程云鵬，孫彥翠，祝艷秋，張 英，路 巖，姜一農(nóng)

(1.大連醫(yī)科大學(xué)附屬第一醫(yī)院 心內(nèi)科，遼寧 大連 116011；2.大連大學(xué)附屬中山醫(yī)院 超聲科，遼寧 大連 116001)

論 著

原發(fā)性高血壓患者血中性粒細(xì)胞/淋巴細(xì)胞比值與微量白蛋白尿的關(guān)系

程云鵬1，孫彥翠1，祝艷秋2，張 英1，路 巖1，姜一農(nóng)1

(1.大連醫(yī)科大學(xué)附屬第一醫(yī)院 心內(nèi)科，遼寧 大連 116011；2.大連大學(xué)附屬中山醫(yī)院 超聲科，遼寧 大連 116001)

目的 探索在原發(fā)性高血壓人群中性粒細(xì)胞/淋巴細(xì)胞比值(NLR)與微量白蛋白尿(MAU)的相關(guān)性，并與傳統(tǒng)預(yù)測(cè)因子同型半胱氨酸及超敏C反應(yīng)蛋白對(duì)MAU的診斷價(jià)值進(jìn)行比較。方法 收集2012年11月至2014年10月大連醫(yī)科大學(xué)附屬第一醫(yī)院高血壓科住院的原發(fā)性高血壓患者222例，分為原發(fā)性高血壓組(n=121)與原發(fā)性高血壓合并微量白蛋白尿組(n=101)。記錄各組性別、年齡、身高、體重、吸煙史、他汀類(lèi)藥物與血管緊張素轉(zhuǎn)換酶抑制劑/血管緊張素受體拮抗劑類(lèi)藥物應(yīng)用史、血壓；入院次日晨收集尿及空腹血，測(cè)量尿微量白蛋白、尿肌酐及血常規(guī)、血脂、血清同型半胱氨酸、超敏C反應(yīng)蛋白、血清肌酐。計(jì)算體重指數(shù)、尿微量白蛋白/尿肌酐比值、肌酐清除率及血中性粒細(xì)胞/淋巴細(xì)胞比值。結(jié)果 原發(fā)性高血壓組與原發(fā)性高血壓合并蛋白尿組的收縮壓、舒張壓、血清同型半胱氨酸、超敏C反應(yīng)蛋白、血中性粒細(xì)胞/淋巴細(xì)胞比值比較有統(tǒng)計(jì)學(xué)差異[(166.16±20.24)vs. (175.24±20.25)mmHg；(104.56±12.74) vs.(109.99±16.35)mmHg；(0.84±0.15)vs.(0.92±0.10)μmol/L；(1.08±1.05)vs.(3.04±6.91)mg/L；(1.78±0.80)vs.(1.29±0.36)；均P<0.05]。 血中性粒細(xì)胞/淋巴細(xì)胞比值與尿微量白蛋白/尿肌酐比值呈正相關(guān)(r=0.260,P=0.000)，且為微量白蛋白尿的獨(dú)立危險(xiǎn)因素；Logistics多元回歸分析提示，其與微量白蛋白尿的相關(guān)系數(shù)小于血清同型半胱氨酸，但明顯大于超敏C反應(yīng)蛋白。 結(jié)論 NLR升高可能是高血壓患者出現(xiàn)微量白蛋白尿的獨(dú)立危險(xiǎn)因素；其與微量白蛋白尿的相關(guān)性可能弱于血清同型半胱氨酸，但明顯強(qiáng)于超敏C反應(yīng)蛋白。

