Modern immunosuppressive regimens in paediatric kidney transplant recipients have contributed to improved long-term allograft survival, but at the expense of an increased incidence of viral infections. Here, we describe, for the first time, the incidence, risk factors and clinical outcome of CMV, EBV, BKV and JCV viraemia in a cohort of paediatric allograft recipients treated with a corticosteroid-minimisation immunosuppressive regimen (CMR).
We retrospectively analysed 98 children treated with a CMR (basiliximab induction, corticosteroids until day 4, long-term tacrolimus and mycophenolate mofetil), who received a kidney transplant in our centre between 2009 and 2019.
Over the first 4 years post-transplant, the incidences of viraemia were as follows: CMV, 25.5%; EBV, 52.0%; JCV, 16.3%; BKV, 26.5%. Younger children at time of transplant were more likely to develop EBV and BKV viraemia. EBV viraemia was also associated with a regimen involving corticosteroids, but lacking MMF. Recipient CMV serology predicted the development of EBV, BKV and CMV viraemia. Fifty-six percent of CMV viraemia episodes in high-risk patients occurred whilst the graft recipients were still receiving anti-viral prophylaxis or within 3 months of cessation. There was no difference in graft function at latest follow-up between those with and without viraemia.
Judicious monitoring of viraemia, coupled with timely clinical intervention, can result in similar long-term outcomes for graft recipients compared to controls. The high incidence of CMV viraemia observed within a short period of cessation of anti-viral prophylaxis supports an extension of the length of prophylactic treatment in high-risk allograft recipients.
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Chua A, Cramer C, Moudgil A, Martz K, Smith J, Blydt-Hansen T, Neu A, Dharnidharka V, NAPRTCS investigators (2019) Kidney transplant practice patterns and outcome benchmarks over 30 years: The 2018 report of the NAPRTCS. Pediatr Transplant 23:e13597. https://doi.org/10.1111/petr.13597
Mumford L, Maxwell H, Ahmad N, Marks S, Tizard J (2019) The impact of changing practice on improved outcomes of paediatric renal transplantation in the United Kingdom: A 25 years review. Transpl Int 32:751–761. https://doi.org/10.1111/tri.13418
Dharnidharka VR, Stablein DM, Harmon WE (2004) Post-transplant infections now exceed acute rejection as cause for hospitalization: A report of the NAPRTCS. Am J Transplant 4:384–389. https://doi.org/10.1111/j.1600-6143.2004.00350.x
Höcker B, Zencke S, Krupka K, Fichtner A, Pape L, Dello Strologo L, Guzzo I, Topaloglu R, Kranz B, König J, Bald M, Webb N, Noyan A, Dursun H, Marks S, Yalcinkaya F, Thiel F, Billing H, Pohl M, Fehrenbach H, Bruckner T, Tönshoff B (2016) Cytomegalovirus infection in pediatric renal transplantation and the impact of chemoprophylaxis with (val-)ganciclovir. Transplantation 100:862–870. https://doi.org/10.1097/TP.0000000000000888
Li L, Chaudhuri A, Weintraub LA, Hsieh F, Shah S, Alexander S, Salvatierra O Jr, Sarwal M (2007) Subclinical cytomegalovirus and Epstein-Barr virus viremia are associated with adverse outcomes in pediatric renal transplantation. Pediatr Transplant 11:187–195. https://doi.org/10.1111/j.1399-3046.2006.00641.x
Comak E, Akman S, Ongut G, Colak D, Koyun M, Dogan C, Mutlu D, Saglik I, Gokceoglu A, Dinckan A (2014) Epstein-Barr virus infection in children with renal transplantation: 17 years experience at a single center. Ren Fail 36:760–766. https://doi.org/10.3109/0886022X.2014.890861
Moudgil A, Martz K, Moore T, Harmon W, Dharnidharka V (2014) Significance of asymptomatic persistent Epstein-Barr viral load in pediatric renal transplant recipients: North American Pediatric Renal Trials and Collaborative Studies Report. Open Urol Nephrol J 7:123–128. https://doi.org/10.2174/1874303x01407010123
