losartan-potassium and Body-Weight

The findings of recent clinical trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors produce effects beyond glucose lowering and have demonstrated beneficial cardiovascular effects that have been observed across a broad range of patients with type 2 diabetes mellitus. In particular, the cardiovascular benefit results largely from substantial and early effects of SGLT2 inhibition on cardiovascular death and hospitalization for heart failure. Recent cardiovascular outcomes trials (CVOTs) have also shown that relative risk reductions in cardiovascular outcomes were observed with SGLT2 inhibition both in patients with current and prior heart failure. Since the observed reductions of cardiovascular outcomes with SGLT2 inhibitor therapy were observed much earlier than would be expected by an anti-atherosclerotic effect, these results have led to speculation about the potential underlying pathways. Suggested mechanisms include natriuresis and osmotic diuresis; reductions in inflammation, oxidative stress, and arterial stiffness; reductions in blood pressure and body weight; and possible renoprotective effects. These effects could produce cardiovascular benefits through a range of cardiac effects, including reduction in left ventricular load, attenuation of cardiac fibrosis and inflammation, and improved myocardial energy production. Other possible mechanisms include inhibition of sodium-hydrogen exchange, increases in erythropoietin levels, and reduction in myocardial ischemia or reperfusion injury. It is likely that a range of mechanisms underlie the observed cardiovascular benefits of SGLT2 inhibitors; further elucidation of these mechanisms will be answered by ongoing research.

Topics: Blood Pressure; Body Weight; Cardiovascular Diseases; Cardiovascular System; Diuresis; Erythropoietin; Heart; Humans; Inflammation; Kidney; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Natriuresis; Oxidative Stress; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchangers; Vascular Stiffness

The aim of this analysis was to develop a population pharmacokinetic model to describe the pharmacokinetics of recombinant human erythropoietin (rHuEPO) in healthy subjects, after intravenous and subcutaneous administration over a wide dose range, and to examine the influence of demographic characteristics and other covariates on the pharmacokinetic parameters of rHuEPO.. Erythropoietin serum concentration data were available from 16 studies comprising 49 healthy subjects who received rHuEPO intravenous doses from 10 to 300 IU/kg, 427 healthy subjects who received rHuEPO subcutaneous doses from 1 to 2400 IU/kg, and 57 healthy subjects who received placebo and where endogenous erythropoietin concentrations were measured. Different pharmacokinetic models were fitted to the dataset using nonlinear mixed-effects modeling software (NONMEM, Version V, Level 1). Several patient covariates were tested in order to quantify the effect on rHuEPO pharmacokinetic parameters. Model evaluation was examined using a posterior predictive check.. Erythropoietin showed a diurnal baseline variation of +/-20%, described with a dual cosine model. Disposition was described with a two-compartment model with a small volume of distribution (6L) and parallel linear and nonlinear clearance. Total clearance varied between 0.3 and 0.9 L/h over the concentration range studied. A dual absorption model was used to characterise the rHuEPO absorption from the subcutaneous formulation and consisted of a faster pathway described as a sequential zero- and first-order absorption process and a parallel slower pathway characterised as a zero-order process. The bioavailability of subcutaneous rHuEPO increased from 30% at low doses to 71% at the highest dose of 160 kIU and was described using a hyperbolic model. The most important covariate effects were a decrease in the first-order absorption rate constant (k(a)) with increasing age, an increase in subcutaneous bioavailability with increasing baseline haemoglobin, and a decrease in bioavailability with increasing bodyweight. A posterior predictive check showed no systematic deviation of the simulated data from the observed values.. The population pharmacokinetic model developed is suitable to describe the pharmacokinetic behaviour of rHuEPO after intravenous and subcutaneous administration in healthy subjects, over a wide dose range.

Topics: Age Factors; Biological Availability; Body Weight; Circadian Rhythm; Computer Simulation; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Intestinal Absorption; Metabolic Clearance Rate; Models, Biological; Nonlinear Dynamics; Predictive Value of Tests; Recombinant Proteins; Reference Values; Reproducibility of Results

Stimulation of red blood cell precursors by Epoetin alfa results in a predictable, dose-dependent increase in red blood cell mass. Iron is an important substrate that supports red blood cell and hemoglobin development. Patients who receive Epoetin alfa therapy typically require intravenous iron supplementation to ensure proper red cell formation. Target and ceiling iron levels should be determined on the basis of safety considerations, the predicted clinical response, and individual patient replacement needs. Nurses can use clinical parameters such as body weight, baseline and target hemoglobin values, and iron losses from blood and other sources to estimate iron replacement doses, thereby providing a guide for appropriate iron replacement.

Topics: Anemia, Iron-Deficiency; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epoetin Alfa; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron Compounds; Iron Overload; Kidney Failure, Chronic; Nurse's Role; Nursing Assessment; Recombinant Proteins; Renal Dialysis; Safety Management; Transferrin

Clinical evidence indicates that maintaining a stable hematocrit (Hct) higher in the target range of 30% to 36% can lead to improvement in overall patient outcomes. On the basis of these data, a recent analysis by the Dialysis Outcomes Quality Initiative Anemia Work Group has recommended a target Hct of 33% to 36% (hemoglobin 11 g/dl to 12 g/dl). Maintaining a stable Hct higher in the target range provides nurses and other dialysis clinicians with two benefits: improved patient care and decreased time and costs for patient management. This article focuses on the data supporting such a policy. Clinical practices from two prominent dialysis centers are presented as models of good anemia management.

Topics: Anemia; Body Weight; Epoetin Alfa; Erythropoietin; Health Status; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Patient Care Planning; Recombinant Proteins; Survival Analysis

This study was performed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and safety of GSK1278863, a novel prolyl hydroxylase inhibitor, following a single oral administration of GSK1278863 from 10 to 100 mg or placebo in Japanese (n = 19), and 10, 25 and 100 mg in Caucasians (n = 14). Dose-proportional increases were observed in AUCinf of GSK1278863 in both ethnic groups, with a 1.3-1.5-fold higher exposure seen in Japanese relative to Caucasians for all doses. This difference in exposure can be mainly explained by the observed differences in body weights between the two groups. Statistically significant increases in erythropoietin (EPO), vascular endothelial growth factor (VEGF) and reticulocyte counts were observed in Japanese subjects after the 50 and 100 mg dose as compared to placebo. In Caucasians, similar to Japanese, EPO and VEGF levels were observed to be increased in response to the 100 mg dose. Drug-related adverse events, including headache and abdominal pain were reported in 3 Japanese subjects, while headache was reported in 3 Caucasians. In conclusion, GSK1278863 was well tolerated, with dose-proportional increases in exposure observed in both groups. There was no evidence of ethnic differences between Japanese and Caucasian with regard to PK or PD.

Topics: Administration, Oral; Adult; Area Under Curve; Asian People; Barbiturates; Body Weight; Dose-Response Relationship, Drug; Enzyme Inhibitors; Erythropoietin; Glycine; Half-Life; Healthy Volunteers; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Japan; Male; Metabolic Clearance Rate; Reticulocytes; Single-Blind Method; Vascular Endothelial Growth Factor A; White People; Young Adult

There is no consensus on the type, time of initiation, or duration of use of enteral nutrition in patients with chronic kidney disease (CKD). This study aimed to compare the effects of a renal-specific oral nutrition supplement (RS-ONS) and a standard recommended nutrition regime on biochemical and nutrition markers in malnourished patients with CKD on hemodialysis.. Sixty-two malnourished patients with CKD, divided into experimental (RS-ONS; n = 32; mean [SD] age, 62.0 [11.3] years; 55.2% female) and control (CON; n = 30; mean [SD] age, 57.2 [12.3] years; 31% female) groups, were evaluated for anthropometric, biochemical, and inflammatory parameters.. Mean (SD) serum albumin levels were significantly increased in the RS-ONS group from 3.5 (0.3) g/dL at baseline to 3.7 (0.2) g/dL at 6 months (P = .028). Significantly fewer patients had serum albumin levels of <3.5 g/dL after month 6. Dry weight of patients significantly increased in the RS-ONS but decreased in the CON groups (P < .001 for each). Percent change from baseline revealed negative results for bioelectrical impedance analysis (P < .001) in the CON group. Malnutrition inflammation score at 6 months (P = .006) and erythropoietin (EPO) dose requirements were higher in the CON group (P = .012).. Our findings indicate that consuming RS-ONS improves serum albumin and anthropometric measures, as well as reduces EPO dose, in patients with CKD.

Topics: Administration, Oral; Aged; Body Weight; Dietary Supplements; Electric Impedance; Erythropoietin; Female; Humans; Male; Malnutrition; Middle Aged; Nutritional Status; Renal Dialysis; Renal Insufficiency, Chronic; Serum Albumin

The quality of the water used for dialysis has been suggested as a factor causing inflammation in patients on hemodialysis (HD). We therefore conducted this study to identify the effect of quality of the water on nutritional state, inflammation and need for human recombinant erythropoietin (EPO) in patients undergoing HD at Agadir, Morocco. This prospective study included patients on HD for at least one year. The water treatment was done according to the standard protocol, which was followed by additional enhancement of ultrafiltration using an additional polysulfone filter (diasafe, Fresenius, Bad Homburg, Germany) before the dialyser. Water was monitored regularly during the study period to ensure acceptable levels of bacterial count as well as endotoxin levels. Various parameters including dry weight, systolic and diastolic blood pressure (PA) before and after an HD session, need for human recombinant EPO, levels of hemoglobin (Hb), albumin, ferritin, C-reactive protein (CRP), and the dose of dialysis delivered (Kt/V) were measured first at the beginning of the study and thereafter, in the third, sixth and 12 th months of the study. The study involved 47 patients, and after 12 months of the study, an improvement in median dry weight (1.2 kg, P = 0017) and a simultaneous median reduction of 20.7 IU/kg/week of EPO, with an in-crease of the median level of Hb, was noted. The results of our study suggest that by improving the biocompatibility of HD with the use of good quality water, patients acquire a better nutritional, inflammatory and hematologic status.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Bacterial Load; Body Weight; C-Reactive Protein; Endotoxins; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morocco; Nutritional Status; Prospective Studies; Renal Dialysis; Ultrafiltration; Water Microbiology; Water Supply; Young Adult

This study sought to investigate whether darbepoetin alfa, an erythropoiesis-stimulating protein (ESP), improves exercise capacity in patients with symptomatic chronic heart failure (CHF) and anemia.. Anemia is common in patients with CHF.. In a multicenter, randomized, double-blind, placebo-controlled study, CHF patients with anemia (hemoglobin > or =9.0 to < or =12.0 g/dl) received subcutaneous placebo (n = 22) or darbepoetin alfa (n = 19) at a starting dose of 0.75 microg/kg every 2 weeks for 26 weeks. The primary end point was change in exercise tolerance from baseline to week 27 as measured by peak oxygen uptake (ml/min/kg body weight). Other end points included changes in absolute peak VO2 (ml/min), exercise duration, and health-related quality of life.. Differences (95% confidence interval) in mean changes from baseline to week 27 between treatment groups were 1.5 g/dl (0.5 to 2.4) for hemoglobin concentration (p = 0.005), 0.5 ml/kg/min (-0.7 to 1.7) for peak VO2 (p = 0.40), 45 ml/min (-35 to 127) for absolute peak VO2 (p = 0.27), and 108 s (-11 to 228) for exercise duration (p = 0.075). Patients receiving darbepoetin alfa compared with placebo had an improvement in self-reported Patient's Global Assessment of Change (79% vs. 41%, p = 0.01) but no significant differences in the Kansas City Cardiomyopathy and Minnesota Living with Heart Failure Questionnaire scores. Darbepoetin alfa was well tolerated.. In patients with symptomatic CHF and anemia, darbepoetin alfa increased and maintained hemoglobin concentrations and improved health-related quality of life. A trend toward increased exercise time but not peak VO2 was observed. (Impact of Darbepoetin Alfa on Exercise Tolerance and Left Ventricular Structure in Subjects With Symptomatic Congestive Heart Failure (CHF) and Anemia; http://clinicaltrials.gov/ct/show/NCT00117234?order = 1; NCT00117234).

Topics: Activities of Daily Living; Aged; Anemia; Body Weight; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Exercise Test; Exercise Tolerance; Female; Heart Failure; Hematinics; Hemoglobins; Hospitalization; Humans; Injections, Subcutaneous; Male; Natriuretic Peptide, Brain; Oxygen Consumption; Quality of Life; Treatment Outcome

The effects of recombinant human erythropoietin (rHuEpo) treatment on aerobic power (VO2max) are well documented, but little is known about the effects of rHuEpo on submaximal exercise performance. The present study investigated the effect on performance (ergometer cycling, 20-30 min at 80% of maximal attainable workload), and for this purpose eight subjects received either 5,000 IU rHuEpo or placebo every second day for 14 days, and subsequently a single dose of 5,000 IU/placebo weekly/10 weeks. Exercise performance was evaluated before treatment and after 4 and 11 weeks of treatment. With rHuEpo treatment VO2max increased (P<0.05) by 12.6 and 11.6% in week 4 and 11, respectively, and time-to-exhaustion (80% VO2max) was increased by 54.0 and 54.3% (P<0.05) after 4 and 11 weeks of treatment, respectively. However, when normalizing the workload to the same relative intensity (only done at time point week 11), TTE was decreased by 26.8% as compared to pre rHuEpo administration. In conclusion, in healthy non-athlete subjects rHuEpo administration prolongs submaximal exercise performance by about 54% independently of the approximately 12% increase in VO2max.

Topics: Absorptiometry, Photon; Adiposity; Adult; Anaerobic Threshold; Athletic Performance; Bicycling; Body Composition; Body Mass Index; Body Weight; Erythropoietin; Exercise Test; Hematocrit; Hemoglobins; Humans; Lactic Acid; Male; Oxygen Consumption; Recombinant Proteins; Single-Blind Method

Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period.. We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH.. The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 +/- 26.4 vs. 9.8 +/- 7.4 ml/session, p < 0.05), frequency (0.60 +/- 0.26 vs. 0.10 +/- 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 +/- 56.4 vs. 104.8 +/- 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 +/- 0.9 vs. 7.9 +/- 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods.. The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Topics: Aged; Anemia; Antihypertensive Agents; Appointments and Schedules; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetic Nephropathies; Echocardiography; Erythropoietin; Female; Ferritins; Humans; Hypertension, Renal; Hypotension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Quality of Life; Recombinant Proteins; Renal Dialysis; Uremia

Drug doses for children are usually calculated by reducing adult doses in proportion to bodyweight. The clinically effective dose of recombinant human erythropoietin (epoetin) in children, however, seems to be higher than predicted by this calculation.. To determine the quantitative relationship between epoetin dose, bodyweight and response in children with end-stage renal disease.. The time-course of haemoglobin in 52 children during long-term treatment with epoetin beta was analysed by population pharmacodynamic modelling. Patients were 5-20 years old and weighed 16-53kg at the beginning of treatment. Epoetin beta was given intravenously three times per week after haemodialysis. Doses ranged from 110 to 7500IU (3-205 IU/kg). Haemoglobin versus time was described by assuming that the haemoglobin level rises after each dose due to the formation of new red blood cells, which then survive according to a logistic function. The initial rise after each dose was modelled in terms of absolute dose (not dose/kg). A parametric analysis was done with NONMEM, followed by a nonparametric analysis with NPAG.. Dose-response was best described by a sigmoid maximum-effect (E(max)) model with median E(max) = 0.29 g/dL, median 50% effective dose (ED(50)) = 2400IU and shape parameter gamma = 2. The estimated median survival time of the epoetin-induced red blood cells, tau, was 76 days. Neither of the dose-response parameters E(max) and ED(50) showed dependence on bodyweight. The median haemoglobin response to a standard dose, 0.042 g/dL for 1000IU, was similar to that reported for adults with intravenous administration.. Doses for children in this age range should be specified as absolute amounts rather than amounts per unit bodyweight. Initial doses can be calculated individually, based on haemoglobin level before treatment, the desired haemoglobin at steady state and the median population parameters E(max), ED(50) and tau.

Topics: Adolescent; Adult; Anemia; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Models, Biological; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric

The effect of using fixed versus weight-based doses for erythropoietic agents has not been reported previously. To investigate this issue, the authors conducted a randomized Phase II study of darbepoetin alfa administered as either a fixed dose or a weight-based dose using an accelerated correction and maintenance dosing regimen (front-loading).. During the correction phase, patients with anemia (hemoglobin < 11.0 g/dL) who had nonmyeloid malignancies and who were receiving chemotherapy were given darbepoetin alfa at a fixed dose of 325 microg (n = 122) or at a weight-based dose of 4.5 microg/kg (n = 120) once weekly until they achieved a hemoglobin concentration > or = 12.0 g/dL. Patients then received darbepoetin alfa (325 microg or 4.5 microg/kg) once every 3 weeks for the remainder of the 16-week treatment period (maintenance phase).. Darbepoetin alfa resulted in high Kaplan-Meier rates of hematopoietic response (> or = 2 g/dL increase from the baseline level or a hemoglobin level > or = 12 g/dL) in both the fixed-dose group (86%; 95% confidence interval [95% CI], 78- 94%) and the weight-based dose group (84%; 95% CI, 76-92%). The median time to hematopoietic response was 34 days (95% CI, 28-44 days) for the fixed-dose group and 36 days (95% CI, 30-45 days) for the weight-based dose group. Hemoglobin concentrations were maintained at target levels for up to 16 weeks in both groups. Darbepoetin alfa was well tolerated, and no clinically significant differences between fixed doses and weight-based doses were observed.. Darbepoetin alfa was effective when administered as either a fixed dose or a weight-based dose using a front-loading approach to rapidly correct anemia and effectively maintain hemoglobin levels in patients with anemia who had malignant disease.

Topics: Aged; Anemia; Body Weight; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome

Darbepoetin alfa is a unique erythropoetic protein whose half-life is 3 times longer than that of recombinant human erythropoetin (rHuEPO). It corrects and maintains haemoglobin (Hb) concentrations at increased dosing intervals as compared to rHuEPO. The aim of this study was to evaluate the efficacy and safety of darbepoetin alfa administered as fixed unit doses. Haemodialysis patients (n = 250) maintained on stable rHuEPO treatment 2-3 times weekly (n = 200) were switched to darbepoetin alfa once weekly (QW). Treatment for patients on rHuEPO QW (n = 50) was changed to darbepoetin alfa every other week (Q2W). The route of administration (i.v. or s.c.) was kept unchanged. The dose of darbepoetin alfa was titrated to maintain Hb levels at 10-13 g/dL between baseline and the evaluation period (weeks 21-24; primary endpoint). There was no clinically relevant change in mean Hb levels between baseline (11.69 g/dL) and evaluation (-0.28 g/dL (95% CI: -0.43; -0.13)). Mean weekly dose requirements of darbepoetin alfa decreased by 13.3% from 36.7 micrograms (95% CI: 33.9; 39.7) to 31.8 micrograms (95% CI: 28.7; 35.2). This decrease was more pronounced in patients receiving darbepoetin alfa i.v. (-18.4%) as compared to those receiving it s.c. (-6.4%). Darbepoetin alfa was well tolerated. Overall safety data were consistent with those observed in other studies. These data confirm that unit dosing with darbepoetin alfa at increased dosing intervals and reduced dose effectively and safely maintains Hb levels in haemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Darbepoetin alfa; Data Interpretation, Statistical; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors

The optimal haemoglobin concentration ([Hb]) for patients with end-stage renal failure is uncertain. In particular, it is unclear whether Hb normalization may be an advantage to such patients who are otherwise well.. A prospective, randomized, double-blind cross-over study was completed in 14 haemodialysis patients (12 male) aged between 23 and 65 years over a period of 18 months, using a variety of measures to examine the effect of epoetin at target [Hb] of 10 g/dl ([Hb](10)) and 14 g/dl ([Hb](14)). Patients were randomized to maintain one or other of the target levels for 6 weeks before being crossed over to the alternative [Hb]. Baseline data (mean [Hb]: 8.5+/-0.2 g/dl) were also included selectively. Six patients were known to be hypertensive. Comparisons were made between 24-h ambulatory blood pressure levels (ABP), echocardiographic findings and estimates of blood volume (BV), plasma volume (PV) and Hb mass. Quality of life estimates were obtained using the Sickness Impact Profile (SIP), and epoetin dosage requirements at target [Hb] were assessed.. Daytime and nocturnal ABP (systolic and diastolic) were not different at the respective target [Hb], although nocturnal diastolic levels were higher compared with baseline (73+/-4 mmHg) at both [Hb](10) (83+/-3, P:<0.01) and [Hb](14) (81+/-6, P:<0.05). Significant reductions in cardiac output (5.2+/-0.3 vs 6.6+/-0.5 l/min, P:<0.01) and left ventricular end-diastolic diameter (4.8+/-0.2 vs 5.2+/-0.2 cm, P:<0. 001) were found at [Hb](14) compared with [Hb](10). Left ventricular mass index was correlated with both PV (P:<0.001) and BV (P:<0.01), but not with Hb mass. The PV decreased as the [Hb] rose (P:<0.001) but BV remained unchanged. Quality of life was significantly improved at [Hb](14) compared with [Hb](10) for both total score (6. 5+/-1.7 vs 13.4+/-3.0, P:=0.01) and psychosocial dimension score (5. 4+/-1.9 vs 15.4+/-4.0, P:<0.01). The maintenance weekly dose of epoetin required was 80% higher at [Hb](14) compared with [Hb](10) (P:<0.001).. These data suggest there may be a significant haemodynamic and symptomatic advantage in maintaining a physiological [Hb] in haemodialysis patients. Although untoward effects were not identified in this study at [Hb](14), a substantially higher dose of epoetin is required to maintain this level.

Topics: Adult; Aged; Blood Pressure; Blood Volume; Body Weight; Cardiovascular System; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Reference Values

Despite a large body of evidence showing the beneficial effects of successful treatment of anemia with recombinant human erythropoietin (EPO) in patients with end-stage renal disease, controversy remains as to whether EPO treatment of anemia can improve the nutritional status in patients on maintenance hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then titrated in the following 12 weeks to maintain the target value. Nutritional status was assessed at baseline and after 6 months of follow-up, using the global protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low global PCM score indicates better nutrition. The results showed that hemoglobin values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5 g/dl in the 6th month (p < 0.001). No significant changes were observed in the normalized protein catabolic rate and Kt/V during the study period. Global PCM scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the correction of anemia by EPO treatment. The data were consistent with a major improvement in the nutritional markers of relative body weight, triceps skinfold, midarm circumference, midarm muscle circumference, serum albumin, serum transferrin and total lymphocyte count in the 6th month as compared to baseline. The percentages of mild and moderate-severe PCM at baseline were 32 and 58%, respectively. These percentages were significantly reduced during the 6th month to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia with EPO improves the nutritional status in hemodialysis patients. A postulated mechanism is that EPO may exhibit anabolic effects, with a better utilization of ingested protein.

Topics: Aged; Anemia; Body Weight; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Prospective Studies; Recombinant Proteins; Renal Dialysis

We studied whether orthopedic surgical patients with rheumatoid arthritis (RA) can generate an erythropoietic response to either endogenous erythropoietin or to recombinant human erythropoietin (EPO) therapy to the same extent as patients without rheumatoid arthritis (non-RA). Seventy patients (10 RA, 60 non-RA) were entered into clinical trials of aggressive autologous blood donation before elective orthopedic surgery at one institution, randomized to receive EPO (600 U/kg, iv, 6 times over 3 weeks) or placebo. RA patients given EPO had red blood cell (RBC) production that was enhanced by 624 +/- 137 ml (mean +/- SD) as compared with 271 +/- 174 ml (p = 0.02) for RA patients given placebo treatment. Preoperative RBC volume expansion in 10 RA patients was 5.9 +/- 3.7 ml/kg as compared with 7.4 +/- 3.9 ml/kg for 60 non-RA patients (p = 0.13). RA patients can benefit to the same extent as non-RA patients from aggressive blood conservation programs that incorporate erythropoietin-modulated erythropoiesis.

