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綜述

腎損傷因子-1與慢性腎臟病

尹彩霞王寧寧

(南京醫(yī)科大學(xué)第一附屬醫(yī)院腎內(nèi)科，江蘇南京210029)

Kidney Injury Molecule-1 in Chronic Kidney Disease

YINCaixiaWANGNingning

DepartmentofNephrology,TheFirstAffliatedHospitalofNanjingMedicalUniversity,Nanjing210029，China

慢性腎臟病是指各種原因引起的慢性腎臟結(jié)構(gòu)和功能障礙(腎臟損傷病史>3個(gè)月)，包括腎小球?yàn)V過率(glomerular filtration rate，GFR)正常或不正常的病理損傷、血液或尿液成分異常及影像學(xué)檢查異常，或不明原因的GFR下降[GFR<60 mL/(min·1.73 m2)]超過3個(gè)月[1]。腎功能評估方法包括血尿素氮、肌酐及評估腎小球?yàn)V過率(estimated glomerular filtration rate，eGFR)的檢測，但這些指標(biāo)通常在腎損傷48~72 h后改變[2]，敏感性、特異性欠佳。近年多項(xiàng)研究表明，腎損傷因子-1(kidney injury molecule-1,KIM-1)是理想的腎損傷及預(yù)后指標(biāo)[3-4]。本文綜述了KIM-1與腎臟損傷尤其是慢性腎臟病的關(guān)系，同時(shí)介紹了KIM-1的結(jié)構(gòu)、表達(dá)、功能及其檢測方法、尿標(biāo)本的存儲條件等。

1KIM-1的結(jié)構(gòu)

KIM-1是1998年由Ichimura等[5]發(fā)現(xiàn)的Ι型膜蛋白。KIM-1在腎臟及肝臟中表達(dá)，相對分子質(zhì)量為104，包括相對分子質(zhì)量14的膜結(jié)合片段以及相對分子質(zhì)量為90的可溶性部分。KIM-1的細(xì)胞外可溶性部分包括6個(gè)半胱氨酸免疫球蛋白結(jié)構(gòu)域以及含有豐富蘇氨酸-絲氨酸-脯氨酸的蛋白結(jié)構(gòu)域，這些蛋白結(jié)構(gòu)域含有豐富的糖基化蛋白[6]。KIM-1細(xì)胞內(nèi)的片段短，有兩個(gè)亞型，分別是KIM-1a和KIM-1b。KIM-1a缺乏酪氨酸激酶磷酸化位點(diǎn)，主要在人類肝臟表達(dá)。KIM-1b 包含兩個(gè)高度保守的酪氨酸殘基及一個(gè)酪氨酸激酶磷酸化位點(diǎn)，主要在人類腎臟表達(dá)[7]。KIM-1的裂解與金屬蛋白酶有關(guān)[6]。Zhang等[7]揭示，KIM-1裂解由活化的細(xì)胞外信號調(diào)節(jié)激酶介導(dǎo)，且活化的P38促分裂原活化蛋白激酶可加速KIM-1的裂解。

2KIM-1在健康人群中的表達(dá)

Pennemans等[8]通過綜合分析可能影響KIM-1分泌的因素(如年齡、性別)后，得出了正常人群中尿KIM-1水平的參考范圍。研究者共留取338位不吸煙的健康志愿者(199位女性，139位男性)的尿標(biāo)本，年齡0~95歲，發(fā)現(xiàn)尿KIM-1的水平與年齡呈顯著正相關(guān)，同時(shí)與性別有關(guān)；用尿肌酐及尿比重校正后，尿KIM-1水平與年齡相關(guān)，與性別無關(guān)。McWilliams等[9]招募了291名健康兒童志愿者，其中120名來自英國，171名來自美國，年齡0~16歲。研究者收集了健康兒童志愿者的晨尿及睡前尿標(biāo)本，其中睡前尿標(biāo)本于留取當(dāng)晚在志愿者家中冰箱保存，次日清晨送至研究中心。該研究也證實(shí)尿KIM-1濃度與年齡相關(guān)[8]，與性別無關(guān)。他們還發(fā)現(xiàn)，非洲裔美國人尿KIM-1濃度比白種人低；每日不同時(shí)段尿KIM-1水平有差異，清晨最高。 Zwiers等[10]招募了106名健康嬰兒，孕37~42周出生，年齡1 d~1歲，其中男性占2/3，其尿KIM-1濃度非常低(平均0.08 ng/mL)，并且與年齡、性別及種族無關(guān)。

