Lisinopril pharmacokinetics and erythropoietin requirement in haemodialysis patients

Eur J Clin Invest 2012; 42 (10): 1087-1093 ABSTRACT: Background There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy. Materials and methods We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6?h thereafter; AUC(1) ), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC(2) . Results The mean ESA index of all patients was 27·90?±?25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC(1) was 1212·48?±?1209·75 [mg*h/L], whereas AUC(2) averaged 947·67?±?977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients. Conclusions Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.     

Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise

Abstract. The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 ± 1.2 to 11.1 ± 1.1 g dl^-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant Pao₂ and Paco₂. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial Pco₂ before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.     

WT1介导的转录调控通路与白血病

WT1基因编码的锌指转录因子能调控下游基因的转录，其中很多靶基因涉及调节细胞周期和增殖分化，而WT1本身也接受其上游基因的调控，如NF-кB和GATA-1等，这样便构成WT1介导的转录调控通路，参与造血系统发育的调控，如果转录因子的表达脱调控以及随之而来的正常基因表达态势受干扰，常会引起造血细胞的增殖，分化及凋亡动态平衡的紊乱，最终导致白血病，本就WT1介导的转录调控通路与白血病的关系作一综述。     

Erythropoietic activity and iron metabolism in autologous blood donors during recombinant human erythropoietin therapy

Abstract. The use of recombinant human erythropoietin (rhEPO) to intensify the erythropoietic response in autologous donors may reduce homologous blood requirement. We studied the effect of subcutaneous rhEPO (500 U kg^-1 body weight twice weekly during a 3 week period) on variables of erythropoiesis and iron metabolism in 62 autologous blood donors, of whom 32 received rhEPO (epo group) and 30 did not (control group). Patients donated only 2 units of blood and received oral iron in order to restrict phlebotomyinduced decrease of iron stores. Pre-phlebotomy haemoglobin concentration (14·0±0·8 g dl^-1) was completely regenerated in the epo group at surgery (13·7±1·3 g dl^-1); haemoglobin concentration in the control group fell from 13·5±1·4 g dl^-1 to 11·6±1·4 g dl^-1 after the phlebotomies and did not improve during the pre-operative phase. Total erythropoietic activity expressed as serum transferrin receptor concentration (sTfR) showed a 4-fold increase from 3·8±0·9 μ g ml^-1 to 14·9±4·8 μ g ml^-1 in the epo group. Effective erythropoietic activity measured by absolute reticulocyte count, however, declined after the fourth rhEPO injection in the epo group. Serum ferritin was lower in the epo group, but no differences in serum iron, transferrin concentration and transferrin saturation were observed between the groups. A marked increase in free erythrocyte protoporphyrin (FEP) was observed in the epo group, whereas FEP levels in the controls remained within normal ranges. Despite oral iron supplementation and the limited number of phlebotomies, the effect of rhEPO therapy in autologous donors is restricted by iron depletion.     

胚胎期造血干细胞来源及其调控

胚胎干细胞是体内各种组织包括造血组织干细胞的来源,在胚胎干细胞向造血干细胞的分化及造血干细胞自身的发育过程中有着复杂的基因调控。原始造血产生于卵黄囊已被普遍认可,但永久造血产生于何处仍有争论。目前认为,至少有两个独立的部位与永久造血有关,即卵黄囊和胚内的ＰＡＳ／ＡＧＭ区。对胚胎期造血及其调控的研究不仅有助于探明某些血液病的发病机制,而且在基因治疗和造血干细胞工程方面也将具有重大作用。     

Brain and cancer: the protective role of erythropoietin

Erythropoietin (Epo) is a pleiotropic agent, that is to say, it can act on several cell types in different ways. An independent system Epo/Epo receptor (EpoR) was detected in brain, leading to the hypothesis that this hormone could be involved in cerebral functions. Epo/EpoR expression changes during ontogenesis, thus indicating the importance of this system in neurodevelopment. Moreover, the hypoxia-induced production of Epo in the adult brain suggests that it could exert a neurotrophic and neuroprotective effect in case of brain injury. Epo could also influence neurotransmission, inducing neurotransmitters (NT) release. Epo therapy in anemic cancer patients is still a controversial issue, because of its possible action as a growth and an angiogenic factor. In our speculative hypothesis Epo could be involved in a "two steps process" that, after a neovascularization phase, leads to its down regulation. Moreover, Epo-activated signaling pathways could be modulated as possible targets to interfere in neoplastic cells cycle. In conclusion, treatment with rHuEpo could change therapeutical perspectives in different pathological conditions, such as central nervous system (CNS) diseases, but further studies are needed to clarify its physiopathological activities in different clinical fields.     

