促红细胞生成素抵抗在维持性血液透析贫血患者中的临床意义

发布时间：2018-09-13 13:32

【摘要】：研究背景与目的贫血是慢性肾脏病(Chronic kidney disease,CKD)的主要并发症之一,随肾功能下降其发生率逐渐增加,对患者的生存质量及长期存活均有重要影响。重组人促红细胞生成素(recombinant human erythropoietin,rHuEPO,简称:促红素)使90%以上的患者得到及时有效治疗,约有5%~10%患者对EPO反应性减低。文献报道,在铁储备充足的情况下,rHuEPO每周静脉应用大于450 IU/kg或皮下注射大于300 IU/kg治疗4-6个月后仍不能达到目标血红蛋白(Hemoglobin,HGB)及血细胞比容(Hematocrit,HCT),即定义为促红素抵抗。目前已经明确导致rHuEPO治疗抵抗有多种因素,其中铁缺乏是主要因素,其次,感染、营养不良、继发性甲状旁腺机能亢进、自身免疫性疾病、铝中毒、血管紧张素转换酶抑制剂等均可引起EP0抵抗。EPO与骨髓红系祖细胞表面的特异性EPO受体(Erythropoietin receptor,EPOR)结合促进红细胞生成,而EP0抗体(Erythropoietin antibody,EPO-Ab)和EPOR抗体(Erythropoietin receptor antibody,EPOR-Ab)均可阻断两者结合,继而影响红细胞生成导致贫血。其中EPO-Ab引起对rHuEPO治疗反应性减低,越来越引起人们的重视。近年来,国内外对于EPO-Ab与促红细胞生成素抵抗之间的的研究已有报道,在部分患者,该抗体还可以导致纯红细胞再生障碍性贫血(Pure red cell anemia PRCA,简称:纯红再障)。然而,维持性性血液透析患者中促红细胞生成素抵抗是否与EPOR-Ab有关还不明确。目前EPOR-Ab的相关研究,国内外报道都比较少,而且大多数研究集中在风湿性血液疾病与EPOR抗体的关系,在尿毒症透析患者中关于EPOR抗体与贫血的报道则较少,有待进一步研究。目的本课题旨以维持性血液透析患者为研究对象,分析ERI与各指标的相关关系,并检测EPO-Ab和EPOR-Ab在患者中的阳性率,探讨促红细胞生成素抵抗在血液透析患者中可能的影响因素,及分析EPO-Ab及EPOR-Ab的临床意义,旨在对血液透析贫血患者促红细胞生成素抵抗的预测、指导rHuEPO的临床应用,提供重要参考价值。方法2015年3月-2016年3月于第三军医大学新桥医院肾内科血液净化中心进行维持性血液透析660例患者,筛选出资料完整的,且应用rHuEPO治疗时间≥6个月的253尿毒症患者。本研究以促红素低反应性指数(erythropoietin resistance index,ERI)作为评估rHuEPO治疗剂量效应的有效指标,ERI定义为每公斤每周使用rHuEPO剂量(IU)除以血红蛋白水平(g/L)。根据第三军医大学附属第二医院检验科血红蛋白检测结果,HGB≥110g/L为达标组,HGB110g/L不达标组。根据每周每千克rHuEPO维持治疗剂量分为3亚组:A组:rHuEPO治疗剂量150 IU/(kg·w);B组:150 IU/(kg·w)≤rHuEPO治疗剂量300 IU/(kg·w);C组:rHuEPO治疗剂量≥300 IU/(kg·w)。根据基础病不同分为:慢性肾小球肾炎组、糖尿病肾病组、高血压肾病组、移植性肾功衰组、其他组(包括痛风性肾病、多囊肾、肾结核、过敏性紫癜性肾病、系统性红斑狼疮性肾病)。观察患者临床基本资料及血常规(包括RDW)、血肌酐(Scr)、尿素氮(BUN)、尿酸(UA)、电解质、C反应蛋白(CRP)、铁蛋白(Ferritin)、血清铁(Fe)、甲状旁腺素(PTH),计算体重指数(Body Mass Index,BMI)=体重kg/(身高*身高)m2,单室尿素清除指数sp Kt/V=-1n(R-0.008×t)+(4-3.5×R)×UF/W,EPO抵抗指数(ERI),ERI=每周EPO剂量/(体重*血红蛋白)。应用酶联免疫法(enzyme--1inked immunosorbent assay ELISA)检测EPO-Ab、EPOR-Ab阳性率。rHuEPO为沈阳三生制药股份有限公司生产的益比奥,均于透析结束后皮下注射。统计分析:各研究因素分别与ERI进行关联性分析,其中两组间比较采用t检验,多组间比较使用方差分析,方差不齐数据行非参数Kruskal-Wallis检验。计数资料比较使用卡方检验。连续性变量正态性分布用Pearson相关分析。应用多元线性逐步回归模型分析ERI的影响因素。以P0.001为差异有统计学意义。结果1.基本资料从660例筛选出病例资料完整的253例患者入选本研究,其中男性147例,女性106例,年龄范围18~75(47.8±13.7)岁。透析龄范围为6~105(43.85±22.70)个月。慢性肾炎131例,占51.78%;糖尿病肾病37例,占14.62%;高血压肾病34例,占13.44%;移植性肾功衰16例,占6.32%;其他35例,占13.83%(包括痛风性肾病、多囊肾、肾结核、过敏性紫癜性肾病、系统性红斑狼疮性肾病)。每周每公斤rHuEPO维持治疗剂量在A、B、C组分别有82例、137例、34例患者,各占32.41%;54.15%;13.44%。应用rHuEPO治疗贫血后HGB达标106例患者,占41.90%,HGB不达标147例患者,占58.10%。2.不同rHuEPO治疗剂量组血液透析患者在年龄、性别、原发病构成、透析龄、HGB、白蛋白、ln Fe、铁蛋白、ln CRP、sp Kt/V、ln PTH无明显差异。RDW、ERI在不同rHuEPO治疗剂量组有显著差异。3.达标组与不达标组在性别、年龄、BMI、RDW、白蛋白、ln Fe、铁蛋白、sp Kt/V无明显差异,在透析龄、HGB、Ln PTH、ERI、Ln CRP差异有统计学意义。4.不同原发病组在性别、年龄、BMI、白蛋白、ln Fe、铁蛋白、HGB、ERI、sp Kt/V、透析龄无统计学意义,在C-反应蛋白、RDW差异有统计学意义。5.ERI在血液透析患者性别组间差异有统计学意义。女性组:ERI为(8.70±3.64)IU/(Kg*Hb),男性组(7.13±3.87)IU/(Kg*Hb),组间t检验结果(P=0.002,t=3.198)。6.血液透析患者各项指标与ERI的双变量相关性分析Person相关分析,结果显示ERI与HGB、ln Fe、BMI呈负相(r=-0.434,r=-0.168,r=-0.155,P0.05),与RDW、透析月龄、Ln CRP呈正相关(r=0.294,r=0.200,r=0.180,P0.05)。ERI与白蛋白、ln PTH、Sp Kt/V关联差异无统计学意义(r=-0.017,r=-0.016.r=-0.014,P0.05)。7.以ERI为因变量,将双变量相关分析结果P0.05的相关因素使用逐步法纳入,建立多元线性逐步回归模型,结果显示,HGB、RDW为ERI的相关变量(P0.001)。