Rheological studies during treatment of renal anaemia with recombinant human erythropoietin

Whole blood, plasma, and serum viscosity together with red cell deformability were measured before and during treatment of renal anaemia with recombinant human erythropoietin (EPO). Whole blood viscosity (WBV) progressively increased during the first 4 months of treatment in association with the rise in haemoglobin concentration. When the WBV was corrected to a standard haemoglobin concentration no change in blood viscosity was observed, neither was there any alteration in a derived index of red cell deformability, or in the plasma and serum viscosities. In addition, a direct measurement of red cell deformability using a filtration technique before EPO therapy was similar to that obtained in 30 healthy volunteers. There was no significant change in this parameter over the first 9 months of treatment. The rheological changes which occur with correction of anaemia with EPO can be explained solely by the increase in circulating haemoglobin mass rather than to any change in the properties of the plasma or red cells themselves.     

Biphasic changes in nitric oxide generation in hemodialyzed patients with end-stage renal disease treated with recombinant human erythropoietin

BACKGROUND: Use of recombinant human erythropoietin (rHuEpo) in patients with end-stage renal disease (ESRD) improves anemia and reduces the need for blood transfusions. However, one third of patients on rHuEpo develop hypertension, aggravation of preexistent hypertension, or other complications. Nitric oxide (NO) plays a role in blood pressure (BP) regulation. Whether rHuEpo treatment in ESRD is accompanied by alterations in NO production was explored in patients undergoing hemodialysis. METHODS: Of 121 consecutive patients in a hemodialysis clinic, 107 were treated with rHuEpo and 14 were untreated. Plasma was collected before and after hemodialysis for quantification of nitrite and nitrate (NOx). Findings were correlated with various routinely monitored parameters. RESULTS: Predialysis NOx levels were lower in the treated than the untreated group; postdialysis NOx levels were virtually the same. Thus, the change was less in the treated group. Urea reduction ratios (URR) and ultrafiltrate volumes were similar. The mean predialysis systolic BP was higher in the treated group than in the untreated group. The dose of rHuEpo did not correlate with the plasma NOx or the predialysis BPs. No correlation was found between NOx levels and Hb or gender. Of the 107 treated patients, 12 had an increased postdialysis NOx without differences in ultrafiltrate volumes or URR. This group had higher total serum calcium levels, faster pulses, and greater BP reductions than other treated patients. No difference was found in the use of calcium-channel blockers and serum phosphorus and intact parathyroid hormone concentrations did not differ significantly among these groups. CONCLUSIONS: Intermittently hemodialyzed ESRD patients treated with rHuEpo accumulate less NOx in the plasma before dialysis but generate more NOx during dialysis than untreated patients. About 11% of treated patients generated excessive amounts of NOx, thereby maintaining plasma concentrations at the predialysis level or higher. This group experienced significant hemodynamic consequences characteristic of the excessive action of NO.     

The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin

Recombinant human erythropoietin was administered subcutaneously to 10 patients with myelodysplasia (MDS) who had haemoglobin concentrations less than 10 g/dl, in an attempt to relieve their anaemia. Doses of 60 units/kg/d rising to 90 units/kg/d were given over a maximum period of 16 weeks. Two out of 10 patients showed a steady rise in haemoglobin concentration during treatment. One patient with refractory anaemia had a sustained rise from 9.9 g/dl to 11.3 g/dl, and one patient with refractory anaemia with excess blasts (RAEB) had a rise from 9.5 g/dl to 11.4 g/dl but then relapsed with the development of an iron deficient state. Serum concentrations of immunoreactive EPO varied considerably between patients, but both responders had relatively low baseline levels. Both responders were also new diagnoses and had received no red cell transfusions. The criteria for response to recombinant human erythropoietin therapy, as well as the indications for therapy remain to be clarified.     

Effective treatment of disease-related anaemia in B-chronic lymphocytic leukaemia patients with recombinant human erythropoietin

Nine B-chronic lymphocytic leukaemia (B-CLL) patients suffering from anaemia, due to no obvious cause except their disease, were treated with recombinant human erythropoietin (r-HuEPO). The treatment protocol provided a closed label phase of 3 months duration, during which the patients received r-HuEPO or placebo in a ratio of 2:1, followed by an open label phase, also of 3 months duration, during which r-HuEPO was administered to all patients three times a week s.c. r-HuEPO was given at a dose of 150 U/kg of body weight with an escalation of 50 U/kg up to a maximum of 300 U/kg three times a week. Complete response was achieved in 5/9 (55%) patients and partial response in 3/9 (33%). The response obtained was independent of the pretreatment serum EPO levels, the duration of anaemia, the concomitant administration of chemotherapy, the presence of splenomegaly, or the degree of bone marrow infiltration by lymphocytes. It appears that r-HuEPO is very effective in reversing the disease-related anaemia of B-CLL patients.     

