梁海峰　楊　明　韓　凌　陳　萍　李曉紅　辛筱茗

?

高尿酸血癥對合并系統(tǒng)性炎癥反應(yīng)綜合征ACS患者PCI術(shù)后造影劑腎病的影響*

梁海峰楊明#韓凌陳萍李曉紅辛筱茗

目的：觀察血尿酸(UA)水平對合并系統(tǒng)性炎癥反應(yīng)綜合征(SIRS)的急性冠脈綜合征(ACS)患者經(jīng)皮冠狀動(dòng)脈介入治療(PCI)術(shù)后造影劑腎病(CIN)的影響。方法：276例接受冠狀動(dòng)脈造影+PCI的ACS患者，根據(jù)是否并發(fā)SIRS分為SIRS組(A組，n=77)和非SIRS組(B組，n=199)；再根據(jù)血UA水平分別將A組分為高UA組(A1組，n=30)和正常UA組(A2組，n=47)，將B組也分為高UA組(B1組，n=42)和正常UA組(B2組，n=157)。觀察各組PCI術(shù)前血UA、超敏C反應(yīng)蛋白(hs-CRP)、白細(xì)胞介素-6(IL-6)水平及術(shù)后CIN發(fā)生率。結(jié)果：術(shù)前，A組、A1組、B1組UA、hs-CRP及IL-6水平分別高于B組、A2組和B2組(P<0.05)，其中A1組最高。術(shù)后3天，A組、A1組、B1組CIN發(fā)生率分別高于B組、A2組及B2組(P<0.05)，其中A1組最高。結(jié)論：高UA合并SIRS的ACS患者PCI術(shù)后易發(fā)CIN。

血尿酸；急性冠脈綜合征；系統(tǒng)性炎癥反應(yīng)綜合征；經(jīng)皮冠狀動(dòng)脈介入治療；造影劑腎病

隨著介入診療技術(shù)的廣泛開展，造影劑腎病(Contrast-induced Nephropathy，CIN)越來越常見，不僅延長患者住院時(shí)間，也增加醫(yī)療費(fèi)用和死亡率[1-4]。目前，臨床治療CIN尚缺乏有效手段；早期篩查CIN危險(xiǎn)因素和高危人群，成為減少CIN的關(guān)鍵[5]。長期以來，臨床一般應(yīng)用Mehran評分[6]預(yù)測CIN的發(fā)生風(fēng)險(xiǎn)，采用術(shù)前及術(shù)后水化、應(yīng)用低滲性造影劑、控制造影劑用量和避免使用腎毒性藥物等方法，以盡量減少CIN的發(fā)生。而對除此以外的其它危險(xiǎn)因素和預(yù)防措施研究尚少。尿酸(UA)為嘌呤代謝產(chǎn)物，其水平升高見于痛風(fēng)、腎小球腎炎等疾病，近年研究認(rèn)為高UA水平可能是CIN的危險(xiǎn)因素[7]。因而本文選擇高血UA水平對合并系統(tǒng)性炎癥反應(yīng)綜合征(SIRS)的急性冠脈綜合征(ACS)患者經(jīng)皮冠狀動(dòng)脈介入治療(PCI)術(shù)后發(fā)生CIN的影響進(jìn)行研究，為臨床防治CIN提供新的思路。

