第八章　肾脏损伤与修复

第一节　肾脏损伤的定义及分类

肾脏损伤是指由内源性或外源性因素所引发的肾脏结构和/或肾脏功能受损。其发病机制涉及免疫反应及非免疫反应。

肾脏损伤种类多样，根据病程、病因及严重程度进行分类。按病程长短可分为：急性肾损伤，慢性肾脏病；按病因可分为原发性肾脏疾病，继发性肾脏疾病；其中继发性肾脏疾病因致病因素不同，可细分为以下种类：外伤所致肾损伤、药物性肾损害、梗阻性肾损害、环境或职业因素所引起的肾损害、感染性疾病所致肾损害、自身免疫性疾病及结缔组织疾病肾损害、代谢性疾病肾损害、副蛋白血症病肾损害、肿瘤相关肾损害；按损伤主要部位可分为肾小球疾病、肾小管疾病、肾间质疾病及肾血管疾病；按肾功能损伤严重程度，其中慢性肾脏病按照肾小球滤过率下降程度可分为5期：正常、轻度下降、中度下降重度下降、肾衰竭，其中的中度下降期又细分为轻中度下降期和中重度下降期[1]；急性肾损伤按照2012KDIGO发布的最新标准可分为1期、2期、3期[2]。

第二节　肾脏损伤的作用机制

各种原因引起的肾脏损伤与肾脏病发生，发展有着十分密切的关系。目前研究证实肾脏损伤的作用机制复杂，目前可分为两大类：免疫[3-5]及非免疫[6-9]机制。临床上常见的肾小球疾病多为免疫介导，主要包括：体液免疫及细胞免疫。体液免疫主要指B淋巴细胞介导的抗原抗体反应，而细胞免疫主要指T淋巴细胞所介导的免疫调节作用，如单核/巨噬细胞活化等所引起的细胞因子，活性氧代谢产物，蛋白酶等释放所引起的肾脏损害。目前证据表明体液免疫及细胞免疫共同在肾小球疾病中发挥了重要作用[10-13]，图2-8-2-1描述了免疫性肾损伤的发生途径。

由图2-8-2-1可知，以下2种方式造成免疫性肾脏损伤：①体液介导免疫肾脏损伤：其发病机制表现为免疫球蛋白或免疫复合物在肾脏的沉积，导致补体激活，引起中性粒细胞及血小板聚集及肾小球内皮细胞脱落；在免疫损伤过程中，活化的巨噬细胞/系膜细胞/中性粒细胞/血小板及受损的内皮细胞大量释放氧化物、蛋白酶，进一步造成肾小球毛细血管及肾小管上皮细胞的损害，导致蛋白尿及新月体的形成。②细胞介导免疫肾脏损伤：当肾脏损伤时，致敏细胞（主要是T淋巴细胞）可进一步激活巨噬细胞/系膜细胞，继而引起大量炎症和生长因子、氧化物、蛋白酶的释放，造成肾小球毛细血管和肾小管上皮细胞的损害，导致蛋白尿及新月体的形成。

多数免疫性肾脏疾病的病因不清，既有外来因素所引发，也有自身免疫因素及遗传因素的参与。目前常见的外来因素所引发的免疫性肾脏疾病，多见于感染后的急性肾小球肾炎，乙型肝炎病毒相关性肾炎，丙型肝炎病毒相关性肾炎，药物性间质性肾损害等；经典的自身免疫性疾病如抗肾小球基底膜病、狼疮性肾炎、ANCA相关性肾炎。不论免疫性肾脏疾病始动病因如何，最终造成的肾脏损害还同时受到患者遗传背景因素的影响，遗传背景与患者的易感性，疾病的严重程度，治疗反应及预后密切相关。总而言之，上述三种因素是导致免疫性肾脏疾病发生的重要病因。

