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Advances in Clinical Medicine
Vol. 10  No. 03 ( 2020 ), Article ID: 34732 , 7 pages
10.12677/ACM.2020.103054

Relationship between Plasma Homocysteine and Estimated Glomerular Filtration Rate in Elderly Patients

Chunxiao Fei, Song Hu, Xinyue Hou, Junqing Zhang, Yongjun Mao, Ang Xing*

Department of Geriatric Medicine, The Affiliated Hospital of Qingdao University, Qingdao Shandong

Received: Mar. 3rd, 2020; accepted: Mar. 18th, 2020; published: Mar. 25th, 2020

ABSTRACT

Objective: To investigate the relationship between homocysteine (Hcy) and estimated glomerular filtration rate (eGFR) in elderly patients. Methods: From January 1, 2017 to December 31, 2018, a total of 399 elderly patients were admitted to the Affiliated Hospital of Qingdao University. They were divided into eGFR ≥ 60 mL/(min∙1.73 m2) group (n = 287) and eGFR < 60 mL/(min∙1.73 m2) group (n = 112), age, eGFR, Hcy, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) were compared between the two groups. The correlation between serum Hcy level and eGFR in elderly patients was analyzed by Pearson’s correlation. Elderly patients were divided into 4 groups according to the interquartile range of Hcy, and Logistic regression analysis was used to analyze the odd ratio of elevated Hcy levels and decreased eGFR. Results: The average level of eGFR was (66.47 ± 13.08) mL/(min∙1.73 m2) and Hcy was (13.36 ± 6.91) umol/L. Pearson correlation analysis showed that Hcy was negatively correlated with eGFR (r = −0.215, P = 0.000). Logistic regression analysis showed that with the increase of the level of Hcy, the risk of the decline of eGFR also increased. Compared with group 1 (Hcy < 9.4 umol/L), group 2 (9.4 umol/L ≤ Hcy < 11.66 umol/L), group 3 (11.66 umol/L ≤ Hcy < 14.28 umol/L) and group 4 (Hcy ≥ 14.28 umol/L) were more likely to have eGFR decline with ORs of 2.752 (95%CI: 1.051 - 7.209), 7.444 (95%CI: 2.885 - 19.211) and 16.488 (95%CI: 6.150 - 44.203). Conclusion: Elevated Hcy is associated with decreased eGFR and increases the risk of kidney injury in elderly patients.

Keywords:Elderly, Homocysteine, Estimated Glomerular Filtration Rate

老年患者同型半胱氨酸与估算肾小球滤过率的相关性研究

费春晓，胡松，侯新月，张俊青，毛拥军，邢昂*

青岛大学附属医院老年医学科，山东 青岛

收稿日期：2020年3月3日；录用日期：2020年3月18日；发布日期：2020年3月25日

摘 要

目的：探讨老年患者同型半胱氨酸(Hcy)与估算肾小球滤过率(eGFR)的关系。方法：选择2017年01月01日至2018年12月31日于青岛大学附属医院老年住院患者(n = 399)，根据eGFR水平是否低于60 mL/(min·1.73 m2)分为eGFR ≥ 60 mL/(min·1.73 m2)组(n = 287)及eGFR < 60 mL/(min·1.73 m2)组(n = 112)，比较两组间年龄、eGFR、Hcy、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)等指标。采用Pearson相关性分析老年人群Hcy与eGFR的相关性。按照Hcy水平四分位间距分为4组，采用Logistic回归分析Hcy水平升高与eGFR下降的风险程度。结果：研究对象eGFR平均(66.47 ± 13.08) mL/(min·1.73m2)，Hcy平均(13.36 ± 6.91) umol/L。Pearson相关性分析显示Hcy与eGFR呈负相关(r = −0.215, P = 0.000)。Logistic回归分析表明，随着Hcy值增高，发生eGFR下降的风险呈增高趋势，校正多因素后，与Hcy第1组(Hcy < 9.4 umol/L)相比，第2组(9.4 umol/L ≤ Hcy < 11.66 umol/L)、第3组(11.66 umol/L ≤ Hcy < 14.28 umol/L)及第4组(Hcy ≥ 14.28 umol/L)发生eGFR下降OR (95%CI)分别为2.752 (1.051~7.209)、7.444 (2.885~19.211)和16.488 (6.150~44.203)。结论：老年人群中，Hcy升高与eGFR下降相关，增加了肾损伤风险。

