IL-1 Inhibition and Vascular Function in CKD

Abstract

Vascular endothelial dysfunction and increased arterial stiffness contribute to increased cardiovascular risk in patients with CKD who exhibit chronic systemic inflammation. Because chronic inflammation contributes to vascular dysfunction, blocking inflammation may reduce cardiovascular risk in patients with CKD. In a two-site, double-blind trial, we randomized 42 adult patients with stage 3-4 CKD who were already receiving optimal background therapy to receive either IL-1 trap rilonacept or placebo for 12 weeks. Coprimary end points included change in brachial artery flow-mediated dilation (FMD_BA) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMD_BA after acute ascorbic acid infusion, and vascular endothelial cell protein expression of NADPH oxidase. Participants were 63±11 (mean±SD) years of age and 24% were women; mean eGFR was 38±13 ml/min per 1.73 m² Compared with placebo, rilonacept improved FMD_BA (baseline: 3.36%±2.06% [mean±SD], 12 weeks: 2.45%±2.29% with placebo and baseline: 3.75%±3.12%, 12 weeks: 4.86%±3.20% with rilonacept; P<0.01), without changing aPWV (P=0.56). Rilonacept also reduced hsCRP levels (median [interquartile range]) (baseline: 4.60 [1.90-8.22] mg/L, 12 weeks: 2.16 [0.92-7.38] mg/L; P<0.01) and endothelial cell NADPH oxidase expression (P<0.05). Acute infusion of ascorbic acid to inhibit superoxide production associated with a nonsignificant trend toward increased FMD_BA in the placebo group (P=0.07) but not the rilonacept group (P=0.56). Rilonacept was well tolerated (five adverse events versus two with placebo). In conclusion, treatment with an IL-1 trap improved FMD_BA without changing aPWV and reduced systemic inflammation in patients with CKD.

Keywords: chronic kidney disease; clinical trial; endothelium; pulse wave velocity; randomized controlled trials; vascular.

Figure 1.

Patient enrollment, randomization, and completion (CONSORT) flow diagram. Note, data from participants who discontinued the intervention were still included in the linear mixed-effects models analysis for the visits completed.

Figure 2.

Changes in FMD_BA and aPWV with rilonacept and placebo. Mean group FMD_BA (A) and aPWV (B) at baseline, 4 weeks, 8 weeks, and 12 weeks according to group (rilonacept or placebo). Values are mean±SEM; *P<0.01 (linear mixed-effects models).

Figure 3.

Change in hsCRP with rilonacept and placebo. (A) Median (interquartile range) group levels of hsCRP at baseline and 12 weeks according to group (rilonacept or placebo). (B) Individual subject levels of hsCRP at baseline and 12 weeks. For A, middle line indicates median, borders of the box indicate the 25th and 75th percentiles, and whiskers indicate the 5th and 95th percentiles. P<0.01 (linear mixed-effects models).