發(fā)布時(shí)間：2018-09-13 13:32

【摘要】：研究背景與目的貧血是慢性腎臟病(Chronic kidney disease,CKD)的主要并發(fā)癥之一,隨腎功能下降其發(fā)生率逐漸增加,對(duì)患者的生存質(zhì)量及長期存活均有重要影響。重組人促紅細(xì)胞生成素(recombinant human erythropoietin,rHuEPO,簡稱:促紅素)使90%以上的患者得到及時(shí)有效治療,約有5%~10%患者對(duì)EPO反應(yīng)性減低。文獻(xiàn)報(bào)道,在鐵儲(chǔ)備充足的情況下,rHuEPO每周靜脈應(yīng)用大于450 IU/kg或皮下注射大于300 IU/kg治療4-6個(gè)月后仍不能達(dá)到目標(biāo)血紅蛋白(Hemoglobin,HGB)及血細(xì)胞比容(Hematocrit,HCT),即定義為促紅素抵抗。目前已經(jīng)明確導(dǎo)致rHuEPO治療抵抗有多種因素,其中鐵缺乏是主要因素,其次,感染、營養(yǎng)不良、繼發(fā)性甲狀旁腺機(jī)能亢進(jìn)、自身免疫性疾病、鋁中毒、血管緊張素轉(zhuǎn)換酶抑制劑等均可引起EP0抵抗。EPO與骨髓紅系祖細(xì)胞表面的特異性EPO受體(Erythropoietin receptor,EPOR)結(jié)合促進(jìn)紅細(xì)胞生成,而EP0抗體(Erythropoietin antibody,EPO-Ab)和EPOR抗體(Erythropoietin receptor antibody,EPOR-Ab)均可阻斷兩者結(jié)合,繼而影響紅細(xì)胞生成導(dǎo)致貧血。其中EPO-Ab引起對(duì)rHuEPO治療反應(yīng)性減低,越來越引起人們的重視。近年來,國內(nèi)外對(duì)于EPO-Ab與促紅細(xì)胞生成素抵抗之間的的研究已有報(bào)道,在部分患者,該抗體還可以導(dǎo)致純紅細(xì)胞再生障礙性貧血(Pure red cell anemia PRCA,簡稱:純紅再障)。然而,維持性性血液透析患者中促紅細(xì)胞生成素抵抗是否與EPOR-Ab有關(guān)還不明確。目前EPOR-Ab的相關(guān)研究,國內(nèi)外報(bào)道都比較少,而且大多數(shù)研究集中在風(fēng)濕性血液疾病與EPOR抗體的關(guān)系,在尿毒癥透析患者中關(guān)于EPOR抗體與貧血的報(bào)道則較少,有待進(jìn)一步研究。目的本課題旨以維持性血液透析患者為研究對(duì)象,分析ERI與各指標(biāo)的相關(guān)關(guān)系,并檢測(cè)EPO-Ab和EPOR-Ab在患者中的陽性率,探討促紅細(xì)胞生成素抵抗在血液透析患者中可能的影響因素,及分析EPO-Ab及EPOR-Ab的臨床意義,旨在對(duì)血液透析貧血患者促紅細(xì)胞生成素抵抗的預(yù)測(cè)、指導(dǎo)rHuEPO的臨床應(yīng)用,提供重要參考價(jià)值。方法2015年3月-2016年3月于第三軍醫(yī)大學(xué)新橋醫(yī)院腎內(nèi)科血液凈化中心進(jìn)行維持性血液透析660例患者,篩選出資料完整的,且應(yīng)用rHuEPO治療時(shí)間≥6個(gè)月的253尿毒癥患者。本研究以促紅素低反應(yīng)性指數(shù)(erythropoietin resistance index,ERI)作為評(píng)估rHuEPO治療劑量效應(yīng)的有效指標(biāo),ERI定義為每公斤每周使用rHuEPO劑量(IU)除以血紅蛋白水平(g/L)。根據(jù)第三軍醫(yī)大學(xué)附屬第二醫(yī)院檢驗(yàn)科血紅蛋白檢測(cè)結(jié)果,HGB≥110g/L為達(dá)標(biāo)組,HGB110g/L不達(dá)標(biāo)組。根據(jù)每周每千克rHuEPO維持治療劑量分為3亞組:A組:rHuEPO治療劑量150 IU/(kg·w);B組:150 IU/(kg·w)≤rHuEPO治療劑量300 IU/(kg·w);C組:rHuEPO治療劑量≥300 IU/(kg·w)。根據(jù)基礎(chǔ)病不同分為:慢性腎小球腎炎組、糖尿病腎病組、高血壓腎病組、移植性腎功衰組、其他組(包括痛風(fēng)性腎病、多囊腎、腎結(jié)核、過敏性紫癜性腎病、系統(tǒng)性紅斑狼瘡性腎病)。觀察患者臨床基本資料及血常規(guī)(包括RDW)、血肌酐(Scr)、尿素氮(BUN)、尿酸(UA)、電解質(zhì)、C反應(yīng)蛋白(CRP)、鐵蛋白(Ferritin)、血清鐵(Fe)、甲狀旁腺素(PTH),計(jì)算體重指數(shù)(Body Mass Index,BMI)=體重kg/(身高*身高)m2,單室尿素清除指數(shù)sp Kt/V=-1n(R-0.008×t)+(4-3.5×R)×UF/W,EPO抵抗指數(shù)(ERI),ERI=每周EPO劑量/(體重*血紅蛋白)。應(yīng)用酶聯(lián)免疫法(enzyme--1inked immunosorbent assay ELISA)檢測(cè)EPO-Ab、EPOR-Ab陽性率。rHuEPO為沈陽三生制藥股份有限公司生產(chǎn)的益比奧,均于透析結(jié)束后皮下注射。統(tǒng)計(jì)分析:各研究因素分別與ERI進(jìn)行關(guān)聯(lián)性分析,其中兩組間比較采用t檢驗(yàn),多組間比較使用方差分析,方差不齊數(shù)據(jù)行非參數(shù)Kruskal-Wallis檢驗(yàn)。計(jì)數(shù)資料比較使用卡方檢驗(yàn)。連續(xù)性變量正態(tài)性分布用Pearson相關(guān)分析。