体外循环手术后肾脏损伤的临床研究进展

李艳丽，高晴云，张成鑫，汪 洋，陶 静，刘海渊，葛圣林

心肺转流(cardiopulmonary bypass,CPB)即体外循环技术作为心脏大血管外科中不可或缺的辅助手段,为心脏大血管外科的发展和进步提供重要的支持。但是,与此同时,由于CPB的特殊性以及相应的局限性,使得手术中和术后与之相关的并发症发病率逐渐增加。其中,肾脏损伤是CPB术后常见且严重的并发症,其对于患者病情预后意义非常重要。本文对于CPB术后肾脏损伤的机制以及相关的诊疗进展进行如下综述。

1 机制

1.1 CPB生理学 CPB由于自身的特殊性使得其在术中表现出不同于其他外科手术的生理学特点,包括炎症反应和血液稀释等。在CPB术中强调持续血气监测实时了解内环境的状态并及时针对异常变化予以干预。

首先,CPB预充过程中所配制的预充液为无细胞成分,故CPB术中会导致血液稀释,红细胞比容(hematocrit,HCT)水平降低。CPB过程中出现的血液稀释降低红细胞的携氧能力增加肾脏的缺血风险［1］。当HCT低于0.21时,血液稀释对于CPB术后肾功能损伤具有统计学意义［2］。在降温阶段,血液黏稠度和HCT均处于下降趋势,肾脏灌注压持续降低,上述机制的联合作用导致肾髓质氧供量急剧减少,而增加动脉血氧浓度仅能部分缓解氧供不足的情况。其次,CPB过程中血管波动性消失,其对于血流动力学产生影响而且可能导致微血栓形成。CPB辅助循环到患者自体循环恢复的过渡时期血流动力学稳定性容易受到干扰。低心排出量状态易造成全身脏器的低灌注以及肾脏的血供不足。同时,CPB系统中的泵,氧合器,引流导管和超滤装置对于红细胞均会造成破坏并增加血浆游离血红蛋白的水平［3］,血浆游离血红蛋白水平在CPB操作期间增加,这与术后早期肾小管损伤之间存在相关性,并且是进展为肾功能不全的独立相关因素［4］。主要原因在于游离血红蛋白能够催化自由基生成并参与肾脏集合管系统中Tamms Horsfall糖蛋白的合成,进而降低循环中结合珠蛋白水平并对于肾脏产生破坏效应。此外,游离血红蛋白抑制一氧化氮的作用导致肾脏小动脉血管收缩［5-7］。有研究表明,在风险因素和CPB时间相似的前提下,CPB术后肾功能损伤的患者在CPB结束时,游离血红蛋白的水平是对照组的2倍［8］。再次,体温变化在CPB对于肾脏血流动力学和氧供/氧耗的影响中也发挥重要作用,低温能够改变血管收缩状态,血液黏稠度,肾小球滤过率(glomerular filtration ratio,GFR)和肾脏代谢功能［9］。而在复温过程中,肾脏由于代谢需求量增加,对于缺氧环境尤为敏感。Newland等［10］的研究中,以接受冠状动脉旁路移植术(coronary artery bypass grafting,CABG)或是瓣膜置换以及成形的患者为对象,分别设定复温温度为 36℃,36.5℃和37℃予以观察,结果表明,高温灌注,即复温温度超过37℃可以作为术后肾脏功能损伤的独立预测因子。不过,浅低温(34～37℃)以及中低温(28～30℃)设置也并未能够改善CABG术后肾功能损伤的发病率［11-12］。这也说明复温程序在CPB中的必要性并且也验证低温灌注增加肾脏血管的阻力［13］。

此外,CPB系统与血液的直接接触导致体内炎性转录因子水平的上调,包括白介素(interleukin,IL)-6,IL-8以及肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)等,其所诱导的炎症反应对于肾小管和上皮细胞均造成破坏［14-16］。而且在细胞因子和炎性介质的作用下,有研究表明,在CPB术后,中性粒细胞/淋巴细胞比值(neutrophil-lymphocyte ratio)和肾功能损伤之间存在相关性［17］。同时,由于在CPB术中出现血液稀释,HCT水平降低,输血则成为重要的改善手段。然而,Karkouti等［18］指出,每单位输血量使得CPB术后肾功能损伤发病率增加10%～20%。Khan等［19］的研究中发现,CPB术中输血超过两单位的患者肾功能损伤的发病率显著升高。不过,上述两项研究由于随机化对照以及相关变量的限制,无法最终确定输血与肾功能损伤之间的相关性。

