谢双燕 何朝生
（广东省人医院 广东 广州 510000）；（广东省人民医院 广东 广州 510000）
摘要：糖尿病肾病（DN）是糖尿病最常见的微血管并发症之一，是终末期肾病的主要原因，也是患者死亡的主要原因。多种危险因素促进糖尿病肾病的发生和发展，包括高血糖、糖尿病病程、高血压、血脂异常、吸烟。而尿微量白蛋白作为诊断早期糖尿病肾病最早的指标，具有一定的局限性，因此发现具有早期诊断价值的新指标，识别和处理糖尿病肾脏疾病的危险因素，可以大大减轻与之相关的医疗和经济负担。本文就糖尿病肾病的危险因素和近年来不断提出的新的早期糖尿病肾病的预测因子的研究进展进行综述。
关键词：糖尿病肾病；危险因素；预测指标；综述
Advances in Research on Risk Factors and Early Predictive Indicators of Diabetic Nephropathy
【Abstract】 Diabetic nephropathy (DN) is one of the most common chronic microvascular complications of diabetes, the main cause of end-stage renal disease, and the main cause of death of patients.Multiple risk factors promote the occurrence and development of diabetic nephropathy, including hyperglycemia, diabetes duration, hypertension, dyslipidemia, and smoking. As the earliest index to diagnose early diabetic nephropathy, urine microalbumin has certain limitations, and identification of novel indicators for early dignosis and prediction of DN, identifying and dealing with risk factors of diabetic nephropathy can greatly reduce the medical and economic burden associated with it.This reviews summaries the advances in the research on risk factors of diabetic nephropathy and new predictors of early diabetic nephropathy that have been proposed continuously in recent years.
【Key words】 Diabetic nephropathy；Risk factors；Predictors；Review
前言：在过去几十年中，全球的糖尿病患病率大幅增加，据预测到2030年，全球约有3.66亿人（4.4%）患有糖尿病[1]，因此，与糖尿病相关的微血管并发症的全球患病率也在急剧增加[2]。而糖尿病肾病（DN）是糖尿病最常见的微血管并发症之一，日益成为终末期肾病和透析的常见病因[3,4]。此外，DN的患病率高，已超过肾小球肾炎相关的慢性肾脏疾病，成为我国慢性肾脏疾病（CKD）的主要病因[5]。目前最常用于预测早期DN的指标尿微量白蛋白（MAU）具有一定的局限性，其敏感性和特异性受到质疑[6]。本文就早期DN的危险因素和预测因子的研究进展进行综述。
