Pediatric renal transplantation: A retrospective single-center study on epidemiology and morbidity due to EBV
Corresponding Author
A. Laurent
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
Correspondence
Audrey Laurent, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Bron, France.
Email: [email protected]
Search for more papers by this authorA. Klich
Hospices Civils de Lyon, Service de Biostatistique et de Bioinformatique, Lyon, France
Université de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Search for more papers by this authorP. Roy
Hospices Civils de Lyon, Service de Biostatistique et de Bioinformatique, Lyon, France
Université de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Search for more papers by this authorB. Lina
Laboratoire de Virologie, Institut des Agents Infectieux IAI, Hospices Civils de Lyon, Hopital de la Croix Rousse, Lyon, France
CIRI, Centre International de Recherche en Infectiologie, Virpath, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Université de Lyon, Lyon, France
Search for more papers by this authorB. Kassai
Université de Lyon, Lyon, France
Centre d'Investigation Clinique de Lyon, 1407 Inserm-Hospices Civils de Lyon, Groupement Hospitalier Est, Hôpital Femme-Mère-Enfant, EPICIME, Bron, France
Search for more papers by this authorJ. Bacchetta
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Laboratoire de Virologie, Institut des Agents Infectieux IAI, Hospices Civils de Lyon, Hopital de la Croix Rousse, Lyon, France
Search for more papers by this authorP. Cochat
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
Université de Lyon, Lyon, France
Search for more papers by this authorCorresponding Author
A. Laurent
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
Correspondence
Audrey Laurent, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Bron, France.
Email: [email protected]
Search for more papers by this authorA. Klich
Hospices Civils de Lyon, Service de Biostatistique et de Bioinformatique, Lyon, France
Université de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Search for more papers by this authorP. Roy
Hospices Civils de Lyon, Service de Biostatistique et de Bioinformatique, Lyon, France
Université de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Search for more papers by this authorB. Lina
Laboratoire de Virologie, Institut des Agents Infectieux IAI, Hospices Civils de Lyon, Hopital de la Croix Rousse, Lyon, France
CIRI, Centre International de Recherche en Infectiologie, Virpath, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Université de Lyon, Lyon, France
Search for more papers by this authorB. Kassai
Université de Lyon, Lyon, France
Centre d'Investigation Clinique de Lyon, 1407 Inserm-Hospices Civils de Lyon, Groupement Hospitalier Est, Hôpital Femme-Mère-Enfant, EPICIME, Bron, France
Search for more papers by this authorJ. Bacchetta
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
CNRS, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
Laboratoire de Virologie, Institut des Agents Infectieux IAI, Hospices Civils de Lyon, Hopital de la Croix Rousse, Lyon, France
Search for more papers by this authorP. Cochat
Hospices Civils de Lyon, Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Lyon, France
Université de Lyon, Lyon, France
Search for more papers by this authorAbstract
Pediatric R-Tx patients are at high risk of developing EBV primary infection. Although high DNA replication is a risk factor for PTLD, some patients develop PTLD with low viral load. In this retrospective single-center study including all pediatric patients having received R-Tx (2003-2012 period), we aimed to identify risk factors for uncontrolled reactions to EBV (defined as the presence of a viral load >10 000 copies/mL or PTLD). A Cox proportional hazard model was performed. A total of 117 patients underwent R-Tx at a mean age of 9.7 ± 5.3 years, 46 of them being seronegative for EBV at the time of R-Tx. During follow-up, 54 patients displayed positive EBV viral load, 22 of whom presenting with primary infection. An uncontrolled reaction to EBV was observed in 24 patients, whilst 4 patients developed PTLD. Univariate and multivariate analyses suggested the following risk factors for an uncontrolled reaction: age below 5 years, graft from a deceased donor, ≥5 HLA mismatches, EBV-seronegative status at the time of R-Tx, and a secondary post-Tx loss of anti-EBNA. Monitoring anti-EBNA after R-Tx may contribute to the early identification of patients at risk for uncontrolled reaction.
