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中性粒与淋巴细胞比值与2型糖尿病肾病的相关性

2019-04-04张宝玉孙荣欣石威等

中国医药导报 2019年4期
关键词:微量肌酐白蛋白

张宝玉 孙荣欣 石威等

[摘要] 目的 探讨中性粒细胞与淋巴细胞比值(NLR)与2型糖尿病肾病(DKD)的相关性。 方法 选取2012年7月~2018年6月于北京潞河医院住院治疗的2型糖尿病患者148例,根据患者8 h尿微量白蛋白排泄率(8°UAER)分为5组:8°UAER<20 μg/min、血清肌酐正常30例为DM1组;20 μg/min≤8°UAER<200 μg/min、血清肌酐正常30例为DM2组;8°UAER≥200 μg/min、血清肌酐正常28例为DM3组;8°UAER≥200 μg/min、血清肌酐>120 μmol/L但尚未透析者29例为DM4组;DM5组为临床诊断DKD行血液透析治疗患者,共31例。选取健康对照者29名为对照组(N组)。空腹静脉采血,检测各组血常规、血糖、血脂、肝肾功,DM1、DM2、DM3、DM4组留取8 h尿,检测8°UAER。 结果 随着DKD进展,NLR逐渐升高,DM4、DM5组高于N、DM1、DM2、DM3组(P < 0.05或P < 0.01),DM3组高于N组和DM1组(P < 0.05)。Pearson相关分析结果显示NLR与年龄(r = 0.317,P < 0.001)、病程(r = 0.306,P < 0.001)、8°UAER(r = 0.293,P = 0.006)、尿素氮(r = 0.404,P < 0.001)、全段甲状旁腺激素(iPTH)(r = 0.465,P < 0.001)呈正相关,与肾小球滤过率(r = -0.438,P < 0.001)、白蛋白(r = -0.194,P = 0.019)、高密度脂蛋白胆固醇(r = -0.182,P = 0.028)呈负相关。多元线性回归方程:YLogNLR = 0.29+0.54Log8°UAER+0.004年龄(R2 = 0.152,P = 0.001);ROC曲线显示,以NLR=2.29作为切点,诊断DKD的灵敏度和特异度分别为52.6%、73.3%(ROC曲线下面积是0.661,95%CI:0.544~0.779,P = 0.014)。 结论 NLR在DKD进展过程中逐渐升高,在临床蛋白尿的2型糖尿病患者中显著升高,与8°UAER呈正相关,但NLR升高晚于8°UAER,提示NLR升高可预测DKD的发生。

