體外循環(huán)手術(shù)后腎臟損傷的臨床研究進(jìn)展

李艷麗，高晴云，張成鑫，汪 洋，陶 靜，劉海淵，葛圣林

心肺轉(zhuǎn)流(cardiopulmonary bypass,CPB)即體外循環(huán)技術(shù)作為心臟大血管外科中不可或缺的輔助手段,為心臟大血管外科的發(fā)展和進(jìn)步提供重要的支持。但是,與此同時(shí),由于CPB的特殊性以及相應(yīng)的局限性,使得手術(shù)中和術(shù)后與之相關(guān)的并發(fā)癥發(fā)病率逐漸增加。其中,腎臟損傷是CPB術(shù)后常見且嚴(yán)重的并發(fā)癥,其對(duì)于患者病情預(yù)后意義非常重要。本文對(duì)于CPB術(shù)后腎臟損傷的機(jī)制以及相關(guān)的診療進(jìn)展進(jìn)行如下綜述。

1 機(jī)制

1.1 CPB生理學(xué) CPB由于自身的特殊性使得其在術(shù)中表現(xiàn)出不同于其他外科手術(shù)的生理學(xué)特點(diǎn),包括炎癥反應(yīng)和血液稀釋等。在CPB術(shù)中強(qiáng)調(diào)持續(xù)血?dú)獗O(jiān)測(cè)實(shí)時(shí)了解內(nèi)環(huán)境的狀態(tài)并及時(shí)針對(duì)異常變化予以干預(yù)。

首先,CPB預(yù)充過(guò)程中所配制的預(yù)充液為無(wú)細(xì)胞成分,故CPB術(shù)中會(huì)導(dǎo)致血液稀釋,紅細(xì)胞比容(hematocrit,HCT)水平降低。CPB過(guò)程中出現(xiàn)的血液稀釋降低紅細(xì)胞的攜氧能力增加腎臟的缺血風(fēng)險(xiǎn)［1］。當(dāng)HCT低于0.21時(shí),血液稀釋對(duì)于CPB術(shù)后腎功能損傷具有統(tǒng)計(jì)學(xué)意義［2］。在降溫階段,血液黏稠度和HCT均處于下降趨勢(shì),腎臟灌注壓持續(xù)降低,上述機(jī)制的聯(lián)合作用導(dǎo)致腎髓質(zhì)氧供量急劇減少,而增加動(dòng)脈血氧濃度僅能部分緩解氧供不足的情況。其次,CPB過(guò)程中血管波動(dòng)性消失,其對(duì)于血流動(dòng)力學(xué)產(chǎn)生影響而且可能導(dǎo)致微血栓形成。CPB輔助循環(huán)到患者自體循環(huán)恢復(fù)的過(guò)渡時(shí)期血流動(dòng)力學(xué)穩(wěn)定性容易受到干擾。低心排出量狀態(tài)易造成全身臟器的低灌注以及腎臟的血供不足。同時(shí),CPB系統(tǒng)中的泵,氧合器,引流導(dǎo)管和超濾裝置對(duì)于紅細(xì)胞均會(huì)造成破壞并增加血漿游離血紅蛋白的水平［3］,血漿游離血紅蛋白水平在CPB操作期間增加,這與術(shù)后早期腎小管損傷之間存在相關(guān)性,并且是進(jìn)展為腎功能不全的獨(dú)立相關(guān)因素［4］。主要原因在于游離血紅蛋白能夠催化自由基生成并參與腎臟集合管系統(tǒng)中Tamms Horsfall糖蛋白的合成,進(jìn)而降低循環(huán)中結(jié)合珠蛋白水平并對(duì)于腎臟產(chǎn)生破壞效應(yīng)。此外,游離血紅蛋白抑制一氧化氮的作用導(dǎo)致腎臟小動(dòng)脈血管收縮［5-7］。有研究表明,在風(fēng)險(xiǎn)因素和CPB時(shí)間相似的前提下,CPB術(shù)后腎功能損傷的患者在CPB結(jié)束時(shí),游離血紅蛋白的水平是對(duì)照組的2倍［8］。再次,體溫變化在CPB對(duì)于腎臟血流動(dòng)力學(xué)和氧供/氧耗的影響中也發(fā)揮重要作用,低溫能夠改變血管收縮狀態(tài),血液黏稠度,腎小球?yàn)V過(guò)率(glomerular filtration ratio,GFR)和腎臟代謝功能［9］。而在復(fù)溫過(guò)程中,腎臟由于代謝需求量增加,對(duì)于缺氧環(huán)境尤為敏感。Newland等［10］的研究中,以接受冠狀動(dòng)脈旁路移植術(shù)(coronary artery bypass grafting,CABG)或是瓣膜置換以及成形的患者為對(duì)象,分別設(shè)定復(fù)溫溫度為 36℃,36.5℃和37℃予以觀察,結(jié)果表明,高溫灌注,即復(fù)溫溫度超過(guò)37℃可以作為術(shù)后腎臟功能損傷的獨(dú)立預(yù)測(cè)因子。不過(guò),淺低溫(34～37℃)以及中低溫(28～30℃)設(shè)置也并未能夠改善CABG術(shù)后腎功能損傷的發(fā)病率［11-12］。這也說(shuō)明復(fù)溫程序在CPB中的必要性并且也驗(yàn)證低溫灌注增加腎臟血管的阻力［13］。