REFERENCES
- 1Holmes MV, Caplin B, Atkinson C, et al. Prospective monitoring of Epstein-Barr virus DNA in adult renal transplant recipients during the early posttransplant period: role of mycophenolate mofetil. Transplantation. 2009; 87: 852-856.
- 2Khanna R, Burrows SR. Role of cytotoxic T lymphocytes in Epstein-Barr virus-associated diseases. Annu Rev Microbiol. 2000; 54: 19-48.
- 3Grywalska E, Markowicz J, Grabarczyk P, Pasiarski M, Rolinski J. Epstein-Barr virus-associated lymphoproliferative disorders. Postepy Hig Med Dosw (Online). 2013; 67: 481-490.
- 4Campe H, Jaeger G, Abou-Ajram C, et al. Serial detection of Epstein-Barr virus DNA in sera and peripheral blood leukocyte samples of pediatric renal allograft recipients with persistent mononucleosis-like symptoms defines patients at risk to develop post-transplant lymphoproliferative disease. Pediatr Transplant. 2003; 7: 46-52.
- 5Suzuki T, Ikezumi Y, Okubo S, et al. Epstein-Barr virus DNA load and seroconversion in pediatric renal transplantation with tacrolimus immunosuppression. Pediatr Transplant. 2007; 11: 749-754.
- 6Shroff R, Rees L. The post-transplant lymphoproliferative disorder-a literature review. Pediatr Nephrol. 2004; 19: 369-377.
- 7Taylor AL, Marcus R, Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit Rev Oncol Hematol. 2005; 56: 155-167.
- 8Höcker B, Böhm S, Fickenscher H, et al. (Val-)Ganciclovir prophylaxis reduces Epstein-Barr virus primary infection in pediatric renal transplantation: (Val-)Ganciclovir reduces EBV primary infection. Transpl Int. 2012; 25: 723-731.
- 9Maksten EF, Vase MØ, Kampmann J, et al. Post-transplant lymphoproliferative disorder following kidney transplantation: a population-based cohort study. Transpl Int. 2016; 29: 483-493.
- 10Glotz D, Chapman JR, Dharnidharka VR, et al. The Seville expert workshop for progress in posttransplant lymphoproliferative disorders. Transplantation. 2012; 94: 784-793.
- 11Mucha K, Foroncewicz B, Ziarkiewicz-Wróblewska B, Krawczyk M, Lerut J, Paczek L. Post-transplant lymphoproliferative disorder in view of the new WHO classification: a more rational approach to a protean disease? Nephrol Dial Transplant. 2010; 25: 2089-2098.
- 12Colombini E, Guzzo I, Morolli F, et al. Viral load of EBV DNAemia is a predictor of EBV-related post-transplant lymphoproliferative disorders in pediatric renal transplant recipients. Pediatr Nephrol. 2017; 32: 1433-1442.
- 13Parker A, Bowles K, Bradley JA, et al. Diagnosis of post-transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS guidelines. Br J Haematol. 2010; 149: 675-692.
- 14Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the north american pediatric renal transplant cooperative study (NAPRTCS) 1. Transplantation. 2001; 71: 1065-1068.
- 15Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in Era of modern immunosuppression. Transplantation. 2005; 80: 1233-1243.
- 16Sampaio MS, Cho YW, Shah T, Bunnapradist S, Hutchinson IV. Impact of Epstein-Barr virus donor and recipient serostatus on the incidence of post-transplant lymphoproliferative disorder in kidney transplant recipients. Nephrol Dial Transplant. 2012; 27: 2971-2979.
- 17Shroff R, Trompeter R, Cubitt D, Thaker U, Rees L. Epstein-Barr virus monitoring in paediatric renal transplant recipients. Pediatr Nephrol. 2002; 17: 770-775.
- 18Baudouin V, Dehée A, Pédron-Grossetete B, et al. Relationship between CD8+ T-cell phenotype and function, Epstein-Barr virus load, and clinical outcome in pediatric renal transplant recipients: a prospective study. Transplantation. 2004; 77: 1706-1713.
