终末期肾病患者血清MIF与hs-CRP及左室肥厚相关性分析

发布时间：2018-05-02 16:45

本文选题：巨噬细胞移动抑制因子 + 超敏C反应蛋白　；参考：《山东大学》2016年博士论文

【摘要】：研究背景：近10年来,全球范围内,慢性肾脏病(CKD)的患病率呈持续增长的趋势。在2007-2010年,在美国地区成年人CKD的患病率已经上升到14%。在我国,2012年张露霞等研究发现CKD在我国成年人中的患病率10.8%,对上海浦东新区、广西省的城市和乡镇地区的调查显示CKD在成年人群中患病率分别达到11%和14.4%,CKD已经成为我们国家常见的疾病之一。但CKD患者如果未能得到及时有效治疗,最终转为终末期肾脏病,需要接受透析或移植治疗,不仅患者的生活质量会显著下降,患者的社会劳动能力也受到很大影响,而且治疗CKD需要高额的医疗费用,给个人和国家均带来了沉重的经济压力。CKD患者也增加了心血管疾病发生的危险性,心血管疾病(CVD)是CKD患者的主要并发症以及主要死亡原因之一。尤其是当CKD持续进展进入到尿毒症即终末期肾病(ESRD)阶段,心血管疾病导致的死亡率占ESRD总病死率的45%-50%,其病死率高出一般人群的10-20倍[12]。在CKD心血管并发症中,尿毒症心肌病是终末期肾病(ESRD)特别是透析患者的首位死亡原因,其最显著特征是左室肥厚(LVH)。LVH是ESRD和透析患者生存率降低的一个独立危险因素,其致病因素较为复杂。LVH在CKD早、中期开始出现,至慢性肾功能衰竭尿毒症期透析病人LVH的发生率达74%,LVH导致了心室舒张功能紊乱、心律失常和心衰的出现。以往的研究发现,尿毒症LVH的发生主要与此类患者普遍存在的高血压和高容量负荷有关,但单纯控制血压和减轻容量负荷并不能显著改善LVH。尿毒症患者LVH出现的可能原因有除了体内甲状旁腺激素继发性升高、钙磷代谢异常和氧化应激反应外可能,微炎症状态是一个重要因素。研究表明,LVH与微炎症状态密切相关,而巨噬细胞移动抑制因子(MIF)是微炎症状态下升高的细胞因子的上游促炎因子,ESRD患者中MIF-173CC基因型表达上调,与血清中微炎症状态的炎症因子标记物超敏C反应蛋白(hs-CRP)的水平直接相关。在研究自身免疫性巨细胞性心肌炎时发现,注射MIF中和抗体后,心肌炎症病变显著减轻。研究发现,推测通过阻断尿毒症患者体内MIF的作用可能会减轻尿毒症心肌病的病变程度,可能是治疗尿毒症心肌病的新的研究方向,但目前尚无相关研究。研究目的：本研究旨在通过研究终末期肾病患者血清MIF与炎症标记物hs-CRP和心肌肥厚的相关性,探讨炎症因子MIF、hs-CRP对终末期肾脏病患者心室重塑的影响,探寻尿毒症心肌病的动态评价指标,对进一步有效治疗尿毒症心肌病具有重要的理论与现实意义。研究方法：1.选择2014年10月至2015年8月期间在山东省泰安市中心医院、青岛市中心医院肾病内科住院的144例终末期肾病患者为研究组。并且选取了30名性别和年龄都与终末期肾病患者符合的健康志愿者作为健康对照组。所有的被研究者均按纳入标准入组并排除不符合入组要求的患者。根据ESRD患者是否进行透析及透析情况将研究组分为终末期肾脏病未透析组(ND,n=63),血液透析组(HD,n=51)和腹膜透析组(PD,n=30),其中血液透析组患者均行低通量血液透析。2.检测指标：(1)收集患者的临床资料和生化指标,包括年龄,性别,血压等。同时分别在泰安市和青岛市中心医院检验科,采用SYSMEX XE2100血液分析仪及配套试剂,分析检测红细胞、血红蛋白等；(2)在泰安市和青岛市中心医院检验科,严格按照ROCHE COBAS 8000全自动电化学发光免疫分析仪及ROCHE配套试剂的常规操作步骤进行操作,检测总胆固醇(TC),甘油三酯(TG),高密度脂蛋白(HDL),低密度脂蛋白(LDL),极低密度脂蛋白(VLDL),载脂蛋白A (APOA),载脂蛋白B(APOB),脂蛋白(α)(LP(α)),前白蛋白(PA),白蛋白(ALB),钾离子(K+),钠离子(Na+),氯离子(Cl-),钙离子(Ca2+),镁离子(Mg2+),磷离子(p3+),尿素氮(BUN),肌酐(Cr),尿酸(UA),β2-微球蛋白(β2-MG),胱抑素C (CysC);使用免疫比浊法检测不同组间的超敏C反应蛋白(hs-CRP)水平,hs-CRP的正常值小于3mg/L；(3)在北医三院实验室,采用液相芯片技术(美国Bio-plex悬浮蛋白芯片系统)检测ESRD患者及健康对照血清MIF水平,通过采用该公司的Bio-Plex human cytokinemulti-plex试剂盒,相应的Bio-Plex cytokines试剂盒及对应的检测仪器,检测不同组别之间的血浆MIF的水平,美国Bio-plex悬浮蛋白芯片技术可实现在一个反应池中同时检测同一标本中的多种细胞因子进行定性、定量的检测,通过在不同荧光编码的微球上进行抗原与抗体,配体与受体,酶与底物,核酸杂交反应,并使红,绿两束激光分别检测微球编码,报告荧光,从而实现定性和定量的目的。该液相芯片技术用于检测细胞因子时大致可分为三步,首先将探针分子固定于芯片表面,其次通过红,绿两束激光分别检测微球编码,再激发荧光的发生,实现荧光报告。数据分析系统应用了Bio-Plex的管理软件(version 4.0),使得检测的敏感性在10pg/mL以下,能够准确检测的细胞因子的浓度范围达到1-32000pg/mL;(4)超声心动图检查：所有患者均采用IU22超声系统(飞利浦医疗系统,波塞尔,华盛顿州,美国)测定左心室舒张末期内径(LVDD),室间隔厚度(IVST),左室射血分数(LVEF%)和左室后壁厚度(LVPWT)。所有测量均由有经验的超声医生进行,重复三次取平均值。左室质量(LVM)由公式计算出,LVM=0.8{1.04×[(LVDD+ IVST+LVPWT)3-LVDD3]}+06,除以体表面积为左室质量指数(LVMI)。左室肥厚诊断条件：男性左室质量指数134g/m2,女性左室质量指数110g/m2。按上述标准将对象分为左室肥厚组和非肥厚组。尿毒症心肌病的诊断标准按照既往的标准[35]。3.数据分析：统计分析采用SPSS21.0分析软件。正态分布的变量用均数±标准差表示,非正态分布的变量用中位数和范围表示。MIF、hs-CRP等非正态分布的变量组间比较采用Mann-Whitney检验或Kruskal-Wallis检验。Spearman秩相关检验用于连续和有序变量。logistic回归分析用于确定相对危险度(RR)。P0.05为差异有统计学意义。研究结果：1.共纳入符合标准的ESRD患者144例,其中男性80例(55.6%),女性64例(44.4%),年龄在19-86岁之间,平均年龄55.3±15.9岁。根据ESRD患者是否进行透析及透析情况,将入选者分为三组：终末期肾脏病未透析组,血液透析组,腹膜透析组。三组之间在年龄和性别上没有统计学差异。在这三组中,导致慢性肾脏病的原发病的主要以慢性肾小球肾炎和高血压肾损害为主。2.ESRD患者血清MIF和hs-CRP水平：经过Kruskal-Wallis检验,结果表明终末期肾病未透析组,腹膜透析组,血液透析组三组与对照组相比较,MIF水平具有统计学意义(p0.05),三组之间两两比较,结果显示终末期肾病未透析组、血液透析组与和腹膜透析组血清MIF相比较,MIF水平均有统计学意义差异(p0.05)。经过Kruskal-Wallis检验,我们发现hs-CRP的水平终末期肾病未透析组,腹膜透析组,血液透析组和健康对照组相比,差异具有统计学意义(p0.05),但是终末期肾病未透析组,血液透析组和腹膜透析组之间两两比较,hs-CRP差异无统计学意义(p0.05)。3.血清MIF水平与各项临床指标的相关分析结果：经过spearman等级相关性分析,E SRD患者血清MIF水平与收缩压,舒张压,红细胞计数,总胆固醇,甘油三酯,载脂蛋白A,载脂蛋白B,肌酐,尿酸,β2微球蛋白,胱抑素C,钠,氯,钙,镁,磷,左心室舒张末期内径,室间隔厚度,左室后壁厚度,左室射血分数之间无相关性(P0.05)。