Topics: Arthritis, Rheumatoid; Blood Transfusion, Autologous; Body Weight; Bone Marrow; Erythrocyte Volume; Erythropoiesis; Erythropoietin; Ferritins; Hematocrit; Humans; Iron; Middle Aged; Recombinant Proteins; Treatment Outcome

Erythropoietin (rHuEPO) therapy has been shown to be beneficial in preventing and treating anaemia of prematurity and to decrease the need for blood transfusions. There is, however, only scanty data on the effect of rHuEPO therapy on iron metabolism. We studied 29 preterm infants (age 34 +/- 14 days) who were randomly assigned to receive either rHuEPO 900 U kg-1 week-1 with 6 mg kg-1 day-1 of iron for 4 weeks (n = 15) or no therapy. The following parameters were evaluated and compared between and within groups at the beginning, during and at the end of the study: Haematocrit (SI), reticulocytes (10(9) micrograms l-1), serum ferritin (microgram 1-1) and iron (mumol l-1). The results were as follows. At the baseline, erythropoietin levels were similar in both groups: 7.2 +/- 5.6 versus 6.2 +/- 3.2 mU ml-1 (NS). In the treated infants the haematocrit remained stable during the study and was significantly higher than in the control group by the end of the study: 0.34 +/- 0.03 versus 0.28 +/- 0.05 (p = 0.001). rHuEPO therapy increased the reticulocyte count from 130 +/- 70 to 430 +/- 200 (p = 0.0002). However, rHuEPO therapy depleted both serum ferritin and iron levels from 321 +/- 191 to 76 +/- 58 micrograms l-1 (p = 0.04) and from 18 +/- 5 to 13 +/- 4 mumol l-1 (p = 0.03), respectively. We conclude that rHuEPO therapy prevented anaemia and its sequelae; however, serum ferritin and iron levels were depleted. We suggest that the effect of rHuEPO may be further increased by higher iron supplementation.

Topics: Anemia, Neonatal; Body Weight; Combined Modality Therapy; Erythropoietin; Ferritins; Ferrous Compounds; Hematocrit; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Recombinant Proteins; Reticulocyte Count

Intravenous recombinant human erythropoietin (Eprex Cilag) was used in 28 hemodialyzed children, treated in 3 French paediatric centers, from November 1989 to November 1990. Transfusion dependency disappeared in all cases: the number of transfusions decreased from 7.3 unit/patient/year to 0.6 unit/pt/year. The mean haemoglobin concentration for the whole group increased from 6.6 +/- 0.8 g/dl, to 9.2 +/- 1.2 at 6 months and 9.7 +/- 0.7 g/dl at 1 year. Twenty-two out of 28 children reached the target haemoglobin value of 9.6 g/dl (6 mmol/dL) within a mean time of 16.5 weeks. Poor responses were due to either a premature withdrawal of treatment because of renal transplantation, or too low a dosage for the age. The study showed indeed that the dose requirement was significantly dependent on physical development: the mean dosage required to maintain haemoglobin concentration at the target value was 300 U/kg/week in children weighing less than 20 kg, 222 U/kg/week in 20-30 kg children, and 135 U/kg/week in those weighing more than 30 kg (p = 0.02). The only complication was an increase in blood pressure, observed in 43% of cases. The increase of anti-hypertensive medication was always successful in controlling blood pressure, and hospitalization was required in only one case. The improvement in general condition was obvious, and in several cases, the cognitive abilities seemed to improve. The growth deficit remained unchanged.

Topics: Adolescent; Anemia; Appetite; Blood Transfusion; Body Weight; Child; Child, Preschool; Cognition Disorders; Dose-Response Relationship, Drug; Erythropoietin; Female; France; Growth Disorders; Hemoglobins; Humans; Hypertension; Immunologic Factors; Infant; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Recombinant human erythropoietin (EPO) therapy has been known to enhance erythropoiesis and facilitate autologous blood donation before elective orthopedic operations. However, the optimal EPO dose in this setting remains undefined. To help determine this, we have examined the effect of patient weight and EPO dose on red blood cell (RBC) volume expansion.. Forty-six nonanemic autologous blood donors enrolled at our institution in two previously reported multicenter clinical trials were analyzed. Patients received either placebo or EPO (150, 300, or 600 units [U] per kg) given intravenously at each of six AB blood type donation visits.. Total preoperative RBC volume expansion over a 22 day period was 465 +/- 135 mL (mean +/- SD) in patients receiving a placebo and 588 +/- 201 mL, 735 +/- 144 mL, and 881 +/- 292 mL in patients receiving graded concentrations of EPO. When RBC volume increase was corrected for patient weight and EPO dose, patients receiving placebo or EPO (150, 300, and 600 U per kg) expanded RBC volume by 5.9 mL per kg in patients receiving placebo and 7.9, 9.1, and 10.9 mL per kg in patients receiving EPO, respectively (p < 0.02 for each EPO group compared with placebo group). A direct relationship between EPO dose and RBC volume increase (response) over 22 days was determined by the linear regression equation: RBC volume (mL per kg) = 6.34 + 0.0013X, r = 0.98, where X equals total units EPO administered (per kg body weight).. We conclude that EPO dose can be based on anticipated blood losses and transfusion needs in autologous blood donors before orthopedic operation.

Topics: Aged; Blood Donors; Blood Transfusion, Autologous; Blood Volume; Body Weight; Bone and Bones; Dose-Response Relationship, Drug; Elective Surgical Procedures; Erythrocyte Volume; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Injections, Intravenous; Iron; Male; Middle Aged; Placebos; Recombinant Proteins

Eleven children aged 0.6-17 years with preterminal chronic renal failure and anemia (mean serum creatinine concentration 4.8 mg/dl; mean hemoglobin concentration 7.9 g/dl) were treated with sc injections of recombinant human erythropoietin (EPO, initial dose 150 U/kg/week) over a mean period of 13 months. When a target hemoglobin concentration of 11.5-13.5 g/dl was reached, the dose was adapted. Iron deficiency was corrected. Hemoglobin concentration increased by > 2 g/dl in all patients within 14-119 (mean 45) days. The last maintenance dose ranged between 75 and 300 (mean 133) U/kg/week. No major adverse effects were observed, except for hypertension which occurred in about half of the patients and necessitated interruption of EPO in one child with advanced renal failure. Additional antihypertensive drugs were given to five patients. Body height increased in two patients by 0.6 and 1.3 SDS/year, respectively. In six patients with a mean observation period of 14 months before and 16 months after the start of EPO, the mean slope of the reciprocal serum creatinine concentration curve improved slightly (p = 0.05). The proposed schedule appears to be safe for the treatment of renal anemia in most pre-dialysis patients. Frequent monitoring of hemoglobin, blood pressure, serum creatinine and ferritin is required.

Topics: Adolescent; Anemia; Antihypertensive Agents; Body Height; Body Weight; Child; Creatinine; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Hypertension; Infant; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Recombinant Proteins

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.

Topics: Anemia, Neonatal; Blood Transfusion; Body Weight; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Fetal Hemoglobin; Hematocrit; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Iron; Leukocyte Count; Male; Neutrophils; Pilot Projects; Platelet Count; Random Allocation; Recombinant Proteins; Reticulocytes

Xenopus liver maintains erythropoietic activity from the larval to the adult stage. During metamorphosis, thyroid hormone mediates apoptosis of larval-type erythroid progenitors and proliferation of adult-type erythroid progenitors, and a globin switch occurs during this time. In addition, the whole-body mass and the liver also change; however, whether there is a change in the absolute number of erythroid progenitors is unclear. To isolate and evaluate erythroid progenitors in the Xenopus liver, we developed monoclonal ER9 antibodies against the erythropoietin receptor (EPOR) of Xenopus. ER9 recognized erythrocytes, but not white blood cells or thrombocytes. The specificity of ER9 for EPOR manifested as its inhibitory effect on the proliferation of a Xenopus EPOR-expressing cell line. Furthermore, ER9 recognition was consistent with epor gene expression. ER9 staining with Acridine orange (AO) allowed erythrocyte fractionation through fluorescence-activated cell sorting. The ER9+ and AO-red (AOr)high fractions were highly enriched in erythroid progenitors and primarily localized to the liver. The method developed using ER9 and AO was also applied to larvae and froglets with different progenitor populations from adult frogs. The liver to body weight and the number of ER9+ AOrhigh cells per unit body weight were significantly higher in adults than in larvae and froglets, and the number of ER9+ AOrhigh cells per unit liver weight was the highest in froglets. Collectively, our results show increased erythropoiesis in the froglet liver and demonstrate growth-dependent changes in erythropoiesis patterns in specific organs of Xenopus.

Topics: Animals; Body Weight; Erythroid Precursor Cells; Erythropoietin; Larva; Liver; Receptors, Erythropoietin; Xenopus; Xenopus laevis

Erythropoietin (EPO) is a hormone, which stimulates the production of red blood cells. Due to its performance-enhancing effect, it is prohibited by the World Anti-Doping Agency (WADA). In order to reduce the detection window of EPO doping, athletes have been applying low doses of recombinant EPO (e.g., <10 IU/kg body weight, daily or every second day) instead of larger doses twice or more per week (e.g., 30 IU/kg). Microdoses of Retacrit (epoetin zeta), an EPO biosimilar, were administered intravenously and subcutaneously to human males and females. Urine and serum samples were collected and analysed applying the new biotinylated clone AE7A5 EPO antibody and a further optimized sarcosyl polyacrylamide gel electrophoresis (SAR-PAGE) protocol. With the improved protocol, microdosed Retacrit (7.5 IU/kg body weight [BW]) was detectable for at least 52 h after intravenous administration. Detection windows were approximately the same for serum and urine and doubled after subcutaneous administration (~104 h). Previous studies applying different electrophoretic techniques and the not further optimized SAR-PAGE protocol revealed considerably shorter detection windows for recombinant human erythropoietin (rhEPO) microdoses. Because the new biotinylated antibody performed significantly more sensitive than the nonbiotinylated version, the new protocol will improve the sensitivity and hence detectability of recombinant EPO in doping control.

Topics: Antibodies; Body Weight; Doping in Sports; Electrophoresis, Polyacrylamide Gel; Epoetin Alfa; Erythropoietin; Female; Humans; Isoelectric Focusing; Male; Recombinant Proteins; Substance Abuse Detection

To investigate the role of stromal cell-derived factor 1 (SDF-1) and C-X-C chemokine receptor type 4 (CXCR-4) in the premature brain with white matter damage (WMD) undergoing treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs) and recombinant human erythropoietin (rhEPO).. Three-day-old Sprague-Dawley (SD) rats were randomly divided into sham operation group, hypoxia-ischemia (HI) group, rhEPO treated HI group, hUC-MSCs treated HI group, and rhEPO + hUC-MSCs treated HI group. WMD was established in all groups except the Sham group. SDF-1 and CXCR-4 levels in each group were detected at postnatal day (P) 5, P7, and P14. Pathological changes were assessed via HE staining at P14 and neuroethological tests were performed at P28.. The rhEPO and hUC-MSCs intervention reduced injury area, increased body weight at P7, and improved neurobehavioral scores at P28. Furthermore, their combined use proved even more beneficial. SDF-1 levels in the rhEPO group were higher than those in the other groups and highest in the hUC-MSCs + rhEPO group (all p < .01). SDF-1 levels in the hUC-MSCs + rhEPO and rhEPO groups were increased at P5 and reached a peak at P7. CXCR-4 levels in the hUC-MSCs group were higher than those in the other groups and highest in the hUC-MSCs + rhEPO group (all p < .01). CXCR-4 levels were also increased at P5 and highest at P14.. hUC-MSCs + rhEPO might reduce nerve cell damage and improve neurobehavioral development, in connection with increased SDF-1 and CXCR-4 expression, in premature rats with WMD due to hypoxic-ischemic injury.

Topics: Animals; Behavior, Animal; Body Weight; Chemokine CXCL12; Disease Models, Animal; Erythropoietin; Female; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pregnancy; Premature Birth; Rats; Rats, Sprague-Dawley; Receptors, CXCR4; Recombinant Proteins; White Matter

Erythropoietin (EPO) is the primary regulator of erythropoiesis in the mammalian fetus and adult. Deficiency of EPO induces anemia. In this study, we investigated the effect of gamma-aminobutyric acid (GABA) on serum EPO levels and erythropoiesis in rats. Expression levels of

Topics: Adenosine Triphosphate; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Weight; Citric Acid Cycle; Creatinine; Erythrocyte Indices; Erythropoietin; Feeding Behavior; gamma-Aminobutyric Acid; Gene Expression Regulation; Gene Ontology; Humans; Hypoxia-Inducible Factor 1; Kidney; Leukocyte Count; Male; NADH Dehydrogenase; Protein Interaction Maps; Rats, Sprague-Dawley; Receptors, Erythropoietin

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (

Topics: Animals; Asphyxia Neonatorum; Birth Weight; Body Weight; Combined Modality Therapy; Dose-Response Relationship, Drug; Embryonic Development; Erythropoietin; Female; Fetus; Gestational Age; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Infusions, Intravenous; Injections, Intravenous; Models, Biological; Neuroprotective Agents; Recombinant Proteins; Sheep; Species Specificity

Linear alkylbenzene sulfonate (LAS) is an anionic surfactant commonly used in cleaning agents such as laundry detergents. Trace amounts of LAS are released into environmental waters after processing in wastewater treatment plants after the use of this chemical. Acute toxicity of LAS has been well-studied using various organisms, and its effects are particularly well known in fish. LAS damages fish gill morphology and induces mucous excretion from these organs. LAS also causes hematological changes. These observations suggest that LAS might induce hypoxic conditions in fish. However, the connections between hypoxia and hematological changes at the cellular and molecular levels remain unknown. Common carp were exposed to LAS at concentrations of 625, 1250, and 2500 μg/L for 96 h. A total of 9-10 fish were sampled at the end of the exposure period for each concentration. For hematological analysis, carp blood was sampled from the caudal vein. Gill tissue was used for real-time PCR analysis to evaluate transcriptional changes of hypoxia-induced genes. The number of normal red blood cells and the number of immature red blood cells were significantly decreased and increased, respectively, in fish exposed to 2500 µg/L LAS. The hypoxic marker genes hypoxia inducible factor 1α, myoglobin 1, and erythropoietin 2 were upregulated in these fish. Our results suggest that LAS decreases erythrocyte numbers and induces hypoxic conditions. In addition, LAS-exposed fish increase production of immature erythrocytes and upregulate myoglobin expression in gills to improve oxygen transport and absorption. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 122-130, 2017.

Topics: Alkanesulfonic Acids; Animals; Blood Cell Count; Body Weight; Carps; Dose-Response Relationship, Drug; Erythrocyte Count; Erythropoietin; Gene Expression; Gills; Growth; Hypoxia; Hypoxia-Inducible Factor 1; Myoglobin; Surface-Active Agents

Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. To date, few therapeutic strategies could provide complete neuroprotection. Erythropoietin (EPO) has been shown to be beneficial in several models of neonatal HI. This study examines the effect of treatment with erythropoietin on postnatal day 2 (P2) rats introduced with HI injury.. Rats at P2 were randomized into four groups: sham, bilateral carotid artery occlusion (BCAO), BCAO + early EPO, and BCAO + late EPO groups. Pups in each group were injected with either saline or EPO (5000U/kg) intraperitoneally once at immediately (early) or 48h (late) after HI induction. Body weight was assessed at P2 before and day 7 after HI. Mortality Rate was assessed at 24h, 48h and 72h after HI and brain water content was assessed at 72h. Brain weight and expression of myelin basic protein (MBP) were assessed at day 7 and day 14. At day 31 to 35 following HI insult, neurological behavior function was assessed via Morris water maze (MWM) test.. HI cause significant higher mortality in male than in female (P=0.0445). Among the surviving animal, HI affect significantly the body growth, brain growth, MBP expression, and neurological behavior. EPO treatments at both early and late time points significantly benefit the rats in injury recovery, in which they promoted weight gains, reduced brain edema, as well as improved spatial learning ability and memory.. We demonstrated a single dose of EPO at 5000U/kg immediately or 48h after HI injury had significant benefit for the P2 rats in injury recovery, and there was no adverse effect associated with either EPO treatment.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Body Weight; Brain Edema; Developmental Disabilities; Disease Models, Animal; Erythropoietin; Hypoxia-Ischemia, Brain; Maze Learning; Myelin Basic Protein; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Aging and obesity exert important effects on disease. Differentiating these effects is difficult, however, because weight gain often accompanies aging. Here, we used a nested design of aged, calorically restricted, and refed rats to measure changes in brain and blood levels of cytokines and gastrointestinal hormones, brain amyloid precursor protein levels, and brain and body weights. By comparing groups and using path analysis, we found divergent influences of chronological aging versus body weight, our main findings being (i) changes in whole brain weight and serum macrophage colony-stimulating factor levels correlated better with body weight than with chronological aging, (ii) a decrease in brain cytokines and brain plasminogen activator inhibitor levels correlated better with chronological aging than with body weight, (iii) serum erythropoietin levels were influenced by both body weight and aging, (iv) serum plasminogen activator inhibitor, serum cytokines, and brain tumor necrosis factor were not influenced by aging or body weight, and (v) brain amyloid precursor protein more closely related to body weight and serum levels of gastrointestinal hormones than to brain weight, chronological aging, or cytokines. These findings show that although aging and body weight interact, their influences are distinct not only among various cytokines and hormones but also between the central nervous system and the peripheral tissue compartments.

Topics: Adipose Tissue; Aging; Amyloid beta-Protein Precursor; Animals; Body Weight; Brain; Erythropoietin; Gastrointestinal Hormones; Leptin; Macrophage Colony-Stimulating Factor; Male; Obesity; Organ Size; Plasminogen Inactivators; Rats; Statistics as Topic; Tumor Necrosis Factor-alpha

Clinical studies showed that high doses of recombinant human erythropoietin (rHuEPO) used to correct anaemia in chronic kidney disease (CKD) hyporesponsive patients may lead to deleterious effects. The aim of this study was to analyze the effects of rHuEPO in doses usually used to correct CKD-anaemia (100, 200 IU/kg body weight (BW) per week) and in higher doses used in the treatment of hyporesponsive patients (400, 600 IU/kg BW per week), focusing on renal damage, hypoxia, inflammation and fibrosis. Male Wistar rats with chronic renal failure (CRF) induced by 5/6 nephrectomy were treated with rHuEPO or with vehicle, over a 3-week period. Haematological, biochemical and renal function analyses were performed. Kidney and liver mRNA levels were evaluated by quantitative real-time polymerase chain reaction (qPCR) and protein expression by Western blot and immunohistochemistry. Kidney histopathological evaluations were also performed. The CRF group developed anaemia, hypertension and a high score of renal histopathologic lesions. Correction of anaemia was achieved with all rHuEPO doses, with improvement in hypertension, renal function and renal lesions. In addition, the higher rHuEPO doses also improved inflammation. Blood pressure was reduced in all rHuEPO-treated groups, compared to the CRF group, but increased in a dose-dependent manner. The current study showed that rHuEPO treatment corrected anaemia and improved urinary albumin excretion, particularly at lower doses. In addition, it is suggested that a short-term treatment with high doses, used to overcome an episode of hyporesponsiveness to rHuEPO therapy, can present benefits by reducing inflammation, without worsening of renal lesions; however, the pro-hypertensive effect should be considered, and carefully managed to avoid a negative cardiorenal impact.

Topics: Anemia; Animals; Blood Pressure; Body Weight; Cell Hypoxia; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Fibrosis; Gene Expression Regulation; Humans; Hypertension; Inflammation; Kidney; Kidney Failure, Chronic; Male; Organ Size; Rats; Recombinant Proteins; Risk; Risk Assessment

To investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change.. Plasma to measure erythropoietin and leptin; data for body composition; 24-h EE measured in a whole-room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full-heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy-nine subjects had data for weight at a later visit (mean follow-up = 4.3 ± 1.9 years) to calculate percent weight change per year.. Erythropoietin, adjusted for covariates, correlated with 24-h EE (r = 0.26, P = 0.007), sleeping EE (r = 0.29, P = 0.003), fat-free mass (r = 0.19, P = 0.05), and fat mass (r = 0.27, P = 0.005), but not insulin or glucose measures. The association of erythropoietin with 24-h EE was fully mediated by fat-free mass. Erythropoietin associated with leptin in women (ρ = 0.36, P = 0.01), but not in men (P = 0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction: P = 0.002) in males (r = -0.35, P = 0.02) versus females (r = 0.37, P = 0.02).. Non-hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women.

Topics: Adolescent; Adult; Body Composition; Body Weight; Energy Metabolism; Erythropoietin; Female; Glucose Tolerance Test; Humans; Indians, North American; Insulin; Leptin; Male; Middle Aged; Obesity; Sex Factors; Young Adult

Erythropoietin administration, which is clinically used in cancer patients with cancer-induced anemia, has also potentially beneficial effects on nonhematopoietic organs. We assessed the effects of erythropoietin on cancer cachexia progression and cardiac wasting compared with placebo using the Yoshida hepatoma model.. Wistar rats were divided in a sham group (n=10) and a tumor-bearing group (n=60). The tumor-bearing group was further randomized to placebo (n=28), 500Unit/kg/day (n=16) or 5000Unit/kg/day of erythropoietin (n=16). Body composition was measured using nuclear magnetic resonance spectroscopy, cardiac function using echocardiography, physical activity using infrared monitoring system.. Tumor-bearing rats with high dose erythropoietin led to a significant improvement on survival compared with placebo (hazard ratio: 0.43, 95%CI: 0.20-0.92, p=0.030), though low dose erythropoietin did not reach significance (hazard ratio: 0.46, 95%CI: 0.22-1.02, p=0.056). Loss of body weight, wasting of lean mass, fat mass, and reduced physical activity were ameliorated in rats treated with both low and high doses of erythropoietin (p<0.05, all). Moreover, reduced left ventricular mass and left ventricular systolic function were also ameliorated in rats treated with low and high doses of erythropoietin (p<0.05, respectively).. Overall, the present data support that cardiac wasting induced by cancer cachexia plays an important role which leads to impaired survival, provided that the erythropoietin could be an effective therapeutic approach for cancer cachexia progression and cardiac wasting.