1　資料與方法

1.1病例和分組

2014-01-2015-12，本科收住院ACS患者276例，男155例，女121例，平均年齡65.22±8.93歲。其中伴SIRS者77例，SIRS同時(shí)合并高UA血癥者30例。ACS診斷符合國內(nèi)指南[8,9]及全球定義[10，11]，且排除以下患者：(1)年齡<20歲或>80歲；(2)估算腎小球過濾率(Estimated Glomerular Filtration rate，eGFR) <60ml/min/1.73m2；(3)左室射血分?jǐn)?shù)<40%；(4)近兩周發(fā)生急性感染；(5)有免疫性疾病且處于活動(dòng)期；(6)惡性腫瘤；(7)應(yīng)用主動(dòng)脈球囊反博(Intra-Aortic Balloon Pump，IABP)輔助循環(huán)；(8)近一周內(nèi)應(yīng)用腎素-血管緊張素-醛固酮系統(tǒng)抑制劑或調(diào)整劑量；(9)兩周內(nèi)應(yīng)用造影劑或有造影劑過敏史；(10)應(yīng)用腎毒性藥物史，如氨基甙類抗生素、環(huán)孢霉素A、兩性霉素B等；(11)收縮壓<90mmHg且持續(xù)1h以上或給予升壓藥物治療；(12)PCI前48h未停用雙胍類藥物；(13)紅細(xì)胞壓積男性<39%或女性<36%；(14)經(jīng)超聲或腎動(dòng)脈造影證實(shí)單側(cè)或雙側(cè)腎動(dòng)脈狹窄>50%。所有患者及家屬均知情同意行PCI治療。高UA血癥診斷標(biāo)準(zhǔn)為男性UA≥417mmol/L，女性UA≥357mmol/L[12]。SIRS診斷根據(jù)Cincent等[13]介紹的標(biāo)準(zhǔn)：(1)體溫>38℃或<36℃；(2) 呼吸頻率>20次/min，或動(dòng)脈血二氧化碳分壓<32mmHg；(3) 外周血白細(xì)胞>12.0G/L或<4.0G/L或幼稚桿狀細(xì)胞>10%；(4)心率>90次/min；符合2項(xiàng)及以上確定為SIRS。

ACS患者根據(jù)是否合并SIRS 分為SIRS組(A組，n=77)和非SIRS組(B組，n=199)；再根據(jù)血UA水平將A組分為高UA血癥組(A1組，n=30)和正常UA組(A2組，n=47)，將B組也分為高UA血癥組(B1組，n=42)和正常UA組(B2組，n=157)。A、B兩組患者年齡、性別、吸煙比例、糖尿病史、高血壓病史等無統(tǒng)計(jì)學(xué)差異(P>0.05)。

eGFR、造影劑用量和冠心病二級預(yù)防藥物應(yīng)用等的差異亦無統(tǒng)計(jì)學(xué)意義(P>0.05)。但A組不穩(wěn)定型心絞痛(UAP)患者比例低于B組，ST段抬高型心肌梗死(STEMI)、非ST段抬高型心肌梗死(NSTEMI)患者比例高于B組，差異有統(tǒng)計(jì)學(xué)意義(P<0.05 或P<0.01)。見表1。

表1　兩組患者臨床基本資料

1.2治療方法

A、B兩組患者均給予標(biāo)準(zhǔn)冠心病二級預(yù)防治療，并按臨床常規(guī)行冠狀動(dòng)脈造影+PCI。術(shù)前6-12h、術(shù)后12-24h均給予0.9%生理鹽水(1ml/kg/min)靜脈滴注水化治療。造影劑均選用歐乃派克注射液(350mgI/ml，通用電氣藥業(yè)有限公司產(chǎn)品)，最大劑量參照Cigarroa公式[14]計(jì)算[=體重(kg)×5/Scr(mg/ml)]。術(shù)前監(jiān)測所有患者血UA、超敏C反應(yīng)蛋白(hs-CRP)和白細(xì)胞介素-6(IL-6)水平。術(shù)后3天通過腎功能檢測評估CIN發(fā)生率。

1.3觀察指標(biāo)和方法

1.3.1血UA、炎性因子水平和腎功能指標(biāo)測定：血UA、hs-CRP、IL-6和Scr檢測：抽取患者前臂空腹靜脈血，2h內(nèi)3 000r/min離心20min，取血清，30min內(nèi)保存在-80℃低溫冰箱中，避免反復(fù)凍融。hs-CRP采用酶法或膠乳凝集反應(yīng)法，IL-6采用ELISA，試劑盒均由加拿大LTD公司提供。血UA采用尿酸酶法，Scr采用苦味酸法，試劑均由中生北控生物科技有限公司提供,使用日本日立公司7600型全自動(dòng)生化分析儀測定。

1.3.2CIN發(fā)生率：PCI術(shù)后48-72h，血Scr較基線值升高25%或達(dá)到44.2μmol/L診斷為CIN[15]。各組發(fā)生CIN例數(shù)與該組總例數(shù)百分比即為該組CIN發(fā)生率。

