內(nèi)皮功能失調(diào)標(biāo)志物Ang-1和Ang-2與危重病人急性腎損傷的相關(guān)研究

陳東溟

內(nèi)皮功能失調(diào)標(biāo)志物Ang-1和Ang-2與危重病人急性腎損傷的相關(guān)研究

陳東溟

（沈陽(yáng)急救中心沈河分中心，遼寧 沈陽(yáng) 110000）

目的 探討內(nèi)皮功能失調(diào)標(biāo)志物在危重病人合并急性腎損傷（AKI）中的作用。方法 對(duì)沈陽(yáng)急救中心948例ICU患者的內(nèi)皮功能標(biāo)志物和炎癥因子與AKI的相關(guān)性進(jìn)行回顧研究，病人住院24小時(shí)內(nèi)取血樣，以血清肌酐定義AKI，在測(cè)定血管生成素1和2（angiopoietin，Ang-1，Ang-2）的同時(shí)也測(cè)定白介素6、17（IL-6、IL-17）和粒細(xì)胞集落刺激因子（G-CSF），以及各因子之間的相關(guān)性，共測(cè)量7天。結(jié)果 所有炎癥因子和內(nèi)皮功能失調(diào)標(biāo)志物都與AKI相關(guān)，經(jīng)過合并癥與IL-6濃度的校正，每一個(gè)Ang-1濃度的標(biāo)準(zhǔn)差均與19%的AKI低風(fēng)險(xiǎn)相關(guān)（相對(duì)危險(xiǎn)度（RR）=0.84，95%可信區(qū)間（CI）0.76～0.92，P＜0.01），而高濃度的Ang-2與AKI的高風(fēng)險(xiǎn)相關(guān)（RR=1.16，95%CI 1.12～1.21，P＜0.01）。結(jié)論 在危重病人中，Ang-1和Ang-2是除去炎癥因子之外AKI的獨(dú)立危險(xiǎn)因素。

急性腎損傷；血管生成素；內(nèi)皮功能失調(diào)；標(biāo)志物；膿血癥

急性腎損傷是（AKI）膿血癥和全身炎癥反應(yīng)綜合征（SIRS）的常見并發(fā)癥，易增加危重患者的住院時(shí)間、透析需求和膿血癥相關(guān)死亡率[1-7]。AKI是指48小時(shí)內(nèi)腎功能突然衰退而至血肌酐升高，尿量減少，需要腎臟替代治療或者以上均出現(xiàn)。然而，血肌酐作為早期AKI的指標(biāo)，落后于腎小球?yàn)V過率[8-10]，以此很難預(yù)期患者的AKI風(fēng)險(xiǎn)和相關(guān)結(jié)局。因此對(duì)于評(píng)估嚴(yán)重AKI風(fēng)險(xiǎn)的化驗(yàn)檢查方法，迫切需要新的敏感并且特異的生物標(biāo)志物。

多年以來(lái)，中性粒細(xì)胞明膠酶蛋白（NGAL）被認(rèn)為是最具希望的AKI標(biāo)志物[11-13]，但是在危重病人范疇內(nèi)的使用受到了限制，這是因?yàn)槟撗Y的炎癥反應(yīng)促使肝和肺中的NGAL合成增加，而與腎無(wú)關(guān)[10,14-16]。因此對(duì)于SIRS和多器官衰竭的病人，NGAL也許不是有效的AKI指標(biāo)。

危重病人的AKI病因復(fù)雜，對(duì)其發(fā)病機(jī)制的深入研究可能發(fā)現(xiàn)新的生物標(biāo)志物，先前認(rèn)為，嚴(yán)重的全身性炎癥提高了腫瘤壞死因子（TNF），白介素（IL）-6，粒細(xì)胞集落刺激因子（G-CSF）和其他炎癥介質(zhì)的表達(dá)，同時(shí)也對(duì)膿血癥引起的器官功能障礙起了重要作用[17-20]。

然而，近來(lái)發(fā)現(xiàn)內(nèi)皮細(xì)胞激活并導(dǎo)致血管屏障破壞成為器官功能障礙的關(guān)鍵病原機(jī)制[21-23]，此背景下的AKI的確切發(fā)病機(jī)制尚不清楚，有證據(jù)提示，微血管內(nèi)皮細(xì)胞受損和功能失調(diào)對(duì)于缺血性AKI再灌注期的上皮細(xì)胞受損起到重要作用[9，24]。

