Incidence, risk factors, management strategies, and outcomes of antibody-mediated rejection in pediatric kidney transplant recipients-a multicenter analysis of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN).

DnDSA development Antibody-mediated rejection BKPyV nephropathy Graft outcome Pediatric kidney transplantation Risk factors

Journal

Pediatric nephrology (Berlin, Germany)

ISSN: 1432-198X

Titre abrégé: Pediatr Nephrol

Pays: Germany

ID NLM: 8708728

Informations de publication

Date de publication:
16 Sep 2024

Historique:

received: 05 03 2024

accepted: 26 07 2024

revised: 26 07 2024

medline: 17 9 2024

pubmed: 17 9 2024

entrez: 16 9 2024

Statut: aheadofprint

Résumé

This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant. The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5 years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age. This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

We performed an international, multicenter, longitudinal cohort study of data reported to the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry. Three hundred thirty-seven pKTR from 21 European centers were analyzed. Clinical outcomes, including kidney dysfunction, rejection, HLA donor-specific antibodies, BK polyomavirus-associated (BKPyV) nephropathy, and allograft loss, were assessed through 5 years post-transplant.

RESULTS RESULTS

The cumulative incidence of de novo donor-specific class I HLA antibodies (HLA-DSA) post-transplant was 4.5% in year 1, 8.3% in year 3, and 13% in year 5; the corresponding data for de novo class II HLA-DSA were 10%, 22.5%, and 30.6%, respectively. For 5 years post-transplant, the cumulative incidence of acute ABMR was 10% and that of chronic active ABMR was 5.9%. HLA-DR mismatch and de novo HLA-DSA, especially double positivity for class I and class II HLA-DSA, were significant risk factors for ABMR, whereas cytomegalovirus (CMV) IgG negative recipient and CMV IgG negative donor were associated with a lower risk. BKPyV nephropathy was associated with the highest risk of graft dysfunction, followed by ABMR, T-cell mediated rejection, and older donor age.

CONCLUSIONS CONCLUSIONS

This study provides an estimate of the incidence of de novo HLA-DSA and ABMR in pKTR and highlights the importance of BKPyV nephropathy as a strong risk factor for allograft dysfunction.

Identifiants

DOI: 10.1007/s00467-024-06487-2 PMID: 39283519

pubmed: 39283519

doi: 10.1007/s00467-024-06487-2

pii: 10.1007/s00467-024-06487-2

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : H2020 European Research Council

ID : grant no. 952512

Informations de copyright

Références

Loupy A, Lefaucheur C (2018) Antibody-mediated rejection of solid-organ allografts. N Engl J Med 379:1150–1160

pubmed: 30231232 doi: 10.1056/NEJMra1802677

Hart A, Singh D, Brown SJ, Wang JH, Kasiske BL (2021) Incidence, risk factors, treatment, and consequences of antibody-mediated kidney transplant rejection: a systematic review. Clin Transplant 35:e14320

pubmed: 33864724 doi: 10.1111/ctr.14320

Süsal C, Fichtner A, Tönshoff B, Mehrabi A, Zeier M, Morath C (2017) Clinical relevance of HLA antibodies in kidney transplantation: recent data from the Heidelberg transplant center and the Collaborative Transplant Study. J Immunol Res 2017:5619402

pubmed: 28660215 pmcid: 5474267 doi: 10.1155/2017/5619402

Ettenger R, Chin H, Kesler K et al (2017) Relationship among viremia/viral infection, alloimmunity, and nutritional parameters in the first year after pediatric kidney transplantation. Am J Transplant 17:1549–1562

pubmed: 27989013 pmcid: 5445007 doi: 10.1111/ajt.14169

Fernandez HE, Foster BJ (2022) Long-term care of the pediatric kidney transplant recipient. Clin J Am Soc Nephrol 17:296–304

pubmed: 33980614 pmcid: 8823932 doi: 10.2215/CJN.16891020

Dharnidharka VR, Fiorina P, Harmon WE (2014) Kidney transplantation in children. N Engl J Med 371:549–558

pubmed: 25099579 doi: 10.1056/NEJMra1314376

Tönshoff B, Krupka K, Köster L, Fichtner A, Pape L, Höcker B (2015) CERTAIN Registry. Der Nephrologe 10:480–487

doi: 10.1007/s11560-015-0004-7

Plotnicki L, Kohl CD, Höcker B et al (2013) The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe. Transplant Proc 45:1414–1417

