Inflammation and Cardio-Renal Interactions in Heart Failure: A Potential Role for Interleukin-6

Abstract

Introduction: Inflammation is considered a key driver of cardio-renal dysfunction in patients with heart failure (HF). Of the myriad of pro-inflammatory cytokines, interleukin 6 (IL-6) is of particular interest; it is a multifunctional effector with a central role in several chronic inflammatory conditions via its influence on ubiquitous cellular pathways. Accordingly, IL-6 has emerged as a promising therapeutic target for several chronic inflammatory states. Whereas IL-6 causes adverse cardio-renal effects in rodent models, its effects on these pathways in humans are less clear. Hypothesis: Plasma and urine IL-6 levels would associate with key parameters of cardio-renal dysfunction such as diuretic resistance, renal filtration, and neurohormonal activation. Methods: We enrolled 98 consecutive patients receiving high-dose loop diuretics in an ambulatory HF unit. IL-6 levels in plasma were used to query systemic inflammation and IL-6 in urine to quantify inflammation at the renal tissue level. Results: Plasma and urine IL-6 levels were modestly correlated (r = 0.40, P < .001), and levels showed varied association with key parameters of cardiorenal syndrome (Fig. 1). Plasma IL-6, a measure of systemic inflammation, showed the strongest relationship with systemic neurohormonal activation (OR for high plasma renin = 1.9 per SD increase, 95% CI 1.2–3.0, P = .008) and risk of mortality (adjusted HR = 2.3 per SD increase, 95% CI = 1.5–3.7, P < .001). Conversely, levels of urine IL-6, which reported on tissue specific inflammation, were closely associated with measures of cardio-renal dysfunction such as diuretic resistance (OR = 2.3 per SD increase, 95% CI 1.4–3.8, P = .001), lower eGFR (OR = 1.9 per SD increase, 95% CI = 1.2–3.1, P = .01) and increased renal tissue-level neurohormonal activation (OR for high urine renin = 2.1 per SD increase, 95% CI 1.3–3.4, P = .002). Conclusion: IL-6 was strongly and independently associated with parameters of cardio-renal dysfunction, neurohormonal activation, and mortality. In the context of existing mechanistic data suggesting a causal role for IL-6 in cardio-renal dysfunction, this pathway represents a potential therapeutic target.