張若林 帥蘭軍 李曉燕 陳海霞 王 英 何慶南

·論著·

出生體重與慢性腎臟病關(guān)聯(lián)性的系統(tǒng)評(píng)價(jià)和Meta分析

張若林 帥蘭軍 李曉燕 陳海霞 王 英 何慶南

目的 系統(tǒng)評(píng)價(jià)出生體重與慢性腎臟病風(fēng)險(xiǎn)的關(guān)聯(lián)性。方法 電子檢索The Cochrane圖書館、MEDLINE、OVID數(shù)據(jù)庫(kù)、Springer數(shù)據(jù)庫(kù)、維普數(shù)據(jù)庫(kù)、萬方數(shù)據(jù)庫(kù)和中國(guó)知網(wǎng)，檢索時(shí)間為建庫(kù)截止至2016年6月，納入以BW為暴露因素、評(píng)估生后發(fā)生CKD或其相關(guān)結(jié)局變量的觀察性研究，文獻(xiàn)需對(duì)CKD或其他結(jié)局變量的診斷標(biāo)準(zhǔn)做出描述并能提取CKD或其相關(guān)結(jié)局變量的OR值及其95%CI，語種限定為中、英文；排除文獻(xiàn)：研究對(duì)象生后12個(gè)月內(nèi)腎功能衰竭和死亡、有宮內(nèi)感染病史或患先天遺傳性疾病，母孕期暴露因素有潛在毒性物質(zhì)接觸史，研究人群包括成人和兒童但無法單獨(dú)提取兒童數(shù)據(jù)。由兩位作者獨(dú)立檢索關(guān)于出生體重(BW)對(duì)CKD風(fēng)險(xiǎn)相關(guān)的觀察性研究，病例對(duì)照和隊(duì)列研究采用NOS量表、橫斷面研究采用AHRQ量表對(duì)文獻(xiàn)進(jìn)行偏倚風(fēng)險(xiǎn)評(píng)價(jià)，提取OR值和95%CI。應(yīng)用Stata 12.0對(duì)文獻(xiàn)進(jìn)行Meta分析，均選用DerSimonian & Laird隨機(jī)效應(yīng)模型分析。結(jié)果 10篇觀察性研究納入本文分析，其中病例對(duì)照4篇(3篇8分，1篇7分)，隊(duì)列研究4篇(3篇7分，1篇8分)，橫斷面研究2篇(1篇7分，1篇8分)。慢性腎臟病風(fēng)險(xiǎn)低出生體重(LBW)較正常BW人群高約80%，OR=1.80，95%CI：1.37～2.35；其中蛋白尿、終末期腎臟病和低eGFR在LBW較正常BW人群的OR及其95%CI分別為2.58(1.49～4.46)、1.42(1.22～1.66)和1.87(1.19～2.94)。終末期腎臟病、低eGFR在高出生體重(HBW)中較正常BW人群的OR及其95% CI分別為1.19(0.94～1.49)和1.09(0.93～1.27)，HBW與生后慢性腎臟病之間無明顯關(guān)聯(lián)；LBW人群作為慢性腎臟病的高危人群僅見于男性人群中，OR=1.83，95%CI：1.10～3.05)。Egger回歸提示納入文獻(xiàn)不存在發(fā)表偏倚。結(jié)論 男性LBW是CKD的高危因素，HBW與生后CKD的發(fā)生無明顯關(guān)聯(lián)。

