劉 雷，徐 璐，魏明明，王 棟，張宜明，李新建

·論著·

尿中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白和腎損傷分子-1在流行性出血熱合并急性腎損傷早期診斷中的價(jià)值研究

劉 雷，徐 璐，魏明明，王 棟，張宜明，李新建*

目的探討尿中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白(NGAL)和腎損傷分子-1(KIM-1)在流行性出血熱(EHF)合并急性腎損傷(AKI)早期診斷中的價(jià)值。方法選取2014年1月—2016年11月濟(jì)寧醫(yī)學(xué)院附屬醫(yī)院腎內(nèi)科、ICU、呼吸科及血液科收治的符合納入排除標(biāo)準(zhǔn)的41例EHF患者。根據(jù)AKI的診斷標(biāo)準(zhǔn)，將患者分為非AKI組和AKI組，收集兩組確診時(shí)、確診后不同時(shí)間點(diǎn)的血清肌酐(Scr)、尿NGAL、尿KIM-1水平。采用受試者工作特征(ROC)曲線評(píng)價(jià)尿NGAL和尿KIM-1對(duì)EHF合并AKI的早期診斷價(jià)值。結(jié)果41例EHF患者中，合并AKI者26例(63.4%)。兩組患者確診時(shí)Scr、確診時(shí)尿KIM-1水平比較，差異無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；兩組患者Scr水平在確診后24、48、72 h比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；尿NGAL水平在確診時(shí)及確診后2、4、8、12、24 h比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；尿KIM-1水平在確診后2、4、8、12、24 h比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。Pearson相關(guān)分析顯示，確診后2 h尿KIM-1水平、確診后2 h尿NGAL水平與確診后24 h Scr水平呈正相關(guān)(r值分別為0.673、0.846，P<0.01)。確診后2 h尿NGAL診斷EHF合并AKI的ROC曲線下面積為0.822〔95%CI(0.692，0.952)〕，截點(diǎn)值為40.15 pg/ml；確診后2 h尿KIM-1的曲線下面積為0.785〔95%CI(0.643，0.927)〕，截點(diǎn)值為0.55 pg/ml。結(jié)論尿NGAL和尿KIM-1可能可以作為EHF患者是否合并AKI的早期診斷標(biāo)志物。

中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白；腎損傷分子-1；流行性出血熱；急性腎損傷

流行性出血熱(epidemic hemorrhagic fever，EHF)又稱腎綜合征出血熱，是由漢坦病毒引起的急性傳染病。在臨床上常有發(fā)熱、出血及腎臟損害，病理檢查可見廣泛的毛細(xì)血管損傷和微血栓形成[1]。EHF合并的急性腎損傷(acute kidney injury，AKI)程度輕重不一，但始終貫穿疾病的始終，這是我國(guó)EHF患者的特點(diǎn)[2]，也是導(dǎo)致患者死亡的主要原因[3]。如何早期識(shí)別和診斷AKI是改善患者不良預(yù)后的重要手段之一。目前臨床上采用的傳統(tǒng)的AKI診斷標(biāo)志物——血清肌酐(serum creatinine，Scr)或尿量在診斷時(shí)間上往往存在一定滯后性，有礙于臨床的早期預(yù)防和干預(yù)[4]。近年來(lái)，早期預(yù)測(cè)AKI發(fā)生的生物學(xué)標(biāo)志物已成為AKI研究領(lǐng)域的熱點(diǎn)，其中包括一些反映腎小管損傷的指標(biāo)，如血清中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白(neutrophil gelatinase-associated lipocalin，NGAL)和腎損傷分子-1(kidney injury molecule-1，KIM-1)[5]。目前尚少見有關(guān)尿NGAL和尿KIM-1與EHF合并AKI關(guān)系的研究，本研究通過(guò)檢測(cè)EHF合并AKI患者的尿NGAL和尿KIM-1水平，探討其在EHF合并AKI早期診斷中的價(jià)值，以期為臨床的早期診斷提供依據(jù)。

