title: 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 (FMDBA) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMDBAafter 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 m2Compared with placebo, rilonacept improved FMDBA(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 FMDBAin 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 FMDBAwithout changing aPWV and reduced systemic inflammation in patients with CKD.
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado; Kristen.Nowak@ucdenver.edu Adriana.hung@vanderbilt.edu.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Nowak
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Michel
authors.initials: M
authors.lastname: Chonchol
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and.|Department of Medicine, Veterans Administration Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Talat Alp
authors.initials: TA
authors.lastname: Ikizler
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Heather
authors.initials: H
authors.lastname: Farmer-Bailey
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Natjalie
authors.initials: N
authors.lastname: Salas
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and.
authors.forename: Rafia
authors.initials: R
authors.lastname: Chaudhry
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Gerard
authors.initials: G
authors.lastname: Smits
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Isak
authors.initials: I
authors.lastname: Tengesdal
authors.affiliation: Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and Kristen.Nowak@ucdenver.edu Adriana.hung@vanderbilt.edu.|Department of Medicine, Veterans Administration Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Hung
mesh_terms: D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D063177:Pulse Wave Analysis; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use*; D012039:Regional Blood Flow / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D007375:Interleukin-1; D011993:Recombinant Fusion Proteins; C531377:rilonacept
keywords: chronic kidney disease; clinical trial; endothelium; pulse wave velocity; randomized controlled trials; vascular