3尿KIM-1的檢測及尿標(biāo)本的存儲

Sabbisetti等[11]介紹了兩種測定小鼠腎臟損傷后尿KIM-1水平的方法：一種是酶聯(lián)免疫吸附法，該方法比較敏感、準(zhǔn)確，只需30 μL尿標(biāo)本，檢測范圍為12.21 pg/mL~50 ng/mL；另一種為層流試紙測定法，可在15 min內(nèi)定量尿KIM-1水平，檢測范圍為195 pg/mL ~50 ng/mL。Sabbisetti 等[12]發(fā)現(xiàn)，血液中也能檢測出KIM-1，并可作為腎臟損傷的觀察指標(biāo)。中毒性肝臟損傷對血液中KIM-1水平無影響。在急慢性腎臟病患者中，尿及血漿中KIM-1片段的相對分子質(zhì)量均接近90。

van de Vrie等[13]證實(shí)，在不添加任何蛋白酶抑制劑的情況下，尿KIM-1標(biāo)本可在-80 °C冰箱中穩(wěn)定保存至少6個(gè)月，而在4°C冰箱中僅能穩(wěn)定保存48 h。Pennemans等[14]發(fā)現(xiàn)，尿KIM-1濃度受到尿標(biāo)本反復(fù)凍融的影響，與是否添加蛋白酶抑制劑及冷藏前的離心處理無關(guān)，因此建議，若不能立即檢測尿標(biāo)本中KIM-1濃度，尿標(biāo)本應(yīng)在采集后3 h內(nèi)冷藏，并在解凍后立即檢測。

4KIM-1與肝臟

KIM-1基因與猴子甲肝病毒細(xì)胞受體基因高度同源。甲肝病毒細(xì)胞受體主要在肝細(xì)胞表達(dá)，在特定條件下促進(jìn)病毒入侵肝細(xì)胞[15-17]。KIM-1因?yàn)榭稍诩せ畹腡細(xì)胞亞群中低表達(dá)，所以又名T細(xì)胞免疫蛋白結(jié)構(gòu)域(T cell immunoglobulin mucin domains-1，TIM-1)。TIM-1 是一種T細(xì)胞輔助刺激因子。它可以促進(jìn)T細(xì)胞增殖及細(xì)胞因子的產(chǎn)生[16, 18]。Tami 等[17]發(fā)現(xiàn)，免疫球蛋白A(immunoglobulin A，IgA)是TIM-1的天然配體，可促進(jìn)甲肝病毒與甲肝病毒細(xì)胞受體的結(jié)合。

5KIM-1與腎小管管腔凋亡細(xì)胞的噬菌作用

腎小管上皮細(xì)胞在損傷后可出現(xiàn)程序性凋亡。凋亡及壞死細(xì)胞的清除對減輕炎性損傷及組織修復(fù)十分重要[19-20]。KIM-1是磷酯酰絲氨酸受體，賦予腎小管上皮細(xì)胞吞噬功能[20]。它可以特異性地識別凋亡細(xì)胞表面的磷酯酰絲氨酸，進(jìn)而清除腎小管內(nèi)的凋亡、壞死物質(zhì)[20]。在小鼠及體外細(xì)胞培養(yǎng)模型中，過氧化氫介導(dǎo)的細(xì)胞損傷可加速KIM-1從細(xì)胞表面脫落。凋亡細(xì)胞的清除作用又名胞葬作用(efferocytosis)。在體外培養(yǎng)的腎小管上皮細(xì)胞，細(xì)胞表面KIM-1的自發(fā)脫落不影響其介導(dǎo)的胞葬作用，而細(xì)胞損傷導(dǎo)致的過多的可溶性KIM-1卻可競爭性地抑制胞葬過程[21]。

6KIM-1與腎臟修復(fù)

在急性腎損傷后，腎小管上皮細(xì)胞可再生。這需要損傷的腎小管上皮細(xì)胞周圍有活性的細(xì)胞的去分化、增殖，從而形成完整的腎小管上皮細(xì)胞功能層。從正常上皮細(xì)胞轉(zhuǎn)變?yōu)槿シ只?xì)胞的過程與KIM-1表達(dá)明顯升高有關(guān)[5]。腎小管上皮細(xì)胞修復(fù)的機(jī)制尚不明確[5]。van Timmeren 等[22]發(fā)現(xiàn)，在人類腎臟疾病中，KIM-1與波形蛋白共同表達(dá)于腎小管。波形蛋白是一種中間絲狀體，參與腎小管上皮細(xì)胞的去分化。KIM-1表達(dá)活躍的腎小管上皮細(xì)胞有去分化表型，且與組織骨橋蛋白水平及α平滑肌肌動蛋白(α-smooth muscle actin ，α-SMA)水平有關(guān)[23-25]。骨橋蛋白來源于腎小管，參與趨化作用及組織修復(fù)。在中毒性或缺血性腎臟損傷后損傷區(qū)域的腎小管上皮細(xì)胞中，KIM-1與溴脫氧尿苷(增殖標(biāo)志)及彈性蛋白(去分化標(biāo)志)共存[5- 6]。由此得出，KIM-1可能在腎小管上皮細(xì)胞再生中有一定作用。