Höcker B, Schneble L, Murer L, Carraro A, Pape L, Kranz B, Oh J, Zirngibl M, Dello Strologo L, Büscher A, Weber L, Awan A, Pohl M, Bald M, Printza N, Rusai K, Peruzzi L, Topaloglu R, Fichtner A, Krupka K, Köster L, Bruckner T, Schnitzler P, Hirsch H, Tönshoff B (2019) Epidemiology of and risk factors for BK polyomavirus replication and nephropathy in pediatric renal transplant recipients: An international CERTAIN registry study. Transplantation 103:1224–1233. https://doi.org/10.1097/TP.0000000000002414
Weikert BC, Blumberg EA (2008) Viral infection after renal transplantation: Surveillance and management. Clin J Am Soc Nephrol 3:S76–S86. https://doi.org/10.2215/CJN.02900707
Höcker B, Tabatabai J, Schneble L, Oh J, Thiel F, Pape L, Rusai K, Topaloglu R, Kranz B, Klaus G, Printza N, Yavascan O, Fichtner A, Krupka K, Bruckner T, Waldherr R, Pawlita M, Schnitzler P, Hirsch H, Tönshoff B (2018) JC polyomavirus replication and associated disease in pediatric renal transplantation: An international CERTAIN registry study. Pediatr Nephrol 33:2343–2352. https://doi.org/10.1007/s00467-018-4029-9
Grenda R, Watson A, Trompeter R, Tönshoff B, Jaray J, Fitzpatrick M, Murer L, Vondrak K, Maxwell H, Damme-Lombaerts R, Loirat C, Mor E, Cochat P, Milford D, Brown M, Webb N (2010) A randomized trial to assess the impact of early steroid withdrawal on growth in pediatric renal transplantation: The twist study. Am J Transplant 10:828–836. https://doi.org/10.1111/j.1600-6143.2010.03047.x
Webb NJA, Douglas SE, Rajai A, Roberts S, Grenda R, Marks S, Watson A, Fitzpatrick M, Vondrak K, Maxwell H, Jaray J, Damme-Lombaerts R, Milford D, Godefroid N, Cochat P, Ognjanovic M, Murer L, McCulloch M, Tönshoff B (2015) Corticosteroid-free kidney transplantation improves growth: 2-year follow-up of the twist randomized controlled trial. Transplantation 99:1178–1185. https://doi.org/10.1097/TP.0000000000000498
Schwartz G, Muñoz A, Schneider M, Mak R, Kaskel F, Warady B, Furth S (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637. https://doi.org/10.1681/ASN.2008030287
Levey AS, Coresh J, Greene T, Stevens L, Zhang Y, Hendriksen S, Kusek J, Lente F, Chronic Kidney Disease Epidemiology Collaboration (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–254. https://doi.org/10.7326/0003-4819-145-4-200608150-00004
Roufosse C, Simmonds N, Clahsen-van Groningen M, Marian M, Haas M, Henriksen K, Horsfield C, Loupy A, Mengel M, Perkowska-Ptasińska A, Rabant M, Racusen L, Solez K, Becker J (2018) A 2018 reference guide to the Banff classification of renal allograft pathology. Transplantation 102:1795–1814. https://doi.org/10.1097/TP.0000000000002366
Höcker B, Fickenscher H, Delecluse H, Böhm S, Küsters U, Schnitzler P, Pohl M, John U, Kemper M, Fehrenbach H, Wigger M, Holder M, Schröder M, Billing H, Fichtner A, Feneberg R, Sander A, Köpf-Shakib S, Süsal C, Tönshoff B (2013) Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: A multicenter, prospective study. Clin Infect Dis 56:84–92. https://doi.org/10.1093/cid/cis823
Griffiths PD, Rothwell E, Raza M, Wilmore S, Doyle T, Harber M, O’Beirne J, Mackinnon S, Jones G, Thorburn D, Mattes F, Nebbia G, Atabani S, Smith C, Stanton A, Emery V (2016) Randomized controlled trials to define viral load thresholds for cytomegalovirus pre-emptive therapy. PLoS One 11:e0163722. https://doi.org/10.1371/journal.pone.0163722
Franceschini E, Plessi J, Zona S, Santoro A, Digaetano M, Fontana F, Alfano G, Guaraldi G, Comoli P, Facchini F, Potenza L, Gennari W, Codeluppi M, Luppi M, Cappelli G, Gyssens I, Mussini C (2017) Clinical utility of Epstein-Barr virus viral load monitoring and risk factors for posttransplant lymphoproliferative disorders after kidney transplantation. Transplant Direct 3:e182. https://doi.org/10.1097/TXD.0000000000000703
