Research progress on molecular markers related to the donor kidney injury from organ donation after citizen's death
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摘要: 供肾短缺是肾移植面临的一大难题,对供肾功能的准确评估可以降低器官的弃用率,以挽救更多的尿毒症患者。与病理学检查相比,循环中的分子标志物检测在临床应用中较为方便。本文就目前已发现的肾损伤标志物血清肌酐和血清胱抑素C(Cys-C)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)、肝型脂肪酸结合蛋白(L-FABP)、线粒体DNA(mtDNA)、肾损伤分子-1(KIM-1)和白细胞介素-18(IL-18)等方面的研究进展进行简要介绍。
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关键词:
- 肾移植 /
- 分子标志物 /
- 扩大标准供者 /
- 线粒体DNA /
- 血清胱抑素C(Cys-C) /
- 中性粒细胞明胶酶相关脂质运载蛋白(NGAL) /
- 肝型脂肪酸结合蛋白(L-FABP) /
- 肾损伤分子-1(KIM-1)
Abstract: Shortage of donor kidney is a major problem in renal transplantation. Accurate evaluation of donor kidney function may reduce the organ rejection rate and save more patients with uremia. Compared with pathological examination, detection of circulating molecular markers is more convenient in clinical application. In this article, the research progress on the markers of kidney injury, such as serum creatinine, serum cystatin C (Cys-C), neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), mitochondrial DNA (mtDNA), kidney injury molecule-1(KIM-1) and interleukin -18 (IL-18), were briefly reviewed. -
对于终末期肾病的患者,肾移植是最有效、最经济的治疗方法。然而,每年登记需要行肾移植术的患者数量远远大于供者数量,并且这种差距还在逐步扩大。另外,随着我国人口的老龄化,扩大标准供者(expanded criteria donor,ECD)在所有供者中占的比例越来越高,这种现象增加了临床医师判断供肾功能好坏的难度,也增加了供肾的弃用率。目前关于供肾功能评估的指标有很多,但是相关研究显示各指标的评估价值差异性较大,因此,寻找到合适的指标评估供肾功能,对于临床工作具有重要的意义。本文就评估供肾损伤的相关分子标志物进行综述,并介绍近期相关研究进展。
1. 血清肌酐和血清胱抑素C
血清肌酐一般认为是内生肌酐,是人体肌肉的代谢产物,释放到血液后随尿排泄。肌酐是小分子物质,可通过肾小球滤过,在肾小管内很少重吸收,每日体内产生的肌酐,几乎全部随尿排出。因此,肌酐基本符合内源性肾小球滤过率(glomerular filtration rate, GFR)标志物的要求,现国内外仍用血清肌酐作为临床供肾功能评估的常用指标。但只有GFR下降1/3~1/2时,血清肌酐才会出现明显的变化,而且当肾损伤到一定的程度后,血清肌酐对肾损伤程度的反应性较差;此外,血清肌酐受患者的年龄、性别、肌肉含量等的影响较大[1],个体之间差异较大。因此,血清肌酐虽然可以提示肾损伤,但反映肾损伤程度的灵敏度和特异度均较差,并不是评估肾功能的理想指标[2]。血清肌酐的测定虽然存在着一定的局限性,但目前仍然作为一个反映肾损伤的常用指标广泛应用于临床。
