INTRA-RENAL MODULATION OF NF-κB ACTIVITY ATTENUATES CARDIAC INJURY IN A SWINE MODEL OF CKD: A RENAL-CARDIO AXIS.

Patients with chronic kidney disease (CKD) have a high cardiovascular mortality. CKD and heart failure (HF) coexist in up to 50% of patients and both associates with inflammation. We aim to define the cardiac phenotype of a novel swine model of CKD and test the hypothesis that inflammation of renal origin propels the development of precursors of HF in CKD. CKD was induced in 14 pigs, which were followed for 14 weeks. Renal (multi-detector CT) and cardiac (echocardiography) hemodynamics were quantified before and 8 weeks after single intra-renal administration of placebo or a biopolymer-fused peptide inhibitor of nuclear-factor kappa B (NF-κB) that blocks NF-κB activity and decreases inflammatory activity (SynB1-ELP-p50i). Blood was collected to quantify cytokines (TNF-α, MCP-1, interleukins), markers of inflammation (C-reactive protein), and biomarkers of HF (ANP, BNP). Pigs were then euthanized and kidneys and hearts were studied ex vivo. Normal pigs were used as time-matched controls. Renal dysfunction in CKD was accompanied by cardiac hypertrophy and fibrosis, diastolic dysfunction, increased renal and cardiac expression of TNF-a, MCP-1 and interleukins, canonical and non-canonical mediators of NF-κB signaling, circulating inflammatory factors and biomarkers of HF. Notably, most of these changes were improved after intra-renal SynB1-SynB1-ELP-p50i, although cardiac inflammatory signaling remained unaltered. The translational traits of this model support its use as a platform to test novel technologies to protect the kidney and the heart in CKD. A targeted inhibition of renal NF-κB signaling improves renal and cardiac function, suggesting an inflammatory renal-cardio axis underlying early HF pathophysiology in CKD.