【作者】 史慧；

【导师】 王俭勤；

【作者基本信息】 兰州大学 ， 肾病科， 2012， 硕士

【摘要】 研究背景：IgA肾病(IgA nephropathy, IgAN)是我国常见的慢性肾小球疾病之一。其临床表现、病理表现多样化,常常伴有微炎症状态、高尿酸血症、脂代谢异常和钙磷代谢紊乱等。这些病理生理变化与血管内皮功能障碍密切相关。后者则是慢性肾脏病患者动脉硬化、心血管疾病(Cardial vessel disease, CVD)发生发展的重要环节。大量研究证明,CVD已经成为危害IgA肾病患者生命的重要杀手。IgA肾病CVD病理改变包括血管病变及心肌病变两大类,其中动脉粥样硬化(Atherosclerosis, AS)在IgA肾病患者CVD的发生过程中占有重要地位。因此,早期、准确诊断AS发生对于IgA肾病患者CVD发生预测至关重要。而今,脂肪组织不单纯被看作是储能器官,它通过产生各种脂肪因子,作用于远程器官,参与细胞基质代谢。随着研究深入发现,这些脂肪因子对于脉管系统同样也产生相应作用,参与CVD,特别是AS的发生。网膜素作为新近发现的脂肪因子,可能成为连接脂肪代谢异常与AS发生的又一重要分子,不仅为AS病理生理研究提供新的研究线索,甚至有望成为潜在的标志性分子及药物作用靶点,而受到大家的广泛关注。网膜素-1是循环中存在的主要亚型,研究表明,网膜素-1表达降低导致腹型肥胖、胰岛素抵抗甚至脂代谢紊乱发生。最新研究表明,网膜素通过增加腺苷酸活化蛋白激酶(AMPK)介导的一氧化氮合酶(Nitric oxide synthase, NOS)氧化磷酸化,促进内皮一氧化氮合酶的激活,使NO表达增加,参与改善内皮细胞功能。由此不难推测网膜素-1表达降低可导致AS发生增加。目前,针对血清网膜素变化的临床研究多集中于代谢综合征及2型糖尿病患者,尚无针对IgA肾病患者AS发生及严重性与血清网膜素-1变化的研究。本研究旨在通过分析IgA肾病患者颈总动脉内中膜厚度(Carotid intra-media thickness, CIMT),判断IgA肾病患者颈AS的发生程度及差异性,结合血清网膜素-1变化,了解网膜素-1与IgA肾病患者AS的相关性。研究目的：(1)探讨IgA肾病患者不同临床分型动脉粥样硬化的分布构成；(2)了解IgA肾病患者不同临床分型血清网膜素-1变化,及其与颈动脉粥样硬化的关系。研究对象与方法：全部研究对象来自于2010-2012年兰州大学第二医院肾病科IgA肾病患者。随机入选IgA肾病患者共150名(男性97名,女性53名,平均年龄35.35±14.23岁)。将其分为孤立性镜下血尿型(I-H组)25例、反复发作肉眼血尿型(R-GH组)25例、大量蛋白尿型(MP组)25例、尿检异常型(U-ab组)25例、高血压型(HT组)25例、终末期IgA肾病型(ESRD组)25例共六个亚组。所有参与者均进行常规病史采集及体格检查,应用彩色多普勒超声检测所有研究人群颈总动脉内中膜厚度(CMIT),采用ELISA法测定血清网膜素-1水平。同时测定血清BUN, SCr, CRP、CHO、TG、LDL、HDL、FBG、空腹胰岛素水平、餐后2小时血糖及餐后2小时胰岛素水平。另外,选择年龄与性别相匹配的健康志愿者20名作为正常对照组。所有数据均使用统计软件SPSS17.0,正态分布数据以x±s表示,两组间比较采用T检验,多组间采用One-way ANOVA检验。偏态分布数据以中位数(M)表示,两组间比较采用Mann-whitney U检验。变量间相关分析采用Pearson分析,单因素相关分析及多因素逐步回归分析。研究结果：(1)IgA肾病组与正常对照组比较,eGFR及网膜素-1水平均低于对照组；CIMT、24小时尿蛋白定量及CRP水平高于正常对照组(P<0.01、P<0.05)；(2)经过统计学分析,ESRD组与其他IgA肾病亚组,年龄、血压(SBP为主)、eGRF、CIMT、HDL、UA、CRP、HOMA-IR及网膜素-1存在显著性差异(P<0.01、P<0.05)；(3)HT组CIMT、SBP、DBP、eGFR、24小时尿蛋白定量、CRP及网膜素-1与Ⅰ-H组、R-GH组及U-ab组相比存在明显统计学差异(P<0.01、P<0.05)：(4)MP组CIMT、TC、TG、LDL、血压、eGFR、24小时尿蛋白定量、HOMA-IR、网膜素-1及CRP与Ⅰ-H组、R-GH组及U-ab组相比存在明显统计学差异(P<0.01、P<0.05)：(5) U-ab组24小时尿蛋白定量高于Ⅰ-H组(P<0.01)；(6) CIMT与年龄、BMI、SBP、UA、TG、LDL、24小时尿蛋白定量、FBG、HOMA-IR、CRP正相关；与eGFR、HDL及网膜素-1负相关(P<0.01、P<0.05)；(7)血清网膜素-1与eGFR、HDL正相关；与CIMT、BMI、SBP、TG、LDL、 CRP、FBG、HOMA-IR负相关(P<0.01、P<0.05)；其中BMI、SBP、 eGFR、LDL、CRP、HOMA-IR是血清网膜素-1的独立危险因素(P<0.01、P<0.05)。研究结论：(1)与正常对照组相比,IgA肾病患者存在AS。其中,以MP组、HT组及ESRD组多见。(2)通过多元线性回归分析,CIMT在排除高血压、高血脂等传统危险因素后,与蛋白尿、高尿酸血症及HOMA-IR独立相关。提示除外高血压、脂代谢异常等心血管病传统危险因素,蛋白尿、尿酸水平等非传统危险因素也参与了IgA肾病AS的发生。(3)IgA肾病组血清网膜素-1水平低于正常对照组,各亚组间比较发现,MP组、HT组、ESRD组血清网膜素-1显著低于I-H组、R-GH组、U-ab组,与各组CIMT结果基本一致。(4)通过相关性分析及多因素逐步回归分析发现,除高血压、高血脂、蛋白尿及eGRF等心血管危险因素外,低血清网膜素-1水平是导致AS的重要危险因素之一,在IgA肾病患者AS过程中可能起保护作用。更多还原