1.4統(tǒng)計(jì)學(xué)處理

2　結(jié)　果

2.1PCI術(shù)前各組血UA、hs-CRP和IL-6水平

PCI術(shù)前，A組血UA、hs-CRP和IL-6水平高于B組(P<0.05,P<0.01)；A1組血UA、hs-CRP和IL-6水平高于A2組(P<0.05，P<0.01)；B1組血UA、hs-CRP和IL-6水平高于B2組(P<0.05，P<0.01)；各指標(biāo)水平均以A1組最高。見表2。

表2　PCI術(shù)前各組間血UA、hs-CRP及IL-6水平比較

2.2各組CIN發(fā)生率

PCI術(shù)后3天，A組CIN發(fā)生率高于B組(P<0.01)；A1組高于A2組(P<0.05)；B1組高于B2組(P<0.01)；以A1組最高。見表3。

表3　PCI術(shù)后各組CIN發(fā)生率(n,%)

3　討　論

在冠狀動(dòng)脈介入領(lǐng)域，CIN已成為繼支架內(nèi)血栓和再狹窄之后的又一難題。近年來，對CIN發(fā)病機(jī)制的研究主要集中在造影劑導(dǎo)致的腎髓質(zhì)缺血性損傷，腎小管堵塞和對腎小管上皮細(xì)胞的直接毒性等方面。臨床上引發(fā)CIN的因素較多，包括心功能、造影劑用量、腎毒性藥物的應(yīng)用等[16]，但少見血UA對CIN影響的報(bào)道，尤其SIRS、高UA血癥對CIN發(fā)生的影響研究甚少。本課題組前期研究顯示，心臟缺血患者h(yuǎn)s-CRP、IL-6高表達(dá)，PCI后發(fā)生CIN較多[12]。提示炎癥反應(yīng)導(dǎo)致冠狀動(dòng)脈斑塊不穩(wěn)定，誘發(fā)缺血事件可能增加其PCI術(shù)后CIN發(fā)生。Ridker等[17]也報(bào)道，接受PCI治療的冠心病患者炎性因子水平與CIN的發(fā)生有一定的相關(guān)性。但高UA并發(fā)炎癥反應(yīng)與CIN的關(guān)系不十分清楚。

Meotti等[18]研究顯示，高UA與炎癥反應(yīng)有一定的聯(lián)系，但對于血UA水平對CIN的影響沒有進(jìn)一步闡明。本研究將接受PCI治療的ACS患者根據(jù)有無SIRS和高UA血癥分組，觀察術(shù)前各組血UA水平和炎性因子hs-CRP、IL-6變化及術(shù)后CIN的發(fā)生率，結(jié)果表明，合并SIRS及高UA血癥的ACS患者CIN的發(fā)生率最高(43.33%)；而且該組患者術(shù)前炎性因子hs-CRP和IL-6水平與血UA水平同步升高，其原因和機(jī)制可能與高UA血癥和SIRS的作用有關(guān)。Ruggiero 等[19]、Nozari等[20]的研究均提示，升高的血UA和尿酸鹽結(jié)晶可以促使IL-1和IL-6誘導(dǎo)CRP升高，IL-6和CRP在心血管疾病和高UA血癥之間起到調(diào)節(jié)作用，特別是升高的血UA通過抑制一氧化氮系統(tǒng)，激活腎素-血管緊張素-醛固酮系統(tǒng)，擴(kuò)大炎癥反應(yīng)，增加氧化應(yīng)激的活性氧成分，導(dǎo)致腎功能受損[21,22]。動(dòng)物實(shí)驗(yàn)也顯示，高血UA可促進(jìn)CRP、IL-6等炎性介質(zhì)釋放，在分子層面促進(jìn)炎癥損害。激發(fā)系統(tǒng)性無菌性炎癥[23-25]；即使調(diào)整體質(zhì)量指數(shù)(BMI)等混雜因素后，血UA與CRP水平仍呈正相關(guān)[26,27]。本研究中B組雖非SIRS患者，但炎性因子及CIN發(fā)生率均高于B2組，這可能是高血UA對炎性因子激活的結(jié)果，即升高的血UA不僅可能抑制腎素-血管緊張素-醛固酮系統(tǒng)，收縮腎動(dòng)脈造成腎臟損傷，同時(shí)通過激活炎性因子，影響機(jī)體內(nèi)環(huán)境和腎臟代謝，增加CIN發(fā)生率。

