplant 2003; 18:1891.
  59. Kotton CN, Kumar D, Caliendo AM, et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010; 89:779.
  60. Moreso F, Serón D, Morales JM, et al. Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses. Clin Transplant 1998; 12:198.
  61. Shelhamer JH, Gill VJ, Quinn TC, et al. The laboratory evaluation of opportunistic pulmonary infections. Ann Intern Med 1996; 124:585.
  62. Stoffel M, Gianello P, Squifflet JP, et al. Effect of 9-(2-hydroxy-1-[hydroxymethyl] ethoxymethyl) guanine (DHPG) on cytomegalovirus pneumonitis after renal transplantation. Transplantation 1988; 46:594.
  63. Harbison MA, De Girolami PC, Jenkins RL, Hammer SM. Ganciclovir therapy of severe cytomegalovirus infections in solid-organ transplant recipients. Transplantation 1988; 46:82.
  64. Snydman DR. Ganciclovir therapy for cytomegalovirus disease associated with renal transplants. Rev Infect Dis 1988; 10 Suppl 3:S554.
  65. Waid TH, McKeown JW. Cytomegalovirus hyperimmune globulin for CMV disease refractory to ganciclovir in renal transplantation. Transplant Proc 1995; 27:46.
  66. Brennan DC, Garlock KA, Lippmann BA, et al. Control of cytomegalovirus-associated morbidity in renal transplant patients using intensive monitoring and either preemptive or deferred therapy. J Am Soc Nephrol 1997; 8:118.
  67. Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N Engl J Med 2002; 346:1119.
  68. Babel N, Gabdrakhmanova L, Juergensen JS, et al. Treatment of cytomegalovirus disease with valganciclovir in renal transplant recipients: a single center experience. Transplantation 2004; 78:283.
  69. Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant 2007; 7:2106.
  70. Asberg A, Humar A, Jardine AG, et al. Long-term outcomes of CMV disease treatment with valganciclovir versus IV ganciclovir in solid organ transplant recipients. Am J Transplant 2009; 9:1205.
  71. Avery RK. Valganciclovir versus IV ganciclovir for therapy of cytomegalovirus viremia: has victory been achieved? Am J Transplant 2007; 7:2062.
  72. Asberg A, Jardine AG, Bignamini AA, et al. Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 2010; 10:1881.
  73. Richardson WP, Colvin RB, Cheeseman SH, et al. Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med 1981; 305:57.
  74. Herrera GA, Alexander RW, Cooley CF, et al. Cytomegalovirus glomerulopathy: a controversial lesion. Kidney Int 1986; 29:725.
  75. Birk PE, Chavers BM. Does cytomegalovirus cause glomerular injury in renal allograft recipients? J Am Soc Nephrol 1997; 8:1801.
  76. Liapis H, Storch GA, Hill DA, et al. CMV infection of the renal allograft is much more common than the pathology indicates: a retrospective analysis of qualitative and quantitative buffy coat CMV-PCR, renal biopsy pathology and tissue CMV-PCR. Nephrol Dial Transplant 2003; 18:397.
  77. Pouteil-Noble C, Ecochard R, Landrivon G, et al. Cytomegalovirus infection--an etiological factor for rejection? A prospective study in 242 renal transplant patients. Transplantation 1993; 55:851.
  78. Pouria S, State OI, Wong W, Hendry BM. CMV infection is associated with transplant renal artery stenosis. QJM 1998; 91:185.
  79. Miller BW, Hmiel SP, Schnitzler MA, Brennan DC. Cyclosporine as cause of thrombotic microangiopathy after renal transplantation. Am J Kidney Dis 1997; 29:813.
  80. Tschuchnigg M, Bradstock KF, Koutts J, et al. A case of thrombotic thrombocytopenic purpura following allogeneic bone marrow transplantation. Bone Marrow Transplant 1990; 5:61.
  81. Jeejeebhoy FM, Zaltzman JS. Thrombotic microangiopathy in association with cytomegalovirus infection in a renal transplant patient: a new treatment strategy. Transplantation 1998; 65:1645.
  82. Hochstetler LA, Flanigan MJ, Lager DJ. Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy. Am J Kidney Dis 1994; 23:444.