Topics: Adipose Tissue; Animals; Body Composition; Body Weight; Cachexia; Erythropoietin; Humans; Liver Neoplasms, Experimental; Magnetic Resonance Spectroscopy; Male; Random Allocation; Rats; Rats, Wistar; Treatment Outcome

Neuroprotection of erythropoietin (EPO) following long-term administration is hampered by the associated undesirable effects on hematopoiesis and body weight. For this reason, we tested carbamylated-EPO (CEPO), which has no effect on erythropoiesis, and compared it with EPO in the AβPP/PS1 mouse model of familial Alzheimer’s disease. Groups of 5-month old wild type (WT) and transgenic mice received chronic treatment consisting of CEPO (2,500 or 5,000 UI/kg) or EPO (2,500 U I/kg) 3 days/week for 4 weeks. Memory at the end of treatment was assessed with the object recognition test. Microarray analysis and quantitative-PCR were used for gene expression studies. No alterations in erythropoiesis were observed in CEPO-treated WT and AβPP/PS1 transgenic mice. EPO and CEPO improved memory in AβPP/PS1 animals. However, only EPO decreased amyloid-β (Aβ)plaque burden and soluble Aβ(40). Microarray analysis of gene expression revealed a limited number of common genes modulated by EPO and CEPO. CEPO but not EPO significantly increased gene expression of dopamine receptors 1 and 2, and adenosine receptor 2a, and significantly down-regulated adrenergic receptor 1D and gastrin releasing peptide. CEPO treatment resulted in higher protein levels of dopamine receptors 1 and 2 in WT and AβPP/PS1 animals, whereas the adenosine receptor 2a was reduced in WT animals. The present results suggest that the improved behavior observed in AβPP/PS1 transgenic mice after CEPO treatment may be mediated, at least in part, by the observed modulation of the expression of molecules involved in neurotransmission.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Body Weight; Disease Models, Animal; Erythropoietin; Gastrin-Releasing Peptide; Gene Expression Regulation; Humans; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; Receptors, Catecholamine; Synapses; Time Factors

Anemia is a common complication of chronic kidney disease (CKD) that develops early and its severity increases as renal function declines. It is mainly due to a reduced production of erythropoietin (EPO) by the kidneys; however, there are evidences that iron metabolism disturbances increase as CKD progresses. Our aim was to study the mechanisms underlying the development of anemia of CKD, as well as renal damage, in the remnant kidney rat model of CKD induced by 5/6 nephrectomy. This model of CKD presented a sustained degree of renal dysfunction, with mild and advanced glomerular and tubulointerstitial lesions. Anemia developed 3 weeks after nephrectomy and persisted throughout the protocol. The remnant kidney was still able to produce EPO and the liver showed an increased EPO gene expression. In spite of the increased EPO blood levels, anemia persisted and was linked to low serum iron and transferrin levels, while serum interleukin (IL)-6 and high sensitivity C-reactive protein (hs-CRP) levels showed the absence of systemic inflammation. The increased expression of duodenal ferroportin favours iron absorption; however, serum iron is reduced which might be due to iron leakage through advanced kidney lesions, as showed by tubular iron accumulation. Our data suggest that the persistence of anemia may result from disturbances in iron metabolism and by an altered activity/function of EPO as a result of kidney cell damage and a local inflammatory milieu, as showed by the increased gene expression of different inflammatory proteins in the remnant kidney. In addition, this anemia and the associated kidney hypoxia favour the development of fibrosis, angiogenesis and inflammation that may underlie a resistance to EPO stimuli and reduced iron availability. These findings might contribute to open new windows to identify putative therapeutic targets for this condition, as well as for recombinant human EPO (rHuEPO) resistance, which occurs in a considerable percentage of CKD patients.

Topics: Anemia; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Erythropoietin; Fibrosis; Hepcidins; Inflammation; Iron; Kidney; Liver; Male; Organ Size; Rats; Rats, Wistar; Receptors, Erythropoietin; RNA, Messenger

Inflammation and increased erythropoiesis stimulating agents (ESA) requirement are frequently associated in patients on dialysis. On-line hemodiafiltration (ol-HDF), putting together high levels of diffusion, and convection could improve both conditions. However, it is still not known which depurative component plays a major role in determining this result. The aim of the study was to evaluate the role of convection and diffusion on long-term variations of serum β2 microglobulin (Δβ2M), high-sensitive C-reactive protein (ΔhsCRP) concentrations, and ESA requirement (ΔESA) in ol-HDF.. Seventy-three patients prevalent on high flux HD (hfHD) were studied. Thirty-eight patients were switched from hfHD to post-dilutional ol-HDF (Study group); the other 35 patients were considered the Control group. At 6 and 12 months, the effects of ol-HDF and hfHD on ΔhsCRP, ΔB2M, and ΔESA (U/kg/week) were evaluated. Other variables considered were body weight (BW), serum albumin (sAlb), hemoglobin (Hb), and equilibrated Kt/V (eKt/V). Iron therapy and ESA were administered intravenously according to the K/DOQI guidelines in order to maintain transferrin saturation between 20 and 40%, serum ferritin between 150 and 500 ng/ml and Hb between 11 and 12 g/dl. Qb, treatment time and Qd remained constant. Ol-HDF and hfHD were performed using membranes of size 1.9-2.1 sqm. Ultrapure dialysate and substitution fluid were employed in both HDF and HD treatments. Data are expressed as mean ± SD. Paired t test, Mann-Whitney U test, and simple and multiple regression analyses were employed for statistical evaluation.. total convective volume (TCV) was 22.1 ± 1.9 l/session. A significant reduction of hsCRP: from 6.8 ± 7.1 to 2.3 ± 2.4 mg/dl (p < 0.001), β2M: from 36.5 ± 14.4 to 24.7 ± 8.6 mg/dl (p < 0.0001) and ESAdose: from 107 ± 67 to 65 ± 44 U/kg/week (p < 0.005) was observed. No significant variations of Hb, BW and sAlb were seen. A significant inverse correlation was found between TCV and Δβ2M (r = -0.627; p < 0.0001), and TCV and ΔhsCRP (r = -0.514; p < 0.0001); no correlation between TCV and ΔESAdose was observed. No correlation was found between eKt/V and Δβ2M, ΔhsCRP, and ΔESAdose. Multiple regression analysis with ΔESAdose as dependent variable showed ΔhsCRP as the only significantly associated independent factor (p < 0.01).. no significant variations of hsCRP, β2M, and ESAdose were observed over time.. Ol-HDF induces a long-term significant reduction in pre-dialysis β2M and hsCRP concentrations. The magnitude of reduction is directly correlated to the amount of TCV achieved but not on eKt/V. The observed reduction in ESAdose requirement is independent either on convection or diffusion, but is directly associated to the concomitant reduction of inflammation.

Topics: Aged; beta 2-Microglobulin; Body Weight; C-Reactive Protein; Convection; Diffusion; Erythropoietin; Female; Ferritins; Hematinics; Hemodiafiltration; Hemoglobins; Humans; Iron; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Serum Albumin; Time Factors; Transferrin

Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1β, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Caspase 3; Cytokines; Disease-Free Survival; Erythropoietin; Hematopoiesis; Hemorrhage; Inflammation; Kidney; Lethal Dose 50; Leukopenia; Male; Mice; MicroRNAs; NF-kappa B; Radiation Injuries; Thrombocytopenia; Water

Chronic kidney disease (CKD) patients have a poor prognosis due to cardiovascular disease. Anemia and endothelial dysfunction are important risk factors for cardiovascular events in CKD patients, and treatment with erythropoiesis-stimulating agent (ESA) has been reported to improve the quality of life in CKD patients. In this study, we evaluated the effect of anemia correcting dose of epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) on endothelial function in 5/6 nephrectomized rats (Nx rats). C.E.R.A. was subcutaneously administered once a fortnight, 5 times in total, from 1 week after nephrectomy. Twenty-four hours after last administration, endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anesthetized Nx rats by ultrasound system. Femoral arteries were harvested for western blot analysis. C.E.R.A. significantly increased FMD of Nx rats. Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. Nox4 expression and nitrotyrosine accumulation were significantly decreased, and phosphorylation of eNOS was significantly enhanced in the femoral arteries of C.E.R.A.-treated rats. C.E.R.A. normalized hemoglobin levels but did not affect body weight, systolic blood pressure, heart rate, urinary protein excretion and plasma creatinine. These results indicate that C.E.R.A. prevented endothelial dysfunction in Nx rats, possibly through reduction of local oxidative stress and enhancement of eNOS phosphorylation in the arteries. This study provides the first evidence that C.E.R.A. prevented endothelial dysfunction in CKD model rats under conditions of amelioration of anemia.

Topics: Animals; Blood Pressure; Body Weight; Creatinine; Disease Models, Animal; Endothelium, Vascular; Erythropoietin; Femoral Artery; Heart Rate; Hemoglobins; Kidney Function Tests; Male; NADPH Oxidase 4; NADPH Oxidases; Nephrectomy; Nitric Oxide Synthase Type III; Nitroglycerin; Polyethylene Glycols; Proteinuria; Rats; Renal Insufficiency, Chronic; Tyrosine; Ultrasonography; Vasodilation

Accumulating evidence has indicated that erythropoietin (EPO) plays a role in anti-apoptosis and tissue protection in a number of human diseases. The present study was implemented to evaluate these anti-apoptotic and tissue-protective effects in glucocorticoid-induced osteonecrosis in rats. Osteonecrosis was induced by low-dose lipopolysaccharide and subsequent high-dose methylprednisolone pulse. Rats in the preventive group were treated with 500 U/kg/day recombinant human EPO (rhuEPO) for 1 week. Hematological and histomorphometric methods were then used to determine the effects of the administration of rhuEPO. An analysis of trabecular bone architecture was performed to evaluate bone mass change in the osteonecrosis zone. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay was performed to determine the apoptotic index of osteoblasts and osteocytes. Immunoblot analysis was performed to assess the expression of caspase-3 and vascular endothelial growth factor (VEGF) in the femoral head. Treatment with rhuEPO greatly improved the histological performance. Additionally, the incidence of osteonecrosis markedly decreased in the rats in the rhuEPO-treated group (22.2%) compared with the control group (66.7%). Furthermore, the expression of caspase-3 markedly decreased in the rhuEPO-treated group. Consistently, the apoptosis of osteoblasts and osteocytes, as determined by TUNEL assays, was inhibited following the administration of rhuEPO. By contrast, the expression of VEGF increased in the osteonecrosis zone in the rats treated with rhuEPO. The results from the present study demonstrate that EPO exerts prominent protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats by inhibiting the apoptosis of osteoblasts and osteocytes and increasing the expression of VEGF.

Topics: Animals; Apoptosis; Body Weight; Caspase 3; Cholesterol; Erythrocyte Count; Erythropoietin; Femur Head; Femur Head Necrosis; Glucocorticoids; Hematocrit; Hemoglobins; Humans; Immunoblotting; In Situ Nick-End Labeling; Male; Organ Size; Protective Agents; Rats; Rats, Wistar; Time Factors; Triglycerides; Vascular Endothelial Growth Factor A

Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin-aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin-angiotensin-aldosterone system in ischemic retinopathy.. Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-α. Macroglial Müller cells maintain the integrity of the blood-retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor-sensitive epithelial sodium channel alpha (ENaCα), which is expressed in Müller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Müller cells, high salt increased ENaCα, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCα, angiotensin type 1 receptor, and mineralocorticoid receptor expression.. An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin-angiotensin-aldosterone system.

Topics: Adaptor Protein Complex 1; Aldosterone; Animals; Animals, Newborn; Aquaporin 4; Body Weight; Cells, Cultured; Diet, Sodium-Restricted; Disease Models, Animal; Drinking Behavior; Ependymoglial Cells; Epithelial Sodium Channels; Erythropoietin; Gliosis; Hematocrit; Ion Transport; Ischemia; Kidney Glomerulus; MAP Kinase Signaling System; Microglia; Phosphorylation; Potassium Channels, Inwardly Rectifying; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Retinal Ganglion Cells; Retinal Neovascularization; Retinopathy of Prematurity; Sodium; Sodium Chloride, Dietary; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Inhibiting VEGF improves adult retino/choroido-vascular diseases, but can lead to recurrent intravitreous neovascularization (IVNV), avascular retina (AVA), and retinal detachment in preterm infants with retinopathy of prematurity (ROP). We sought to understand causes of late-onset IVNV and AVA following anti-VEGF using an ROP model.. In the Penn model of ROP, postnatal day (p)12 pups received 1 μL intravitreal VEGFA164 antibody (anti-VEGF; 25-100 ng) or IgG control in each eye. Analyses included lectin-stained percent IVNV and AVA; VEGF protein, erythropoietin, phosphorylated extracellular signal-related kinases and signal transducer and activator of transcription-3 (p-STAT3); and immunohistochemistry of retinal sections for p-VEGFR2. Western blots of human retinal microvascular endothelial cells (hRMVECs) stimulated with VEGF or erythropoietin were analyzed for p-STAT3. Statistical analysis was performed with one-way ANOVA or two-tailed t-tests.. At p18, 50 ng anti-VEGF reduced IVNV, and at p25, caused increased IVNV and AVA compared with controls. VEGF and p-VEGFR2 labeling increased following 100 ng anti-VEGF. Following 50 ng anti-VEGF, reduced p-STAT3 and increased erythropoietin occurred at p18. Erythropoietin or VEGF stimulated hRMVEC proliferation and STAT3 activation. In vivo, anti-VEGF reduced pup growth.. Increases in erythropoietin and angiogenic signaling following anti-VEGF may account for recurrent IVNV. Anti-VEGF reduced pup growth. Research is needed regarding safety, dose, and type of antiangiogenic treatment for ROP.

Topics: Animals; Antibodies; Biomarkers; Blotting, Western; Body Weight; Case-Control Studies; Disease Models, Animal; Erythropoietin; Humans; Infant, Newborn; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Retina; Retinopathy of Prematurity; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

The protective role of recombinant human erythropoietin (RHE) against cisplatin-induced nephrotoxicity has been reported, but the role of sex differences is not clearly known. The aim of this study was to determine the sex-based difference in the protective effect of RHE against cisplatin-induced nephrotoxicity.. Thirty-three Wistar rats were divided into 6 groups. According to protocol l, male and female rats were treated with RHE (100 IU/kg/d) for 3 days and then received a single dose of cisplatin (7 mg/kg). According to protocol 2, the rats received the same single dose of cisplatin and then were treated with RHE for 7 days. Two other groups of male and female rats received a similar regimen of protocol 2 except for saline instead of RHE. All the animals were sacrificed 1 week after cisplatin administration.. All of the experimental animals experienced weight loss. The percentage change of weight in male rats with protocol 1 was significantly less than that in male rats in protocol 2 and control groups. However, in female groups, the percentage of change in weights was slightly higher with protocol 2 than with protocol 1 and control treatment. Administration of RHE significantly decreased changes in serum creatinine, BUN, and malondialdehyde levels in male rats, but not in females. No significant difference was observed in serum nitrite level, kidney weight, and kidney damage score between the groups.. This study suggested that erythropoietin may lead to different responses against cisplatin-induced nephrotoxicity in male and female rats.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Blood Urea Nitrogen; Body Weight; Cisplatin; Creatinine; Disease Models, Animal; Erythropoietin; Female; Kidney; Male; Malondialdehyde; Nitrites; Organ Size; Random Allocation; Rats; Rats, Wistar; Sex Characteristics; Sex Factors

When medications are modified in response to changing clinical conditions, confounding by indication arises that cannot be controlled using traditional adjustment. Inverse probability of treatment weights (IPTWs) can address this confounding given assumptions of no unmeasured confounders and that all patients have a positive probability of receiving all levels of treatment (positivity). We sought to explore these assumptions empirically in the context of epoetin-alfa (EPO) dosing and mortality.. We developed a single set of IPTWs for seven EPO dose categories and evaluated achieved covariate balance, mortality hazard ratios, and confidence intervals using two levels of treatment model parameterization and weight deletion.. We found that IPTWs improved covariate balance for most confounders, but was not optimal for prior hemoglobin. Including more predictors in the treatment model or retaining highly weighted individuals resulted in estimates closer to the null, although precision decreased.. We chose to evaluate weights and covariate balance at a single time-point to facilitate an empirical analysis of model assumptions. These same assumptions are applicable to a time-dependent analysis, although empirical examination is not straight forward in that case. We find that the inclusion of rare treatment decisions and the high weights that result is needed for covariate balance under the positivity assumption. Removal of these influential weights can result in bias in either direction relative to the original confounding. It is therefore important to determine the reason for these rare patterns and whether inference is possible for all treatment levels.

Topics: Adult; Aged; Body Weight; Decision Making; Erythropoietin; Female; Humans; Male; Middle Aged; Models, Biological; Probability; Renal Dialysis; Treatment Outcome

Erythropoietin (EPO) has multiple biological functions, including the modulation of glucose metabolism. However, the mechanisms underlying the action of EPO are still obscure. This study is aimed at investigating the potential mechanisms by which EPO improves glucose tolerance in an animal model of type 2 diabetes. Male C57BL/6 mice were fed with high-fat diet (HFD) for 12 weeks and then treated with EPO (HFD-EPO) or vehicle saline (HFD-Con) for two week. The levels of fasting blood glucose, serum insulin and glucose tolerance were measured and the relative levels of insulin-related phosphatidylinositol 3-kinase (PI3K)/Akt, insulin receptor (IR) and IR substrate 1 (IRS1) phosphorylation were determined. The levels of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6- phosphatase (G6Pase), toll like receptor 4 (TLR4), tumor necrosis factor (TNF)-α and IL-6 expression and nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK), extracellular-signal-regulated kinase (ERK) and p38 MAPK activation in the liver were examined. EPO treatment significantly reduced the body weights and the levels of fasting blood glucose and serum insulin and improved the HFD-induced glucose intolerance in mice. EPO treatment significantly enhanced the levels of Akt, but not IR and IRS1, phosphorylation, accompanied by inhibiting the PEPCK and G6Pase expression in the liver. Furthermore, EPO treatment mitigated the HFD-induced inflammatory TNF-α and IL-6 production, TLR4 expression, NF-κB and JNK, but not ERK and p38 MAPK, phosphorylation in the liver. Therefore, our data indicated that EPO treatment improved glucose intolerance by inhibiting gluconeogenesis and inflammation in the livers of HFD-fed mice.

Topics: Animals; Blood Glucose; Body Weight; Diet, High-Fat; Erythropoietin; Fasting; Feeding Behavior; Gene Expression Regulation; Gluconeogenesis; Glucose Intolerance; Glucose Tolerance Test; Glucose-6-Phosphatase; Humans; Inflammation; Insulin; Insulin Receptor Substrate Proteins; Liver; Mice; Mice, Inbred C57BL; Obesity; Phosphoenolpyruvate Carboxykinase (ATP); Proto-Oncogene Proteins c-akt; Receptor, Insulin; Receptors, Erythropoietin; RNA, Messenger; Signal Transduction

Rapid growth during adolescence caused by metabolic changes and their metabolic response to anaerobic and aerobic exercise differs considerably from that in adults and this is especially true in the responses to stresses, such as altitude exposure. However, there is little information on the suitability of exercise training at altitude for young athletes.. Six male Korean adolescent alpine skiers (13-17 yr), with a skiing career of 3-5 yr, participated in the study. All subjects were exposed to an altitude of 2700 m (8858 ft) for 5 wk and altitude exposure consisted of 6 d/wk of training (4-5 h/d), with living quarters at 2100 m (-6890 ft) (Tignes, France). The 5 wk of ski training at altitude were maintained at the same level (the same number of slalom and giant slalom skiing trials) as at sea level.. There was a significant increase in oxygen transport capacity, despite decreased erythropoietin (EPO) production (-31%) after altitude training. Red blood cell (RBC), hemoglobin (Hb), hematocrit (Hct), and 2,3 DPG concentrations increased significantly during altitude exposure and after return to sea level.. Results indicate that applying altitude training in adolescent skiers may improve their endurance performance. However, EPO production during altitude training needs to be evaluated in larger future studies.

Topics: 2,3-Diphosphoglycerate; Acclimatization; Adolescent; Altitude; Body Composition; Body Mass Index; Body Weight; Erythropoietin; Humans; Male; Oxygen; Skiing

Erythropoietin (EPO), used clinically for renal anemia, reportedly exerts beneficial pleiotropic effects in various tissues. Recent studies suggest that nitric oxide (NO) plays an important role in EPO-induced tissue protection. The present study investigated whether recombinant human EPO (rHuEPO) exhibits vasoprotective effects even in the NO synthase-inhibited state. Rats that received a NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), in drinking water (0.7 mg/ml) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. The administration of rHuEPO to L-NAME-treated rats had no effect on hematocrit values or increased blood pressure. Vasodilation in response to acetylcholine in the aortic ring was impaired in the L-NAME-treated rats, and improved by rHuEPO. Immunohistochemical staining revealed that infiltration by macrophages and expression of osteopontin were enhanced in the L-NAME-treated rat aorta, and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Activation of Akt signaling was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt. rHuEPO enhanced the expression of antioxidant enzymes such as Cu/Zn-superoxide dismutase and heme oxygenase-1 in the aorta. In addition, rHuEPO reduced NADPH oxidase-dependent superoxide production and enhanced the expression of suppressor of cytokine signaling-1(SOCS-1) in the L-NAME-treated rat aorta. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function and vascular inflammation beyond hematopoiesis even in a pharmacologically NO synthase-inhibited state. These effects might be due to the antioxidant properties of rHuEPO. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation.

Topics: Acetylcholine; Adventitia; Animals; Aorta; Blood Pressure; Body Weight; Erythropoietin; Gene Expression Regulation; Hematocrit; Heme Oxygenase-1; Humans; Hypertension; Inflammation; Macrophages; Male; NADPH Oxidases; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroprusside; Osteopontin; Phosphoproteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins

Normal brain function is dependent on continuous and controlled oxygen delivery. Chronic moderate hypoxia leads to angiogenesis, suggesting a modulatory role for oxygen in determining capillary density. The objective of this study was to determine physiologic and brain angiogenic adaptational changes during chronic moderate normobaric hyperoxia in mice. Four-month old C56BL/6J mice were kept in a normobaric chamber at 50% O(2) for up to 3 weeks. Normoxic littermates were kept in the same room outside the chamber. Freshly collected or fixed brain specimens were analyzed by RT-PCR, Western blot analysis and immunohistochemistry. Results show accumulation of hypoxia inducible factors 1 and 2α (HIF-1 and 2α), and increased expression of erythropoietin (EPO), cyclooxygenase-2 (COX-2) and angiopoietin-2 (Ang-2). Conversely, vascular endothelial growth factor (VEGF), and VEGF receptor-2 (KDR/Flk-1), Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and prolylhydroxylase-2 (PHD-2) expressions were decreased. VEGF mRNA level was diminished but there was no change in HIF-1α mRNA and von Hippel Lindau E3 ubiquitin ligase (VHL) protein expression. Microvascular density was significantly diminished by the end of the 3rd week of hyperoxia. Overall, our results are: (1) increased expression of the potent neuroprotective molecule, EPO; (2) diminished expression of the potent angiogenic factor, VEGF; and (3) decreased microvascular density. We can, therefore, conclude that brain microvascular density can be controlled by HIF-independent mechanisms, and that brain capillary density is a continuously adjusted variable with tissue oxygen availability as one of the controlling modulators.

Topics: Angiopoietin-2; Animals; Basic Helix-Loop-Helix Transcription Factors; Body Weight; Cerebral Cortex; Cyclooxygenase 2; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Hematocrit; Hyperoxia; Hypoxia-Inducible Factor 1; Male; Mice; Mice, Inbred C57BL; Microvessels; Oxygen; RNA, Messenger; Time Factors; Vascular Endothelial Growth Factor A

Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 months) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: (1) saline group (n=7); (2) EPO-6h group (n=8); and (3) EPO-24h group (n=8). EPO (5000 U/kg in saline) was administered intraperitoneally at 6h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) postinjury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 months after injury and brain sections were stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO.