此外,CPB系統(tǒng)與血液的直接接觸導(dǎo)致體內(nèi)炎性轉(zhuǎn)錄因子水平的上調(diào),包括白介素(interleukin,IL)-6,IL-8以及腫瘤壞死因子-α(tumor necrosis factor-α,TNF-α)等,其所誘導(dǎo)的炎癥反應(yīng)對(duì)于腎小管和上皮細(xì)胞均造成破壞［14-16］。而且在細(xì)胞因子和炎性介質(zhì)的作用下,有研究表明,在CPB術(shù)后,中性粒細(xì)胞/淋巴細(xì)胞比值(neutrophil-lymphocyte ratio)和腎功能損傷之間存在相關(guān)性［17］。同時(shí),由于在CPB術(shù)中出現(xiàn)血液稀釋,HCT水平降低,輸血?jiǎng)t成為重要的改善手段。然而,Karkouti等［18］指出,每單位輸血量使得CPB術(shù)后腎功能損傷發(fā)病率增加10%～20%。Khan等［19］的研究中發(fā)現(xiàn),CPB術(shù)中輸血超過(guò)兩單位的患者腎功能損傷的發(fā)病率顯著升高。不過(guò),上述兩項(xiàng)研究由于隨機(jī)化對(duì)照以及相關(guān)變量的限制,無(wú)法最終確定輸血與腎功能損傷之間的相關(guān)性。

1.2 缺血缺氧和再灌注損傷 腎臟的灌注機(jī)制非常復(fù)雜且具有高度的調(diào)控性。CPB過(guò)程中血管無(wú)波動(dòng)性且對(duì)于腎皮質(zhì)和髓質(zhì)之間的流量平衡狀態(tài)調(diào)節(jié)并不滿意。腎皮質(zhì)灌注量增加反而會(huì)由于髓質(zhì)的高氧耗導(dǎo)致皮髓質(zhì)交界區(qū)血供不足［20］。而皮髓質(zhì)交界區(qū)和外部髓質(zhì)的腎單位對(duì)于缺血再灌注損傷尤為敏感［2,15,21］。腎臟缺氧的主要機(jī)制系腎臟的氧供和氧耗出現(xiàn)失衡［22］。腎臟的氧供主要取決于腎臟的血流量,而氧耗則是取決于GFR［23］。因此,腎臟血流量和GFR之間的動(dòng)態(tài)變化是造成腎臟功能損傷的主要因素。氧化應(yīng)激是缺血再灌注過(guò)程中主要的心肌損傷機(jī)制,同時(shí)其也被認(rèn)為能夠?qū)е履I臟功能損傷。CPB過(guò)程中缺血再灌注損傷加劇氧化炎性反應(yīng)從而促使循環(huán)中游離鐵含量增加。游離鐵對(duì)于腎小管上皮細(xì)胞功能產(chǎn)生影響包括破壞細(xì)胞增殖以及誘導(dǎo)自由基損傷。此外,缺血再灌注損傷消耗細(xì)胞內(nèi)高能磷酸鹽,誘發(fā)鈣沉積,氧自由基生成,細(xì)胞因子活化進(jìn)而導(dǎo)致上皮細(xì)胞損傷進(jìn)而造成腎臟自調(diào)節(jié)功能缺失,對(duì)于縮血管藥物和一氧化氮的敏感度下降［15,22］。

1.3 CPB術(shù)后腎臟損傷風(fēng)險(xiǎn)因素 術(shù)前因素分析中,年齡、性別、術(shù)前腎功能狀態(tài)、心臟射血分?jǐn)?shù)、急診手術(shù)和糖尿病可以作為主要風(fēng)險(xiǎn)因素［24］。除此以外,患者于術(shù)前所接受的藥物因素也對(duì)于CPB術(shù)后的腎功能狀態(tài)產(chǎn)生影響?；仡櫺匝芯恐赋?術(shù)前接受血管緊張素轉(zhuǎn)化酶抑制劑(angiotensin converting enzyme inhibitors,ACEI)/血管緊張素Ⅱ受體阻滯劑治療的患者CPB術(shù)后腎功能損傷的發(fā)病率顯著升高［25-27］。而與之形成對(duì)比的是,在 CPB下行CABG的患者中,ACEI因素卻與術(shù)后腎功能損傷的發(fā)病率呈負(fù)相關(guān)［28］。而對(duì)于術(shù)前給藥他汀類和阿司匹林治療的患者,其在CPB術(shù)后的腎功能損傷未見有顯著統(tǒng)計(jì)學(xué)意義［29-31］。