[关键词] 糖尿病肾病;中性粒细胞与淋巴细胞比值;2型糖尿病;8 h尿微量白蛋白排泄率

[中图分类号] R587.2          [文献标识码] A          [文章編号] 1673-7210(2019)02(a)-0083-05

[Abstract] Objective To investigate the relationship between neutrophil-to-lymphocyte ratio (NLR) and type 2 diabetic kidney disease (DKD). Methods A total of 148 patients with type 2 diabetes mellitus admitted to Beijing Luhe Hospital from July 2012 to June 2018, and they were divided into 5 groups according to urine albumer excretion rate in 8 h (8°UAER). Thirty patients with 8°UAER<20 μg/min and normal serum creatinine were DM1 group; 30 patients with 20 μg/min≤8°UAER<200 μg/min and normal serum creatinine were DM2 group; 28 patients with 8°UAER≥200 μg/min and normal serum creatinine were DM3 group; 29 patients with 8°UAER≥200 μg/min and serum creatinine>120 μmol/L, not yet been dialysis were DM4 group; 31 patients diagnosed as DKD and been dialysis were DM5 group. Twenty-nine health control individuals were selected as control group (N group). Blood was collected by fasting vein. Blood routine examination, glucose, lipid, liver and kidney function were examined in each group. Eight-hour urine in DM1, DM2, DM3 and DM4 group were collected and 8°UAER were detected. Results NLR gradually increased in DKD progress and NLR in DM4 and DM5 group were higher than that in N, DM1, DM2, DM3 group (P < 0.05 or P < 0.01), NLR in DM3 group was higher than that in N and DM1 group (P < 0.05). The results of Pearson correlation analysis showed that NLR was positively correlated with age (r = 0.317, P < 0.001), course of disease (r = 0.306, P < 0.001), 8°UAER (r = 0.293, P = 0.006), urea nitrogen (r = 0.404, P < 0.001), total parathyroid hormone (iPTH) (r = 0.465, P < 0.001) and was negatively correlated with glomerular filtration rate (r = -0.438, P < 0.001), albumin (r = -0.194, P = 0.019), high-density lipoprotein cholesterol (r = -0.182, P = 0.028). Multiple linear regression equation: YLogNLR = 0.29+0.54Log8°UAER+0.004 age (R2 = 0.152, P = 0.001). ROC curve showed NLR=2.29 as the cut point, and the sensitivity and specificity of DKD diagnosis were 52.6% and 73.3% (area under the ROC curve is 0.661, 95%CI: 0.544-0.779, P = 0.014). Conclusion NLR gradually increases during the progression of diabetic nephropathy, and is significantly high in patients with type 2 diabetes mellitus with proteinuria. It is positively correlated with 8°UAER, but the increase of NLR is later than 8°UAER, suggesting that increasing NLR may predict the occurrence of diabetic kidney disease.

[Key words] Diabetic kidney disease; Neutrophils to lymphocytes ratio; Type 2 diabetes mellitus mellitus; Urinary albumin excretion rate in 8 h

糖尿病的患病人数迅猛增长,2017年全球约有4.25亿2型糖尿病患者[1],我国20岁以上人群2型糖尿病患病率为10.9%[2]。糖尿病肾病(diabetic kidney disease,DKD)是糖尿病最主要的微血管并发症之一,是终末期肾病(end stage renal disease,ESRD)的首要原因[3],早期诊断、预防与延缓DKD的发生发展具有重要意义。目前DKD的诊断主要依靠尿微量白蛋白和肾小球滤过率,但尿微量白蛋白受影响因素多,肾小球滤过率变化相对滞后,因此,需要探讨早期诊断DKD的新型生物标志物。糖尿病及其微血管并发症的发生和慢性炎症及免疫紊乱有关[4]。中性粒与淋巴细胞比值(NRL)可以反映机体的炎性反应状态[5],NLR越高提示炎性反应越剧烈[6]。本文探讨NLR与2型糖尿病肾病的相关性,具体报道如下:

1 资料与方法

1.1 一般资料

收集2012年7月~2018年6月于首都医科大学附属北京潞河医院(以下简称“我院”)住院治疗的2型糖尿病患者148例,符合WHO糖尿病诊断及分型标准[7]。排除标准:①急、慢性尿路感染,肾结石,急、慢性肾炎;②糖尿病酮症、高血糖高渗透压综合征、乳酸酸中毒等;③3个月内的急性心肌梗死、脑梗死、脑出血等;④伴有心力衰竭、肝功能不全、风湿性疾病、甲状旁腺功能亢进、妊娠、肿瘤、骨折等;⑤曾接受过肾移植,半年内服用糖皮质激素、免疫抑制剂及肾毒性药物;⑥剧烈运动、发热、感染性疾病、严重高血压、高血糖等引起蛋白尿者。

将148例2型糖尿病患者根据8 h尿微量白蛋白排泄率(8°UAER)分为5组:8°UAER<20 μg/min、血清肌酐正常30例为DM1组;20 μg/min≤8°UAER<200 μg/min、血清肌酐正常30例为DM2组;8°UAER≥200 μg/min、血清肌酐正常28例为DM3组;8°UAER≥200 μg/min、血清肌酐>120 μmol/L但尚未透析的29例为DM4组;DM5组为临床诊断DKD行血液透析治疗患者,共31例。选取29例健康对照者为对照组(N组),符合条件:①无内分泌、免疫系统疾病和肿瘤病史;②一级亲属无糖尿病病史;③无长期服用影响糖代谢药物史;④无心、肝、肾功能异常;⑤非妊娠状态;⑥无急慢性感染。