1.2 缺血缺氧和再灌注损伤 肾脏的灌注机制非常复杂且具有高度的调控性。CPB过程中血管无波动性且对于肾皮质和髓质之间的流量平衡状态调节并不满意。肾皮质灌注量增加反而会由于髓质的高氧耗导致皮髓质交界区血供不足［20］。而皮髓质交界区和外部髓质的肾单位对于缺血再灌注损伤尤为敏感［2,15,21］。肾脏缺氧的主要机制系肾脏的氧供和氧耗出现失衡［22］。肾脏的氧供主要取决于肾脏的血流量,而氧耗则是取决于GFR［23］。因此,肾脏血流量和GFR之间的动态变化是造成肾脏功能损伤的主要因素。氧化应激是缺血再灌注过程中主要的心肌损伤机制,同时其也被认为能够导致肾脏功能损伤。CPB过程中缺血再灌注损伤加剧氧化炎性反应从而促使循环中游离铁含量增加。游离铁对于肾小管上皮细胞功能产生影响包括破坏细胞增殖以及诱导自由基损伤。此外,缺血再灌注损伤消耗细胞内高能磷酸盐,诱发钙沉积,氧自由基生成,细胞因子活化进而导致上皮细胞损伤进而造成肾脏自调节功能缺失,对于缩血管药物和一氧化氮的敏感度下降［15,22］。

1.3 CPB术后肾脏损伤风险因素 术前因素分析中,年龄、性别、术前肾功能状态、心脏射血分数、急诊手术和糖尿病可以作为主要风险因素［24］。除此以外,患者于术前所接受的药物因素也对于CPB术后的肾功能状态产生影响。回顾性研究指出,术前接受血管紧张素转化酶抑制剂(angiotensin converting enzyme inhibitors,ACEI)/血管紧张素Ⅱ受体阻滞剂治疗的患者CPB术后肾功能损伤的发病率显著升高［25-27］。而与之形成对比的是,在 CPB下行CABG的患者中,ACEI因素却与术后肾功能损伤的发病率呈负相关［28］。而对于术前给药他汀类和阿司匹林治疗的患者,其在CPB术后的肾功能损伤未见有显著统计学意义［29-31］。

CPB术中和术后存在多种风险因素被证实与CPB术后肾脏功能损伤具有相关性。首先,在CPB术中红细胞的破坏具有显著意义。CPB术中游离血红蛋白或是游离肌红蛋白释放入血以及瓣膜置换、输血等机械性破坏因素均会导致红细胞膜稳定性被减弱。CPB的红细胞破坏效应随着CPB运行时间的延长而加剧。其次,Chiravuri等［31］指出,低龄、重复多次阻断以及手术时间延长与术后肾脏损害或是功能衰竭存在相关性。再次,CPB术中的尿量水平也被发现与肾脏功能损伤之间具有关联性。有研究指出,术中尿量低于4 ml/(kg·h)患者中术后肾功能损伤的发病率显著增加具有统计学意义,由此可见,CPB术中尿量对于术后肾脏功能损伤具有预测效应。此外,包括乳酸水平和心脏疾病的类型与CPB术后的肾脏损伤之间也存在相关性,CPB术中乳酸最大浓度超过6 mmol/L,以及紫绀型先天性心脏病患儿行CPB手术后肾脏功能损伤的发病率显著增加且具有统计学意义［32］。除常规手术外,对于复杂性心脏手术中风险因素的评估也有所报道。在全主动脉弓选择性脑灌注深低温停循环的大血管手术中(25℃),术后肾脏功能损伤组相比较于非损伤组,手术时间、CPB时间、停循环时间以及脑流量灌注时间均显著延长［33］。其中,停循环时间超过60 min以及术前患者合并基础慢性肾脏疾病是主动脉大血管CPB术后并发肾脏功能损伤的独立因素。此外,Kahli等［34］在CABG患者中进行肾脏功能评估中发现,相比较于传统的方式,生长分化因子15更能够有效预测冠状动脉粥样硬化性心脏病患者CPB手术的肾脏功能的预后结局。

术后管理过程中,ICU时间延长的潜在风险也不容忽视。Ruf等［35］在婴幼儿CPB手术中和术后使用肾脏近红外分光光谱仪评估局部血氧定量和急性肾功能损伤发展之间的关系中发现,术后24小时高乳酸水平、24小时低静脉血氧饱和度、低血压以及大剂量血管升压药物均是具有意义的风险因素。

