药物相关肾实质性急性肾衰竭患者的贫血特征、红细胞生成素水平及其与肾损害的关系

目的:回顾性分析药物相关的不同原因急性肾衰竭(acute renal failure, ARF)患者的临床病理特点及血清学指标,探讨其贫血特征、红细胞生成素(erythropoietin, EPO)水平及与肾小管间质损害的关系.方法:选择近5年的药物相关肾实质性ARF住院患者[16例,包括急性肾小管坏死(acute tubular necrosis, ATN)组和急性肾小管间质肾病(acute tubular-interstitial nephropathy, ATIN)组]以及健康志愿者(正常对照组,8例)为观察对象,回顾性分析其肾活检时的贫血相关指标、血清EPO、肌酐水平和肾小管功能.对ARF各组患者的肾小管功能和肾病理改变进行半定量评分.对血红蛋白(hemoglobin, Hb)、EPO水平与肾功能和肾病理损伤指数进行相关分析.结果:(1)药物相关肾实质性急性肾衰竭各组患者血清肌酐(serum creatinine, Scr)水平均较对照组明显增高(P<0.05),肾小管功能损伤指数和肾小管间质病理损伤指数较对照组有所增高,以ATIN组为最高(P<0.01).(2)ATIN组患者Hb、红细胞压积(haematocrit, Hct)、红细胞(red blood cell, RBC)的水平较对照组明显降低(P<0.01).(3)ATN组、ATIN组EPO水平较对照组分别明显下降84.8%和70.7%(P<0.01).(4)肾实质性ARF患者的Hb与EPO呈正相关(r=0.589,P<0.01);而EPO则与Scr、肾小管功能损伤指数及肾小管、间质病理损伤指数之间均呈负相关(P<0.05).结论:ATIN是药物相关急性肾衰竭伴贫血患者的主要原因之一,该组患者贫血的机制可能与急性肾小管间质损伤导致内源性EPO分泌不足、进而引起红细胞生成减少有关.     

促红细胞生成素对心肌缺血再灌注后诱导型一氧化氮合酶蛋白的影响

目的:探讨促红细胞生成素对大鼠心肌缺血再灌注后诱导型一氧化氮合酶蛋白的影响及其对心肌保护作用与机制。方法:采用结扎左冠状动脉前降支30min,再灌注120min的方法,建立大鼠模型缺血再灌注损伤模型,将30只大鼠随机分为对照组、缺血再灌注组、治疗组(EPO 5000IU/kg)3组,每组10只,测定再灌注末血清和心肌组织磷酸肌酸激酶(CK)、丙二醛(MDA)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)的变化,应用免疫组织化学方法检测iNOS蛋白的表达,用TUNEL法检测心肌细胞凋亡的变化。结果:与正常对照组相比,缺血再灌注组细胞上清液中LDH、MDA含量明显升高(P<0.01),SOD活力则显著降低(P<0.01),缺血组再灌注组凋亡率均升高明显(P<0.01)。治疗组的LDH、MDA显著低于对照组和缺血再灌注组(P<0.01),SOD则高于对照组和缺血再灌注组(P<0.01),缺血再灌注后细胞凋亡率与对照组相比均明显升高(P<0.01),治疗组再灌组的凋亡率与对照组相比均显著下降(P<0.01)。对照组有少量iNOS表达,缺血再灌注组iNOS表达升高(P<0.01)而EPO治疗组表达减少(P<0.01),与缺血再灌注组相比差异有显著性意义(P<0.01)。结论:EPO抑制iNOS蛋白的表达以减少心肌细胞凋亡,减轻大鼠心肌缺血再灌注损伤,从而对心肌有保护作用。     

Pharmacokinetics of recombinant human erythropoietin in children treated with continuous ambulatory peritoneal dialysis

In children treated by continuous ambulatory peritoneal dialysis (CAPD) renal anaemia is preferably treated by intraperitoneal administration of erythropoietin, since subcutaneous administration is painful and frightening for the child. Pharmacokinetics of erythropoietin were studied in three groups of children treated by CAPD. In group subcutaneous (SC) (n=5) erythropoietin was administered subcutaneously, whereas in group intraperitoneal 1 (IP1) (n=8) and intraperitoneal 2 (IP2) (n=8) erythropoietin was given intraperitoneally during a 12-h dwell. Group IP1 received erythropoietin in 20 ml/kg of dialysis fluid, while in group IP2 the hormone was added to only 50 ml of dialysate, irrespective of body weight. The median area under the curve (AUC) was 4064 mU·h/ml (range 2647–24357) in group SC, 1698 (570–5514) in group IP1 and 3577 (1225–6555) in group IP2. In comparison to group SC the AUC was significantly lower in group IP1 (Wilcoxon;P=0.02). The difference between group SC and group IP2 was not statistically significant.In children on CAPD the resorption of erythropoietin after intraperitoneal administration, measured as AUC, is similar to subcutaneous administration, when erythropoietin is administered in 50 ml of dialysate. The dose needed to treat renal anaemia with erythropoietin administered intraperitoneally this way will have to be established in a therapeutic study.     

Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants

The aim of this study was to compare two different doses and means of administration of iron in recombinant human erythropoietin (rHuEPO)-treated very low birth-weight (VLBW) infants. VLBW infants (n = 41) were randomized to one of three groups. Fourteen infants were treated with rHuEPO (300 IU/kg three times a week s.c.) and oral iron (ferrofumarate, 6 mg of iron/kg per day). Another 14 infants received the same erythropoietin dose and intramuscular iron (ferroxypolymaltose, once 12 mg of iron/kg weekly). Thirteen infants were treated with the same dose of intramuscular iron but did not receive rHuEPO. After the 3-week study period, haemoglobin concentrations and reticulocyte counts were similar in the rHuEPO-treated groups and both were higher than in the group not receiving rHuEPO (P < 0.001). In both rHuEPO-treated groups the transferrin receptor concentration increased from 6.8–7.2 mg/l to 10.5–11.3 mg/l. Conclusion In erythropoietin-treated very low birth weight infants the iron need for erythropoiesis can be met by oral administration of iron. Received: 17 November 1997 and in revised form: 6 March 1998 / Accepted: 30 April 1998     

慢性肾功能不全患者血清促红细胞生成素水平的观察

应用酶联免疫分析法测定慢性肾功能不全（CRI）不同时期血清促红细胞生成素（EPO）水平．结果发现，CRI患者氮质血症期、尿毒症或血清EPO浓度与正常对照组无明显差异，且与肾功能损害程度、贫血程及无显著相关．透析和体外给予重组人红细胞生成素，可改善尿毒症患者的贫血状态，但基础血清EPO浓度无明显变化．以上结果提示CRI患者不仅EPO生成缺乏，而且存在EPO生以氧依赖调控系统异常。     

Training induced effects on blood volume,erythrocyte turnover and haemoglobin oxygen binding properties

Summary The effect of three weeks ergometer training (Tr) 5 times a week for 45 min at 70% by 6 subjects on erythrocyte turnover and haemoglobin O₂ affinity has been studied. Increased reticulocytosis could be observed from the second day after beginning Tr until a few days after its end, probably caused by increased erythropoietin release by the kidney. Erythrocyte destruction was most pronounced in the first and markedly reduced in the third week of Tr. Elevated glutamate oxalacetate transaminase activity and creatine as well as lowered mean corpuscular haemoglobin indicate a younger erythrocyte population in the first week of recovery. Total blood volume increased during the course of Tr by 700 ml, mainly caused by a raised plasma volume (74%). Red cell volume increased later with maximal values one week after Tr (+280 ml). In this week the standard oxygen dissociation curve was most shifted to the right (P₅₀ increased from 3.77±0.05 kPa to 3.99±0.07 kPa) and the Bohr coefficients had their lowest values. Both effects are completely explainable by the haemoglobin O₂ binding properties of young erythrocytes.After training, all parameters of physical performance ( , maximal workload, heart rate during rest and exercise) were markedly improved, indicating fast adaptation mechanisms. The increased erythrocyte turnover, including higher erythropoiesis, seems to be one important part of these effects.A preliminary report was presented at the National Congress of Sports Medicine in Cologne, 1982. Furthermore, the content of this paper was part of the doctoral thesis of the first author     

Are elevated fetal nucleated red blood cell counts an indirect reflection of enhanced erythropoietin activity?

OBJECTIVE: Animal and human studies demonstrated elevated erythropoietin (EPO) levels in response to intrauterine hypoxic events. Other studies documented an association between fetal hypoxia and elevated nucleated red blood cell (NRBC) counts and have speculated that it is the elevation of EPO that results in an increase in NRBC counts. Thus, the purpose of our study was to determine the correlation between EPO levels and NRBC counts in the human fetus. STUDY DESIGN: Data were collected prospectively between April and July of 2003. Term singleton pregnancies were eligible to participate in the study. Umbilical cord blood was collected immediately after birth for determination of fetal EPO levels and NRBC counts. RESULTS: Forty pregnancies formed the study population. The mean gestational age at delivery was 39.5 +/- 1.2 weeks (+/-SD) and the mean birth weight was 3500 +/- 372 g. The median EPO (mU/mL) was 34 (range 13-427). The median NRBC/100 white blood cells was 10 (range 0-150). A simple regression analysis indicated that NRBC counts are significantly and positively correlated with EPO (P=.0004, R(2)=0.287). CONCLUSION: Our results suggest a significant association between EPO and NRBC counts in term singleton fetuses. These results support the hypothesis that fetal NRBC and EPO are interrelated. However, the relatively low R(2) indicates that there are other (yet to be determined) hypoxia-derived mediators that result in an elevation of fetal NRBC counts.     

Darbepoetin alfa in lung cancer patients on chemotherapy: a retrospective comparison of outcomes in patients with mild versus moderate-to-severe anaemia at baseline

Goals Currently, there is some debate concerning the haemoglobin level at which treatment of anaemia with erythropoiesis-stimulating agents should be initiated in cancer patients on chemotherapy. We report several analyses of data from a phase III trial of darbepoetin alfa versus placebo, comparing outcomes for patients with mild and moderate-to-severe anaemia.Patients and methods Data were obtained from a phase III trial of darbepoetin alfa versus placebo in anaemic patients with lung cancer receiving chemotherapy (n=314). Outcomes were compared for patients with baseline haemoglobin 10–11 g/dl and <10 g/dl.Results Darbepoetin alfa significantly reduced transfusions compared with placebo, irrespective of haemoglobin level at treatment initiation. For patients with baseline haemoglobin <10 g/dl, 31% and 59% of those receiving darbepoetin alfa and placebo, respectively, required a transfusion from week 5 to the end of the treatment phase (P<0.038). For patients with baseline haemoglobin 10 g/dl, the proportions were 15% and 41%, respectively (P<0.001). Darbepoetin alfa also improved fatigue compared with placebo in both haemoglobin categories.Conclusions These findings show that initiating treatment at haemoglobin levels both <10 g/dl and 10–11 g/dl results in substantial clinical benefits, supporting the use of erythropoietic therapy also in patients with mild anaemia.J. Vansteenkiste is the beneficiary of the Amgen Fund in Supportive Cancer Care at the Catholic University, Leuven, Belgium.This work was supported by Amgen Inc., Thousand Oaks, California, USA     

Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings

Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar.