HFpEF in CKD is Associated with Elevated TNF‐α/IL‐6 Inflammatory Signaling from the Kidney

Chronic kidney disease (CKD) is independently associated with incident heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms remain unknown. We recently developed a translational swine model of CKD-HF that replicates many features of human HFpEF. This study tested the hypothesis that CKD-induced HFpEF associates with increased pro-inflammatory cytokine signaling of renal origin.CKD and normal pigs (n=4 each) were studied for 14 weeks. Renal hemodynamics (multi-detector CT) and cardiac morphology and function (echocardiography) were quantified in vivo. Tumor necrosis factor (TNF)- α and interleukin (IL)-6 levels (ELISA) were measured in circulating, renal vein, and coronary sinus blood, and their renal and cardiac gradients quantified. Systemic TNF-α and IL-6 levels (Luminex) were also measured in patients with CKD and age/gender-matched healthy volunteers (n=12 each) and correlated with biomarkers of heart failure.Pigs with CKD developed hypertension, renal failure (stage 3), left ventricular (LV) hypertrophy, and abnormal LV strain and diastolic dysfunction (E/A, E/e' ratio) with pEF, accompanied by positive renal (renal release) and negative cardiac (cardiac retention) gradients of TNF-α and IL-6 (Fig. 1A). Circulating TNF-α and IL-6 were also higher in patients with CKD compared to normal subjects (Fig. 1B), which correlated directly with ANP and NT-proBNP levels (Fig. 1C).Our experimental and clinical data supports a crosstalk between the kidney and the heart in CKD, suggesting that inflammatory signaling led by TNF-α and IL-6 of renal origin may impose cardiac abnormalities towards development of HFpEF.