1 DN的危险因素
高血糖、糖尿病病程、高血压、血脂异常、吸烟等促进DN发生发展的危险因素，大多数可通过降糖、降压、或降脂治疗和改变生活方式来改变，因此识别和处理DN的危险因素，是预防和延缓肾功能下降的关键。
1.1 高血糖和糖尿病病程
高血糖对肾脏的直接影响是血糖在近端小管过度重吸收，通过2型钠-葡萄糖协同转运蛋白（SGLT2）使得钠的重吸收大幅增加，引起一系列血流动力学改变，导致肾脏肥大。结果，肾小球毛细血管的通透性受损，从而导致蛋白尿和糖尿病肾小球硬化[7]。有研究发现，长期的血糖暴露是1型糖尿病（T1DM）患者晚期肾脏疾病最大的原因，甚至比其他如高血压、血脂异常或吸烟都要大[8]。因此，血糖未控制的糖尿病患者发生肾病的凤险很高。而糖尿病病程较长的患者发生肾病的风险更高[9,10]。
1.2 高血压和血脂异常
糖尿病患者中高血压的患病率是普通人群的两倍。有大量的研究证实动脉高血压是糖尿病进展的危险因素，且被认为是DN发生的关键因素[11-13]。而降压和血管紧张素转化酶抑制剂能减缓，但不能阻止糖尿病肾病的患者肾功能的进行性下降[14]。关于血脂异常，一项研究表明，甘油三酯/高密度脂蛋白胆固醇比率高，是DN患者的重要危险因素，且对他汀类药物的干预研究也证实降低LDL-C水平与DN的延迟进展有关[15-19]。最近的一项DCCT/EDIC研究也发现，较高的甘油三酯水平和高血压也是大量蛋白尿和EGFR降低相关的危险因素[8]，与上述研究成果相符。
1.3 吸烟
有研究发现，吸烟是通过烟雾暴露通过增加肾小球系膜扩张而加重DN的进展，且尼古丁对DN的恶化有相加作用[20,21]。但也有研究指出，吸烟与1型糖尿病患者DN的发生无关[22]，而一项吸烟与DN的荟萃（meta）分析表明，吸烟是DN的一个具有统计学意义的风险因素[23]。同时，吸烟也是心血管事件的独立危险因素，而DN的主要死亡原因为心血管事件。
综上，高血糖、糖尿病病程长、高血压、血脂异常和吸烟与DN的进展显著相关。因此，及早识别DN的高危患者，预防或减缓DN的进展将提高患者的生活质量，并减少公共卫生支出[24]。
2 尿微量白蛋白（MAU）的局限性
DN是一种基于蛋白尿和估计的肾小球滤过率（EGFR）的临床诊断。尿微量白蛋白（MAU）是临床上最早和最常用的DN指标，但近来其早期诊断的敏感性和特异性受到质疑[6]。最初认为，高达80%的微量白蛋白尿患者进展为临床DN，然而，最近有研究表明，经过10年的随访，只有大约30%的微量白蛋白尿患者进展为临床肾病[6,25]。另外有研究证实，微量白蛋白尿并不是DN的独有症状，进行性慢行肾病的非糖尿病患者也可能出现微量白蛋白尿[26]。而且值得注意的是，部分DN患者的微量白蛋白尿可恢复之正常蛋白尿[27,28]。关于肾小球滤过率（GFR），血肌酐（Sr）是最常用用于评估GFR的指标，但其在肾损害早期敏感性很差，当检测血清水平升高时，GFR已显著下降[29]，而且有研究认为，最近常推荐使用的CKD-EPI公式也明显低估了糖尿病患者的肾功能损害[30]。因此，迫切需要寻找新的，有效的生物标志物用于DN的早期诊断。
3 DN的发病机制包括肾小球损伤、肾小管损伤、氧化应激和炎症[31]，因此，参与这些过程的生物标志物有可能作为早期DN的预测因子。
3.1 肾小球损伤标志物
肾小球的损伤增加了对血浆蛋白的通透性，导致其在尿液中排泄异常，因此通过检测尿液中这些生物标志物，有助于判断肾小球有无损伤。而与DN相关的肾小球损伤的标志物有转铁蛋白（TF）、免疫球蛋白G（IgG）、IV型胶原和纤维连接蛋白（FN）等
