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通讯作者:

刘必成(1964-),男,江苏涟水人,博士生导师,主要从事糖尿病肾病诊断标志物及慢性肾脏病诊治新技术研究。E-mail:Liubc64@163.com

中图分类号:R587.2,R-1

文献标识码:A

文章编号:2096-8965(2021)01-0028-05

DOI:10.12287/j.issn.2096-8965.20210104

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目录contents

    摘要

    糖尿病肾病(Diabetic Kidney Disease, DKD)是糖尿病(Diabetes Mellitus, DM)患者发生终末期肾病和死亡的主要原因。对 DKD 患者进行预后评估有助于降低疾病进展的风险及减少并发症和死亡的发生。本综述主要讨论 DKD 进展性生物标志物的现状和研究进展,包括常用的白蛋白尿和肾小球滤过率(Glomerular Filtration Rate, GFR),以及新型生物标志物如肿瘤坏死因子受体(Tumor Necrosis Factor Alpha Receptor, TNFR)和肾小管标志物等。同时,本文还对 DKD 进展性标志物的开发和应用存在的挑战进行了讨论。

    Abstract

    Diabetic kidney disease (DKD) is the main cause of end stage renal disease and death in patients with diabetic mellitus (DM) . Prognostic assessment for patients with DKD is critical to reduce the risk of disease progression and incidence of complications or deaths. This review mainly discussed the current research status of biomarkers which might predict the progression of DKD, including the commonly used albuminuria and glomerular filtration rate (GFR) , as well as novel biomarkers like tumor necrosis factor receptor (TNFR) and renal tubular markers. Meanwhile, we discussed the potential challenges in the development and application of these biomarkers in progressive DKD.

  • 糖尿病肾病(Diabetic Kidney Disease, DKD) 是糖尿病(Diabetes Mellitus, DM)常见的慢性并发症,是导致终末期肾脏病(End Stage Renal Disease, ESRD)的主要原因。多中心流行病学调查显示, 我国成人中DM的患病率已高达12.8%[1]。 DM基数增加必然导致DKD患病率升高,我国现约有2 430万DKD患者[2],2015年的CK-NET(China Kidney Disease Network, CK-NET)年度报告显示,因肾脏疾病住院的患者中,DKD的比例为26.7%,在病因中位居第一位 [3]。DKD总体预后较差,即使积极规范治疗,仍有20%~30%的患者肾功能进行性下降 [4],最终发生ESRD。

  • DKD生物标志物的检测是预测疾病进展的重要方法,白蛋白尿和肾小球滤过率(GlomerularFiltration Rate, GFR)是目前最常用的生物标志物。然而,在临床研究和实践中,两者仍存在敏感性和特异性的不足。开发新型生物标志物有助于更好地对患者进行风险分层、分级管理和个体化治疗,对改善预后具有重要意义。本文对DKD进展性生物标志物的研究现状进行综述。

  • 1 反映DKD进展的生物标志物研究现状

  • 目前,临床上最常用的DKD风险分层和预后评估的指标依然是GFR和白蛋白尿,两者能够在一定程度上预测ESRD、心血管事件及全因死亡的发生风险 [5]

  • 1.1 GFR

  • GFR是预测ESRD发生最有价值的指标,且肾脏预后的结局终点也是基于GFR定义的。测定GFR的方法繁琐,不适合临床推广,一般采用估测的GFR(estimated GFR, eGFR)来代替,CKDEPI和MDRD方程是准确性较高的计算公式。然而有研究报道,在T2DM(Type2DM)患者中, CKD-EPI或MDRD公式均可能低估GFR[6]。即使如此,多项研究报道了eGFR预测DKD患者发生ESRD、心血管疾病和全因死亡的重要价值 [7, 8]。一项在2 420例T2DM中随访10.2年的研究发现, eGFR 15~29mL/min/1.73m2 的患者发生ESRD的风险是eGFR 90mL/min/1.73m2 以上患者的81.9倍 [9]