1 對(duì)象與方法

1.1 研究對(duì)象 選取2014年1月—2016年11月濟(jì)寧醫(yī)學(xué)院附屬醫(yī)院腎內(nèi)科、ICU、呼吸科及血液科收治的EHF患者41例。納入標(biāo)準(zhǔn)：(1)確診為EHF，診斷標(biāo)準(zhǔn)為患者血清漢坦病毒抗體陽(yáng)性，且抗體滴度4倍以上升高[1]；(2)年齡≥18歲；(3)無(wú)基礎(chǔ)腎臟疾病。排除標(biāo)準(zhǔn)：(1)入院前已發(fā)生AKI；(2)近期接受造影劑檢查、使用過(guò)腎毒性藥物；(3)拒絕參加本研究者。AKI的診斷標(biāo)準(zhǔn)：(1)48 h內(nèi)Scr升高≥28.6 μmol/L；(2)Scr升高超過(guò)基礎(chǔ)值的1.5倍及以上，且明確或者經(jīng)推斷上述情況發(fā)生在7 d之內(nèi)；(3)尿量減少，即尿量<0.5 ml·kg-1·h-1，時(shí)間持續(xù)6 h以上。符合以上情況之一者即可診斷[6]。根據(jù)AKI診斷標(biāo)準(zhǔn)，將所有患者分為非AKI組和AKI組。所有入選患者均簽署知情同意書。

1.2 研究方法 收集EHF患者的基本資料，包括性別、年齡、血紅蛋白、清蛋白及丙氨酸氨基轉(zhuǎn)移酶。收集患者確診時(shí)及確診后24、48、72 h的靜脈血標(biāo)本2 ml，采用酶促法檢測(cè)Scr水平。收集患者確診時(shí)、確診后2、4、8、12、24 h的新鮮尿液標(biāo)本15 ml，3 000 r/min離心5 min后取上清液置于Eppendorf管，-80 ℃保存，采用酶聯(lián)免疫吸附試驗(yàn)法(ELISA)測(cè)定NGAL、KIM-1水平。試劑盒由美國(guó)R&D公司生產(chǎn)，嚴(yán)格按照試劑盒說(shuō)明書進(jìn)行操作，均經(jīng)復(fù)孔后取均值。

2 結(jié)果

2.1 患者的基本資料 41例EHF患者中，男29例(70.7%)；年齡18～72歲，平均年齡(51.0±12.7)歲；合并AKI者26例(63.4%)。確診EHF時(shí)，患者血紅蛋白水平為(144±13)g/L，清蛋白水平為(34.0±3.2)g/L，丙氨酸氨基轉(zhuǎn)移酶水平為(137±77)U/L。

2.2 非AKI組與AKI組患者基本資料及Scr、尿NGAL、KIM-1水平比較 兩組患者年齡、血紅蛋白、清蛋白、丙氨酸氨基轉(zhuǎn)移酶、確診時(shí)Scr、確診時(shí)尿KIM-1水平比較，差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05)；兩組性別比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；兩組Scr水平在確診后24、48、72 h比較，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)；尿NGAL水平在確診時(shí)及確診后2、4、8、12、24 h比較，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)；尿KIM-1水平在確診后2、4、8、12、24 h比較，差異均有統(tǒng)計(jì)學(xué)意義(P<0.05，見表1)。

表1 非AKI組與AKI組患者基本資料及Scr、尿NGAL、KIM-1水平比較

注：AKI=急性腎損傷，Scr=血清肌酐，NGAL=中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白，KIM-1=腎損傷分子-1；a為χ2值

2.3 尿NGAL、KIM-1與Scr的相關(guān)性 Pearson相關(guān)分析顯示，確診后2 h尿KIM-1水平、確診后2 h尿NGAL水平與確診后24 h Scr水平呈線性正相關(guān)(r值分別為0.673、0.846，P<0.01)。

