Organ resilience contributes to different impact of delayed graft function on graft survival in kidneys donated by brain death and circulatory death donors

M.J.C. de Kok, A.F.M. Schaapherder, L.G.M. Wijermars, D.K. de Vries, L. Verschuren, J.H.N. Lindeman

Thursday 14 march 2019

12:00 - 12:15h at Tropentheater

Categories: Best abstracts, Parallelsessie

Parallel session: Parallelsessie XII – Best abstracts III

Background: Despite a three times higher incidence of delayed graft function (DGF) in kidney grafts Donated after Circulatory Death (DCD) donors compared to those Donated after Brain Death (DBD), large studies show equivalent long-term graft survival with DBD and DCD grafts. This implies differential impacts of DGF on DCD and DBD graft survival. Maybe DGF is more severe in DBD grafts, and/or DCD grafts are more resilient. The aim of this study was to assess the biological basis of differential impacts of DGF on long-term outcome of DBD and DCD grafts.

Methods: The impact of DGF on long-term graft survival was analysed for 3744 DBD and 2891 DCD kidney transplants performed in The Netherlands between 2000 and 2018. The severity of DGF was estimated for 640 DBD and DCD kidneys transplanted at the LUMC by evaluating the number of posttransplant dialyses and postoperative functional recovery (eGFR).

In parallel to findings in tumour biology, where p53, phospho-EGFR, IGF-1R, phospho-mTOR, phospho-MAPK14, PCNA, BCL2 and PPARγare associated with tumour resilience, we determined expression of these factors by immunohistochemistry in pre-reperfusion kidney biopsies (DBD n=40; DCD n=40). Gene expression profiles (array analysis) followed by Ingenuity Pathway Analysis was performed to identify pathways differentially activated in 8 DBD and 7 DCD grafts.

Results: Our data confirmed a higher incidence of DGF in DCD grafts (DCD 42% vs. DBD 18%). This higher incidence of DGF did not impact long-term graft survival. Multivariate analysis showed that this was mainly due to differential impact of DGF on long-term outcomes, with a major impact in DBD grafts (RR: 1.62, 95%CI: 1.24-2.11) but no significant impact in DCD grafts (RR: 1.29, 95%CI: 0.96-1.73). This was not caused by a more severe form of DGF in DBD grafts, a conclusion based on equal numbers of DGF-associated dialyses and superior posttransplant eGFRs in DBD grafts.

Immunohistochemistry showed expression of all components of the resilience network in biopsies. Pathway analysis identified 24 differentially expressed pathways with the resilience associated pathways EGF-signalling (p:0.003), BRCA1 (p:0.005) and p38-MAPK-signalling (p:0.009) in the top-6.

Conclusions: The absent impact of DGF on long-term graft survival in DCD kidneys is paralleled by activation of dedicated resilience pathways. Targeting of these pathways may provide a major opportunity to modulate organ resilience in kidney transplantation.