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 three rat models: 6 h of BD [donor after brain death (DBD, n = 10)]; donor after circulatory death (DCD, n = 10) with 20 min of warm ischemia; and 6-h BD with renal denervation before 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 preimplantation 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 with 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 TNFα (21.98 [16.48-32.60] vs. 9.64 pg/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 TNFα-driven injury (P = 7.34 × 10-7; z-score = 2.475), whereas 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 with DCD, with 6 out of the top 15 pathways shared across species. Our findings highlight specific mechanisms affecting differently kidneys derived from DBD versus DCD donors, with a potential role of TNFα in BD-associated kidney injury. Kidney denervation before BD does not prevent kidney injury.NEW & NOTEWORTHY Kidney transplantation outcomes are influenced by donor type. Brain death has been associated with significant kidney injury, with long-term sequelae. We established two rat models mimicking human conditions of kidney donation after brain death or circulatory arrest. We identified TNFα as the main driver of BD-induced kidney injury, as validated in human pretransplant biopsies. Notably, kidney denervation before BD failed to prevent TNFα-mediated damage. Targeting TNFα signaling in DBD donors may improve transplant outcomes.