但是血清MIF水平与超敏C反应蛋白,血钾和尿素氮呈正相关(p0.05),与血红蛋白,白蛋白之间呈负相关(p0.05)。4.血清MIF水平与左心室肥厚的关系：根据超声结果将ESRD患者分为左心室肥厚患者和非左心室肥厚患者,伴有左心室肥厚的ESR D患者血清MIF水平1186.0(170.0-3862.0) pg/mL,明显高于非左室肥厚的ESRD患者228.5(55.0-2079.0)pg/mL (P0.05)。血清MIF水平与左心室质量指数呈正相关。血清MIF大于1100pg/mL作为异常,低于或等于1100pg/mL为正常,logistic回归分析用于验证血清MIF对左室肥厚的相对危险度(RR)。结果表明,当考虑优势比(OR)时,高水平的血清MIF左室肥厚的发病率是低水平的血清MIF13.063倍,结果显示MIF进入回归模型且有统计学意义(p0.05),提示血清MIF与ESRD患者的左室肥厚有相关性,血清MIF是ESRD患者左室肥厚的危险因素。结论：1.终末期肾病(ESRD)患者的血清MIF和hs-CRP水平明显升高,表明ESRD患者具有高MIF血症和微炎症状态。2.终末期肾病(ESRD)患者的血清MIF和hs-CRP可能共同参与了ESRD患者左心室肥厚的发生和发展。3.血清高MIF水平是ESRD患者左心室肥厚病变的危险因素。阻断尿毒症患者体内MIF的作用可能会减轻尿毒症心肌病的病变程度,从而为治疗尿毒症心肌病患者提供了临床依据和理论基础。
[Abstract]:Background: the prevalence of chronic kidney disease (CKD) has continued to increase over the past 10 years. In the 2007-2010 years, the prevalence of CKD in adults in the United States has risen to 14%. in China. In 2012, Zhang Luxia and other studies found that the prevalence rate of CKD in Chinese adults was 10.8%, to Pudong New Area, Shanghai, and Guangxi. The prevalence of CKD in the adult population is 11% and 14.4%, respectively, and CKD has become one of the common diseases in our country. But if CKD patients fail to get timely and effective treatment and eventually turn to end-stage renal disease, it is necessary to receive dialysis or transplant, not only the quality of life of the patients will be significantly reduced, but also the patient's quality of life will decrease significantly. Social labour capacity has also been greatly affected, and the treatment of CKD requires high medical costs and heavy economic pressure on both individuals and countries..CKD patients also increase the risk of cardiovascular disease, and cardiovascular disease (CVD) is one of the major complications of CKD patients and one of the main causes of death. Especially when CKD continues to progress. In the stage of uremia, end-stage renal disease (ESRD), the mortality of cardiovascular disease is 45%-50% of the total mortality of ESRD, and its mortality is 10-20 times higher than that of the general population [12]. in CKD cardiovascular complications. Uremic cardiomyopathy is the first cause of death in end-stage renal disease (ESRD), especially in dialysis patients. The most significant feature is the left ventricle. Hypertrophy (LVH).LVH is an independent risk factor for the decrease of survival rate in ESRD and dialysis patients. The pathogenicity of.LVH is more complex in the early stage of CKD and in the middle of the middle period. The incidence of LVH in patients with chronic renal failure uremia is 74%, and LVH leads to ventricular diastolic disorder, arrhythmia and heart failure. Previous studies found that The occurrence of uremia LVH is mainly associated with high blood pressure and high volume load prevalent in such patients. But the simple control of blood pressure and relieving capacity load can not significantly improve the possible causes of the occurrence of LVH in LVH. uremia patients, except for the secondary elevation of parathyroid hormone, abnormal calcium and phosphorus metabolism and oxidative stress reaction. Inflammatory state is an important factor. Studies have shown that LVH is closely related to microinflammatory state, and macrophage migration inhibitory factor (MIF) is the upstream proinflammatory factor of cytokines in the