8.EPO-Ab、EPOR-Ab在血液透析患者中的情况经过ELISA检测,253例血液透析患者中EPO-Ab阳性41例,占16.21%;EPOR-Ab阳性59例,占23.32%。除外铁缺乏,218例血液透析患者中EPO-Ab阳性37例,占16.97%;EPOR-Ab阳性53例,占24.31%。EPO-Ab和EPOR-Ab在除外铁缺乏的血液透析患者不同分组中情况如下:在达标组92例中有9例EPO-Ab阳性,16例EPOR-Ab阳性;不达标组126例中有28例EPO-Ab阳性;37例EPOR-Ab阳性;EPO-Ab和EPOR-Ab在达标组与不达标组间差异有统计学意义(X2=5.839,P=0.016)(X2=4.143,P=0.042)。在慢性肾炎组110例患者中EPO-Ab阳性15例,EPOR-Ab阳性24例;糖尿病肾病组33例患者中EPO-Ab阳性7例,EPOR-Ab阳性13例;高血压肾病31例患者中EPO-Ab阳性3例,EPOR-Ab阳性9例;移植性肾功衰组15例患者中EPO-Ab阳性3例,EPOR-Ab阳性2例;其他组31例患者中EPO-Ab阳性9例,EPOR-Ab阳性5例。EPO-Ab阳性/阴性和EPOR-Ab阳性/阴性在不同原发病组差异无统计学意义(X2=5.982,P=0.2000)(X2=7.268,P=0.122)。在不同rHuEPO剂量组A组75例患者中EPO-Ab阳性16例,EPOR-Ab阳性18例;B组117例患者中EPO-Ab阳性12例,EPOR-Ab阳性28例;C组26例患者中EPO-Ab阳性9例,EPOR-Ab阳性7例。EPO-Ab阳性/阴性在不同rHuEPO剂量组差异有统计学意义(X2=10.500,P=0.005);EPOR-Ab阳性/阴性在不同rHuEPO剂量组差异无统计学意义(X2=0.109,P=0.947)。结论维持性血液透析患者促红细胞生成素抵抗的形成,除了与体重指数、C反应蛋白、透析龄等因素有关外,也与EPO-Ab、EPOR-Ab形成有关,RDW增高是促红细胞生成素抵抗的重要表现。
[Abstract]:BACKGROUND AND OBJECTIVE Anemia is one of the major complications of chronic kidney disease (CKD). The incidence of anemia increases with the decrease of renal function, which has an important impact on the quality of life and long-term survival of patients. About 5% to 10% of the patients were treated promptly and effectively, and their responsiveness to EPO was reduced. It was reported in the literature that when iron reserve was sufficient, rHuEPO could not reach the target hemoglobin (HGB) and hematocrit (HCT) after 4-6 months of intravenous administration of more than 450 IU/kg per week or subcutaneous injection of more than 300 IU/kg. There are many factors that lead to resistance to rHuEPO therapy. Iron deficiency is the main factor. Secondly, infection, malnutrition, secondary hyperparathyroidism, autoimmune diseases, aluminum poisoning, angiotensin converting enzyme inhibitors, etc. can cause resistance to EP0. EPO and the surface characteristics of bone marrow erythroid progenitor cells The binding of heterosexual EPO receptors (EPORs) promotes erythropoiesis, whereas both EPO-Ab and EPOR-Ab can block the binding of the two receptors, which in turn affects erythropoiesis and leads to anemia. EPO-Ab leads to decreased responsiveness to rHuEPO treatment and is increasingly attracted to anemia. In recent years, studies on the relationship between EPO-Ab and erythropoietin resistance have been reported at home and abroad. In some patients, the antibody can also lead to pure red cell aplastic anemia (PRCA). It is not clear whether EPOR-Ab is related to EPOR-Ab. At present, there are few reports about EPOR-Ab at home and abroad, and most of the studies focus on the relationship between rheumatic blood disease and EPOR antibody. In uremic dialysis patients, there are few reports about EPOR antibody and anemia, which need further study. To analyze the correlation between ERI and various indexes, to detect the positive rate of EPO-Ab and EPOR-Ab in patients, to explore the possible influencing factors of erythropoietin resistance in hemodialysis patients, and to analyze