Topics: Analysis of Variance; Animals; Body Weight; Brain Injuries; Bromodeoxyuridine; Cell Count; Cell Proliferation; Disease Models, Animal; Erythropoietin; Gait Disorders, Neurologic; Male; Maze Learning; Neovascularization, Pathologic; Phosphopyruvate Hydratase; Rats; Rats, Wistar; Recovery of Function; Severity of Illness Index; von Willebrand Factor

Recombinant human erythropoietin (rHuEPO), used clinically for renal anemia, reportedly exhibits pleiotropic properties in various tissues. To test whether it ameliorates vascular injury, rHuEPO (75U/kg) was administered subcutaneously every 3days for 10days to 5/6 nephrectomized hypertensive rats (5/6Nx) treated with 1% NaCl. rHuEPO had no effect on increased systolic blood pressure or decreased hematocrit values, but normalized levels of proteinuria and creatinine clearance. Vasodilation in response to acetylcholine in the aortic ring was impaired in the 5/6Nx, and improved by treatment with rHuEPO. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin were enhanced in the 5/6Nx aorta and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Akt signaling was activated by the increased expression of phosphorylated Akt and GSK-3β in aorta from rHuEPO-treated 5/6Nx. rHuEPO restored plasma NOx (NO(2)(-)+NO(3)(-)) levels and endothelial nitric oxide synthase (eNOS) content in the 5/6Nx aorta. Treatment with an eNOS substrate, l-arginine, which caused a similar increase in plasma NOx levels as the rHuEPO treatment, resulted in a normalization of endothelial dysfunction and vascular inflammation. These results suggest that a low dose of rHuEPO exerted vasoprotective effects in rats with hypertensive renal failure.

Topics: Acetylcholine; Animals; Aorta; Aorta, Thoracic; Blood Pressure; Body Weight; Connective Tissue; Dose-Response Relationship, Drug; Endothelium, Vascular; Erythropoietin; Gene Expression Regulation, Enzymologic; Hematocrit; Hematopoiesis; Humans; Hypertension; Macrophages; Male; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase Type III; Nitrogen Dioxide; Nitrogen Oxides; Nitroprusside; Osteopontin; Phosphoproteins; Rats; Rats, Wistar; Recombinant Proteins

A feedback receptor regulation model was incorporated into a pharmacodynamic model to describe the stimulation of hemoglobin (Hb) production by endogenous erythropoietin (EPO). The model considers the dynamic changes that take place in the EPO receptor (EPOR) pool under phlebotomy-induced anemia. Using a (125)I-rhEPO tracer the EPO clearance changes are evaluated longitudinally prior to and following phlebotomy-induced anemia indirectly to evaluate changes in the EPOR pool size, which has been shown to be linearly related to the clearance. The proposed model simultaneously captures the general behavior of temporal changes in Hb relative to EPO plasma clearance in five lambs (r = 0.95), while accounting for the confounding variables of phlebotomy and changes in the blood volume in the growing animals. The results indicate that under anemia the EPOR pool size is up-regulated by a factor of nearly two over baseline and that the lowest and highest EPOR pool sizes differ by a factor of approximately four. The kinetic model developed and the data-driven mechanism proposed serves as a starting point for developing an optimal EPO dosing algorithm for the treatment of neonatal anemia.

Topics: Animals; Body Weight; Erythropoiesis; Erythropoietin; Hemoglobins; Models, Biological; Phlebotomy; Receptors, Erythropoietin; Recombinant Proteins; Sheep

Pediatric scoliosis surgery is associated with considerable blood loss and allogenic transfusions. Transfusions contribute to morbidities and cost. A perioperative pediatric blood management program was implemented at our institution. Patients received preoperative evaluation, cell salvage, topical hemostasis, antifibrinolytics, and hypotensive anesthesia.. The study was a 2-year retrospective cohort review of the program's population from September 2007 through August 2009.. A total of 110 scoliosis surgeries were performed with only 34 and 12% of the patients requiring preoperative oral iron and erythropoietin, respectively. Neuromuscular scoliosis patients had more repaired segments and a larger transfusion rate than idiopathic scoliosis patients (36% vs. 1.7%, p = 0.001). Transfused patients had more blood loss relative to their blood volume (p = 0.001) and blood loss was associated with higher Cobb angles (p = 0.04). Logistic regression revealed that blood loss (p = 0.001), number of segments fused (p = 0.004), and lower patient weight (p = 0.007) are associated with increased odds for transfusion. Twelve patients (10.9%) were identified with low von Willebrand activity with a trend toward higher blood losses (p = 0.07) with lower activity levels.. Transfusion requirements in scoliosis patients are dependent on blood loss as determined by Cobb angles and number of segments fused relative to the patients' blood volume as determined by weight. Implementation of a blood management protocol resulted in a low transfusion rate and unexpectedly led to the preoperative diagnosis of a number of patients with low levels of von Willebrand activity.

Topics: Adolescent; Blood Coagulation Disorders; Blood Loss, Surgical; Blood Transfusion; Blood Volume; Body Weight; Cohort Studies; Dietary Supplements; Erythropoietin; Female; Folic Acid; Hemostasis, Surgical; Humans; Iron; Logistic Models; Male; Outcome Assessment, Health Care; Retrospective Studies; Scoliosis; Spinal Fusion; Thrombophilia

Clinical gene transfer holds promise for the treatment of many inherited and acquired disorders. A key consideration for all clinical gene transfer applications is the tight control of transgene expression. We have examined the safety and biodistribution of a serotype 2, recombinant adeno-associated viral (AAV2) vector that encodes a rapamycin-responsive chimeric transcription factor, which regulates the expression of a therapeutic transgene (human erythropoietin [hEpo]). The vector, AAV2-TF2.3w-hEpo (2.5 × 10(7)-2.5 × 10(10) particles), was administered once to a single submandibular gland of male and female mice and mediated hEpo expression in vivo following a rapamycin injection but not in its absence. Control (saline treated) and vector-treated animals maintained their weight, and consumed food and water, similarly. Vector delivery led to no significant toxicological effects as judged by hematology, clinical chemistry, and gross and microscopic pathology evaluations. On day 3 after vector delivery, vector copies were not only abundant in the targeted right submandibular gland but also detected in multiple other tissues. Vector was cleared from the targeted gland much more rapidly in female mice than in male mice. Overall, our results are consistent with the notion that administration of the AAV2-TF2.3w-hEpo vector to salivary glands posed no significant risk in mice.

Topics: Animals; Body Weight; Dependovirus; Erythropoietin; Female; Gene Transfer Techniques; Genetic Vectors; Male; Mice; Mice, Inbred BALB C; Risk Assessment; Sex Factors; Sirolimus; Submandibular Gland; Toxicity Tests

Painful stimuli during neonatal stage may affect brain development and contribute to abnormal behaviors in adulthood. Very few specific therapies are available for this developmental disorder. A better understanding of the mechanisms and consequences of painful stimuli during the neonatal period is essential for the development of effective therapies. In this study, we examined brain reactions in a neonatal rat model of peripheral inflammatory pain. We focused on the inflammatory insult-induced brain responses and delayed changes in behavior and pain sensation. Postnatal day 3 pups received formalin injections into the paws once a day for 3 days. The insult induced dysregulation of several inflammatory factors in the brain and caused selective neuronal cell death in the cortex, hippocampus and hypothalamus. On postnatal day 21, rats that received the inflammatory nociceptive insult exhibited increased local cerebral blood flow in the somatosensory cortex, hyperalgesia, and decreased exploratory behaviors. Based on these observations, we tested recombinant human erythropoietin (rhEPO) as a potential treatment to prevent the inflammatory pain-induced changes. rhEPO treatment (5,000 U/kg/day, i.p.), coupled to formalin injections, ameliorated neuronal cell death and normalized the inflammatory response. Rats that received formalin plus rhEPO exhibited normal levels of cerebral blood flow, pain sensitivity and exploratory behavior. Treatment with rhEPO also restored normal brain and body weights that were reduced in the formalin group. These data suggest that severe inflammatory pain has adverse effects on brain development and rhEPO may be a possible therapy for the prevention and treatment of this developmental disorder.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Brain; Cell Death; Cerebrovascular Circulation; Cytokines; Disease Models, Animal; Erythropoietin; Exploratory Behavior; Formaldehyde; Humans; Hyperalgesia; Inflammation; Inflammation Mediators; Neurons; Neuroprotective Agents; Organ Size; Pain; Rats

Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquitous tamoxifen-inducible recombinase Cre-ER(T2). Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed)-UBC-Cre-ER(T2) adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

Topics: Animals; Animals, Newborn; Body Weight; Cells, Cultured; Diet; Erythropoietin; Gene Expression Regulation; Gene Silencing; Glucose Transporter Type 1; Hypoxia-Inducible Factor 1, alpha Subunit; Integrases; Mice; Myocardium; Myocytes, Cardiac; Organ Specificity; Tamoxifen; Von Hippel-Lindau Tumor Suppressor Protein

The Akita mouse is a robust model of diabetic autonomic neuropathy which develops severe diabetes following beta cell death, which occurs reproducibly at 3-4 weeks of age, and maintains the diabetic state without therapy for as long as 11 additional months. Neuritic dystrophy and neuronopathy involving prevertebral sympathetic superior mesenteric and celiac ganglia begin to develop within the first two months of onset of diabetes and are progressive with time. We have examined the effect of insulin implants resulting in normoglycemia and injections of ARA290, a small erythropoietin peptide which has no effect on glycemic parameters, on the reversal of established neuritic dystrophy and neuronopathy. We have found that 4 weeks of insulin therapy beginning at 2 months of diabetes resulted in normalization of blood glucose, body weight and HbA1c. Insulin therapy successfully reversed established neuritic dystrophy and neuronopathy to control levels. Numbers of sympathetic neurons were not significantly changed in either 3 month diabetic or insulin-treated Akita mice. Treatment with ARA290 for 7 weeks beginning at 4 months of diabetes did not result in altered metabolic severity of diabetes as measured by blood glucose, body weight or HbA1c levels. ARA290 treatment was able to decrease neuritic dystrophy by 55-74% compared to untreated diabetics or in comparison to a separate group of diabetic animals representing the 4 month treatment onset point. Surprisingly, there was no effect of ARA290 on ganglionic neuron number or ongoing neuronopathy (pale/degenerating neurons) in diabetic Akita mice during this time period. The development of neuroprotective EPO-like peptides may provide a possible future therapy for this debilitating complication of diabetes; however, it appears that discrete elements may be differentially targeted by the diabetic state and may require selective therapy.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Disease Models, Animal; Erythropoietin; Ganglia, Sympathetic; Hypoglycemic Agents; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Nerve Degeneration; Neurites; Peptides

The use of Cyclosporine A (CsA) as rejection prophylaxis following organ transplantation is limited by its nephrotoxicity. CsA induces renal damage that is associated with tubulo-interstitial injury and parenchymal sequestration of macrophages, perpetuating pro-inflammatory processes. Furthermore, CsA exerts a diabetogenic effect by damaging pancreatic islet cell integrity. Continuous Erythropoietin Receptor Activator (CERA) was shown to mediate tissue-protective and anti-inflammatory effects in various settings of organ injury. Here, we investigated the effect of low dose CERA in a model of CsA-induced renal and pancreatic injury. Rats were exposed to medium-dose CsA for 28 days. Low-dose CERA was given to the treatment group (CERA) (n=6) once per week vs. a CsA-treated control group (CONTROL) (n=6). The effect of CERA on renal and pancreatic injuries was analyzed by organ function, histology, immunohistochemistry (CD68(+)-macrophages, insulin), ELISA (TGF-β1) and RT-PCR (TGF-β1, Osteopontin, IL-10). CsA induced functional kidney damage. Low dose CERA did not lead to improved kidney function in the treatment group. However, low dose CERA showed a trend toward upregulation of osteopontin accompanied by increased renal macrophage-infiltration and enhanced parenchymal TGF-β1 and IL-10 when compared to controls. Moreover, CERA treated animals showed amelioration of pancreatic islet cell injury. In this model of acute CsA-mediated renal injury, low dose CERA administration was associated with anti-inflammatory effects and preservation of pancreatic islet cell viability.

Topics: Acute Kidney Injury; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Body Weight; Cell Survival; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Erythropoietin; Gene Expression Regulation; Glucose; Hematologic Tests; Interleukin-10; Islets of Langerhans; Kidney; Macrophages; Male; Osteopontin; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

Narrowing of the arteries due to atherosclerosis may lead to congestive heart failure (CHF). It is advantageous to perform atherosclerosis studies in apolipoprotein E-deficient (Apo E(-/-)) mice models, which develop atherosclerosis very rapidly in comparison to humans. Darbepoetin is a synthetic erythropoietin analogue and stimulates erythropoiesis. The aim of this study was to explore the effect of 16 weeks of darbepoetin treatment on serum protein profiles in Apo E(-/-) mice during atherosclerosis progression. Serum proteomic analyses were performed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) in the darbepoetin-treated and non-treated (control) Apo E(-/-) mice groups. The protein profiles obtained using three different chips, CM-10 (weak cation exchange), H50 (reversed-phase) and IMAC-30 (immobilized metal affinity capture), were statistically analyzed using the ProteinChip data manager 3.0 program. At the end of 16 weeks of darbepoetin treatment, there was no significant difference in the size and degree of atherosclerotic lesions between the darbepoetin and control mice groups. In contrast, 145 protein/peptide-clustering peaks, >5 kDa, had statistically significant differences in their peak intensities between the darbepoetin and control mice groups (p<0.05). That the proteomic profiles of darbepoetin-treated Apo E(-/-) mice were found to differ from those of the control group indicates a potential beneficial role of darbepoetin in atherosclerosis. Our study contributes to understanding the effects of darbepoetin on protein/peptide expressions during atherosclerosis development.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Blood Proteins; Body Weight; Darbepoetin alfa; Down-Regulation; Erythropoietin; Gene Expression; Hematinics; Male; Mice; Mice, Knockout; Molecular Weight; Plaque, Atherosclerotic; Protein Array Analysis; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Up-Regulation

The organism is exposed to a considerable hypoxic stress at high altitude, and the well-known polyglobulia is an effective strategy to sustain oxygen delivery to the tissue at reduced saturation of hemoglobin. In general, an increasing erythropoiesis is thought to be the reason, although this increase of red blood count can be observed after a short time of altitude exposure and the parameters are expressed as water-depending concentrations. Therefore, the influence of water distribution on hemoglobin (Hb) and hematocrit (Hct) values during a long-term exposure at high altitude was investigated.. Measurements were performed in 12 mountaineers before, during, and either 7/8 or 11/12 days after a Himalaya expedition (26-29 days at 4,850 to 7,600 m altitude). Arriving at 4,850 m an initial increase of Hb and Hct was followed by a short decrease during the first week and a continuous increase during the further stay.. In maximum, 131.3% (Hb) and 117.4% (Hct) of the starting point were reached during the fourth week at altitude after the attempt to reach the summit of Broad Peak (8,047 m). Parallel the dehydration in the beginning turned to a hyperhydration at the end of the stay (D(2)O method).. Erythropoietin rose only temporarily at altitude (max. +11 +1 mU/ml serum). Upon return, Hb and Hct normalized within a few days whereas hemoglobin mass (initially 881+ 44 g, CO-Hb method) was still increased by 13% (p < 0.01).. In conclusion, a hemoconcentration effect (dehydration) is the reason of the initial peak of Hb and Hct. The further increase can only partially be explained by an absolute increase of Hb and Hct caused by stimulated erythropoiesis. A shift of intravasal fluid to the interstitial space is the other main reason of the observed changes in red blood count.

Topics: Acclimatization; Adult; Altitude Sickness; Body Composition; Body Water; Body Weight; Cold Climate; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Male; Mountaineering; Oxygen; Reference Values; Water-Electrolyte Balance

Erythropoietin (EPO) regulates proliferation and differentiation of erythroid precursor cells into erythrocytes. The last decade has revealed non-renal sites of EPO production and extrahematopoietic expression of the EPO receptor, thus suggesting that EPO has pleiotropic functions. Here, we addressed the interplay between EPO/glucose metabolism/body weight by employing a panel of relevant experimental murine models. The models focused on situations of increased EPO levels, including EPO-injected C57BL/6 and BALB/c mice, as well as transgenic mice (tg6) constitutively overexpressing human EPO, thus exposed to constantly high EPO serum levels. As experimental models for diabetes and obesity, we employed protein Tyr phosphatase 1B (PTP1B) knockout mice associated with resistance to diabetes (PTP1B(-/-)), and ob/ob mice susceptible to diabetes and obesity. The data presented herein demonstrate EPO-mediated decrease in blood glucose levels in all mice models tested. Moreover, in the ob/ob mice, we observed EPO-mediated attenuation of body weight gain and reduction of hemoglobin A1c. Taken together, our data bear significant clinical implications of EPO treatment in the management of a wide range of metabolic diseases, thus adding an important novel therapeutic potential to this pleiotropic hormone.

Topics: Animals; Blood Glucose; Body Mass Index; Body Weight; Erythropoietin; Female; Glycated Hemoglobin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Models, Animal; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Voluntary activity is a complex trait, comprising both behavioral (motivation, reward) and anatomical/physiological (ability) elements. In the present study, oxygen transport was investigated as a possible limitation to further increases in running by four replicate lines of mice that have been selectively bred for high voluntary wheel running and have reached an apparent selection limit. To increase oxygen transport capacity, erythrocyte density was elevated by the administration of an erythropoietin (EPO) analogue. Mice were given two EPO injections, two days apart, at one of two dose levels (100 or 300 microg kg(-1)). Hemoglobin concentration ([Hb]), maximal aerobic capacity during forced treadmill exercise (VO2,max) and voluntary wheel running were measured. [Hb] did not differ between high runner (HR) and non-selected control (C) lines without EPO treatment. Both doses of EPO significantly (P<0.0001) increased [Hb] as compared with sham-injected animals, with no difference in [Hb] between the 100 microg kg(-1) and 300 microg kg(-1) dose levels (overall mean of 4.5 g dl(-1) increase). EPO treatment significantly increased VO2,max by approximately 5% in both the HR and C lines, with no dosexline type interaction. However, wheel running (revolutions per day) did not increase with EPO treatment in either the HR or C lines, and in fact significantly decreased at the higher dose in both line types. These results suggest that neither [Hb] per se nor VO2,max is limiting voluntary wheel running in the HR lines. Moreover, we hypothesize that the decrease in wheel running at the higher dose of EPO may reflect direct action on the reward pathway of the brain.

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Least-Squares Analysis; Mice; Muscles; Organ Size; Oxygen; Oxygen Consumption; Physical Conditioning, Animal; Recombinant Proteins

The liver presents a remarkable capacity for regeneration after hepatectomy but the exact mechanisms and mediators involved are not yet fully clarified. Erythropoietin (EPO) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) have been shown to promote liver regeneration after major hepatectomy.Aim of this experimental study is to compare the impact of exogenous administration of EPO, GM-CSF, as well as their combination on the promotion of liver regeneration after major hepatectomy.. Wistar rats were submitted to 70% major hepatectomy. The animals were assigned to 4 experimental groups: a control group (n = 21) that received normal saline, an EPO group (n = 21), that received EPO 500 IU/kg, a GM-CSF group (n = 21) that received 20 mcg/kg of GM-CSF and a EPO+GMCSF group (n = 21) which received a combination of the above. Seven animals of each group were killed on the 1st, 3rd and 7th postoperative day and their remnant liver was removed to evaluate liver regeneration by immunochemistry for PCNA and Ki 67.. Our data suggest that EPO and GM-CSF increases liver regeneration following major hepatectomy when administered perioperatively. EPO has a more significant effect than GM-CSF (p < 0.01). When administering both, the effect of EPO seems to fade as EPO and GM-CSF treated rats have decreased regeneration compared to EPO administration alone (p < 0.01).. EPO, GM-CSF and their combination enhance liver regeneration after hepatectomy in rats when administered perioperatively. However their combination has a weaker effect on liver regeneration compared to EPO alone. Further investigation is needed to assess the exact mechanisms that mediate this finding.

Topics: Animals; Body Weight; Drug Combinations; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatectomy; Ki-67 Antigen; Liver; Liver Regeneration; Male; Postoperative Period; Preoperative Period; Proliferating Cell Nuclear Antigen; Rats; Rats, Wistar

The aim of this study was to determine the effects of intermittent hypoxia training (IHT), with and without fatty-diet, on bodyweight, serum glucose, leptin, insulin, and their receptors, and to test whether erythropoietin (EPO) mediates these effects.. Kunming mice were divided into four groups. 1: untreated control; 2: IHT; 3: fatty-diet; 4: fatty-diet and IHT. After 40 days exposure to IHT, the bodyweight, serum glucose, serum leptin, insulin and EPO were measured by ELISA. Liver leptin and insulin receptors were quantified. A separate set of mice were treated with several doses of EPO (0-320 U/kg i.p.) for 5 days. In addition, human hepatic cell lines were treated with EPO for 24h and the expression of genes OB-Ra, OB-Rb and IR were measured using RT-PCR.. IHT reduced bodyweight and serum glucose, with corresponding increases in the serum levels of leptin, insulin, EPO and expression of leptin and insulin receptors in liver. Repeated EPO treatment increased serum leptin concentration, but had no effects on insulin levels. The expression of the genes OB-Ra, OB-Rb and IR were increased after EPO treatment.. We postulate that, in mice, IHT reduces bodyweight and serum glucose by increasing EPO synthesis which secondarily increases leptin and insulin production in liver.

Topics: Animals; Blood Glucose; Body Weight; Cell Line; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Hypoxia; Leptin; Liver; Mice; Receptor, Insulin; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction

In the early weeks of life, very low birth weight (VLBW) infants experience intense laboratory blood sampling leading to clinically significant anemia and the need for red blood cell transfusion. Although controversial, treatment with recombinant human erythropoietin (EPO) and iron has been recommended to stimulate erythropoiesis; optimal dosing of EPO and iron is still uncertain.. To assess the validity of a four-quadrant diagnostic plot of iron availability (ferritin index) versus iron demand for erythropoiesis (reticulocyte hemoglobin content, CHr) for differentiating iron status in anemic VLBW infants.. Study subjects were enrolled in a previously reported randomized controlled trial of clinically stable VLBW infants <31 weeks' gestation and <1,300 g at birth to receive 18 days of treatment with: group 1: oral iron; group 2: EPO + oral iron, and group 3: EPO + intravenous + oral iron.. At the end of treatment the ferritin index was significantly higher in both EPO groups compared to the control group. By day 18, CHr of the control group declined into the quadrant of the diagnostic plot characteristic of functional iron deficiency and anemia of chronic disease. Both EPO groups ended in the quadrants that are characteristic for latent iron deficiency and iron deficiency anemia, respectively.. The diagnostic plot for differentiating anemia in VLBW infants may be an informative, clinically useful tool for iron status assessment under different physiologic and therapeutic erythropoietic states. Larger additional studies in difficult patient populations are needed before the clinical utility of this diagnostic procedure can be unequivocally confirmed.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Body Weight; Drug Therapy, Combination; Erythropoietin; Ferric Compounds; Ferritins; Hemoglobins; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Injections, Intravenous; Iron; Nomograms; Randomized Controlled Trials as Topic; Recombinant Proteins; Reticulocytes

Anemia and hypoxia in rats result in an increase in factors potentially involved in cerebral angiogenesis. Therefore, the aim of this study was to assess the effect of chronic anemia and/or chronic hypoxia on cerebral cellular responses and angiogenesis in wild-type and anemic transgenic mice. These studies were done in erythropoietin-deficient mice (Epo-TAg(h)) in normoxia and following acute (one day) and chronic (14 days, barometric pressure = 420 mmHg) hypoxia. In normoxia, Epo-TAg(h) mice showed an increase in transcript and protein levels of hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), erythropoietin receptors (EpoR), phospho-STAT-5/STAT-5 ratio, and neuronal neuronal nitric oxide synthase (nNOS) along with a higher cerebral capillary density. In wild-type (WT) mice, acute hypoxia increased all of the studied factors, while in chronic hypoxia, HIF-1alpha, EpoR, phospho-STAT-5/STAT-5 ratio, nNOS, and inducible NOS remained elevated, with an increase in capillary density. Surprisingly, in Epo-TAg(h) mice, chronic hypoxia did not further increase any factor except the nitric oxide metabolites, while HIF-1alpha, EpoR, and phospho-STAT-5/STAT-5 ratio were reduced. Normoxic Epo-TAg(h) mice developed cerebral angiogenesis through the HIF-1alpha/VEGF pathway. In acute hypoxia, WT mice up-regulated all of the studied factors, including cerebral NO. Polycythemia and angiogenesis occurred with acclimatization to chronic hypoxia only in WT mice. In Epo-TAg(h), the decrease in HIF-1alpha, VEGF proteins, and phospho-STAT-5 ratio in chronic hypoxia suggest that neuroprotective and angiogenesis pathways are altered.