綜上所述，高血UA誘導(dǎo)的炎性因子高表達(dá)可能增加PCI術(shù)后患者CIN發(fā)生率。提示除了傳統(tǒng)危險(xiǎn)因素外，高血UA的直接作用及其對體內(nèi)炎癥反應(yīng)的激活是CIN發(fā)生的又一重要因素，應(yīng)引起臨床的足夠重視并對其進(jìn)行早期干預(yù)，以降低CIN的發(fā)生。

?

本文第一作者簡介：

梁海峰(1975-)，男，漢族，醫(yī)學(xué)碩士，副主任醫(yī)師，主要從事心血管疾病的臨床防治

1James MT,Gali WA,Tonelli M,et al.Acute kidney injury following coronary angiography is associated with a long-term decline in kidney function[J].Kidney Int,2010,78(8):803-809.

2Kim KS,Kim K,Hwang SS,et al.Risk stratification nomogram for nephropathy after abdominal contrast-enhanced computed tomography[J].Am J Emerg Med,2011,29(4):412-417.

3Mehran R,Brar S,Dangas G.Contrast-induced acute kidney injury Underappreciated or a new marker of cardiovascular mortality[J].J Am Coll Cardiol,2010,55(20):2 210-2 211.

4Franke RP,Jung F.Pathophysiology of the contrast media-induced nephropathy (CIN) in patients undergoing coronary interventions[J].Clin Hemorheol Microcirc,2013,53(1-2):143-153.

5Marenzi G,De Metrio M,Rubino M,et al.Acute hyperglycemia and contrast induced nephropathy in primary percutaneous coronary intervention[J].Am Heart J,2010,160(6):1 170-1 177.

6Mehran R,Aymong ED,Nikolsky E,et al.A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention:development and initial validation[J].J Am Coll Cardiol,2004,44(7):1 393-1 399.

7Lbasan Z,Sahin DY,Gur M,et al.Conirast-induced nephropathy in pationts with ST elevation myocardial infarction treated with primary percutaneous coronary intorvontion[J].Angiology,2014,65(1):37-42.

82012年中華醫(yī)學(xué)會(huì)心血管病學(xué)分會(huì).非ST段抬高急性冠脈綜合征診斷與治療指南[J].中華心血管病雜志,2012,40(5):353-367.

92015年中華醫(yī)學(xué)會(huì)心血管病學(xué)分會(huì).ST段抬高型心肌梗死診斷與治療指南[J].中華心血管病雜志,2015,43(5):380-389.

10Jaffe AS.Third universal definition of myocardial infarction[J].Clin Biochem,2013,46(1-2):1-4.

11White HD,Thygese K,Alpert JS,et al.Clinical implication of the third universal definition of mycardial infarction[J].Heart,2014,100(5):424-432.

12Chiou WK,Wang MH,Huang DH,et al.The relationship between serum uric acid level and metabolic syndrome:Differences by sec and age in taiwanese[J].Epidemiol,2010,20(3):219-224.

13Cincent JL.Dear SIRS,I'm sorry to say I don't like you[J].Crit Care Med,1997,25(2)：372-374.

14Cigarroa RG,Lange RA,Williams RH,et al.Dosing of contrart material to prevent contrast nephropathy in patients with renal disease[J].Am J Med,1989,86(6):649-652.

15Sholy H,Zukermann R,Soni A,et al.Contrast-induced nephropathy:an update on diagnosis,predictors,implications and preventive strategies[J].Minerva Med,2012,103(6):465-486.

16梁海峰,楊明,韓凌，等.炎癥反應(yīng)對接受PCI治療的非ST段抬高ACS患者造影劑腎病的影響[J].微循環(huán)學(xué)雜志,2013,23(1):21-23.

17Ridker PM,Danielson E,Fonseca FA,et al.Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin:a prospective study of the JUPITER trial[J].Lancet,2009,37(3):1 175-1 182.