  • 除eGFR的基线值外,eGFR的斜率(定义为eGFR每年平均变化值)逐渐受到关注。Joslin研究中,作者评估了T1DM(Type1DM)患者既往8年的eGFR变化轨迹,将患者分为肾功能快速下降、中度下降和最低下降3个亚组 [10],发现快速下降组的ESRD和全因死亡的风险明显增加。 ADVANCE-ON研究中 [11],8 879名T2DM患者随访7.6年后发现,eGFR的快速下降与发生ESRD的风险密切相关。本团队研究认为,eGFR的斜率突出体现了DKD患者肾功能的变化而非基础肾功能水平,在由非DKD疾病本身造成的肾功能不同的患者中,具有较好的研究意义。

  • 1.2 白蛋白尿

  • 白蛋白尿是DKD的主要诊断依据,美国糖尿病学会(American Diabetes Association,ADA)糖尿病诊疗指南 [12] 和中国糖尿病肾脏疾病防治临床指南 [5] 提出,尿白蛋白肌酐比值(urine AlbuminCreatinine Ratio,uACR)≥ 30mg/g为尿白蛋白升高。在GFR正常的T2DM患者中,uACR的增加能够反映肾小球的结构改变,包括基底膜增厚和系膜增宽等。DCCT/EDIC研究发现,T1DM患者中,白蛋白尿与发生心血管疾病及eGFR降低的风险有关 [13]。 JDCS研究 [14] 发现,日本T2DM患者中,微量白蛋白尿是发生肾脏终点事件的独立危险因素。但是,随着研究证据不断增加,uACR的价值逐渐受到质疑。研究显示,仅30%左右的DM患者微量白蛋白尿呈持续进展;约1/3可以逆转为正常;正常白蛋白尿的DM患者也可出现GFR下降和肾脏结构异常 [15]

  • 1.3 与发病机制相关的DKD新型生物标志物

  • 白蛋白尿和eGFR能够提供DKD患者的预后信息,有助于指导治疗,但仍存在不足。近年来,反映肾小球或肾小管损伤、慢性炎症、肾间质纤维化和氧化应激等DKD发病机制的多种新型生物标志物被报道。例如,反映慢性炎症的肿瘤坏死因子 α 受体(Tumor Necrosis Factor Alpha Receptor, TNFR)和单核细胞趋化蛋白-1(Monocyte Chemoattractant Protein-1, MCP-1),以及肾小管损伤性标志物等,在预测DKD进展方面的证据相对充分,具有较好的临床转化和应用前景。

  • 1.3.1 TNFR

  • TNFα 是一种与肾脏疾病进展有关的炎症因子,已知有两种不同的受体,TNFR1和TNFR2,胞外结构域能够被裂解进入血液循环,形成可溶性的TNFR(soluble TNFR,sTNFR)。sTNFR的发现是DKD进展性标志物中值得关注的重要进展。

  • 2012年,Niewczas等 [17] 首次证明,sTNFR可以预测不同疾病阶段的T1DM和T2DM患者的肾功能下降。在肾功能和尿白蛋白水平正常的T1DM患者中随访12年后发现,处于sTNFR2最高四分位数的患者的CKD3期的累积发生率为60%,而其他患者CKD3期的发生率为5%~19%[16]。该团队的另一项研究发现,在大量白蛋白尿和eGFR进展期的DKD患者中,sTNFR1最高四分位数的患者12年的随访期间有近54%进展为ESRD,而其他患者发生ESRD的比例仅为3%[17]。之后,多项临床研究验证了这一发现。例如ACCORD和VA NEPHRON-D研究报道,在早期和进展期的DKD研究队列中,sTNFR 1和sTNFR 2与肾脏预后风险之间显著相关 [18]。此外,在校正eGFR和白蛋白尿的差异后,亦有多个研究发现sTNFR 1和/或sTNFR 2的浓度升高是DKD进展的危险因素,并能够优化DKD临床预测模型的效能 [19, 20]。笔者认为,TNFR可能是eGFR和白蛋白尿之外最有应用前景的DKD进展性生物标志物。

