中华急诊医学杂志  2019, Vol. 28 Issue (9): 1066-1070   DOI: 10.3760/cma.j.issn.1671-0282.2019.09.002
“肾”事风云——再谈急性肾损伤的基础与临床研究
吴淡森 , 石松菁     
福建省立医院重症医学二科,福州 350001

急性肾损伤(acute kidney injury, AKI)作为常见的临床症候,与重症患者的不良预后密切相关。AKI以肾功能迅速恶化为特征,是危重症常见的并发症[1],也是造成危重症患者死亡的主要原因之一,AKI患者病死率是未发生AKI患者的2~5倍[2]。高发病率、高病死率、高医疗费用、预后差等特点,使AKI成为一个备受关注的健康问题[3]。因此,阐明其发病机制,早期诊断,提高治疗效果,降低病死率及终末期肾脏病(end stage renal disease, ESRD)比例,具有重要的临床意义。

1 AKI发病机制进展

传统观点认为,心输出量和(或)血压下降,导致肾脏灌注减少,同时引起ATP耗竭,能量代谢障碍进一步导致急性肾小管坏死,脱落的肾小管上皮细胞堵塞肾小管,以及原尿经裸露的肾小管壁通过“反流”机制回吸收入血,导致肾小球滤过率显著下降和肾功能延迟恢复,被认为是AKI的主要发病机制。目前研究发现,炎症反应也参与了AKI发生和发展:⑴肾小管上皮细胞变性、坏死、脱落,释放肿瘤坏死因子-α(TNF-α)、单核细胞趋化蛋白-1(MCP-1)、白介素-1(IL-1)等因子,活化T细胞,导致炎症反应放大,加重损伤[4-5];⑵肾小管间质的微血管内皮功能及结构受损[6];⑶线粒体的适应性反应[7]。因此,需要更多的基础与临床研究,充分明确AKI病理生理过程,更好地了解炎症反应的作用,以便尽早采取最适宜的干预措施来减少AKI发生,以及减少远隔器官损伤,提高生存率。

2 AKI早期诊断与新型生物分子

早期诊断是AKI治疗的关键。AKI病程早期是可逆的,但治疗窗较窄[8]。一旦进入损伤期,终点事件(死亡或尿毒症)发生率超过30%[9]。基于此,改善全球肾脏病预后组织(Kidney Disease: Improving Global Outcomes, KDIGO)2012年发布临床指南[10],目的是早期诊断AKI,降低漏诊率[8]。然而,血清肌酐(serum creatinine, sCr)易受多种因素影响,不能正确反映AKI过程中肾小球滤过率(glomerular filtration rate,GFR)变化。尿量也易受利尿剂、尿路梗阻等因素影响。两者作为诊断与分期指标,不能及时准确地反映肾功能。因此,有待进一步研究以发现监测肾脏早期损伤的敏感特异性指标。

过去的十几年,人们致力于发现和验证新标志物,以期能找到评估病理生理的特征性生物分子,提高早期诊断率。有研究者尝试将白介素-18(IL-18)[11]、肾脏损伤分子-1(kidney injury molecule 1, KIM-1)[12]、尿谷胱甘肽S转移酶(glutathione-S-transferases, GSTs)[13]、富半胱氨酸肝素结合蛋白61(cysteine-rich protein 61,Cyt61)[14]等用于早期诊断。尽管在许多动物实验及小规模Ⅰ期临床试验中取得了很大进展,但仍需要在不同病因和临床情况基础上,通过大规模、多中心的临床试验来验证其有效性及实用性。

近年来,随着腹部MRI技术发展,一些功能磁共振成像(functional magnetic resonance imaging,fMRI)技术被用于评估肾组织灌注、肾组织氧合、肾间质弥散以及细胞代谢和分子表达等,如磁共振弥散加权成像(diffusion-weighted imaging,DWI)、弥散张量成像(diffusion-tensor imaging,DTI)和血氧水平依赖成像(blood oxygen level dependent,BOLD)等。研究发现,fMRI可以识别AKI的肾脏灌注和组织水肿情况[15]。DWI可早期识别AKI的发生[16]。BOLD能敏感且可靠地反映急性肾缺血[17],但这些研究还没有在临床患者中得到有效的证实。

3 AKI防治现状

理论上肾脏替代治疗(renal replacement therapy, RRT)利于维持血流动力学稳定及内环境稳态,提高生存率[18]。但RRT存在导管感染、出血等风险,且患者的液体管理存在个体差异。因此,寻找理想的新治疗方法是目前AKI相关研究的难点及突破口。

3.1 液体管理

传统观点认为,血容量不足是AKI的高危因素。积极补液治疗有利于维持有效的心输出量,保证肾脏灌注,同时配合利尿剂能够促进肾脏对代谢毒物的排出[8]。然而不恰当的快速和过量补液可增加肾间质水肿和肾实质压力,加重AKI[19]。采用包括平均动脉压(MAP)、中心静脉压(CVP)在内的早期目标导向治疗不能预防脓毒症患者的AKI发生[20-22]。然而采用限制性扩容策略则可减少其发生,且额外的液体并不能增加尿量[23]。临床上对AKI和AKI高风险者,强调个体化的液体输注。AKI预防及治疗过程中,应监测CVP、肺动脉楔压(PCWP)以及其他动态指标如动脉血压变异率(PPV)、每搏量变异(SVV)等,综合评估患者对容量的反应性。