本研究经我院医学伦理委员会批准,所有受试者均签署知情同意书。

1.2 观察指标及检测方法:

①受试者隔夜空腹8 h以上,次日清晨抽取静脉血,全自动生化分析仪检测肝肾功能、血糖、血脂;高压液相色谱法检测糖化血红蛋白(HbA1c),血液分析仪检测血常规。②受试者(N、DM5组除外)留取10:00 pm至次晨6:00 am尿液,应用免疫投射比浊法测定尿液中微量白蛋白的浓度,计算8°UAER。

1.3 统计学方法

采用SPSS 22.0统计学软件进行数据分析,符合正态分布计量资料的均数用均数±标准差(x±s)表示,两组间比较采用t检验,多组间比较采用重复测量方差分析;不符合正态分布的改用中位数(M)或四分位数间距(P25~P75)表示,两组间比较采用非参数检验(秩和检验)。计数资料用率表示,组间比较采用χ2检验。简单相关分析采用Pearson相关分析;危险因素采用多元线性回归分析。以P < 0.05为差异有统计学意义。

2 结果

2.1 各组一般资料比较

各组受试者年龄、性别、舒张压比较,差异无统计学意义(P > 0.05),DM5组性别男性比例高于N组(P < 0.05)。DM4、DM5组收缩压均高于N组和DM1组,DM3组高于N组,差异均有统计学意义(P < 0.05或P < 0.01)。N组体重指数低于糖尿病各组,差异均有高度统计学意义(P < 0.05或P < 0.01),DM5组病程长于DM1、DM2组,差异均有高度统计学意义(P < 0.01或P < 0.05)。见表1。

2.2 各组生化指标比较

糖尿病各组的总蛋白(TP)低于N组(P < 0.01),在糖尿病各组中,DM4组TP低于DM2、DM3、DM5、组(P < 0.05或P < 0.01)。糖尿病各组白蛋白(ALB)低于N组(P < 0.01)。糖尿病各组的血葡萄糖(GLU)均显著高于N组(P < 0.01);DM1、DM2、DM3、DM4组HbA1c显著高于N组和DM5组(P < 0.01)。DM4、DM5组肾小球滤过率(GFR)低于N、DM1、DM2、DM3组(P < 0.01)。糖尿病各组三酰甘油(TG)水平高于N组(P < 0.05或P < 0.01),各组间LDL-C比较差异无统计学意义(P > 0.05)。见表2。

2.3 各组全血细胞分析结果比较

中性粒细胞(NEUT)计数DM4组高于N、DM1、DM2、DM5组,差异均有统计学意义(P < 0.05或P < 0.01)。淋巴细胞(LYMPH)计数DM5、DM4组显著低于N、DM1、DM2、DM3组,差异均有高度统计学意义(P < 0.01),MD3组低于DM1、DM2组(P < 0.05或P < 0.01),隨着DKD进展,NRL逐渐升高,DM5、DM4组显著高于N、DM1、DM2、DM3组,差异均有高度统计学意义(P < 0.05或P < 0.01),DM3组高于N、DM1组(P < 0.05)。见表3。

2.4 Pearson相关分析和多元线性回归分析

Pearson相关分析显示,NLR与年龄(r = 0.317,P < 0.001)、病程(r = 0.306,P < 0.001)、8°UAER(r = 0.293,P = 0.006)、尿素氮(BUN)(r = 0.404,P < 0.001)、全段甲状旁腺素(iPTH)(r = 0.465,P < 0.001)呈正相关,与GFR(r = -0.438,P < 0.001)、ALB(r = -0.194,P = 0.019)、高密度脂蛋白胆固醇(HDL-C)(r = -0.182,P = 0.028)呈负相關。多元线性回归分析中,对NLR进行Log转换并作为因变量,将年龄、病程、Log8°UAER、eGFR、iPTH、LogCHO为自变量,回归方程为YLogNLR = 0.29+0.54Log8°UAER+0.004年龄(R2 = 0.152,P = 0.001),NLR与8°UAER和年龄呈正相关。以8°UAER≥20 μg/min为诊断DKD的标准,ROC曲线显示以NLR=2.29作为切点,诊断DKD的灵敏度是52.6%,特异度是73.3%(AUC=0.661,95%CI:0.544~0.779,P = 0.014)。见图1。

