The effect of serum from uremic patients on erythropoietin

Serum from patients with chronic renal failure (CRF serum) contains a substance inhibitory to erythropoiesis in vitro. This paper explores the mechanism of the inhibition. Four experiments were performed to evaluate the effects of CRF serum on erythropoietin (EP). In the first 2 experiments, the effect of exposure of EP solutions to CRF serum was evaluated using the plethoric mouse EP assay system and a tissue culture system containing normal dog marrow cells. In the third study, dog marrow cells were preincubated with CRF serum before being stimulated with EP. Finally, EP-dose response curves were constructed in the dog marrow tissue culture system and analyzed using an enzyme kinetic model. The results show no evidence of inhibition or inactivation of EP by CRF serum, although in vitro heme synthesis is clearly depressed in the presence of CRF serum. We conclude that CRF serum inhibits erythropoiesis by directly, although reversibly, impairing the ability of erythroblasts to synthesize heme.     

Therapeutic effect of recombinant human erythropoietin on anaemia with erythropoietin deficiency in diabetic patients.

AIMS: The aim of this study was to investigate the therapeutic effect of recombinant human erythropoietin (rHuEpo) on anaemia with erythropoietin deficiency in diabetic patients. METHODS: Twenty diabetic patients with anaemia and Epo deficiency were enrolled. All patients were treated with rHuEpo (Epokine; 4000 U/day s.c., three times a week) for 8 weeks. RESULTS: The responder group (n = 14) had significant increments in haemoglobin compared with the non-responder group (n = 6) (P < 0.05). No significant differences were found between the responder and non-responder groups in terms of duration of diabetes mellitus, serum creatinine level, 24-h urine albumin excretion rates, frequency of diabetic microangiopathy, or HbA1c. There was no difference between the two groups in terms of serum iron and total iron-binding capacity (TIBC). Serum ferritin level was significantly higher in the responder group than in the non-responder group (240.3 +/- 108.4, 25.8 +/- 3.0 micro g/l, P < 0.05), as was transferrin saturation (32.7 +/- 7.9%, 21.2 +/- 5.3%, P < 0.05). CONCLUSIONS: rHuEpo could be useful in the treatment of anaemia with erythropoietin deficiency in diabetic patients, and the degree of iron storage and functional iron deficiency might be the main cause of hyporesponsiveness to rHuEpo.     

促红细胞生成素对尿毒症患者中性粒细胞功能的影响

目的　观察促红细胞生成素 ( EPO)对尿毒症患者中性粒细胞功能的影响。方法　分三组进行中性粒细胞墨汁吞噬试验、粘附试验和硝基兰四唑试验 ( NBT)。结果　三组吞噬率分别为 38 7%± 6 4%、 16 0 %± 5 1%和 2 1 9%± 6 3% ( P<0 0 5 ) ;粘附率分别为 67 6%±10 7%、 37 4%± 15 1%和 5 3 3%± 15 9% ( P<0 0 5 ) ;NBT阳性率分别为 4 3%± 2 7%、 3 6%± 2 9%和 5 8%± 4 5 % ( P>0 0 5 )。结论　尿毒症患者中性粒细胞功能受损 ,接受 EPO治疗后 ,其功能得到改善。     

Inhibitors of recombinant human erythropoietin in chronic renal failure.

This study investigates which factors influence the response of administered recombinant human erythropoietin (Re-HuEPO) with respect to the increase of haemoglobin in patients with end-stage renal disease. Pharmacokinetic parameters of administered Re-HuEPO in patients with end-stage renal disease and considerable differences in the amount of Re-HuEPO required ("Re-HuEPO-need") to obtain an increase of haemoglobin, revealed a pattern of dose-dependent first-order elimination without significant interindividual differences between the patients. As variable immunological inhibitors of erythropoietin are also absent, the administered Re-HuEPO seems to be equally available to the erythron in the various patients. In vitro incubation experiments with bone marrow cells show that the sera from patients with end-stage renal disease contain inhibitors of the erythropoietin-induced stimulation of bone marrow cells. As the patients' sera differ with regard to the degree of inhibition of erythropoietin bioactivity, this inhibition may also be responsible for the interindividual differences in amount of erythropoietin required. Besides a reduced endogenous production of erythropoietin, these inhibitors of the bioactivity of erythropoietin may also contribute to the pathogenesis of anaemia in patients with chronic renal failure.     