state of microinflammation. The expression of MIF-173CC genotype in ESRD patients is up-regulated and hypersensitive C reaction protein (H) with inflammatory factor markers in serum microinflammation state (H) S-CRP is a direct correlation. In the study of autoimmune giant cell myocarditis, it was found that after the injection of MIF neutralizing antibodies, the lesions of the myocarditis were significantly reduced. The study found that the role of MIF in uremic patients may reduce the degree of uremia cardiomyopathy, and may be a new research in the treatment of uremia cardiomyopathy. The purpose of this study is to investigate the relationship between serum MIF and inflammatory markers hs-CRP and myocardial hypertrophy in patients with end-stage renal disease, and to explore the effect of inflammatory factors MIF and hs-CRP on ventricular remodeling in patients with end-stage renal disease, and to explore the dynamic evaluation index of uremic cardiomyopathy. Effective treatment of uremic cardiomyopathy has important theoretical and practical significance. 1. the study group was selected from October 2014 to August 2015 in 144 patients with end-stage renal disease hospitalized in Tai'an Central Hospital of Shandong province and Qingdao Central Hospital of nephrology. And 30 sex and age were selected and the patients with end-stage nephrosis were selected. All the subjects were included in the healthy volunteers as a healthy control group. All the subjects were enrolled in the group according to the inclusion criteria and excluded the patients who did not meet the requirements of the group. According to the condition of ESRD patients undergoing dialysis and dialysis, the study group was divided into the end stage renal disease group (ND, n=63), the hemodialysis group (HD, n=51) and the peritoneal dialysis group (PD, n=30). The patients in the hemodialysis group received low flux hemodialysis.2. indicators: (1) collect the patients' clinical data and biochemical indexes, including age, sex, blood pressure, etc. at the same time in Tai'an and Qingdao City Center Hospital, using SYSMEX XE2100 blood analyzer and matching reagents, analysis and detection of red blood cells, hemoglobin and so on; (2) in Thai. An inspection department in an City and Qingdao Central Hospital, strictly according to the routine operation steps of the ROCHE COBAS 8000 full automatic electrochemiluminescence immunoanalyzer and the ROCHE kit, detected the total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), extremely low density lipoprotein (VLDL), and apolipoprotein A (APOA). Apolipoprotein B (APOB), lipoprotein (alpha) (alpha) (LP (alpha)), prealbumin (PA), albumin (ALB), potassium ion (K+), sodium ion (Cl-), calcium ion (Ca2+), magnesium ion (Mg2+), phosphorus ion (p3+), urea nitrogen (BUN), creatinine, uric acid (beta), beta microglobulin (beta), cystatin, and immunoturbidimetry At the level of hs-CRP, the normal value of hs-CRP is less than 3mg/L; (3) in the laboratory of No.3 Hospital of Beijing University, the serum MIF level of ESRD patients and healthy controls was detected by liquid chip technology (American Bio-plex suspension protein chip system) by using the company's Bio-Plex human cytokinemulti-plex kit and the corresponding Bio-Plex cytokines kit. And the corresponding detection instruments to detect the level of plasma MIF