rHuEPO Group Research Articles

Erythropoietin Treatment Decreases Cardiovascular Morbidity and Mortality in Capd Patients

To analyze the effects of recombinant human erythropoietin (rHuEPO) therapy on cardiovascular (CV) morbidity and mortality among continuous ambulatory peritoneal dialysis (CAPD) patients. Retrospective comparative study. CAPD unit in a university hospital. Forty-two patients on rHuEPO treatment for at least one year were compared with an rHuEPO nonuser group of 113 patients. Subcutaneous rHuEPO doses were adjusted to a hemoglobin objective level of 10.5-13.5 g/dL. Fifty-seven patients were considered as high cardiovascular risk (HCVR), 17 in the rHuEPO group and 40 in the rHuEPO nonuser group. Ninety-eight patients were classified as low cardiovascular risk (LCVR), 25 of whom were in the rHuEPO group. The incidence of cardiovascular morbidity was more frequent in the rHuEPO nonuser than in the rHuEPO user group (40% vs 22%) and in HCVR than in LCVR patients (59.6% vs 20.4%). By multiple logistic regression analysis, the best model to explain the development of cardiovascular morbidity comprises rHuEPO treatment, CV risk, and age. In the rHuEPO user group, HCVR and LCVR patients did not show significant differences in survival, while in the rHuEPO nonuser group, HCVR patients had a lower survival rate than LCVR patients (p = 0.0003). Cox proportional hazards model revealed that LCVR patients had an excellent prognosis compared with HCVR patients in the rHuEPO nonuser group, but this difference disappeared in the rHuEPO user group. These data show a beneficial effect of rHuEPO treatment on cardiovascular morbidity and mortality in CAPD patients, evidenced by the elimination of the correlation between prior cardiovascular risk and subsequent mortality.

Angiotensin I converting enzyme inhibitor and worsening of anemia in hemodialysis patients: Prevention with rHuEPO.

Angiotensin I converting enzyme inhibitor (ACEI) is known to worsen anemia in hemodialysis (HD) patients. The effect of rHuEPO on ACEI-induced worsening of anemia was evaluated in 19 hypertensive HD patients. Patients were subdivided into two groups according to rHuEPO administration, being rHuEPO (+) group (n=10, 56±4 years old, rHuEPO 1500 units, 3 times a week) and rHuEPO (-) group (n=9, 52±3 years old). Age, HD duration, blood pressure (BP) and hematocrit (Ht) before ACEI (lisinopril) were not significantly different between rHuEPO (+) and rHuEPO (-) group. Lisinopril was started with a dose of 2.5mg once a day in the morning on non-HD day. BP decreased significantly in both groups and adequately maintained throughout the study period. Ht decreased significantly in rHuEPO (-) group from 30±2 to 26±1% (p<0.05), whereas it remained unchanged in rHuEPO (+) group. The dose of lisinopril of 5.0±2.0mg/day in rHuEPO (+) group was significantly higher than that of 3.0±1.0mg/day in rHuEPO (-) group (p<0.05). Serum erythropoietin and plasma angiotensin II concentration decreased but the changes were not significant in both groups. Plasma angiotensin I converting enzyme activity decreased significantly from 51±5 to 30±4U/L only in rHuEPO (-) group (p<0.05). In conclusion, we suggest that the ACEI-induced worsening of anemia could be prevented by a concomitant use of rHuEPO in hypertensive HD patients. However, the higher dose of ACEI was required to control BP in rHuEPO-treated HD patients.

Recombinant Human Erythropoietin Stimulates Erythropoiesis and Reduces Erythrocyte Transfusions in Very Low Birth Weight Preterm Infants