出生體重； 慢性腎臟?。?蛋白尿； 觀察性研究； Meta分析

新生兒重癥監(jiān)護(hù)技術(shù)在過去50年中取得了重大突破，牛津大學(xué)最近數(shù)據(jù)顯示，超過90%的低出生體重(LBW)兒得以挽救，其中60%以上無嚴(yán)重并發(fā)癥[1]。然而， LBW是否為某些慢性疾病的前驅(qū)因素，目前仍不明朗。胎兒起源學(xué)說推測(cè)宮內(nèi)營(yíng)養(yǎng)不良將導(dǎo)致胎兒永久性的生理及代謝異常，從而增加成年期慢性疾病的風(fēng)險(xiǎn)[2]，例如高血壓、糖耐量異常、血脂異常、心血管疾病以及神經(jīng)系統(tǒng)認(rèn)知異常等[2～5]。同時(shí)“營(yíng)養(yǎng)過剩學(xué)說”指出，高出生體重(HBW)是肥胖和代謝異常的高危因素[6, 7]，并可能通過此途徑而增加慢性腎臟病(CKD)的患病風(fēng)險(xiǎn)。近年來，CKD發(fā)病率呈逐漸上升趨勢(shì)[8～10]。在美國(guó)約11.5%的成年人患有CKD，為終末期腎臟病(ESRD)所支出的醫(yī)療費(fèi)用占總醫(yī)療預(yù)算的6.7%[11]。迄今為止，CKD仍無法治愈[12]。對(duì)CKD的高危人群進(jìn)行早期監(jiān)測(cè)和篩選非常重要。

出生體重(BW)是胎兒宮內(nèi)發(fā)育的重要指標(biāo)，可用于評(píng)價(jià)器官發(fā)育的程度。Hughson和Manalich等[13, 14]研究指出，BW與生后腎小球?yàn)V過率(GFR)正相關(guān)，與尿蛋白定量負(fù)相關(guān)。目前關(guān)于BW與腎臟病潛在相關(guān)機(jī)制的觀點(diǎn)各異[15]?；诹餍胁W(xué)和動(dòng)物模型的研究[16～18]認(rèn)為，BW和腎單位數(shù)目變化的關(guān)聯(lián)是最直接的機(jī)制[19]；也有學(xué)者認(rèn)為[20]，心血管疾病的高危因素和CKD有明顯的家族聚集性，如何區(qū)分遺傳因素和環(huán)境因素的影響目前尚無定論。

本研究旨在通過Meta分析方法評(píng)價(jià)BW與CKD的關(guān)聯(lián)性，為臨床對(duì)高危人群CKD監(jiān)測(cè)的選擇提供參考。

1 方法

1.1 文獻(xiàn)納入標(biāo)準(zhǔn) ①觀察性研究(病例對(duì)照研究、隊(duì)列研究和橫斷面研究)；②以BW為暴露因素,評(píng)估生后CKD或其相關(guān)結(jié)局變量；③文獻(xiàn)中描述了CKD或其他結(jié)局變量(蛋白尿、低eGFR)的診斷標(biāo)準(zhǔn)；④能提取CKD或其相關(guān)結(jié)局變量的OR值及其95%CI；⑤重復(fù)發(fā)表的文獻(xiàn)，取樣本量較大的文獻(xiàn)，同一研究不同觀察時(shí)間發(fā)表的文獻(xiàn)，取觀察時(shí)間最長(zhǎng)的文獻(xiàn)；⑥語種限定為中、英文。

1.2 文獻(xiàn)排除標(biāo)準(zhǔn) ①研究對(duì)象生后12個(gè)月內(nèi)發(fā)生腎功能衰竭或死亡的文獻(xiàn)；②研究對(duì)象有宮內(nèi)感染病史；③母孕期暴露因素有潛在毒性物質(zhì)；④研究對(duì)象患先天遺傳性疾病；⑤無法單獨(dú)提取兒童數(shù)據(jù)的文獻(xiàn)。

1.3 結(jié)局指標(biāo) BW與生后CKD發(fā)病風(fēng)險(xiǎn)關(guān)聯(lián)強(qiáng)度的OR及其95% CI。