【Abstract】 Objrctive(1) To identify the distribution constitute of atherosclerosis in the different classification of IgA nephropathy;(2) To identify serum level of omentin-1in patients with IgA nephropathy;(3) To clariy the associaton between serum level of omentin-1and carotid atherosclerosis in patients with IgA nephropathy.MethodsThis study was carried out at the Second Hospital of Lanzhou University between2010and2012. We enrolled randomly150people with IgAN, evaluated their carotid atherosclerosis employing ultrasonography and then divided them into six subgroups, isolated microscopic hematuria(I-H), recurrent gross hematuria(R-GH), massive proteinuria(MP), urinalysis abnormal(U-ab), Hypertension(HT) and end-stage renal disease(ESRD), Height, weight and blood pressure(BP) were measured. Fasting blood sample was collected to determine to biochemical indicators and insulin resistance index(HoMA-IR). Serum omentin-1levels was assessed by with omentin enzyme-linked immunosorbent assay.And20controls were healthy volunteers enrolled in the study.Continuous variables with normal distributions were expressed as mean±SD. Differences in the mean values between groups were compared by One-Way Analysis of Variance. Correlation between serum concentrations of omentin-1and other parameters were studied by Pearson correlation analysis. Moreover, to study whether there was an independent relationship between omentin-1and IgA nephropathy, multiple linear regression was performed.SPSS17.0software was used for statistical analysis. P<0.05was considered statistically significant.Result(1) The eGFR and serum omentin-1were markedly lower and CIMT,24-hour urinary protein quantification and CRP were significant greater in IgA nephropathy patients than in control group (P<0.01、P<0.05)(2) Age, SBp, CIMT, TG, LDL, HDL, FBG, and HOMA-1R were higher and Serum omentin-1levels and eGFR were lower with ESRD compared with the other IgA nephropathy group (P<0.01、P<0.05)(3) CIMT, SBP, DBP,24-hour urinary protein quantification and CRP were significant greater and Serum omentin-1levels and eGFR were lower with H-T patients compared with I-H or R-GH group (P<0.01、P<0.05)(4) CIMT,TC,TG,LDL,CIMT, HOMA-IR,SBP,24-hour urinary protein quantification and CRP were significant greater and Serum omentin-1levels and eGFR were lower with MP patients compared with I-H or R-GH group (P<0.01、P<0.05)(5)24-hour urinary protein quantification significant higher in U-ab group than in I-H or R-GH (P<0.01)(6) Correlation analysis showed that were positive correlations between age, BMI, SBP, UA, TG. LDL, FBG, HOMA-IR, CRP and24-hour urinary protein quantification and CIMT, negative correlations between eGFR、HDL and Serum omentin-1levels and CIMT (P<0.O1、P<0.05)(7) Significant negative correlations were noted between serum omentin-1levels and CIMT, BMI, SBP, TG, LDL, CRP, FBG and HOMA-IR, while eGFR, HDL showed positive associations(P<0.01、P<0.05).In a multiple linear regression using omentin-1as dependent variable, the independent predictors were BMI, SBP, eGFR, LDL, CRP and HOMA-IR (P<0.O1、P<0.05)Conclusions(1) The CIMT was markedly higher in IgA nephropathy patients than in control group, and significant greater with MP, H-T and ESRD patients compared with I-H or R-GH and U-ab group.which suggesting that IgA nephropathy patients (the MP group, HT group, ESRD group) predispose to atherosclerosis compared to control group.(2) In a multiple linear regression using CIMT as dependent variable, the independent predictors were24-hour urinary protein quantification, UA and HOMA-IR, implicating that the non-classical risk factor of eGFR and proteinuria were involved in the occurrence of carotid atherosclerosis in IgA nephropathy.(3) Serum omentin-1levels were lower with IgA nephropathy compared with control group.(4) Serum omentin-1levels were ignificant lower in MP, H-T and ESRD group than in I-H, R-GH or U-ab.(5) Significant negative correlations were noted between serum omentin-1levels and CIMT, In a multiple linear regression using CIMT as dependent variable, the independent predictors were omentin-1, implicating that High Serum level of omentin-1might play a protective role in the occurrence of carotid atherosclerosis in IgA nephropathy.更多还原