pubmed: 23726585 doi: 10.1016/j.transproceed.2013.01.007

Tambur AR, Campbell P, Claas FH et al (2018) Sensitization in transplantation: assessment of risk (STAR) 2017 Working Group Meeting Report. Am J Transplant 18:1604–1614

pubmed: 29603613 doi: 10.1111/ajt.14752

Hirsch HH, Randhawa PS (2019) AST infectious diseases community of practice. BK Polyomavirus in solid organ transplantation - guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 33:e13528

pubmed: 30859620 doi: 10.1111/ctr.13528

Loupy A, Haas M, Roufosse C et al (2020) The Banff 2019 kidney meeting report (i): updates on and clarification of criteria for T cell– and antibody-mediated rejection. Am J Transplant 20:2318–2331

pubmed: 32463180 pmcid: 7496245 doi: 10.1111/ajt.15898

Schwartz GJ, Munoz A, Schneider MF et al (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637

pubmed: 19158356 pmcid: 2653687 doi: 10.1681/ASN.2008030287

Schwartz GJ, Schneider MF, Maier PS et al (2012) Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Kidney Int 82:445–453

pubmed: 22622496 pmcid: 3433576 doi: 10.1038/ki.2012.169

Loucks-DeVos JM, Eagar TB, Osama Gaber A et al (2017) The detrimental impact of persistent vs an isolated occurrence of de novo donor-specific antibodies on intermediate-term renal transplant outcomes. Clin Transplant 31:e13025

doi: 10.1111/ctr.13025

Ginevri F, Nocera A, Comoli P et al (2012) Posttransplant de novo donor-specific HLA antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection. Am J Transplant 12:3355–3362

pubmed: 22959074 doi: 10.1111/j.1600-6143.2012.04251.x

Cioni M, Nocera A, Innocente A et al (2017) De novo donor-specific HLA antibodies developing early or late after transplant are associated with the same risk of graft damage and loss in nonsensitized kidney recipients. J Immunol Res 2017:1747030

pubmed: 28367453 pmcid: 5358457 doi: 10.1155/2017/1747030

Miettenen J, Peräsaari J, Lauronen J et al (2012) Donor-specific HLA antibodies and graft function in children after renal transplantation. Pediatr Nephrol 27:1011–1019

doi: 10.1007/s00467-012-2101-4

Chaudhuri A, Ozawa M, Everly MJ et al (2013) The clinical impact of humoral immunity in pediatric renal transplantation. J Am Soc Nephrol 24:655–664

pubmed: 23449533 pmcid: 3609135 doi: 10.1681/ASN.2012070663

Kim JJ, Balasubramanian R, Michaelides G et al (2014) The clinical spectrum of de novo donor-specific antibodies in pediatric renal transplant recipients. Am J Transplant 14:2350–2358

pubmed: 25167892 doi: 10.1111/ajt.12859

Lefaucheur C, Louis K, Morris AB et al (2023) Clinical recommendations for posttransplant assessment of anti-HLA (Human Leukocyte Antigen) donor-specific antibodies: a sensitization in transplantation: assessment of risk consensus document. Am J Transplant 23:115–132

pubmed: 36695614 doi: 10.1016/j.ajt.2022.11.013

Offner G, Tönshoff B, Höcker B et al (2008) Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids. Transplantation 86:1241–1248

pubmed: 19005406 doi: 10.1097/TP.0b013e318188af15

Grenda R, Watson A, Vondrak K et al (2006) A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation. Am J Transplant 6:1666–1672

pubmed: 16827869 doi: 10.1111/j.1600-6143.2006.01367.x

Twombley K, Thach L, Ribeiro A, Joseph C, Seikaly M (2013) Acute antibody-mediated rejection in pediatric kidney transplants: a single center experience. Pediatr Transplantation 17:E149–E155

doi: 10.1111/petr.12129

Gulleroglu K, Baskin E, Bayrakci US et al (2013) Antibody-mediated rejection and treatment in pediatric patients: one center’s experience. Exp Clin Transplant 11:404–407

pubmed: 24128133 doi: 10.6002/ect.2012.0242

Steggerda JA, Kim IK, Haas M et al (2017) Clinical and histopathologic features of antibody-mediated rejection among pediatric renal transplant recipients with preformed vs de novo donor-specific antibodies. Pediatr Transplant 21:8

doi: 10.1111/petr.13079

Schuster AM, Miesgang N, Steines L, Bach C, Banas B, Bergler B (2021) B-cell activating factor BAFF as a novel alert marker for the immunological risk stratification after kidney transplantation. Immunol Res 69:487–495