the clinical significance of EPO-Ab and EPOR-Ab in hemodialysis anemia patients, in order to predict erythropoietin resistance in hemodialysis anemia patients. Methods From March 2015 to March 2016, 660 patients with maintenance hemodialysis were selected from the Hemodialysis Center of Nephrology, Xinqiao Hospital, Third Military Medical University, and 253 uremic patients with complete data were treated with rHuEPO for more than 6 months. The erythropoietin resistance index (ERI) is an effective index to evaluate the dose-response of rHuEPO. ERI is defined as the weekly dose of rHuEPO divided by the hemoglobin level (g/L) per kilogram. According to the results of hemoglobin test in the laboratory of the Second Affiliated Hospital of the Third Military Medical University, HGB (> 110g/L) is regarded as the standard group and HGB110g/L is not up to the standard. Group A was divided into three subgroups according to the weekly dose of rHuEPO: group A: rHuEPO treatment dose 150 IU / (kg) group B: 150 IU / (kg) less than rHuEPO treatment dose 300 IU / (kg) group C: rHuEPO treatment dose (> 300 IU / (kg) according to the different basic diseases: chronic glomerulonephritis group, diabetic nephropathy group, hypertensive nephropathy group, transplantation group. Clinical data and blood routine (including RDW), serum creatinine (Scr), urea nitrogen (BUN), uric acid (UA), electrolyte, C-reactive protein (CRP), ferritin (Ferritin), serum iron (Fe), parathyroid hormone (PTH) were observed. Body Mass Index (BMI) = body weight kg / (height * height) m2, one-compartment urea clearance index sp Kt / V = - 1n (R-0.008 * t) + (4-3.5 * R) * UF / W, EPO resistance index (ERI), ERI = weekly EPO dose / (body weight * hemoglobin). EPO-Ab and EPOR-Ab positive rate were detected by enzyme-1 inked immunosort assay ELISA. Statistical analysis: Correlation analysis was carried out between each research factor and ERI, among which t test was used for comparison between the two groups, analysis of usage difference among multiple groups, non-parametric Kruskal-Wallis test for uneven variance data. Results 1. The basic data of 253 patients with complete data from 660 cases were selected and enrolled in this study, including 147 males and 106 females, aged 18-75 (4). The dialysis age ranged from 6 to 105 (43.85 (+ 22.70) months. 131 cases were chronic nephritis, accounting for 51.78%; 37 cases were diabetic nephropathy, accounting for 14.62%; 34 cases were hypertensive nephropathy, accounting for 13.44%; 16 cases were allograft renal failure, accounting for 6.32%; the other 35 cases, accounting for 13.83% (including gouty nephropathy, polycystic kidney disease, renal tuberculosis, allergic Pura nephropathy, systemic lupus erythematosus nephropathy). The weekly maintenance dose of rHuEPO was 82 in group A, 137 in group B and 34 in group C, accounting for 32.41%, 54.15% and 13.44% respectively. 