1.4 文獻(xiàn)檢索 以修訂版的觀察性研究Meta分析指南(MOOSE)[21]為指導(dǎo)。檢索數(shù)據(jù)庫(kù)包括The Cochrane Library、MEDLINE、 OVID 、Springer和維普數(shù)據(jù)庫(kù)、萬方數(shù)據(jù)庫(kù)、中國(guó)知網(wǎng)。中文檢索詞為：出生體重、慢性腎臟病、腎衰竭、蛋白尿、腎小球?yàn)V過率、觀察性研究；英文數(shù)據(jù)庫(kù)以MEDLINE為例，檢索檢索詞和檢索式如下：(AB birth weight OR AB low birth weight OR AB high birth weight OR AB very low birth weight)AND ((AB ( kidney disease or renal disease ) OR AB ( chronic kidney disease or chronic renal failure ) OR AB ( kidney failure or renal failure ) OR AB glomerular filtration function OR AB glomerular filtration rate OR AB albuminuria ；回溯納入文獻(xiàn)的參考文獻(xiàn)。檢索時(shí)間均為建庫(kù)至 2016年6月24日。

1.5 文獻(xiàn)篩選、資料提取和偏倚風(fēng)險(xiǎn)評(píng)估 由張若林和帥蘭軍各自獨(dú)立完成，如遇分歧由李曉燕決定。采用自制資料登記表提取納入文獻(xiàn)數(shù)據(jù)，包括題目、發(fā)表年份、研究設(shè)計(jì)、受試對(duì)象、樣本量、結(jié)局指標(biāo)和暴露因素等。隊(duì)列、病例對(duì)照研究采用NOS量表[22,23]行偏倚風(fēng)險(xiǎn)評(píng)價(jià)，總分為 9 分，評(píng)分≥7分為高質(zhì)量研究。橫斷面研究采用AHRQ量表[24]行偏倚風(fēng)險(xiǎn)評(píng)價(jià)，共包含11個(gè)條目，各條目均評(píng)為“是”(1分)、“否”和“不清楚”(0分)；評(píng)分0～3分為低質(zhì)量文獻(xiàn)，～7分為中等質(zhì)量文獻(xiàn)，～11分為高質(zhì)量文獻(xiàn)。

1.6 統(tǒng)計(jì)學(xué)方法 采用Stata 12.0軟件進(jìn)行 Meta 分析，效應(yīng)量以O(shè)R及其 95%CI表示。納入文獻(xiàn)由于樣本量不同、年齡段不同以及結(jié)局變量測(cè)量的時(shí)間不定，不可避免地造成偏倚，均選擇DerSimonian & Laird隨機(jī)效應(yīng)模型分析。應(yīng)用Egger回歸對(duì)文獻(xiàn)進(jìn)行發(fā)表偏倚分析。

2 結(jié)果

2.1 一般情況 初步檢索到919篇相關(guān)文獻(xiàn)，符合本文納入和排除標(biāo)準(zhǔn)的10篇文獻(xiàn)進(jìn)入本文Meta分析，文獻(xiàn)篩選流程見圖1。表1顯示納入文獻(xiàn)的基本特征，其中病例對(duì)照研究4篇[26, 28, 30, 34]，隊(duì)列研究4篇[25, 31～33]，橫斷面研究2篇[27, 29]。

圖1 文獻(xiàn)篩選流程圖

2.2 文獻(xiàn)偏倚評(píng)價(jià)結(jié)果 ①4篇隊(duì)列研究的NOS量表評(píng)價(jià)：3篇[25,31,33]總分8分，文獻(xiàn)[32]為7分。條目8“觀察到結(jié)局發(fā)生隨訪是否充分”和條目9“隨訪的完整性”，4篇文獻(xiàn)均為0分。文獻(xiàn)[32]條目6“研究控制了其他重要的混雜因素”為0分。②4篇病例對(duì)照研究的NOS量表評(píng)價(jià)：3篇[26,28,30]總分為7分，1篇[34]為8分。條目1～5、7和8，4篇文獻(xiàn)均為1分，條目6“研究控制了重要的混雜因素”除文獻(xiàn)[34]外均為0分，條目9“無應(yīng)答率”均被評(píng)為0分。 ③ 2篇橫斷面研究的AHRQ量表評(píng)價(jià)：條目4“如果不是人群來源的話，研究對(duì)象是否連續(xù)？”和條目11“如果有隨訪，查明預(yù)期的患者不完整數(shù)據(jù)所占的百分比或隨訪結(jié)果”不適用；條目10“總結(jié)了患者的應(yīng)答率及收集的完整性”，2篇文獻(xiàn)均為“否”；條目2、3、5～9均為“是”；條目1 “是否明確了資料的來源”，文獻(xiàn)[27]為“不清楚”。