中性粒細(xì)胞/淋巴細(xì)胞比值；早期腎損害；原發(fā)性高血壓

高血壓嚴(yán)重威脅人類(lèi)健康，腎臟是高血壓作用的重要靶器官，其早期異?？杀憩F(xiàn)為微量白蛋白尿(microalbuminuria，MAU)的出現(xiàn)，后者與心血管事件增加、心血管死亡率及全因死亡率呈正相關(guān)[1-4]。外周血中性粒細(xì)胞/淋巴細(xì)胞比值(neutrophil/lymphocyte ratio，NLR)為全血中性粒細(xì)胞計(jì)數(shù)與淋巴細(xì)胞計(jì)數(shù)的比值。作為一種新型炎癥與氧化應(yīng)激標(biāo)志物，其比全血白細(xì)胞計(jì)數(shù)或單獨(dú)的中性粒細(xì)胞計(jì)數(shù)對(duì)臨床心血管不良事件更加具有預(yù)測(cè)價(jià)值[5-6]。本研究旨在探索高血壓人群NLR與MAU的相關(guān)性，并與傳統(tǒng)預(yù)測(cè)因子，如同型半胱氨酸、超敏C反應(yīng)蛋白對(duì)MAU的診斷價(jià)值進(jìn)行比較。

1 資料與方法

1.1 研究對(duì)象與篩選方法

收集2012年11月至2014年10月大連醫(yī)科大學(xué)附屬第一醫(yī)院高血壓科收治的18～74歲原發(fā)性高血壓患者222例，根據(jù)是否合并MAU，分為原發(fā)性高血壓組(essential hypertension, EH)組(n=121)與EH合并MAU組(MAU組，n=101)。高血壓的診斷根據(jù)《中國(guó)高血壓防治指南2010》[7]。排除標(biāo)準(zhǔn)：繼發(fā)性高血壓或白大衣性高血壓；可導(dǎo)致NLR升高的疾病，包括結(jié)締組織病、自身免疫性疾病、血液病、周?chē)苄约膊?、血脂代謝異常、冠狀動(dòng)脈粥樣硬化性心臟病、感染性疾病、創(chuàng)傷或2周以?xún)?nèi)的外科手術(shù)、惡性腫瘤、嚴(yán)重心力衰竭、合并嚴(yán)重心臟瓣膜病、心肌病、先天性心臟病、肺源性心臟??；近期使用可影響血常規(guī)的藥物，如免疫抑制劑或類(lèi)固醇類(lèi)藥物；嚴(yán)重肝、腎功能障礙。

1.2 臨床資料

記錄入選病例的臨床資料，包括性別、年齡、身高、體質(zhì)量、高血壓病史、吸煙史、服藥史。計(jì)算體質(zhì)量指數(shù)。入院第二日晨收集空腹靜脈血與尿液標(biāo)本，檢測(cè)全血細(xì)胞計(jì)數(shù)、總膽固醇、甘油三酯、高密度脂蛋白膽固醇、低密度脂蛋白膽固醇、血糖、血肌酐、同型半胱氨酸、超敏C反應(yīng)蛋白、尿微量白蛋白及尿肌酐。計(jì)算下列數(shù)據(jù)：(1)腎小球?yàn)V過(guò)率，根據(jù)MDRD公式計(jì)算：Ccr (mL/min) = (140-年齡)×體質(zhì)量(kg)×72-1×血肌酐濃度(mg/dL)(男性)或(140-年齡) ×體質(zhì)量(kg)×85-1×血肌酐濃度(mg/dL)(女性)；(2)尿微量白蛋白/肌酐比值(UACR)：UACR (mg/g) = 尿白蛋白(mg/L) /尿肌酐(μmol/L)× 88.4；MAU定義為UACR≥30 mg/g[7]；(3)體質(zhì)量指數(shù)(kg/m2)=體質(zhì)量/身高2；(4)NLR=外周血中性粒細(xì)胞計(jì)數(shù)/外周血淋巴細(xì)胞計(jì)數(shù)。

1.3 統(tǒng)計(jì)學(xué)方法

2 結(jié) 果

2.1 EH組與MAU組間臨床資料比較

兩組間性別、年齡、吸煙史、體質(zhì)量指數(shù)、總膽固醇、甘油三酯、高密度脂蛋白膽固醇、低密度脂蛋白膽固醇、空腹血糖、血清肌酐、肌酐清除率、服藥史及外周血淋巴細(xì)胞計(jì)數(shù)無(wú)統(tǒng)計(jì)學(xué)差異(P>0.05)。MAU組收縮壓、舒張壓、同型半胱氨酸、超敏C反應(yīng)蛋白、UACR、外周血白細(xì)胞計(jì)數(shù)、外周血中性粒細(xì)胞計(jì)數(shù)及NLR明顯高于EH組，具有統(tǒng)計(jì)學(xué)差異(P<0.05)。見(jiàn)表1。