  • 1.3.2 MCP-1

  • MCP-1是在炎症中具有招募T淋巴细胞和单核细胞作用的趋化因子。在DKD患者和实验性DM动物模型中,尿MCP-1表达升高,并与蛋白尿的水平存在相关性。前瞻性研究发现,T2DM患者的尿MCP-1与大量蛋白尿的发生有关,并与6年随访期间的eGFR下降呈正相关 [21]。另有研究报道,T2DM患者随访30.7个月后发现,校正eGFR和尿白蛋白后,尿MCP-1依然可以作为ESRD发生和全因死亡率增加的危险因素 [22]。然而,尿MCP-1与DKD进展关系的前瞻性研究相对较少,且多为小样本的单中心研究,目前尿MCP-1在DKD进展预测中的价值尚不能确定。

  • 1.4 肾小管损伤性标志物

  • 近年研究发现,在急性肾损伤(Acute Kidney Disease, AKI)中开发的肾小管损伤标志物在评估DKD进展中也具有作用,如肾损伤分子-1(Kidney Injury Molecule-1,KIM-1)、中性粒细胞明胶酶相关脂质运载蛋白(Neutrophil Gelatinase-associated Lipocalin, NGAL)和肝型脂肪酸结合蛋白(Liver Fatty Acid Binding Protein, L-FABP)等,其中, KIM-1的证据较为充分。在T1DM患者中,低水平的尿KIM-1与随访2年后微量白蛋白尿的消退有关 [23]。在ACCORD和VA NEPHRON-D研究队列中发现,进展期DKD患者的血浆KIM-1水平是早期DKD的2倍左右,是预测肾功能下降以及ESRD发生的独立危险因素 [18]。另有研究发现,尿KIM-1与心血管死亡风险有关 [24]。然而,在校正已知的危险因素如eGFR和uACR后,尿KIM-1不能作为DKD进展的独立危险因素 [25, 26]。病理研究表明,肾小管损伤是影响DKD进展和预后的重要因素,肾小管损伤标志物检测在DKD预后判断中的价值值得进一步深入研究。

  • 1.5 基于组学技术发现的新型标志物

  • 组学技术的优势是在无假设的前提下分析,减少了研究的选择性偏倚。借助于大数据平台,能够发现与DKD进展相关的单一分子标记或多个分子标记的组合。然而,由于检测费用较高,此类研究的样本量普遍较小;此外,组学标志物的重复性欠佳,目前在DKD进展中的价值尚不能明确,还有待进一步研究证实。

  • 1.5.1 尿液蛋白质组学

  • 尿液中含有可用于质谱分析和定量的多种蛋白质和多肽,蛋白组学分析已成为开发DKD生物标志物的理想方法。CKD273分类器是一个273个多肽的组合,在早期诊断DKD方面具有重要价值 [27]。前瞻性研究发现,校正其他已知的危险因素后,CKD273依然可以预测DKD患者的远期死亡风险 [28]。目前CKD273分类器已实现临床转化,但是,由于检测的费用较高、需要借助于特定的设备,且分析结果不易解读,目前尚未在DKD患者中广泛应用。

  • 1.5.2 代谢组学

  • DM为代谢性疾病,代谢组学分析在DM并发症的筛查中具有独特的价值。Niewczas等 [29] 在Joslin研究队列中对CKD3期伴白蛋白尿的T1DM患者进行了血清代谢组学分析,发现有7种代谢物与T1DM的eGFR下降和ESRD终点之间存在密切关联。在T2DM患者中,CRIC研究在平均8年的随访期间发现,代谢产物3-羟基异丁酸(3-hydroxyisobutyrate, 3-HIBA)和3-methylcrotonyglycin水平与eGFR的下降斜率密切相关,有助于发现高危的DKD患者 [30]