Chaiyapak T, Borges K, Williams A, Banh T, Vasilevska-Ristovska J, Allen U, Parekh R, Hébert D (2018) Incidence of cytomegalovirus DNAemia in pediatric kidney transplant recipients after cessation of antiviral prophylaxis. Transplantation 102:1391–1396. https://doi.org/10.1097/TP.0000000000002115
Humar A, Lebranchu Y, Vincenti F, Blumberg E, Punch J, Limaye A, Abramowicz D, Jardine A, Voulgari A, Ives J, Hauser I, Peeters P (2010) The efficacy and safety of 200 days valganciclovir cytomegalovirus prophylaxis in high-risk kidney transplant recipients. Am J Transplant 10:1228–1237. https://doi.org/10.1111/j.1600-6143.2010.03074.x
Pembrey L, Waiblinger D, Griffiths P, Patel M, Azad R, Wright J (2017) Cytomegalovirus, Epstein-Barr virus and varicella zoster virus infection in the first two years of life: A cohort study in Bradford, UK. BMC Infect Dis 17:220. https://doi.org/10.1186/s12879-017-2319-7
Goodier MR, White MJ, Darboe A, Nielsen C, Goncalves A, Bottomley C, Moore S, Riley E (2014) Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions. Blood 124:2213–2222. https://doi.org/10.1182/blood-2014-05-576124
Dowd JB, Palermo T, Brite J, McDade T, Aiello A (2013) Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6-19, 2003-2010. PLoS One 8:e64921. https://doi.org/10.1371/journal.pone.0064921
Knowles W, Pipkin P, Andrews N, Vyse A, Minor P, Brown D, Miller E (2003) Population-based study of antibody to the human polyomaviruses BKV and JCV and the Simian polyomavirus SV40. J Med Virol 71:115–123. https://doi.org/10.1002/jmv.10450
Voigt S, Rosario A, Mankertz A (2016) Cytomegalovirus seroprevalence among children and adolescents in Germany: Data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003-2006. Open Forum Infect Dis 3:ofv193. https://doi.org/10.1093/ofid/ofv193
Reischig T, Kacer M, Hes O, Machova J, Nemcova J, Lysak D, Jindra P, Pivovarcikova K, Kormunda S, Bouda M (2019) Cytomegalovirus prevention strategies and the risk of BK polyomavirus viremia and nephropathy. Am J Transplant 19:2457–2467. https://doi.org/10.1111/ajt.15507
Höcker B, Böhm S, Fickenscher H, Küsters U, Schnitzler P, Pohl M, John U, Kemper M, Fehrenbach H, Wigger M, Holder M, Schröder M, Feneberg R, Köpf-Shakib S, Tönshoff B (2012) (Val-)ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation. Transpl Int 25:723–731. https://doi.org/10.1111/j.1432-2277.2012.01485.x
Paulsen G, Cumagun P, Mixon E, Fowler K, Feig D, Shimamura M (2019) Cytomegalovirus and Epstein-Barr virus infections among pediatric kidney transplant recipients at a center using universal valganciclovir prophylaxis. Pediatr Transplant 23:e13382. https://doi.org/10.1111/petr.13382
Blazquez-Navarro A, Dang-Heine C, Wittenbrink N, Bauer C, Wolk K, Sabat R, Westhoff T, Sawitzki B, Reinke P, Thomusch O, Hugo C, Or-Guil M, Babela N (2018) BKV, CMV, and EBV interactions and their effect on graft function one year post-renal transplantation: Results from a large multi-centre study. EBioMedicine 34:113–121. https://doi.org/10.1016/j.ebiom.2018.07.017
We thank Prof. Rachel Lennon and Dr. Nick Plant for their advice during the preparation of this manuscript.
The study was supported by a Jean Shanks/Pathological Society Clinical Lecturer Grant (Grant reference: JSPS CLG 2019 02) (awarded to JM).
The study was assessed by the RMCH Research and Development Department at the time of study inception. It was confirmed that formal ethical approval was not required for this case note review study. No patient identifiable data was recorded.
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McCaffrey, J., Bhute, V.J. & Shenoy, M. CMV, EBV, JCV and BKV infection and outcome following kidney transplantation in children initiated on a corticosteroid-minimisation immunosuppressive regimen. Pediatr Nephrol (2021). https://doi.org/10.1007/s00467-021-05047-2
- CMV viraemia
- JCV viraemia
- EBV viraemia
- BKV viraemia
- Paediatric kidney transplantation