3.1.1 TF TF是一种相对分子质量（76.5KDa）略大于白蛋白的血浆蛋白[32]，因为其分子量低和较少的离子负荷，很容易通过肾小球滤过屏障[6]，被认为是糖尿病患者肾小球损伤更敏感的生物标志物[33]。有研究发现，尿转铁蛋白的增加可预测Ｔ2DM患者MAU的发生[32]，但是有报道TF与原发性肾小球肾炎和非糖尿病人群的高血压相关[34,35]，因此其对DN的预测缺乏特异性。
3.1.2 IV型胶原 基底膜成分的积累和分布改变是DN的结构特征之一，且发生在MA前[36]。IV型胶原是肾小球基底膜和系膜基质的重要组成成分，分子量为540KDa。尿液IV型胶原与UAE、糖尿病病程、血压和血肌酐密切相关[37,38]，尿液IV型胶原在正常白蛋白尿的1型糖尿病患者中也显著增加，表明其可作为MAU出现前预测早期DN患者的肾损伤[38,39]。而且尿IV型胶原还可反映2型糖尿病患者肾脏形态学改变和组织学损害程度[40]。值得注意的是，在一项对近700名糖尿病患者进行的亚洲多中心的研究的结果显示，随着DN的发展，尿IV型胶原的排泄逐渐增加[41]，综上，提示IV型胶原可作为预测早期DN的特异性指标[42]。
3.1.3 IgG 与TF不同，IgG是一种大分子量（150KDa）阴离子血浆蛋白，很难通过肾小球滤过屏障。研究发现，尿IgG的检出早于MAU，同时伴有尿转铁蛋白的升高[43]，可作为早期诊断DN的生物学指标[44]。非蛋白尿的T2DM患者可排出尿IgG，有学者认为是由于肾血流动力学改变导致[45]。临床研究发现尿TF和IgG可以单独或联合其他生物标志物用于早期DN的诊断[46]。
3.14 FN FN主要由肝脏、血管内皮细胞和血小板产生，是一种高分子量的血浆糖蛋白。早前的研究发现，与健康对照组相比，T1DM或T2DM患者的尿FN排泄量更高，但这种差异仅在大量蛋白尿患者中显著[47,48]。同时，研究表明尿纤维连接蛋白的升高与弥漫性肾小球病变进展有关[47,49,50]。但这些只是零星的研究，尚未有足够的数据支持FN作为早期DN的预测指标，需要进一步的研究确定FN和DN的相关性。
3.2 肾小管损伤标志物
除了肾小球外，肾小管与DN的发病也密切相关。肾小管损伤是DN早期病程的重要组成，因此，对尿中肾小管标志物的检测有助于评估DN的早期的肾小管功能障碍。与DN相关的肾小管损伤标志物有：视黄醇结合蛋白（RBP）、N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、胱抑素C、 β2-微球蛋白（β2-MG）、a1微球蛋白（A1M）和中性粒明胶酶脂质运载蛋白（NGAL）。
3.2.1 RBP RBP是由肝脏合成的一种低分子量蛋白，可在肾小球自由滤过，并且在近端小管几乎完全重吸收，因此，其在尿液中检出可表明即使是非常轻微的肾小管功能障碍[32]。一项评估DN尿液生物标志物的研究观察到，单一的RBP预测价值最高，而且不同的生物标志组合的诊断价值并不优于单一RBP的[51]。尿RBP已确定是近端肾小管障碍的生物标志物，特别是对糖尿病合并大量白蛋白尿的患者有良好的诊断价值[52]，但有研究发现其在MAU患者中诊断价值较低[53]。
3.2.2 NAG NAG是一种主要存在近曲小管的溶酶体酶，正常情况下，NAG通过尿液排出的量很少，但在近端肾小管损伤时，NAG会大量排入尿液，是肾小管损伤的一种敏感标志物。近年来，围绕NAG进行了大量研究，尿NAG升高可以先于MAU出现，提示NAG可作为早期发现DN的标志物[54,55]。在另一项研究中，与血肌酐（Scr）、肌酐清除率（CrCl）和MAU的敏感性和特异性相比，尿NAG的敏感性和特异性最高（分别为100%和87.5%），因此该研究人员建议将尿NAG作为DN早期诊断的筛查试验[56]。但Ambade等[57]没有发现尿NAG作为DN早期生物标志物具有临床意义。