  • 1.5.3 mRNA与microRNA

  • 尿液中有多种脱落细胞成分,如足细胞和肾小管上皮细胞等。研究证实,尿液足细胞标记和肾小管上皮细胞间质转化分子的mRNA可能能够作为DKD新型诊断性生物标志物 [31-33]。一项进行了23个月随访的前瞻性研究发现,尿脱落细胞Nephrin和Podocin等足细胞标记mRNA水平与肾功能下降的斜率相关 [34]。但亦有研究报道,足细胞标记分子mRNA虽然在DKD尿液中表达升高,却并不能独立预测DKD患者的eGFR下降 [35]。 microRNA(miRNA)是长度为20~22bp的参与转录后调控的非编码RNA。Pezzolesi等 [36] 对T1DM进行了7-20年的随访,发现循环中的let-7b-5p和miR-21-5p可能是DKD向ESRD进展的预测因子。

  • 1.6 尿液外泌体来源的生物标志物

  • 外泌体具有磷脂双分子层结构,包裹母细胞来源的miRNA、mRNA、蛋白质和脂质等活性分子。尿液外泌体内的多种组分能够参与肾脏疾病的发生和进展,并可作为潜在的生物标志物 [37]。Lv等 [38] 在经肾活检证实DKD患者中发现,尿外泌体miR19b-3p的表达显著增高,并与肾间质损害程度呈正相关。前瞻性研究发现,尿外泌体中足细胞标记分子WT-1mRNA的水平能够预测DKD患者eGFR的下降 [39]

  • 2 挑战和展望

  • 综上,尽管eGFR和白蛋白尿在评估DKD疾病进展方面存在不足,但目前仍未出现可取代eGFR或白蛋白尿的新型生物标志物。DKD进展性生物标志物的研究面临诸多挑战,原因在于:多数生物标志物的研究基于DKD的发病机制,证据主要来源于体外实验和动物模型;大多临床研究为单中心的横断面研究,单纯描述DKD中生物标志物的变化或与eGFR、白蛋白尿的相关性不能作为预测DKD进展的证据;DKD疾病进展的原因非常复杂,多种因素可以影响疾病的预后;此外,基因组学和表观遗传学研究发现,DM患者对DKD的易感性和疾病进展的风险存在遗传学的差异。

  • 未来,应更加注重系统生物学的思想,借助人工智能技术,依托多中心的大样本临床随访队列,开发综合性、多维度的DKD进展临床预测模型,这是提高DKD患者预后评估的有效途径。多组学平台和高通量筛选技术为DKD生物标志物的研究提供了更多的思路 [40]。首先,基于组学平台筛选出候选的标志物,进一步在前瞻性多中心队列中进行验证,根据随访周期设置适宜的临床观察终点,评估其在疾病进展和预后评估中的价值。同时,构建和优化DKD疾病进展的预测模型,对于开发DKD新型进展性生物标志物具有重要意义,并能够为DKD的发病机制和治疗靶点提供新的线索,更有助于DKD分层管理和个体化治疗的实现。

  • 参考文献

    • [1] LI Y,TENG D,SHI X,et al.Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association:national cross sectional study[J].BMJ,2020,369:m997.

    • [2] ZHANG L,LONG J,JIANG W,et al.Trends in chronic kidney disease in China[J].N Engl J Med,2016,375(9):905-906.

    • [3] ZHANG L,ZHAO M H,ZUO L,et al.China Kidney Disease Network(CK-NET)2015 annual data report[J].Kidney Int Suppl(2011),2019,9(1):e1-e81.

    • [4] ZHANG W R,PARIKH C R.Biomarkers of acute and chronic kidney disease[J].Annu Rev Physiol,2019,81(1):309-333.

    • [5] 中华医学会糖尿病分会微血管并发症学组.中国糖尿病肾脏疾病防治临床指南 [J].中华糖尿病杂志,2019,11(1):15-28.

    • [6] SILVEIRO S P,ARAÚJO G N,FERREIRA M N,et al.Chronic kidney disease epidemiology collaboration(CKD-EPI)equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes[J].Diabetes Care,2011,34(11):2353-2355.

    • [7] LU J,MU Y,SU Q,et al.Reduced kidney function is associated with cardiometabolic risk factors,prevalent and predicted risk of cardiovascular disease in Chinese adults:results from the REACTION study[J].J Am Heart Assoc,2016,5(7):e003328.

