JC polyomavirus replication and associated disease in pediatric renal transplantation: an international CERTAIN Registry study
JC polyomavirus (JCPyV)-associated nephropathy (JCPyVAN) is a severe, but rare complication in adult renal transplant (RTx) recipients. Related data in pediatric patients are scarce.
Based on the CERTAIN Registry, we therefore performed a multi-center, retrospective study on the JCPyV antibody status, prevalence of JCPyV replication, and its associated disease in 139 pediatric RTx recipients (mean age, 8.5 ± 5.3 years). JCPyV DNA in plasma and/or urine was measured by quantitative PCR at a median time of 3.2 (IQR, 0.3–8.1) years post-transplant.
53.2% of patients were JCPyV-seronegative prior to transplantation; younger age was associated with JCPyV seronegativity. 34/139 (24.5%) patients post-transplant showed active JCPyV replication in either urine (22.0%), plasma (13.4%), or both (7.6%). JCPyV viremia occurred significantly (p < 0.001) more often in patients with viruria (34.6%) than in those without (7.6%), but 7/118 (5.9%) had isolated viremia. High-level viruria (> 107 copies/mL) was found in 29.6% of viruric patients. A higher net state of immunosuppression constituted an independent risk factor for JCPyV replication both in urine and plasma (OR 1.2, p < 0.02). Male patients tended to have a higher risk of JCPyV viremia than females (OR 4.3, p = 0.057). There was one male patient (0.7%) with JCPyVAN 7 years post-transplant, which resolved after reduction of immunosuppressive therapy. No patient exhibited progressive multifocal leukoencephalopathy.
This first multi-center study on JCPyV in pediatric renal transplant recipients shows that JCPyV replication is common (24.5%), with strong immunosuppression being a significant risk factor, but associated nephropathy is rare.
KeywordsJC polyomavirus JC virus Polyomavirus Nephropathy Pediatric renal transplantation Pediatric kidney transplantation
The authors wish to thank study nurse Annette Mechler for her continuous excellent contributions to the CERTAIN Registry. BH is an awardee of the “DZIF Clinical Leave Stipend” from the German Center for Infection Research (DZIF).
BH: study design, data collection and analysis, preparation of manuscript, principal investigator. JT and LS: study design, data collection and analysis. JO, FT, LP, KR, RT, BK, GK, NP, OY, JT, AF, and KK: data collection. TB: statistical analysis. RW: histopathological evaluation. MP and PS: virological methodology and analyses, data collection. HHH: study design, preparation of the manuscript. BT: study design, data analyses, preparation of manuscript.
The authors acknowledge their gratitude to the Dietmar Hopp Stiftung as well as to the pharmaceutical companies Astellas, Novartis, and Roche for their grants in support of the CERTAIN Registry.
Compliance with ethical standards
Conflict of interests
B.H. received travel grants and participated in advisory boards of Astellas, Novartis, and Roche. H.H.H. reported consultant and speaker honoraria by Novartis, and Chimerix. B.T. received research grants, travel grants, lecture fees, and participated in advisory boards of Astellas, Bristol-Myers Squibb, Novartis, and Roche. J.T., L.S., J.O., F.T., L.P., K.R., R.T. B.K., G.K. N.P., O.Y., A.F., K.K., T.B., R.W., M.P., and P.S. declare no conflict of interests.