2.3 Meta分析結(jié)果

2.3.1 LBW與CKD的定量分析 10篇文獻(xiàn)均具體描述了以CKD為結(jié)局變量的相應(yīng)指標(biāo)，且均提供了完整的Logistic回歸的OR值以及95%CI。圖2顯示，LBW人群較正常BW人群CKD的發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P<0.001)，OR=1.79，95%CI：1.37～2.34。4篇文獻(xiàn)[25～27,29]報(bào)道了LBW與蛋白尿的關(guān)聯(lián)性，LBW人群較正常BW人群CKD的發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P<0.001)，OR=2.58，95%CI：1.49～4.46。3篇文獻(xiàn)[28,30,31]以ESRD為結(jié)局變量并報(bào)道了LBW與ESRD的關(guān)聯(lián)性，LBW人群較正常BW人群CKD的發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P<0.001)，OR=1.42，95%CI：1.22～1.66。3篇文獻(xiàn)[32～34]報(bào)道LBW與低eGFR和其他類型CKD關(guān)聯(lián)性，LBW人群較正常BW人群CKD的發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，OR=1.87，95% CI：1.19～2.94。

圖2 LBW與CKD關(guān)聯(lián)的Meta分析

圖3 敏感性分析

圖4 HBW與CKD關(guān)聯(lián)的Meta分析

2.3.2 敏感性分析 剔除2篇橫斷面研究，行LBW與CKD的關(guān)系亞組分析，圖3顯示，病例對(duì)照研究和隊(duì)列研究中LBW人群較正常BW人群CKD的風(fēng)險(xiǎn)均增高，差異有統(tǒng)計(jì)學(xué)意義(P<0.05)，OR=1.69，95%CI：1.23～2.30；OR=1.79，95%CI：1.18～2.72。

2.3.3 HBW與CKD的定量分析 圖4顯示，6篇文獻(xiàn)[25, 28, 30, 31, 33, 34]同時(shí)比較了巨大兒(≥4 000 g)和正常BW人群的CKD發(fā)生風(fēng)險(xiǎn)。其中，Nelson等[25]以蛋白尿?yàn)榻Y(jié)局變量，描述了HBW人群與蛋白尿的關(guān)聯(lián)性，OR=3.2，95% CI：0.75～13.4。3篇文獻(xiàn)[28, 30, 31]報(bào)道了HBW與ESRD的關(guān)聯(lián)性，HBW人群與正常BW人群差異無統(tǒng)計(jì)學(xué)意義(P=0.144)，OR=1.19，95%CI：0.94～1.49。2篇文獻(xiàn)[33, 34]報(bào)道了HBW與低eGFR以及其他CKD的關(guān)聯(lián)性，HBW與正常BW人群差異無統(tǒng)計(jì)學(xué)意義(P=0.311)，OR=1.09，95% CI：0.93～1.27。

2.3.4 LBW人群中性別差異與CKD的定量分析 圖5顯示，3篇文獻(xiàn)可以提取到LBW男性或女性人群與CKD之間關(guān)聯(lián)性的數(shù)據(jù)，經(jīng)Meta分析，男性中LBW人群較正常BW人群CKD發(fā)生率差異有統(tǒng)計(jì)學(xué)意義(P=0.021)，OR=1.83，95%CI：1.10～3.05；女性中差異無統(tǒng)計(jì)學(xué)意義。

