Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease
Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease
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DOI：
10.1016/j.jacc.2018.03.490
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发表时间：
2018-05-29
影响因子：
24
通讯作者：
Cornel, Jan H.
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文献类型：
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作者：
Ridker, Paul M.;MacFadyen, Jean G.;Cornel, Jan H.
炎症导致慢性肾脏疾病（CKD），其部分通过肾脏内的NLRP 3炎性体激活白细胞介素（IL）-1 β介导。这一过程也可能导致与肾病相关的动脉粥样硬化加速。作者假设，靶向IL-1 β的人单克隆抗体canakinumab，心肌梗死后高敏C-反应蛋白（hsCRP）≥ 2mg/L的稳定期患者，给予高敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的低敏C-反应蛋白（hsCRP）2mg/L的稳定期患者，给予高敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的稳定期患者，给予高敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的低敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的稳定期患者，给予高敏C-反应蛋白（hsCRP）2mg/L的高敏C-反应蛋白（hsCRP）2mg/L的稳定期患者，给予高敏C-反应蛋白（hsCRP）2mg l被随机分配至安慰剂组或3个剂量的卡那单抗（50、150或300 mg）中的1个，每3个月皮下给药一次。在中位随访期3.7年（最长5年）内，对参与者进行了心肌梗死、卒中、因不稳定型心绞痛需要紧急血运重建而住院、心血管死亡或任何原因死亡的随访。所有患者还接受了估计肾小球滤过率（eGFR）、肌酐、尿白蛋白与肌酐比值（uACR）的系列监测，并监测了不良肾脏和泌尿系统事件。（18.6%）基线eGFR = 60 ml/min/1.73 m（2）（6.92 vs. 4.13/100人-年; p <0.0001）。随机分配至canakinumab可降低CKD患者发生主要不良心血管事件的风险（风险比：0.82; 95%置信区间：0.68至1.00; p = 0.05），在首次给药后测量的治疗中hsCRP水平低于2 mg/l的患者中，心血管获益最大（风险比：0.68; 95%置信区间：0.53至0.86; p = 0.0015）。在基线白蛋白尿或糖尿病患者中观察到了类似的效果。canakinumab既没有临床意义的好处，也没有实质性的伤害，相对于一系列措施的eGFR，肌酐，uACR，或报告的不良肾脏事件在试验follow-updating. CONCLUSIONS IL-1 β抑制与canakinumab降低主要不良心血管事件发生率在高风险动脉粥样硬化患者CKD，特别是在那些具有强大的抗炎反应的初始治疗。这些心血管获益累积，无不良临床肾脏事件。(C)2018年由美国心脏病学会基金会。
BACKGROUND Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1 beta by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy.OBJECTIVES The authors hypothesized that canakinumab, a human monoclonal antibody targeting IL-1 beta, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD.METHODS Stable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) >= 2mg/l were randomly allocated to placebo or to 1 of 3 doses of canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events.RESULTS Of 10,061 participants, 1,875 (18.6%) had baseline eGFR = 60 ml/min/1.73 m(2) (6.92 vs. 4.13 per 100 person-years; p < 0.0001). Random allocation to canakinumab reduced the risk of major adverse cardiovascular events among those with CKD (hazard ratio: 0.82; 95% confidence interval: 0.68 to 1.00; p = 0.05) with the largest cardiovascular benefits accruing among those who achieved on-treatment hsCRP levels below 2 mg/l measured after taking the first dose (hazard ratio: 0.68; 95% confidence interval: 0.53 to0.86; p = 0.0015). Comparable effects were observed among those with baseline albuminuria or diabetes. Canakinumab had neither clinically meaningful benefits nor substantive harms with respect to serial measures of eGFR, creatinine, the uACR, or reported adverse renal events during trial follow-up.CONCLUSIONS IL-1 beta inhibition with canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (C) 2018 by the American College of Cardiology Foundation.