IL-1 Inhibition and Vascular Function in CKD

• Published in: Journal of the American Society of Nephrology Vol. 28; no. 3; pp. 971 - 980
• Main Authors: Nowak, Kristen L., Chonchol, Michel, Ikizler, Talat Alp, Farmer-Bailey, Heather, Salas, Natjalie, Chaudhry, Rafia, Wang, Wei, Smits, Gerard, Tengesdal, Isak, Dinarello, Charles A., Hung, Adriana M.
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.03.2017
• Subjects: Clinical Research; Double-Blind Method; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Female; Humans; Inflammation - prevention & control; Interleukin-1 - antagonists & inhibitors; Male; Middle Aged; Oxidative Stress - drug effects; Pulse Wave Analysis; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Regional Blood Flow - drug effects; Renal Insufficiency, Chronic - drug therapy; Renal Insufficiency, Chronic - metabolism; Renal Insufficiency, Chronic - physiopathology; clinical trial; endothelium; chronic kidney disease; pulse wave velocity; randomized controlled trials; vascular
• ISSN: 1046-6673; 1533-3450; 1533-3450
• DOI: 10.1681/ASN.2016040453

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 m 2 . 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.