血液透析病人应用促红细胞生成素体会

贫血是慢性肾功能不全(尿毒症期)严重并发症,发生率几乎为100%,原因为肾脏分泌促红细胞生成素不足.以往输血是常用的手段,但即使反复输血,由于输入尿毒症患者循环中的红细胞寿命缩短,故不能满意改善症状,又增加了输血相关疾病的发生。从2000年1月开始我院应用人类重组红细胞生成素(EPO)纠正肾性贫血,使90%尿毒症患者贫血得到改善,弥补了以往输血的不足,也深刻认识到贫血对于尿毒症患者生活质量影响程度以及贫血与存活率,脏器功能、特别是左心室肥厚、心脏缺血耐受的关系。现将我院近5年我们应用EPO纠正血液透析病人贫血情况报道如下。1 资料与方法     

左旋卡尼丁联合促红细胞生成素治疗尿毒症贫血的效果分析

目的：分析左旋卡尼丁联合促红细胞生成素（EPO）治疗尿毒症贫血的临床效果。方法资料随机选自2011年2月~2014年2月在本院接受维持性血液透析治疗的尿毒症贫血患者60例，按照完全随机法1：1分成两组，均予以常规内科对症支持治疗与血液透析治疗（3次/周），在此基础上，对照组透析结束后行EPO皮下注射，研究组在对照组基础上加用左旋卡尼丁静脉滴注，分析两组患者治疗后的贫血指标、临床症状改善情况、临床效果与不良反应。结果研究组患者的高血压、总不良反应发生率分别为3.33%、16.67%，均低于对照组的20.00%、43.33%（P〈0.05）；与治疗前、同期对照组比较，研究组治疗4、8、12周时的Hb、Hct浓度均有所上升、ERI均有所下降（P〈0.05）；研究组治疗4、8周与达到目标浓度的EPO用量均明显少于对照组（P〈0.05）；研究组的典型临床表现改善情况明显优于对照组、贫血改善与达到Hb目标浓度所用时间短于对照组（P〈0.05）。结论左旋卡尼丁联合EPO治疗尿毒症贫血的临床效果显著，具有临床推广应用与研究价值。     

慢性肾功能衰竭患者红细胞膜免疫分子表达的临床研究

目的观察慢性肾功能衰竭（肾衰）患者外周血红细胞膜免疫分子的表达特点及血液透析前后的变化,促红细胞生成素（EPO）对其的调节作用。方法采用流式细胞仪（FCM）对42例慢性肾衰患者外周血红细胞膜免疫分子CD35、CD58、CD59进行检测,同时观察血透前后的变化及EPO治疗纠正肾性贫血后红细胞膜免疫分子的变化情况。结果42例慢性肾衰患者红细胞膜免疫分子表达异常,与正常对照组比较治疗纠正肾性表达低下（P〈0．01）。血液透析前后无明显变化,促红细胞生成素治疗纠正肾性贫血后,CD35、CD58、CD59也随之显著上升（P〈0．01）。结论慢性肾衰患者存在红细胞免疫功能低下,其免疫功能低下与贫血有关,EPO对改善肾衰患者红细胞免疫分子有积极的调节作用。     

大剂量促红细胞生成素治疗肾性贫血

目的观察大剂量促红细胞生成素治疗肾性贫血的临床疗效及其在尿毒症血透患者体内的代谢。方法尿毒症贫血血透患者28例,随机分为2组,观察组给予大剂量促红细胞生成素、多糖铁复合物和高通量血透,对照组给予常规剂量促红细胞生成素、右旋糖酐铁和低通量血透。两组均于治疗16周后观察相关贫血和生化指标及血清促红细胞生成素浓度变化。结果观察组血红蛋白、红细胞压积、血清铁蛋白、转铁蛋白饱和度升高均较对照组明显(P<0.05)。两组血清促红细胞生成素浓度均较治疗前升高(P<0.05),大剂量促红细胞生成素注射7d内各项血清指标浓度稳定,注射16周后各项指标无进一步改变。结论大剂量促红细胞生成素联合多糖铁复合物和高通量透析能更有效的改善尿毒症血透患者的缺铁和贫血,且大剂量促红细胞生成素长间隔治疗可使血清促红细胞生成素水平维持稳定。     