2.2 所有入組患者收縮壓、舒張壓、同型半胱氨酸、超敏C反應(yīng)蛋白、NLR與UACR的相關(guān)性分析

Pearson相關(guān)分析顯示，UACR與收縮壓、舒張壓、同型半胱氨酸、超敏C反應(yīng)蛋白及NLR呈正相關(guān)(P<0.05)，且UACR與NLR的相關(guān)性最強(qiáng)。見(jiàn)表2。將上述變量代入多因素Logistic回歸方程，校正相關(guān)因素后，同型半胱氨酸、超敏C反應(yīng)蛋白及NLR為高血壓微量白蛋白尿的獨(dú)立危險(xiǎn)因素。見(jiàn)表3。

表1 高血壓組與高血壓合并微量白蛋白尿組臨床資料比較

ACEI：血管緊張素轉(zhuǎn)換酶抑制劑；ARB：血管緊張素受體阻滯劑；1)與高血壓組相比，P<0.05

表2 UACR與各因子的相關(guān)性分析

Tab 2 Correlation of UACR with SBP,DBP,Hcy,hs-CRP and NLR

自變量rP收縮壓0.2330.000舒張壓0.1950.004同型半胱氨酸0.1880.005超敏C反應(yīng)蛋白0.1580.019NLR0.2600.000

表3 Logistic回歸模型中與高血壓微量白蛋白尿相關(guān)因素的分析

Tab 3 Multifactor Logistic regression analysis of risk factor of microalbuminuria in hypertensive patients

因素OR95%CIP收縮壓1.0240.994-1.0550.119舒張壓1.0090.989-1.0300.375同型半胱氨酸9.2811.428-60.3280.020超敏C反應(yīng)蛋白1.3611.069-1.7340.012NLR4.2272.161-8.2670.000

3 討 論

NLR可通過(guò)血細(xì)胞計(jì)數(shù)獲得，其通過(guò)中性粒細(xì)胞與淋巴細(xì)胞計(jì)數(shù)獲得，整合了這兩種白細(xì)胞亞型的信息，受其它因素影響較單一種類(lèi)細(xì)胞小，使得其在臨床應(yīng)用中可能較白細(xì)胞計(jì)數(shù)或中性粒細(xì)胞計(jì)數(shù)有更好的預(yù)測(cè)價(jià)值[4,8]。NLR升高在多種心血管疾病中提示預(yù)后不良，如冠狀動(dòng)脈疾病[9-12]、心力衰竭[13-15]、及心房纖顫[16-18]，并可作為發(fā)生高血壓的預(yù)測(cè)因子[19-21]。

在本研究中，我們發(fā)現(xiàn)高血壓合并蛋白尿組的NLR明顯高于高血壓組，且NLR與MAU呈正相關(guān)，提示NLR升高可能促進(jìn)高血壓患者M(jìn)AU的發(fā)生。劉建峰等[8]發(fā)現(xiàn)，高血壓人群中，腎小球?yàn)V過(guò)率估值(eGFR)下降者NLR水平明顯高于eGFR正常者，eGFR與NLR呈負(fù)相關(guān)，提示NLR水平的變化可能反映腎功能的變化。以上研究均提示，NLR可能是原發(fā)性高血壓患者早期腎功能損害的獨(dú)立危險(xiǎn)因素。