关键词 :老年人，同型半胱氨酸，估算肾小球滤过率

Copyright © 2020 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

同型半胱氨酸(homocysteine, Hcy)是甲硫氨酸与半胱氨酸代谢过程中的重要产物 [1]，也是甲基化、再甲基化和转硫途径交叉的关键代谢产物，通过维生素B12和叶酸依赖的甲硫氨酸合成酶或β-同型半胱氨酸甲基转移酶反应合成甲硫氨酸 [2]。研究发现Hcy升高不仅与心血管疾病如内皮功能障碍、动脉粥样硬化等密切相关 [3] [4] [5] [6]，也能影响肾脏疾病的产生与发展 [7] [8]。近年国内外多项研究表明Hcy与以血清肌酐(serum creatinine, Scr)得到的估算肾小球滤过率(estimated glomerular filtration rate, eGFR)定义的肾功能呈负相关性 [9] [10] [11]。然而目前针对老年人群Hcy水平与肾功能损伤关系的研究较少，本研究为此探讨65岁及以上人群两者的相关性。

2. 对象与方法

2.1. 研究对象

选取2017年01月01日至2018年12月31日青岛大学附属医院老年住院患者399例。纳入标准：1) 年龄 ≥ 65岁；2) 签署知情同意书。排除恶性肿瘤、全身感染性疾病、原发性肾脏病及其他疾病引起的继发性肾脏病患者。本研究入选患者资料及血样的采集获得受试者的知情同意，并在我院伦理委员会备案。

2.2. 研究方法

2.2.1. 一般临床资料

自患者入院后，记录患者基本临床资料包括性别、年龄、生命体征、既往病史(高血压、糖尿病、冠心病等)，嘱患者空腹8~12小时次日抽取静脉血，完善相关血清学指标如血常规、肝肾功、Hcy、电解质等。

2.2.2. 颈部血管超声检查

采用HITACHI日立ARIETTA 70型号彩色多普勒超声仪，探头频率为4~9 MHz，由经验丰富的超声科医师专门负责。患者取仰卧位，头部偏向检查对侧。充分暴露颈部，探头取长轴切面，自颈总动脉开始，分别于双侧颈内、外动脉水平上下1.0~1.5 cm范围观察颈部血管解剖结构并测量颈动脉内膜中层厚度(intima media thickness, IMT)。IMT ≥ 1.0 mm被定义为颈动脉内–中膜增厚 [12]。

2.2.3. eGFR的计算

根据改善全球肾脏病预后组织(Kidney Disease: Improving Global Outcomes, KDIGO) 2012年发布的慢性肾脏病评估及管理临床实践指南，建议以Scr和肾小球滤过率(glomerular filtration rate, GFR)估算公式进行初步评估，使用CKD-EPI肌酐方程估算GFR，见表1。

Table 1. CKD-EPI equation [13]

表1. CKD-EPI计算方程 [13]

注：Scr：血清肌酐；Age：年龄。

2.2.4. 分组方法

根据KDIGO指南对CKD定义 [13]，将老年患者根据eGFR水平是否低于60 mL/(min·1.73 m2)分为两组，其中eGFR ≥ 60 mL/(min·1.73 m2)组287例，eGFR < 60 mL/(min·1.73 m2)组112例。根据Hcy水平四分位间距分为4组，其中第1组100例(Hcy < 9.4 umol/L)，第2组100例(9.4 umol/L ≤ Hcy < 11.66 umol/L)、第3组100例(11.66 umol/L ≤ Hcy < 14.28 umol/L)，第4组99例(Hcy ≥ 14.28 umol/L)。

2.3. 统计学方法

所有数据采用SPSS22.0统计软件进行统计学处理。计量资料以均数 ± 标准差( ±s)表示，计数资料以百分比(%)表示。两组间比较，计量资料采用独立样本t检验分析，计数资料采用χ2检验。采用Pearson相关性分析评估Hcy与eGFR的相关性。采用二元Logistic回归分析评估Hcy水平与eGFR下降的风险。以P < 0.05为差异具有统计学意义。