    • [8] LAMBERS HEERSPINK H J,WELDEGIORGIS M,INKER L A,et al.Estimated GFR decline as a surrogate end point for kidney failure:a post hoc analysis from the reduction of end points in Non-Insulin-Dependent diabetes with the angiotensin II antagonist losartan(RENAAL)study and irbesartan diabetic nephropathy trial(IDNT)[J].Am J Kidney Dis,2014,632(2):244-250.

    • [9] BERHANE A M,WEIL E J,KNOWLER W C,et al.Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death[J].Clin J Am Soc Nephrol,2011,6(10):2444-2451.

    • [10] KROLEWSKI A S.Progressive renal decline:the new paradigm of diabetic nephropathy in type 1 diabetes[J].Diabetes Care,2015,38(6):954-962.

    • [11] OSHIMA M,JUN M,OHKUMA T,et al.The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes:the ADVANCE-ON study[J].Diabetologia,2019,62(11):1988-1997.

    • [12] American Diabetes Association.11.Microvascular complications and foot care:standards of medical care in diabetes-2019[J].Diabetes Care,2019,42(Suppl 1):S124-S138.

    • [13] DE BOER I H,GAO X,CLEARY P A,et al.Albuminuriachanges and cardiovascular and renal outcomes in type 1 diabetes:the DCCT/EDIC study[J].Clin J Am Soc Nephrol,2016,11(11):1969-1977.

    • [14] MORIYA T,TANAKA S,KAWASAKI R,et al.Diabetic retinopathy and microalbuminuria can predict macroalbuminuria and renal function decline in Japanese type 2 diabetic patients:Japan diabetes complications study[J].Diabetes Care,2013,36(9):2803-2809.

    • [15] 汪志红,何慈江.糖尿病肾病早期生物标志物预测疾病进展的可能性 [J].中华糖尿病杂志,2018,10(4):251-255.

    • [16] GOHDA T,NIEWCZAS M A,FICOCIELLO L H,et al.Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes[J].J Am Soc Nephrol,2012,23(3):516-524.

    • [17] NIEWCZAS M A,GOHDA T,SKUPIEN J,et al.Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes[J].J Am Soc Nephrol,2012,23(3):507-515.

    • [18] COCA S G,NADKARNI G N,HUANG Y,et al.Plasma biomarkers and kidney function decline in early and established diabetic kidney disease[J].J Am Soc Nephrol,2017,28(9):2786-2793.

    • [19] BARR E,BARZI F,HUGHES J T,et al.High baseline levels of tumor necrosis factor receptor 1 are associated with progression of kidney disease in Indigenous Australians with diabetes:the eGFR follow-up study[J].Diabetes Care,2018,41(4):739-747.

    • [20] NOWAK N,SKUPIEN J,SMILES A M,et al.Markers of early progressive renal decline in type 2 diabetes suggest diff erent implications for etiological studies and prognostic tests development[J].Kidney Int,2018,93(5):1198-1206.

    • [21] TAM F W,RISER B L,MEERAN K,et al.Urinary monocyte chemoattractant protein-1(MCP-1)and connective tissue growth factor(CCN2)as prognostic markers for progression of diabetic nephropathy[J].Cytokine,2009,47(1):37-42.

    • [22] TITAN S M,VIEIRA J M,DOMINGUEZ W V,et al.Urinary MCP-1 and RBP:independent predictors of renal outcome in macroalbuminuric diabetic nephropathy[J].J Diabetes Complications,2012,26(6):546-553.

    • [23] VAIDYA V S,NIEWCZAS M A,FICOCIELLO L H,et al.Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers,kidney injury molecule-1,and N-acetyl-beta-D-glucosaminidase[J].Kidney Int,2011,79(4):464-470.

    • [24] CHEN Y H,CHEN H S,TARNG D C.More impact of microalbuminuria on retinopathy than moderately reduced GFR among type 2 diabetic patients[J].Diabetes Care,2012,354(4):803-808.

    • [25] FUFAA G D,WEIL E J,NELSON R G,et al.Association of urinary KIM-1,L-FABP,NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus[J].Diabetologia,2015,58(1):188-198.