血管生成素（Ang）是血管發(fā)育成熟和炎癥反應(yīng)的必要因子，Ang-1和拮抗劑Ang-2是分泌型內(nèi)皮生長(zhǎng)因子，與酪氨酸激酶受體（Tie2）的細(xì)胞外區(qū)域結(jié)合，后者主要在內(nèi)皮細(xì)胞上表達(dá)，Ang-1具有穩(wěn)定內(nèi)皮的保護(hù)性，而Ang-2增加血管通透性，使膿血癥結(jié)局惡化[25，28]。隨著內(nèi)皮激活，血管粘附分子上調(diào)，其中包括可溶性血管細(xì)胞粘附分子-1（sVCAM-1）[29]。內(nèi)皮損傷和功能障礙的生物標(biāo)志物與伴有全身性炎癥的疾病的不良結(jié)局密切相關(guān)[30-32]，但其對(duì)AKI的臨床意義有待進(jìn)一步研究。

1 資料與方法

1.1 臨床資料 納入研究的患者年齡44～71歲，平均年齡（55.49±6.81）歲，其中36%為女性。在ICU住院24 h以上，同時(shí)具備SIRS診斷標(biāo)準(zhǔn)中的至少2項(xiàng)[33-34]。排除標(biāo)準(zhǔn)包括：主要臟器創(chuàng)傷，顱內(nèi)出血，HIV，免疫抑制或者癌癥。所有患者在進(jìn)ICU后的第1天采血化驗(yàn)，隨訪至出院或死亡。本研究經(jīng)過本中心倫理道德委員會(huì)批準(zhǔn)。

1.2 方法 將所有血樣稀釋到合適范圍，在同一天以電化學(xué)發(fā)光免疫測(cè)定法測(cè)試IL-6，IL-8，G-CSF，TNFR-1，Ang-1，Ang-2，和sVCAM-1，界定各個(gè)因子的范圍如下，IL-6，IL-8和TNFR-1：0.08～2 500 pg/mL；G-CSF：0.12～5 000 pg/mL；Ang-1：3～100 000 pg/mL；Ang-2：0.5～10 000 pg/mL；sVCAM-1：0.05～1 000 pg/mL。超出范圍的只取界值，部分測(cè)量值缺失歸因?yàn)闃悠妨坎蛔悖ā?%）。

1.3 診斷標(biāo)準(zhǔn) 從入ICU至住院7 d，每天測(cè)量血肌酐，以KDIGO標(biāo)準(zhǔn)定義[35]AKI，即48 h內(nèi)血肌酐升高0.3 mg/dL，或7 d內(nèi)升高1.5倍。嚴(yán)重的AKI是指KDIGO的2或者3期。因?yàn)楸狙芯坎灰訟KI為主要終點(diǎn)，所以未測(cè)量每小時(shí)尿量與腎臟替代治療的數(shù)據(jù)。

1.4 協(xié)變量 從住院的電子病歷中調(diào)取病人的自然情況，診療過程和并發(fā)癥等信息。急性生理學(xué)及慢性健康狀況評(píng)分系統(tǒng)Ⅲ（Acute Physiology，Age，Chronic EvaluationⅢ，APACHEⅢ）和序貫器官衰竭估計(jì)評(píng)分（Sequential Organ Failure Assessment，SOFA）計(jì)算同上[36-37]。入院時(shí)血肌酐為基礎(chǔ)血肌酐，慢性腎臟?。–KD）定義為CKD-EPI[38]公式計(jì)算的腎小球?yàn)V過率低于60 mL/min/1.73 m2。

1.5 統(tǒng)計(jì)學(xué)方法 以SPSS19.0統(tǒng)計(jì)分析數(shù)據(jù)，連續(xù)變量以“x±s”或中位數(shù)表示，組間比較用方差分析；分類變量用頻數(shù)和百分?jǐn)?shù)表示，組間比較用χ2檢驗(yàn)或Fisher精確檢驗(yàn)；生存分析用Kaplan-Meier生存分析曲線，Log-Rank檢驗(yàn)；死亡危險(xiǎn)因素分析用Cox回歸分析；以P＜0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1 根據(jù)KDIGO標(biāo)準(zhǔn)，506（53%）例出現(xiàn)AKI。正如預(yù)期的那樣，患者出現(xiàn)越嚴(yán)重的AKI則具有越高的APACHE III評(píng)分和SOFA評(píng)分，也越有可能以內(nèi)科原因入ICU治療。見表1。

