Circulating tumor necrosis factor α in deceased donors promotes kidney injury and associates with inferior short- and long-term graft function and survival

Key findings from this study

• The study found that high plasma TNFα in brain-dead donors associates with inferior graft function up to 60 months and reduced graft survival up to 96 months after transplantation.
• The researchers demonstrate that elevated donor plasma TNFα correlates with increased expression of injury markers within donor kidney tissue.
• The authors report that TNFα-driven podocyte injury operates through TNFR1 signaling and responds to infliximab-mediated blockade in vitro.

Overview

This study quantified circulating tumor necrosis factor alpha and its receptors in plasma samples from deceased and living organ donors to assess associations with donor kidney injury and posttransplant graft outcomes.

Methods and approach

The researchers measured TNFα, TNFR1, and TNFR2 in 1018 longitudinal plasma samples collected during donor management from 596 deceased and 34 living donors across multiple UK centers. Paired plasma and kidney biopsy samples underwent analysis for injury markers. In vitro studies exposed human podocytes to TNFα-containing donor plasma to examine signaling pathways and treatment responses.

Results

High donor plasma TNFα levels associated significantly with inferior graft function at 12 months through 60 months and reduced graft survival extending to 96 months, but only in donations after brain death rather than circulatory death. The associations persisted after adjustment for donor and recipient covariates in linear mixed models and replicated in a validation cohort. Elevated plasma TNFα correlated with increased injury marker expression in donor kidney tissue, while podocyte exposure to TNFα-rich plasma triggered TNFR1-mediated injury responses that infliximab ameliorated in vitro.

Implications

Circulating TNFα levels during donor management may serve as a biomarker for identifying deceased donor kidneys at elevated risk for poor posttransplant outcomes. The differential impact between brain death and circulatory death donations suggests distinct inflammatory mechanisms warrant investigation between these donation types. Monitoring systemic inflammation offers a potential intervention window during donor management to assess organ quality and implement optimization strategies prior to transplantation.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.