3. 结果

3.1. 老年患者不同eGFR组临床资料比较

老年患者人群平均年龄(75.32 ± 6.97)岁，其中男性199例(49.9%)，平均年龄(75.64 ± 6.83)岁，女性200例(50.1%)，平均年龄(75.01 ± 7.10)岁。平均Hcy (13.36 ± 6.91) umol/L，平均eGFR (66.47 ± 13.08) mL/(min·1.73 m2)。按照eGFR水平分为两组，相比于eGFR ≥ 60 mL/(min·1.73 m2)组，eGFR < 60 mL/(min·1.73 m2)组患者年龄更大(P < 0.01)，收缩压(systolic blood pressure, SBP)、Hcy、血尿素氮(blood urea nitrogen, BUN)、胱抑素C(cystatin C, CysC)、尿酸(uric acid, URIC)、Scr数值更高(均P < 0.05)。而性别构成、舒张压(diastolic blood pressure, DBP)、IMT、高密度脂蛋白胆固醇(high density lipoprotein cholesterol, HDL-C)、低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)、总胆固醇(Total cholesterol, TC)及三酰甘油(Triacylglycerol, TG)比较，差异无统计学意义(P > 0.05)。见表2。

Table 2. Comparison of clinical data of patients with different eGFR levels

表2. 不同eGFR水平患者临床资料比较

注：SBP：收缩压；DBP：舒张压；IMT：颈动脉内膜中层厚度；Hcy：同型半胱氨酸；BUN：血尿素氮；CysC：胱抑素C；URIC：尿酸；Scr：肌酐；eGFR：估算肾小球滤过率；HDL-C：高密度脂蛋白胆固醇；LDL-C：低密度脂蛋白胆固醇；TC：总胆固醇；TG：三酰甘油。

3.2. 老年患者eGFR与年龄、Hcy水平的相关性分析

对老年患者eGFR与年龄及Hcy水平进行Pearson相关性分析，结果显示两者均与eGFR呈负相关性(r = −0.377, P < 0.01; r = −0.215, P< 0.01)。见表3。

Table 3. Correlation analysis of eGFR with Hcy and age

表3. eGFR与Hcy及年龄的相关性分析

注：r为相关系数。

3.3. 老年患者Hcy与eGFR下降风险的Logistic回归分析

将老年患者以eGFR < 60 mL/(min·1.73 m2)与否为因变量，以Hcy分组为协变量进行Logistic回归分析，回归方程中变量赋值为：性别，男性 = 1，女性 = 2；吸烟，是 = 1，否 = 0；高血压，是 = 1，否 = 0；冠心病，是 = 1，否 = 0。结果显示，校正年龄、性别、高血压、冠心病及吸烟后，相比于第一组，后三组发生eGFR下降风险的OR分别为2.983 (95%CI: 1.157, 7.693, P < 0.05)、7.689 (95%CI: 3.025, 19.544, P < 0.01)、17.270 (95%CI:6.601, 45.183, P < 0.01)。继续校正收缩压、舒张压、IMT、HDL-C、LDL-C、TC及TG后，OR仍呈上述增高趋势，差异具有统计学意义(P < 0.05)。见表4。

Table 4. Logistic regression analysis of Hcy level and eGFR in elderly patients

表4. 老年患者Hcy水平与eGFR的Logistic回归分析

模型1：校正年龄、性别、高血压、冠心病、吸烟；模型2：在模型1的基础上校正收缩压、舒张压、IMT、HDL-C、LDL-C、TC、TG。

4. 讨论

2012年KDIGO发布了CKD评估及管理临床实践指南 [14]，指出可以根据GFR对CKD进行诊断及分期，并建议使用CKD-EPI公式计算得到eGFR。Hcy作为一种含硫氨基酸，是半胱氨酸的同源物。高同型半胱氨酸血症(hyperhomocysteinimia, HHcy)定义为血同型半胱氨酸浓度超过15 μmol/L [15]，甲硫氨酸代谢过程中酶和辅因子的缺乏、营养不良、甲硫氨酸过多摄入、肾脏清除能力受损、恶性肿瘤等因素可导致HHcy [15] [16]。国内外多项研究在不同人群中发现Hcy与eGFR密切相关，Hcy或成为肾功能下降的预测因素。其中国内一项前瞻性研究 [17] 定义eGFR < 60 mL/(min·1.73 m2)为CKD，根据Hcy水平四分位数将研究对象分为四组，CKD发病率随着Hcy水平升高逐渐升高(P＜0.001)。在调整年龄、性别、高血压、LDL-C等因素后，Hcy与eGFR降低的风险呈独立相关性(OR = 1.07, 95%CI: 1.04~1.10)，与CKD发生的风险也呈独立相关性(OR = 1.04, 95%CI: 1.02~1.07)。FU等人 [18] 纳入1499例人群，排除eGFR < 60 mL/(min·1.73 m2)人群，年龄范围(25~96)岁，使用MDRD公式计算eGFR，eGFR范围(79.27~96.89) mL/(min·1.73 m2)，eGFR每年下降超过3 mL/(min·1.73 m2)被定义为肾功能快速下降。线性回归分析显示Hcy对肾功能快速下降具有独立预测作用(OR = 1.048, 95%CI: 1.024~1.072, P < 0.001)。Chen等人 [9] 在平均年龄34岁的台湾人群中经过线性回归分析后，发现Hcy水平与eGFR有显著负相关性(P < 0.001)。另外在原发性肾小球肾炎、肾移植及高血压人群中 [19] [20] [21] 均能发现两者的密切联系。