Topics: Anemia; Animals; Body Weight; Brain; Cerebral Cortex; Chronic Disease; Erythropoietin; Hemoglobins; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunoassay; Immunohistochemistry; Male; Mice; Mice, Inbred CBA; Mice, Knockout; Nitric Oxide; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA; STAT5 Transcription Factor; Vascular Endothelial Growth Factor A

Anemia is common in patients with chronic heart failure and an independent predictor of poor prognosis. Chronic anemia leads to left ventricular (LV) hypertrophy and heart failure, but its molecular mechanisms remain largely unknown. We investigated the mechanisms, including the molecular signaling pathway, of cardiac remodeling induced by iron deficiency anemia (IDA). Weanling Sprague-Dawley rats were fed an iron-deficient diet for 20 wk to induce IDA, and the molecular mechanisms of cardiac remodeling were evaluated. The iron-deficient diet initially induced severe anemia, which resulted in LV hypertrophy and dilation with preserved systolic function associated with increased serum erythropoietin (Epo) concentration. Cardiac STAT3 phosphorylation and VEGF gene expression increased by 12 wk of IDA, causing angiogenesis in the heart. Thereafter, sustained IDA induced upregulation of cardiac hypoxia inducible factor-1alpha gene expression and maintained upregulation of cardiac VEGF gene expression and cardiac angiogenesis; however, sustained IDA promoted cardiac fibrosis and lung congestion, with decreased serum Epo concentration and cardiac STAT3 phosphorylation after 20 wk of IDA compared with 12 wk. Upregulation of serum Epo concentration and cardiac STAT3 phosphorylation is associated with a beneficial adaptive mechanism of anemia-induced cardiac hypertrophy, and later decreased levels of these molecules may be critical for the transition from adaptive cardiac hypertrophy to cardiac dysfunction in long-term anemia. Understanding the mechanism of cardiac maladaptation to anemia may lead to a new strategy for treatment of chronic heart failure with anemia.

Topics: Adaptation, Physiological; Anemia, Iron-Deficiency; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Erythropoietin; Heart; Heart Failure; Heart Rate; Hypertrophy, Left Ventricular; Hypoxia-Inducible Factor 1, alpha Subunit; Iron; Kidney; Male; Myocardial Contraction; Myocardium; Neovascularization, Physiologic; Phosphorylation; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Receptors, Erythropoietin; STAT3 Transcription Factor; Time Factors; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Ventricular Function, Left; Ventricular Pressure; Ventricular Remodeling

Dialysis patients have a greater number of hospitalization events compared to patients without renal failure. Here we studied the relationship between different post-discharge interventions and repeat hospitalization in over 126,000 prevalent hemodialysis patients to explore outpatient strategies that minimize the risk of repeat hospitalization. The primary outcome was repeat hospitalization within 30 days of discharge. Compared to pre-hospitalization values, the levels of hemoglobin, albumin, phosphorus, calcium, and parathyroid hormone and weight were significantly decreased after hospitalization. Using covariate-adjusted models, those patients whose hemoglobin was monitored within the first 7 days after discharge, followed by modification of their erythropoietin dose had a significantly reduced risk for repeat-hospitalization when compared to the patients whose hemoglobin was not checked, nor was the dose of erythropoietin changed. Similarly, administration of vitamin D within the 7 days following discharge was significantly associated with reduced repeat hospitalization when compared to patients on no vitamin D. Therefore, it appears that immediate re-evaluation of anemia management orders and resumption of vitamin D soon after discharge may be an effective way to reduce repeat hospitalization.

Topics: Aged; Anemia; Body Weight; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Readmission; Renal Dialysis; Retrospective Studies; Vitamin D

Alteration in endoplasmic reticulum (ER) stress in diabetic hearts and its effect on cytoprotective signaling are unclear. Here, we examine the hypothesis that ER stress in diabetic hearts impairs phospho-glycogen synthase kinase (GSK)-3beta-mediated suppression of mitochondrial permeability transition pore (mPTP) opening, compromising myocardial response to cytoprotective signaling.. A rat model of type 2 diabetes (OLETF) and its control (LETO) were treated with tauroursodeoxycholic acid (TUDCA) (100 mg . kg(-1) . day(-1) for 7 days), an ER stress modulator. Infarction was induced by 20-min coronary occlusion and 2-h reperfusion.. Levels of ER chaperones (GRP78 and GRP94) in the myocardium and level of nonphoshopho-GSK-3beta in the mitochondria were significantly higher in OLETF than in LETO rats. TUDCA normalized levels of GRP78 and GRP94 and mitochondrial GSK-3beta in OLETF rats. Administration of erythropoietin (EPO) induced phosphorylation of Akt and GSK-3beta and reduced infarct size (% risk area) from 47.4 +/- 5.2% to 23.9 +/- 3.5% in LETO hearts. However, neither phosphorylation of Akt and GSK-3beta nor infarct size limitation was induced by EPO in OLETF rats. The threshold for mPTP opening was significantly lower in mitochondria from EPO-treated OLETF rats than in those from EPO-treated LETO rats. TUDCA restored responses of GSK-3beta, mPTP opening threshold, and infarct size to EPO receptor activation in OLETF rats. There was a significant correlation between mPTP opening threshold and phospho-GSK-3beta-to-total GSK-3beta ratio in the mitochondrial fraction.. Disruption of protective signals leading to GSK-3beta phosphorylation and increase in mitochondrial GSK-3beta are dual mechanisms by which increased ER stress inhibits EPO-induced suppression of mPTP opening and cardioprotection in diabetic hearts.

Topics: Animals; Blood Glucose; Body Weight; Calcium; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Immunoblotting; Intracellular Membranes; Male; Membrane Potential, Mitochondrial; Mitochondria, Heart; Myocardial Infarction; Myocardial Reperfusion; Myocardium; Myocytes, Cardiac; Permeability; Phosphorylation; Rats; Rats, Inbred OLETF; Taurochenodeoxycholic Acid

Many pharmacodynamic (PD) models of cellular response assume a single and time invariant lifespan of all cells, despite the existence of a true underlying distribution of cellular lifespans and known changes in the lifespan distributions with time. To account for these features of cellular populations, a time variant cellular lifespan distribution PD model was formulated and theoretical aspects of modeling cellular populations presented. The model extends prior work assuming time variant "point distributions" of cellular lifespans (Freise et al. J Pharmacokinet Pharmacodyn 34:519-547, 2007) and models assuming a time invariant lifespan distribution (Krzyzanski et al. J Pharmacokinet Pharmacodyn 33:125-166, 2006). The formulated time variant lifespan distribution model was fitted to endogenous plasma erythropoietin (EPO), reticulocyte, and red blood cell (RBC) concentrations in sheep phlebotomized on two occasions, 8 days apart. The time variant circulating reticulocyte lifespan was modeled as a truncated and scaled Weibull distribution, with the location parameter of the distribution non-parametrically represented by an end constrained quadratic spline function. The formulated time variant lifespan distribution model was compared to the identical time invariant distribution, time variant "point distribution", and time invariant "point distribution" cellular lifespan models. Parameters of the time variant lifespan distribution model were well estimated with low standard errors. The mean circulating reticulocyte lifespan was estimated at 0.304 days, which rapidly increased over 3-fold following the first phlebotomy to a maximum of 1.03 days (P = 0.009). On average, the percentage of erythrocytes being released as reticulocytes maximally increased an estimated two-fold following the phlebotomies. The primary features of immature RBC physiology were captured by the model and gave results consistent with other estimates in sheep and humans. The comparison of the four lifespan models gave similar parameter estimates of the stimulation function and fits to the RBC data. However, the time invariant models fit the reticulocyte data poorly, while the time variant "point distribution" cellular lifespan model gave physiologically unrealistic estimates of the changes in the circulating reticulocyte lifespan under stress erythropoiesis. Thus the underlying physiology must be considered when selecting the most appropriate cellular lifespan model and not just the goodnes

Topics: Algorithms; Animals; Blood Volume; Body Weight; Cell Cycle; Computer Simulation; Erythrocyte Count; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Models, Statistical; Pharmacokinetics; Phlebotomy; Reticulocytes; Sheep

The aim of our study was to determine the effect of recombinant human erythropoietin (rhEPO) on cyclosporine (CsA) nephrotoxicity. Twenty-six female Wistar rats were injected with 15 mg/kg subcutaneous CsA and intraperitoneal saline/rhEPO for 28 days. Four groups were formed: Group 1 (n = 5), a control group; Group 2 (n = 7), CsA + saline; Group 3 (n = 7), CsA + low dose (20 U/kg per day) rhEPO; Group 4 (n = 7), CsA + high dose (100 U/kg per day) rhEPO. Body weights, creatinine clearance, urinary protein/creatinine, hematocrit, serum creatinine levels, histopathological parameters, apoptosis and lipid peroxidation tests were compared between the three groups. Body weights and renal functions were similar in Groups 2, 3 and 4 rats but significantly lower than the values found for the control group at the end of the study. The hematocrit was significantly different between the four groups, showing a positive association with the strength of the injected rhEPO doses. Tubular and arteriolar damage was significantly lower in Groups 3 and 4 rats than in Group 2 rats, while chronic changes were similar between the three groups. TUNEL-positive cells and thiobabarbituric acid reacting substance (TBARS) levels were significantly higher in Group 2 rats, whereas superoxide dismutase levels were significantly lower in Group 2 rats than in those of the other three groups. Low or high dose rhEPO had no significant protective effects on body weight, renal functions, chronic fibrotic changes, but both doses reduced tubular and arteriolar changes, apoptotis and oxidative stress.

Topics: Animals; Apoptosis; Body Weight; Cyclosporine; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematopoiesis; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins

This study aims to evaluate the laboratory variables in Iranian hemodialysis pa-tients. We studied 338 patients in 6 dialysis centers around the country. Sixty four percent of the patients were anemic, and the mean of hemoglobin levels in the patients was 9.6 +/- 1.9 g/dL. Women had a significantly higher prevalence of anemia (p= 0.004); however, considering the absolute hemoglobin values, there was no significant difference between genders (p> 0.05). The mean urea reduction ratio (URR) and Kt/V in the patients were 62.6 +/- 12.8 and 1.17 +/- 0.31, respectively. Hyperphosphatemia and hyperkalemia were observed in 50% and 58%, respectively. We conclude that our study demonstrated a relatively high prevalence of anemia and hyper-phosphatemia, however, a surprisingly good dialysis urea clearance in the Iranian hemodialysis patients. We should exploit more effort to maintain hemoglobin and serum phosphate levels with-in the target ranges.

Topics: Anemia; Blood Chemical Analysis; Body Weight; Cross-Sectional Studies; Erythropoietin; Female; Humans; Iran; Male; Middle Aged; Nutritional Status; Prevalence; Renal Dialysis; Sex Characteristics

Protein-energy malnutrition is a syndrome in which anaemia together with multivitamin and mineral deficiency may be present. The pathophysiological mechanisms involved have not, however, yet been completely elucidated. The aim of the present study was to evaluate the pathophysiological processes that occur in this anaemia in animals that were submitted to protein-energy malnutrition, in particular with respect to Fe concentration and the proliferative activity of haemopoietic cells. For this, histological, histochemical, cell culture and immunophenotyping techniques were used. Two-month-old male Swiss mice were submitted to protein-energy malnutrition with a low-protein diet (20 g/kg) compared with control diet (400 g/kg). When the experimental group had attained a 20 % loss of their original body weight, the animals from both groups received, intravenously, 20 IU erythropoietin every other day for 14 d. Malnourished animals showed a decrease in red blood cells, Hb concentration and reticulocytopenia, as well as severe bone marrow and splenic atrophy. The results for serum Fe, total Fe-binding capacity, transferrin and erythropoietin in malnourished animals were no different from those of the control animals. Fe reserves in the spleen, liver and bone marrow were found to be greater in the malnourished animals. The mixed colony-forming unit assays revealed a smaller production of granulocyte-macrophage colony-forming units, erythroid burst-forming units, erythroid colony-forming units and CD45, CD117, CD119 and CD71 expression in the bone marrow and spleen cells of malnourished animals. These findings suggest that, in this protein-energy malnutrition model, anaemia is not caused by Fe deficiency or erythropoietin deficiency, but is a result of ineffective erythropoiesis.

Topics: Anemia; Animals; Blood Proteins; Body Weight; Bone Marrow Cells; Colony-Forming Units Assay; Dietary Proteins; Disease Models, Animal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Flow Cytometry; Immunophenotyping; Iron; Male; Mice; Protein-Energy Malnutrition; Spleen; Transferrin

Recombinant human EPO (r-Hu-EPO) protects cultured motor neurons from kainate- and serum deprivation-induced toxicity and readily enters the CNS after systemic injection. We examined the effect of rHuEPO in transgenic mice expressing the human Cu/Zn dependent-superoxide dismutase with G93A mutation (SOD1G93A), a model of familial amyotrophic lateral sclerosis. rHuEPO (4 unit/g BW s.c. three times/week), increased the haematocrit and induced a slight delay in impairment of motor function as measured by the rotating bar test. However, it did not prolong life span or reduce motor neuron loss in lumbar spinal cord. The effect on motor function may be due to the improvement of skeletal muscle oxygenation induced by chronic EPO administration.

Topics: Age Factors; Amyotrophic Lateral Sclerosis; Analysis of Variance; Animals; Body Weight; Choline O-Acetyltransferase; Disease Models, Animal; Erythropoietin; Female; Hematocrit; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Psychomotor Performance; Recombinant Proteins; Superoxide Dismutase

Hypertension is the most significant complication from treatment with erythropoietin (Epo). Can Epo-induced hypertension be eliminated? We examined systemic and local effects of our genetically engineered products, Epo-binding protein (Epo-bp) and anti-Epo-bp antibodies, on randomly assigned Sprague-Dawley rats at midnight, 4 am, 8 am, noon, 4 pm, and 8 pm. Blood pressure, hematocrit, and body weight were measured immediately before and after the completion of a 4-week, twice-weekly course of Epo (50 U/kg), Epo-bp, anti-Epo-bp antibodies, or physiological saline injections. Epo treatment increased hematocrit markedly overall as compared with the saline, Epo-bp, and anti-Epo-bp antibody groups (0.616 versus 0.427, 0.439, and 0.441, respectively) and at each of the 6 test times (all P<0.0001). Epo-bp and anti-Epo-bp antibody treatment with Epo had almost no effect on the Epo-induced hematocrit increase (0.616 versus 0.580 or 0.591, respectively). Circadian blood pressures for Epo versus saline, Epo-bp, and anti-Epo-bp antibody groups were 136.2+/-2.3 versus 116.2+/-1.7, 118.4+/-2.1, and 116.6+/-2.1 mm Hg, respectively (each P<0.0001). Significantly increased blood pressure was detected at noon, 4 pm, 8 pm, and midnight in Epo treatment. When Epo was given with Epo-bp or anti-Epo-bp antibodies, blood pressure was maintained at similar levels as in saline treatment (each P<0.0001) as compared with Epo treatment alone. Overall, body, brain, and heart weights were significantly lower in Epo treatment than those of other groups. Thus, Epo-bp and anti-Epo-bp antibodies eliminate Epo-induced hypertension without affecting hematocrit and blood volume.

Topics: Animals; Blood Pressure Determination; Body Weight; Circadian Rhythm; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematocrit; Hypertension; Probability; Protein Binding; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reference Values; Risk Factors; Sensitivity and Specificity

Erythropoietin (EPO) has a highly conserved structure among mammals, and thus recombinant human EPO (rHuEPO) has biological activity in various species. This study explores the interspecies relationships of the pharmacokinetics (PK) and pharmacodynamics (PD) of rHuEPO. The PK parameters such as clearance (CL) and volume of distribution (V(ss)) after i.v. doses of rHuEPO were obtained in several species via noncompartmental analysis and were assessed using the traditional allometric approach. Also, PK/PD modeling of rHuEPO concentrations and responses [reticulocytes, red blood cells (RBCs), and hemoglobin] was performed following a range of i.v. and s.c. doses in rats, monkeys, and humans. Nonlinear disposition (V(max), K(m)) and s.c. absorption rate and bioavailability parameters of rHuEPO were examined. A cascade, indirect, lifespan PD model was applied to recover efficacy (S(max)) and potency (SC(50)) of rHuEPO on erythropoiesis and erythroid cell lifespan parameters. Despite nonlinear rHuEPO disposition, CL and V(ss) were highly correlated with body weight (R(2) > 0.92) with allometric scaling exponents of 0.708 for CL and 0.853 for V(ss). The s.c. bioavailability increased with dose in monkeys and humans but appeared to be dose-independent in rats. A correlation between S(max) or SC(50) and body weight was not obvious. However, RBC lifespans obeyed allometric principles. Size dependence was found for PK and lifespan parameters, whereas pharmacologic parameters were independent of body weight.

Topics: Animals; Biological Availability; Body Weight; Dogs; Erythropoietin; Haplorhini; Humans; Injections, Intravenous; Injections, Subcutaneous; Intestinal Absorption; Nonlinear Dynamics; Rabbits; Rats; Recombinant Proteins; Sheep; Species Specificity

Salivary glands (SGs) have proven useful targets for clinical applications of gene therapeutics. In this toxicology and biodistribution study, which conforms to U.S. Food and Drug Administration Good Laboratory Practice regulations, four doses (10(7)-10(10) particles) of a serotype 2 adeno-associated viral (AAV2) vector encoding human erythropoietin were directly administered to the right submandibular gland of male and female BALB/c mice (n = 21 per gender dose group). Control-treated (saline administered; n = 66) and vector-treated (n = 168) animals did not differ in clinical appearance, morbidity and mortality rates, food and water consumption, weight gain ratios, and final weight. Clinical hematology values also were unaffected by AAV2 administration except for parameters influenced by the expression of the recombinant protein (e.g., hematocrit). Mice were killed on days 3, 30, 55, and 92. No major vector-related toxicity was uncovered after complete pathology and histopathology review. However, a significant gender-related difference in vector biodistribution was revealed by quantitative polymerase chain reaction. In male mice vector (group receiving 10(10) particles/animal) effectively transduced, and was primarily confined within, the SGs (i.e., approximately 800 times more copies in SGs than in liver; day 3) and long lived. In contrast, in female mice, SG transduction was less efficient (260-fold less than in males; day 3) and short lived, and vector was disseminated widely via both the bloodstream (SG:liver copy ratio, approximately 1) and saliva (30-fold greater than in males). The observed vector biodistribution is likely due to differences in AAV2 receptor targets and structural differences affecting SG integrity. Sexual dimorphism is a factor of major significance that could potentially affect gene therapy clinical applications in SGs.

Topics: Animals; Blood; Body Weight; Dependovirus; Eating; Erythropoietin; Female; Genetic Therapy; Genetic Vectors; Humans; Injections; Leukocyte Count; Male; Mice; Mice, Inbred BALB C; Saliva; Sex Characteristics; Submandibular Gland; Tissue Distribution

To investigate the effect of exogenous erythro-poietin (EPO) administration on acute lung injury (ALI) in an experimental model of sodium taurodeoxycholate- induced acute necrotizing pancreatitis (ANP).. Forty-seven male Wistar albino rats were randomly divided into 7 groups: sham group (n = 5), 3 ANP groups (n = 7 each) and 3 EPO groups (n = 7 each). ANP was induced by retrograde infusion of 5% sodium taurodeoxycholate into the common bile duct. Rats in EPO groups received 1000 U/kg intramuscular EPO immediately after induction of ANP. Rats in ANP groups were given 1 mL normal saline instead. All animals were sacrificed at postoperative 24 h, 48 h and 72 h. Serum amilase, IL-2, IL-6 and lung tissue malondialdehyde (MDA) were measured. Pleural effusion volume and lung/body weight (LW/BW) ratios were calculated. Tissue levels of TNF-alpha, IL-2 and IL-6 were screened immunohistochemically. Additionally, ox-LDL accumulation was assessed with immune-fluorescent staining. Histopathological alterations in the lungs were also scored.. The mean pleural effusion volume, calculated LW/BW ratio, serum IL-6 and lung tissue MDA levels were significantly lower in EPO groups than in ANP groups. No statistically significant difference was observed in either serum or tissue values of IL-2 among the groups. The level of tumor necrosis factor-alpha (TNF-alpha) and IL-6 and accumulation of ox-LDL were evident in the lung tissues of ANP groups when compared to EPO groups, particularly at 72 h. Histopathological evaluation confirmed the improvement in lung injury parameters after exogenous EPO administration, particularly at 48 h and 72 h.. EPO administration leads to a significant decrease in ALI parameters by inhibiting polymorphonuclear leukocyte (PMNL) accumulation, decreasing the levels of proinflammatory cytokines in circulation, preserving microvascular endothelial cell integrity and reducing oxidative stress-associated lipid peroxidation and therefore, can be regarded as a cytoprotective agent in ANP-induced ALI.

Topics: Amylases; Animals; Body Weight; Disease Models, Animal; Erythropoietin; Interleukin-2; Interleukin-6; Lipoproteins, LDL; Lung; Male; Malondialdehyde; Neutrophils; Pancreatitis, Acute Necrotizing; Pleural Effusion; Pulmonary Alveoli; Rats; Rats, Wistar; Respiratory Distress Syndrome; Taurodeoxycholic Acid

Erythropoietin (EPO) mediates a wide range of neuroprotective activities, including amelioration of disease and neuroinflammation in rat models of EAE. However, optimum dosing parameters are currently unknown. In the present study, we used a chronic EAE model induced in mice by immunization with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) to compare the effect of EPO given with different treatment schedules. EPO was administered intraperitoneally at 0.5, 5.0 or 50 microg/kg three times weekly starting from day 3 after immunization (preventive schedule), at the onset of clinical disease (therapeutic schedule) or 15 days after the onset of symptoms (late therapeutic schedule). The results show that EPO is effective even when given after the appearance of clinical signs of EAE, but with a reduced efficacy compared to the preventative schedule. To determine whether this effect requires the homodimeric EPO receptor (EPOR2)-mediated hematopoietic effect of EPO, we studied the effect of carbamylated EPO (CEPO) that does not bind EPOR2. CEPO, ameliorated EAE without changing the hemoglobin concentration. Another non-erythropoietic derivative, asialoEPO was also effective. Both EPO and CEPO equivalently decreased the EAE-associated production of TNF-alpha, IL-1beta and IL-1Ra in the spinal cord, and IFN-gamma by peripheral lymphocytes, indicating that their action involves targeting neuroinflammation. The lowest dosage tested appeared fully effective. The possibility to dissociate the anti-neuroinflammatory action of EPO from its hematopoietic action, which may cause undesired side effects in non-anemic patients, present new avenues to the therapy of multiple sclerosis.