CPB術(shù)中和術(shù)后存在多種風(fēng)險(xiǎn)因素被證實(shí)與CPB術(shù)后腎臟功能損傷具有相關(guān)性。首先,在CPB術(shù)中紅細(xì)胞的破壞具有顯著意義。CPB術(shù)中游離血紅蛋白或是游離肌紅蛋白釋放入血以及瓣膜置換、輸血等機(jī)械性破壞因素均會(huì)導(dǎo)致紅細(xì)胞膜穩(wěn)定性被減弱。CPB的紅細(xì)胞破壞效應(yīng)隨著CPB運(yùn)行時(shí)間的延長(zhǎng)而加劇。其次,Chiravuri等［31］指出,低齡、重復(fù)多次阻斷以及手術(shù)時(shí)間延長(zhǎng)與術(shù)后腎臟損害或是功能衰竭存在相關(guān)性。再次,CPB術(shù)中的尿量水平也被發(fā)現(xiàn)與腎臟功能損傷之間具有關(guān)聯(lián)性。有研究指出,術(shù)中尿量低于4 ml/(kg·h)患者中術(shù)后腎功能損傷的發(fā)病率顯著增加具有統(tǒng)計(jì)學(xué)意義,由此可見,CPB術(shù)中尿量對(duì)于術(shù)后腎臟功能損傷具有預(yù)測(cè)效應(yīng)。此外,包括乳酸水平和心臟疾病的類型與CPB術(shù)后的腎臟損傷之間也存在相關(guān)性,CPB術(shù)中乳酸最大濃度超過(guò)6 mmol/L,以及紫紺型先天性心臟病患兒行CPB手術(shù)后腎臟功能損傷的發(fā)病率顯著增加且具有統(tǒng)計(jì)學(xué)意義［32］。除常規(guī)手術(shù)外,對(duì)于復(fù)雜性心臟手術(shù)中風(fēng)險(xiǎn)因素的評(píng)估也有所報(bào)道。在全主動(dòng)脈弓選擇性腦灌注深低溫停循環(huán)的大血管手術(shù)中(25℃),術(shù)后腎臟功能損傷組相比較于非損傷組,手術(shù)時(shí)間、CPB時(shí)間、停循環(huán)時(shí)間以及腦流量灌注時(shí)間均顯著延長(zhǎng)［33］。其中,停循環(huán)時(shí)間超過(guò)60 min以及術(shù)前患者合并基礎(chǔ)慢性腎臟疾病是主動(dòng)脈大血管CPB術(shù)后并發(fā)腎臟功能損傷的獨(dú)立因素。此外,Kahli等［34］在CABG患者中進(jìn)行腎臟功能評(píng)估中發(fā)現(xiàn),相比較于傳統(tǒng)的方式,生長(zhǎng)分化因子15更能夠有效預(yù)測(cè)冠狀動(dòng)脈粥樣硬化性心臟病患者CPB手術(shù)的腎臟功能的預(yù)后結(jié)局。

術(shù)后管理過(guò)程中,ICU時(shí)間延長(zhǎng)的潛在風(fēng)險(xiǎn)也不容忽視。Ruf等［35］在嬰幼兒CPB手術(shù)中和術(shù)后使用腎臟近紅外分光光譜儀評(píng)估局部血氧定量和急性腎功能損傷發(fā)展之間的關(guān)系中發(fā)現(xiàn),術(shù)后24小時(shí)高乳酸水平、24小時(shí)低靜脈血氧飽和度、低血壓以及大劑量血管升壓藥物均是具有意義的風(fēng)險(xiǎn)因素。

