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Modelling acute antibody-mediated rejection of human kidney transplants using ex-vivo warm machine perfusion

Research output: Contribution to journalArticlepeer-review

Pankaj Chandak, Benedict L Phillips, Danothy Bennett, Raphael Uwechue, Nicos Kessaris, Olivia Shaw, Tim Maggs, Luke Woodford, David Veniard, Ranmith Perera, Kiran Parmar, Beverley J Hunt, Chris Callaghan, Anthony Dorling, Nizam Mamode

Original languageEnglish
Article number104365
Pages (from-to)104365
JournalEBioMedicine
Volume86
Early online date22 Nov 2022
DOIs
Accepted/In press27 Oct 2022
E-pub ahead of print22 Nov 2022
PublishedDec 2022

Bibliographical note

Funding Information: We gratefully acknowledge the teams at Guy's and St Thomas' NHS Foundation Trust, King's College London and Viapath and who have been integral in facilitating our work, including haematology and blood bank (Priti Patel, Lauren Bamford), nephrology (Theo Kasimatis) our surgical colleagues and theatre staff. We thank Eon Cort, Viapath, Renal Biomedical Scientist and Deputy Training Officer, Department of Cellular Pathology, St Thomas Hospital for the processing and interpretation of the biopsy slides. This research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London and/or the NIHR Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. We thank NHSBT and the donor families for allowing us to use human organs for research purposes. Funding: Pankaj Chandak was funded by a Royal College of Surgeons of England Research Fellowship, The Rosetrees Trust (M727), The Stoneygate Trust and a NIHR Biomedical Research Centre/King's College London Early Career Grant (Precision Medicine Cluster). Benedict L. Phillips was funded by Kidney Research UK (SP/MEKC/1/2014). Funding Information: Funding : Pankaj Chandak was funded by a Royal College of Surgeons of England Research Fellowship , The Rosetrees Trust (M727) , The Stoneygate Trust and a NIHR Biomedical Research Centre / King’s College London Early Career Grant (Precision Medicine Cluster). Benedict L. Phillips was funded by Kidney Research UK ( SP/MEKC/1/2014 ). Publisher Copyright: © 2022 The Authors

King's Authors

Abstract

BACKGROUND: Transplant rejection is a major cause of graft loss and morbidity. Currently, no human models of antibody-mediated rejection (AMR) exist, limiting mechanistic investigation and organ-specific targeted therapy. Here, using 12 human kidneys and ex-vivo normothermic machine perfusion, we demonstrate phenotypes of AMR after addition of antibodies against either human HLA class I or blood group antigens (A, B), thus modelling clinical AMR that can follow HLA incompatible (HLAi) or blood group incompatible (ABOi) transplantation.

METHODS: Discarded human kidneys with wide ranging demographics and cold ischaemia times (11-54 h) were perfused with red blood cells and fresh frozen plasma (FFP) as a source of complement/coagulation factors. For the HLAi model, 600 μg of W6/32 anti-class 1 HLA antibody was added to the circuit (time '0'). For the ABOi model, high titre FFP of the relevant blood group antibody was added. Renal blood flow index (RBFi, mL/min/100 g), C3 desArg, prothrombin fragments 1 + 2 and histology were determined. Our endpoints included haemodynamic changes, thrombosis, and biopsy proven complement deposition.

FINDINGS: Compared to control kidneys perfused without anti-donor antibodies, both models demonstrated haemodynamic collapse after antibody perfusion with only the HLAi model showing glomerular C4d deposition.

INTERPRETATION: We show that a clinically relevant human kidney model of AMR is feasible, and anticipate that these models, with refinements, could provide a basis to test different strategies to prevent AMR.

FUNDING: The Rosetrees and Stonygate Trust, The Royal College of Surgeons of England Fellowship Grant, NIHR Biomedical Research Centre/KCL Early Career Grant, Kidney Research U.K.

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