- 19Toyoda M, Moudgil A, Warady BA, Puliyanda DP, Jordan SC. Clinical significance of peripheral blood Epstein-Barr viral load monitoring using polymerase chain reaction in renal transplant recipients. Pediatr Transplant. 2008; 12: 778-784.
- 20Tanaka E, Sato T, Ishihara M, et al. Asymptomatic high Epstein-Barr viral load carriage in pediatric renal transplant recipients: asymptomatic high EBV load in renal transplantation. Pediatr Transplant. 2011; 15: 306-313.
- 21Riddler SA, Breinig MC, McKnight JL. Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients. Blood. 1994; 84: 972-984.
- 22Zhao W, Elie V, Roussey G, et al. Population pharmacokinetics and pharmacogenetics of tacrolimus in de novo pediatric kidney transplant recipients. Clin Pharmacol Ther. 2009; 86: 609-618.
- 23Zhao W, Fakhoury M, Deschênes G, et al. Population pharmacokinetics and pharmacogenetics of mycophenolic acid following administration of mycophenolate mofetil in de novo pediatric renal-transplant patients. J Clin Pharmacol. 2010; 50: 1280-1291.
- 24Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958; 53: 457.
- 25Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. In: K Dietz, M Gail, K Krickeberg, J Samet, A Tsiatis, eds. Statistics for Biology and Health. New York, NY: Springer; 2000: 1-287.
- 26Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966; 50: 163-170.
- 27Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009; 20: 629-637.
- 28Duclaux-Loras R, Bacchetta J, Berthiller J, et al. Pediatric combined liver–kidney transplantation: a single-center experience of 18 cases. Pediatr Nephrol. 2016; 31: 1517-1529.
- 29Hocker B, Fickenscher H, Delecluse H-J, et al. Epidemiology and morbidity of Epstein-Barr virus infection in pediatric renal transplant recipients: a multicenter, prospective study. Clin Infect Dis. 2013; 56: 84-92.
- 30Holmes RD, Sokol RJ. Epstein-Barr virus and post-transplant lymphoproliferative disease. Pediatr Transplant. 2002; 6: 456-464.
- 31McDonald RA, Smith JM, Ho M, et al. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant. 2008; 8: 984-989.
- 32Sampaio MS, Cho YW, Shah T, Bunnapradist S, Hutchinson IV. Association of immunosuppressive maintenance regimens with posttransplant lymphoproliferative disorder in kidney transplant recipients. Transplantation. 2012; 93: 73-81.
- 33Mañez R, Breinig MC, Linden P, et al. Posttransplant lymphoproliferative disease in primary Epstein-Barr virus infection after liver transplantation: the role of cytomegalovirus disease. J Infect Dis. 1997; 176: 1462-1467.
- 34Jordan CL, Taber DJ, Kyle MO, et al. Incidence, risk factors, and outcomes of opportunistic infections in pediatric renal transplant recipients. Pediatr Transplant. 2016; 20: 44-48.
- 35 EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV: long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment. Nephrol Dial Transplant. 2002; 17(Suppl 4): 31-33, 35-36.
- 36Hierro L, Díez-Dorado R, Díaz C, et al. Efficacy and safety of valganciclovir in liver-transplanted children infected with Epstein-Barr virus. Liver Transpl. 2008; 14: 1185-1193.
- 37Sato T, Fujieda M, Tanaka E, et al. Monitoring of Epstein-Barr virus load and antibody in pediatric renal transplant patients. Pediatr Int. 2008; 50: 454-458.
- 38Ishihara M, Tanaka E, Sato T, et al. Epstein-Barr virus load for early detection of lymphoproliferative disorder in pediatric renal transplant recipients. Clin Nephrol. 2011; 76: 40-48.
- 39Smith JM, Dharnidharka VR. Viral surveillance and subclinical viral infection in pediatric kidney transplantation. Pediatr Nephrol. 2015; 30: 741-748.
- 40Hopwood P, Crawford D. The role of EBV in post-transplant malignancies: a review. J Clin Pathol. 2000; 53: 248-254.
- 41Tierney RJ, Steven N, Young LS, Rickinson AB. Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol. 1994; 68: 7374-7385.
Citing Literature