2.3.5 發(fā)表偏倚分析 圖6顯示，應(yīng)用Egger回歸對(duì)納入文獻(xiàn)進(jìn)行發(fā)表偏倚風(fēng)險(xiǎn)分析，P>|t|= 0.06，提示不存在明顯發(fā)表偏倚。

圖5 LBW人群性別與CKD關(guān)聯(lián)的Meta分析

圖6 Egger回歸的漏斗圖

3 討論

20世紀(jì)90年代“胎兒起源學(xué)說”提出后，Brenner等在1993將這一假說應(yīng)用于腎臟[35]，指出宮內(nèi)營(yíng)養(yǎng)不良可能導(dǎo)致腎單位顯著減少，正常新生兒與LBW相比其腎單位較多[36]；這與高血壓、損傷后漸行性腎功能減退以及年齡相關(guān)性腎小球硬化密切相關(guān)。因此，宮內(nèi)營(yíng)養(yǎng)不良可能作為預(yù)測(cè)生后遠(yuǎn)期高血壓、ESRD和其他腎臟病發(fā)生的風(fēng)險(xiǎn)指標(biāo)。此外，研究顯示LBW能引起成人系統(tǒng)性高血壓和CKD[37, 38]。

本文納入10篇文獻(xiàn)均為觀察性研究，其中隊(duì)列研究 4 項(xiàng)，病例對(duì)照研究4篇，橫斷面研究2篇。納入文獻(xiàn)存在一定的異質(zhì)性，如研究設(shè)計(jì)方法多樣、CKD測(cè)量指標(biāo)不同、年齡段不同、人種差異以及納入人群的性別差異等均不可避免地造成一定偏倚。因此，進(jìn)一步以CKD相關(guān)指標(biāo)蛋白尿、ESRD、低eGFR、體重和性別進(jìn)行亞組分析，同時(shí)根據(jù)文獻(xiàn)設(shè)計(jì)類型的不同行亞組分析。Egger檢驗(yàn)顯示，文獻(xiàn)之間發(fā)表偏倚較低。Meta分析結(jié)果顯示，LBW與CKD關(guān)聯(lián)性密切，可作為CKD的預(yù)測(cè)指標(biāo)，與其他系統(tǒng)綜述和Meta分析的結(jié)果[39]相一致。本文首次就HBW作為CKD的高危因素進(jìn)行分析，結(jié)果顯示，HBW與蛋白尿、ESRD、低eGFR及其他CKD指標(biāo)關(guān)聯(lián)性不大，并非CKD的高危因素，與Das等[39]報(bào)道一致，但其機(jī)制目前仍無定論。HBW 通常提示巨大兒、糖尿病母親所生嬰兒、胰島素抵抗以及對(duì)CKD的基因易感性。均提示HBW亦可能作為CKD的預(yù)測(cè)指標(biāo)之一。為了消除妊娠期糖尿病、高血壓以及指標(biāo)測(cè)定時(shí)間差異等混雜因素，需要更加嚴(yán)格控制的大樣本觀察性研究。

本文Meta分析顯示，LBW人群中男性與CKD的關(guān)聯(lián)性顯著，而女性人群則無明顯關(guān)聯(lián)，與Li等[33]的研究結(jié)果相一致。有文獻(xiàn)指出成年女性的腎單位較男性明顯減少，可能解釋了為何LBW以及宮內(nèi)營(yíng)養(yǎng)不良所致腎單位減少對(duì)女性影響較男性小的原因[40]。此外，雌激素作為一種腎臟保護(hù)激素，能通過抑制系膜細(xì)胞的增生、硬化和減少膠原蛋白的合成來抵消宮內(nèi)營(yíng)養(yǎng)不良所致腎臟損害[41]。也有人認(rèn)為，男性高血壓、糖耐量異常較女性出現(xiàn)早，使男性更容易因腎單位減少而出現(xiàn)CKD[42]。由于本文中各文獻(xiàn)納入男女病例差異較大，且未就胎齡、早產(chǎn)以和其他未知因素排除，都不可避免地對(duì)研究結(jié)果造成偏倚。