3.2.3 胱抑素C 胱抑素C是1983年首次分离得到的有核细胞产生的半胱氨酸蛋白酶抑制剂，由122个氨基酸组成，可自由滤过肾小球，主要由近端肾小管细胞分解代谢。许多研究报道血清胱抑素C在估计GFR方面优于血清肌酐，因为其不受性别、肌肉质量、年龄和蛋白质摄入量的影响[58,59]。同时，血清胱抑素可检测轻微的肾小球损伤[60]，尿胱抑素C提示肾小管损伤，有MAU者的尿胱抑素C高于无MAU者，因此血清和尿胱抑素C是评估DN早期的有用生物标志物[61]。而一项以日本糖尿病患者为对象的研究提示血清胱抑素C可用于评价DN的肾功能，但不适用于早期肾病[62]。
3.2.4 β2-MG β2-MG是一种小分子量（11.8KDa），被肾小球滤过，而且几乎完全被近端小管的细胞重新吸收和分解。尿液中的β2-MG升高提示肾小管功能障碍[63]，重要的是，尿β2-MG能可靠鉴别DN和经活检证实的非糖尿病肾病[64]。Petrica等[65]发现，23.5%正常白蛋白尿的T2DM患者尿β2-MG升高，提示尿β2-MG是早期DN的敏感标志物。但尿β2-MG在酸性环境下不稳定[66]，易分解破坏，使其诊断作用受到限制。
3.2.5 A1M A1M是由肝脏产生的一种糖蛋白，于1975年被分离出来[67]，可在肾小球自由滤过，在近端小管几乎完全重吸收，因此即使轻微的肾小管功能障碍也会导致尿A1M排泄增加[68,69]。Hong等[69]一项横断面研究中发现尿A1M和MAU在评估早期DN方面互补，33.6%非蛋白尿患者尿A1M升高可用肾小管损伤先于MAU发生解释，表明尿A1M是更早，更敏感的生物标志物。此外，与尿β2-MG不同的是，A1M在广泛的生理条件下都是稳定的，且已有可用于临床测定的灵敏免疫分析法[66]。事实上，尿A1M是早期诊断DN的一种廉价生物标志物[70]。
3.2.6 NGAL NGAL是由中性粒细胞和包括肾小管上皮细胞在在内的多种上皮细胞分泌的糖蛋白，主要储存在中性粒细胞的特定颗粒中，在胃、肺和肾脏中少量表达。近来NGAL已成为急性或慢性肾损伤的早期生物标志物[71,72]。研究证实尿NGAL在正常白蛋白尿患者中也会升高[73]，甚至先于MAU出现[74]，并有证据证明NGAL是DN潜在的诊断标志物[75]。而且Hasegawa等[76]发现血浆NGAL是慢性肾脏病患者发生心血管事件的预测独立预测因子。但也有一些研究结果并不一致，尿NGAL在正常白蛋白尿组和MAU中并没有升高，而且我国有学者发现尿NGAL可能不是T2DM患者肾功能下降的预测因素[77]。
3.3 氧化应激相关生物标志物
氧化应激是糖尿病血管并发症的关键介质之一。高血糖导致的活性氧可诱导多种损伤介质，导致肾小球纤和小管间质纤维化。与DN相关的氧化应激标志物有8-羟基脱氧鸟苷（8-OHdG）和尿酸（UA）等
3.3.1 8-OHdG 8-OHdG是DNA氧化损伤的直接指标，也是确定DNA氧化损伤最常用的方法[78]。经过5年的随访，Hinokio等[79]发现尿8-OHdG可预测DN的发展，Brodbaek等表明其还是糖尿病长期死亡率的预测因子[80]。但有研究发现，DN患者和正常蛋白尿的糖尿病患者的尿8-OHdG水平相似[81]，提示8-OHdG不是早期DN有价值的诊断标志物。而且值得注意的是，8-OHdG在尿液的排泄不是某组织特有的，其反映的是全身DNA氧化损伤。因此对8-OHdG仍需进入深入研究及进一步明确氧化应激和DN间的联系