Topics: Analysis of Variance; Animals; Body Weight; Chronic Disease; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Erythropoietin; Female; Glycoproteins; Hematocrit; Humans; Immunohistochemistry; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Peptide Fragments; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Spinal Cord; Spleen; Statistics, Nonparametric; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha

Chronic kidney disease patients who are resistant to erythropoietin (EPO) treatment may suffer from malnutrition and/or inflammation.. In a cross-sectional study of haemodialysis patients, we investigated the relationship between the natural logarithm of the weekly EPO dose normalized for post-dialysis body weight and outcome measures of nutrition and/or inflammation [BMI, albumin and C reactive protein (CRP)] by means of multiple linear regression analysis. On the basis of the decile distribution of weekly EPO doses, we also evaluated four groups of patients: untreated, hyper-responders, normo-responders and hypo-responders.. Six hundred and seventy-seven adult haemodialysis patients were recruited from five Italian centres. BMI and albumin were lower in the hypo-responders than in the other groups (21.3+/-3.8 vs 24.4+/-4.7 kg/m(2), P<0.001; and 3.8+/-0.6 vs 4.1+/-0.4 g/dl, P<0.001), whereas the median CRP level was higher (1.9 vs 0.8 mg/dl, P = 0.004). The median weekly EPO dose ranged from 30 IU/kg/week in the hyper-responsive group to 263 IU/kg/week in the hypo-responsive group. Transferrin saturation linearly decreased from the hyper- to hypo-responsive group (37+/-15 to 25+/-10%, P = 0.003), without any differences in transferrin levels. Ferritin levels were lower in the hypo-responsive than in the other patients (median 318 vs 445 ng/ml, P = 0.01). At multiple linear regression analysis, haemoglobin, BMI, albumin, CRP and serum iron levels were independently associated with the natural logarithm of the weekly EPO dose (R(2) = 0.22).. Our findings support a clear association between EPO responsiveness and nutritional and inflammation variables in haemodialysis patients; iron deficiency is still a major cause of hypo-responsiveness.

Topics: Aged; Body Weight; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Humans; Inflammation; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Renal Dialysis

The concomitant manifestations of proximal renal tubular dysfunction and anemia with erythropoietin (Epo) deficiency observed in chronic cadmium (Cd) intoxication, such as Itai-itai disease, suggest a close local correlation between the Cd-targeted tubular cells and Epo-producing cells in the kidney. Therefore, we investigated the local relationship between hypoxia-induced Epo production and renal tubular injury in rats injected with Cd at 2 mg/kg twice a week for 8 months. Anemia due to insufficient production of Epo was observed in Cd-intoxicated rats. In situ hybridization detected Epo mRNA expression in the proximal renal tubular cells of hypoxic rats without Cd intoxication, and the Cd-intoxicated rats showed atrophy of Epo-expressing renal tubules and replacement of them with fibrotic tissue. A single dose of cisplatin at 8 mg/kg, which can induce clinical manifestations similar to those of Cd including renal tubular damage along with Epo-deficient anemia, resulted in Epo-expressing renal tubule destruction on day 4. These data indicate that Cd and cisplatin would induce anemia through the direct injury of the proximal renal tubular cells that are responsible for Epo production.

Topics: Anemia, Hypochromic; Animals; Antineoplastic Agents; Body Weight; Cadmium Chloride; Cisplatin; Environmental Pollutants; Erythropoietin; Female; Hematologic Tests; Hypoxia; In Situ Hybridization; Kidney Tubules, Proximal; Liver; Organ Size; Rats; Rats, Wistar; RNA, Messenger; Spleen; Time Factors

Correcting anemia with recombinant human erythropoietin (rhEPO) in chronic renal failure has been associated with an increased blood pressure (BP), which may accelerate the decline in renal function. This has been attributed, in part, to the activation of the renin-angiotensin system. The present study was designed to investigate the protective effect of the angiotensin II-receptor blocker losartan compared with the angiotensin-converting enzyme inhibitor captopril and conventional triple therapy (TRx) in uremic rats receiving rhEPO therapy.. Renal failure was induced by renal mass ablation followed by a 3-week stabilization period. Uremic rats were then divided into five groups with similar systolic BP: vehicle; rhEPO (100 U/kg, subcutaneously, three times per week); rhEPO + losartan (20 mg/kg/d); rhEPO + captopril (20 mg/kg/d); and rhEPO + TRx (reserpine 5 mg/L, hydralazine 80 mg/L, hydrochlorothiazide 20 mg/L). Systolic BP as well as blood and renal parameters were assessed before and after a 3-week treatment period. Renal histology was evaluated at the end of the study.. The uremic rats developed hypertension, anemia, proteinuria, and increased urinary endothelin-1 (ET-1) excretion. The rhEPO corrected the anemia but aggravated the hypertension (P < .01), glomerular sclerosis, tubular atrophy, and interstitial fibrosis. Treatment with losartan, captopril, and the TRx prevented the rhEPO-induced increased in systolic BP. The TRx was less effective in preventing histologic injuries despite similar systolic BP reduction.. Blockade of the renin-angiotensin system is highly effective in preventing both hypertension and renal histologic damage in rhEPO-treated uremic rats and this benefit seems to extend beyond the antihypertensive effect.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Captopril; Disease Models, Animal; Drug Therapy, Combination; Erythropoietin; Hydralazine; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Losartan; Nephrectomy; Rats; Rats, Wistar; Recombinant Proteins; Renin-Angiotensin System; Reserpine; Time Factors; Uremia

Pulmonary oxygen toxicity is believed to play a prominent role in the lung injury that leads to the development of bronchopulmonary dysplasia (BPD). To determine whether human recombinant erythropoietin (rhEPO) treatment reduces the risk of developing BPD, we investigated the effect of rhEPO treatment on the histopathologic changes seen in hyperoxia-induced lung injury of BPD. Twenty-five rat pups were divided into four groups: air-exposed control group (n = 5), hyperoxia-exposed placebo group (n = 7), hyperoxia-exposed rhEPO-treated group (n = 6), and air-exposed rhEPO-treated group (n = 7). Measurement of alveolar surface area, quantification of secondary crest formation, microvessel count, evaluation of alveolar septal fibrosis, and smooth muscle actin immunostaining were performed to assess hyperoxia-induced changes in lung morphology. Treatment of hyperoxia-exposed animals with rhEPO resulted in a significant increase in the mean alveolar area, number of secondary crests formed, and the microvessel count in comparison with hyperoxia-exposed placebo-treated animals. There was significantly less fibrosis in rhEPO-treated animals. However, treatment of hyperoxia-exposed animals with rhEPO did not result in a significant change in smooth muscle content compared with hyperoxia-exposed placebo treated animals. Our results suggest treatment with rhEPO during hyperoxia exposure is associated with improved alveolar structure, enhanced vascularity, and decreased fibrosis. Therefore, we conclude that treatment of preterm infants with EPO might reduce the risk of developing BPD.

Topics: Animals; Animals, Newborn; Body Weight; Erythropoietin; Fibrosis; Hypoxia; Immunohistochemistry; Lung; Lung Injury; Microcirculation; Neovascularization, Pathologic; Oxygen; Pulmonary Alveoli; Rats; Rats, Wistar; Recombinant Proteins

The interaction of blood with the arterial tree may play an important role in the development of atherosclerotic lesions. The aims of this study were (1) to determine how anemia or increased hematocrit affect the development of atherosclerosis and (2) to find relationships between hematologic and hemorrheologic variables in apolipoprotein (apo) E-deficient mice. Forty-two mice were randomly divided into 3 groups of 14 mice each. There was no further manipulation in the control group. To induce anemia, the mice from one of the groups were repeatedly bled, drawing approximately 250 microL blood from each mouse twice a week. To increase the hematocrit levels in another group of mice, we injected 20 U recombinant human erythropoietin every other day. The development of lesions and the main variables involved in atherogenesis were compared among groups. Our results show that atherosclerosis was attenuated in the mice that were bled, and this was not accounted for by changes in plasma lipid levels, the distribution of lipoprotein particles, the body iron distribution, or oxidation parameters. Moreover, atherosclerosis was enhanced in the mice treated with the continuous administration of erythropoietin. To ascertain the relationship between hematocrit and whole blood viscosity, we measured both variables in pooled blood from 24 additional mice, which were manipulated to ensure a wide range of values. We found a direct and significant correlation between hematocrit and blood viscosity and between hematocrit and lesion size. Our data support in vivo the idea that hemorrheology has an important role in atherogenesis in this particular animal model.

Topics: Anemia; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Blood Cells; Blood Viscosity; Body Weight; Disease Models, Animal; Erythropoietin; Ferritins; Hematocrit; Hemorheology; Humans; Iron; Lipids; Lipoproteins; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Nutritional Status; Oxidation-Reduction; Phlebotomy; Recombinant Proteins; Spleen

This study was designed to investigate the effects of adrenocorticotropic hormone (ACTH) on systolic blood pressure (BP) and serum erythropoietin (EPO) concentrations in two strains of rats. We hypothesized that ACTH-induced hypertension in the rat is characterized by increased EPO production.. Male Sprague-Dawley (SD) and Wistar out-bred (Wistar) rats were treated with saline or ACTH (0.2 mg/kg/d). Systolic BP was measured using the tail-cuff method. Serum EPO concentrations were assayed using an ELISA kit for human EPO, which cross-reacts with but underestimates rat EPO. Thymus weight was used as a marker of glucocorticoid activity.. In SD rats, ACTH increased systolic BP (from 109 +/- 4 to 142 +/- 5 mm Hg, P <.0005), significantly greater than in saline-treated rats (P <.01). Systolic BP in ACTH-treated Wistar increased from 120 +/- 3 to 133 +/- 4 mm Hg (P <.05), but was not significantly different from saline-treated Wistar rats. The ACTH-induced increase in systolic BP was greater in SD than in Wistar rats (P <.05). Serum EPO levels were 5.6 +/- 0.4 in SD and 5.9 +/- 0.3 IU/L in Wistar rats, and decreased to undetectable levels with ACTH treatment in 10 of 10 SD and 7 of 10 Wistar rats. The ACTH treatment increased hemoglobin and hematocrit, and decreased thymus weight in both strains.. 1) ACTH decreased serum EPO concentrations in both strains; 2) EPO is inversely related to ACTH-induced hypertension in the rat; and 3) Wistar rats are relatively resistant to the BP raising effects of ACTH treatment but not to the ACTH-induced decrease in thymus weight. These data suggest that EPO is not causal in ACTH-induced hypertension.

Topics: Adrenocorticotropic Hormone; Animals; Biomarkers; Blood Glucose; Blood Pressure; Body Weight; Erythropoietin; Hematocrit; Hemoglobins; Injections, Intravenous; Male; Models, Animal; Models, Cardiovascular; Placebos; Rats; Rats, Sprague-Dawley; Rats, Wistar; Sodium Chloride; Systole; Thymus Gland

The changes in cytokines and hormones involved in hematopoiesis were studied in the serum of 7 girls with anorexia nervosa, 15-24 yr old, on admission and after 5% and 10% weight gain. Hematopoiesis was studied by in-vitro culturing of circulating granulocyte-macrophage colony forming cells and erythroid burst forming cells. Nutritional status was studied by anthropometric measurements and resting energy expenditure. On admission, granulocyte-macrophage colony forming cells and erythroid burst forming cells were significantly lower than in age-matched controls and increased significantly along weight gain. Blood leptin and erythropoietin levels increased significantly with weight gain. TNF-alpha levels tended to decrease while IL-1beta levels were lower than in the controls on admission (p <0.05) and did not change significantly during weight gain. IL-3, GM-CSF and IL-6 were undetected on admission or along weight gain. The changes in granulocyte-macrophage colony forming cells and erythroid burst forming cells positively correlated with changes in resting energy expenditure and fat free mass. These results may suggest that undernutrition affects hematopoiesis as indicated by the reduction of hematopoietic progenitor cells before treatment and the significant increase with weight gain. The changes in the levels of hormones and cytokines known to be involved in hematopoiesis along refeeding may suggest a role for these factors in anorexia nervosa.

Topics: Adolescent; Adult; Anorexia Nervosa; Body Weight; Cells, Cultured; Cytokines; Erythropoietin; Female; Hematopoiesis; Hormones; Humans; Leptin; Nutritional Status

One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.

Topics: Active Transport, Cell Nucleus; Animals; Apoptosis; Body Weight; Brain; Caspase 3; Caspase 9; Caspase Inhibitors; Caspases; Cell Death; Cell Proliferation; DNA Fragmentation; Dose-Response Relationship, Radiation; Enzyme Activation; Enzyme Inhibitors; Erythropoietin; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Ki-67 Antigen; Mice; Mice, Inbred C57BL; Myelin Basic Protein; Proteins; Rats; Rats, Wistar; Stem Cells; Time Factors; Tumor Suppressor Protein p53; X-Linked Inhibitor of Apoptosis Protein

Our objective was to assess, using clinical trial simulation, the feasibility of a fixed 200-microg dose of darbepoetin alfa (Aranesp) administered every 2 weeks in chemotherapy-induced anemia. A pharmacokinetic/pharmacodynamic model was developed using clinical data from 547 cancer patients who received darbepoetin alfa at various doses and schedules. Monte Carlo simulations were performed for weight-based (3 microg/kg every 2 weeks) and fixed-dose (200 microg every 2 weeks) regimens and were compared with observed clinical data. Mean hemoglobin changes from baseline to end of treatment were +1.61 g/dL, +1.83 g/dL, and +1.79 g/dL for observed data, the weight-based simulation, and the fixed-dose simulation, respectively. The rates of required transfusions (hemoglobin < or = 8 g/dL) were also similar between groups. For patients between 45 and 95 kg (over 90% of the population), the impact of a fixed dose on mean hemoglobin change was negligible. There was a slight weight effect at body weight extremes (< 45 kg and > 95 kg). Clinical outcomes from simulations of weight-based andfixed dosing of darbepoetin alfa were similar to those of observed weight-based data. Given the weight distribution of a typical cancer population, the majority would be expected to benefit equally from weight-based and fixed-dose darbepoetin alfa in the amelioration of chemotherapy-induced anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Breast Neoplasms; Clinical Trials as Topic; Computer Simulation; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Genital Neoplasms, Male; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Monte Carlo Method

Survey the dialysis practices and nutritional status-related patient characteristics.. Cross-sectional survey.. Twenty-eight randomly selected Korean hemodialysis facilities.. Medical record review of 140 randomly selected patients in 28 Korean dialysis facilities. The Student t test and chi-square tests were used to compare facility types and locations.. The mean number of dialysis treatments per week was 2.7 +/- 0.4. Mean dialysis treatment length was 253 +/- 27.5 minutes. Rural dialysis centers reported fewer treatments per week and shorter dialysis treatment times than did urban centers but, otherwise, there were few differences by either location (urban v rural) or by facility type (hospital affiliated v freestanding facility). The mean age of the patients surveyed by record review was 51 +/- 14 years, and 59% of the patients were men. The primary causes of end-stage renal disease were chronic glomerulonephritis, hypertension, and diabetes. Average vintage of dialysis was 53 +/- 46 months. Adequacy of dialysis was usually assessed by using clinical judgment; urea kinetic modeling and urea reduction ratios were used less frequently. Patients' mean body mass index was 20.7 +/- 2.3, which was at the lower end of the healthy range of 18.5 to 25, and most (93%) of their weights had been stable over the previous 6 months. Their mean serum albumin level was 4.0 +/- 0.4 g/dL. Forty-two percent of patients used iron supplements and 68% of them received erythropoietin treatment. However, their mean hematocrit levels were only 25.9% +/- 4.2%, suggesting that iron supplements were underused or erythropoietin doses were lower than optimal. Virtually all patients (94%) had received initial diet instruction but few (6%) received follow-up nutrition counseling.. Greater attention to dialysis adequacy, hematocrit levels, nutrition assessment, weight monitoring, and diet therapy are recommended.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Cross-Sectional Studies; Erythropoietin; Female; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Korea; Male; Middle Aged; Nutritional Status; Renal Dialysis; Retrospective Studies; Serum Albumin; Surveys and Questionnaires; Time Factors

American guidelines for the management of renal anemia by recombinant human erythropoietin (rHuEPO) recommend collecting a predialysis blood sample to evaluate hemoglobin (Hb) and hematocrit (Hct) levels in hemodialysis patients. Although a predialysis blood sample is appropriate for evaluating when to start rHuEPO treatment, the same sample would not be appropriate for evaluating the target Hb/Hct to be maintained, particularly when normal or near-normal values are pursued. We measured the degree of intradialytic and extradialytic variation of Hb, Hct, and body weight in 68 stable hemodialysis patients on maintenance subcutaneous rHuEPO treatment. Hb and Hct concentrations were determined before and after dialysis. In 16 patients, Hb and Hct concentrations also were assessed 24 hours after the end of dialysis. Predialysis versus postdialysis Hb and Hct concentrations for all patients were 10.5 +/- 1.3 g/dL versus 11.5 +/- 1.3 g/dL (P < 0.0001) and 32 +/- 4% versus 35 +/- 4% (P < 0.0001). The intradialytic percent variation (%Delta) of Hct and body weight were 10 +/- 6% and -6.3 +/- 3.5%. There was a close inverse correlation between %Delta of Hct and Hb and %Delta of body weight (P < 0.0001). In patients with body weight losses 2.5 kg or more per session, the mean %Delta of Hct was 12 +/- 7%. In the 16 patients studied 24 hours after the end of the dialysis session, Hct and Hb values remained significantly higher compared with the predialysis levels (P < 0.001), suggesting a slow reequilibration of the intravascular volume in the first 24 hours after hemodialysis. For these reasons, predialysis samples for monitoring the target Hb and Hct levels in patients treated by rHuEPO should be considered with caution.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency

An adequate iron supplement is crucial not only for prompt erythropoiesis but also for the restoration of tissue iron reserves in haemodialysis patients receiving recombinant human erythropoietin (r-HuEPO). An attempt was made to establish a comprehensive nomogram that allows individualization of intravenous (i.v.) iron doses according to patients' body weights, the initial status of tissue iron reserves and desired increases in haemoglobin levels.. Clinical and laboratory data retrieved from 95 haemodialysis patients who received r-HuEPO with or without iron supplements for at least 12 weeks were used to construct the nomogram. It was assumed that the administered iron was either incorporated into newly synthesized haemoglobin and tissue iron reserves or eliminated from the body at a constant rate. Tissue iron reserves of the patients were estimated by serum ferritin levels using van Wyck's equation (Kidney Int., 1989, 35, 712). The rate of iron loss in the patients was estimated by the data obtained from 15 of the above patients who exhibited stable haemoglobin levels but decreases in serum ferritin levels with no iron supplements. The validity of the equation was ascertained by comparing the measured serum ferritin levels at the end of r-HuEPO therapy and those predicted by the nomogram. The proposed nomogram was then validated prospectively in 24 haemodialysis patients to determine whether the nomogram-recommended iron doses would increase both haemoglobin and serum ferritin levels within 12 weeks.. The mean (+/-SD) iron loss of haemodialysis patients was calculated to be 10.5 +/- 7.4 mg/week. There was a significant correlation (r=0.77, P < 0.001) between the measured serum ferritin levels, an index of tissue iron reserves, at the end of r-HuEPO therapy and those predicted by the equations used for formulating the nomogram. The prospective study indicated that the nomogram-recommended supplementary iron doses attained haemoglobin and serum ferritin levels of > 95 g/L and >100 microg/L in 79 and 50% of the patients, respectively, within 12 weeks.. The present nomogram may be useful for individualizing supplementary i.v. iron doses for haemodialysis patients undergoing r-HuEPO therapy.

Topics: Adult; Aged; Body Weight; Erythropoietin; Female; Ferritins; Forecasting; Hemoglobins; Humans; Injections, Intravenous; Iron; Male; Middle Aged; Prospective Studies; Renal Dialysis; Retrospective Studies; Tissue Distribution

The anemia associated with acute renal failure (ARF) is currently treated with blood transfusions, while the anemia of chronic renal failure is treated with recombinant erythropoietin (EPO). We hypothesized that EPO treatment during ARF could rapidly improve hemoglobin levels and be a useful therapeutic approach. In addition, as tubular epithelial cells have EPO receptors that can mediate proliferation, enhanced recovery of renal function may occur with EPO use.. An established rat model of ischemic ARF was studied, using either moderate or severe ischemia. EPO was administered in a dose of 500 or 3000 U/kg starting at time of ischemia. Hematocrit (Hct), serum creatinine, reticulocyte count, and mortality rate were measured.. EPO treatment led to a rapid and significant increase in Hct at 48 and 72 hours after moderate ischemic renal reperfusion injury (IRI) in EPO (500 U/kg)-treated rats compared with control (saline treated) rats (mean +/- SE; 45.6 +/- 0.3% vs. 42.0 +/- 1.0%, P < 0.01) and (46.6 +/- 0.3 vs. 41.0 +/- 1.0, P < 0.01, N = 3 per group). In severe renal IRI, EPO treatment also led to significantly increased Hct at 48 (40.0 +/- 4.4% vs. 36.8 +/- 0.3%, P < 0.01, N = 3 per group) and 72 hours (43.5 +/- 1.5% vs. 34.7 +/- 2.3%, P < 0.01, N = 3 per group). Higher dose (3000 U/kg) EPO led to a more pronounced Hct increase after severe IRI at 48 hours compared with the 500 U/kg dose (43.5 +/- 0.3 vs. 40.3 +/- 0.3, P < 0.01, N = 3 per group). EPO treatment during moderate or severe renal IRI did not change the course of the renal dysfunction. EPO treatment (N = 19) had a significant protective effect on mortality during severe IRI. In addition, loss of body weight during ARF was not affected by EPO therapy.. Recombinant EPO can rapidly increase Hct and improve mortality during ARF. Human studies are warranted to evaluate the clinical applicability of this important finding.

Topics: Acute Kidney Injury; Anemia; Animals; Body Weight; Creatinine; Erythropoietin; Ischemia; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renal Circulation; Reperfusion Injury; Reticulocyte Count; Severity of Illness Index

To identify the factors determining a high recombinant human erythropoietin (rHuEPO) dose requirement and associated side effects in children undergoing hemodialysis.. We retrospectively analyzed the clinical data of 23 children (aged 5-20 years) undergoing long-term hemodialysis. All subjects received intravenous rHuEPO to maintain hemoglobin levels > or = 10 g/dL and had iron supplement. Subjects were divided into 2 groups: those receiving high-dose rHuEPO (> or = 450 U/kg/wk) and those receiving an average dose (< 450 U/kg/wk). We compared the specific variables between both groups by using Mann-Whitney, Fisher exact, and linear regression tests; a P value < .05 was considered significant.. Four of 23 subjects (17%) received high-dose rHuEPO despite iron repletion. These subjects were small and young and had frequent bacterial infections, high ferritin levels, and severe hyperparathyroidism. Two patients with human immunodeficiency virus infection required high-dose rHuEPO. The main adverse effect of high-dose rHuEPO was an increase in the heparin requirement during hemodialysis.. Age, body weight, inflammatory status, and severity of hyperparathyroidism should be taken into account when adjusting rHuEPO dose for children undergoing hemodialysis. Furthermore, we suggest that high rHuEPO doses are related to an increase in the heparin requirement in these children.