Modulation of erythropoietin production by adenosine

Adenosine is an important regulatory molecule that increases in hypoxic and ischemic tissues and has been proposed to mediate blood flow in response to oxygen availability. The current study ascribes another oxygen-responsive role to adenosine, that of regulating synthesis of the erythropoiesis-stimulating hormone, erythropoietin. When perfused through isolated rat kidneys, exogenous adenosine in nanomolar concentrations increased erythropoietin production, whereas inosine, the deaminated nucleoside, had no effect. In addition, an adenosine antagonist, and adenosine deaminase, diminished erythropoietin titers in renal perfusates. In intact rats, adenosine deaminase injections followed by a hypoxic stimulus slightly reduced erythropoietin serum concentrations, whereas an adenosine deaminase inhibitor sharply increased erythropoietin titers. The results suggest that adenosine may function as a mediator to link oxygen supply with erythropoietin production.     

Use of recombinant human erythropoietin in combination with parenteral iron in the treatment of postpartum anaemia

The authors compared the effect of recombinant human erythropoietin (rhEPO) in combination with iron with that of iron therapy only in the treatment of postpartum anaemia. Ninety patients (30 patients/group) received either rhEPO (300 U kg⁻¹, i.v. or s.c., once) and iron (parenteral and oral), or iron therapy only. Erythropoiesis was assessed by haemoglobin and haematocrit increase, absolute reticulocyte counting and reticulocyte flow cytometry. Ferrokinetics was assessed by serum ferritin, transferrin and transferrin saturation measurements. There was no difference before therapy for baseline haematological values or iron status. Patients with endogenous EPO levels below 145 mU mL⁻¹ had a significant benefit from intravenous rhEPO administration with highest haematocrit and haemoglobin levels 4 and 14 days after therapy. rhEPO-treated groups showed a higher absolute reticulocyte count 1 and 4 days after therapy and an elevated percentage of high fluorescent reticulocytes (HFRs). Parenteral iron therapy caused a significant increase of ferritin and transferrin saturation, while transferrin concentration decreased. Ferritin and transferrin levels were lowest after i.v. administration of rhEPO, 1 and 4 days after therapy. C-reactive protein concentration was highest in patients who underwent caesarean section until the end of the observation period. A single dose of rhEPO in combination with iron was more effective in treating postpartum anaemia than iron therapy only, in patients who had low EPO levels despite peripartal blood loss. Postpartum low endogenous EPO levels might be a consequence of inhibiting inflammatory cytokines that are released after spontaneous or operative deliveries.     

Serum hepcidin concentration in chronic haemodialysis patients: associations and effects of dialysis, iron and erythropoietin therapy

Background Hepcidin, a liver‐derived peptide induced by iron overload and inflammation, is a major regulator of iron homeostasis. As hepcidin decreases gastrointestinal iron absorption and recirculation from monocytes, over‐expression is associated with the development of anaemia. Methods We studied the associations between circulating hepcidin levels and various laboratory parameters related to anaemia and/or inflammation in 20 patients on chronic haemodialysis. Furthermore, we determined the impact of dialysis and iron and/or erythropoietin (rhEpo) supplementation therapy on hepcidin serum concentrations. The patients were withheld from iron and rhEpo for 2 weeks before study entry. Hepcidin was measured by liquid chromatography‐mass spectrometry (LC‐MS/MS); serum iron and haematological parameters, cytokines and pro‐hepcidin by commercially available enzyme‐linked immunosorbent assays (ELISA) or standard automated methods. Results While hepcidin levels at baseline were not correlated to pro‐hepcidin, interleukin‐6 or transforming growth factor‐beta concentrations, we found significant associations with reticulocyte count (r = ?0·55; P = 0·015), serum iron (r = 0·7; P = 0·004) and ferritin levels (r = 0·63; P = 0·004) and transferrin saturation (r = 0·69, P = 0·001). Dialysis using either a high or a low flux biocompatible dialyser resulted in a significant decrease of hepcidin concentrations, which returned to pre‐dialysis values before the next dialysis session. When studying the effects of anaemia treatment, we observed a significant reduction of hepcidin levels following administration of rhEpo but not iron. Conclusions Hepcidin levels in stable haemodialysis patients appear to reflect systemic iron load, but not inflammation. Due to the negative association between reticulocyte counts and hepcidin, the reduction of circulating hepcidin concentrations by dialysis and/or rhEpo treatment may positively affect erythropoiesis.     

人类ERMAP基因在诱导K562细胞向红系和巨噬系细胞分化过程中表达的研究

为了探讨人类ERMAP基因在红细胞分化发育过程中的作用,以Ara-C诱导K562细胞向红系方向分化,以十二氟波酯钠盐(TPA)诱导K562细胞向巨噬系方向分化,用荧光定量PCR检测上述过程中人类ERMAP基因表达量的变化。结果发现:终浓度为2.5×10-6mmol/L/L及1.0×10-6mmol/L/L的Ara-C可诱导K562细胞向红系方向分化,在此过程中人类ERMAP基因的表达量逐渐增加;终浓度为2.0×10-6mmol/L/L及1.0×10-6mmol/L/L的TPA可诱导K562细胞向巨噬系方向分化,在此过程中人类ERMAP基因的表达量无变化。结论:人类ER-MAP基因与红系分化增殖密切相关。     

Effectiveness of recombinant erythropoietin and iron sucrose vs. iron therapy only, in patients with postpartum anaemia and blunted erythropoiesis

