PMID- 28918487 OWN - NLM STAT- MEDLINE DCOM- 20180618 LR - 20210109 IS - 1432-198X (Electronic) IS - 0931-041X (Print) IS - 0931-041X (Linking) VI - 33 IP - 1 DP - 2018 Jan TI - Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies. PG - 167-174 LID - 10.1007/s00467-017-3772-7 [doi] AB - INTRODUCTION: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. METHODS: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan-Meier estimator. RESULTS: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R (2) 0.072; C3d: adjusted R (2) 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 +/- 0.18 (C1q+) vs. 0.25 +/- 0.08 (C1q-) episodes per patient (mean +/- standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q-) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30-1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d-); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d-) years; HR 0.38; 95% CI 0.15-0.97; p = 0.04]. CONCLUSION: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction. FAU - Kim, Jon Jin AU - Kim JJ AD - Department of Paediatric Nephrology, Nottingham University Hospital, Nottingham, UK. AD - Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, WC1N 3JH, London, UK. AD - MRC Centre for Transplantation, Guy's Hospital, London, UK. FAU - Shaw, Olivia AU - Shaw O AD - Viapath Clinical Transplantation Laboratory, Guy's Hospital, London, UK. FAU - Martin, Chloe AU - Martin C AD - Viapath Clinical Transplantation Laboratory, Guy's Hospital, London, UK. FAU - Michaelides, George AU - Michaelides G AD - Department of Organisational Psychology, Birkbeck, University of London, London, UK. FAU - Balasubramaniam, Ramnath AU - Balasubramaniam R AD - Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, WC1N 3JH, London, UK. FAU - Sebire, Neil J AU - Sebire NJ AD - Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, WC1N 3JH, London, UK. AD - University College London Great Ormond Street Institute of Child Health, London, UK. FAU - Mamode, Nizam AU - Mamode N AD - MRC Centre for Transplantation, Guy's Hospital, London, UK. FAU - Dorling, Anthony AU - Dorling A AD - MRC Centre for Transplantation, Guy's Hospital, London, UK. FAU - Vaughan, Robert AU - Vaughan R AD - Viapath Clinical Transplantation Laboratory, Guy's Hospital, London, UK. FAU - Marks, Stephen D AU - Marks SD AUID- ORCID: 0000-0001-9850-8352 AD - Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, WC1N 3JH, London, UK. Stephen.Marks@gosh.nhs.uk. AD - University College London Great Ormond Street Institute of Child Health, London, UK. Stephen.Marks@gosh.nhs.uk. LA - eng GR - 11/100/34/DH_/Department of Health/United Kingdom GR - MC_PC_15031/MRC_/Medical Research Council/United Kingdom GR - MR/J006742/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article DEP - 20170916 PL - Germany TA - Pediatr Nephrol JT - Pediatric nephrology (Berlin, Germany) JID - 8708728 RN - 0 (HLA Antigens) RN - 9007-36-7 (Complement System Proteins) SB - IM MH - Adolescent MH - Child MH - Child, Preschool MH - Complement Activation/*immunology MH - Complement System Proteins/immunology MH - Female MH - Glomerular Filtration Rate/immunology MH - Graft Rejection/*immunology MH - HLA Antigens/*immunology MH - Humans MH - Kidney/immunology MH - Kidney Transplantation/*adverse effects MH - Male MH - Prognosis MH - Prospective Studies MH - Risk Assessment/methods MH - Survival Analysis MH - Tissue Donors MH - Transplant Recipients MH - Transplantation, Homologous/adverse effects PMC - PMC5700253 OTO - NOTNLM OT - Complement fixation OT - Donor-specific antibodies OT - HLA antibodies OT - Prognosis OT - Renal transplant COIS- AUTHORSHIP: JJK, OS, NJS, NM, AD, RV and SDM designed the study. JJK, OS, CM and RB collected the data and performed the experiments. JJK, OS, GM and RV analysed the data. JJK, OS, AD, RV and SDM wrote the paper. All authors reviewed the paper. The results presented in this paper have not been published previously in whole or part, except in abstract form. FUNDING: This study was funded in part by Kids Kidney Research. The authors also acknowledge financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Great Ormond Street Hospital for Children NHS Foundation Trust (NJS, SDM); and Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust (JJK, NM, AD). ETHICAL APPROVAL: Ethical approval for this study was obtained from the University College London Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust Research Ethics Committee. CONFLICT OF INTEREST: The authors declare no conflicts of interest. EDAT- 2017/09/18 06:00 MHDA- 2018/06/19 06:00 PMCR- 2017/09/16 CRDT- 2017/09/18 06:00 PHST- 2017/04/20 00:00 [received] PHST- 2017/06/30 00:00 [accepted] PHST- 2017/06/28 00:00 [revised] PHST- 2017/09/18 06:00 [pubmed] PHST- 2018/06/19 06:00 [medline] PHST- 2017/09/18 06:00 [entrez] PHST- 2017/09/16 00:00 [pmc-release] AID - 10.1007/s00467-017-3772-7 [pii] AID - 3772 [pii] AID - 10.1007/s00467-017-3772-7 [doi] PST - ppublish SO - Pediatr Nephrol. 2018 Jan;33(1):167-174. doi: 10.1007/s00467-017-3772-7. Epub 2017 Sep 16.