2 诊疗

2.1 肾功能损伤标记物 相关标记物在肾功能损伤的诊疗中具有极为关键的作用。目前,血肌酐和尿素氮是常规的肾功能检测指标,但是二者在敏感度和特异性方面均存在一定的限制性,使得其在应用方面的价值受到影响。因此,近年来新型简易经济的标记物逐渐被发掘并用于CPB术后早期肾功能损伤的诊断中,包括中性粒细胞明胶酶相关载脂蛋白(neutrophilgelatinaseassociatedlipocalin,NGAL),肝脏型脂肪酸(L-type fatty acid-binding protein,L-FABP)和胱抑素C(cystatin C,Cys C)等。当前的研究多围绕CPB术后上述标记物之间比以及与常规肾功能指标之间的效应对比,并由此了解其在CPB术后对于预测肾功能损伤的优势。其中,在NGAL和L-FABP的对比性研究中发现,CPB术后即刻,对比于非肾功能损伤组,肾功能损伤组中L-FABP显著升高,而在术后3小时,两项指标均显著升高。但是由于NGAL在术后3小时的受试者工作特征曲线面积显著高于L-FABP,故前者对于诊断CPB术后早期肾功能损伤意义更大［36］。在与肌酐的对比研究中,NGAL提前数小时至数天能够体现出CPB术后肾功能损伤状态［37］。Fatina等在儿科心血管手术的研究中发现,NGAL在CPB术后2小时即显著升高且持续至术后24小时,由此可见,NGAL可以作为CPB术后早期肾脏功能损伤较为理想的标记物［38］。 Seitz 等［39］的研究中,将NGAL和Cys C在CPB术后对于肾脏损伤评估的敏感度和特异性进行对比,结果发现,相比较于NGAL,Cys C在CPB术后肾脏损伤的预测效应方面更具优势,CPB术后2小时Cys C水平达到0.995 mg/L时,急性肾功能损伤的结局基本明确。Herbert等［40］对于1岁以内先天性心脏病患儿的CPB术后以NGAL为参照,将肌酐和Cys C的敏感度和特异性进行对比,结果显示,在NGAL阳性的肾脏损伤病例中,相比较于肌酐,Cys C的特异性具有显著优势。在Cys C与肌酐的对比研究中发现,Cys C的预测效应不如肌酐显著且水平变化的时间滞后于肌酐,但是Cys C水平异常的急性肾功能损伤患者中不良预后的发生率更高［41］。此外,部分细胞炎性因子如IL-6和IL-8也被证实在CPB术后肾功能损伤的预测中发挥不同程度的作用［42-43］。除新近的检测标记物外,较为传统的检测指标仍然发挥着一定的作用,如尿蛋白测试,虽然是肾功能评估的早期手段,但是由于其操作成本低且结果易于获取,所以在临床实践中也占据重要的地位。不过,在队列研究中发现,各年龄组患儿中尿蛋白水平无显著差异,仅在更为年少的患儿中有所升高［44］。上述的研究群体主要集中于儿科患者,各种标记物针对成人患者的临床意义还需要相关研究材料支持。在目前的临床实践中,不同标记物的联合应用正逐渐成为趋势。

2.2 防治 近年来,远端缺血预处理(remote ischemic preconditioning,RIPC)的概念被广泛提及。心脏外科手术的不良预后主要与术中心肌损伤相关,因此,多项研究着眼于通过RIPC方式降低心肌损伤和缺血的发病率。Zarbock等［45］在临床研究中发现,经RIPC组的患者术后72小时内肾功能损伤的发病率显著低于对照组。RIPC对于2期和3期肾功能损伤的控制效果更为显著。另外,在CPB术中利用超滤装置将过量液体排出体外改善心肺功能。维持较高水平的灌注压力,肾脏自调节功能通常在灌注压力降至80 mm Hg左右时启动。为避免血液的过度稀释,CPB术中HCT维持在0.24以上。

治疗方面,营养支持的重要性显而易见,肾功能损伤患者治疗期间所需的目标能量为20～30 kcal/(kg·d)［46］。如果病情严重需要进行持续肾脏替代治疗(continuous renal replacement therapy,CRRT),则有必要以补充蛋白的形式予以提供高能量摄取［47］。肾功能损伤患者需要严格控制葡萄糖的摄取量以避免高血糖,Oezkur等［48］的研究中发现,高血糖水平合并糖化血红蛋白(HbA1c)超过6.0%时,CABG术后肾功能损伤的发病率显著增加。肾功能重度受损患者接受CRRT治疗有利于纠正高钾血症以及酸中毒并代谢体内过剩液体。在临床研究中,对于CPB术后肾功能损伤患者早期进行CRRT治疗能够降低死亡率并缩短住院时间［49］。此外,相比较于间断的肾替代治疗,CRRT的优势在于维持血流动力学的稳定性［50］。