2.2 所有測(cè)得的血清標(biāo)志物濃度與AKI各階段相關(guān)（P＜0.0025）。較高階段AKI病人具有更高中位數(shù)濃度的炎癥標(biāo)志物：IL-6，IL-8，IL-17，G-CSF和TNFR-1，同時(shí)具有更高中位數(shù)濃度的內(nèi)皮標(biāo)志物Ang-2，Ang-2/Ang-1和sVCAM-1，而Ang-1中位數(shù)濃度較低。見表2。

2.3 內(nèi)皮因子與炎癥因子之間及各自內(nèi)部亦有中度相關(guān)，其中，最明顯的是Ang-2和TNFR-1（P=0.60）以及Ang-2和IL-6（P=0.49）。

表1 AKI患者基本資料（x±s，n=948）Table 1 Baseline characteristics by AKIstage(x±s,n=948)

2.4 在經(jīng)過人口特征、生活方式和合并癥的校正之后，所有標(biāo)志物的高表達(dá)與患者住院期間各個(gè)階段的AKI風(fēng)險(xiǎn)相關(guān)。特別是標(biāo)準(zhǔn)差高表達(dá)的Ang-1伴隨著預(yù)計(jì)降低19%的AKI校正風(fēng)險(xiǎn)（P＜0.01）而標(biāo)準(zhǔn)差高表達(dá)的Ang-2伴隨著預(yù)計(jì)升高22%的AKI校正風(fēng)險(xiǎn)（P＜0.01）。見表3。

2.5 與之相類似的是，所有高濃度的內(nèi)皮因子和炎癥因子均與住院期間2～3階段的AKI相關(guān)，而且內(nèi)皮因子與住院期間2～3階段的AKI相關(guān)性需要經(jīng)過APACHEⅢ評(píng)分和循環(huán)IL-6的校正。

3 討論

本研究報(bào)道了總體的ICU患者人群中內(nèi)皮標(biāo)志物與AKI的相關(guān)性，結(jié)果與先前的研究一致，即炎癥標(biāo)志物與多種危重疾病人群的AKI相關(guān)[40]。近來(lái)有幾個(gè)相對(duì)小規(guī)模的研究探索了內(nèi)皮標(biāo)志物與AKI的相關(guān)性，其中，心外科病人的病例對(duì)照研究發(fā)現(xiàn)，在術(shù)后發(fā)展成為AKI的病人中，血清Ang-2水平比對(duì)照組有很大程度的增加[41-42]。在一個(gè)ICU危重病人初始腎臟替代治療的橫向研究中發(fā)現(xiàn)，循環(huán)Ang-2與AKI發(fā)展和28天的死亡風(fēng)險(xiǎn)有關(guān)[43]。

越來(lái)越多的證據(jù)提示全身炎癥和內(nèi)皮激活構(gòu)成AKI的基礎(chǔ)[41，43-46]。TNF是一種由活化的巨噬細(xì)胞、單核細(xì)胞和中性粒細(xì)胞釋放的炎癥標(biāo)志物，已經(jīng)顯露出對(duì)膿血癥和感染性AKI的重要作用[20，47-49]。腎臟內(nèi)皮細(xì)胞被TNF激活，進(jìn)而保持促炎癥反應(yīng)狀態(tài)，并且潛在地使腎組織對(duì)后續(xù)的損害敏感[47-48]。對(duì)動(dòng)物模型的研究成果論證了Ang-1可能提高了鼠科動(dòng)物AKI時(shí)內(nèi)皮增值細(xì)胞的保護(hù)能力[50-51]。急性的內(nèi)皮細(xì)胞病變可能導(dǎo)致了血管反應(yīng)性、通透性、白細(xì)胞粘附，凝血和微血管收縮自動(dòng)調(diào)節(jié)的改變，從而使AKI持續(xù)進(jìn)展。

表2 AKI各階段的血清標(biāo)志物濃度Table 2 Plasma biomarkers concentrations according to AKIstage

表3 血清標(biāo)志物濃度與AKI各階段相關(guān)Table 3 Associations of biomarkers with acute kidney injury in any stage

在這個(gè)大的ICU病人隊(duì)列研究中，我們發(fā)現(xiàn)循環(huán)中的炎癥和內(nèi)皮標(biāo)志物濃度與AKI的高風(fēng)險(xiǎn)顯著相關(guān)。

