Kidney transplant injury associated with brain death is mediated by TNFα, independently of renal innervation.

Kidney transplant outcomes depend on various factors, including donor type. Brain death (BD) has been associated with significant kidney injury, with long-term sequelae. Deciphering the impact of BD versus circulatory death on kidney pathophysiology may help to prevent kidney transplant injury. We developed 3 rat models: 6h of BD (DBD, n=10); circulatory death (DCD, n=10) with 20min of warm ischemia; and 6-hour BD with renal denervation prior to BD (DNRV, n=6). RNA-seq was performed on kidney tissue, followed by differential gene expression and pathway enrichment analyses. Circulating cytokines were measured by Luminex/ELISA. Our findings were validated in 10 human pre-implantation biopsies matching our rat models (n=5 DBD; n=5 DCD). After BD, serum creatinine levels increased from 0.33 [0.31-0.38] to 0.61 [0.59-0.67]mg/dL (p<0.0001). Compared to DCD, DBD rats exhibited significantly higher levels of IL-6 (26.67 [19.10-32.35] vs. 10.32 [9.76-13.28]ng/mL, p=0.006) and TNFᵬ (21.98 [16.48-32.60] vs. 9.64pg/mL [7.96-11.13], p=0.0012), and lower levels of IL-10 (1.28 [1.11-1.65] vs. 1.79 [1.46-2.18]ng/mL, p=0.049). Differential expression analysis revealed that DBD kidneys exhibited CD11b-associated inflammation, caspase-3-mediated apoptosis, and TNFᵬ-driven injury (p=7.34×10-7; z-score=2.475), while DCD kidneys activated EIF2/NRF2 stress-response pathways. Notably, denervation did not mitigate BD-induced injury. Human biopsies confirmed the positive enrichment of inflammatory pathways (p=0.01 to 1.18×10-7) in DBD compared to DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD vs. DCD donors, with a potential role of TNFᵬ in BD-associated kidney injury. Kidney denervation prior to BD does not prevent kidney injury.