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.     

Impaired erythrocyte fluidity during treatment of renal anaemia with erythropoietin.

Seventeen haemodialysis patients with renal anaemia were treated with recombinant human erythropoietin (rhEPO) and observed for 30 weeks. The viscosity of whole blood and plasma, the erythrocyte aggregation tendency, and the erythrocyte deformability, measured as fluidity, were analysed every second week. All patients responded with increasing haematocrit and whole-blood viscosity. The plasma viscosity and the erythrocyte aggregation tendency were already increased before the start of treatment, and remained unchanged during treatment. The basal erythrocyte fluidity tended to be impaired, although not significantly so. During treatment, significant impairment of fluidity was observed at the beginning of the treatment period. After 24 weeks the fluidity started to increase, and it later reached values observed before the start of treatment. Hence, the quality of the erythrocytes formed during the corrective phase of rhEPO treatment differs in some respects from that of cells formed at a normal production rate. The impaired fluidity might have important implications for the flow resistance in small vessels, and contribute to the development or aggravation of hypertension that is often seen during rhEPO treatment.     

Effective treatment of the anaemia associated with multiple myeloma by recombinant human erythropoietin

We administered recombinant human erythropoietin to an anaemic patient with multiple myeloma (IgD, λ type) who had been dependent on blood transfusions. The recombinant human erythropoietin (60 units/kg) was given intravenously three times weekly and transfusion requirements, haemoglobin level, and reticulocyte responses were monitored. The patient had an increase in haemoglobin level and reticulocyte counts within 14 days, and no longer needed transfusions. No organ dysfunction or other toxic effects were observed. We consider that recombinant human erythropoietin may be a new method to treat anaemia associated with multiple myeloma.     

Response of anaemia in rheumatoid arthritis to treatment with subcutaneous recombinant human erythropoietin.

Eleven patients with chronic inflammatory arthritides and haemoglobin concentrations less than 105 g/l with symptoms from their anaemia were treated with a dose of 250 IU/kg/week of recombinant human erythropoietin for six weeks. The treatment was given as subcutaneous injections five days a week. All patients had active inflammatory disease. Nine patients responded to treatment with an increase in haemoglobin of more than 15 g/l. The mean (SD) haemoglobin concentration increased from 93.0 (8.0) g/l before treatment to 115.0 (12.0) g/l after six weeks. There was no correlation between the initial serum concentration of erythropoietin and the response. It was concluded that anaemia in chronic inflammatory arthritides responds to treatment with subcutaneous injections of recombinant human erythropoietin.     

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.     

Evaluation of erythroid marrow response to recombinant human erythropoietin in patients with cancer anaemia.

BACKGROUND. Anaemia is a frequent finding in patients with cancer and may be due to different causes, including blunted erythropoietin production. MATERIALS AND METHODS. In a pilot study, we administered recombinant human erythropoietin (rHuEPO) to twelve patients with solid tumours and secondary anaemia. rHuEPO was given subcutaneously 5 d per week at escalating doses (75 to 150 U/kg per day): the aim of treatment was a Hb level > or = 10 g/dl without blood transfusion. We evaluated endogenous EPO production through serum EPO levels and erythroid marrow activity by means of serum transferrin receptor (TfR). RESULTS. Six out of 12 subjects had defective endogenous EPO production. All patients but two responded to treatment with steady increases in Hb levels above 10 g/dl, and the median dose of rHuEPO required for correction of anaemia was 75 U/kg. Response was associated with an early increase in serum TfR. Six patients developed functional iron deficiency and required iron supplementation to obtain response. Treatment improved functional ability in 4/10 responders. CONCLUSIONS. Subcutaneous rHuEPO can stimulate erythroid marrow activity in cancer anaemia, even in patients with advanced disease, and marrow response can be adequately monitored by serum TfR. Functional iron deficiency as a cause of nonresponse to rHuEPO is frequent in these patients and may require parenteral iron administration. Although erythropoietin can improve the anaemia of cancer, the decision to treat should be individualised for each patient, looking more at the quality of life and cost-effectiveness than at cosmetic increases in the haemoglobin level.     