7KIM-1與急性腎損傷

急性腎損傷是指7 d內(nèi)血肌酐較基線上升≥50%，或48 h內(nèi)血肌酐上升≥0.3 mg/dL[26]。急性腎損傷的診斷主要依靠血肌酐的升高及尿量的減少，而這可能延誤腎損傷的早期診斷[27]。KIM-1是新發(fā)現(xiàn)的早期腎損傷生物學(xué)標(biāo)志物。Ichimura等[5]利用代表性差異分析 (representational difference analysis，RDA) 技術(shù)研究缺血再灌注后腎臟再生細(xì)胞及正常腎臟細(xì)胞mRNA數(shù)量的變化情況，發(fā)現(xiàn)KIM-1 相關(guān)的mRNA及蛋白在再生的腎小管上皮細(xì)胞內(nèi)高表達(dá)；在缺血損害最敏感的腎小管S3段，KIM-1相關(guān)的mRNA數(shù)量明顯增多。Han等[28]發(fā)現(xiàn)在急性腎小管壞死的腎臟，KIM-1在腎小管上皮細(xì)胞表面高表達(dá)，而在腎小球不表達(dá)；在腎臟缺血損傷12 h內(nèi)，可溶性的KIM-1持續(xù)表達(dá)，并且能夠迅速裂解進(jìn)入尿液中，其裂解速度明顯快于腎小管上皮細(xì)胞的再生。在腎臟缺血損傷10、20、30 min后，尿KIM-1水平較無腎臟缺血損傷的小鼠模型分別高出16、48、60倍[12]。Sabbisetti等[12]還發(fā)現(xiàn)在急性腎損傷患者中，血漿KIM-1與尿KIM-1水平(無論是否用尿肌酐校正)呈正相關(guān)，且兩者與尿白蛋白濃度(無論是否用尿肌酐校正)呈正相關(guān)。經(jīng)氧化應(yīng)激激活的G蛋白α12亞基(G protein α12，Gα12)是腎臟缺血再灌注損傷的主要因素之一[29]。Gα12是一個(gè)分子開關(guān)，當(dāng)其與鳥苷三磷酸腺苷結(jié)合時(shí)被激活；若鳥苷三磷酸降解為鳥苷二磷酸腺苷，Gα12則不能被激活[30]。Ismail等[31]發(fā)現(xiàn)，KIM-1可阻止鳥苷三磷酸腺苷與Gα12的結(jié)合，抑制Gα12的激活。在缺血性急性腎損傷中，KIM-1能夠抑制Gα12介導(dǎo)的損傷。然而，KIM-1抑制Gα12的激活是暫時(shí)的，因?yàn)镵IM-1只在損傷的腎小管上皮細(xì)胞表達(dá)增加，在腎臟功能恢復(fù)后(缺血再灌注損傷7 d后)可降至正常[32]。

8KIM-1與慢性腎臟病

KIM-1在慢性腎臟病中也有一定作用[33]。Sabbisetti等[12]發(fā)現(xiàn)在單側(cè)輸尿管梗阻7 d的小鼠模型中，血KIM-1及尿KIM-1水平升高，而血肌酐沒有改變。尿KIM-1的含量與腎組織中KIM-1的水平及腎臟損傷密切相關(guān)[11, 19, 34-35]。