3.3.2 UA UA是嘌呤核苷酸代谢的产物，有证据表明，UA进入细胞后可能诱导氧化应激[82]。近来关于UA作为早期DN肾功能标志物的研究不多，血清UA受到关注大多是其作为多种疾病（慢性肾脏疾病和心血管疾病等）危险因素的原因。Jalal等[83]发现血清UA与肾功能受损有关，是Ｔ1DM患者蛋白尿发展的预测因子，同时另一项研究表明UA是独立于MA的DN早期标志物[84]。
3.4 炎症标志物
炎症在DN的发生发展中的参与包括趋化因子产生的增加、炎症细胞向肾脏的浸润、促炎细胞因子的产生和组织损伤，同时DN被证明是一种低度炎症性疾病[31]。与DN有关的炎症标志物包括中性粒细胞-淋巴细胞比值（NLR）、肿瘤坏死因子（TNF-α）和血清骨桥蛋白（OPN）等。
3.4.1 NLR NLR是近年新提出来的一种炎症指标，已被证实在多种慢性疾病不良预后的预测价值[85,86]，还可作为大规模的人群筛查、疾病和药物监测的工具。一项针对糖尿病患者进行的横断面研究的关键发现，在早期DN患者中，NLR水平和肾功能下降有关[87]，而Huang等[88]发现DN患者NLR值明显高于糖尿病无DN患者，而且NLR容易获得，易于实验室检测，因此可作为早期DN更经济的生物标志物。
3.4.2 TNF-α TNF-α是由浸润的单核细胞、巨噬细胞、T淋巴细胞及肾脏细胞产生的一种炎性细胞因子，通过两种不同的受体—肿瘤坏死因子受体1（TNFR-1）和受体2（TNFR-2）起作用，而这两种受体的的血清水平已被证明与糖尿病患者的肾功能有关[89]。据报道，尿TNF-α与尿白蛋白排泄和DN的严重程度有关[90]，同时在实验小鼠模型中观察到尿中TNF-α升高是蛋白尿出现的先兆[91]。此外，有实验研究表明，抑制TNF-α可有效治疗DN，其疗效与安全性与卡托普利相当[92]。
3.4.3 OPN OPN是一种具有粘附和细胞信号功能的唾液酸蛋白，主要由成骨性骨细胞和活化性t细胞表达，通过影响t淋巴细胞分化，参与细胞诱导的免疫应答。Yamaguchi等[93]发现，血浆OPN在DN进展中升高，特别是肾功能衰竭阶段，而尿中OPN水平与肾脏疾病无关，Kitagori等[94]通过研究也得出类似结论。同时，血清DN被证明与儿童T1DM患者独立相关[95]。有趣的是，相比于其他炎症细胞因子，对DN最有诊断价值的细胞因子是血清OPN和白细胞介素-18（IL-18）[53]，但需要进一步进行前瞻性研究评估血清OPN对DN的预测能力。
3.5 代谢组学
除了上述生物标志物，代谢组学也是近年在不断研究的预测早期DN的方法。代谢组学指对生物样本的代谢物（即糖、氨基酸、有机酸、脂类）进行全面和系统的分析，其应用方法有核磁共振、质谱联合等。考虑到DN机制复杂，存在糖、脂肪和氨基酸等多种代谢通路异常[96]，仅单一的生物标志物可能难以实现对DN的最佳预测和诊断，而代谢组学被认为是生物标志物领域的有力工具[97,98]。但与蛋白组学不同，代谢组学作为生物标志物仍处于初级阶段，用代谢组学分析预测DN的前瞻性研究较少，因此仍需深入研究和严格验证。
4 小结
DN是糖尿病最严重的并发症之一，而DN的发病机制复杂，表现为肾小球损伤、肾小管损害、氧化应激和炎症反应，但尚未完全阐明，因此防治DN是一个难点。因此早期评估高危人群和早期预测DN至关重要。DN的危险因素有高血糖、糖尿病病程、高血压、血脂异常和吸烟，其中血糖暴露是T1DM患者发生肾脏疾病的最大原因。近年来虽不断有新的早期DN的预测指标的研究出现，但大多为横断面研究，缺少纵向研究，而且目前的数据尚不支持它们在临床中常规使用，因此目前为止，还没有新的生物标志物可代替MAU。
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