第三节　肾脏修复的定义、分型、作用及机制

一、肾脏修复的定义及形式

何谓肾脏修复？简单而言，就是肾脏结构受到损害后自我恢复的一种过程。肾脏组织与脑及心脏等不同，肾组织急性受损后可以依靠存活细胞的自我增殖完全修复，恢复肾功能[14]。但实际上，临床上急性肾损伤完全恢复的比例很少，相当比例的患者会慢慢逐步进展到慢性肾脏病[15]，这与预先存在的慢性肾脏损害[16]及肾损伤的严重程度，持续时间及恢复情况有关。肾脏损伤后，有以下几种修复形式：一是具有细胞增殖导致功能组织的恢复；二是细胞外基质的增生导致瘢痕组织形成；三是通过再生修复的过程重启原始组织结构的恢复[17]。既往的研究对于肾脏修复主要是集中在细胞外基质增生所导致的肾脏间质纤维化这一领域，而近些年随着对急性肾损伤研究领域的展开，人们已经把研究热点开始转向细胞修复和组织重构方面[18]。在本章节中，我们主要集中在急性肾损伤受损肾小管上皮细胞再生增殖修复领域上。

二、肾脏修复在肾脏损伤中的作用

随着近年来急性肾损伤的定义，诊断标准全球化，急性肾损伤的发病率及重要性越来越受到大家重视，目前急性肾损伤已成为慢性肾脏病的重要危险因素[19,20]。研究表明肾脏体积及单位的丧失，血管功能不全，细胞周期的异常及不适当的肾脏修复机制都是导致肾脏病进展的重要因素[20]。目前临床对于急性肾损伤的防治仍缺乏特殊有效的方法，急性肾损伤已成为重症患者死亡的重要原因[21,22]；社区获得性急性肾损伤的发生率也逐步显著增加，已成为当今世界一项重要的公共健康问题[23]。

由于急性肾损伤是一种早期可以自我修复的可逆性疾病，因此近年来如何促进急性肾损伤细胞再生修复已成为全球关注的研究热点。研究表明，动物及人类组织都具有细胞再生修复的能力。事实上，急性肾小管损伤后，大部分健存的肾单位组织已经开始启动细胞再生修复这一过程，所有的动物种类自原始胚胎肾组织开始都长期保留有这一能力。急性肾损伤后的再生修复主要是指细胞再生修复这一过程[17]；最重要的受损肾单位组织结构的完全修复目前只在低等动物中观察到[24]，在成熟的哺乳动物中未观察到这一现象[25]。

在肾脏的修复过程中，细胞增殖再生修复所引起的功能组织的恢复具有特别重要的意义，有利于加速肾脏损伤的恢复进程，促进肾功能好转，这一点已被很多研究证实[26]。目前研究表明受损肾脏小管，小球及间质均存在修复，并且受到多种因素的调控影响。

受损肾脏细胞再生修复受到多种因素的影响，如细胞因子、肾脏来源的祖/干细胞[27]和信号通路等[28-32]。肾小管上皮细胞是肾脏结构中最重要的一种细胞，肾小管上皮细胞的损伤程度与肾脏功能丧失密切相关[33]。肾脏急性受损后，损伤区域周围的肾小管上皮细胞立即启动修复机制，丧失细胞刷状缘，去分化成间充质表型。去分化后的小管细胞迁移到细胞坏死/凋亡或裸露的小管基底膜等区域，然后增殖，再分化成上皮样细胞，完成修复[26]。图2-8-3-1阐述了缺血再灌注急性肾损伤肾小管上皮细胞正常修复的过程。

肾脏细胞再生修复的程度及形式对于肾损伤的恢复及预后具有非常重要的作用：适应性好的修复能够恢复肾小管上皮细胞的完整性，肾功能得到完全恢复；适应性差的修复，如不完全的肾小管上皮修复，持续的小管-间质炎症，成纤维细胞的增生及细胞外基质的沉积等，最终形成慢性肾脏病，甚至可进展到终末期肾脏病（图2-8-3-2）。

三、肾脏修复的机制

大量研究表明肾脏组织具有一定的自我修复的能力，促进肾脏组织修复能够显著改善肾脏病的预后，加速急性肾损伤恢复，延缓慢性肾脏病进程。因此，积极寻求受损肾脏再生修复的机制已成为当前肾脏病领域的研究重点。