2.4 尿NGAL和尿KIM-1診斷EHF合并AKI的 ROC曲線 確診后2 h尿NGAL診斷EHF合并AKI的曲線下面積為0.822〔95%CI(0.692，0.952)〕，截點(diǎn)值為40.15 pg/ml；確診后2 h尿KIM-1的曲線下面積為0.785〔95%CI(0.643，0.927)〕，截點(diǎn)值為0.55 pg/ml(見圖1)。

注：EHF=流行性出血熱，AKI=急性腎損傷，NGAL=中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白，KIM-1=腎損傷分子-1

圖1 尿KIM-1和尿NGAL診斷EHF合并AKI的受試者工作特征曲線

Figure1 ROC curve of urine KIM-1 and NGAL for diagnosing EHF with AKI

3 討論

EHF基本病理變化是全身小血管及毛細(xì)血管廣泛損傷，在此基礎(chǔ)上可引發(fā)全身各組織器官及多系統(tǒng)的損傷和功能障礙[1]。患者的臨床經(jīng)過(guò)相差甚大，但均有不同程度的腎臟損傷，輕者僅有一過(guò)性蛋白尿，50%～60%的患者可出現(xiàn)AKI[7]。合并AKI時(shí)大多病情危重，治療困難，是EHF患者死亡的主要原因之一[3]。因此，及早發(fā)現(xiàn)并及時(shí)、有效的治療AKI，是提高EHF合并AKI治愈率的關(guān)鍵。

目前對(duì)于AKI的診斷標(biāo)準(zhǔn)仍以Scr和尿量的變化為依據(jù)，但由于Scr水平受性別、年齡、藥物及肌肉等的影響，尿量受血容量及利尿藥的影響，且這兩項(xiàng)指標(biāo)在診斷時(shí)間上往往存在一定滯后性，故單純靠Scr和尿量來(lái)作為AKI的診斷標(biāo)準(zhǔn)，無(wú)法提供臨床干預(yù)的最佳時(shí)機(jī)，會(huì)延誤治療，增加了住院患者的住院時(shí)間和經(jīng)濟(jì)負(fù)擔(dān)，故迫切需要靈敏度和特異度高的生物標(biāo)志物[8-9]。目前研究較多的血清和尿生物標(biāo)志物有NGAL、KIM-1 及胱抑素C等[10-11]，較傳統(tǒng)指標(biāo)在早期診斷、評(píng)估嚴(yán)重程度及預(yù)后方面有一定的優(yōu)勢(shì)。

NGAL是屬于載脂蛋白超家族的一員，正常情況下，NGAL在腎組織中微弱表達(dá)[12]。近期，ASSADI等[13]觀察了86例循環(huán)衰竭的兒童，發(fā)現(xiàn)尿NGAL在患兒入院時(shí)即開始升高，一直持續(xù)到第6天，尿NGAL預(yù)測(cè)兒童循環(huán)衰竭合并AKI的ROC曲線下面積為0.77，明顯早于Scr的升高。MISHRA 等[14]在缺血再灌注鼠腎損傷模型中發(fā)現(xiàn)，尿NGAL在腎受損后 2 h 即可檢測(cè)到，而此時(shí)的Scr仍為正常。YAN等[15]在探討尿NGAL和白介素18(IL-18)對(duì)膿毒血癥患者并發(fā)AKI的早期診斷價(jià)值中發(fā)現(xiàn)，AKI患者在膿毒血癥確診后2 h尿NGAL水平開始明顯升高，尿NGAL診斷AKI的ROC曲線下面積為0.93。MELNIKVO等[16]觀察了20例行心臟分流術(shù)后發(fā)生AKI的患者，發(fā)現(xiàn)術(shù)后2 h尿中NGAL水平明顯升高，而Scr在滯后1～3 d才開始升高，當(dāng)以50 μg/L作為截點(diǎn)值時(shí)，尿NGAL檢出AKI的靈敏度和特異度分別為100%和98%。以上研究結(jié)果顯示NGAL在腎損傷發(fā)生后很短時(shí)間內(nèi)迅速升高，比Scr有好的靈敏度和特異度。本研究中，AKI組尿NGAL指標(biāo)在確診時(shí)及確診后2、4、8、12、24 h與非AKI組均有差異，確診后2 h尿 NGAL預(yù)測(cè) EHF合并AKI 的 ROC 曲線下面積為 0.822，截點(diǎn)值是40.15 pg/ml。

KIM-1是一種Ⅰ型跨細(xì)胞膜糖蛋白，其存在于CD4+T細(xì)胞核腎近曲小管上皮細(xì)胞內(nèi)，又被稱為T細(xì)胞免疫球蛋白和黏蛋白分子1或A型肝炎病毒細(xì)胞受體I[17-18]。KIM-1在正常腎組織中表達(dá)水平極低，但在腎損傷因素的作用下，可特征性升高，表達(dá)于腎損傷的腎小管上皮細(xì)胞頂膜并持續(xù)到細(xì)胞損傷完全修復(fù)；而完全萎縮的腎小管則不表達(dá)[19-20]。HAN等[17]研究發(fā)現(xiàn)，AKI患者的尿液中可檢測(cè)到KIM-1，且在腎缺血損傷發(fā)生后12 h升高，比尿顆粒管型出現(xiàn)得更早。此外，HAN等[21]以接受心臟外科手術(shù)患兒為研究對(duì)象對(duì)KIM-1與 AKI 的關(guān)系進(jìn)行了研究，結(jié)果發(fā)現(xiàn)無(wú)論 AKI 患兒還是非 AKI 患兒尿 KIM-1 水平都明顯升高，手術(shù)后 12 h 尿 KIM-1水平預(yù)測(cè) AKI 的 ROC 曲線下面積為 0.83。LUO等[22]研究了慶大霉素引起的中毒性腎損傷時(shí)KIM-1的變化，體外試驗(yàn)發(fā)現(xiàn)，血KIM-1的mRNA在給藥后第1天就明顯表達(dá)，免疫組化顯示KIM-1在腎臟外髓部外層及皮質(zhì)髓射線的近曲小管S3區(qū)上皮細(xì)胞中表達(dá)；而Scr在給藥7 d后才明顯升高[22]。本研究中，AKI組尿KIM-1指標(biāo)在確診后2、4、8、12、24 h與非AKI組均有差異。尿 KIM-1 2 h水平預(yù)測(cè) EHF合并AKI 的 ROC 曲線下面積為 0.785，截點(diǎn)值是0.55 pg/ml。

綜上所述，尿NGAL、KIM-1不受尿液理化性質(zhì)的干擾，且為無(wú)創(chuàng)性檢查，因此，NGAL、KIM-1可能可以作為一種靈敏度和特異度較高的早期診斷EHF合并AKI的標(biāo)志物。本次研究樣本量小，多個(gè)對(duì)尿NGAL、KIM-1存在影響的混雜因素沒(méi)有得到控制，所以其診斷價(jià)值還需要大規(guī)模、多中心和前瞻性的試驗(yàn)提供足夠的證據(jù)支持。

作者貢獻(xiàn)：劉雷負(fù)責(zé)研究設(shè)計(jì)與實(shí)施、資料整理、撰寫論文、成文并對(duì)文章負(fù)責(zé)；徐璐負(fù)責(zé)數(shù)據(jù)采集、匯總及統(tǒng)計(jì)學(xué)分析；魏明明負(fù)責(zé)收集資料包括數(shù)據(jù)采集；王棟負(fù)責(zé)檢測(cè)尿NGAL和尿KIM-1指標(biāo)；張宜明負(fù)責(zé)撰寫英文摘要；李新建負(fù)責(zé)修改論文。