We hypothesized that treatment with recombinant human erythropoietin (r-HuEPO) would stimulate erythropoiesis and would thereby reduce the need for erythrocyte transfusions in preterm infants. We treated 157 preterm infants born at 26.9 +/- 1.6 weeks of gestation who weighed 924 +/- 183 g at birth with either subcutaneous r-HuEPO (100 U/kg/d, 5 days per week) or placebo for 6 weeks in a randomized, double-blind, controlled clinical trial. All patients received oral iron and were managed according to uniform conservative transfusion guidelines. Treatment with r-HuEPO was associated with fewer erythrocyte transfusions (1.1 +/- 1.5 per infant in the r-HuEPO group versus 1.6 +/- 1.7 per infant in the placebo group; P = .046) and with a reduction in the volume of packed erythrocytes transfused (16.5 +/- 23.0 mL versus 23.9 +/- 25.7 mL per infant; P = .023). Overall, 43% of the infants in the r-HuEPO group and 31% of placebo-treated infants were transfusion-free during the study (P = .18). The volume of blood removed for laboratory tests and the need for respiratory support at the start of treatment had major effects on transfusion requirements independent of r-HuEPO. Reticulocyte counts were higher during treatment in the r-HuEPO group (P = .0001), and r-HuEPO-treated infants had higher hematocrit values at the end of the study (32% versus 27.3% in the placebo group; P = .0001). We found no differences in the incidence of major complications of prematurity between the treatment groups. We conclude that treatment with r-HuEPO at a weekly dose of 500 U/kg stimulates erythropoiesis, moderates the course of anemia, is associated with a reduction in erythrocyte transfusions, and appears safe in very low birth weight preterm infants who are receiving iron supplements. Conservative transfusion criteria, minimization of phlebotomy losses, and treatment with r-HuEPO are complementary strategies to reduce erythrocyte transfusions in these infants.

Erythropoietin increases hemoglobin during radiation therapy for cervical cancer

Purpose : Anemia during radiation therapy independently predicts poor outcome in patients with cervical cancer. Despite a randomized trial demonstrating red cell transfusions improve local control and survival, many patients are not transfused due to toxicity concerns. This study evaluates the efficacy of recombinant human erythropoietin (r-HuEPO) in reversing anemia in patients undergoing radiation therapy. Methods and Materials : Twenty patients with criteria of anemia (Hgb < 12.5 g/dL) and surgically staged cervical cancer FIGO stages IB ( n = 7), IIA ( n = 1), IIB ( n = 9), and IIIB ( n = 3), ranging in ages from 23–75 years (median 43), were included in this Phase I/II study. Fifteen were treated with r-HuEPO (200 U/kg/day) and ferrous sulfate 5–10 days prior to initiation of external beam radiation therapy, continuing until Hgb was ≤ 14 g/dL or completion of radiation therapy. Five patients were treated with ferrous sulfate alone. An additional 61 historical controls meeting eligibility criteria were analyzed. All received external beam radiation therapy and two intracavitary cesium applications. Cisplatinum chemotherapy (20 mg/m 2/week) was given as a radiosensitizer in 14 r-HuEPO patients, 4 concurrent controls, and 17 historical controls. Results : A marked reticulocytosis was seen in the r-HuEPO group, but not the study controls. In the r-HuEPO group, the mean ± SD serum Hgb rose +30% over the course of radiation therapy from a baseline of 10.3 ± 1.04 g/dL to 13.2 ± 1.7 g/dL. Average increase in Hgb was 0.5 g/dL per week. Average Hgb during RT was 13.4 g/dL. In study and historical controls, mean initial Hgb levels were 10.7 ± 1.04 g/dL and 11.1 ± 1.3g/dL, respectively, remaining unchanged over the course of radiation therapy. Average Hgb levels during radiation therapy were 11.1 g/dL in study controls and 11.4 g/dL in historical controls, significantly lower than r-HuFP0 patients ( p = 0.0001). Erythropoietin was well tolerated. There were no significant differences in white blood counts ( p = 0.6) or platelet counts ( p = 0.4) between r-HuEPO patients and both control groups. No patients had blood pressure changes during r-HuEPO therapy. The only possible side effect was deep venous thrombosis, occurring in two patients who were withdrawn from r-HuFP0 therapy. Two additional patients developed deep venous thrombosis 9 and 10 days after radiation therapy and r-HuFP0 were completed. Conclusion : Erythropoietin appears to be both safe and effective at raising Hgb levels in anemic cervical cancer patients receiving radiation therapy and chemotherapy.