2 診療

2.1 腎功能損傷標(biāo)記物 相關(guān)標(biāo)記物在腎功能損傷的診療中具有極為關(guān)鍵的作用。目前,血肌酐和尿素氮是常規(guī)的腎功能檢測(cè)指標(biāo),但是二者在敏感度和特異性方面均存在一定的限制性,使得其在應(yīng)用方面的價(jià)值受到影響。因此,近年來(lái)新型簡(jiǎn)易經(jīng)濟(jì)的標(biāo)記物逐漸被發(fā)掘并用于CPB術(shù)后早期腎功能損傷的診斷中,包括中性粒細(xì)胞明膠酶相關(guān)載脂蛋白(neutrophilgelatinaseassociatedlipocalin,NGAL),肝臟型脂肪酸(L-type fatty acid-binding protein,L-FABP)和胱抑素C(cystatin C,Cys C)等。當(dāng)前的研究多圍繞CPB術(shù)后上述標(biāo)記物之間比以及與常規(guī)腎功能指標(biāo)之間的效應(yīng)對(duì)比,并由此了解其在CPB術(shù)后對(duì)于預(yù)測(cè)腎功能損傷的優(yōu)勢(shì)。其中,在NGAL和L-FABP的對(duì)比性研究中發(fā)現(xiàn),CPB術(shù)后即刻,對(duì)比于非腎功能損傷組,腎功能損傷組中L-FABP顯著升高,而在術(shù)后3小時(shí),兩項(xiàng)指標(biāo)均顯著升高。但是由于NGAL在術(shù)后3小時(shí)的受試者工作特征曲線面積顯著高于L-FABP,故前者對(duì)于診斷CPB術(shù)后早期腎功能損傷意義更大［36］。在與肌酐的對(duì)比研究中,NGAL提前數(shù)小時(shí)至數(shù)天能夠體現(xiàn)出CPB術(shù)后腎功能損傷狀態(tài)［37］。Fatina等在兒科心血管手術(shù)的研究中發(fā)現(xiàn),NGAL在CPB術(shù)后2小時(shí)即顯著升高且持續(xù)至術(shù)后24小時(shí),由此可見,NGAL可以作為CPB術(shù)后早期腎臟功能損傷較為理想的標(biāo)記物［38］。 Seitz 等［39］的研究中,將NGAL和Cys C在CPB術(shù)后對(duì)于腎臟損傷評(píng)估的敏感度和特異性進(jìn)行對(duì)比,結(jié)果發(fā)現(xiàn),相比較于NGAL,Cys C在CPB術(shù)后腎臟損傷的預(yù)測(cè)效應(yīng)方面更具優(yōu)勢(shì),CPB術(shù)后2小時(shí)Cys C水平達(dá)到0.995 mg/L時(shí),急性腎功能損傷的結(jié)局基本明確。Herbert等［40］對(duì)于1歲以內(nèi)先天性心臟病患兒的CPB術(shù)后以NGAL為參照,將肌酐和Cys C的敏感度和特異性進(jìn)行對(duì)比,結(jié)果顯示,在NGAL陽(yáng)性的腎臟損傷病例中,相比較于肌酐,Cys C的特異性具有顯著優(yōu)勢(shì)。在Cys C與肌酐的對(duì)比研究中發(fā)現(xiàn),Cys C的預(yù)測(cè)效應(yīng)不如肌酐顯著且水平變化的時(shí)間滯后于肌酐,但是Cys C水平異常的急性腎功能損傷患者中不良預(yù)后的發(fā)生率更高［41］。此外,部分細(xì)胞炎性因子如IL-6和IL-8也被證實(shí)在CPB術(shù)后腎功能損傷的預(yù)測(cè)中發(fā)揮不同程度的作用［42-43］。除新近的檢測(cè)標(biāo)記物外,較為傳統(tǒng)的檢測(cè)指標(biāo)仍然發(fā)揮著一定的作用,如尿蛋白測(cè)試,雖然是腎功能評(píng)估的早期手段,但是由于其操作成本低且結(jié)果易于獲取,所以在臨床實(shí)踐中也占據(jù)重要的地位。不過(guò),在隊(duì)列研究中發(fā)現(xiàn),各年齡組患兒中尿蛋白水平無(wú)顯著差異,僅在更為年少的患兒中有所升高［44］。上述的研究群體主要集中于兒科患者,各種標(biāo)記物針對(duì)成人患者的臨床意義還需要相關(guān)研究材料支持。在目前的臨床實(shí)踐中,不同標(biāo)記物的聯(lián)合應(yīng)用正逐漸成為趨勢(shì)。

2.2 防治 近年來(lái),遠(yuǎn)端缺血預(yù)處理(remote ischemic preconditioning,RIPC)的概念被廣泛提及。心臟外科手術(shù)的不良預(yù)后主要與術(shù)中心肌損傷相關(guān),因此,多項(xiàng)研究著眼于通過(guò)RIPC方式降低心肌損傷和缺血的發(fā)病率。Zarbock等［45］在臨床研究中發(fā)現(xiàn),經(jīng)RIPC組的患者術(shù)后72小時(shí)內(nèi)腎功能損傷的發(fā)病率顯著低于對(duì)照組。RIPC對(duì)于2期和3期腎功能損傷的控制效果更為顯著。另外,在CPB術(shù)中利用超濾裝置將過(guò)量液體排出體外改善心肺功能。維持較高水平的灌注壓力,腎臟自調(diào)節(jié)功能通常在灌注壓力降至80 mm Hg左右時(shí)啟動(dòng)。為避免血液的過(guò)度稀釋,CPB術(shù)中HCT維持在0.24以上。

治療方面,營(yíng)養(yǎng)支持的重要性顯而易見,腎功能損傷患者治療期間所需的目標(biāo)能量為20～30 kcal/(kg·d)［46］。如果病情嚴(yán)重需要進(jìn)行持續(xù)腎臟替代治療(continuous renal replacement therapy,CRRT),則有必要以補(bǔ)充蛋白的形式予以提供高能量攝?。?7］。腎功能損傷患者需要嚴(yán)格控制葡萄糖的攝取量以避免高血糖,Oezkur等［48］的研究中發(fā)現(xiàn),高血糖水平合并糖化血紅蛋白(HbA1c)超過(guò)6.0%時(shí),CABG術(shù)后腎功能損傷的發(fā)病率顯著增加。腎功能重度受損患者接受CRRT治療有利于糾正高鉀血癥以及酸中毒并代謝體內(nèi)過(guò)剩液體。在臨床研究中,對(duì)于CPB術(shù)后腎功能損傷患者早期進(jìn)行CRRT治療能夠降低死亡率并縮短住院時(shí)間［49］。此外,相比較于間斷的腎替代治療,CRRT的優(yōu)勢(shì)在于維持血流動(dòng)力學(xué)的穩(wěn)定性［50］。