3.2 药物治疗

正如KDIGO指南所描述:没有药物被推荐用于治疗和预防成人AKI[10]。但是,一些有前景的药物在动物实验中仍取得一定进展[24]。多西环素能防止肾缺血-再灌注损伤激活的氧化应激,同时抑制金属蛋白酶(matrix metalloproteinase,MMP)活性,抑制促炎因子产生和细胞凋亡[25],还可通过增加肾小球滤过和肾小球上皮钠离子移动以保护肾功能[26]。谷胱甘肽是参与防御氧化损伤的重要物质。在肾缺血-再灌注损伤中,谷胱甘肽的消耗、丙二醛的增加均提示脂质过度氧化[27-28]。线粒体靶向抗氧化剂SKQRI可预防肾血管功能障碍和保护内皮细胞损伤[29-30]。含锰的CORM-401(一氧化碳释放因子)可以有效地输送一氧化碳,减少炎症反应及氧化应激[31]。然而,上述结果仅仅是在动物实验中获得,缺少临床试验依据。

3.3 肾脏替代治疗

RRT承担着重症AKI治疗重任。但RRT最佳治疗时机仍具有争议,主要是由于肾功能能否恢复以及何时恢复的不确定性。因此,KDIGO指南推荐:当出现威胁生命的水、电解质与酸碱平衡紊乱时,应急诊RRT;如无急诊RRT指征,则视临床状况而定,而不是根据单一血尿素氮(BUN)和肌酐(Cr)值决定RRT时机[10]。AKIKI研究结果显示,RRT时机选择并不影响AKI患者60 d病死率[32]。而ELAIN研究结果显示,早期RRT能降低AKI患者90 d病死率;超早期的连续性血液透析滤过(continuous veno-venous hemodialysis filtration, CVVHDF)可使中度AKI患者获益[33]。这两项研究在设计、纳入人群等方面均有很多不同,武断地将两组研究结果进行比较,可能会误导临床决策[34]。个体、精准化的滴定治疗可能是未来急危重症AKI的RRT方向。

以精准连续肾脏替代疗法(continuous renal replacement therapy,CRRT)为主题的第17届ADQI会议[35]推荐:⑴当代谢和液体需求超过肾脏功能时应开始RRT,供需平衡是关键;⑵对肾脏需求取决于非肾脏性合并症、急性疾病严重程度、溶质和液体负荷程度;⑶通过肾损伤指标预测肾功能变化;⑷每天至少评估1次肾脏供需失衡的变化;⑸多脏器支持状态下,RRT时机需要与其他治疗综合考虑;⑹决定开始治疗后, 应在3 h内尽快开始。这或许给RRT治疗时机选择带来了曙光。

至于哪种RRT治疗模式会获得更好的临床预后仍存在争议。观察不同RRT治疗模式对AKI结局的影响比较复杂,因为选择CRRT或延长透析治疗时间的患者可能因为疾病更为严重并且血流动力学不稳定,导致队列研究的观察对象存在选择性偏倚[36]。设计合理、入选标准严格的前瞻性临床研究是今后需要开展的。

3.4 治疗新方法 3.4.1 细胞疗法

目前细胞疗法治疗AKI的研究仍处于动物实验阶段[37-39]。间充质干细胞(mesenchymal stem cell,MSC)被认为是预防或治疗AKI的细胞疗法中最有前景的细胞之一[40-41],主要机制是MSC的旁分泌及免疫调节功能[42-43],抑制邻近细胞的凋亡和诱导细胞增殖,促进受损肾细胞的再生。此外,MSC还可改善肾动脉灌注[45]。目前MSC治疗AKI的循证证据尚少,需要更多的临床试验以确定其效果。

3.4.2 microRNA

有研究发现,microRNA表达变化调控肾细胞的增殖与凋亡,且与AKI发生发展有关。microRNA作为一类调节因子,在AKI发病机制中的重要性首次在转基因小鼠模型(肾近端小管特异性基因组缺失Dicer酶)中得到了证实。基因敲除小鼠肾皮质内microRNA表达下调,肾功能明显改善,AKI减少,生存期延长[46]。miR-21能够抑制缺血-再灌注后的肾小管上皮细胞凋亡并促进其增殖[47]。此外,miR-101-3p,miR-127-3p,miR-210-3p,miR-126-3p,miR-26b-5p,miR-29a-3p,miR-146a-5p,miR-27a-3p,miR-93-3p和miR-10a-5p具有判断危重症AKI患者预后的潜力[48-49]。研究microRNA与AKI的关系,将为理解AKI发病机制和进展过程提供新角度,并可能成为AKI新的诊断标志物及治疗靶点。

3.4.3 缺血预处理(ischemic preconditioning,IPC)

IPC是指先将器官暴露于非致死缺血中以保护其免于随后的缺血性损伤。肾缺血预处理是一种通过间断夹闭肾门(或肾动脉)从而出现多个缺血-再灌注-缺血的循环,机体上调保护机制,诱导器官耐受,适应随后的缺血性损伤[50-51]。研究表明,远端缺血预处理(remote ischemic preconditioning,rIPC)可预防造影剂急性肾损伤[51],也可通过促进扩血管物质释放而发挥肾功能保护作用[52]。此外,缺血后处理(postconditioning,POC)也可以明显改善肾功能[53],可能与核转录因子红细胞系相关因子2(Nrf2)激活有关[53-54]。然而,并非所有IPC都可以防止缺血性损伤,这取决于机体的适应性机制[53]。遗憾的是,这些保护性策略的有效性缺乏大型临床研究验证[55]

4 未来研究方向

AKI不容忽视,早期诊断对于AKI防治尤为重要。缺血-再灌注、氧化应激、炎症反应等可能参与AKI发生与发展。基于以上机制开展的药物研究正在有序进行,有望成为AKI治疗的新希望。另外,一些新兴的治疗方法,如细胞疗法、基因疗法、远端缺血-再灌注拥有良好的前景,可能具有改变疾病进程的潜力。AKI治疗方法的机制并非相互独立的,而是相互影响、相互促进,应更多地强调多种疗法的综合化和个体精准化。

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