    • [26] PANDURU N M,SANDHOLM N,FORSBLOM C,et al.Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy:a likely causal link in patients with type 1 diabetes[J].Diabetes Care,2015,38(6):1130-1137.

    • [27] ZURBIG P,MISCHAK H,MENNE J,et al.CKD273 enables efficient prediction of diabetic nephropathy in nonalbuminuric patients[J].Diabetes Care,2019,42(1):e4-e5.

    • [28] CURRIE G E,VON SCHOLTEN B J,MARY S,et al.Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria[J].Cardiovasc Diabetol,2018,17(1):50.

    • [29] NIEWCZAS M A,MATHEW A V,CROALL S,et al.Circulating modified metabolites and a risk of ESRD in patients with type 1 diabetes and chronic kidney disease[J].Diabetes Care,2017,40(3):383-390.

    • [30] KWAN B,FUHRER T,ZHANG J,et al.Metabolomic markers of kidney function decline in patients with diabetes:evidence from the Chronic Renal Insuffi ciency Cohort(CRIC)study[J].Am J Kidney Dis,2020,76(4):511-520.

    • [31] ZHENG M,LV L L,NI J,et al.Urinary podocyteassociated mRNA profile in various stages of diabetic nephropathy[J].PLoS One,2011,6(5):e20431.

    • [32] ZHENG M,LV L L,CAO Y H,et al.A pilot trial assessing urinary gene expression profiling with an mRNA array for diabetic nephropathy[J].PLoS One,2012,7(5):e34824.

    • [33] ZHENG M,LV L L,CAO Y H,et al.Urinary mRNA markers of epithelial-mesenchymal transition correlate with progression of diabetic nephropathy[J].Clin Endocrinol(Oxf),2012,76(5):657-664.

    • [34] SZETO C C,LAI K B,CHOW K M,et al.Messenger RNA expression of glomerular podocyte markers in the urinary sediment of acquired proteinuric diseases[J].Clin Chim Acta,2005,361(1/2):182-190.

    • [35] WANG G,LAI F M,LAI K B,et al.Messenger RNA expression of podocyte-associated molecules in the urinary sediment of patients with diabetic nephropathy[J].Nephron Clin Pract,2007,34(12):2358-2364.

    • [36] PEZZOLESI M G,SATAKE E,MCDONNELL KP,et al.Circulating TGF-β1-regulated miRNAs and the risk of rapid progression to ESRD in type 1 diabetes[J].Diabetes,2015,649(9):3285-3293.

    • [37] LV L L,FENG Y,TANG T T,et al.New insight into the role of extracellular vesicles in kidney disease[J].J Cell Mol Med,2019,23(2):731-739.

    • [38] LV L L,FENG Y,WU M,et al.Exosomal miRNA-19b3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury[J].Cell Death Differ,2020,27(1):210-226.

    • [39] ABE H,SAKURAI A,ONO H,et al.Urinary exosomal mRNA of WT1 as diagnostic and prognostic biomarker for diabetic nephropathy[J].J Med Invest,2018,65(3/4):208-215.

    • [40] ZHOU L T,LV L L,QIU S,et al.Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease[J].J Transl Med,2019,17(1):59.

  • 参考文献

    • [1] LI Y,TENG D,SHI X,et al.Prevalence of diabetes recorded in mainland China using 2018 diagnostic criteria from the American Diabetes Association:national cross sectional study[J].BMJ,2020,369:m997.

    • [2] ZHANG L,LONG J,JIANG W,et al.Trends in chronic kidney disease in China[J].N Engl J Med,2016,375(9):905-906.

    • [3] ZHANG L,ZHAO M H,ZUO L,et al.China Kidney Disease Network(CK-NET)2015 annual data report[J].Kidney Int Suppl(2011),2019,9(1):e1-e81.

    • [4] ZHANG W R,PARIKH C R.Biomarkers of acute and chronic kidney disease[J].Annu Rev Physiol,2019,81(1):309-333.

    • [5] 中华医学会糖尿病分会微血管并发症学组.中国糖尿病肾脏疾病防治临床指南 [J].中华糖尿病杂志,2019,11(1):15-28.