慢性呼吸衰竭血清促红细胞生成素水平的研究

通过比较Ⅰ、Ⅱ型呼吸衰竭（简称呼衰）外周血红细胞（RBC）、血红蛋白（Hb）、血球压积（Hct）及血清促红细胞生成素（EPO）浓度的变化，发现伴有CO2潴留的Ⅱ型呼衰外周血RBC、Hb、Hct及血清EPO水平显著高于Ⅰ型呼哀。慢性呼衰动脉血PCO2及pH值与血清EPO浓度显著相关。提示CO2潴留及酸血症协同低氧血症刺激肾脏EPO的生成，而发生继发性红细胞增多。     

左卡尼汀联合促红细胞生成素治疗肾性贫血临床观察

目的：探讨左卡尼汀联合促红细胞生成素治疗肾性贫血的临床疗效。方法：56例血液透析（hemodialysis,HD）伴有肾性贫血的尿毒症患者随机分为治疗组与对照组,每组28例。全部患者均应用促红细胞生成素（EPO）4000u,皮下注射,每周2次。治疗组于HD结束后静脉注射左卡尼汀1．0g,每周2次,疗程12周。所有患者分别记录治疗前和治疗开始后12周的血红蛋白、红细胞压积、C-反应蛋白。结果：两组患者经治疗后,贫血指标均得以改善,但治疗组升高的幅度更明显（P〈0．05）,炎症指标CRP水平均较治疗前下降,但治疗组下降的幅度更明显（P〈0．05）。治疗组总有效率达到92．85％,亦明显高于对照组（P〈0．05）。治疗组2例患者出现轻度恶心。结论：左卡尼汀可加强EPO的疗效。左卡尼汀联合EPO治疗肾性贫血安全有效。     

促红细胞生成素不同给药次数对防治早产儿贫血的临床研究

目的：探讨促红细胞生成素（EPO）防治早产儿贫血的最佳治疗方案。方法：将78例早产儿随机分为对照组,治疗1组和治疗2组,对照组口服维生素,治疗1组用EPO按750IU/（kg·周）,分4次皮下注射,治疗2组用EPO按750IU/（kg·周）,分2次皮下注射,动态观察患者的血色素、网织红细胞比例、血清铁蛋白变化,记录输血次数,相关数据进行统计学处理。结果：对照组与治疗组（治疗1组＋治疗2组）比较,血红蛋白、网织红细胞比例、输血次数均存在显著差异,未见明显毒副作用,说明EPO对防治早产儿贫血安全、有效;治疗1组与治疗2组比较,血红蛋白、网织红细胞比例在治疗后期及输血次数的差异具有显著性,治疗1组优于治疗2组。结论：促红细胞生成素（EPO）在大剂量、早治疗的前提下,分多次给药对防治早产儿贫血疗效更好。     

左卡尼汀联合促红细胞生成素治疗肾性贫血

目的：探讨左卡尼汀联合促红细胞生成素对尿毒症血液透析患者贫血的疗效.方法：将2007年6月至2009年7月间在我院接受血液透析治疗的尿毒症患者90例,随机分为治疗组与对照组两组,治疗组采用左卡尼汀联合促红细胞生成素（EPO）治疗,对照组只采用EPO进行治疗.观察两组的Hb、Hct的变化及疗效.结果：经过治疗后,两组的Hb含量及血细胞比容均出现上升现象,且治疗组的上升幅度远大于对照组.治疗后,两组疗效的差异具有统计学意义（P〈0.01）,治疗组的疗效优于对照组.结论：左卡尼汀联合EPO治疗尿毒症血液透析患者的贫血,效果显著,值得进一步推广应用.     