應(yīng)用多元線性逐步回歸模型分析ERI的影響因素。以P0.001為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果1.基本資料從660例篩選出病例資料完整的253例患者入選本研究,其中男性147例,女性106例,年齡范圍18~75(47.8±13.7)歲。透析齡范圍為6~105(43.85±22.70)個(gè)月。慢性腎炎131例,占51.78%;糖尿病腎病37例,占14.62%;高血壓腎病34例,占13.44%;移植性腎功衰16例,占6.32%;其他35例,占13.83%(包括痛風(fēng)性腎病、多囊腎、腎結(jié)核、過敏性紫癜性腎病、系統(tǒng)性紅斑狼瘡性腎病)。每周每公斤rHuEPO維持治療劑量在A、B、C組分別有82例、137例、34例患者,各占32.41%;54.15%;13.44%。應(yīng)用rHuEPO治療貧血后HGB達(dá)標(biāo)106例患者,占41.90%,HGB不達(dá)標(biāo)147例患者,占58.10%。2.不同rHuEPO治療劑量組血液透析患者在年齡、性別、原發(fā)病構(gòu)成、透析齡、HGB、白蛋白、ln Fe、鐵蛋白、ln CRP、sp Kt/V、ln PTH無明顯差異。RDW、ERI在不同rHuEPO治療劑量組有顯著差異。3.達(dá)標(biāo)組與不達(dá)標(biāo)組在性別、年齡、BMI、RDW、白蛋白、ln Fe、鐵蛋白、sp Kt/V無明顯差異,在透析齡、HGB、Ln PTH、ERI、Ln CRP差異有統(tǒng)計(jì)學(xué)意義。4.不同原發(fā)病組在性別、年齡、BMI、白蛋白、ln Fe、鐵蛋白、HGB、ERI、sp Kt/V、透析齡無統(tǒng)計(jì)學(xué)意義,在C-反應(yīng)蛋白、RDW差異有統(tǒng)計(jì)學(xué)意義。5.ERI在血液透析患者性別組間差異有統(tǒng)計(jì)學(xué)意義。女性組:ERI為(8.70±3.64)IU/(Kg*Hb),男性組(7.13±3.87)IU/(Kg*Hb),組間t檢驗(yàn)結(jié)果(P=0.002,t=3.198)。6.血液透析患者各項(xiàng)指標(biāo)與ERI的雙變量相關(guān)性分析Person相關(guān)分析,結(jié)果顯示ERI與HGB、ln Fe、BMI呈負(fù)相(r=-0.434,r=-0.168,r=-0.155,P0.05),與RDW、透析月齡、Ln CRP呈正相關(guān)(r=0.294,r=0.200,r=0.180,P0.05)。ERI與白蛋白、ln PTH、Sp Kt/V關(guān)聯(lián)差異無統(tǒng)計(jì)學(xué)意義(r=-0.017,r=-0.016.r=-0.014,P0.05)。7.以ERI為因變量,將雙變量相關(guān)分析結(jié)果P0.05的相關(guān)因素使用逐步法納入,建立多元線性逐步回歸模型,結(jié)果顯示,HGB、RDW為ERI的相關(guān)變量(P0.001)。8.EPO-Ab、EPOR-Ab在血液透析患者中的情況經(jīng)過ELISA檢測(cè),253例血液透析患者中EPO-Ab陽性41例,占16.21%;EPOR-Ab陽性59例,占23.32%。除外鐵缺乏,218例血液透析患者中EPO-Ab陽性37例,占16.97%;EPOR-Ab陽性53例,占24.31%。EPO-Ab和EPOR-Ab在除外鐵缺乏的血液透析患者不同分組中情況如下:在達(dá)標(biāo)組92例中有9例EPO-Ab陽性,16例EPOR-Ab陽性;不達(dá)標(biāo)組126例中有28例EPO-Ab陽性;37例EPOR-Ab陽性;EPO-Ab和EPOR-Ab在達(dá)標(biāo)組與不達(dá)標(biāo)組間差異有統(tǒng)計(jì)學(xué)意義(X2=5.839,P=0.016)(X2=4.143,P=0.042)。在慢性腎炎組110例患者中EPO-Ab陽性15例,EPOR-Ab陽性24例;糖尿病腎病組33例患者中EPO-Ab陽性7例,EPOR-Ab陽性13例;高血壓腎病31例患者中EPO-Ab陽性3例,EPOR-Ab陽性9例;移植性腎功衰組15例患者中EPO-Ab陽性3例,EPOR-Ab陽性2例;其他組31例患者中EPO-Ab陽性9例,EPOR-Ab陽性5例。EPO-Ab陽性/陰性和EPOR-Ab陽性/陰性在不同原發(fā)病組差異無統(tǒng)計(jì)學(xué)意義(X2=5.982,P=0.2000)(X2=7.268,P=0.122)。在不同rHuEPO劑量組A組75例患者中EPO-Ab陽性16例,EPOR-Ab陽性18例;B組117例患者中EPO-Ab陽性12例,EPOR-Ab陽性28例;C組26例患者中EPO-Ab陽性9例,EPOR-Ab陽性7例。EPO-Ab陽性/陰性在不同rHuEPO劑量組差異有統(tǒng)計(jì)學(xué)意義(X2=10.500,P=0.005);EPOR-Ab陽性/陰性在不同rHuEPO劑量組差異無統(tǒng)計(jì)學(xué)意義(X2=0.109,P=0.947)。結(jié)論維持性血液透析患者促紅細(xì)胞生成素抵抗的形成,除了與體重指數(shù)、C反應(yīng)蛋白、透析齡等因素有關(guān)外,也與EPO-Ab、EPOR-Ab形成有關(guān),RDW增高是促紅細(xì)胞生成素抵抗的重要表現(xiàn)。
[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.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R692.5

