Circulating TNFα in deceased donors promotes kidney injury and associates with inferior short- and long-term graft function and survival.

In deceased donation, donor management and organ procurement may contribute to donor organ injury, particularly through triggering systemic inflammation. Despite the important clinical implications, the impact of circulating inflammation on donor kidney injury, and short- and long-term posttransplant outcomes are unknown. We quantified TNFα and its receptors TNFR1 and TNFR2 in 1018 longitudinal plasma samples collected during donor management from 596 deceased and 34 living donors, from multiple centres across the United Kingdom. High donor plasma TNFα levels significantly associated with 12 and up to 60 months inferior graft function and up to 96 months reduced survival, only in DBDs but not in DCDs. Associations were replicated in a validation cohort and withstood linear mixed model adjustments for donor and recipient covariates. Analysis of paired plasma and kidney biopsy samples revealed that high plasma TNFα levels correlated with increased expression of injury markers in donor kidney. Further in vitro investigations confirmed that human podocytes, exposed to TNFα donor plasma, demonstrated TNFR1 signaling driven injury profiles, a response that was ameliorated by infliximab. Our data provide evidence that monitoring plasma inflammation levels during donor management offers a window of opportunity to intervene and improve optimisation and quality of deceased donor organs.