近年来,血清胱抑素C(serum cystatin C, Cys-C)被认为是临床上判断肾功能较理想的指标[3]。Cys-C是一种低分子量蛋白质,广泛存在于各种组织的有核细胞和体液中,Cys-C基因属于“管家基因”,在所有的有核细胞中表达,无组织学特异性,因此机体Cys-C的产生率非常固定。肾脏是清除Cys-C的唯一器官,Cys-C在肾小球自由滤过,在肾小管重吸收并降解。Cys-C和血清肌酐相比,不受患者年龄、性别以及肌肉含量的影响,是一种比较理想的反映肾损伤的标志物[4]。
对于急性肾损伤(acute kidney injury,AKI)的患者,Cys-C与血清肌酐相比,能否更准确地反映肾功能的变化,并未得到广泛的认可[5]。研究表明,供者的血清肌酐和Cys-C水平与肾移植术后受者移植物功能延迟恢复(delayed graft function,DGF)的发生率相关[6-9],但是相关的研究结论差异性较大,血清肌酐和Cys-C与供肾损伤的相关性还有待商榷。
2. 中性粒细胞明胶酶相关脂质运载蛋白
中性粒细胞明胶酶相关脂质运载蛋白(neutrophil gelatinase-associated lipocalin,NGAL)是1993年在研究中性粒细胞明胶酶时发现的一种相对分子量为25 000的蛋白质[10],属于lipocalin家族的成员,在正常情况下表达较低,但在各种原因导致的肾损伤时,NGAL大量表达于缺血的近端肾小管上皮细胞[11]。同时,它可以诱导浸润在肾小管间质的中性粒细胞凋亡并且促进肾小管上皮细胞再生,在肾损伤时起到保护性的作用[12]。既往的研究发现,对于心脏手术后出现AKI的患者,血液和尿液中的NGAL和术前相比明显升高,并且和患者肾损伤程度直接相关[13]。不仅如此,在肾毒性的相关性研究中也发现,NGAL可以早期预测肾损伤的程度和患者的转归[14]。在急性肾衰竭的动物模型中也得到类似的结论,小鼠肾脏缺血2 h后即可在尿液中检测到NGAL,并且与肾脏缺血时间呈正相关[15]。
NGAL在肾移植领域的研究主要集中于预测尿毒症患者术后的恢复情况,2015年Cui等[16]在肾移植的研究中发现,检测肾移植术后受者尿液中的NGAL可以早期反映肾脏的恢复情况,准确地预测DGF的发生。2017年,Moledina等[17]通过对581例供者的血尿标本研究发现,供者尿中的NGAL水平对于诊断急性肾小管损伤的准确性较低,但是与血清肌酐相比,NGAL对于肾损伤的预测价值明显较高,与其他指标相比,NGAL具有相对较高的诊断价值。2016年Koo等[18]通过检测供者尿液中的NGAL水平预测DGF的发生,其受试者工作特征(receiver-operating characteristic,ROC)曲线下面积可达0.758,证明可以通过供者尿液中的NGAL水平判断肾损伤程度进而预测受者的转归,这对NGAL的临床应用起到一定的推广作用[19]。Hollmen等[20]亦发现,与供者NGAL水平 < 18 ng/mL对应的受者相比,供者尿液中的NGAL水平 > 18 ng/mL对应的受者肾移植术后DGF发生率更高,而且移植肾术后1年存活率也明显更低。
3. 肝型脂肪酸结合蛋白
肝型脂肪酸结合蛋白(liver-type fatty acid-binding protein, L-FABP)属于脂肪酸结合蛋白的家族成员之一,是一种相对分子量为15 000,可以结合长链脂肪酸的高保守性胞质蛋白。L-FABP主要表达于人的肝脏、肾脏、小肠和胰腺等组织细胞中,主要功能包括脂肪酸的摄取、转运和代谢。近年来研究表明L-FABP与AKI以及移植物的存活有关。
