Circulating tumor necrosis factor α 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 is unknown. We quantified tumor necrosis factor (TNF)α and its receptors TNF receptor (TNFR)1 and TNFR2 in 1018 longitudinal plasma samples collected during donor management from 596 deceased and 34 living donors, from multiple centers across the UK. High donor plasma TNFα levels are significantly associated with inferior graft function at 12 months and up to 60 months and with reduced graft survival up to 96 months, but only in donations after brain death and not in donations after circulatory death. 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 the 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 assess and intervene to improve optimization and quality of deceased donor organs.