這些生物標(biāo)志物可能揭示了危重患者腎臟損傷的途徑，同時(shí)也可能被用來(lái)預(yù)測(cè)個(gè)體的AKI風(fēng)險(xiǎn)。我們的研究結(jié)果支持如下的假說：在明顯的腎臟細(xì)胞損害發(fā)生之前，微循環(huán)和組織氧化的變化使病人傾向于發(fā)生腎臟損害[52]。這個(gè)概念特別適用于炎癥細(xì)胞和內(nèi)皮細(xì)胞被明顯激活的SIRS[16]。微血管系統(tǒng)和內(nèi)皮細(xì)胞共同調(diào)節(jié)組織血流灌注、凝血、炎癥和血管通透性。AKI嚴(yán)重?fù)p害了腎臟的內(nèi)皮系統(tǒng)，導(dǎo)致了微血管功能失調(diào)，進(jìn)行性的缺血和進(jìn)一步的病變[53-54]。

雖然我們找到了在危重患者中內(nèi)皮標(biāo)志物與AKI的獨(dú)立相關(guān)性，但是我們的研究仍有局限性。其中最重要的是，我們的觀察研究的準(zhǔn)確性有潛在地不確定因素，這是因?yàn)橹T如疾病的嚴(yán)重性等特征很可能與內(nèi)皮功能失調(diào)和AKI的風(fēng)險(xiǎn)都有關(guān)。雖然我們努力對(duì)潛在的混雜因素進(jìn)行了校正，但是通過我們的研究仍然不能建立內(nèi)皮功能失調(diào)和AKI發(fā)生發(fā)展之間的因果關(guān)系。第二，本研究不是把AKI作為主要終點(diǎn)，沒有收集足夠詳細(xì)的尿量數(shù)據(jù)；AKI僅僅通過肌酐的改變進(jìn)行回顧性評(píng)價(jià)[34]。沒有獲得腎臟替代治療的數(shù)據(jù)，該數(shù)據(jù)原本可以提供附加的AKI嚴(yán)重性分級(jí)。此外，膿血癥降低了肌酐的生成，也就限制了肌酐作為AKI標(biāo)志物的作用[55]。一小部分病人沒有足夠的血樣用來(lái)同時(shí)測(cè)量生物標(biāo)志物。這些問題可能導(dǎo)致相關(guān)性的減弱。第三，我們未能排除反轉(zhuǎn)因果關(guān)系的可能性，其中，在肌酐升高之前，受損的腎臟自身可能釋放內(nèi)皮標(biāo)志物，從而參與了Ang-2的升高和Ang-1的降低[56]。最后，本研究的目標(biāo)人群來(lái)自同一家醫(yī)院，這可能使得研究結(jié)果有狹義。

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Relationship between markers ofendothelial dysregulation(Ang1,Ang2)and acute kidney injury in criticalpatients

Chen Dong-ming
(Shenhe Sub Centre,Shenyang Emergency Centre,Shenyang,Liaoning,110000,China)

Objective To search the role of endothelialdysregulation with acute kidney injury(AKI)in criticalpatients.Methods We retrospectively assessed the associations of AKIwith biomarkers of endothelialfunction and inflammation among 948 subjects admitted to the intensive care unit(ICU)atShenyang emergency centre.From plasma obtained within 24 h ofenrollment,we measured angiopoietin(Ang)-1 and Ang-2 alongside biomarkers of inflammation,including interleukin(IL)-6,IL-17 and granulocyte colony-stimulating factor.We tested for associations between standardized concentrations of biomarkers and AKI,defined by serum creatinine,from ICU admission to up to 7 days later.Results Allbiomarkers of inflammation and endothelialdysfunction were associated with AKI.After adjustmentfor comorbidities,and IL-6 concentration,every standard deviation of Ang-1 concentration was associated with a 19%lower risk of AKI(relative risk(RR)=0.84,95%confidence interval(CI)0.76-0.92,P＜0.01).Conversely,higher Ang-2 concentration was associated with higher risk of AKI(RR per standard deviation=1.16,95%CI 1.12-1.21,P＜0.01).Conclusion In critically patients,plasma concentration of the Ang-1 and Ang-2 are associated with AKI,independently of inflammation.

Acute kidney injury;Angiopoietin;Endothelialdysfunction;Marker;Sepsis

10.3969/j.issn.1009-4393.2017.22.024