    • [6] SILVEIRO S P,ARAÚJO G N,FERREIRA M N,et al.Chronic kidney disease epidemiology collaboration(CKD-EPI)equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes[J].Diabetes Care,2011,34(11):2353-2355.

    • [7] LU J,MU Y,SU Q,et al.Reduced kidney function is associated with cardiometabolic risk factors,prevalent and predicted risk of cardiovascular disease in Chinese adults:results from the REACTION study[J].J Am Heart Assoc,2016,5(7):e003328.

    • [8] LAMBERS HEERSPINK H J,WELDEGIORGIS M,INKER L A,et al.Estimated GFR decline as a surrogate end point for kidney failure:a post hoc analysis from the reduction of end points in Non-Insulin-Dependent diabetes with the angiotensin II antagonist losartan(RENAAL)study and irbesartan diabetic nephropathy trial(IDNT)[J].Am J Kidney Dis,2014,632(2):244-250.

    • [9] BERHANE A M,WEIL E J,KNOWLER W C,et al.Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death[J].Clin J Am Soc Nephrol,2011,6(10):2444-2451.

    • [10] KROLEWSKI A S.Progressive renal decline:the new paradigm of diabetic nephropathy in type 1 diabetes[J].Diabetes Care,2015,38(6):954-962.

    • [11] OSHIMA M,JUN M,OHKUMA T,et al.The relationship between eGFR slope and subsequent risk of vascular outcomes and all-cause mortality in type 2 diabetes:the ADVANCE-ON study[J].Diabetologia,2019,62(11):1988-1997.

    • [12] American Diabetes Association.11.Microvascular complications and foot care:standards of medical care in diabetes-2019[J].Diabetes Care,2019,42(Suppl 1):S124-S138.

    • [13] DE BOER I H,GAO X,CLEARY P A,et al.Albuminuriachanges and cardiovascular and renal outcomes in type 1 diabetes:the DCCT/EDIC study[J].Clin J Am Soc Nephrol,2016,11(11):1969-1977.

    • [14] MORIYA T,TANAKA S,KAWASAKI R,et al.Diabetic retinopathy and microalbuminuria can predict macroalbuminuria and renal function decline in Japanese type 2 diabetic patients:Japan diabetes complications study[J].Diabetes Care,2013,36(9):2803-2809.

    • [15] 汪志红,何慈江.糖尿病肾病早期生物标志物预测疾病进展的可能性 [J].中华糖尿病杂志,2018,10(4):251-255.

    • [16] GOHDA T,NIEWCZAS M A,FICOCIELLO L H,et al.Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes[J].J Am Soc Nephrol,2012,23(3):516-524.

    • [17] NIEWCZAS M A,GOHDA T,SKUPIEN J,et al.Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes[J].J Am Soc Nephrol,2012,23(3):507-515.

    • [18] COCA S G,NADKARNI G N,HUANG Y,et al.Plasma biomarkers and kidney function decline in early and established diabetic kidney disease[J].J Am Soc Nephrol,2017,28(9):2786-2793.

    • [19] BARR E,BARZI F,HUGHES J T,et al.High baseline levels of tumor necrosis factor receptor 1 are associated with progression of kidney disease in Indigenous Australians with diabetes:the eGFR follow-up study[J].Diabetes Care,2018,41(4):739-747.

    • [20] NOWAK N,SKUPIEN J,SMILES A M,et al.Markers of early progressive renal decline in type 2 diabetes suggest diff erent implications for etiological studies and prognostic tests development[J].Kidney Int,2018,93(5):1198-1206.

    • [21] TAM F W,RISER B L,MEERAN K,et al.Urinary monocyte chemoattractant protein-1(MCP-1)and connective tissue growth factor(CCN2)as prognostic markers for progression of diabetic nephropathy[J].Cytokine,2009,47(1):37-42.

    • [22] TITAN S M,VIEIRA J M,DOMINGUEZ W V,et al.Urinary MCP-1 and RBP:independent predictors of renal outcome in macroalbuminuric diabetic nephropathy[J].J Diabetes Complications,2012,26(6):546-553.