藥物層面,促紅細(xì)胞生成素(erythropoietin,EPO)主要在腎臟中合成,作用在于調(diào)節(jié)造血功能。除造血功能調(diào)節(jié)功能外,EPO還被發(fā)現(xiàn)具有通過(guò)抗氧化、抗炎癥和抗凋亡效應(yīng)防止缺血再灌注損傷的效應(yīng),其是改善腎臟損傷的代表成分［51-52］。Kim等［53］在誘導(dǎo)麻醉后靜脈予以重組人促紅細(xì)胞生成素(recombinant human erythropoietin,rhEPO)-α給藥,劑量300 IU/kg,對(duì)照組則是同時(shí)予以等量生理鹽水。然而,結(jié)果表明,rhEPO單一給藥并未降低術(shù)后腎臟功能損傷的發(fā)病率,分析原因在于樣本量并不充分進(jìn)而導(dǎo)致腎臟損傷發(fā)病率低于預(yù)期,而其次rhEPO組中患者合并糖尿病,而糖尿病則能夠拮抗rhEPO對(duì)于組織的保護(hù)效應(yīng)［54-55］。另外,萬(wàn)汶的使用對(duì)于研究結(jié)果產(chǎn)生干擾,因?yàn)榱u乙基淀粉溶液易于加重腎臟功能惡化［56］。 Liu 等［57］的研究表明,5 000 U/kg的rhEPO預(yù)處理可以有效調(diào)節(jié)選擇性Ca2＋通道瞬時(shí)受體電位陽(yáng)離子通道蛋白6及其信號(hào)傳導(dǎo)通路活化T細(xì)胞核轉(zhuǎn)錄因子1在腎小球中的表達(dá)水平進(jìn)而控制CPB腎臟功能損傷［58］。在CABG患者的隨機(jī)對(duì)照雙盲研究中,以等量rhEPO和生理鹽水進(jìn)行預(yù)處理,術(shù)前三天劑量為200 U/kg,術(shù)中為100 U/kg,觀察結(jié)果顯示,rhEPO的預(yù)處理組中患者尿NGAL水平顯著降低臨床預(yù)后得以改善［58］。

此外,較為常用的是非洛多泮,作為選擇性多巴胺受體激動(dòng)劑,其低劑量使用時(shí)能夠在不改變血壓的情況下改善腎臟灌注。Caimmi等［60］研究中分別在CPB過(guò)程中以及術(shù)后早期予以小劑量非洛多泮0.1～0.3 μg/(kg·min)觀察腎臟功能的改善效應(yīng)。結(jié)果顯示,對(duì)于擬行手術(shù)治療的腎臟功能受損患者,非洛多泮靜脈用藥有助于改善術(shù)后腎功能。

其它輔助藥物方面的評(píng)估研究中,Narin等［61］提出在CPB過(guò)程中多巴胺［2 μg/(kg·min)］聯(lián)合甘露醇(1 g/kg)使用對(duì)于預(yù)防術(shù)后腎功能不良事件效果更為理想。動(dòng)物CPB模型中發(fā)現(xiàn),提取于綠色蔬菜中的蘿卜硫素具有良好的抗炎效應(yīng)。其對(duì)于CPB術(shù)后腎臟功能的保護(hù)機(jī)制主要是抑制淋巴細(xì)胞中的炎性反應(yīng)信號(hào)通路［62］。右美托咪定由于能夠有效抑制超氧化物歧化酶活性,因此,其在CPB術(shù)中以及術(shù)后使用均能取得滿意的腎臟保護(hù)作用［63-64］。不過(guò),部分藥物的療效并未達(dá)到預(yù)期水平。Le等［65］對(duì)于CPB術(shù)后6小時(shí)患者予以重組人腦鈉肽(recombinant human B-type natriuretic peptide,rhBNP)靜脈用藥,劑量 0.0075～0.01 μg/(kg·min),持續(xù)72 h,結(jié)果顯示,相比較于對(duì)照組,rhBNP組患者的CPB術(shù)后腎臟功能得到顯著改善,但是兩者間的預(yù)后無(wú)統(tǒng)計(jì)學(xué)差異。不過(guò),對(duì)于CPB中常規(guī)藥物烏司他汀,其在腎臟保護(hù)中的效應(yīng)并未得到肯定。在術(shù)前腎功能正常的患者接受主動(dòng)脈瓣置換手術(shù)中,分別在誘導(dǎo)麻醉后,CPB轉(zhuǎn)流開始時(shí)以及停機(jī)后予以烏司他汀給藥,其中轉(zhuǎn)流開始時(shí)給藥40萬(wàn)單位,而誘導(dǎo)麻醉和停機(jī)時(shí)均給藥30萬(wàn)單位,結(jié)果顯示,烏司他汀對(duì)于CPB術(shù)后腎功能的改善不具有統(tǒng)計(jì)學(xué)意義［66］。

3 展望

總而言之,腎臟損傷是CPB手術(shù)常見的并發(fā)癥。如何在CPB過(guò)程中采取有效的腎臟保護(hù)是當(dāng)前CPB領(lǐng)域中的熱點(diǎn)問(wèn)題。多種藥物和技術(shù)手段的相繼應(yīng)用極大程度緩解腎臟功能損傷與破壞。但是,其中存在的問(wèn)題也不容忽視,如藥物是否存在不良反應(yīng),CPB時(shí)間和溫度的控制在特定環(huán)境中是否能夠執(zhí)行,部分手段還處于動(dòng)物實(shí)驗(yàn)階段尚不完善等。遠(yuǎn)期還需要針對(duì)CPB腎臟損傷更為微觀的層面開展,對(duì)于損傷的分子甚至基因機(jī)制進(jìn)行有效的研究以期進(jìn)一步控制CPB相關(guān)損傷的發(fā)生。

［1］Haase M,Bellomo R,Story D,et al.Effect of mean arterial pressure,haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury［J］.Nephrol Dial Transplant,2012,27(1):153-160.