3 讨论

DKD是糖尿病患者死亡的独立危险因素,DKD导致的ESRD患者每年死亡率约为20%,高于前列腺癌、乳腺,甚至肾细胞瘤等[8]。DKD进展到临床蛋白尿期,则无法逆转,快速进展为ESRD,需要血液透析或肾脏移植维持生命。DKD的发病机制尚不清楚,代谢紊乱[9]、炎性反应[10]、细胞因子[11]、遗传因素、氧化应激[12]、激肽系统及自噬[13]等均参与DKD的发生。有学者认为慢性炎症状态是DKD发生、发展的重要因素[10]。高血糖和氧化应激可以诱导核因子κβ(NF-κβ)的分泌增多,刺激ICAM-1、前炎症因子、趋化因子等,最终导致NEUT增加。2型糖尿病及其并发症患者中,由于慢性炎症状态下氧化的DNA损伤和外周血LYMPH凋亡,LYMPH减少[14]。NLR反映慢性炎症状态下该两种细胞比例的失衡。NLR与高血压[15]、糖尿病[16]、恶性肿瘤等[6]相关。

本研究显示,糖尿病组NLR显著高于N组,和既往研究一致[16-17]。在糖尿病患者中,随着DKD的进展,NRL水平逐渐升高,DM4组、DM5组NLR水平最高。Pearson相关分析提示NLR和8°UAER、年龄、病程、BUN、iPTH呈正相关。Afsar[18]在新诊断的2型糖尿病患者中发现NLR与尿微量白蛋白排泄率正相关。Huang等[19]研究发现NLR和早期DKD的相关,且NLR值升高可能预测DKD发生。本研究DM2组NLR值较正常组升高,但差异无统计学意义(P > 0.01),考虑本研究UAER为一次尿检结果,不能完全代表患者肾脏损伤程度,可能有些受试者为一过性微量白蛋白尿,也可能与本研究样本量小有关。

相关文献[20]报道,DKD患者的白细胞计数及NEUT绝对值随着DKD进展,逐渐增加,但具体机制不明确,在本研究未观察到。本研究中糖尿病患者随着DKD的进展,LYMPH绝对值逐渐减少。Lorenzo等[21]研究显示LYMPH计数与胰岛素的敏感指数呈负相关,LYMPH的减少与糖尿病的发生相关。在糖尿病并发症中的发生、发展中,淋巴细胞的作用还有待于进一步研究。

本研究根据8°UAER和肌酐水平诊断DKD,以NLR=2.29作为切点,用NLR诊断DKD的灵敏度是52.6%,特异度是73.3%,提示NLR变化晚于尿微量白蛋白排泄率,仍不是DKD理想的预测指标。但NLR检测简单、快捷、价格低廉。对NLR的重视有助于临床医师对DKD的筛查,可以协助基层医务工作者预测DKD的发生。相对于其他的炎症指标,如C反应蛋白、肿瘤坏死因子-α、白细胞介素(IL)-6、IL-1β等,NLR价格低廉,多数实验室都可以完成,可以作为筛查指标。

本研究的局限性在于是横断面研究,不能推断NRL和DKD的因果关系,如需推断NLR与2型糖尿病肾病之间的因果关系,需要扩大样本含量,进行多中心研究。部分患者有高血压,DM5组性别和N组男性比例较高,可能存在混杂偏倚,研究样本量少,需要更大规模的进一步研究。

综上所述,NLR作为一种新的炎症指标,在DKD进展过程中逐渐升高,在临床蛋白尿的2型糖尿病患者中显著升高,与8°UAER呈正相关,但NLR升高晚于8°UAER,提示NLR升高有可能预测糖尿病肾病的发生。

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(收稿日期:2018-06-25  本文編辑:金   虹)

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