移植肾切除可逆转移植肾功能衰竭患者的促红细胞生成素抵抗

目的研究移植肾切除对移植肾功能衰竭患者促红细胞生成素（EPO）抵抗的治疗作用。方法以移植肾功能衰竭进行规律性血液透析的患者为观察对象，在移植肾切除术前、术后采用EPO及补充造血原料治疗肾性贫血，检测患者血红蛋白、C反应蛋白、血清肌酐、血清铁蛋白水平。结果规律性透析患者移植肾切除术前采用EPO治疗3月血红蛋白水平改变不明显，血清C反应蛋白显著高于正常；移植肾切除后3月血红蛋白升高明显，血清C反应蛋白恢复正常，血红蛋白水平改变与C反应蛋白呈明显负相关。结论移植肾切除可逆转移植肾功能衰竭患者EPO抵抗，改善肾性贫血。     

透析患者残余肾功能与EPO使用的关系

尿毒症血液透析患者普遍存在贫血问题,而输血又存在着感染等诸多不利,只有使用重组人红细胞生成素(EPO)才能改善贫血问题。透析患者可存在一定的残余肾功能,而且能保存残余内分泌功能。本文就血液透析患者残余肾功能与EPO使用的关系进行探讨。     

Effect of recombinant human erythropoietin on new anaemic model rats induced by gentamicin

The effects of recombinant human erythropoietin (r-HuEPO) on haematological parameters were studied in rats in which uraemia and anaemia had been induced by gentamicin, an aminoglycoside antibiotic and a nephrotoxic agent. After the occurrence of slight polycythaemia, the red blood cell count, haematocrit and haemoglobin concentration decreased by 20-30% compared with those of the control (saline-injected) rats. At the end of gentamicin treatment, the endogenous serum EPO level had decreased to about 40% compared with that of control rats. Gentamicin-treated rats showed marked elevation of blood urea nitrogen, extensive tubular necrosis in the kidney and haemosiderin deposition in the spleen. In the osmotic fragility test, the fragility of erythrocytes significantly increased compared with that of control rats. These findings indicate that the anaemia induced by gentamicin is due not only to a deficiency of EPO but also to an enhancement of fragility of erythrocytes in an azotaemic environment. The administration of r-HuEPO during anaemia markedly increased red blood cell count, haematocrit and haemoglobin concentration. It is suggested that a gentamicin-treated rat is a useful and convenient anaemic model and r-HuEPO is useful for treatment of anaemia in acute renal failure.     

Recombinant human erythropoietin, but not iron supplementation, improves anemia in rats with adjuvant-induced arthritis.

Pathophysiological and therapeutic properties of anemia in rats with adjuvant-induced arthritis (AA) were investigated. Both anemia and chronic inflammation were induced in rats by a single injection of Freund's complete adjuvant. This study confirmed other earlier data that these anemic rats with AA had reduced serum iron levels and that the anemia was characterized as mild, non-progressive, hypochromic, microcytic. In addition, our studies showed that these anemic rats had slightly but significantly enhanced erythropoietin titers, but not renal failure; there was no significant difference in blood urea nitrogen and creatinine levels in anemic and normal groups. The anemia in rats with AA was improved by recombinant human erythropoietin (r-HuEPO) at 30 and 100 U/kg/day, given i.v. for 5 days. In contrast, iron-chondroitin-sulfate colloid (10 mg/kg/day, i.v. for 5 days) failed to improve the anemia and to enhance the effects of r-HuEPO. These data suggest that anemia in rats with adjuvant-induced arthritis is distinguished, pathophysiologically and therapeutically, from iron deficiency anemia, hemolytic anemia, and renal anemia.     