Recombinant Human Erythropoietin in the Treatment of the Anemia of Prematurity: Results of a Double-Blind, Placebo-Controlled Study

To assess the efficacy of recombinant human erythropoietin (rHuEpo) in the treatment of the anemia of prematurity. A double-blind, placebo-controlled study was conducted on 80 preterm infants (< or = 32 weeks; postnatal age, 2 to 8 weeks; central hematocrit < or = 35%). Patients were randomly assigned to receive subcutaneous rHuEpo (Eprex, 600 U/kg per week) or an equivalent volume of placebo, for up to 6 weeks. All patients received supplements of vitamin E (25 IU) and iron (3 mg/kg per day). The iron supplement was increased if declining serum ferritin measurements were noted. Treatment and placebo groups did not differ significantly with respect to mean gestational age, birth weight, hematocrit, or reticulocyte count at study entry. Fewer transfusions were administered to those receiving erythropoietin (7 compared with 21; P = .002). Compared with the placebo group, the infants receiving rHuEpo had a higher mean hematocrit (32.3 +/- 4% vs 29.3 +/- 6.2%; P = .014) and absolute reticulocyte count (223 +/- 73 vs 124.9 +/- 73 x 10(9)/L; P < .001) at the end of the study. The mean neutrophil count was not significantly reduced at study exit (P = .8), nor at any other period during the trial in the rHuEpo group. Intercurrent events (mostly infections) were not increased in the treatment group, although there was one case of sudden infant death syndrome at age 4 months. Using a dose of rHuEpo of 600 U/kg per week, this study has shown a clear reduction in the requirement for blood transfusion in preterm infants.

Erythropoietin increases hemoglobin in cancer patients during radiation therapy

Purpose : The hemoglobin (Hgb) level of patients during radiation therapy is associated with both survival and local tumor control in several organ sites. This clinical trial tested whether administering recombinant human erythropoietin (r-HuEPO) to cancer patients would increase their Hgb level during the course of radiation therapy without adverse effects. Methods and Materials : The 40 participating patients had a Hgb value < 13.5 g/dL and a malignant tumor located above the diaphragm without evidence of distant metastasis for which they were scheduled to undergo a 5–8 week course of daily radiation therapy. All 40 patients were given oral ferrous sulfate throughout their radiation therapy course. Half the patients also received 150–300 mg/kg of r-HuEPO subcutaneously three times per week starting 0–10 days prior to the first dose of radiation. Results : The r-HuEPO and control groups did not differ significantly in patient age, gender, tumor type, initial hemoglobin, erythropoietin, or iron bioavailability. The Hgb level increased more than 6% during radiation therapy in all 20 of the r-HuEPO patients but in only 2 20 of the control patients p < 0.001. The Hgb rose from a mean ± standard deviation of 11.9 ± 1.3 g/dL to > 14 g/dL during radiation therapy in 80% of the r-HuEPO group compared to in 5% of the control group ( p < 0.001). The mean±s.d. change in Hgb concentration during radiation therapy was 27 ± 15% (an average rise of 5% per week) in the r-HuEPO group and 0 ± 6% in the control group ( p < 0.001). r-HuEPO had no significant measurable effect on blood pressure, white blood cell, neutrophil or platelet count, or liver or renal function. The only reported adverse effect of r-HuEPO administration was an asymptomatic skin rash in one patient. Conclusion : r-HuEPO with ferrous sulfate significantly increased the Hgb level in cancer patients without interfering with their course of radiation therapy, whereas ferrous sulfate alone did not. r-HuEPO appears to be a safe and effective means of increasing red cell mass during radiation therapy.

Long-term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin

Quality of life assessments were performed in 24 haemodialysis patients (10 males, 14 females, age 45 +/- 15 years) undergoing rHuEpo treatment. The results in the rHuEpo-treated patients were compared with those in eight haemodialysis patients not on rHuEpo and with the results of a nationwide study of dialysis patients in Sweden (carried out before rHuEpo was registered). Survey questionnaires (112 items, divided into three dimensions, i.e. physical, social, and emotional wellbeing) were completed before treatment (Hb 73 +/- 1.1 g/l), when the target Hb value of 10 g/dl was reached (1-7 months) and in 14 patients 1 year after correction of the anaemia. Before treatment, the rHuEpo group had significantly more complaints about poor appetite, fatigue, and irritability than the controls. After the anaemia was corrected, the rHuEpo group had significantly improved physical and emotional wellbeing. The most significant changes occurred in satisfaction with health, physical activities of daily life, and fatigue. Alterations in emotional symptoms, such as depression and apathy, were less pronounced. Only minor changes were observed in their social wellbeing. One year after correction of the anaemia, the improvements in physical and emotional wellbeing were still present in the rHuEpo-treated patients. A positive effect was also noted on hospitalization rate. Scores for the subdimensions of satisfaction with health, sexual adjustment, physical symptoms, and emotional wellbeing improved in the rHuEpo-treated group and reached a level that was the same, or even higher, than the scores in the dialysis patients in the nationwide study. In conclusion, the quality of life improved during rHuEpo treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced platelet reactivity with erythropoietin but not following transfusion in dialysis patients