重组人促红细胞生成素治疗心衰合并慢性肾脏病患者的疗效

目的：观察重组人促红细胞生成素（rhEPO）治疗心力衰竭合并慢性肾脏病患者的临床疗效。方法：选择84例心力衰竭合并肾功能不全的患者,采用随机数字表的方法分为常规治疗组（42例）和 rhEPO组（42例,在常规治疗基础上加用 rhEPO）,治疗12周后,对比两组心脏超声及肾功能。结果：与常规治疗组比较, rhEPO组左室舒张末期内径[LVEDd,（6.12±0.67）mm比（5.01±0.54）mm]显著减小,左室射血分数[LVEF,（37.2±10.3）％比（45.4±11.4）％]和左室短轴缩短率[LVFS,（19.6±4.3）％比（24.5±3.8）％]显著提高,24h尿蛋白定量[（0.76±0.1）g比（0.24±0.09）g]、24h尿微量白蛋白[（319.6±39.6）mg比（107.3±26.7） mg]、血尿素氮[（10.3±1.9）mmol/L 比（6.2±1.5）mmol/L]、血肌酐[（97.2±16.8）μmol/L 比（79.3±15.7）μmol/L]显著改善（P均＜0.01）。结论：重组人促红细胞生成素可显著改善心力衰竭合并肾功能不全患者的心、肾功能。     

Long-term effects of recombinant human erythropoietin therapy on growth hormone secretion in uremic patients undergoing peritoneal dialysis

Recombinant human erythropoietin (rhEPO) is being successfully used for the treatment of uremic anemia. Short-term studies have proved that correction of anemia with rhEPO therapy is accompanied by several changes in growth hormone (GH) secretion in uremic patients. The present study aimed to assess the influence of long-term rhEPO therapy on baseline and stimulated GH concentrations in a group of uremic patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Seven well-nourished and clinically stable CAPD patients were studied. Ten normal subjects were studied as controls. GH responses to direct pituitary stimulation with GH-releasing hormone (GHRH) (100 microg intravenously [i.v.]) and indirect hypothalamic stimulation with insulin-induced hypoglycemia (0.1 U/kg body weight i.v.) and clonidine (0.15 mg/m2 orally), were assessed before and after 3, 6, and 12 months of subcutaneously administered rhEPO therapy. After rhEPO administration, an increase of the hemoglobin concentration was observed in all patients and maintained at about 12 g/dL throughout the study period. rhEPO therapy did not induce any significant change in baseline concentrations of GH and insulin-like growth factor I. Correction of the anemia was accompanied by a clear increase in the area under the curve (AUC) and the area above the baseline (AAB) of GH secretion in response to GHRH stimulation. These changes were statistically significant after 3 and 6 months of therapy, although at 12 months no significant differences in relation to pretreatment values could be observed. rhEPO treatment was associated with a progressive decrement in the GH AUC and AAB in response to hypoglycemic challenge, reaching statistically significant values at months 6 and 12. On the other hand, compared with the control group, GH responses to clonidine were blunted at the start of the study in CAPD patients, and rhEPO therapy was not accompanied by any modification. In conclusion, long-term treatment with rhEPO in CAPD patients is associated with complex and profound effects on somatotrope cell function, characterized by diverse effects on GH responses to stimuli that release GH through different mechanisms. Some of these rhEPO-induced alterations in somatotrope function are dependent on the duration of treatment.     

Pharmacokinetics of intravenous recombinant human erythropoietin in patients with chronic renal failure

In order to improve our understanding of the dose-concentration and concentration-effect relationships, the pharmacokinetics of recombinant erythropoietin were studied after the initial dose (n = 6) and after repeated doses (n = 9) administered intravenously in patients with chronic renal failure. Several venous blood samples were collected before (to obtain the baseline concentration) and after an intravenous dose of erythropoietin. A radioimmunoassay was used to determine the erythropoietin concentration in the samples. The apparent volume of distribution at steady state was 4.2 +/- 0.91 (initial dose) and 3.7 +/- 0.61 (repeated dosing), which is close to the assumed plasma volume in these patients. The half-life was 5.3 +/- 1.3 h and 5.8 +/- 1.2 h in the two groups, respectively, and is therefore too short for any accumulation to be expected when dosing three times per week. Consequently, no difference in baseline values could be detected between the groups. The clearance of erythropoietin in the groups was estimated to be 11.4 +/- 7.0 ml min-1 and 7.8 +/- 3.8 ml min-1, respectively. Erythropoietin kinetics did not differ after repeated dosing compared to the single initial dose. Intravenous administration of erythropoietin will result in high peak concentrations followed by a rapid decline to basal values.     