近年来关于肾脏损伤后增殖修复肾小管上皮细胞主要起源于何种细胞一直备受争议，成为目前急性肾损伤再生修复的研究热点。目前研究表明，肾脏局部存活的上皮细胞[34,35]，骨髓间充质干细胞[36,37]，和肾脏祖细胞[35,38-40]都可能增生分化成肾小管上皮细胞。有研究指出骨髓间充质干细胞并不直接分化形成肾小管上皮细胞，而是通过对内环境的调整，以旁分泌方式促进肾小管上皮细胞的再生增殖[41,42]。也有研究发现，肾小管上皮细胞的修复来源于肾脏局部稀少，但具有分化能力的祖细胞[43]。所以，急性肾损伤的小管再生修复可能主要是通过局部存活的肾小管上皮细胞[44]去分化-增殖-再分化的过程实现的。

由于肾脏修复是一个复杂的病理生理过程，在整个修复进程中除了再生细胞的来源，参与肾脏细胞修复的内环境因素极其重要。细胞因子，炎症/免疫细胞，信号通路等交织而成复杂信号网络在肾脏损伤修复进程中扮演了十分重要的作用。研究表明，肾脏损伤后细胞因子在修复过程了发挥了重要作用[45,46]：其中包括各种促肾生长细胞因子[47]、如肝细胞生长因子[48]、表皮生长因子[49]、胰岛素生长因子[50]、肝素结合表皮生长样因子[51]、血小板衍生长因子[52]、干细胞因子[53]、促红素[54]、骨形态发生蛋白-7[55]和血管生成因子[56]。也有研究发现转录调节因子通过调控参与肾脏修复的因子表达也主动参与了肾脏修复，如Pax-2[57]和Hnf-1beta[58]。不少急性炎症因子，如C-反应蛋白（CRP），在急性肾损伤患者血清中高度表达，与肾脏不良预后密切相关[59-61]。为了揭示CRP在急性肾损伤中的作用，我们应用人CRP转基因小鼠，建立了肾脏急性缺血再灌注模型。结果显示，CRP转基因小鼠较野生型小鼠肾脏功能及结构损害显著，予以阻断CRP后可改善这一情况，促进受损小管上皮细胞增殖[62]。这一结果在体外培养HK-2细胞也得到证实。

众所周知，肾脏病与免疫炎症密切相关，肾脏损伤后，各种炎症/免疫细胞迅速激活并聚集到受损区域：如中性粒细胞[63]、单核/巨噬细胞[64,65]、树突状细胞[66]、T淋巴细胞[67,68]等共同参与了急性肾损伤-修复过程。值得注意的是，巨噬细胞[69,70]及T淋巴细胞[67,68,71]因表型不同，在肾脏损伤不同阶段发挥了不同作用，这一现象在其他器官损伤中也有同样发生[72]，但具体机制尚不十分明确，值得进一步探讨。最近研究发现，调节性T细胞（Treg）在急性肾损伤早期可通过抑制CD4+T淋巴细胞释放炎症细胞因子，促进肾脏修复[73]；Aghdami等发现在运用骨髓间充质干细胞治疗恒河猴急性缺血-再灌注模型时，治疗组较对照组肾小管出现大量的Foxp3+的Treg细胞，与肾脏预后密切相关[74]。目前关于Treg细胞在肾脏损伤修复中的作用报道尚不多，待于进一步的研究及观察。这也让我们重新审视。在肾损伤-修复进程中除了如前所述的促肾脏细胞增殖修复因子外，同时还有一些负反馈调节因子抑制肾脏修复：如细胞因子信号3的抑制剂[75]，反馈调节因子Activin A[76,77]等可抑制肾脏修复，加剧肾脏损害。这些研究结果为将来临床治疗肾损伤提供可能的科学依据。最后，需要提出的是，在整个肾脏损伤-修复进程中，信号通路发挥了不同的重要调控作用。如Wnt、JAK2/STAT[57]、Bcl-2[78]等信号通路参与了肾脏增殖修复的过程。同时，Wnt信号通路的激活也参与慢性肾脏病的修复进程。如过度激活，与肾脏纤维化密切相关[79]。所以，阻断Wnt信号后可以减轻肾脏纤维化程度[80]，改善预后。相反，如敲除巨噬细胞的Wnt7b表达，则显著抑制了急性缺血-再灌注肾脏小管上皮细胞增殖再生，延缓了肾脏修复[81]。