本文局限性：①納入的觀察性研究樣本量較少；②納入研究文獻(xiàn)的人群年齡段差別較大、劃分不明確，以至于無法有效量化各年齡段CKD發(fā)生風(fēng)險(xiǎn)的比較；③納入文獻(xiàn)的觀察對(duì)象大部分為歐美地區(qū)人群；④近3年關(guān)于宮內(nèi)發(fā)育遲緩相關(guān)文獻(xiàn)缺乏，可能有文獻(xiàn)選擇偏倚。

結(jié)論：男性LBW是CKD的高危因素。HBW與生后CKD發(fā)生無明顯關(guān)聯(lián)。

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(本文編輯：張崇凡，孫晉楓)

The relationship between birth weight and chronic kidney disease：a systematic review and meta-analysis

ZHANGRuo-lin,SHUAILan-jun,LIXiao-yan,CHENHai-xia,WANGYing,HEQing-nan

(LaboratoryofPediatricNephrology，InstituteofPediatrics，CentralSouthUniversity,TheSecondXiang-YaHospital,Changsha410011,China)

Corresponding Author： HE Qing-nan, E-mail: heqn2629@163.com

ObjectiveTo systematically review the association between birth weight with risk of the chronic kidney disease.MethodsThe Cochrane Library, MEDLINE, OVID, Springer, VIP, WangFang Data and CNKI up to June 30, 2016 were searched to retrieve the online observation studies about birth weight and chronic kidney disease and other relative outcomes. The articles were selected if they were published in English or Chinese regarding the association between birth weight and CKD, which included the exact information on OR and 95%CI. Excluded studies: Studies that assessed the final outcome among neonates or children less than 1 year old, the participants of studies who were infected in utero, congenital abnormalities, the mothers who were exposed to toxins, as well as the incompletely information literature. Two reviewers inspected the included studies on the association between birth weight and chronic kidney disease independently. Quality assessment was performed based on the Newcastle Ottawa Scale( case-control study and cohort study) and AHRQ(cross-sectional study). OR and 95%CI were extracted from the selected articles and then analyzed with Stata 12.0 software by the way of DerSimonian & Laird.ResultsTen observational studies containing four case-control studies(three articles in 8 points and one article in 7 points ), four cohort studies(three articles in 7 points and one article in 8 points ) and two cross-sectional studies(7 points and 8 points for the two articles ) were selected finally. The overall combination of weighted estimates from the selected 10 studies about low birth weight associated with risk of the chronic kidney disease was 1.80 (1.37-2.35). The risks of albuminuria (OR, 2.58; 95% CI, 1.49-4.46), end-stage renal disease (OR, 1.42; 95% CI, 1.22-1.66), or lower estimated glomerular filtration rate (OR, 1.87; 95% CI, 1.19-2.94) were similar with the chronic kidney disease. However,according to the subgroup analysis that the combined OR of high birth weight between end-stage renal disease and lower estimated glomerular filtration rate was OR, 1.19; 95% CI, 0.94-1.49 and OR, 0.09; 95% CI, 0.93-1.27,which showed no significant impact. In the subgroup analysis by gender,increased risk was only found in men:1.83 (1.10-3.05),unexpectedly.Finally, the Egger regression method showed no publication bias.ConclusionOnly men with low birth weight had a greater CKD risk in later life. And the high birth weight did not show any significant impact on CKD.

Birth weight; Chronic kidney disease; Albuminuria; Observation study; Meta-analysis

中南大學(xué)湘雅二醫(yī)院兒科 長(zhǎng)沙，410011

何慶南 ，E-mail: heqn2629@163.com

10.3969/j.issn.1673-5501.2017.02.003

2017-03-07

2017-04-18)