between different groups. The Bio-plex suspension protein chip technology in the United States can detect the multiple cytokine in the same specimen in a reaction pool for qualitative, quantitative detection, antigen and antibody, ligand and receptor, enzyme and enzyme on different fluorescent microspheres. The substrate, nucleic acid hybridization reaction, and the red and green two beam lasers are used to detect the microspheres encoding and report the fluorescence to achieve the purpose of qualitative and quantitative. The liquid chip technology can be roughly divided into three steps when used to detect cell factors. First, the probe molecules are fixed on the chip surface, and then the microspheres are encoded by red and green laser beams respectively. The data analysis system used the Bio-Plex management software (version 4), which made the sensitivity of the detection less than 10pg/mL, and the concentration range of the cytokine that could be accurately detected to reach 1-32000pg/mL; (4) the ultrasonic cardiogram examination: all patients adopted the IU22 ultrasound system (PHILPS medical system) The left ventricular end diastolic diameter (LVDD), interventricular septum thickness (IVST), left ventricular ejection fraction (LVEF%) and left ventricular posterior wall thickness (LVPWT) were measured. All measurements were performed by experienced ultrasound doctors and repeated three times. The left ventricular mass (LVM) was calculated by formula, LVM=0.8{1.04 * [(LVDD+ IVST+LVPWT) 3-LVDD3]}. +06, divided by the surface area of the left ventricular mass index (LVMI). Diagnostic criteria for left ventricular hypertrophy: the male left ventricular mass index 134g/m2. The female left ventricular mass index 110g/m2. was divided into the left ventricular hypertrophy group and the non hypertrophic group according to the above criteria. The diagnostic criteria for uremic cardiomyopathy were analyzed according to the previous standard [35].3. data: statistical analysis adopted SPS S21.0 analysis software. The variables of normal distribution are expressed by mean number and standard deviation, and the variables of non normal distribution are expressed in the median and range of.MIF, hs-CRP and other non normal distribution are compared by Mann-Whitney test or Kruskal-Wallis test.Spearman rank correlation test for.Logistic regression analysis of continuous and ordered variables for determination. The relative risk degree (RR).P0.05 was statistically significant. 1. a total of 144 cases of ESRD patients were included, including 80 men (55.6%), 64 women (44.4%), age 19-86, and the average age of 55.3 + 15.9. According to the condition of dialysis and dialysis for ESRD patients, the patients were divided into three groups: end-stage kidney There was no statistically significant difference in age and sex between the three groups. In these three groups, the main causes of chronic renal disease were chronic glomerulonephritis and hypertensive renal damage in the.2.ESRD patients' serum MIF and hs-CRP levels: Kruskal-Wallis test, the results showed the end of the end. The MIF level of the three groups in the non dialysis group, the peritoneal dialysis group and the hemodialysis group, compared with the control group, was statistically significant (P0.05), and 22 compared between the three groups. The results showed that the serum MIF