慢性肾衰竭患者高同型半胱氨酸血症、氧化应激和微炎症反应间的关系及其在动脉粥样硬化中的作用

Hyperhomocysteinemia,oxidative stress and microinflammation in chronic renal failure:their roles in atherogene

目的 探讨同型半胱氨酸 (Hcy)血症和氧化应激、微炎症反应之间的关系 ,及其在慢性肾衰竭 (CRF)患者动脉粥样硬化 (AS)形成中的作用。方法 测 114例CRF患者 (CRF组 ,其中 6 2例行血液透析 ,非透析治疗 5 2例 )和 37例健康对照者 (健康对照组 )血浆总Hcy(tHcy)水平、循环丙二醛 (MDA)、谷胱苷肽过氧化物酶活性 (GSHPx)及血清C 反应蛋白 (CRP)、白细胞介素 (IL) 6、肿瘤坏死因子 (TNF)α水平 ,高分辨超声技术测颈动脉内膜 中层厚度 (IMT)及粥样硬化斑块。结果 非透析CRF患者血浆tHcy、MDA、CRP和TNFα水平高于健康对照组 ,且随肾功能损害程度的加重而升高 ,GSHPx则低于健康对照组 ;血液透析患者tHcy、MDA、CRP、IL 6和TNFα水平均高于非透析患者 ,GSHPx进一步降低。CRF患者IMT增厚阳性率、平均IMT及颈动脉粥样斑块检出率明显高于健康对照组。动脉病变越重 ,血浆tHcy、MDA及CRP水平越高 ,GSHPx越低。多因素逐步回归分析显示 ,tHcy、MDA、CRP、血糖和极低密度脂蛋白水平是影响颈总动脉IMT的危险因素 (R2 =0 5 72 ,P<0 0 0 1) ,影响CRF患者血浆MDA水平的因素有血浆GSHPx、tHcy、血肌酐 ,影响CRF患者血清CRP水平的因素有血清IL 6、TNFα、MDA、血浆白蛋白。

Objective To investigate the relationship between hyperhomocysteinemia,oxidative stress and microinflammation in patients with chronic renal failure (CRF),and its role in the pathogenesis of atherosclerosis seen in these patients. Methods One hundred and fourteen CRF patients and 37 healthy volunteers were involved in the study. The levels of plasma total homocysteine (tHcy) were determined by fluorescence polarization immunoassay. Plasma malondialdehyde (MDA) levels were analyzed by thiobarbituric acid reaction. The activity of glutathione peroxidase (GSHPx) in plasma was measured by spectrophotometry. Serum C-reactive protein (CRP),interleukin (IL)-6 and tumor necrosis factor(TNF)α were determined by ELISA. Intima-medial thickness (IMT) of extracranial common carotid artery and the presence of atherosclerotic plaques was determined by using noninvasive high-resolution B-mode ultrasonography. Results Levels of tHcy,MDA,CRP and TNFα in the non-dialysis CRF patients were significantly higher than those in the healthy controls and increased with the progression of renal insufficiency,while plasma activity of GSHPx decreased progressively with decline of renal function. Compared with the pre-dialysis patients,hemodialysis patients exhibited higher levels of tHcy,MDA,CRP,IL-6 and TNFα,and lower levels of GSHPx activity. There were no significant difference in the levels of tHcy,MDA,CRP,IL-6,TNFα,and GSHPx activity between patients dialyzed with hemophan,polysulfone and cellulose triacetate membrane. Prevalence of atherosclerotic plaque and increased IMT in carotid artery were significantly higher in CRF patients compared with the age-matched controls and associated with the levels of tHcy,MDA and CRP. Multivariate stepwise regressive analysis showed that increased IMT in CRF patients was closely related to the levels of tHcy,MDA,CRP,blood glucose,and very low density lipoproteins (R 2= 0.572, P <0.001). The factors associated with plasma MDA (representing lipid peroxidation level) were GSHPx activity (standard regressive coefficient,β=-0.651, P <0.01),tHcy level (β=0.229, P <0.01),and serum creatinine (β=0.163, P <0.05). The factors associated with serum CRP (representing microinflammation state) were IL-6 (β=0.532, P <0.01),TNFα(β=0.212, P <0.01),MDA (β=0.209, P <0.05),and plasma albumin (β=-0.297, P <0.05). Conclusion Hyperhomocysteinemia in CRF patients may accelerate oxidative stress,and lipid peroxidation may be involved in the occurrence of microinflammation state. The complex interaction between hyperhomocysteinemia,oxidative stress and microinflammation may result in accelerated atherosclerosis seen in CRF.