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ValueofUrineNeutrophilGelatinase-associatedLipocalinandKidneyInjuryMolecule-1forEarlyDiagnosisofAcuteKidneyInjuryinPatientswithEpidemicHemorrhagicFever

LIULei，XULu，WEIMing-ming，WANGDong，ZHANGYi-ming，LIXin-jian*

ObjectiveTo assess the value of urine neutrophil gelatinase-associated lipocalin(NGAL) and kidney injury molecule-1(KIM-1) for early diagnosis of acute kidney injury(AKI) in patients with epidemic hemorrhagic fever(EHF).MethodsThe enrolled participants were 41 cases of EHF who

treatment in Department of Nephrology,ICU,Department of Respiratory Medicine,or Department of Haematology,Affiliated Hospital of Jining Medical University from January 2014 to November 2016 and met the inclusion and exclusion criteria of this study.Based on the diagnostic standard of AKI,patients with AKI symptoms were assigned to the AKI group and the others were assigned to the non-AKI group.Levels of Scr,urine NGAL and KIM-1 were measured at the time of diagnosis,2 h,4 h,8 h,12 h,24 h after diagnosis,respectively.The receiver operating characteristic(ROC) curve of urine NGAL and urine KIM-1 was used to evaluate their values for early diagnosis of AKI.ResultsAmong the 41 cases of EHF，26(63.4%) had concomitant AKI.At the time of diagnosis,the levels of Scr and urine KIM-1 were similar in both groups (P>0.05).Compared with the non-AKI group,AKI group had significantly increased Scr levels at 24 h,48 h,72 h after the diagnosis(P<0.05).The levels of urine NGAL varied significantly by the time of measurement in both groups(P<0.05).The levels of urine KIM-1 varied obviously by the time of measurement after diagnosis in both groups(P<0.05).Pearson′s correlation analysis found that,the level of Scr measured at 24 h after diagnosis was positively correlated with that of urine KIM-1 measured at 2 h after diagnosis (r=0.673,P<0.01),and it presented a linear positive correlation with the level of urine NGAL measured at 2 h after diagnosis(r=0.846,P<0.01 ).The AUC of ROC curve of level of urine NGAL measured at 2 h after diagnosis for the prediction of EHF with AKI was 0.822〔95%CI(0.692，0.952)〕 with a cutoff value of 40.15 pg/ml.For the prediction of EHF with AKI,the AUC of ROC curve of level of urine KIM-1 was 0.785〔95%CI(0.643，0.927)〕 with a cutoff value of 0.55 pg/ml.ConclusionUrine NGAL and KIM-1 may be used as the markers for early diagnosis of EHF with AKI.

Neutrophil gelatinase-associated lipocalin;Kidney injury molecule-1;Epidemic hemorrhagic fever;Acute kidney injury

濟(jì)寧市科技發(fā)展計(jì)劃項(xiàng)目(2014jnnk04)

272000 山東省濟(jì)寧市，濟(jì)寧醫(yī)學(xué)院附屬醫(yī)院

*通信作者：李新建，教授,主任醫(yī)師；E-mail:lixinjian8018@163.com

R 692

A

10.3969/j.issn.1007-9572.2017.31.014

劉雷，徐璐，魏明明，等.尿中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白和腎損傷分子-1在流行性出血熱合并急性腎損傷早期診斷中的價(jià)值研究[J].中國(guó)全科醫(yī)學(xué)，2017，20(31)：3902-3906.[www.chinagp.net]

LIU L,XU L,WEI M M,et al.Value of urine neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for early diagnosis of acute kidney injury in patients with epidemic hemorrhagic fever[J].Chinese General Practice，2017，20(31)：3902-3906.

AffiliatedHospitalofJiningMedicalUniversity,Jining272000,China

*Correspondingauthor:LIXin-jian,Professor,Chiefphysician；E-mail:lixinjian8018@163.com

2017-03-10；

2017-08-30)

(本文編輯：殷麗剛)