［2］Rosner MH,Portilla D,Okusa MD.Cardiac surgery as a cause of acute kidney injury:pathogenesis and potential therapies［J］.J Intensive Care Med,2008,23(1):3-18.

［3］Billings FT 4th,Yu C,Byrne JG,et al.Heme oxygenase-1 andacute kidney injury following cardiac surgery［J］.Cardiorenal Med,2014,4(1):12-21.

［4］Vermeulen Windsant IC,Snoeijs MG,Hanssen SJ,et al.Hemolysis is associated with acute kidney injury during major aortic surgery ［J］.Kidney Int,2010,77(10):913-920.

［5］Loebl EC,Baxter CR,Curreri PW.The mechanism of erythrocyte destruction in the early postburn period［J］.Ann Surg,1973,178(176):681-686.

［6］Haase M,Haase-Fielitz A,Bagshaw SM,et al.Cardiopulmonary bypass-associated acute kidney injury:a pigment nephropathy［J］？ Contrib Nephrol,2007,156:340-353.

［7］Keene WR,Jandl JH.The sites of hemoglobin catabolism［J］.Blood,1965,26(6):705-719.

［8］Billings FT 4th,Ball SK,Roberts LJ 2nd,et al.Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response［J］.Free Radic Biol Med,2011,50(11):1480-1487.

［9］Sgouralis I,Evans RG,Gardiner BS,et al.Renal hemodynamics,function,and oxygenation during cardiac surgery performed on cardiopulmonary bypass:a modeling study ［J］.Physiol Rep,2015,3(1):e12260.

［10］Newland RF,Baker RA,Mazzone AL,et al.Rewarming Temperature During Cardiopulmonary Bypass and Acute Kidney Injury:A Multicenter Analysis ［J］.Ann Thorac Surg,2016,101(5):1655-1662.

［11］Boodhwani M,Rubens FD,Wozny D,et al.Effects of mild hypothermia and rewarming on renal function after coronary artery bypass grafting［J］.Ann Thorac Surg,2009,87(2):489-495.

［12］Swaminathan M,East C,Phillips-Bute B,et al.Report of a substudy on warm versus cold cardiopulmonary bypass:changes in creatinine clearance［J］.Ann Thorac Surg,2001,72(5):1603-1609.

［13］Lazenby WD,Ko W,Zelano JA,et al.Effects of temperature and flow rate on regional blood flow and metabolism during cardiopulmonary bypass［J］.Ann Thorac Surg,1992,53(6):957-964.

［14］Hudson C,Hudson J,Swaminathan M,et al.Emerging concepts in acute kidney injury following cardiac surgery［J］.Semin Cardiothorac Vasc Anesth,2008,12(4):320-330.

［15］Stafford-Smith M,Patel UD,Phillips-Bute BG,et al.Acute kidney injury and chronic kidney disease after cardiac surgery［J］.Adv Chronic Kidney Dis,2008,15(3):257-277.

［16］Hall RI,Smith MS,Rocker G.The systemic inflammatory response to cardiopulmonary bypass:pathophysiological,therapeutic,and pharmacological considerations［J］.Anesth Analg,1997,85(4):766-782.

［17］Kim WH,Park JY,Ok SH,et al.Association between the neutrophil/lymphocyte ratio and acute kidney injury after cardiovascular surgery［J］.Medicine(Baltimore),2015,94(43):e1867

［18］Karkouti K.Transfusion and risk of acute kidney injury in cardiac surgery［J］.Br J Anaesth,2012,109(51):i29-i38.

［19］Khan UA,Coca SG,Hong K,et al.Blood transfusions are associated with urinary biomarkers of kidney injury in cardiac surgery［J］.J Thorac Cardiovasc Surg,2014,148(2):726-732.

［20］Ricksten SE,Bragadottir G,Redfors B.Renal oxygenation in clinical acute kidney injury［J］.Crit Care,2013,17(2):221.

［21］Garwood S.Cardiac surgery-associated acute renal injury:new paradigms and innovative therapies［J］.J Cardiothorac Vasc Anesth,2010,24(6):990-1001.

［22］Evans RG,Ince C,Joles JA,et al.Haemodynamic influences on kidney oxygenation:the clinical implications of integrative physiology ［J］.Clin Exp Pharmacol Physiol,2013,40(2):106-122.