BACKGROUND: To compare efficacy between recombinant human erythropoietin (rhEPO) plus parenteral iron vs. iron alone (parenteral vs. oral) in postpartum anaemia. METHODS: Sixty patients (haemoglobin 8.6 +/- 1.1 g dL-1) were randomized to rhEPO plus intravenous (i.v.) iron sucrose (group 1), rhEPO placebo plus i.v. iron sucrose (group 2), or oral iron alone (group 3), daily for 4 days beginning 48-72 h postpartum. Erythropoiesis and iron status were assessed before, and on 4, 7 and 14 days after, starting therapy. RESULTS: On day 7 the group 1 haematocrit increase was 7.7 +/- 3.1% vs. 5.3 +/- 1.9% (group 2, P < 0.01) and 4.4 +/- 3.2% (group 3, P < 0.01), and on day 14, 11.3 +/- 2.9% vs. 9.2 +/- 3.4% (group 2, P < 0.05) and 8 +/- 2.8% (group 3, P < 0.01). The odds of achieving a target haematocrit > 32% on day 7 and > 35% on day 14 were higher on rhEPO (1.5-2.7) than on either iron regimen alone. Group 1 reticulocyte counts were also higher on days 4 (P < 0.05 vs. oral iron) and 7 (P < 0.01 vs. oral and parenteral iron). CONCLUSION: All three regimens were effective in postpartum anaemia, but the haematocrit and reticulocyte responses to rhEPO plus parenteral iron were significantly greater than to iron alone. Benefit was greatest in the blunted erythropoiesis subgroup with elevated post-Caesarean section C-reactive protein levels.     

逆行胰胆管造影术中患者缺氧原因分析与护理

为探讨逆行胰胆管造影术（ERCP）中患者者氧发生原因及规律、吸氧的有效性及其适宜浓度,对290例ERCP受检者进行脉搏血氧饱和度（SPO2）监测术中,实验组患者检查前5min开始吸氧直至结束;对照组不吸氧。每5min记录一个血氧饱和度最低值。结果表明,两组患者在扬人十二指肠镜过程中SPO2皆明显下降,经术中给氧,实验组术中患者缺氧的发生率明显低于对照组（P＜0．05）;实验组氧流量2L／min时,16．5％的患者仍发生不同程度缺氧。作者认为（1）进镜过程是护主监测的一个重点;（2）镇静药作用下行ERCP检查,预防性吸氧可以降低ERCP检查中缺氧的发生率。     

氧疗对模拟急性高原缺氧兔脑线粒体氧化呼吸功能的影响

[目的]探讨不同浓度氧疗对急性高原缺氧兔线粒体氧化呼吸功能的影响。[方法]模拟4500m海拔高原建立急性缺氧模型,将28只新西兰大白兔分为5组,A组为正常对照组,B组、C组、D组置于低压舱内,分别给予体积百分比为25%、30%、35%的氧氮混合气体持续吸入10h、5h、3h,E组（缺氧对照组）直接暴露于低压舱内,电镜观察脑线粒体形态学改变,应用差速离心法提取脑皮质线粒体,Clark氧电极法测定线粒体呼吸功能。[结果]B组、C组与E组比较,Ⅲ态呼吸（ST3）、呼吸控制率（RCR）、氧化磷酸化效率（OPR）显著提高,差异有统计学意义（P〈0.01）;B组Ⅳ态呼吸（ST4）较C组、D组显著降低,差异有统计学意义（P〈0.01）,D组ST3、ST4、OPR较E组显著提高,差异有统计学意义（P〈0.01）,其中B组影响最明显,接近正常水平。[结论]当吸氧总量相同时,对于脑线粒体氧化呼吸功能的保护作用,采用25%浓度的氧疗效果优于30%、35%浓度的氧疗。     

Regulation of the ferritin heavy-chain homologue gene in the yellow fever mosquito, Aedes aegypti

In the yellow fever mosquito Aedes aegypti, the ferritin heavy-chain homologue (HCH) gene is induced by blood feeding. This suggests that ferritin may serve as a cytotoxic protector against the oxidative challenge of the blood meal and may be essential for the survival of the insect. In this study, various cis-acting elements for the gene were identified and mapped. Transfection assays showed that the strength and activity of a subset of these elements are orientation-dependent. The shift observed for the ferritin HCH cis-acting elements is unique among known ferritin genes. DNase I footprinting data together with Transfac analyses identified a number of putative sites known for their involvement in developmental and cell proliferation processes.     

spo0A对艰难梭菌毒素A/B蛋白表达的调节作用

目的 研究spo0A基因对艰难梭菌毒素A和毒素B蛋白表达的调控作用.方法 采用ClosTron基因敲除技术构建艰难梭菌C25菌株spo0A基因突变模型.实时定量反转录PCR方法测不同生长时期(培养后5、12、24、48 h)突变株和亲代株的毒素基因tcdA、tcdB和毒素调控基因tcdC、tcdR、tcdE的表达量,分...