在高血壓患者，與微量白蛋白尿明確相關(guān)且常用的炎癥指標(biāo)為超敏C反應(yīng)蛋白[22]及同型半胱氨酸[23]，在本研究中，亦發(fā)現(xiàn)微量白蛋白尿與上述兩種指標(biāo)呈正相關(guān)。同時(shí)，在Logistics多元回歸中，NLR與MAU的相關(guān)系數(shù)小于同型半胱氨酸，但明顯大于超敏C反應(yīng)蛋白，提示其與MAU的相關(guān)性可能強(qiáng)于超敏C反應(yīng)蛋白。由于血細(xì)胞分析是臨床工作實(shí)踐中的常規(guī)檢查，與同型半胱氨酸及超敏C反應(yīng)蛋白相比，無(wú)需進(jìn)一步特殊化驗(yàn)，價(jià)格低廉，因此，其可能具有一定的臨床參考價(jià)值。

但目前仍有些問(wèn)題尚未解決。首先，NLR的正常值范圍尚未建立；其次，高血壓患者經(jīng)常合并各種疾病，如糖尿病、腎病等，且常同時(shí)服用多種藥物，這些均可在一定程度上影響中性粒細(xì)胞計(jì)數(shù)與淋巴細(xì)胞計(jì)數(shù)；最后，本文入選樣本量偏小，且為單中心研究，需要進(jìn)一步擴(kuò)大樣本量及多中心抽樣，以進(jìn)一步完善相關(guān)根據(jù)。

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Relationship between neutrophil to lymphocyte ratio and microalbuminuriain essential hypertensive patients

CHENG Yunpeng1, SUN Yancui1, ZHU Yanqiu2, ZHANG Ying1, LU Yan1, JIANG Yinong1

(1.DepartmentofCardiology，theFirstAffiliatedHospitalofDalianMedicalUniversity，Dalian116011，China；2.DepartmentofUltrasonic，theAffiliatedZhongshanHospitalofDalianUniversity，Dalian116001，China)

Objective To assess the relationship between neutrophil to lymphocyte ratio (NLR) and microalbuminuria (MAU) in essential hypertensive (EH) patients and to compare the diagnostic efficacy of microalbuminuria between NLR and homocysteine (Hcy), high sensitivity C-reactive protein (hs-CRP). Methods A total of 222 adult hospitalized EH subjects were divided into EH+MAU (MAU) group (n=101) and EH group (n=121) according to whether combined with MAU. Background data, including gender, age, smoking, body weight, height, systolic blood pressure (SBP), diastolic blood pressure (DBP), cholesterol, glycerides, low density lipoprotein (LDL), high density lipoprotein (HDL), fasting blood glucose (FBG), Hcy, hs-CRP, creatinine, and history of medication of statins or ACEI/ARB were collected. BMI, creatinine clearance, urine microalbumin/creatinine ratio (UACR), and NLR were calculated respectively. Results Compared with the EH group, the SBP, DBP, Hcy, hs-CRP and NLR of MAU group were significantly increased (166.16±20.24) vs. (75.24±20.25) mmHg, (104.56±12.74) vs. (109.99±16.35) mmHg, (0.84±0.15) vs. (0.92±0.10) μmol/L, (1.08±1.05) vs. (3.04±6.91) mg/L, (1.78±0.80) vs. (1.29±0.36),P<0.05, respectively. NLR was positively correlated with UACR (r=0.260,P=0.000). Logistics multivariate regression analysis showed that the correlation coefficient of NLR and MAU was lower than that of Hcy, but significantly higher than that of hs-CRP. Conclusion NLR could probably be an independent risk factor of MAU in hypertensive patients, the association of NLR with MAU might be weaker than that of Hcy, but higher than that of hs-CRP.

neutrophil to lymphocyte ratio; early renal damage; essential hypertension

程云鵬(1981-)，男，副教授。E-mail：yunpeng_cheng@hotmail.com

姜一農(nóng)，教授。E-mail：yinongjiang@126.com

10.11724/jdmu.2017.01.13

R544

A

1671-7295(2017)01-0058-04

程云鵬，孫彥翠，祝艷秋，等.原發(fā)性高血壓患者血中性粒細(xì)胞/淋巴細(xì)胞比值與微量白蛋白尿的關(guān)系[J].大連醫(yī)科大學(xué)學(xué)報(bào)，2017,39(1)：58-61.

2016-11-03；

2016-12-25)