Etanercept Attenuates TNFα-mediated Kidney Injury in a Rat Model of Brain Death Kidney Donation.

Brain death (BD) induces a robust inflammatory response that impairs kidney quality before transplantation. Given that TNFα is a central upstream mediator of BD-related injury, we investigated whether selective TNFα inhibition using etanercept could mitigate renal damage in a rat model of BD. BD was maintained for 6 h in anesthetized rats (n = 6 controls; n = 12 etanercept-treated; balanced for sex), after which animals were randomized to receive either etanercept (ETNCPT) or vehicle (CTL). We evaluated serum biomarkers, histological kidney injury, immune cell infiltration, and whole-kidney transcriptomic profiles. Etanercept significantly reduced circulating TNFα levels (15.25 [12.30-21.05] vs. 34.23 [26.03-50.19] pg/mL; P < 0.001), whereas other cytokines remained unchanged. Kidney function parameters [serum creatinine and blood urea nitrogen (BUN)], electrolytes, and hemodynamics were similar across groups. In contrast, etanercept markedly attenuated renal injury, reducing acute tubular necrosis (30.0 [15.0-35.0]% vs. 42.5 [40.0-51.3]%; P < 0.001), CD11b+ myeloid infiltration (0.13 [0.11-0.15]% vs. 0.21 [0.19-0.27]%; P < 0.001), tubular kidney injury molecule-1 expression (0.04 [0.01-0.08]% vs. 0.17 [0.13-0.18]%; P < 0.001), and apoptosis (-69%; P = 0.036). Transcriptomic analysis identified 281 differentially expressed genes after TNFα blockade, with strong inhibition of inflammatory and apoptotic pathways including TNF signaling, TNFR1/TNFR2 activation, death receptor signaling, and cytokine storm signaling. Predicted downstream effects included reduced kidney cell death and inflammation. Sex-stratified analyses showed similar directional effects in males and females. In summary, early TNFα blockade after BD selectively neutralizes TNFα, limits immune recruitment, and suppresses injury and inflammatory signaling at cellular and transcriptomic levels. Targeting TNFα during kidney donor management may offer a promising strategy to improve kidney quality before transplantation.NEW & NOTEWORTHY Brain death (BD) remains a major contributor to kidney injury in deceased donors. In this study, we demonstrate that selective TNFα blockade with etanercept during donor management markedly reduces BD-induced renal damage. Using a rat model of 6-h BD, we show that etanercept selectively neutralizes circulating TNFα without altering hemodynamics or kidney function markers yet significantly decreases tubular injury, myeloid infiltration, KIM-1 expression, and apoptosis. Whole-kidney transcriptomics confirmed broad suppression of TNF-dependent inflammatory and apoptotic pathways. These findings confirm TNFα as a central mediator of BD-associated renal injury and support TNFα-targeted interventions as a promising strategy to improve the quality of BD donor kidney before transplantation.