促红细胞生成素对实验性肾性贫血的作用

促红细胞生成素(erythropoietin,EPO)是由肾细胞分泌的一种糖蛋白激素。从人胚肾细胞中诱导,经生物化学方法分离、提纯得到此品。本试验用5/6肾切除的方法造成大鼠慢性肾衰性(CRF)贫血,研究不同剂量EPO对CRF贫血的作用。结果表明EPO有显著的促进红细胞生成,改善CRF贫血状态,使其接近或达到正常水平,最佳剂量为1000 U/kg,并可预防实验性贫血,对正常鼠未见明显作用。     

r-HuEPO低反应性患者应用骨化三醇治疗的临床观察

目的探讨应用骨化三醇对血液透析促红细胞生成素（r-HuEPO）低反应性患者的影响。方法随机将20例r-HuEPO低反应性患者分成观察组和对照组各10例,观察组给予骨化三醇口服治疗,对照组未给予骨化三醇治疗,两组均常规进行血液透析,并补充铁剂、r-HuEPO、叶酸、维生素B12;观察分析两组患者治疗前后血清甲状旁腺激素（iPTH）、血红蛋白（Hb）、血细胞比容（Hct）、血钙（Ca）、血磷（P）检测结果。结果观察组治疗后血清iPTH、P下降明显,Ca、Hb、Hct升高明显,差异有统计学意义（P〈0.05）,对照组治疗前后患者iPTH、Hb、Hct、Ca、P水平差异无统计学意义（P〉0.05）;两组患者治疗前血清iPTH、Hb、Hct、Ca、P水平差异无统计学意义（P〉0.05）,治疗后观察组比对照组血清iPTH、P下降明显,Ca、Hb、Hct升高明显,差异有统计学意义（P〈0.05）。结论对于维持性血液透析促红细胞生成素低反应性患者给予口服骨化三醇治疗,可以降低患者血清iPTH水平,从而提高患者对r-HuEPO的反应性,对于改善贫血等治疗效果满意。     

表达人红细胞生成素裸质粒治疗肾性贫血的实验研究

目的：观察表达人红细胞生成素(EPO)基因裸质辛立通过电脉冲转移法导入大鼠和猕猴体内治疗腺嘌呤所致的肾性贫血的效果。方法：实验选择了喂含腺嘌呤饲料所致大鼠和猕猴的肾性贫血模型，电脉冲转移法把质粒导入动物股四头肌。实验分正常组、模型组、表达大鼠EPO基因裸质粒对照组(仅在大鼠肾性模型中)和不同剂量表达人EPO基因裸质粒组。动态检测血细胞比容(HCT)水平；提取给药部位肌肉组织总RNA进行逆转录PCR，检测EPO基因在肌细胞当中的表达；用EPO酶联免疫(ELISA)试利盒测定血清EPO水平。结果：电脉冲肌肉转移表达EPO裸质粒可在局部有效表达和分泌。在大鼠模型中，给药后第2～5周，表达大鼠EPO基因裸质粒对照组和表达人EPO基因裸质粒组的HCT水平明显高于模型组。在猕猴模型中，表达人EPO基因裸质粒组在给药后第4～5周HCT水平明显高于模型组。在大鼠模型中，表达人EPO基因裸质粒组的血清有明显的中和活性，可抑制BEF-2细胞的增殖。结论：电脉冲转移表达EPO基因裸质粒对腺嘌呤所致猕猴肾性贫血和大鼠肾性贫血具有明显的治疗作用。     

肝炎病毒感染对维持性血液透析患者贫血的影响

目的 回顾性分析乙型和(或)丙型病毒性肝炎感染对于慢性血液透析患者贫血状况的影响.方法 52例终末期肾脏病(ESRD)接受血液透析患者,根据肝炎病毒检测分为两组,HBV阳性及(或)HCV阳性22例为A组,HBV阴性并HCV阴性30例为B组.比较两组间人重组促红细胞生成素的使用剂量,以及两组间血红蛋白和红细胞压积的差异.结果 两组病人人重组促红细胞生成素的用量差异无显著性(P＞0.05),而A组病人血红蛋白和红细胞压积均较B组高,差异存在显著性(P＜0.05).结论 HBV及(或)HCV的感染可能启动了肝脏产生EPO途径,在一定程度上改善了ESRD患者的贫血状态.     