Although the haemostatic defects that occur in uraemia are complex, a major factor is the anaemia of renal failure. This may now be corrected by recombinant human erythropoietin (rHuEpo) therapy rather than by repeated blood transfusion. Platelet reactivity to shear stress and collagen was measured using non-anticoagulated blood to study the effect of erythropoietin or blood transfusion on platelet function. Twenty dialysis patients were commenced on 25-50 U/kg rHuEpo twice weekly. The dose was adjusted after 3 months to maintain target Hb 10-10.5 g/dl. A further 15 patients were studied before and 10-12 days after receiving blood transfusion. Baseline platelet reactivity was subnormal in both groups versus control (P < 0.0001). In the rHuEpo group, a significant increase in platelet reactivity was observed at 2 months (P < 0.005) which disappeared at 3 months. This was not related to the increase in Hb (7.3 +/- 0.3 to 10.2 +/- 0.3 g/dl, P < 0.0001). There was no change in platelet reactivity after transfusion, despite an increase in Hb (6.2 +/- 0.2 to 8.8 +/- 0.2 g/dl, P < 0.0001) similar to that occurring in the rHuEpo group. We conclude that after rHuEpo therapy but not after transfusion a transient increase in platelet reactivity occurs which is dissociated from changes in platelet and red cell numbers.

Effects of Erythropoietin on Trace Elements in Patients with Chronic Renal Failure Undergoing Hemodialysis

We examined the relationship between recombinant human erythropoietin (rHuEPO) therapy and serum levels of the trace elements aluminum, silicon, zinc, nickel, and manganese in 55 patients undergoing chronic hemodialysis (HD) in whom rHuEPO (for 12 weeks) was effective in reducing anemia, and in 55 patients undergoing HD without rHuEPO treatment. In the rHuEPO group, serum Al level was significantly decreased and Si level showed a tendency to decrease. Zn, Ni, and Mn levels, however, were significantly increased.

Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: A pilot study

We randomly assigned eight concurrently symptom-free premature infants (birth weight less than or equal to 1250 gm) at high risk of requiring erythrocyte transfusions for anemia of prematurity to 6 weeks of intensive treatment with either subcutaneous recombinant human erythropoietin (r-HuEPO group) or a placebo (control group). Treatment with r-HuEPO was initiated at a dose of 100 units/kg per day 5 days a week, and was increased to 200 units/kg per day after 2 or 3 weeks if target reticulocyte counts were not achieved. All patients were given supplemental oral iron therapy at a dose of 6 mg/kg per day, as tolerated. Mean reticulocyte counts in r-HuEPO-treated and control infants were 64,600 versus 67,500 cells/mm3 at entry; were 245,600 versus 78,000 cells/mm3 after 1 week; and averaged 262,600 versus 136,400 cells/mm3 during the study. Mean reticulocyte counts in r-HuEPO-treated infants were 251,200 cells/mm3 during the week when r-HuEPO, 100 units/kg per day, was given, and were 269,500 cells/mm3 after the dose was increased to 200 units/kg per day. Mean hematocrit values at entry were 33.4% in babies who received r-HuEPO versus 33.6% in the control subjects, and were 31.4% in r-HuEPO-treated and 25.2% in the control subjects at the end of treatment. One r-HuEPO-treated and three control babies received transfusions during the study; the total volume of blood given was 17 ml in the r-HuEPO group and 101 ml in the control subjects. The percentage of hemoglobin F increased in infants not given transfusions. We conclude that r-HuEPO stimulates endogenous erythropoiesis in small premature babies who are receiving supplemental oral iron therapy. A controlled multicenter trial has been undertaken to confirm these promising preliminary observations.

