• J Chen, J Kieswich, F Chiazza, T Gobbetti, N S A Patel, M Perretti, M Collino, M M Yaqoob, and C Thiemermann.
• 1Queen Mary University of London, William Harvey Research Institute, London, UK 2University of Turin, Department of Drug Science and Technology, Turin, Italy.
• Shock. 2015 Oct 1;44 Suppl 2:16.

IntroductionPatients with chronic kidney disease (CKD) requiring dialysis have a higher risk of sepsis and a 100-fold higher mortality. The severity of cardiac dysfunction predicts mortality among septic patients. Here we investigated the roles of pre-existing CKD on the cardiac outcome in mice with sepsis, and whether inhibition of IκB kinase (IKK) reduces the cardiac dysfunction in these animals.MethodsMale C57BL/6 mice were subjected to 5/6th nephrectomy (SNX) for 8 weeks, and were further subjected to either low dose LPS (2 mg/kg) or cecum ligation and puncture (CLP) (fluid and antibiotics given at 6 h and 18 h). CKD mice underwent CLP received IKK inhibitor IKK 16 (1 mg/kg, 1h-post CLP).ResultsSNX resulted in significant rises in urea and creatinine, and a small (P < 0.05) reduction in ejection fraction (EF) as assessed via echocardiography, as well as increases in the cardiac phosphorylation of IκBα, nuclear translocation of the NF-κB subunit p65, iNOS expression, and phosphorylation of Akt and ERK1/2. When subjected to LPS or CLP, CKD mice exhibited exacerbation of cardiac dysfunction (Fig. A), increased lung inflammation and plasma cytokine levels (TNF-α, IL-1β, IL-6, IL-10) as well as further increased phosphorylation of IκBα, nuclear translocation of p65 and iNOS expression (heart). IKK 16 attenuated cardiac dysfunction (Fig. B), systemic inflammation and cardiac activation of NF-κB in CKD mice underwent CLP.ConclusionPre-existing CKD aggravates the cardiac dysfunction caused by LPS or CLP in mice; this may (at least in part) be due to increased cardiac activation of NF-κB and iNOS expression.(Figure is included in full-text article.).

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