第四节　减少肾脏损伤、促进肾脏修复的治疗手段

近期研究已证实，急性肾损伤是慢性肾脏病的重要原因之一，早期预防及干预急性肾损伤是降低慢性肾脏病发病率、延缓终末期肾病进程及促进肾脏修复的最积极有效的方法。但是，目前临床对于防治肾脏损伤的手段十分有限，效果也不理想。临床常见的治疗手段还是基于对病因及危险因素的控制：如控制血压、血糖、水电解质紊乱纠正、肾毒性药物的慎用、低血容量的纠正、造影剂使用前的水化处理等。

近10年来，由于干细胞在肾脏修复过程中的作用越来越受到重视，越来越多研究者把干细胞治疗急性肾损伤放在了极其重要的位置[27,82,83]，而且在基础研究中也得到很好的证实[43,84]。研究发现骨髓间充质干细胞[85,86]、造血干细胞[37]、羊水干细胞[87,88]、肾脏来源的祖/干细胞[89,90]、存活的肾小管上皮细胞[91,92]、内皮祖细胞[93]等均可促进肾脏细胞增殖再生修复，减轻肾脏损伤，改善肾功能。尽管很多基础研究证实干细胞的运用对于肾脏损伤修复具有很好的效果，但同时也有研究发现，如果补充注入的干细胞长期分化不佳，可以引起肾脏纤维化[94]。除此之外，干细胞疗效的程度还受到很多因素的影响，如干细胞干预的时间、干细胞移植的数量、干细胞到达受损区域的能力等。正是由于这些原因的存在使得目前干细胞治疗手段在临床干预治疗急性肾损伤还处于探索阶段，因此，预计干细胞临床干预治疗肾脏病还有相当长的一段路要走。

需要指出的是，虽然目前很多研究表明骨髓间充质干细胞对肾脏损伤修复有作用，但也有研究者提出不同观点：促进肾脏损伤修复的并不是间充质干细胞本身，骨髓间充质干细胞不能直接分化为肾脏上皮细胞，而是归咎于干细胞产生分泌的细胞因子[46,47,95]及干细胞所分泌exosome（膜性小囊泡）[96]等对微环境的影响，刺激促进存活的肾小管上皮细胞去分化或肾脏固有的祖细胞增殖，使受损小管上皮细胞得以修复[97]。因此研究者们又把目光聚焦在干细胞及微环境相互之间的作用对于肾脏损伤修复的影响。有学者发现预先用IGF-1因子预处理的干细胞能促进干细胞的迁移，提高其聚集到受损区域的能力，促进肾脏修复[98]。经CXCR4基因修饰后的骨髓间充质干细胞可通过激活下游的P13K/AKT和MAPK信号通路促进骨髓间充质干细胞迁移到肾损伤区域，加速肾功能的恢复[99]。另外，体内外研究发现，补充EPO可促进干细胞的迁移能力，促进急性肾损伤功能恢复[100]。目前对于干细胞在肾脏损伤修复中的运用还存在很多疑问，如该选取何种干细胞用于干预治疗？干预的时间应多长？干预的剂量应多少？内环境的调控因素有哪些？目前尚无统一认识[101,102]。继续探索干细胞在肾脏损伤修复的作用及相关调节机制仍将是肾脏病研究者们在今后所持续关注重点，这与全球的肾脏病预后密切相关，具有十分重要的意义。

（汤　颖　蓝辉耀）

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