The pharmacokinetics of erythropoietin in the cerebrospinal fluid after intravenous administration of recombinant human erythropoietin

Objectives Erythropoietin (EPO) was originally described as a regulator of erythropoiesis. Recently, synthesis of EPO and expression of the EPO receptor (EPO-R) have been reported for the central nervous system (CNS). The potential use of EPO to prevent or reduce CNS injury and the paucity of information regarding its entry into the human CNS led us to examine the pharmacokinetics (PK) of recombinant human EPO (r-HuEPO) in the serum and cerebrospinal fluid (CSF).Methods Four patients with Ommaya reservoirs were enrolled to facilitate serial CSF sampling. R-HuEPO was given intravenously (IV) in single doses of 40,000 IU or 1,500 IU/kg and in multiple doses of 40,000 IU daily for 3 days.Results The EPO concentrations in the CSF increased after a period of slow equilibration. Linear first-order distribution kinetics were observed for serum and CSF. The concentration of EPO in the CSF was proportional to the serum concentration of EPO and the permeability of the blood-brain barrier (BBB), as determined by the albumin quotient (Q_A=[albumin] CSF/[albumin] serum). A rise in the CSF concentration was seen as early as 3 h after IV administration. Peak levels (C_max) were reached between 9 h and 24 h. After a single dose of 1,500 IU/kg, the C_max in the CSF ranged from 11 mIU/ml to 40 mIU/ml, and the ratios of CSF/serum C_max ranged from 3.6×10^–4 to 10.2×10^–4. The terminal half-life (t_1/2) values of EPO in serum and CSF were similar. The t_1/2 of r-HuEPO in the CSF ranged from 25.6 h to 35.5 h after a single dose of 1,500 IU/l. Using these parameters a PK model was generated that predicts the concentration-time profile of EPO in the CSF.Conclusions We report that r-HuEPO can cross the human BBB and describe for the first time the PK of EPO in the CSF after IV administration. Our data suggest that the concentration-time profile of EPO in the CSF can be predicted for individual patients if the serum concentration of EPO and the Q_A are known. This information may be useful in the design of clinical trials to explore the potential therapeutic effects of EPO during CNS injury.     

Long-term cadmium exposure induces anemia in rats through hypoinduction of erythropoietin in the kidneys

 Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells. Received: 2 May 1996/Accepted: 29 May 1996     

促红细胞生成素对实验性肝硬化内皮素-1的影响及意义

目的探讨促红细胞生成素对实验性肝硬化大鼠动脉血浆内皮素-1的影响及意义。方法45只实验SD大鼠随机分成3组:肝硬化组(n=17)、r-HuEPO干预组(n=15)和正常对照组(n=13)。用四氯化碳制备肝硬化模型,成模后干预组予r-HuEPO干预2周。血浆内皮素-1含量采用放免法测定,自动血气分析仪测PaO2、PaCO2、AaDO2(肺泡-动脉血氧分压差)。结果肝硬化组血浆ET-1、PaO2、AaDO2含量与正常组、r-HuEPO干预组比较差异有显著性,正常组与r-HuEPO干预组间差异不显著,肝硬化组与r-HuEPO干预组动脉血浆ET-1及PaO2呈显著正相关(r=0.733,P<0.05;r=0.652,P<0.05),与AaDO2呈显著负相关(r=-0.755,P<0.01;r=-0.732,P<0.05),在其它两组无显著相关性。结论ET-1在肝硬化大鼠低氧血症发生机制中可能起重要作用,r-HuEPO可改善肝硬化低氧血症状态。