Long-term echocardiographic examinations in chronic hemodialysis patients substituted with recombinant human erythropoietin

Cardiomegaly and impaired cardiac function induced by renal anemia are frequent findings in patients with chronic renal failure. The present investigation was performed to study the cardiac effects of a therapy with recombinant human erythropoietin in patients on maintenance hemodialysis. Echocardiographic examinations showed a decrease in cardiac size and left-ventricular mass continuously over 12 months of effective erythropoietin substitution. Cardiac output was reduced, and ejection fraction and myocardial contractility increased. The development of aggravation of arterial hypertension did not counteract the beneficial effects of erythropoietin on cardiac performance.     

重组人促红细胞生成素治疗慢性心力衰竭的临床对照研究

目的观察重组人促红细胞生成素(erythropoietin,EPO)治疗慢性心力衰竭(chronic heart failure,CHF)患者的临床疗效,并评估其药物安全性。方法依据相应纳入及排除标准入选住院期间CHF患者80例,按随机数字表法随机分为EPO治疗组和对照组。在常规CHF治疗基础上,EPO组加用依普定,对照组为单纯常规CHF药物治疗。共双盲治疗两个月。比较两组患者用药前后临床症状、心功能情况及远期预后。结果 EPO治疗组治疗两个月后,患者运动耐量显著提高、心功能有所改善,心率显著低于对照组,尿量较对照组增多,左心室射血分数较对照组提高,差异有统计学意义(P0.05);EPO治疗组CHF急性加重发生率显著低于对照组,差异有统计学意义(P0.05);但两组治疗前、后左心室舒张末内径(LVDD)及左心室收缩末内径(LVSD)比较,差异无统计学意义(P0.05)。不良反应为部分患者应用EPO一个月后出现血压升高,但与对照组比较,差异无统计学意义(P0.05)。结论 EPO作为CHF的辅助治疗药物,治疗效果显著,且安全可行。     

The effect of intravenous iron on the reticulocyte response to recombinant human erythropoietin

We studied the effect of intravenous (i.v.) adminisration of 200 mg of iron sucrose following an i.v. bolus injection of recombinant human erythropoietin (r-HuEPO; 300 U/kg body weight) in seven subjects and compared it with seven subjects treated with r-HuEPO alone. Reticulocytes, serum erythropoietin (EPO) and ferritin levels were studied at baseline and daily for the following 8 d. Use of i.v. iron abolished the marked reduction in serum ferritin observed with r-HuEPO administration. Although the total number of reticulocytes was not affected by i.v. iron administration, the reticulocyte Hb content and retHb (a measure in g/l of the Hb contained in all reticulocytes) were increased in the i.v. iron/r-HuEPO group compared with the group who received r-HuEPO alone. Therefore i.v. iron significantly potentiates the haemopoietic response to r-HuEPO in normal subjects.     

重组人红细胞生成素对维持性血液透析的慢性肾功能衰竭患者血清瘦素水平的影响

目的　探讨重组人红细胞生成素 (rHuEPO)对维持性血液透析 (HD)的慢性肾功能衰竭 (CRF)患者血清瘦素水平的影响及其意义。方法　 80例行HD的CRF患者分为不用rHuEPO治疗组和使用rHuEPO治疗组 ;使用rHuEPO治疗的又分三组 (3个月组 ,6个月组 ,12个月组 )。采用ELISA法测定血清瘦素水平 ,放免法测定血清TNF α水平。结果　使用rHuEPO治疗 6个月后 ,血清瘦素水平明显低于治疗前及未用rHuEPO治疗组 (P <0 .0 5 ) ;血清TNF α、CRP水平也明显低于治疗前及未用rHuEPO治疗组 (P <0 .0 5 )。结论　使用rHuEPO治疗 6个月后血清瘦素水平明显下降     

Erythroid progenitor cell kinetics in chronic haemodialysis patients responding to treatment with recombinant human erythropoietin

The response of bone marrow and peripheral blood erythroid progenitors to human recombinant erythropoietin (rHuEPO) was studied in nine haemodialysed renal failure patients receiving this hormone for the correction of their anaemia. The haematocrit rose in all patients in response to thrice weekly injections of escalating rHuEPO doses (12-192 IU/kg). Both the numbers of CUF-e and BFU-e and their proliferative state in the bone marrow as well as BFU-e numbers in the peripheral blood were estimated before treatment and again after correction of the anaemia, at 16 h following an intravenous dose of rHuEPO. Following treatment bone marrow BFU-e numbers fell to a mean of 24.5% (P less than 0.01) of the pre-treatment values although there was no significant change in CFU-e or circulating BFU-e numbers. The mitotic rate (percentage S-phase cells) estimated by tritiated thymidine suicide rose from 45.2% to 68.4% (P less than 0.05) in the case of CFU-e and from 16.4% to 45.1% (P less than 0.05) for BFU-e following treatment with rHuEPO thus indicating in-vivo sensitivity of both the primitive as well as the mature erythroid progenitors to the hormone. The fall in BFU-e numbers in the bone marrow after several months of treatment may be due to a loss of cells from this progenitor pool by maturation that is uncompensated by replacement from the pluripotential stem cell compartment.     