8.1KIM-1與腎臟炎性反應(yīng)及纖維化KIM-1 在各種原因?qū)е碌脑l(fā)性、繼發(fā)性腎臟病及移植腎病中高表達(dá)[22, 28]。KIM-1和腎臟炎性反應(yīng)及纖維化有關(guān)[22]。腎小管KIM-1表達(dá)活躍與巨噬細(xì)胞聚集及肌成纖維細(xì)胞轉(zhuǎn)化標(biāo)志物α-SMA表達(dá)增多有關(guān)[22]。Humphreys 等[33]建立了小鼠腎小管上皮細(xì)胞KIM-1轉(zhuǎn)基因模型，表現(xiàn)為出生時(shí)腎小管上皮細(xì)胞局灶空泡化，而腎功能及腎小管組織正常；發(fā)現(xiàn)KIM-1的長期表達(dá)可促進(jìn)單核細(xì)胞趨化因子-1的表達(dá)及其介導(dǎo)的巨噬細(xì)胞聚集，從而促進(jìn)腎臟炎性反應(yīng)及腎小管間質(zhì)纖維化；而內(nèi)生KIM-1基因突變的小鼠模型腎臟纖維化減輕，單核細(xì)胞趨化因子-1減少。KIM-1表達(dá)活躍的腎小管間隙包含大量的平滑肌肌動蛋白活化的肌成纖維細(xì)胞[33]，而肌成纖維細(xì)胞的大量增殖促進(jìn)細(xì)胞外基質(zhì)形成，最終導(dǎo)致纖維化[19]。

8.2KIM-1與IgA腎病在IgA腎病患者中，尿KIM-1水平升高，并且與蛋白尿顯著相關(guān)[36-37]，且與每年eGFR下降呈正相關(guān)[38]。研究[37]表明，在IgA腎病患者中，尿KIM-1濃度的中位數(shù)是1.7 ng/min，相比于健康人(0.6 ng/min)明顯升高，且高表達(dá)的KIM-1是預(yù)測IgA腎病進(jìn)展至終末期腎臟病的獨(dú)立預(yù)測指標(biāo)。在IgA腎病缺氧條件下，KIM-1表達(dá)的細(xì)胞能產(chǎn)生大量的趨化因子及細(xì)胞因子，最終導(dǎo)致腎臟間質(zhì)纖維化[38-39]。在IgA腎病中，腎小管KIM-1的表達(dá)水平與CD68表達(dá)活躍的單核/巨噬細(xì)胞及CD3表達(dá)活躍的T細(xì)胞數(shù)量呈正相關(guān)[38]。 Xu 等[40]研究了51例IgA腎病患者，并根據(jù)尿KIM-1水平將其分成兩組，一組包括18例尿KIM-1水平升高的患者，另一組包括33名尿KIM-1水平正常的患者，發(fā)現(xiàn)腎小管萎縮及間質(zhì)纖維化在尿KIM-1升高組更嚴(yán)重。

KIM-1在慢性腎損傷中的作用仍不清楚。Waanders等[41]發(fā)現(xiàn)，非糖尿病慢性腎臟病患者尿KIM-1增多，并且隨著蛋白尿減少而減少。Nakagawa等[42]發(fā)現(xiàn)在大鼠慢性腎衰竭模型中，mTOR抑制劑依維莫司可抑制巨噬細(xì)胞聚集、減少尿KIM-1在腎小管的表達(dá)以及改善尿白蛋白的重吸收。Kramer等[23]在阿霉素誘導(dǎo)的大鼠腎病模型中發(fā)現(xiàn)，通過血管緊張素轉(zhuǎn)化酶抑制劑及血管緊張素II拮抗劑抗蛋白尿治療后，KIM-1表達(dá)可隨蛋白尿減少而減少。

8.3KIM-1與糖尿病腎病糖尿病腎病是最常見的微血管并發(fā)癥之一。隨著糖尿病病進(jìn)展，患者有不同程度的腎功能下降。臨床研究[43]表明相對于健康人，有或無蛋白尿的2型糖尿病患者尿KIM-1均增多。尿KIM-1可利于早期發(fā)現(xiàn)無蛋白尿的2型糖尿病患者腎小管損傷。Sabbisetti等[12]觀察了兩組患者，一組是由于各種原因?qū)е碌穆阅I臟病患者，另一組是24 h尿白蛋白定量>500 mg的1型糖尿病患者，發(fā)現(xiàn)兩組觀察對象血KIM-1水平隨著慢性腎臟病分期進(jìn)展而增高；校正其他基線變量如eGFR、尿白蛋白肌酐比、糖化血紅蛋白的影響后，血清KIM-1水平與終末期腎臟病預(yù)后明顯相關(guān)。因此，血KIM-1水平可作為預(yù)測1型糖尿病腎病進(jìn)展的指標(biāo)。Lim等[44]觀察到在體外培養(yǎng)的人近端腎小管上皮細(xì)胞中，人血白蛋白及糖化白蛋白可使尿KIM-1增加，而高糖不能增加尿KIM-1。氧化應(yīng)激可介導(dǎo)KIM-1短期表達(dá)，JAK/STAT通路可介導(dǎo)KIM-1長期表達(dá)。Carlsson等[45]發(fā)現(xiàn)，胰島素敏感性與尿KIM-1濃度呈負(fù)相關(guān)。