106 patients (41.90%) had reached the standard of HGB and 147 patients (58.10%) had failed to reach the standard of HGB after rHuEPO treatment. RDW, ERI in different rHuEPO dosage groups had significant differences. 3. There was no significant difference in sex, age, BMI, RDW, albumin, ln Fe, ferritin, sp Kt / V, dialysis age, HGB, Ln PTH, ERI, Ln CRP in different primary diseases There was no significant difference in sex, age, BMI, albumin, ln Fe, ferritin, HGB, ERI, sp Kt/V, dialysis age, and C-reactive protein, RDW. There was a significant difference in ERI between the two groups. There was a significant difference in ERI between the two groups of hemodialysis patients. The results showed that ERI was negatively correlated with HGB, ln Fe and BMI (r = - 0.434, r = - 0.168, r = - 0.155, P 0.05), and positively correlated with RDW, dialysis age, Ln CRP (r = 0.294, r = 0.200, r = 0.180, P 0.05). There was no significant difference between ERI and albumin, ln PTH, Sp Kt / V. Meaning (r = - 0.017, r = - 0.016.r = - 0.014, P 0.05). 7. Taking ERI as dependent variable, the related factors of bivariate correlation analysis result P 0.05 were included by stepwise method, and a multivariate linear stepwise regression model was established. The results showed that HGB, RDW were the related variables of ERI (P 0.001). 8. EPO-Ab, EPOR-Ab were detected by ELISA in 253 hemodialysis patients. EPO-Ab was positive in 41 dialysis patients, accounting for 16.21%; EPOR-Ab was positive in 59 patients, accounting for 23.32%. There were 28 EPO-Ab positive cases in 126 cases of chronic nephritis group, 37 cases of EPOR-Ab positive cases, EPO-Ab and EPOR-Ab positive differences between the standard group and non-standard group (X2 = 5.839, P = 0.016) (X2 = 4.143, P = 0.042). There were 7 cases with EPO-Ab positive, 13 cases with EPOR-Ab positive, 3 cases with EPO-Ab positive and 9 cases with EPOR-Ab positive in 31 patients with hypertension nephropathy, 3 cases with EPO-Ab positive and 2 cases with EPOR-Ab positive in 15 patients with allograft renal failure, 9 cases with EPO-Ab positive and 5 cases with EPOR-Ab positive in 31 patients with other groups. Significance (X2 = 5.982, P = 0.2000) (X2 = 7.268, P = 0.122). There were 16 cases of EPO-Ab positive and 18 cases of EPOR-Ab positive in group A with different rHuEPO doses, 12 cases of EPO-Ab positive and 28 cases of EPOR-Ab positive in group B with 117 cases, 9 cases of EPO-Ab positive and 7 cases of EPO-Ab positive and 7 cases of EPO-Ab negative in group C with different rHuEPO doses. (X2 = 10.500, P = 0.005); EPOR-Ab positive / negative in different rHuEPO dosage groups had no significant difference (X2 = 0.109, P = 0.947). Conclusion The formation of erythropoietin resistance in maintenance hemodialysis patients is related to body mass index, C-reactive protein, dialysis age and other factors, but also to the formation of EPO-Ab and EPOR-Ab, and the increase of RDW is erythropoietin. The important expression of resistin.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R692.5

【参考文献】