IL-1 Inhibition and Vascular Function in CKD

被引:71
作者
Nowak, Kristen L. [1 ]
Chonchol, Michel [1 ]
Ikizler, Talat Alp [2 ,3 ]
Farmer-Bailey, Heather [1 ]
Salas, Natjalie [2 ]
Chaudhry, Rafia [2 ]
Wang, Wei [1 ]
Smits, Gerard [1 ]
Tengesdal, Sal [1 ]
Dinarello, Charles A. [1 ]
Hung, Adriana M. [2 ,3 ]
机构
[1] Univ Colorado Denver, Dept Med, Aurora, CO USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
[3] Tennessee Valley Healthcare Syst, Vet Adm Med Ctr, Dept Med, Nashville, TN USA
来源
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2017年 / 28卷 / 03期
基金
美国国家卫生研究院;
关键词
DIETARY-SODIUM RESTRICTION; CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR MASS; CHRONIC-RENAL-FAILURE; ENDOTHELIAL DYSFUNCTION; OXIDATIVE STRESS; CARDIOVASCULAR EVENTS; BRACHIAL-ARTERY; HABITUAL EXERCISE; OLDER-ADULTS;
D O I
10.1681/ASN.2016040453
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
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), FMDBA 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 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 FMDBA 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 FMDBA without changing aPWV and reduced systemic inflammation in patients with CKD.
引用
收藏
页码:971 / 980
页数:10
相关论文
共 57 条
  • [1] The Inflammasomes in Kidney Disease
    Anders, Hans-Joachim
    Muruve, Daniel A.
    [J]. JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2011, 22 (06): : 1007 - 1018
  • [2] Arginine, arginine analogs and nitric oxide production in chronic kidney disease
    Baylis, C
    [J]. NATURE CLINICAL PRACTICE NEPHROLOGY, 2006, 2 (04): : 209 - 220
  • [3] Bonizzi G, 1999, MOL CELL BIOL, V19, P1950
  • [4] Arterial stiffness and enlargement in mild-to-moderate chronic kidney disease
    Briet, M
    Bozec, E
    Laurent, S
    Fassot, C
    London, GM
    Jacquot, C
    Froissart, M
    Houillier, P
    Boutouyrie, P
    [J]. KIDNEY INTERNATIONAL, 2006, 69 (02) : 350 - 357
  • [5] Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease
    Cachofeiro, Victoria
    Goicochea, Marian
    Garcia de Vinuesa, Soledad
    Oubina, Pilar
    Lahera, Vicente
    Luno, Jose
    [J]. KIDNEY INTERNATIONAL, 2008, 74 : S4 - S9
  • [6] Rosiglitazone does not improve vascular function in subjects with chronic kidney disease
    Chan, Doris T.
    Watts, Gerald F.
    Irish, Ashley B.
    Dogra, Gursharan K.
    [J]. NEPHROLOGY DIALYSIS TRANSPLANTATION, 2011, 26 (11) : 3543 - 3549
  • [7] Arterial stiffness in chronic kidney disease: causes and consequences
    Chue, Colin D.
    Townend, Jonathan N.
    Steeds, Richard P.
    Ferro, Charles J.
    [J]. HEART, 2010, 96 (11) : 817 - 823
  • [8] DESCAMPSLATSCHA B, 1995, J IMMUNOL, V154, P882
  • [9] Don BR, 2010, CLIN NEPHROL, V73, P431
  • [10] Direct evidence of endothelial oxidative stress with aging in humans -: Relation to impaired endothelium-dependent dilation and upregulation of nuclear factor-κB
    Donato, Anthony J.
    Eskurza, Iratxe
    Silver, Annemarie E.
    Levy, Adam S.
    Pierce, Gary L.
    Gates, Phillip E.
    Seals, Douglas R.
    [J]. CIRCULATION RESEARCH, 2007, 100 (11) : 1659 - 1666