phase of the hemodialysis group and the peritoneal dialysis group were significantly different (P0.05). After Kruskal-Wa, the level of MIF was statistically significant (P0.05). After Kruskal-Wa, the level of the hemodialysis group was significantly different. LLIS test, we found that the difference between the hs-CRP level end-stage renal disease group, the peritoneal dialysis group, the hemodialysis group and the healthy control group was statistically significant (P0.05), but the 22 ratio between the end stage renal disease group and the hemodialysis group and the peritoneal dialysis group was not statistically significant (P0.05).3. serum MIF level. Correlation analysis with various clinical indicators: after Spearman level correlation analysis, serum MIF level and systolic pressure, diastolic pressure, red blood cell count, total cholesterol, triglyceride, apolipoprotein A, apolipoprotein A, apolipoprotein B, creatinine, uric acid, beta 2 microglobulin, Cystatin C, sodium, chlorine, calcium, magnesium, phosphorus, left ventricular end diastolic diameter, ventricular septum, and interventricular septum were analyzed. There was no correlation between thickness, left ventricular posterior wall thickness and left ventricular ejection fraction (P0.05). But serum MIF level was positively correlated with hypersensitive C reactive protein, blood potassium and urea nitrogen (P0.05), and the relationship between serum MIF level and left ventricular hypertrophy was negatively correlated with hemoglobin and albumin (P0.05).4.: according to ultrasonic results, ESRD patients were divided into left ventricular fertilizer. Serum MIF level 1186 (170.0-3862.0) pg/mL in patients with thick and non left ventricular hypertrophy with left ventricular hypertrophy was 1186 (170.0-3862.0) pg/mL, significantly higher than 228.5 (55.0-2079.0) pg/mL (P0.05) in non left ventricular hypertrophy ESRD patients. Serum MIF level was positively correlated with the left ventricular mass index. Serum MIF was larger than 1100pg/mL as an anomaly, lower or equal to that of the ESRD. For normal, logistic regression analysis was used to verify the relative risk degree of serum MIF to left ventricular hypertrophy (RR). The results showed that the incidence of high level serum MIF left ventricular hypertrophy was MIF13.063 times at low level when considering the dominance ratio (OR). The results showed that MIF entered the regression model and had statistical significance (P0.05), suggesting that serum MIF and ESRD patients were in serum. The serum MIF is a risk factor for left ventricular hypertrophy in patients with ESRD. Conclusion: serum MIF and hs-CRP levels in patients with 1. end-stage renal disease (ESRD) are significantly higher, indicating that the serum MIF and hs-CRP in patients with ESRD and.2. end-stage renal disease (ESRD) in ESRD patients may participate in the left ventricle of the patients with ESRD. The occurrence and development of hypertrophy of.3. serum high MIF level is a risk factor for left ventricular hypertrophy in ESRD patients. Blocking the role of MIF in uremic patients may reduce the degree of uremic cardiomyopathy, thus providing a clinical basis and theoretical basis for the treatment of uremic cardiomyopathy.

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R692.5;R54

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