18Meotti FC,Jameson GN,Turner R,et al.Urate as a physiological substrate for myeloperoxidase:implications for hyperuricemia and inflammation[J].J Biol Chem,2011,286(15):12 901-12 911.

19Ruggiero C,Cherubini A,Miller E,et al.Usefulness of uric acid to predict changes in C-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years[J].Am J Cardiol,2007,100(1):115-121.

20Nozari Y,Geraiely B.Correlation between the serum levels of uric acid and HS-CRP with the occurrence of early systolic failure of left ventricle following acute myocardial infarction[J].Acta Med Iran,2011,49(8):531-535.

21Elbasan Z,Sahin DY,Gür M,et al.Contrast-induced nephropathy in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention[J].Angiology,2014,65(1):37-42.

22Filiopoulus V,Hadjiyannakos D,Vlassopoulos D.New insights into uric acid effects on the progression and prognosis of chronic kidney disease[J].Ren Fail,2012,34(4):510-520.

23Kono H,Chen CJ,Ontiveros F,et al.Uric acid promotes an acute inflammatory response to sterile cell death in mice[J].J Clin Invest,2010,120(6):1 939-1 949.

24Ruggiero C,Cherubini A,Ble A,et al.Uric acid and inflammatory markers[J].Eur Heart J,2006,27(10):1 174-1 181.

25Lyngdoh T,Marques-Vidal P,Paccaud F,et al.Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based Colaus study[J].PLoS One,2011,6(5):e19901.

26Saito M,Ishimitsu T,Minami J,et al.Relations of plasma high-sensitivity C-reactive protein to traditional cardiovascular risk factors[J].Atherosclerosis,2003,167(1):73-79.

27Frohlich M,Imhof A,Berg G,et al.Association between C-reactive protein and features of the metabolic syndrome:a population-based study[J].Diabetes Care,2000,23(12):1 835-1 839.

Influence of Hyperuricemia on Contrast-induced Nephropathy in Patients with ACS and SIRS Undergoing Percutaneous Coronary Intervention

LIANG Haifeng,YANG Ming#,HAN Ling,CHEN Ping,LI Xiaohong,XIN Xiaoming

Department of Cardiology,Fuxing Hospital Affiliated to Capital Medical University,Beijing 100038,China；#Corresponding author

Objective:To observe the influence of serum uric acid(UA) on contrast-induced nephropathy (CIN) in patients with acute coronary syndrome (ACS) and systemic inflammatory response syndrome (SIRS) undergoing percutaneous coronary intervention (PCI).Method:A total of 276 patients with ACS undergoing coronary angiography and PCI were assigned to SIRS group (group A,n=77) and no-SIRS group (group B,n=199).Then,according to the level of serum uric acid,group A was assigned into hyperuricemia group (group A1,n=30) and normal serum uric acid group (group A2,n=47),group B also was assigned into hyperuricemia group (group B1,n=42) and normal serum uric acid group (group B2,n=157).The serum levels of hs-CRP,IL-6 and uric acid at pre-stenting and after PCI were detected.The incidence rate of contrast-induced nephropathy was monitored after PCI.Results:At pre-stenting,the serum levels of UA,hs-CRP and IL-6 in group A,A1 and B1 were significantly higher than group B,A2 and B2,respectively (P<0.05).The serum levels of UA,hs-CRP and IL-6 in group A was the highest.The 3rd day after PCI,the accidence rate of contrast-induced nephropathy in group A,A1 and B1 were higher than group B,A2 and B2,respectively (P<0.05).The incidence rate of CIN in group A1 was the highest.Conclusion:The hyperuricemia is a influential factor of CIN in patients with ACS and SIRS after PCI.

Serum uric acid; Acute coronary syndrome; Systemic inflammatory response syndrome; Percutaneous coronary intervention; Contrast-induced nephropathy

北京市優(yōu)秀人才培養(yǎng)專項(xiàng)課題 (2013D008007000001)

單位]首都醫(yī)科大學(xué)附屬復(fù)興醫(yī)院心內(nèi)科,北京100038；#

,E-mail:Lianghaifeng_dty@126.com

本文2016-03-22收到，2016-06-13修回

R541.3R692[文獻(xiàn)標(biāo)識(shí)碼]A

1005-1740(2016)03-0031-05