冷凍保存法による自己血輸血開心術における遺伝子の組み換えヒトエリスロポエチン（ｒＨｕＥＰＯ）の術後貧血に対する有用性について

Recently, recombinant human erythropoietin (rHuEPO) has been administrered in order to increase preoperative blood store. Otherwise, the effect of rHuEPO for postopertive anemia is unknown. We used rHuEPO to improve postoperative anemia. The patients were twenty-one person who were not transfused homologous blood but autologous blood perioperatively, since April 1988 to March 1991. They were divided into two groups. There were no statistical significance in sex, age, body weight, and extra corporeal circuration time between non rHuEPO group and rHuEPO group. Autologous blood collection was started several months before operation and separated into concentrated red cell (CRC) and plasma to freeze. They were thawed on the day of operation to transfuse. 6.000 IU rHuEPO was administrered intervenously three times per week for two weeks pre-and postoperatively. Iron was administrated more than 100mg per day P. O. or more than 40mg per day I. V. The standard for homologous blood transfusion were, 1) less than 7.0mg/dl in Hb concentration, 2) unstable hemodynamics, and 3) deterioration of general condition. In our method of rHuEPO administration, rHuEPO group showed higher Hb concentration level than that of non rHuEPO group at 14 POD and 21 POD, so that rHuEPO administration is effective to improve postoperative anemia.

Erythropoietin for anaemia in haemodialysis patients: results of a maintenance study (The Canadian Erythropoietin Study Group)

Most published studies of recombinant human erythropoietin (rHuEpo) have been of limited duration and in small patient populations. The present study examines the long-term effects of rHuEpo in 98 haemodialysis patients treated for up to 18 months. All patients had completed a 6 month placebo-controlled study of rHuEpo. Patients previously on placebo (group 1; n = 31) received rHuEpo at an initial dose of 50 U/kg thrice weekly with subsequent dose adjustments to maintain haemoglobin (Hb) in the range 105-120 g/l. Patients previously on rHuEpo (group 2; n = 67) continued on their usual dose with adjustments made to maintain Hb at 105-120 g/l. Haematological parameters were measured every 2 weeks. Quality of life, assessed by a disease-specific kidney disease questionnaire (KDQ), was measured every 6 months. Mean Hb in group 1 increased from 74.2 +/- 11.4 g/l at baseline to 112.9 +/- 12.6 g/l after 12 months of rHuEpo therapy. After 12 weeks of rHuEpo therapy Hb in groups 1 and 2 was indistinguishable. Hb remained constant in both groups throughout the period of follow-up. Mean rHuEpo dose requirements were similar in both groups. At the end of the study the mean intravenous rHuEpo dose in group 1 patients was 176.6 +/- 154.4 and in group 2 patients was 210.0 +/- 144.0 U/kg per week. Access failure was increased during rHuEpo therapy in patients with synthetic grafts (46% versus 7% failures compared to fistulae; P less than 0.001). Group 1 patients receiving rHuEpo had a significant increase in diastolic but not systolic blood pressure despite a 32% increase in overall antihypertensive prescriptions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of recombinant human erythropoietin on HLA sensitization and cell mediated immunity

Highly presensitized patients wait longer for a renal allograft than unsensitized patients and have a poorer allograft survival rate. Repeated blood transfusions have been implicated in the induction and maintenance of sensitization. To determine the effect of recombinant human erythropoietin (rHuEPO) therapy on five transfusion dependent, highly sensitized adolescents on dialysis, we serially measured percentage panel reactive antibody (%PRA) levels, titers of identifiable discrete anti-HLA Class I antibody specificities, and non-specific indices of cellular immunity before and following initiation of rHuEPO therapy. Although four of the five patients had previously rejected at least one renal allograft, the removal of chronic antigenic stimulation from blood transfusions led to a marked reduction in anti-HLA antibody titers to recognizable private and public specificities (P less than 0.001) and a reduction of mean %PRA from 80% to 56% (P less than 0.05). Each patient demonstrated a reduction of two or more dilutions to at least two anti-HLA antibody specificities. A control group of five patients matched for age, transfusion dependence and sensitization status demonstrated no change during a comparable time interval. PHA responsiveness decreased significantly in the rHuEPO group whereas autologous and allogenic mixed lymphocyte response, spontaneous blastogenesis and T-cell subsets did not. These data indicate that in highly sensitized dialysis patients rHuEPO may lead to decreased sensitization, shorter waiting time on dialysis and possibly improved allograft survival rates.