8.4KIM-1與狼瘡性腎炎在系統(tǒng)性紅斑狼瘡患者中，尿KIM-1水平與組織KIM-1表達(dá)密切相關(guān)；系統(tǒng)性紅斑狼瘡活動期患者尿KIM-1水平較非活動期患者增高，且活動期狼瘡腎炎患者尿KIM-1水平與蛋白尿及腎小管損傷相關(guān)，因此尿KIM-1可作為狼瘡活動度的觀察指標(biāo)之一。評估腎活檢組織中KIM-1表達(dá)可預(yù)測腎臟損傷，分析腎小管萎縮、腎小球腎炎的進(jìn)展等[46]。

8.5KIM-1與多囊腎病常染色體顯性多囊腎病由多囊腎病基因1(PKD1)及多囊腎病基因2(PKD2)突變所導(dǎo)致。在小鼠模型中，多囊腎病組小鼠組織KIM-1表達(dá)比非多囊腎病對照組上調(diào)[24]。KIM-1存在于大小不同、來源不同的囊腔及囊腔周圍的近端腎小管。KIM-1表達(dá)活躍的腎小管細(xì)胞增殖活躍并且有大量α-SMA聚集[24]。研究[47]表明，腎小管KIM-1的表達(dá)可與多囊蛋白2(由PKD2編碼)相互作用，并調(diào)節(jié)多囊蛋白2在腎小管細(xì)胞的功能。盡管KIM-1在多囊腎中的作用仍不十分清楚，但腎小管KIM-1的表達(dá)與其上皮細(xì)胞局部去分化密切相關(guān)，表達(dá)KIM-1的腎小管上皮細(xì)胞增殖增加，且周圍有大量肌成纖維細(xì)胞，推測KIM-1在腎間質(zhì)纖維化中可能起一定作用[24]。

9KIM-1與腎移植

移植腎慢性腎功能不全診斷主要依據(jù)腎功能下降及蛋白尿[36]。但腎移植患者急性腎損傷診斷的金標(biāo)準(zhǔn)仍是移植腎活檢發(fā)現(xiàn)的形態(tài)學(xué)改變[48]。多項(xiàng)研究表明，移植腎患者尿KIM-1增多，并且與移植腎功能喪失有關(guān)[36, 49]。在腎移植患者中，尿KIM-1的增加與蛋白尿、低肌酐清除率及捐贈者年齡過大有關(guān)[36]。Zhang等[50]發(fā)現(xiàn)，組織KIM-1表達(dá)在早期檢測腎小管損傷方面比腎組織形態(tài)學(xué)改變更敏感。高表達(dá)的組織KIM-1與移植腎功能喪失的程度平行，是預(yù)測移植腎功能喪失的敏感指標(biāo)。組織KIM-1水平也可作為腎移植早期腎功能恢復(fù)的觀察指標(biāo)[49-50]。腎活檢證實(shí)有急性腎小管損傷形態(tài)學(xué)改變且腎功能惡化的患者進(jìn)行18個(gè)月的隨訪后發(fā)現(xiàn)，組織KIM-1水平高的患者血尿素氮、肌酐明顯下降，eGFR則上升[50]。目前，移植腎間質(zhì)纖維化及腎小管萎縮的診斷主要依靠腎活檢，因此尋找無創(chuàng)指標(biāo)監(jiān)測移植腎功能尤為重要。Nogare等[51]評估了移植腎功能不全患者的腎組織及尿沉渣細(xì)胞中mRNA轉(zhuǎn)錄及KIM-1基因的表達(dá)情況，發(fā)現(xiàn)腎功能不全與腎組織及尿沉渣細(xì)胞中KIM-1基因的表達(dá)密切相關(guān)。Nogare等[52]發(fā)現(xiàn)，在腎移植患者纖維化腎間質(zhì)及萎縮腎小管的活檢組織中，KIM-1蛋白表達(dá)較經(jīng)鈣調(diào)神經(jīng)磷酸酶抑制劑治療的腎活檢組織表達(dá)增多，且尿沉渣細(xì)胞中KIM-1 mRNA可作為預(yù)測移植腎間質(zhì)纖維化及腎小管萎縮的非侵襲性指標(biāo)[51]。因此，KIM-1表達(dá)或許對預(yù)測慢性移植腎纖維化和功能不全有重要意義[36, 53-54]。

