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 pathophysiologic role in several chronic inflammatory conditions and has emerged as a promising therapeutic target.(1, 2) IL-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 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. IL-6 levels in plasma were used to query systemic inflammation and IL-6 in a pre-diuretic spot urine samples were 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 (Supplementary Methods).

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 pro-BNP and lower eGFR (Supplementary Table 1). As shown in Figure 1, plasma, but not urine, IL-6 was associated with systemic neurohormonal activation (OR for high plasma renin=1.9, 95% CI 1.2-3.0, P=0.008) and higher risk of mortality (adjusted HR=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.

Figure 1.

Association between Urine and Plasma IL-6 and Parameters of Cardiorenal Syndrome.

Whiskers represent 95% CI. Analyses of urine IL-6 were adjusted for plasma IL-6; analyses of plasma IL-6 were adjusted for urine IL-6. IL=interleukin. SD=standard deviation. eGFR=estimated glomerular filtration rate. *adjusted for use of ACEI/ARB. **adjusted for baseline characteristics including age, race, NT-proBNP, use of ACE-I/ARB, home loop diuretic dose, and eGFR. Urine IL-6 levels indexed to urinary creatinine. Due to the skewed distribution of urine and plasma IL-6 variables, a log transform was applied before performing logistic and Cox regressions.

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. Though the role of IL-6 in renal disease progression is less well understood, animal model data indicates 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-center, cross-sectional nature and 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.