pubmed: 34373996 pmcid: 8580904 doi: 10.1007/s12026-021-09205-4

Alfaro R, Rodríguez-Aguilar L, Llorente S et al (2023) Early cytomegalovirus reactivation in renal recipients is associated with high levels of B cell maturation antigen transcript expression prior to transplantation. Int J Mol Sci 24:10491

pubmed: 37445668 pmcid: 10341624 doi: 10.3390/ijms241310491

Michelo CM, van Cranenbroek B, Touw P, Claas FHJ, van der Meer A, Joosten I (2017) Human cytomegalovirus infection increases both antibody- and non–antibody-dependent cellular reactivity by natural killer cells. Transplantation Direct 3:e335

pubmed: 29536036 pmcid: 5828690 doi: 10.1097/TXD.0000000000000750

Couzi L, Pitard V, Moreau J, Merville P, Déchanet-Merville J (2017) Direct and indirect effects of cytomegalovirus-induced γδ T cells after kidney transplantation. Front Immunol 6:3

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

pubmed: 20616168 pmcid: 3013517 doi: 10.1681/ASN.2009111188

Saldan A, Mengoli C, Sgarabotto D et al (2023) Human cytomegalovirus and Epstein-Barr virus infections occurring early after transplantation are risk factors for antibody-mediated rejection in heart transplant recipients. Front Immunol 15:14

Boutolleau D, Coutance G, Désiré E, Bouglé A, Bréchot N, Leprince P, Varnous S (2021) Association between cytomegalovirus infection and allograft rejection in a large contemporary cohort of heart transplant recipients. Transpl Infect Dis 23:e13569

pubmed: 33452851 doi: 10.1111/tid.13569

Doberer K, Duerr M, Halloran PF et al (2021) A randomized clinical trial of anti-IL-6 antibody clazakizumab in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol 32:708–722

pubmed: 33443079 doi: 10.1681/ASN.2020071106

Pearl M, Weng PL, Chen L et al (2022) Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients. Clin Transplant 36:e14734

pubmed: 35657013 pmcid: 9378624 doi: 10.1111/ctr.14734

National Library of Medicine. National Center for Biotechnology Information (2022) BIVV020 in prevention and treatment of Antibody-mediated Rejection (AMR). https://clinicaltrials.gov/ct2/show/NCT05156710 . Accessed 25 February 2022

Schinstock CA, Mannon RB, Budde K et al (2020) Recommended treatment for antibody-mediated rejection after kidney transplantation: the 2019 expert consensus from the Transplantation Society Working Group. Transplantation 104:911–922

pubmed: 31895348 pmcid: 7176344 doi: 10.1097/TP.0000000000003095

Rostaing LPE, Böhmig GA, Gibbons B, Taqi MM (2023) Post-transplant surveillance and management of chronic active antibody-mediated rejection in renal transplant patients in Europe. Transpl Int 36:11381

pubmed: 37529383 pmcid: 10389272 doi: 10.3389/ti.2023.11381

Höcker B, Schmidt J, Süsal C et al (2022) Risk of cellular and/or antibody-mediated transplant rejection in pediatric kidney transplant recipients with BK polyomavirus DNAemia – a multicenter CERTAIN analysis. Transplant Int 35:23

Dragun D, Müller DN, Bräsen JH et al (2005) Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 352:558–569

pubmed: 15703421 doi: 10.1056/NEJMoa035717

Fichtner A, Süsal C, Schröder C et al (2018) Association of angiotensin II type 1 receptor antibodies with graft histology, function and survival in paediatric renal transplant recipients. Nephrol Dial Transplant 33:1065–1072

pubmed: 29444269 doi: 10.1093/ndt/gfy008

Fichtner A, Süsal C, Höcker B et al (2021) Association of non-HLA antibodies against endothelial targets and donor-specific HLA antibodies with antibody-mediated rejection and graft function in pediatric kidney transplant recipients. Pediatr Nephrol 36:2473–2484

pubmed: 33759004 pmcid: 8260519 doi: 10.1007/s00467-021-04969-1

Lefaucheur C, Louis K, Philippe A, Loupy A, Coates PT (2021) The emerging field of non-human leukocyte antigen antibodies in transplant medicine and beyond. Kidney Int 100:787–798

pubmed: 34186057 doi: 10.1016/j.kint.2021.04.044

Hogan J, Divard G, Aubert O et al (2023) Validation of a prediction system for risk of kidney allograft failure in pediatric kidney transplant recipients: an international observational study. Am J Transplant 23:1561–1569

pubmed: 37453485 doi: 10.1016/j.ajt.2023.07.004