在肾脏中,L-FABP主要由近端肾小管产生,并且反映肾小管间质的损伤程度[21]。AKI患者由于血流动力学的改变,导致单核细胞过度激活,L-FABP分泌增多;同时,由于L-FABP羟基末端含有糖蛋白结合区域,诱导下游细胞对于肾间质的浸润,进而加重AKI[22]。在一项针对L-FABP和AKI关系的研究中,对92例AKI和62例无AKI的患者进行横断面研究发现,L-FABP对于AKI的诊断价值极高,其ROC曲线下面积可达0.93,并且L-FABP的值越高,患者肾脏的恢复越差[23]。Matsui等[24]的研究发现,在接受心脏手术的患者发生AKI前的30 h,尿液中的L-FABP水平即明显升高,说明L-FABP可以早期预测肾小管的损伤程度。L-FABP的敏感性可以帮助我们对供肾质量进行早期评估,也将有助于预测受者术后排斥反应。
在肾移植领域,Koo等[18]通过检测供者尿液中的L-FABP水平对供肾功能进行判断,并预测肾移植术后受者的恢复水平,其ROC曲线下面积可达0.704,相对于血清肌酐是一个较好的预测指标。2016年,Reese等[25]通过对1 304例供者的尿液标本进行检测,发现L-FABP与AKI的发生具有很强的相关性,相对危险度(relative risk, RR)为7.28;对于肾移植术后受者,L-FABP仅与未出现DGF的受者术后6个月的肾功能呈线性相关,而对于预测DGF发生率和移植肾的存活率不具有任何意义。也有部分学者对术后受者尿液中的L-FABP进行检测,例如Pajek等[26]通过检测肾移植术后受者尿液中的L-FABP水平,预测受者DGF的发生率,其ROC曲线下面积可达0.85,提示L-FABP对于肾移植术后受者的肾功能恢复预测价值较大。目前L-FABP在供肾功能评估的研究中,得出的结论差异较大。
4. 线粒体DNA
线粒体是细胞内的细胞器,主要功能为参与三磷酸腺苷(adenosine triphosphate,ATP)的合成,它包含了多种线粒体DNA(mitochondrial DNA, mtDNA),并且对于缺氧非常敏感[27]。mtDNA位于线粒体基质中,是一种环状双链DNA分子,对多种蛋白质进行编码,包括与转移和核糖体RNA相关的蛋白质,以及参与氧化磷酸化的蛋白质[28]。当线粒体受到损伤时,mtDNA会裂解成片段,释放到细胞的胞浆中,然后进入到外周血液循环[29]。既往的研究表明,当机体受到外伤时,外周血液循环中的mtDNA含量明显增加[30]。mtDNA在高血压肾病中也有一定的预测作用[31]。在AKI的动物模型中发现,尿液中的mtDNA含量和血清肌酐水平呈正相关[32],并且肾损伤越严重,尿液中的mtDNA含量越高,这些证据表明,mtDNA含量和肾损伤相关。
2019年孙启全课题组在《Transplantation》中发表论文,mtDNA可以作为供肾功能判断的一个指标,并且能准确地预测患者的恢复情况,在预测AKI时,ROC曲线下面积可达到0.703[33]。对DGF的预测建立相关计算模型发现,mtDNA单独对DGF的预测,ROC曲线下面积可达0.880;通过模型预测,ROC曲线下面积可达0.930。肾损伤越严重,外周血mtDNA含量越高,尤其是肾移植术后出现原发性无功能(primary non-function, PNF)的受者,对应的供者外周血mtDNA含量越高。研究显示,当mtDNA含量 > 0.243时,DGF发生率为100%;当mtDNA含量 > 0.285时,PNF的发生率可高达80%[34]。mtDNA的应用,有助于临床医师判断供肾的功能,有望减少肾脏的弃用率。当然,mtDNA的临床价值还需要更多的研究进行证实。
5. 肾损伤分子-1
肾损伤分子-1(kidney injury molecule-1, KIM-1)是1型跨膜糖蛋白,属于免疫球蛋白基因超家族,在正常肝、肾、脾中微量表达。在正常的肾组织中检测不到KIM-1,而在人类和啮齿类动物发生肾损伤(缺血或中毒)时,其高表达于近端肾小管[34]。KIM-1的胞外域非常稳定,能在尿液中保存较久,因此在肾损伤时,可以在病理组织以及尿液中检测到[35]。KIM-1对于缺血性或肾毒性肾损伤更为特异,不受氮质血症、尿路感染或慢性肾病的影响[36]。KIM-1可作为一种检测早期肾损伤的可靠分子标志物,在临床上具有广阔的应用前景。