10KIM-1與腎細(xì)胞癌

研究[25]表明，KIM-1可在腎細(xì)胞癌患者尿液中檢出。尿KIM-1的濃度在未行手術(shù)切除的腎細(xì)胞癌患者中明顯增多[55]。 KIM-1可能有助于早期發(fā)現(xiàn)腎細(xì)胞癌。Morrissey等[55]發(fā)現(xiàn)，在未行手術(shù)切除的腎細(xì)胞癌患者中，尿KIM-1水平與腫瘤大小及分期呈正相關(guān)；在腎細(xì)胞癌手術(shù)切除1個(gè)月后，尿KIM-1的濃度中位數(shù)較未手術(shù)前可下降50%。如果腎細(xì)胞癌切除術(shù)后尿KIM-1濃度未恢復(fù)至正常水平，多預(yù)示著疾病的進(jìn)展，包括可能存在對側(cè)腎細(xì)胞癌或其他侵及腎小管的腎臟病[25]。

11總結(jié)

KIM-1是主要表達(dá)于腎小管上皮細(xì)胞表面的Ι型膜蛋白，在正常腎臟中低表達(dá)，而在多種原因?qū)е碌脑l(fā)性腎臟病、繼發(fā)性腎臟病腎移植的腎組織中表達(dá)增多。在腎臟損傷后，KIM-1的胞外片段可迅速裂解并進(jìn)入尿中，是敏感、特異性的腎小管組織損傷的標(biāo)志物。尿KIM-1可能與腎小管上皮細(xì)胞再生有關(guān)。在慢性腎臟病中，尿KIM-1水平與腎臟纖維化、炎性反應(yīng)相關(guān)。移植腎組織KIM-1水平與腎功能下降程度平行。腎細(xì)胞癌患者尿KIM-1高水平可能預(yù)示著腎臟腫瘤的進(jìn)展。因此，KIM-1對預(yù)測慢性腎臟病的進(jìn)展及預(yù)后評估有重要意義。

參考文獻(xiàn)

[ 1 ]Foundation NK. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification[J]. Am J Kidney Dis,2002,39(2 Suppl 1):S1-266.

[ 2 ]Shao X, Tian L, Xu W,et al. Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: a meta-analysis[J]. PLoS One,2014,9(1):e84131.

[ 3 ]Vaidya VS, Ferguson MA，Bonventre JV. Biomarkers of acute kidney injury[J]. Annu Rev Pharmacol Toxicol,2008,48:463-493.

[ 4 ]Rees AJ，Kain R. Kim-1/Tim-1: from biomarker to therapeutic target?[J]. Nephrol Dial Transplant,2008,23(11):3394-3396.

[ 5 ]Ichimura T, Bonventre JV, Bailly V,et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury[J]. J Biol Chem,1998,273(7):4135-4142.

[ 6 ]Bailly V, Zhang Z, Meier W,et al. Shedding of kidney injury molecule-1, a putative adhesion protein involved in renal regeneration[J]. J Biol Chem,2002,277(42):39739-39748.

[ 7 ]Zhang Z, Humphreys BD，Bonventre JV. Shedding of the urinary biomarker kidney injury molecule-1 (KIM-1) is regulated by MAP kinases and juxtamembrane region[J]. J Am Soc Nephrol,2007,18(10):2704-2714.

[ 8 ]Pennemans V, Rigo JM, Faes C,et al. Establishment of reference values for novel urinary biomarkers for renal damage in the healthy population: are age and gender an issue?[J]. Clin Chem Lab Med,2013,51(9):1795-1802.

[ 9 ]McWilliam SJ, Antoine DJ, Sabbisetti V,et al. Reference intervals for urinary renal injury biomarkers KIM-1 and NGAL in healthy children[J]. Biomark Med,2014,8(10):1189-1197.

[10]Zwiers AJ, de Wildt SN, de Rijke YB,et al. Reference intervals for renal injury biomarkers neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 in young infants[J]. Clin Chem Lab Med,2015,53(8):1279-1289.

[11]Sabbisetti VS, Ito K, Wang C,et al. Novel assays for detection of urinary KIM-1 in mouse models of kidney injury[J]. Toxicol Sci,2013,131(1):13-25.

[12]Sabbisetti VS, Waikar SS, Antoine DJ,et al. Blood kidney injury molecule-1 is a biomarker of acute and chronic kidney injury and predicts progression to ESRD in type I diabetes[J]. J Am Soc Nephrol,2014,25(10):2177-2186.