［23］Evans RG,Harrop GK,Ngo JP,et al.Basal renal oxygen consumption and the efficiency of oxygen utilization for sodium reabsorption ［J］.Am J Physiol Renal Physiol,2014,306(5):F551-F560.

［24］Kumar A,Ba SM.Cardiopulmonary bypass-associated acute kidney injury［J］.Anesthesiology,2011,114(4):964-970.

［25］Bandeali SJ,Kayanim WT,Lee VV,et al.Outcomes of preopertaive angiotensin-converting enzyme inhibitor therapy in patients undergoing isolated coronary artery bypass grafting［J］.Am J Cardiol,2012,110(7):919-923.

［26］Miceli A,Capoun R,Fino C,et al.Effects of angiotensin-converting enzyme inhibitor therapy on clinical outcome in patients undergoing coronary artery bypass grafting［J］.J Am Coll Cardiol,2009,54(19):1778-1784.

［27］Arora P,Rajagopalam S,Ranjan R,et al.Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in associated with increased risk for acute kidney injury after cardiovascular surgery［J］.Clin J Am Soc Nephrology,2008,3(5):1266-1273.

［28］Benedetto U,Sciarretta,S,Roscitano A,et al.Preoperative angiotensin-converting enzyme inhibitors and acute kidney injury after coronary artery bypass grafting［J］.Ann Thorac Surg,2008,86(4):1160-1168.

［29］Lewicki M,Ng I,Schneider AG.HMG CoA reductase inhibitors(statins)for preventing acute kidney injury after surgical procedures requiring cardiac bypass［J］.Cochrane Database Syst Rev,2015,(3):CD010480.

［30］Myles PS,Smith JA,Forbes A,et al.For the ATACAS Investigators of the ANZCA clinical trials network.Stopping vs continuing aspirin before coronary artery surgery［J］.N Engl J Med,2016,374(8):728-737.

［31］Chiravuri SD,Riegger LQ,Christensen R,et al.Factors associated with acute kidney injury or failure in children undergoing cardiopulmonary bypass:a case-controlled study ［J］.Pediatr Anesth,2011,21(8):880-886.

［32］Reyes-Flandes EN,Herrera-Landero A,Bobadilla-González P,et al.Risk factors associated with postoperative acute renal failure in pediatric patients undergoing cardiopulmonary bypass surgery［J］.Rev Chil Pediatr,2017,88(2):209-215.

［33］Nota H,Asai T,Suzuki T,et al.Risk factors for acute kidney injury in aortic arch surgery with selective cerebral perfusion and mild hypothermic lower body circulatory arrest［J］.Interact CardioVasc Thorac Surg,2014,19(6):955-961.

［34］Kahli A,Guenancia C,Zeller M,et al.Growth differentiation factor-15(GDF-15)levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass［J］.PLoS One,2014,9(8):e105759.

［35］Ruf B,Bonelli V,Balling G,et al.Intraoperative renal near-infrared spectroscopy indicates developing acute kidney injury in infants undergoing cardiac surgery with cardiopulmonary bypass:a case-control study ［J］.Crit Care,2015,19:27.

［36］Moriyama T,Hagihara S,Shiramomo T,et al.Comparison of three early biomarkers for acute kidney injury after cardiac surgery under cardiopulmonary bypass ［J］.J Intensive Care,2016,4:41.

［37］Dent CL,Ma Q,Dastrala S,Bennett M,et al.Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury,morbidity and mortality after pediatric cardiac surgery:a prospective uncontrolled cohort study ［J］.Crit Care,2007,11(6):R127.

［38］Fadel FI,Abdel Rahman AM,Mohamed MF,et al.Plasma neutrophil gelatinase-associated lipocalin as an early biomarker for prediction of acute kidney injury after cardio-pulmonary bypass in pediatric cardiac surgery ［J］.Arch Med Sci,2012,8(2):250-255.

［39］Seitz S,Rauh M,Gloeckler M,et al.Cystatin C and neutrophil gelatinase-associated lipocalin:biomarkers for acute kidney injury after congenital heart surgery ［J］.Swiss Med Wkly,2013,143:w13744.

［40］Herbert C,Patel M,Nugent A,et al.Serum cystatin C as an early marker of neutrophil gelatinase-associated lipocalin-positive acute kidney injury resulting from cardiopulmonary bypass in infants with congenital heart disease ［J］.Congenit Heart Dis,2015,10(4):E180-E188.

［41］Spahillari A,Parikh CR,Sint K,et al.Serum cystatin C-versus creatinine-based definitions of acute kidney injury following cardiac surgery:a prospective cohort study［J］.Am J Kidney Dis,2012,60(6):922-929.

［42］Miklaszewska M,Korohoda P,Zachwieja K,et al.Serum interleukin 6 levels as an early marker of acute kidney injury in children after cardiac surgery ［J］.Adv Clin Exp Med,2013,22(3):377-386.

［43］Krawczeski CD,Goldstein SL,Woo JG,et al.Temporal relationship and predictive value of urinary acute kidney injury biomarkers after pediatric cardiopulmonary bypass ［J］.J Am Coll Cardiol,2011,58(22):2301-2309.