KIM-1在AKI中的研究是过去几十年的热点之一,其在AKI中的预测作用已经被大量的研究证实。既往的研究发现,当肾损伤时,KIM-1表达量明显升高,并于24 h内达到高峰[37]。Liangos等[38]证明,尿液中的KIM-1水平不仅与肾损伤相关,也与患者肾脏的预后相关,患者尿液中的KIM-1水平越高,死亡或者透析的发生率越大。由于KIM-1的特异度和灵敏度较高,病理组织的KIM-1染色也常常用于判断肾损伤程度。
在肾移植领域,KIM-1病理学检查常常用于判断供肾的损伤程度,对AKI的诊断价值较高,但是通过其在尿液中的水平去判断供肾的质量以及患者的预后价值较低。2019年Koyawala等[39]在《Transplantation》上发表论文,对1 298例供者的尿液标本进行检测,得出与血清肌酐相比,KIM-1对AKI的诊断价值更高,但是与肾移植术后受者的恢复无相关性的结论。最近的一篇Meta分析也指出,通过对15 345例供者的数据分析发现,AKI和非AKI的供肾与肾移植术后移植肾的存活并没有相关性[40]。因此,建议临床医师可以考虑其他影响肾脏存活的供、受者因素,而不是通过KIM-1进行预测。
6. 白细胞介素-18
白细胞介素-18(interleukin -18,IL-18)是一个相对分子量为22 000、具有多种功能的促炎症细胞因子,主要由活化的T细胞、B细胞、自然杀伤(natural killer,NK)细胞等分泌产生,并与多种肾脏疾病、自身免疫性疾病的发生发展密切相关[41]。IL-18是一种前细胞因子,随后被caspase-1酶裂解成为多蛋白复合物的一部分,它和IL-1β具有相同的成熟途径[42]。成熟的IL-18通过IL-18受体-α /辅助蛋白-异源二聚体发出信号,从而促进炎症[43]。它通过核因子(nuclear factor,NF)-κB途径促进急性损伤,诱导其他炎症介质[包括肿瘤坏死因子(tumor necrosis factor,TNF)-α和诱导性一氧化物合酶(inducible nitric oxide synthase,iNOS)以及趋化因子单核细胞趋化蛋白(monocyte chemotactic protein,MCP)-1和巨噬细胞炎症蛋白(macrophage inflammatory protein,MIP)-2]的上调,这些因子驱动肾内巨噬细胞和中性粒细胞的浸润[44]。在异常情况下,IL-18的升高可能会给机体带来负面的影响,导致疾病加重或组织损伤。IL-18可能在慢性肾衰竭的代谢紊乱和免疫紊乱中起重要作用,肾间质纤维化是各种疾病发展成肾衰竭的共同途径,IL-18可促进肾小管上皮细胞的凋亡从而引起间质纤维化。由于各种原因(缺血-再灌注损伤、药物毒性等)导致肾损伤时,IL-18会高表达并随着尿液排出。已有研究证实,在AKI动物模型中,阻断IL-18信号传导途径的靶向疗法可以减轻肾损伤[45]。实际上,在AKI缺血-再灌注损伤模型中,用外源IL-18结合蛋白进行的预处理已显示出对肾脏的保护作用[46]。对于心脏手术的患者,术后0~6 h尿液中的IL-18含量 > 60 pg/mL时,对于AKI的预测价值较高,灵敏度和特异度分别为0.54和0.82 [47]。
因此有学者通过研究IL-18判断供肾质量并预测肾移植术后受者的恢复情况。但通过供者尿液中的IL-18预测受者的预后,并未得出有效的结论。多项研究表明,IL-18和供肾的AKI相关,但是不能作为受者术后的预测指标[17, 39]。亦有研究报道,肾移植术后受者尿液中的IL-18可能和移植肾的存活相关[48]。
7. 小结
除上述的标志物之外,还有一些其他的标志物对供肾损伤的判断也有一定的作用,比如血管紧张素原、金属蛋白酶2组织抑制剂(tissue inhibitors of metalloproteinases-2,TIMP-2)、胰岛素样生长因子结合蛋白7(insulin-like growth factor-binding protein 7,IGFBP7)等[49-51],相关的分子标志物在AKI中的研究较多,但在供肾功能判断的研究中并未发现相关文献报道。
综上所述,对供肾损伤评估的指标有很多,然而各种指标的研究结果差异性较大,其中mtDNA的检测有望广泛地应用于临床,帮助临床医师判断供肾损伤。
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