Interleukin-6 and renal outcomes after heart failure hospitalization: a post-hoc analysis of the JROADHF-NEXT

Background Renal function decline is common in heart failure and is strongly associated with adverse outcomes; however, its precise mechanisms remain incompletely understood. Inflammation has been implicated in cardiorenal interaction, and interleukin-6 (IL-6), a key upstream mediator of the inflammatory cascade, may play a pivotal role in renal deterioration in heart failure. We hypothesized that IL-6 would provide superior prognostic value compared with high-sensitivity C-reactive protein (hsCRP) for predicting subsequent renal decline. Methods We analyzed 3,160 patients (median age 76 years; 61.8% male) hospitalized for heart failure from the JROADHF-NEXT, a prospective, nation-wide registry. Serum IL-6 and hsCRP levels were measured at discharge. We also measured urine albumin-creatinine ratio (UACR) at discharge. The primary outcome was a composite renal endpoint, defined as a ≥ 40% decline in eGFR, end-stage kidney disease, new–onset dialysis, or renal death. We also tested the association between IL-6 and hsCRP values and subsequent changes in eGFR observed 1-year after discharge. Results Median levels of IL-6 and hsCRP were 3.8 (IQR 2.1-7.3) pg/mL and 3.0 (IQR 0.9-8.6) mg/L, respectively, and patients were stratified into four groups according to quartiles (Q1–Q4). Analysis of covariance (ANCOVA) revealed that higher IL-6 showed a trend toward steeper decline in the adjusted mean eGFR over 12 months (Q1: -2.2, Q2: -3.0, Q3: -3.4, and Q4: -4.0 mL/min/1.73 m2; P for trend = 0.008). Conversely, eGFR decline was not significant across hsCRP quartiles (P for trend = 0.229). During a follow-up of 2 years, 197 composite renal endpoints were observed. Higher IL-6 levels were significantly associated with a stepwise increase in the incidence of the composite renal endpoint (Q1: 5.0%, Q2: 5.1%, Q3: 7.0%, and Q4: 7.9%; P for trend = 0.005), whereas no significant trend was observed across hsCRP quartiles (Q1: 5.8%, Q2: 5.5%, Q3: 5.9%, and Q4: 7.7%; P for trend = 0.121). In adjusted model, each 1-log unit increase in IL-6 remained an independent predictor of the composite renal endpoint independent of age, sex, eGFR and UACR measured at discharge (OR 1.25; 95% CI 1.10–1.43; P < 0.001). However, log hsCRP was not significantly associated with composite renal endpoint (OR 1.07; 95% CI 0.97–1.19; P = 0.154) Conclusions Among hospitalized patients with heart failure, elevated IL-6 level at discharge was independently associated with subsequent renal function decline and adverse renal outcomes independent of other covariates including baseline eGFR and UACR, whereas hsCRP was not. These findings suggest that IL-6 may provide incremental prognostic information for renal risk stratification in heart failure.