Topics: Age Factors; Anemia, Iron-Deficiency; Body Weight; Child; Erythropoietin; Female; Ferritins; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Linear Models; Male; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Topics: Adult; Algorithms; Artifacts; Blood Volume; Body Weight; Data Display; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Humans; Polycythemia; Reference Values; Research Design; Statistical Distributions

During advanced renal failure, particularly in patients with end-stage renal disease (ESRD), proteins are carbamylated as a result of a reaction with cyanate. Some or all of the cyanate is derived from urea. If the carbamylation of proteins adversely alters their biologic activities, then urea must be viewed as an uremic toxin, rather than a surrogate. Therefore, we studied the effect of cyanate carbamylation on the erythropoietic activity of erythropoietin (EPO) in a rodent model.. EPO was carbamylated by incubation with cyanate at 37 degrees C. The extent of carbamylation was monitored using trinitrobenzenesulfonic acid. In Sprague-Dawley rats the erythrocyte count, hemoglobin concentration, and hematocrit were measured after the twice-weekly subcutaneous injection of either EPO or carbamylated EPO for 3 weeks. Two additional control groups received physiologic saline or 0.2 ml of 1 M cyanate.. The level of carbamylated EPO was increased as the time of exposure to cyanate increased from 1 to 6 h, and as the cyanate concentration increased from 8 to 2,000 mM. EPO injections caused significantly large increases in all erythropoietic measures. Physiologic saline or 1 M cyanate-injected controls and the carbamylated EPO-injected animals demonstrated no change from baseline in erythropoietic parameters.. These results support that EPO exposed to high levels of cyanate in vitro demonstrates diminished biologic activity in healthy Sprague-Dawley rats. This effect may be manifested by the carbamylation of EPO by the cyanate. Should this occur in ESRD patients, it may contribute to the suboptimal erythropoietic response to EPO therapy associated with high urea levels, especially related to inadequate dialysis. Targeting dialysis doses specifically to urea concentrations may be more important than previously considered.

Topics: Animals; Body Weight; Carbamates; Cyanates; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Male; Rats; Rats, Sprague-Dawley; Sodium Chloride; Time Factors

Changing financial incentives have strongly influenced dosing patterns of recombinant human erythropoietin (rHuEPO) since its introduction in 1989. Although guidelines for prescribing rHuEPO exist, the extent to which they are adhered to is unknown. Using a retrospective cohort observational study design, the factors influencing the initial dosing of rHuEPO prescribed to 413 hemodialysis patients in 1994 were examined. Patient weight, the only recommended guideline, was not found to be a significant predictor of dosing of rHuEPO after controlling for selected patient demographic and clinical characteristics. The strongest predictor for initial rHuEPO dosing was hematocrit followed by White race (p < 0.05). Finally, each subsequent month was associated with a significantly larger initial rHuEPO dose, reflecting the general trend in increasing dose since 1991 (p < 0.001). In conclusion, despite the recent DOQI guidelines for treatment of anemia among persons with chronic renal failure, providers are not using patient weight as an independent criterion for determining dosing of rHuEPO.

Topics: Adolescent; Adult; Anemia; Body Weight; Cohort Studies; Erythropoietin; Female; Forecasting; Hematocrit; Humans; Kidney Failure, Chronic; Least-Squares Analysis; Male; Middle Aged; Multivariate Analysis; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Regression Analysis; Renal Dialysis; Retrospective Studies; Transferrin; White People

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.. 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.. 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.. 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.

Topics: Blood Pressure; Body Weight; Erythropoietin; Female; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Recombinant Proteins; Renal Dialysis

We investigated to see whether an altered role of nitric oxide (NO) system is involved in erythropoietin (EPO)-induced hypertension in chronic renal failure (CRF). Male Sprague-Dawley rats were five-sixths nephrectomized to induce CRF. Six weeks after the operation, EPO or vehicle was injected for another 6 weeks. Plasma and urine nitrite/nitrate (NOx) levels were determined. Expression of NO synthase (NOS) proteins in the aortae and kidneys were also determined. In addition, the isometric tension of isolated aorta in response to acetylcholine and nitroprusside was examined. Blood pressure progressively rose in CRF groups, the degree of which was augmented by EPO treatment. Plasma NOx levels did not differ among the groups, while urine NOx levels were lower in CRF groups. Endothelial NOS expression was lower in the kidney and aorta in CRF rats, which was not further affected by EPO-treatment. The inducible NOS expression in the kidney and aorta was not different among the groups. Acetylcholine and sodium nitroprusside caused dose-dependent relaxations of aortic rings, the degree of which was not altered by EPO-treatment. Taken together, EPO-treatment aggravates hypertension in CRF, but altered role of NO system may not be involved.

Topics: Acetylcholine; Anemia; Animals; Aorta, Thoracic; Body Weight; Erythropoietin; Hypertension, Renal; Isometric Contraction; Kidney; Kidney Failure, Chronic; Male; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitroprusside; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

Several growth factors, such as growth hormone and insulin-like growth factor-1, have been used to reverse the high rate of catabolism observed either after an operation or during serious illness. We conducted a pilot study in Wistar rats in an attempt to assess whether regulatory peptides widely used in clinical practice, such as erythropoietin (EPO) and granulocyte macrophage colony-stimulating factor (GM-CSF), alone or in combination, might influence the metabolism after surgery. Forty animals were randomly allocated into four groups (one control group and three experimental groups; 10 animals per group). The rats in the control group received isotonic NaCl; the rats in one experimental group received recombinant human EPO (rHuEPO) at a dose of 500 IU/kg (EPO group) and those in another received recombinant GM-CSF at a dose of 20 microg/kg (GM-CSF group); in the fourth group, each animal received the two drugs in combination (EPO/GM-CSF group). In all groups, rats were given the drug(s) or NaCl daily for 15 days before the operation and for 7 days after the operation until they were killed. We estimated the body weight (g) and the hematocrit (%) on the first day of the experiment (baseline values) and on the seventh day after the operation, and we estimated the rate of healing and the breaking strength of the intestinal anastomosis on the day the rats were killed. At the end of the study we found that the body weight (median 250 g, minimum 230 g, maximum 270 g) and the levels of hematocrit (median 64%, minimum 60%, maximum 65%) were significantly increased in the EPO group (P < .001 and P < .005, respectively) as compared with the baseline values (median 217.5 g, minimum 200 g, maximum 250 g; median 51.5%, minimum 45%, maximum 55%, respectively). A similar significant increase in body weight (median 230 g; minimum 200 g; maximum 250 g) and hematocrit (median 64%; minimum 59%; maximum 67%) was found at the end of the study in the EPO/GM-CSF group (P = .01 and P < .005, respectively) as compared with the baseline values (median 210 g; minimum 200 g; maximum 250 g; median 50%, minimum 48%, maximum 54%, respectively). The breaking strength (in newtons (N)) statistically differed in the four groups (Kruskal-Wallis, P = .0008). A comparison between groups showed that the breaking strength had been significantly increased in the animals in the EPO group (median 2.18 N, minimum 1.98 N, maximum 2.44 N) as compared with those in the control group (median 1.66 N,

Topics: Animals; Body Weight; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematocrit; Humans; Male; Pilot Projects; Postoperative Care; Postoperative Complications; Preoperative Care; Rats; Rats, Wistar; Recombinant Proteins; Tensile Strength; Wound Healing

Hemodialysis (HD) of infants with end-stage renal disease (ESRD) is technically difficult and labor intensive, although there are few data in the literature to document the outcomes of this treatment. We retrospectively reviewed all patients with ESRD who received HD between 1983 and 1997 who weighed <10 kg at the beginning of HD. A total of ten patients aged 2-27 months, weighing 3.5-9.5 kg, were identified. All patients were dialyzed through a central venous line; three had a failed sapheno-femoral loop and one a failed brachial shunt. Line clot was observed in nine and line sepsis in six patients. Subclavian vein stenosis was documented in one patient following removal of a clotted subclavian line. The mean urea reduction ratios calculated during the 1st and 3rd month of HD were only 54% and 49%, respectively. Anemia was a frequent problem, despite the use of erythropoietin in seven of the infants. Outcomes included: successful renal transplant in four, switch back to peritoneal dialysis in two, improved renal function and dialysis discontinuation in one, and death after withdrawal of treatment in three patients. All three patients who died were <5 months of age, weighed <5 kg, and were anuric; two of the three had congenital nephrotic syndrome. In conclusion, successful HD is possible in small children with ESRD, but morbidity is substantial and mortality is high.

Topics: Age Factors; Anemia; Body Weight; Child, Preschool; Erythropoietin; Humans; Infant; Kidney Failure, Chronic; Nephrotic Syndrome; Renal Dialysis; Retrospective Studies; Treatment Outcome

We have evaluated the efficacy of administering recombinant human erythropoietin (rh-Epo) to 11 healthy bone marrow donors weighing less than 30 kg. Three weeks before harvesting, the donors received 100 units/kg/day rh-Epo subcutaneously and oral iron supplementation (2.5 mg/kg twice daily). Six children with hematocrit values below the normal ranges for their ages after bone marrow harvesting received 150 units/kg rh-Epo three times a week for 2 weeks and oral iron supplementation at the same dose. No rh-Epo side-effects were observed. Hematocrit values before harvesting increased to between 5.7 and 18.5 (mean 10.6 +/- 1.2) above the baseline values (P = 0.0001). Hematocrit after harvesting decreased to between 4 and 19.5% (mean, 11.1) below the day 0 pre-harvest values. On day + 15 all but one patient had a hematocrit value > or = baseline value. No patient required transfusion during or after bone marrow harvest. Our results show that rh-Epo administration can avoid transfusion and has no side-effects in low weight child bone marrow donors.

Topics: Administration, Cutaneous; Body Weight; Bone Marrow; Bone Marrow Transplantation; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Male; Recombinant Proteins; Tissue Donors

Moderate-altitude living (2,500 m), combined with low-altitude training (1,250 m) (i.e., live high-train low), results in a significantly greater improvement in maximal O2 uptake (V(02)max) and performance over equivalent sea-level training. Although the mean improvement in group response with this "high-low" training model is clear, the individual response displays a wide variability. To determine the factors that contribute to this variability, 39 collegiate runners (27 men, 12 women) were retrospectively divided into responders (n = 17) and nonresponders (n = 15) to altitude training on the basis of the change in sea-level 5,000-m run time determined before and after 28 days of living at moderate altitude and training at either low or moderate altitude. In addition, 22 elite runners were examined prospectively to confirm the significance of these factors in a separate population. In the retrospective analysis, responders displayed a significantly larger increase in erythropoietin (Epo) concentration after 30 h at altitude compared with nonresponders. After 14 days at altitude, Epo was still elevated in responders but was not significantly different from sea-level values in nonresponders. The Epo response led to a significant increase in total red cell volume and V(O2) max in responders; in contrast, nonresponders did not show a difference in total red cell volume or V(O2)max after altitude training. Nonresponders demonstrated a significant slowing of interval-training velocity at altitude and thus achieved a smaller O2 consumption during those intervals, compared with responders. The acute increases in Epo and V(O2)max were significantly higher in the prospective cohort of responders, compared with nonresponders, to altitude training. In conclusion, after a 28-day altitude training camp, a significant improvement in 5,000-m run performance is, in part, dependent on 1) living at a high enough altitude to achieve a large acute increase in Epo, sufficient to increase the total red cell volume and V(O2)max, and 2) training at a low enough altitude to maintain interval training velocity and O2 flux near sea-level values.

Topics: Acclimatization; Adult; Altitude; Blood Volume; Body Height; Body Weight; Erythrocyte Volume; Erythropoietin; Female; Hemoglobins; Humans; Lung; Male; Physical Endurance; Prospective Studies; Retrospective Studies; Running

To determine whether slow nocturnal hemodialysis (SNHD) can be safely performed in patients with end-stage renal disease to improve the biochemical and clinical outcome.. We conducted an 8-week pilot study in nondiabetic adult patients, who underwent dialysis 6 nights per week for 8 hours each night. A dialysate flow rate of 300 mL/min and a blood flow rate of 250 mL/min, through an internal jugular dual-lumen venous catheter, were used. The equipment used was a COBE Centry System 3 dialysis machine and Fresenius F-80 (1.8 m2) or Baxter CT 190 (1.9 m2) dialyzers. Five patients were enrolled in the study.. Two patients did not complete the study because of catheter-related infections--one at day 7 and one after 4 weeks of SNHD. All patients had improved blood pressure control, and no intradialytic adverse events occurred. Dietary intake improved, urea and creatinine levels significantly decreased, and weekly delivery of dialysate increased on SNHD. Potassium, chloride, beta 2-microglobulin, phosphorus, calcium, and high-density lipoprotein cholesterol all improved on SNHD. Serum testosterone increased in the three men on SNHD, but parathyroid hormone, luteinizing hormone, and follicle-stimulating hormone remained unchanged. Erythropoietin levels increased on SNHD, despite no change in exogenous erythropoietin doses in three patients and discontinuation of administration of erythropoietin in one. The following biochemical factors did not change significantly: serum sodium, bicarbonate, vitamin B12, folate, alkaline phosphatase, total cholesterol, triglycerides, and albumin.. Higher doses of hemodialysis benefit nutrition, improve biochemical variables, and may improve many hormonal systems.

Topics: Adult; Aged; Blood Pressure; Body Weight; Electrolytes; Energy Intake; Erythropoietin; Female; Hemodynamics; Hemoglobins; Hormones; Humans; Kidney Failure, Chronic; Male; Middle Aged; Pilot Projects; Renal Dialysis; Treatment Outcome; Water-Electrolyte Balance

To establish a pharmacodynamic model that allows one to predict the haemoglobin (Hb) response to EPO in children as a function of dose and time, and to derive recommendations for initial dosing and subsequent dose adjustment.. Haemoglobin was monitored in eight children aged 8-15 years with anaemia due to renal failure during treatment with EPO. All patients were free of conditions known to impair the response to EPO. Pretreatment Hb was 4.9-9.0 g dl(-1). The drug was administered once weekly by subcutaneous injection; doses ranged from 1700 to 6800 U week (-1). Hb was monitored for 4-38 months. The Hb-time data were analysed by applying a population pharmacodynamic model proposed for EPO in adult haemodialysis patients. Internal model validation was carried out by using a bootstrap procedure.. The increase of Hb during treatment with EPO was linear until steady state was reached after 103+/-33 days (mean +/- interindividual s.d.). The weekly gain in Hb from the onset of therapy to steady state was 0.0805+/-0.026 g dl(-1) (mean +/- interindividual s.d.) for every 1000 U EPO week (-1); it did not exhibit a dependence on body weight. Estimated mean prediction errors are +/-1.53 g dl(-1) for predictions that are based on the mean population parameters and +/-0.83 g dl(-1) for predictions that take into account the complete individual Hb-time data up to and including steady state.. The model describes the time course of the Hb response to EPO in children with renal anaemia. The required weekly EPO dose should initially be calculated from the individual pretreatment Hb and the desired Hb at steady state by using the mean population estimates of the weekly gain in Hb per dose unit before steady state (beta) and the time needed to reach steady state (tau). A reduction of the initial dose according to body weight is not justified by the available evidence. beta should be re-estimated individually after 6 weeks of treatment and dose should be adjusted accordingly. A final dose adjustment should be made when steady state has been reached based on individual estimates of beta and tau.

Topics: Adolescent; Anemia; Body Weight; Child; Erythropoietin; Female; Hemoglobins; Humans; Male; Renal Insufficiency; Time Factors

The results of anemia correction by recombinant human erythropoietin (rHuEPO) therapy with regard to cardiac function and left ventricular hypertrophy in dialysis patients are controversially discussed. The aim of the study was to assess the effects of therapy rHuEPO on cardiac morphology and function in dialysis patients. We studied 11 clinically stable hemodialysis patients with severe renal anemia (hematocrit <27%) and increased left ventricular mass index (LVMi) with no history of coronary or valvular heart disease, systemic disease, severe hyperparathyroidism, hypertension stage 2 or higher, transfusion-dependent anemia, and concurrent rHuEPO treatment. The patients were treated with rHuEPO administered subcutaneously once or twice weekly at a mean dose of 80 +/- 31 IU/kg week until the hematocrit was >30% and underwent a complete Doppler echocardiographic study at baseline and at follow-up (after 12.2 +/- 2.9 months). At follow-up, ejection fraction and fractional shortening significantly increased from 62.7 +/- 13.8 to 67.8 +/- 9. 7% (p < 0.05) and from 35.5 +/- 9.8 to 39.4 +/- 7.1% (p < 0.05), respectively, whereas mean velocity of circumferential fiber shortening demonstrated a trend towards amelioration from 1.18 +/- 0. 23 to 1.27 +/- 0.27 circ/s (n.s.). LVMi and morphological data remained unchanged throughout the study. Nevertheless, LVMi changes showed two different behaviors with respect to baseline values: in 6 patients with higher baseline values, LVMi decreased from 229 +/- 36 to 191 +/- 45 g/m2 (p < 0.05), while it worsened in 5 patients with less marked LVMi, increasing from 141 +/- 32 to 186 +/- 40 g/m2 (p < 0.05). Our data demonstrate that partial correction of renal anemia with rHuEPO therapy seems to improve cardiac performance and to induce a regression of left ventricular hypertrophy, particularly in patients with greater baseline hypertrophy, ultimately confirming the multifactorial pathogenesis of left ventricular hypertrophy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Echocardiography, Doppler; Erythropoietin; Female; Heart Function Tests; Hematocrit; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Ventricular Function, Left

The effects of recombinant human erythropoietin (rHuEPO) administration on blood pressure and urinary albumin excretion were studied in normotensive Wistar-Kyoto rats (WKY), in spontaneously hypertensive rats (SHR), and in SHR rats treated with an angiotensin converting enzyme inhibitor (SHR-ACEi). Rats were housed in metabolic cages and treated with rHuEPO (150 U/kg body weight [bw] three times a week) for 6 weeks. Control animals received the vehicle only (0.25 mL of physiological saline). An angiotensin converting enzyme inhibitor was administered in the drinking water for 6 weeks (spirapril 5 mg/kg bw). Systolic blood pressure (SBP), and 24 h urinary albumin excretion (UAE) were measured once a week. No significant differences in SBP were observed between rHuEPO and vehicle-treated normotensive animals at the end of the treatment (171.9 +/- 4.9 v 172.1 +/- 5.6 mm Hg, respectively). After 6 weeks, SBP was significantly higher in SHR and SHR-ACEi groups treated with rHuEPO than in control groups (239.8 +/- 7.3 and 243.0 +/- 7.3 mm Hg v 218.1 +/- 6.0 and 187.9 +/- 4.6 mm Hg, respectively); UAE was significantly higher in groups treated with rHuEPO than in control groups (WKY: 265.9 +/- 19.5 v 127.0 +/- 12.3 microg/100 g bw, SHR: 1668.4 +/- 564.6 v 234.8 +/- 22.9 microg/100 g bw, and SHR-ACEi: 1522.7 +/- 448.3 v 143.0 +/- 18.9 microg/100 g bw, respectively). We concluded that erythropoietin treatment causes an increase in arterial pressure in SHR only, and an increase in UAE in both normotensive and hypertensive rats. The albuminuric effect was not entirely dependent on increased blood pressure. The treatment with an angiotensin converting enzyme inhibitor did not modify either the proteinuric or the pressor effects.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Drinking; Erythropoietin; Hematocrit; Hemoglobins; Humans; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Recombinant Proteins; Sodium; Urodynamics

The 1995 Peritoneal Dialysis Core Indicators Study was conducted by the Health Care Financing Administration to ascertain standard practices and outcomes in chronic peritoneal dialysis patients. Data from 1,202 patients who did not receive hemodialysis but who were on chronic ambulatory peritoneal dialysis (CAPD) for at least part of the 6-month period between November 1, 1994, and April 30, 1995, are reported. The mean serum albumin level for this cohort was 3.5 g/dL by the bromcresol green method and 3.2 g/dL by the bromcresol purple method. Data sufficient to calculate a weekly Kt/V(urea) or weekly creatinine clearance were available for only 34% of patient submissions. In these patients, the median weekly Kt/V(urea) was 1.7 using a fixed value for V of 0.58 x body weight and was 2.0 using the Watson equation to calculate V; the median weekly creatinine clearance was 60.7 L/wk/1.73 m2. The mean hematocrit for this cohort was 32% and the average weekly recombinant human erythropoietin (rHmEPO) dose was 115 u/kg. Hematocrit values < or = 30% were found in 50% of black patients and 31% of white patients. The average blood pressure among peritoneal dialysis patients was 139/80 mm Hg, with 29% of patients having a systolic blood pressure exceeding 150 mm Hg and 18% a diastolic blood pressure greater than 90 mm Hg. In summary, serum albumin levels were significantly lower in peritoneal dialysis patients than in hemodialysis patients. Approximately one third of peritoneal dialysis patients did not have an adequacy measure obtained during the 6-month observation period. A significant minority of patients had either inadequately treated anemia of chronic renal disease or hypertension. There is an opportunity to substantially improve the medical care provided to chronic peritoneal dialysis patients.

Topics: Adolescent; Adult; Aged; Blood Pressure; Body Weight; Cohort Studies; Creatinine; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Serum Albumin; Urea

Erythropoiesis was investigated in 32 children wih short stature and in eight children with skeletal dysplasia by studying blood hemoglobin in relation to growth and to serum concentrations of insulin-like growth factor I (IGF-I), IGF binding protein-3 (IGFBP-3), and erythropoietin (EPO) before, during, and after 12 months of recombinant human growth hormone (GH) treatment. Blood hemoglobin concentration was positively correlated with relative body height and with serum IGF-I and IGFBP-3 levels (P = .001 to .02), but not with the concentrations of EPO. The normal age-dependency of hemoglobin was lacking. Hemoglobin levels and their responses to GH treatment were similar in the patients with GH deficiency and those with normal GH secretion. Treatment with GH accelerated growth and elevated the concentrations of hemoglobin, IGF-I, and IGFBP-3. In the eight patients with skeletal dysplasia, body mass increased similarly, but gain in height was less than in the other patients, and the increase in hemoglobin was markedly pronounced. In this group, the correlations between hemoglobin, IGF-I, and IGFBP-3 were extremely close (r = 0.80 to 0.85, P = .031 to .008). These findings are in accord with earlier observations from in vitro and animal studies, and suggest that the GH-IGF axis is involved in the physiologic elevation of hemoglobin levels during childhood.