药物层面,促红细胞生成素(erythropoietin,EPO)主要在肾脏中合成,作用在于调节造血功能。除造血功能调节功能外,EPO还被发现具有通过抗氧化、抗炎症和抗凋亡效应防止缺血再灌注损伤的效应,其是改善肾脏损伤的代表成分［51-52］。Kim等［53］在诱导麻醉后静脉予以重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)-α给药,剂量300 IU/kg,对照组则是同时予以等量生理盐水。然而,结果表明,rhEPO单一给药并未降低术后肾脏功能损伤的发病率,分析原因在于样本量并不充分进而导致肾脏损伤发病率低于预期,而其次rhEPO组中患者合并糖尿病,而糖尿病则能够拮抗rhEPO对于组织的保护效应［54-55］。另外,万汶的使用对于研究结果产生干扰,因为羟乙基淀粉溶液易于加重肾脏功能恶化［56］。 Liu 等［57］的研究表明,5 000 U/kg的rhEPO预处理可以有效调节选择性Ca2＋通道瞬时受体电位阳离子通道蛋白6及其信号传导通路活化T细胞核转录因子1在肾小球中的表达水平进而控制CPB肾脏功能损伤［58］。在CABG患者的随机对照双盲研究中,以等量rhEPO和生理盐水进行预处理,术前三天剂量为200 U/kg,术中为100 U/kg,观察结果显示,rhEPO的预处理组中患者尿NGAL水平显著降低临床预后得以改善［58］。

此外,较为常用的是非洛多泮,作为选择性多巴胺受体激动剂,其低剂量使用时能够在不改变血压的情况下改善肾脏灌注。Caimmi等［60］研究中分别在CPB过程中以及术后早期予以小剂量非洛多泮0.1～0.3 μg/(kg·min)观察肾脏功能的改善效应。结果显示,对于拟行手术治疗的肾脏功能受损患者,非洛多泮静脉用药有助于改善术后肾功能。

其它辅助药物方面的评估研究中,Narin等［61］提出在CPB过程中多巴胺［2 μg/(kg·min)］联合甘露醇(1 g/kg)使用对于预防术后肾功能不良事件效果更为理想。动物CPB模型中发现,提取于绿色蔬菜中的萝卜硫素具有良好的抗炎效应。其对于CPB术后肾脏功能的保护机制主要是抑制淋巴细胞中的炎性反应信号通路［62］。右美托咪定由于能够有效抑制超氧化物歧化酶活性,因此,其在CPB术中以及术后使用均能取得满意的肾脏保护作用［63-64］。不过,部分药物的疗效并未达到预期水平。Le等［65］对于CPB术后6小时患者予以重组人脑钠肽(recombinant human B-type natriuretic peptide,rhBNP)静脉用药,剂量 0.0075～0.01 μg/(kg·min),持续72 h,结果显示,相比较于对照组,rhBNP组患者的CPB术后肾脏功能得到显著改善,但是两者间的预后无统计学差异。不过,对于CPB中常规药物乌司他汀,其在肾脏保护中的效应并未得到肯定。在术前肾功能正常的患者接受主动脉瓣置换手术中,分别在诱导麻醉后,CPB转流开始时以及停机后予以乌司他汀给药,其中转流开始时给药40万单位,而诱导麻醉和停机时均给药30万单位,结果显示,乌司他汀对于CPB术后肾功能的改善不具有统计学意义［66］。

3 展望

总而言之,肾脏损伤是CPB手术常见的并发症。如何在CPB过程中采取有效的肾脏保护是当前CPB领域中的热点问题。多种药物和技术手段的相继应用极大程度缓解肾脏功能损伤与破坏。但是,其中存在的问题也不容忽视,如药物是否存在不良反应,CPB时间和温度的控制在特定环境中是否能够执行,部分手段还处于动物实验阶段尚不完善等。远期还需要针对CPB肾脏损伤更为微观的层面开展,对于损伤的分子甚至基因机制进行有效的研究以期进一步控制CPB相关损伤的发生。

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