[13]van de Vrie M, Deegens JK, van der Vlag J,et al. Effect of long-term storage of urine samples on measurement of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL)[J]. Am J Kidney Dis,2014,63(4):573-576.

[14]Pennemans V, Rigo JM, Penders J,et al. Collection and storage requirements for urinary kidney injury molecule-1 (KIM-1) measurements in humans[J]. Clin Chem Lab Med,2012,50(3):539-543.

[15]Kaplan G, Totsuka A, Thompson P,et al. Identification of a surface glycoprotein on African green monkey kidney cells as a receptor for hepatitis A virus[J]. EMBO J,1996,15(16):4282-4296.

[16]Silberstein E, Dveksler G，Kaplan G G. Neutralization of hepatitis A virus (HAV) by an immunoadhesin containing the cysteine-rich region of HAV cellular receptor-1[J]. J Virol,2001,75(2):717-725.

[17]Tami C, Silberstein E, Manangeeswaran M,et al. Immunoglobulin A (IgA) is a natural ligand of hepatitis A virus cellular receptor 1 (HAVCR1), and the association of IgA with HAVCR1 enhances virus-receptor interactions[J]. J Virol,2007,81(7):3437-3446.

[18]Rodriguez-Manzanet R, DeKruyff R, Kuchroo VK,et al. The costimulatory role of TIM molecules[J]. Immunol Rev,2009,229(1):259-270.

[19]Waanders F, van Timmeren MM, Stegeman CA,et al. Kidney injury molecule-1 in renal disease[J]. J Pathol,2010,220(1):7-16.

[20]Ichimura T, Asseldonk EJ, Humphreys BD,et al. Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells[J]. J Clin Invest,2008,118(5):1657-1668.

[21]Gandhi R, Yi J, Ha J,et al. Accelerated receptor shedding inhibits kidney injury molecule-1 (KIM-1)-mediated efferocytosis[J]. Am J Physiol Renal Physiol,2014,307(2):F205-F221.

[22]van Timmeren MM, van den Heuvel MC, Bailly V,et al. Tubular kidney injury molecule-1 (KIM-1) in human renal disease[J]. J Pathol,2007,212(2):209-217.

[23]Kramer AB, van Timmeren MM, Schuurs TA,et al. Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time[J]. Am J Physiol Renal Physiol,2009,296(5):F1136-F1145.

[24]Kuehn EW, Park KM, Somlo S,et al. Kidney injury molecule-1 expression in murine polycystic kidney disease[J]. Am J Physiol Renal Physiol,2002,283(6):F1326-F1336.

[25]Han WK, Alinani A, Wu CL,et al. Human kidney injury molecule-1 is a tissue and urinary tumor marker of renal cell carcinoma[J]. J Am Soc Nephrol,2005,16(4):1126-1134.

[26]James M, Bouchard J, Ho J,et al. Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury[J]. Am J Kidney Dis,2013,61(5):673-685.

[27]Waikar SS, Betensky RA, Emerson SC,et al. Imperfect gold standards for kidney injury biomarker evaluation[J]. J Am Soc Nephrol,2012,23(1):13-21.

[28]Han WK, Bailly V, Abichandani R,et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury[J]. Kidney Int,2002,62(1):237-244.

[29]Yu W, Beaudry S, Negoro H,et al. H2O2activates G protein, alpha 12 to disrupt the junctional complex and enhance ischemia reperfusion injury[J]. Proc Natl Acad Sci U S A,2012,109(17):6680-6685.

[30]Dhanasekaran N，Dermott JM. Signaling by the G12 class of G proteins[J]. Cell Signal,1996,8(4):235-245.

[31]Ismail OZ, Zhang X, Wei J ,et al. Kidney injury molecule-1 protects against Galpha12 activation and tissue damage in renal ischemia-reperfusion injury[J]. Am J Pathol,2015,185(5):1207-1215.

[32]Ko GJ, Grigoryev DN, Linfert D,et al. Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition[J]. Am J Physiol Renal Physiol,2010,298(6):F1472-F1483.

[33]Humphreys BD, Xu F, Sabbisetti V,et al. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis[J]. J Clin Invest,2013,123(9):4023-4035.

[34]Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more[J]. Nephrol Dial Transplant,2009,24(11):3265-3268.

[35]Luo QH, Chen ML, Sun FJ,et al. KIM-1 and NGAL as biomarkers of nephrotoxicity induced by gentamicin in rats[J]. Mol Cell Biochem,2014,397(1-2):53-60.

[36]van Timmeren MM, Vaidya VS, van Ree RM,et al. High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients[J]. Transplantation,2007,84(12):1625-1630.