- 10.Drachenberg CB, Hirsch HH, Papadimitriou JC, Gosert R, Wali RK, Munivenkatappa R, Nogueira J, Cangro CB, Haririan A, Mendley S, Ramos E (2007) Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation. Transplantation 84:323–330CrossRefPubMedCentralGoogle Scholar
- 19.Koster L, Krupka K, Hocker B, Rahmel A, Samuel U, Zanen W, Opelz G, Susal C, Dohler B, Plotnicki L, Kohl CD, Knaup P, Tonshoff B (2015) Integrating data from multiple sources for data completeness in a web-based registry for pediatric renal transplantation—the CERTAIN Registry. Stud Health Technol Inform 216:1049PubMedPubMedCentralGoogle Scholar
- 20.Plotnicki L, Kohl CD, Hocker B, Krupka K, Rahmel A, Pape L, Hoyer P, Marks SD, Webb NJ, Soylemezoglu O, Topaloglu R, Szabo AJ, Seeman T, Marlies Cornelissen EA, Knops N, Grenda R, Tonshoff B (2013) The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe. Transplant Proc 45:1414–1417CrossRefPubMedCentralGoogle Scholar
- 21.Chisolm JJHH, Eberlein WR, Harrison HE (1955) Aminoaciduria, hypophosphatemia, and rickets in lead poisoning. Am J Dis Child 89:159–168Google Scholar
- 22.Hocker B, Bohm S, Fickenscher H, Kusters U, Schnitzler P, Pohl M, John U, Kemper MJ, Fehrenbach H, Wigger M, Holder M, Schroder M, Feneberg R, Kopf-Shakib S, Tonshoff B (2012) (Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation. Transpl Int 25:723–731CrossRefPubMedCentralGoogle Scholar
- 23.Hocker B, Fickenscher H, Delecluse HJ, Bohm S, Kusters U, Schnitzler P, Pohl M, John U, Kemper MJ, Fehrenbach H, Wigger M, Holder M, Schroder M, Billing H, Fichtner A, Feneberg R, Sander A, Kopf-Shakib S, Susal C, Tonshoff B (2013) Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis 56:84–92CrossRefPubMedCentralGoogle Scholar
- 26.Hocker B, Aguilar M, Schnitzler P, Pape L, Bald M, Konig J, Marks SD, Genc G, Buscher A, Kemper MJ, Billing H, Pohl M, Dello Strologo L, Webb NJA, Rieger S, Mankertz A, Krupka K, Bruckner T, Fichtner A, Tonshoff B (2018) Vaccination titres pre- and post-transplant in paediatric renal transplant recipients and the impact of immunosuppressive therapy. Pediatr Nephrol 33:897–910CrossRefPubMedCentralGoogle Scholar
- 27.Hocker B, Zencke S, Krupka K, Fichtner A, Pape L, Dello Strologo L, Guzzo I, Topaloglu R, Kranz B, Konig J, Bald M, Webb NJ, Noyan A, Dursun H, Marks S, Yalcinkaya F, Thiel F, Billing H, Pohl M, Fehrenbach H, Bruckner T, Tonshoff B (2016) Cytomegalovirus infection in pediatric renal transplantation and the impact of chemoprophylaxis with (val-)ganciclovir. Transplantation 100:862–870CrossRefPubMedCentralGoogle Scholar
- 30.Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M, Banff meeting report writing c (2014) Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 14:272–283CrossRefPubMedCentralGoogle Scholar
- 31.Adam B, Randhawa P, Chan S, Zeng G, Regele H, Kushner YB, Colvin RB, Reeve J, Mengel M (2014) Banff initiative for quality assurance in transplantation (BIFQUIT): reproducibility of polyomavirus immunohistochemistry in kidney allografts. Am J Transplant 14:2137–2147CrossRefPubMedCentralGoogle Scholar
- 34.Ettenger R, Chin H, Kesler K, Bridges N, Grimm P, Reed EF, Sarwal M, Sibley R, Tsai E, Warshaw B, Kirk AD (2017) Relationship among viremia/viral infection, alloimmunity, and nutritional parameters in the first year after pediatric kidney transplantation. Am J Transplant 17:1549–1562CrossRefPubMedCentralGoogle Scholar
- 37.Chang H, Wang M, Tsai RT, Lin HS, Huan JS, Wang WC, Chang D (2002) High incidence of JC viruria in JC-seropositive older individuals. J Neuro-Oncol 8:447–451Google Scholar
- 42.Hirsch HH, Babel N, Comoli P, Friman V, Ginevri F, Jardine A, Lautenschlager I, Legendre C, Midtvedt K, Munoz P, Randhawa P, Rinaldo CH, Wieszek A, Hosts ESGoIiC (2014) European perspective on human polyomavirus infection, replication and disease in solid organ transplantation. Clin Microbiol Infect 20(Suppl 7):74–88CrossRefPubMedCentralGoogle Scholar
- 45.Wunderink HF, van der Meijden E, van der Blij-de Brouwer CS, Mallat MJ, Haasnoot GW, van Zwet EW, Claas EC, de Fijter JW, Kroes AC, Arnold F, Touze A, Claas FH, Rotmans JI, Feltkamp MC (2017) Pretransplantation donor-recipient pair seroreactivity against BK polyomavirus predicts viremia and nephropathy after kidney transplantation. Am J Transplant 17:161–172CrossRefPubMedCentralGoogle Scholar