Nononcologic use of human recombinant erythropoietin therapy in hospitalized patients

BACKGROUND: Human recombinant erythropoietin (rHuEPO) is widely used to stimulate red blood cell production in patients with anemia due to cancer, renal disease, and other medical conditions, but concern has grown about its overuse and potential for harm. Little is known about the nature of rHuEPO use in hospitalized patients who receive rHuEPO therapy for nononcologic indications. METHODS: We reviewed the drug utilization data from a large academic medical center for all patients admitted during 3 years to identify all patients without cancer who received at least 1 dose of rHuEPO, including their age and sex; diagnoses; hematocrit and hemoglobin and iron levels; and use of supplemental iron. We also compared the rates of laboratory testing and iron supplementation in patients with and without chronic kidney disease (CKD). RESULTS: A total of 1360 distinct patients with 3094 hospitalizations received at least 1 dose of rHuEPO. In 2959 admissions for which hematocrit was determined within 14 days before rHuEPO use, mean values were less than 33% in 1792 (61%) and greater than 36% in 553 (19%). Patients with CKD were more likely than patients without CKD to receive rHuEPO with hematocrit greater than 36% (22% vs 8%; P<.001). Monitoring of iron status was more common in patients with CKD than in those without CKD (64% vs 45%; P <.001). Almost one fourth (23%) of rHuEPO recipients in whom iron levels were measured had absolute iron deficiency (serum ferritin concentration <100 ng/mL). In patients with CKD, only about half (54%) had adequate iron stores at the time of rHuEPO administration; this rate was even lower in patients without CKD (33%; P<.001). Only 66% of patients with documented iron deficiency who were receiving rHuEPO also received concomitant iron supplementation; this rate did not differ between patients with or without CKD. CONCLUSIONS: There is significant variability in the degree of anemia, completeness of iron measurement, and use of iron supplementation in hospitalized patients without cancer who are prescribed rHuEPO. Our results identify potential targets for quality improvement in patients both with and without CKD.     

重组人红细胞生成素对尿毒症患者生活质量的影响

应用肾脏病调查表和Ｋａｒｎｏｆｓｋｙ指数等方法，前瞻性研究了重组人红细胞生成素（ｒＨｕＥＰＯ）对１０４例尿毒症患者生活质量的影响，结果显示，治疗３～５个月所有患者贫血均有明显纠正，Ｈｃｔ维持在３０％～３５％，生活质量有显著改善（Ｐ＜０．００１）；家庭透析显著优于住院透析（Ｐ＜０．０１），青壮年组显著高于老年组（Ｐ＜０．０５）；腹透患者体力改善情况显著优于血透患者（Ｐ＜０．０５）．高血压、血栓形成等副作用明显影响生活质量的提高，尤其在血透和老年患者中，研究表明，ｒＨｕＥＰＯ在纠正尿毒症患者贫血的同时能明显提高患者生活质量，治疗过程中应及时防治高血压等副作用。     

Effect of recombinant human erythropoietin in preterm infants.

Twenty-five premature infants (mean gestational age+/-SD, 31.4+/-1.9 weeks) were administered subcutaneously recombinant human erythropoietin (rHuEpo) at a dose of 300 u/kg of body weight three times a week beginning on the third day of life and continuing for 6 weeks. The controls (n=23) were premature infants with a mean gestational age of 32.2+/-2.3 weeks who did not receive rHuEpo. Haematological indices, haemoglobin and serum phosphate (Pi), and red blood cell (RBC) phosphate metabolites (ATP, 2,3-DPG, RBCPi) were tested monthly until the 6th month and thereafter at the 9th and 12th months of life. The level of serum soluble transferrin receptors (sTfR) correlated significantly with rHuEpo (p<0.05). The ratio of sTfR to log (ferritin) was significantly higher (p<0.001) in the infants treated with rHuEpo than the controls. Intracellular organic and inorganic Pi changes were not affected by the Epo administration. The RBC 2,3-DPG seemed adequate in infants receiving rHuEpo.