    • [23] VAIDYA V S,NIEWCZAS M A,FICOCIELLO L H,et al.Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers,kidney injury molecule-1,and N-acetyl-beta-D-glucosaminidase[J].Kidney Int,2011,79(4):464-470.

    • [24] CHEN Y H,CHEN H S,TARNG D C.More impact of microalbuminuria on retinopathy than moderately reduced GFR among type 2 diabetic patients[J].Diabetes Care,2012,354(4):803-808.

    • [25] FUFAA G D,WEIL E J,NELSON R G,et al.Association of urinary KIM-1,L-FABP,NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus[J].Diabetologia,2015,58(1):188-198.

    • [26] PANDURU N M,SANDHOLM N,FORSBLOM C,et al.Kidney injury molecule-1 and the loss of kidney function in diabetic nephropathy:a likely causal link in patients with type 1 diabetes[J].Diabetes Care,2015,38(6):1130-1137.

    • [27] ZURBIG P,MISCHAK H,MENNE J,et al.CKD273 enables efficient prediction of diabetic nephropathy in nonalbuminuric patients[J].Diabetes Care,2019,42(1):e4-e5.

    • [28] CURRIE G E,VON SCHOLTEN B J,MARY S,et al.Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria[J].Cardiovasc Diabetol,2018,17(1):50.

    • [29] NIEWCZAS M A,MATHEW A V,CROALL S,et al.Circulating modified metabolites and a risk of ESRD in patients with type 1 diabetes and chronic kidney disease[J].Diabetes Care,2017,40(3):383-390.

    • [30] KWAN B,FUHRER T,ZHANG J,et al.Metabolomic markers of kidney function decline in patients with diabetes:evidence from the Chronic Renal Insuffi ciency Cohort(CRIC)study[J].Am J Kidney Dis,2020,76(4):511-520.

    • [31] ZHENG M,LV L L,NI J,et al.Urinary podocyteassociated mRNA profile in various stages of diabetic nephropathy[J].PLoS One,2011,6(5):e20431.

    • [32] ZHENG M,LV L L,CAO Y H,et al.A pilot trial assessing urinary gene expression profiling with an mRNA array for diabetic nephropathy[J].PLoS One,2012,7(5):e34824.

    • [33] ZHENG M,LV L L,CAO Y H,et al.Urinary mRNA markers of epithelial-mesenchymal transition correlate with progression of diabetic nephropathy[J].Clin Endocrinol(Oxf),2012,76(5):657-664.

    • [34] SZETO C C,LAI K B,CHOW K M,et al.Messenger RNA expression of glomerular podocyte markers in the urinary sediment of acquired proteinuric diseases[J].Clin Chim Acta,2005,361(1/2):182-190.

    • [35] WANG G,LAI F M,LAI K B,et al.Messenger RNA expression of podocyte-associated molecules in the urinary sediment of patients with diabetic nephropathy[J].Nephron Clin Pract,2007,34(12):2358-2364.

    • [36] PEZZOLESI M G,SATAKE E,MCDONNELL KP,et al.Circulating TGF-β1-regulated miRNAs and the risk of rapid progression to ESRD in type 1 diabetes[J].Diabetes,2015,649(9):3285-3293.

    • [37] LV L L,FENG Y,TANG T T,et al.New insight into the role of extracellular vesicles in kidney disease[J].J Cell Mol Med,2019,23(2):731-739.

    • [38] LV L L,FENG Y,WU M,et al.Exosomal miRNA-19b3p of tubular epithelial cells promotes M1 macrophage activation in kidney injury[J].Cell Death Differ,2020,27(1):210-226.

    • [39] ABE H,SAKURAI A,ONO H,et al.Urinary exosomal mRNA of WT1 as diagnostic and prognostic biomarker for diabetic nephropathy[J].J Med Invest,2018,65(3/4):208-215.

    • [40] ZHOU L T,LV L L,QIU S,et al.Bioinformatics-based discovery of the urinary BBOX1 mRNA as a potential biomarker of diabetic kidney disease[J].J Transl Med,2019,17(1):59.

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