［44］Sanchez-Bayle M,Rodriguez-Cimadevilla C,Asensio C,et al.Urinary albumin excretion in Spanish children.Nino Jesus Group［J］.Pediatr Nephrol,1995,9(4):428-430.

［45］Zarbock A,Schmidt C,Van Aken H,et al.Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery［J］.JAMA,2015,313(21):2133-2141.

［46］Khwaja A.KDIGO clinical practice guidelines for acute kidney injury［J］.Nephron Clin Pract,2012,120(4):c179-184.

［47］Brochard L,Abroug F,Brenner M,et al.An Official ATS/ERS/ESICM/SCCM/SRLF Statement:Prevention and Management of Acute Renal Failure in the ICU Patient:an international consensus conference in intensive care medicine［J］.Am J Respir Crit Care Med,2010,181(10):1128-1155.

［48］Oezkur M,Wagner M,Weismann D,et al.Chronic hyperglycemia is associated with acute kidney injury in patients undergoing CABG surgery--a cohort study［J］.BMC Cardiovascular Disorders,2015,15:41.

［49］Liu Y,Davari-Farid S,Arora P,et al.Early versus late initiation of renal replacement therapy in critically ill patients with acute kidney injury after cardiac surgery:a systematic review and meta-analysis［J］.J Cardiothorac Vasc Anesth,2014,28(3):557-563.

［50］Leite TT,Macedo E,Pereira SM,et al.Timing of renal replacement therapy initiation by AKIN classification system［J］.Crit Care,2013,17(2):R62.

［51］Moore E,Bellomo R.Erythropoietin(EPO)in acute kidney injury ［J］.Ann Intensive Care,2011,1(1):3.

［52］Shen Y,Wang Y,Li D,et al.Recombinant human erythropoietin pretreatment attenuates heart ischemia-reperfusion injury in rats by suppressing the systemic inflammatory response ［J］.Transplant Proc,2010,42(5):1595-1597.

［53］Kim JH,Shim JK,Song JW,et al.Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery:a double blind,randomized clinical trial of efficacy and safety ［J］.Critical Care,2013,17(5):R254.

［54］Ghaboura N,Tamareille S,Ducluzeau PH,et al.Diabetes mellitus abrogates erythropoietin-induced cardioprotection against ischemic-reperfusion injury by alteration of the RISK/GSK-3beta signaling ［J］.Basic Res Cardiol,2011,106(1):147-162.

［55］Jensen RV,Stottrup NB,Kristiansen SB,et al.Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients［J］.Basic Res Cardiol,2012,107(5):285.

［56］Myburgh JA,Finfer S,Bellomo R,et al.Hydroxyethyl starch or saline for fluid resuscitation in intensive care［J］.New Engl J Med,2012,367(20):1901-1911.

［57］Liu X,Zhang T,Xia W,et al.Recombinant human erythropoietin pretreatment alleviates renal glomerular injury induced by cardiopulmonary bypass by reducing transient receptor potential channel 6–nuclear factor of activated T-cells pathway activation［J］.J Thorac Cardiovas Surg,2013,146(3):681-687.

［58］Tasanarong A,Duangchana S,Sumransurp S,et al.Prophylaxis with erythropoietin versus placebo reduces acute kidney injury and neutrophil gelatinase-associated lipocalin in patients undergoing cardiac surgery:a randomized,double-blind controlled trial［J］.BMC Nephrology,2013,14:136.

［59］Oh SW,Chin HJ,Chae DW,et al.Erythropoietin Improves Long-Term Outcomes in Patients with Acute Kidney Injury after Coronary Artery Bypass Grafting ［J］.J Korean Med Sci,2012,27(5):506-511.

［60］Caimmi PP,Pagani L,Micalizzi E,et al.Fenoldopam for Renal Protection in Patients Undergoing Cardiopulmonary Bypass［J］.J Cardiothorac Vasc Anesth,2003,17(4):491-494.

［61］Narin EB,Oztekin I,Oztekin S,et al.The pharmacological protection of renal function in patients undergoing cardiac surgery［J］.Pak J Med Sci,2015,31(5):1057-1061.

［62］Nguyen B,Luong L,Naase H,et al.Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass ［J］.J Thorac Cardiovasc Surg,2014,148(2):690-697.

［63］Zhai M,Kang F,Han M,et al.The effect of dexmedetomidine on renal function in patients undergoing cardiac valve replacement under cardiopulmonary bypass:A double-blind randomized controlled trial［J］.J Clin Anesth,2017,40:33-38.

［64］Ji F,Li Z,Young JN,et al.Post-Bypass Dexmedetomidine Use and Postoperative Acute Kidney Injury in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass ［J］.PLoS ONE,2013,8(10):e77446.

［65］Le S,Xiao J,Li W,et al.Continuous administration of recombinant human B-type natriuretic peptide can improve heart and renal function in patients after cardiopulmonary bypass surgery ［J］.J Thorac Dis,2017,9(3):692-701.

［66］Oh SY,Kim JC,Choi YS,et al.Effects of ulinastatin treatment on myocardial and renal injury in patients undergoing aortic valve replacement with cardiopulmonary bypass ［J］.Korean J Anesthesiol,2012,62(2):148-153.