本研究纳入老年人群平均年龄(75.64 ± 6.83)岁，将老年人群按照eGFR水平是否低于60 mL/(min·1.73 m2)分为两组，结果显示eGFR < 60 mL/(min·1.73 m2)组Hcy水平更高。Pearson相关性分析发现Hcy与eGFR呈负相关性(P < 0.001)。Logistic回归分析在调整年龄、性别、SBP、DBP等因素后，eGFR降低风险随Hcy水平升高(P < 0.05)。其中第4组Hcy水平(Hcy ≥ 14.28 umol/L)已经接近HHcy诊断标准，eGFR降低风险较前三组明显增高(OR = 16.488, 95%CI: 6.150~44.203)。

Hcy导致eGFR降低可能的机制如下：1) 氧化应激机制：Hcy发生自氧化增强活性氧的产生 [22]，其中NADPH氧化酶是主要来源，Hcy能增加它的表达 [23]。氧化应激导致内皮功能障碍，改变肾小球滤过膜的通透性导致eGFR降低 [24]。有研究发现患有HHcy的大鼠接受NADPH氧化酶抑制剂的治疗之后，肾小球损伤减轻 [25]。2) 腺苷的降低：Hcy高浓度可能增强双向酶-S-腺苷-L-高半胱氨酸(S-Adenosyl-L-homocysteine, SAH)水解酶的活性，导致腺苷浓度降低 [26]，腺苷水平减低与血管平滑肌的增殖及肾小球硬化相关 [27]。3) 蛋白质同型半胱氨酸化：血浆蛋白可通过不同机制被同型半胱氨酸化，其中某些同型半光氨酸化的蛋白质参与了肾小球的硬化过程 [28]。除此之外内质网应激 [29] 、足细胞相关肾素蛋白表达下降、转化生长因子β1 (transforming growth factor-β1, TGF-β1)的上调 [30] 、Hcy关键代谢酶-5、10亚甲基四氢叶酸还原酶(5,10-methylenetetrahydrofolate reductase, MTHFR) C677T基因多态性 [31] 等机制都可能参与Hcy导致的肾损伤过程中。

本研究也存在一些局限性：1) 本研究未单独纳入CKD人群、高血压人群或者糖尿病人群进一步分析Hcy与eGFR两者之间的联系。2) 本研究不是前瞻性研究，未能分析叶酸等药物降低Hcy水平是否能升高eGFR水平、延缓CKD的发生。

本研究显示老年人群中Hcy升高与eGFR下降密切相关，Hcy水平升高增加了老年人群肾损伤发生的风险。随着老龄化现象不断加重，慢性非传染性疾病如高血压、糖尿病、冠心病及慢性肾脏病等疾病越来越常见，老年人群又常存在共病现象，多种因素可导致肾功能下降。早期进行HHcy的筛查并进行治疗干预，减少慢性肾脏病及其并发症的发生，提升老年人的生活质量是需要被目前社会所重视的。

基金项目

山东省卫计委：老年综合评估技术在三甲保健定点医院住院患者中的应用研究(2015BJYB21)；国家科技部：国家重点研发计划(2018YFC2002100)。

文章引用

费春晓,胡 松,侯新月,张俊青,毛拥军,邢 昂. 老年患者同型半胱氨酸与估算肾小球滤过率的相关性研究
Relationship between PlasmaHomocysteine and Estimated Glomerular Filtration Rate in Elderly Patients[J]. 临床医学进展, 2020, 10(03): 339-345. https://doi.org/10.12677/ACM.2020.103054

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