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

Inflammation is considered a key driver of cardio-renal dysfunction in heart failure (HF). Among pro-inflammatory cytokines, interleukin-6 (IL-6) is of particular interest as it occupies a central pathophysiological role in several chronic inflammatory conditions and has emerged as a promising therapeutic target.1, 2 Interleukin-6 has theoretical clinical relevance to cardio-renal syndrome (CRS) as it has been shown, in murine models, to stimulate the renal epithelial sodium (ENaC) channel and to worsen neurohormonal activation.3 Our goal was to understand the relationship between IL-6 and parameters of renal dysfunction in human HF. We enrolled 98 consecutive patients receiving high-dose loop diuretics in an ambulatory HF unit at the Yale University School of Medicine. Interleukin-6 levels in plasma were used to query systemic inflammation and IL-6 in a pre-diuretic spot urine sample was used to quantify inflammation at the level of renal tissue. Cumulative urine collection during the treatment period was performed to determine total sodium output and efficacy of the administered diuretic (see Supplementary Methods online). Plasma and urine IL-6 were modestly correlated (r = 0.40, P < 0.001). Higher levels of either plasma or urine IL-6 were associated with parameters consistent with greater disease severity including higher NT-proBNP and lower estimated glomerular filtration rate (eGFR) (see Supplementary material online, Table S1). As shown in Figure 1, plasma, but not urine, IL-6 was associated with systemic neurohormonal activation [odds ratio (OR) for high plasma renin 1.9, 95% confidence interval (CI) 1.2–3.0, P = 0.008] and higher risk of mortality (adjusted hazard ratio 2.3, 95% CI 1.5–3.7, P < 0.001). However, levels of urine IL-6 were closely and independently associated with measures of renal dysfunction such as diuretic resistance (OR 2.3, 95% CI 1.4–3.8, P = 0.001), lower eGFR (OR 1.9, 95% CI 1.2–3.1, P = 0.01) and increased renal tissue-level neurohormonal activation (OR for high urine renin 2.1, 95% CI 1.3–3.4, P = 0.002; OR for high urine angiotensinogen 4.2, 95% CI 2.2–7.9, P < 0.001). Plasma IL-6 was not independently associated with diuretic efficiency or tissue-level neurohormonal activation. In this contemporary HF cohort, IL-6 elevations in both plasma and urine were associated with features of CRS including decreased GFR, decreased diuretic responsiveness, and increased neurohormonal activation. Plasma IL-6 was associated primarily with systemic neurohormonal activation and risk of death. This is consistent with prior studies that have shown plasma IL-6 levels to be strongly associated with adverse outcomes in HF patients, presumably via directly induced myocardial dysfunction.4 Conversely, urine IL-6 was linked to indicators of local renal processes but not risk of mortality, suggesting a primarily tissue-level importance for this molecule. Although the role of IL-6 in renal disease progression is less well understood, animal model data indicate that IL-6 can exacerbate acute kidney injury, mediate the damaging effects of angiotensin II, and activate renal ENaC channels, promoting sodium retention.3, 5, 6 To our knowledge, this is the first examination of urine IL-6 and cardio-renal parameters in HF patients. Overall, our results suggest that plasma and urine IL-6 reflect distinct aspects of cardio-renal pathophysiology. The following limitations of our study should be considered. It is a single-centre, cross-sectional study with small sample size. There is potential for selection bias given that the defining clinical phenotype of our cohort was requirement for focused outpatient diuresis. The study focused on IL-6 as a marker of inflammation. Therefore, additional studies will be necessary to evaluate multiple markers of inflammation in CRS and validate our results in clinically distinct cohorts. Nonetheless, these intriguing results indicate that further research is required to determine whether a therapeutically modifiable relationship exists between IL-6 and features of CRS in HF. This publication was made possible, in part, by CTSA grant no. UL1TR001863 and by the George M. O'Brien Kidney Center at Yale, NIH grant P30DK079310. NIH grants K23HL114868, L30HL115790, and R01HL128973 to J.M.T.; NIH grant K23DK097201 to F.P.W.; research grant from Corvidia Therapeutics. The funding sources had no role in study design, data collection, analysis, or interpretation. Conflict of interest: research support from Corvidia Therapeutics. R.K. is an employee of Corvidia Therapeutics. Methods. Supplementary methods. Table S1. Baseline characteristics of the study population. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.