Activation of HMGB1-TLR4 Pathway and Inflammasome Contribute to Enhanced Inflammatory Response in Extended Criteria and Kidneys With KDPI >= 85%

Background. Metrics for evaluating low-quality kidneys have failed to predict outcomes or reduce the kidney refusal and discard rates. Kidneys from extended-criteria donors (ECDs) and kidneys with >= 85% kidney donor profile indexes (KDPIs) might have different sensitivities to the proinflammatory milieu generated by brain death. We aimed to identify gene expression profile differences in innate immunity pathways between low-quality and ideal kidneys. Methods. Preimplantation kidney biopsies from ECD (n = 41) and standard-criteria donor (n = 39) were evaluated for real-time quantitative polymerase chain reaction gene expression using the TaqMan Gene Expression Array Plates system for genes Toll-like receptor-4 (TLR4), high-mobility group box 1, nuclear factor kappa beta, myeloid differentiation primary response 88, interferon (IFN)-gamma, interleukin (IL)1-beta, tumor necrosis factor alpha, caspase-1 (CASP1), intercellular adhesion molecule 1, IL-10, heme oxygenase 1 hypoxia-inducible factor 1 (HIF-1), monocyte chemotactic protein 1, transforming growth factor beta 1, TIR-domain containing adapter inducing interferon-beta (TRIF), TRIF-related adaptor molecule, interferon regulatory factor 3 (IRF-3), receptor-interacting protein 1, IFN beta-1, and nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex. Gene expression was also evaluated in kidneys with KDPI >= 85. Results. ECD biopsies showed significantly higher expression of IL-10, TLR4, high-mobility group box 1, IFN-gamma, TRIF-related adapter molecule, IRF-3, HIF-1, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin protein 3 complex, CASP1, and IL-1 beta (P < 0.05) compared with standard-criteria donor biopsies. IRF-3, HIF-1, and CASP1 were exclusively upregulated in ECD kidneys. Compared with kidneys with KDPIs <85%, kidneys with KDPIs >= 85% had very similar gene transcripts as those observed in ECD kidneys, except that tumor necrosis factor alpha and monocyte chemotactic protein 1 expression was only elevated in kidneys with KDPIs >= 85%. Significant positive correlations were found between the different genes upregulated and the increase in KDPIs. Conclusions. Our results showed that TLR4 and inflammasome pathways are enhanced in low-quality kidneys and suggest that blocking of some targets might improve transplant outcomes and reduce discard rates. (AU)