【參考文獻(xiàn)】

相關(guān)期刊論文 前5條

1 楊琨;賈慶齡;唐莎;王衛(wèi)黎;袁發(fā)煥;張瑩;;紅細(xì)胞分布寬度在維持性血液透析患者促紅細(xì)胞生成素抵抗中的臨床意義[J];免疫學(xué)雜志;2017年05期

2 蒲蕾;阮一哲;洪大情;吳姝q;馮韻霖;楊鴻玲;鄧菲;何強(qiáng);王莉;;維持性血液透析患者對(duì)紅細(xì)胞生成素低反應(yīng)性的影響因素[J];中國血液凈化;2016年03期

3 文建國;馮錦錦;;促紅細(xì)胞生成素的研究進(jìn)展和臨床應(yīng)用[J];鄭州大學(xué)學(xué)報(bào)(醫(yī)學(xué)版);2015年06期

4 沈波;劉中華;鄒建洲;徐少偉;徐磊;潘文志;滕杰;鐘一紅;丁小強(qiáng);;維持性血液透析患者紅細(xì)胞體積分布寬度及相關(guān)影響因素研究[J];中國臨床醫(yī)學(xué);2012年05期

5 趙穎丹;顧波;;促紅細(xì)胞生長素抵抗的發(fā)病機(jī)制研究新進(jìn)展[J];中國中西醫(yī)結(jié)合腎病雜志;2012年10期

，

本文編號(hào)：2241317