Effects of recombinant human erythropoietin on haemolytic anaemia in mice

The effects of repeated administration of recombinant human erythropoietin (rHuEPO) were investigated in mice with haemolytic anaemia. Mice with haemolytic anaemia induced by phenylhydrazine (PHZ mice) were examined as an acute model and New Zealand black mice (NZB mice) at 13 months of age were examined as a chronic model. The plasma erythropoietin (EPO) level in PHZ mice was high and showed a strong inverse correlation with the Hb in the anaemia development period. However, it was relatively low in the recovery period from anaemia. On the other hand, the plasma EPO level in NZB mice showed a simple inverse correlation with the Hb. The rHuEPO was injected every day for a week into these mice. While a high plasma EPO level was maintained in PHZ mice, no significant effect was observed by injection with rHuEPO at dose of 600 IU/kg. However, in the recovery period from anaemia, RBC and haemoglobin in PHZ mice were increased by the rHuEPO treatment and recovered more quickly to their normal levels. In NZB mice, RBC and haemoglobin were also increased by treatment with rHuEPO at dose of 600 IU/kg. Anti-RBC autoantibodies and anti-EPO antibodies did not increase, while RBC and plasma EPO levels were increased by the rHuEPO treatment. These results suggest that some types of haemolytic anaemia are not always combined with high endogenous EPO levels and that exogenous rHuEPO may be effective for use in the treatment of haemolytic anaemia.     

终末期肾病患者糖代谢紊乱的研究进展

糖尿病已成为导致终末期肾病(ESRD)的首要原因。糖尿病合并ESRD的患者血糖变异性较大,易出现高血糖及低血糖事件,这与ESRD患者的糖代谢紊乱有密切关联。ESRD患者血糖波动的风险因肾脏糖异生减少、肾脏胰岛素清除受损、尿毒症导致的胰岛素降解缺陷、血液透析过程中红细胞葡萄糖摄取增加、拮抗胰岛素激素(皮质醇、生长激素)反应受损、营养缺乏等因素而增加。了解ESRD患者糖代谢紊乱的变化,有助于临床医生更好地管理糖尿病合并ESRD患者的血糖,提高生存质量。     

Effect of recombinant human erythropoietin on anticancer drug-induced anaemia

Anaemia was induced in rats with fluorouracil (5-FU) or cisplatin (CDDP) and the mechanisms of anaemia induction were analysed. Furthermore, the therapeutic effects of recombinant human erythropoietin (rHu Epo) on these anticancer drug-induced anaemias were investigated. In 5-FU-induced anaemia, marked serum erythropoietin (Epo) elevation was observed in inverse correlation to blood Hb concentration and Hb concentration rapidly recovered to normal levels. On the other hand, in CDDP-induced anaemia, serum Epo elevation was modest and the lowered Hb concentration persisted longer. Treatment with rHu Epo significantly improved both anticancer drug-induced anaemias but rHu Epo was more effective on CDDP-induced anaemia. These results suggest that rHu Epo might be useful for the therapy of anaemia associated with anticancer chemotherapy.     

Iron metabolism in transgenic mice with hypoplastic anaemia due to incomplete deficiency of erythropoietin

Iron overload is a serious complication of many forms of anaemia, arising in part from mechanisms associated with compensatory increases in erythropoiesis. To investigate other mechanisms by which anaemia itself may perturb iron metabolism, without the confounding effects of compensatory erythropoiesis, we studied transgenic mice with a partially disabling insertion in the erythro-poietin gene, which manifested as incomplete erythropoietin deficiency.
Mice were studied aged 7–8 weeks. Haemoglobin concentrations were 6.6 ± 0.8 g/dl in mice homozygous for the modified erythropoietin gene, 12.9 ± 2.2 g/dl in heterozygous mice and 14.1 ± 1.0 g/dl in controls. Homozygous mice showed significant hepatic iron loading (2-fold increase in liver non-haem iron, compared with heterozygous mice and normal controls, with iron staining principally in the periportal hepatocytes). Absorption studies using ⁵⁹Fe showed increased uptake from the lumen of an in vivo isolated duodenal segment in homozygous mice, although at this point in time overall transfer of radioiron to the circulation and other tissues (mucosal transfer) was not different from controls. These observations demonstrate that anaemia can lead to hepatic iron loading even in the absence of increased erythropoiesis, and are consistent with the possibility that anaemic hypoxia can enhance mucosal iron uptake by the duodenal enterocyte.     

Recombinant human erythropoietin in the treatment of cancer-related anaemia

Abstract: The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000–10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions, was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.