[37]Peters HP, Waanders F, Meijer E,et al. High urinary excretion of kidney injury molecule-1 is an independent predictor of end-stage renal disease in patients with IgA nephropathy[J]. Nephrol Dial Transplant,2011,26(11):3581-3588.

[38]Lin Q, Chen Y, Lv J,et al. Kidney injury molecule-1 expression in IgA nephropathy and its correlation with hypoxia and tubulointerstitial inflammation[J]. Am J Physiol Renal Physiol,2014,306(8):F885-F895.

[39]Zheng G, Wang Y, Mahajan D,et al. The role of tubulointerstitial inflammation[J]. Kidney Int Suppl,2005,94:S96-100.

[40]Xu PC, Wei L, Shang WY,et al. Urinary kidney injury molecule-1 is related to pathologic involvement in IgA nephropathy with normotension, normal renal function and mild proteinuria[J]. BMC Nephrol,2014,15:107.

[41]Waanders F, Vaidya VS, van Goor H,et al. Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial[J]. Am J Kidney Dis,2009,53(1):16-25.

[42]Nakagawa S, Masuda S, Nishihara K,et al. mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats[J]. Biochem Pharmacol,2010,79(1):67-76.

[43]Hosohata K, Ando H, Takeshita Y,et al. Urinary Kim-1 is a sensitive biomarker for the early stage of diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats[J]. Diab Vasc Dis Res,2014,11(4):243-250.

[44]Lim A I, Chan LY, Tang SC,et al. Albumin and glycated albumin activate KIM-1 release in tubular epithelial cells through distinct kinetics and mechanisms[J]. Inflamm Res,2014,63(10):831-839.

[45]Carlsson AC, Calamia M, Riserus U,et al. Kidney injury molecule (KIM)-1 is associated with insulin resistance: results from two community-based studies of elderly individuals[J]. Diabetes Res Clin Pract,2014,103(3):516-21.

[46]Nozaki Y, Kinoshita K, Yano T,et al. Estimation of kidney injury molecule-1 (Kim-1) in patients with lupus nephritis[J]. Lupus,2014,23(8):769-777.

[47]Kuehn EW, Hirt MN, John AK,et al. Kidney injury molecule 1 (Kim1) is a novel ciliary molecule and interactor of polycystin 2[J]. Biochem Biophys Res Commun,2007,364(4):861-866.

[48]Abulezz S. KIM-1 expression in kidney allograft biopsies: Improving the gold standard[J]. Kidney Int,2008,73(5):522-523.

[49]Malyszko J, Koc-Zorawska E, Malyszko JS,et al. Kidney injury molecule-1 correlates with kidney function in renal allograft recipients[J]. Transplant Proc,2010,42(10):3957-3959.

[50]Zhang PL, Rothblum LI, Han WK,et al. Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury[J]. Kidney Int,2008,73(5):608-614.

[51]Nogare AL, Dalpiaz T, Veronese FJ,et al. Noninvasive analyses of kidney injury molecule-1 messenger RNA in kidney transplant recipients with graft dysfunction[J]. Transplant Proc,2012,44(8):2297-2299.

[52]Nogare AL, Veronese FV, Carpio VN,et al. Kidney injury molecule-1 expression in human kidney transplants with interstitial fibrosis and tubular atrophy[J]. BMC Nephrol,2015,16:19.

[53]Song L, Xue L, Yu J,et al. Kidney injury molecule-1 expression is closely associated with renal allograft damage[J]. Bosn J Basic Med Sci,2013,13(3):170-4.

[54]Schroppel B, Kruger B, Walsh L,et al. Tubular expression of KIM-1 does not predict delayed function after transplantation[J]. J Am Soc Nephrol,2010,21(3):536-542.

[55]Morrissey JJ, London AN, Lambert MC,et al. Sensitivity and specificity of urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 for the diagnosis of renal cell carcinoma[J]. Am J Nephrol,2011,34(5):391-398.

中圖分類號R692.5

文獻(xiàn)標(biāo)志碼A

通訊作者王寧寧，E-mail: wangnn@njmu.edu.cn

基金項(xiàng)目：國家自然科學(xué)基金(編號：81270408、81570666)；中華醫(yī)學(xué)會臨床科研專項(xiàng)基金首屆腎臟病青年研究基金(編號：13030300415)；江蘇省“醫(yī)學(xué)重點(diǎn)人才”項(xiàng)目(編號：RC201162)；江蘇省“六大高峰人才”編號：2010(IB10))。