Topics: Achondroplasia; Adolescent; Body Height; Body Weight; Bone Diseases, Developmental; Child; Child, Preschool; Dwarfism; Dwarfism, Pituitary; Erythropoiesis; Erythropoietin; Female; Growth Hormone; Hemoglobins; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Puberty, Precocious; Recombinant Proteins

Impaired omega-6 essential fatty acid metabolism and exaggerated polyol pathway flux contribute to the neurovascular abnormalities in streptozotocin-diabetic rats. The potential interactions between these mechanisms were examined by comparing the effects of threshold doses of aldose reductase inhibitors and evening primrose oil, alone and in combination, on neurovascular deficits. In addition, high-dose aldose reductase inhibitor and evening primrose oil treatment effects were challenged by co-treatment with the cyclo-oxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-L-arginine. Eight weeks of diabetes caused an 18.9% reduction in sciatic motor conduction velocity (p < 0.001). This was only modestly ameliorated by a 0.1% dietary supplement of evening primrose oil or the aldose reductase inhibitors ZD5522 (0.25 mg.kg-1.day-1 and WAY121 509 (0.2 mg.kg-1.day-1 for the final 2 weeks. However, joint treatment with primrose oil and ZD5522 or WAY121 509 caused marked 71.5 and 82.4% corrections, respectively, of the conduction deficit. Sciatic nutritive blood flow was 43.1% reduced by diabetes (p < 0.001) and this was corrected by 67.8% with joint ZD5522 and primrose oil treatment (p < 0.001). High-dose WAY121 509 (10 mg. kg-1.day-1 and primrose oil (10% dietary supplement) prevented sciatic conduction velocity and nutritive blood flow deficits in 1-month diabetic rats (p < 0.001). However, these effects were abolished by flurbiprofen (5 mg.kg(-1).day-1 and NG-nitro-L-arginine (10 mg.kg-1.day-1) co-treatment (p < 0.001). Thus, the data provide evidence for synergistic interactions between polyol pathway/nitric oxide and essential fatty acid/cyclo-oxygenase systems in the control of neurovascular function in diabetic rats, from which a potential therapeutic advantage could be derived.

Topics: Acetanilides; Aldehyde Reductase; Analysis of Variance; Animals; Arginine; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dietary Fats, Unsaturated; Enzyme Inhibitors; Erythropoietin; Fatty Acids, Essential; Flurbiprofen; Fructose; gamma-Linolenic Acid; Inositol; Linoleic Acids; Male; Neural Conduction; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oenothera biennis; Plant Oils; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Regression Analysis; Sciatic Nerve; Sorbitol; Sulfones

Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5 mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure-induced nephrotoxicity and anemia were investigated. The rats treated with 0.05 mg/kg Cd showed no apparent hematological, urinary, and histopathological abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at 16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks. Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin concentration was noted at 50 weeks. The blood chemistry from the same group revealed a decrease in plasma iron levels and an increase in total iron binding capacity throughout the administration period. The erythropoietin (EPO) level was increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level was not elevated even when the hemoglobin level was decreased at 50 weeks. These findings showed that renal anemia also occurred in addition to the iron deficiency anemia at 50 weeks.

Topics: Anemia; Animals; Body Weight; Cadmium; Cadmium Poisoning; Drinking; Erythropoietin; Female; Ferritins; Hemoglobins; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Metallothionein; Ovariectomy; Rats; Rats, Sprague-Dawley; Urine

The purposes of this study were to determine whether (1) erythropoietin (Epo) gene expression could be stimulated, by severe hemorrhage, in both kidney and liver, at three stages of gestation (75-80, 106-112, and 140-142 days; term approximately equal to 150 days) in chronically-cannulated ovine fetuses and (2) whether the liver would compensate for the lack of kidneys at 110 days. Blood was removed (20% of estimated blood volume) at each of 0, 1, 19 h, and tissues collected at 24 h. In hemorrhaged fetuses (H) the liver mRNA levels were 2.7-, 5-, and 3-times that of control fetuses (C) at 78, 110 and 141 days, respectively. The kidney H:C ratios, for Epo mRNA, were 5, 6.4 and 43, respectively, at these three stages of gestation. In six fetuses at 108 days, nephrectomized 5-7 days before hemorrhage (HN) Epo mRNA increased 5-fold in the liver, and plasma Epo values were significantly lower (P < 0.05) than in intact (H). Thus hemorrhage stimulates increased Epo gene expression in both liver and kidney from mid-gestation, in the ovine fetus, but the liver does not compensate for the lack of kidneys at 110 days.

Topics: Animals; Body Weight; Erythropoietin; Gene Expression; Hemorrhage; Kidney; Liver; Nephrectomy; Organ Size; RNA, Messenger; Sheep

Hematocrit increase with recombinant erythropoietin (rEPO) has been associated with increased progression of renal insufficiency in experimental models of renal mass reduction. The aim of the present study was to assess the effects of therapy with rEPO and various antihypertensives on the progression of chronic renal insufficiency and on arterial hypertension in an experimental model of renal mass reduction. Rats subjected to a two-thirds nephrectomy were randomly assigned to an untreated control group or to therapy with rEPO (subcutaneously, at an initial dose of 40 U/kg thrice weekly), rEPO plus verapamil (subcutaneously, 0.5 mg/kg/day), or rEPO plus enalapril (orally, 50 mg/l in the drinking water). Combining enalapril and rEPO therapy controlled systemic blood pressure (BP) and the increase in proteinuria. Glomerular injury, as assessed 16 weeks after renal ablation, was more marked in the animals treated with rEPO with or without either antihypertensive. The morphometric analyses showed greater glomerular tuft areas in the three groups receiving rEPO than in the controls. The glomerular tuft area was directly correlated with the rate of glomerulosclerosis. In about 11% of the rEPO-treated hypertensive rats, the lesions showed severe hypertensive vasculopathy; in the animals treated with rEPO plus enalapril, the lesions were less severe. We conclude that therapy with rEPO was associated to renal damage which could not be attenuated by enalapril despite controlling BP and proteinuria, and may have a nonhemodynamic cause. Therapy with rEPO might trigger lesions usually associated with severe arterial hypertension; concomitant therapy with enalapril attenuates hypertensive vasculopathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Calcium Channel Blockers; Creatinine; Erythropoietin; Hematocrit; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Recombinant Proteins; Vasodilation

Hematologic studies were performed on 21 ground control rats and 21 rats flown during the Spacelab Life Sciences-2 14-day mission. Group A (n = 5) was used to collect blood in flight and 9 days postflight, group B (n = 5) was injected with recombinant human erythropoietin (rhEpo), group C (n = 5) received saline as a control, and group D (n = 6) was killed in flight and tissues were collected. Results indicated no significant changes in peripheral blood erythroid elements between flight and ground control rats. The nonadherent bone marrow on flight day 13 showed a lower number of recombinant rat interleukin-3 (rrIL-3)-responsive and rrIL-3 + rhEpo-responsive blast-forming unit erythroid (BFU-e) colonies in flight rats compared with ground control rats. On landing day, a slight increase in the number of rhEpo + rrIL-3-responsive BFU-e colonies of flight animals compared with ground control rats was evident. Nine days postflight, bone marrow from flight rats stimulated with rhEpo alone or with rhEpo + rrIL-3 showed an increase in the number of colony-forming unit erythroid colonies and a decrease in BFU-e colonies compared with ground control rats. This is the first time that animals were injected with rhEpo and subsequently blood and tissues were collected during the spaceflight to study the regulation of erythropoiesis in microgravity.

Topics: Animals; Blood Cell Count; Body Weight; Bone Marrow; Bone Marrow Cells; Erythrocyte Count; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Humans; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reticulocyte Count; Space Flight; Weightlessness

Erythropoietin is a glycoprotein produced endogenously in the kidney, which stimulates red blood cell production. We evaluated the effects of chronic treatment with recombinant human erythropoietin (epoetin alfa: EPO) on the performance of 6-month-old male C57BL/6J mice in a spatial learning task, the Morris water maze. Mice were treated with either EPO (1.5 U injected SC every other day) or vehicle (PBS also injected SC every other day). Results indicated that the treatment had no effect on maze performance after 8 weeks, but after 19 weeks the EPO-treated mice showed better performance compared to controls as measured by mean distance (centimeters) to reach the goal platform. The improved performance in EPO-treated mice at 19 weeks was accompanied by an increased hematocrit. After 32 wk of EPO-treatment, the hematocrit returned to baseline levels even though the size and density of the red blood cells were increased.

Topics: Animals; Body Weight; Erythrocytes; Erythropoietin; Hematocrit; Humans; Male; Maze Learning; Mice; Mice, Inbred C57BL; Recombinant Proteins

The study investigated the influence of prolonged physical stress during survival training with food and fluid deprivation on the serum concentrations of erythropoietin (EPO). A group of 29 male subjects [mean age 22.2 (SD 2.8) years, height 1.78 (SD 0.06) m, and body mass (m(b)) 73.5 (SD 8.6) kg] were studied for 5 days of multifactorial stress including restricted water intake (11 H2O. day(-1)) and food intake (628 kJ. day(-1)) combined with physical exercise (estimated energy expenditure approximately 24000 kJ.day(-1)) and sleep deprivation (20 h within 5 days). Blood samples were taken before (T1), after 72 h (T2) and 120 h (T3) of physical stress, and after 48 h, (T4) and 72 h (T5) of recovery. The samples were analysed for EPO, and concentrations of serum iron (Fe), haptoglobin (Hapto), transferrin (Trans), ferritin (Fer), haemoglobin (Hb) and packed cell volume (PCV). The m(b) had decreased by 6.77 kg at T3 (P <0.01) and 0.68 kg at T5. The EPO and Hapto decreased during the survival training (P <0.01) and increased during the recovery period (P <0.01). The Fe increased during the survival training (P <0.01) and remained above the control concentrations during recovery (P <0.01). The Hapto decreased during the survival training (P <0.01) and remained below control concentration at T4 and T5 (P <0.01). The Trans decreased continuously over the week (P <0.01). The Fer increased during the survival training (P <0.01) and returned to control concentration at T5. The Hb increased from T1 to T2 (P <0.01) and had decreased significantly at T5 (P <0.01). The PCV increased from T1 to T2 (P <0.01) and remained below control levels afterwards (P <0.01). From our study it was concluded that, in humans, prolonged physical stress with food and fluid deprivation induces a marked EPO decrease, which is followed by a rapid increase during recovery to restore the reduced O2 transport capacity.

Topics: Adult; Body Weight; Erythropoietin; Food Deprivation; Hemoglobins; Humans; Male; Middle Aged; Osmolar Concentration; Physical Endurance; Physical Exertion; Time Factors; Water Deprivation

Cadmium (Cd), a highly toxic heavy metal, is distributed widely in the general environment of today. The characteristic clinical manifestations of chronic Cd intoxication include renal proximal tubular dysfunction, general osteomalacia with severe pains, and anemia. We have recently reported that the serum level of erythropoietin (EPO) remained low despite the severe anemia in patients with Itai-itai disease, the most severe form of chronic Cd intoxication. In order to prove that the anemia observed in chronic Cd intoxication arises from low production of EPO in the kidneys following the renal injury, we administered Cd to rats for a long period and performed the analysis of EPO mRNA inducibility in the kidneys. The rats administered Cd for 6 and 9 months showed anemia with low levels of plasma EPO as well as biochemical and histological renal tubular damage, and also hypoinduction of EPO mRNA in the kidneys. The results indicate that chronic Cd intoxication causes anemia by disturbing the EPO-production capacity of renal cells.

Topics: Anemia; Animals; Blotting, Northern; Body Weight; Bone Marrow; Cadmium Chloride; Erythropoietin; Female; Hematologic Tests; Kidney; Organ Size; Rats; Rats, Wistar; RNA, Messenger

This study was performed to investigate the factors that influence intraperitoneal absorption of recombinant human erythropoietin (rHuEPO) and to evaluate the differences of the pharmacokinetics of intraperitoneally administered rHuEPO before peritonitis and after recovery. First, the pharmacokinetics in different groups of continuous ambulatory peritoneal dialysis (CAPD) patients was studied. Thirty-six CAPD patients were enrolled and divided into four groups. Group 1 included 20 patients who were either just placed on CAPD therapy or had been on CAPD for < 1 year, but with a low frequency of peritonitis episodes. Group 1 was divided into four subgroups by body weight (20-30, 31-45, 46-55, and > 55 kg). Group 2, patients who had received CAPD treatment for more than 1 year, was further divided into group 2a and group 2b according to a low or a high frequency of peritonitis episodes, respectively. rHuEPO (100 U/kg) was administered as a single bolus of intravenous, subcutaneous, or intraperitoneal injection. Intraperitoneal rHuEPO was retained for 10 h. The results showed no significant differences between subcutaneous and intraperitoneal administration in group 1 patients. However, peak concentration, time to reach peak serum level, area under the curves, and bioavailability were substantially lower after intraperitoneal than after subcutaneous administration in group 2a and group 2b patients. There was no influence of body size on peak concentration and area under the curve in group 1 patients. Second, comparison of the pharmacokinetics of intraperitoneal administration before and after recovery from peritonitis in group 1 patients revealed that the serum levels of rHuEPO became lower after the occurrence of peritonitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Body Weight; Child; Drug Administration Routes; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Longitudinal Studies; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Peritonitis; Recombinant Proteins; Retrospective Studies; Time Factors

The purpose of the investigation was to study the metabolism of erythropoietin (EPO) in patients with liver disease. Twelve patients with liver cirrhosis and 10 healthy volunteers were studied. The patients were moderately anemic with a hematocrit of 33 vs 42% (medians) in the volunteers. The pharmacokinetic parameters were calculated after an intravenous (i.v.) injection of 100 U/kg of recombinant human EPO. The serum EPO was measured by radioimmunoassay at regular intervals until 48 h. The median terminal elimination half life in the cirrhosis patients was 5.15 h vs 5.37 h in the control subjects. The clearance was 7.78 vs 7.52 ml/min/1.73 m2 (ns). The steady-state volume of distribution was 3.69 vs 3.09 1/1.73 m2 (ns). The estimated endogenous EPO production was significantly higher in liver cirrhosis (486 vs 290 U/d/1.73m2, p < 0.01). The basal serum EPO was significantly higher in the cirrhosis patients (43.5 vs 26.3 U/l, p < 0.01). The hematocrit correlated inversely with the basal serum EPO level in the cirrhosis patients (r = -0.63, p < 0.04). The EPO-clearance was not related to the presence of ascites, esophageal varices, or to abnormal blood chemistry. It was concluded that normal metabolism of EPO was maintained in liver cirrhosis and that the cirrhotic patients had a moderate compensatory increase of EPO production in response to anemia.

Topics: Adult; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Injections, Intravenous; Liver Cirrhosis; Male; Middle Aged; Recombinant Proteins

The effects on Wistar rat body weight were examined after a single subcutaneous (s.c.) or oral (p.o.) administration of dipalmitoylphosphatidylcholine (DPPC) liposomes composed of soybean-derived sterols (SS) and their glucosides (SG) with or without entrapping recombinant human erythropoietin (Epo) for 1 week. Body weight increased significantly after both types of administration compared with the control groups irrespective of the existence of Epo. The neutral lipid concentration in plasma increased with the increase in body weight whereas the total contents of cholesterol and high density lipoprotein cholesterol in the plasma did not change significantly. The SS and SG suspensions following p.o. administration, however, did not alter the body weight. These findings suggest that liposomal SS and SG may be absorbed through the intestinal membrane and induce a change in the uptake of lipid, in contrast to the suspension state. SS in liposomes significantly increased body weight more than SG after p.o. administration.

Topics: 1,2-Dipalmitoylphosphatidylcholine; Administration, Oral; Animals; Body Weight; Drug Carriers; Erythropoietin; Glucosides; Glycine max; Injections, Subcutaneous; Lipids; Liposomes; Male; Phytosterols; Rats; Rats, Wistar

Subcutaneous recombinant human erythropoietin (rHuEpo) treatment of renal anemia was performed in four boys and eight girls on CAPD, aged 0.8-12.5 (mean 7.4) years. In contrast to previous studies, our therapeutic goal was not set with a hematocrit of 30% but with full correction of anemia. Following a maximum weekly rHuEpo dosage of median 120 (range 100-240) IU/kg body weight, hematocrit increased in 10 children from 24 (14-29)% within 12 (4-17) weeks to 40.1 (33.5-48.4)%. The weekly increase in hematocrit was 1.27 (0.5-3.1)%. The corrected reticulocyte count increased from 1.3 (0.7-1.8)% to 2.3 (1.4-3.9)% within 4 (2-6) weeks. Eight children fulfilled the protocol; six with an uncomplicated course were able to maintain a hematocrit of 37.1 (35.1-42.7)% with only one sc medication per week of approximately two-thirds of their highest weekly rHuEpo dosage. No serious adverse effect of rHuEpo therapy was observed.

Topics: Anemia; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Infant; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Reticulocyte Count

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Drug Synergism; Erythropoietin; Female; Hematopoiesis; Hematopoietic Stem Cells; Heme; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neutropenia; Thrombocytopenia; Weight Loss; Zidovudine

The purpose of this study was to define the physiologic responses of the heart and peripheral circulation to chronic anemia using noninvasive measurements while eliminating confounding biochemical, pharmacologic and physiologic variables. Stable chronic hemodialysis patients were studied at the University Hospital based chronic dialysis unit and echocardiography laboratory before and after therapy with human recombinant erythropoietin (rHuEPO). Subjects included maintenance hemodialysis patients free of left ventricular regional wall motion abnormalities discernible by echocardiography, rhythm disturbance, significant valvular or ischemic heart disease. Two-dimensional echocardiograms and simultaneous targeted M-mode echocardiograms, phonocardiograms and externally acquired subclavian artery pulse tracings were used to measure whole blood viscosity, arterial blood gases and ionized calcium, complete blood count, electrolytes, creatinine, blood urea nitrogen (BUN), and inorganic phosphate. All measurements were made immediately post-dialysis before and after therapy with rHuEPO. The interval between pre- and post-rHuEPO studies was 8.3 +/- 2.3 months. We found that post-dialysis hematocrit rose from 24.7 +/- 0.9 to 36.4 +/- 0.9%, hemoglobin from 83 +/- 3 to 121 +/- 3 g/liter and whole blood viscosity from 2.87 +/- 0.11 to 3.71 +/- 0.18 centipoise (all, P < 0.001 after therapy with rHuEPO). The remaining biochemical measurements did not change. Heart rate fell from 83 +/- 3 to 77 +/- 3 beats/min (P = 0.013). Left ventricular preload and afterload were not statistically different before and after rHuEPO. Total vascular resistance rose from 1313 +/- 84 to 1568 +/- 129 dynes.sec.cm-5, P = 0.029. Cardiac output and cardiac index fell by 12 and 15% (P = 0.024 and 0.030), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Body Weight; Cardiovascular System; Erythropoietin; Female; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Models, Cardiovascular; Myocardial Contraction; Recombinant Proteins; Ventricular Function, Left

The nude (athymic) mouse was used as a novel test system for the evaluation of genotoxicity of genetic recombinant human erythropoietin (rhEPO). A fibroblast cell line derived from the kidneys of baby hamsters, BHK-21, or a subclone of BHK-21 transfected with an expression vector containing the human EPO gene, named BXE cells, were implanted in nude mice. The concentration of EPO in the plasma of mice bearing BXE increased in relation to the increase in the weight of the tumor formed from growth of BXE cells. Increased values of hematocrit (Ht), ratio of reticulocytes to erythrocytes (RET ratio) and the number of red blood cells in mice bearing BXE indicated that excessive hematopoiesis was occurring in the host. However, the concentrations of EPO in the plasma of the mice bearing BHK-21 did not increase in relation to the cell mass and consequently the Ht values and RET ratios in these mice were not affected. Marked increases in the frequencies of micronucleated polychromatic erythrocytes (MNPCE) and micronucleated RET (MNRET) were noted in the mice bearing BXE, although no chromosomal aberrations were found in the spleen and marrow cells of the same mice. The increased levels of RET, MNRET and MNPCE seemed to result from acceleration of erythroblastic maturation and proliferation by rhEPO. It is, therefore, concluded that errors in the processes of enucleation or differentiation of erythrocytes should be equally considered as possible mechanisms alongside errors in genetic repair processes for the increased frequencies of MNPCE and MNRET.

Topics: Animals; Body Weight; Cell Differentiation; Cell Line; Chromosome Aberrations; Clone Cells; Cricetinae; Erythrocytes; Erythropoietin; Humans; Kidney; Mice; Mice, Nude; Micronucleus Tests; Mutagenicity Tests; Mutagens; Neoplasms, Experimental; Recombinant Proteins; Transfection

Seventeen patients--10 females, 7 males--mean age 52 years (range: 21-77 years), on CAPD for an average of 35 months (range 10-160 months) were studied. Mean initial dose of EPO was 114 +/- 45 U/kg/week subcutaneously (range: 59-209). The dose was adjusted to achieve and maintain a target Hb of 100 g/L and Hct 30%. Fifteen of the patients (88.2%) achieved this target within 6 months [baseline to month 6 changes: Hb 72 +/- 10 g/L to 107 +/- 12 g/L (p = 0.0001); Hct 22 +/- 3% to 33 +/- 4% (p = 0.0001)]. Serum total protein also increased significantly over the time of EPO use (p = 0.0133); changes from baseline were significant by the fourth month [68 +/- 9 g/L to 72 +/- 9 g/L (p = 0.0115)]. Serum albumin also increased significantly over time (p = 0.0157). The change from the baseline result (37 +/- 4 g/L) was statistically significant by month 2 (p = 0.0060) and was maintained over the following 4 months [month 6 result: 40 +/- 3 g/L (p = 0.0180)]. The increase was greater for 8 patients with initial serum albumin < 35 g/L (mean change 5.75 g/L) than for the 9 subjects with levels > 35 g/L (mean change 0.11 g/L). In a comparison group of 17 patients (matched for age, sex, duration of CAPD, underlying disease and antihypertensive treatment), who did not receive EPO treatment, albumin and protein did not appear to increase over time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Proteins; Body Weight; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Peritoneal Dialysis, Continuous Ambulatory; Retrospective Studies

To assess the efficacy of blood pressure control in continuous ambulatory peritoneal dialysis (CAPD), blood pressure was examined sequentially in 63 CAPD patients transferred from hemodialysis (HD), and in 97 patients started de novo on CAPD (NEW), over periods ranging from 3 to 63 months. Blood pressure changes were related to changes in body weight, hematocrit, and treatment with recombinant human erythropoietin (rHu-EPO), as well as to changes in antihypertensive drug requirements. Both groups of patients showed an immediate improvement in blood pressure control at 1 month, as manifested by an absolute decrease in blood pressure in HD patients (-4.3% +/- 2.1% [SEM], P < 0.05) and by a decrease in antihypertensive drug requirements in NEW patients (from 78% to 43.3%). This early improvement in blood pressure appeared to be volume-related, as reflected by changes in body weight. Both groups showed an additional decrement in blood pressure at approximately 6 months (-7.8% +/- 2.6% [SEM], P < 0.05, HD group; -3.4% +/- 2.4% [SEM], P < 0.05, NEW group). Treatment of anemia with rHu-EPO in 22 of the CAPD patients had no effect on blood pressure. CAPD thus appears to be more effective than HD in controlling blood pressure.

Topics: Anemia; Antihypertensive Agents; Blood Pressure; Body Weight; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Time Factors

The purpose of this study is to compare the direct vasopressor effects of erythropoietin between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The aortic rings from SHR or WKY were suspended in tissue baths coupled with tension-recording devices. High concentrations of recombinant human erythropoietin (more than 20 U/ml) induced vasoconstriction in the aortic ring of genetically hypertensive SHR. Furthermore, only in SHR, 10 U/ml erythropoietin enhanced contraction induced by 10(-7) M norepinephrine (+145% vs +121%, p < 0.04) and reduced relaxation by 10(-7) M acetylcholine (-69% vs -96%, p < 0.05). On the other hand, erythropoietin did not influence the contractility of aortic ring in normotensive WKY. These results suggest that erythropoietin exhibits its direct vasopressor effect preferentially in the blood vessels of genetically hypertensive animals.

Topics: Acetylcholine; Angiotensin II; Animals; Blood Pressure; Body Weight; Erythropoietin; Hematocrit; Hypertension; In Vitro Techniques; Male; Norepinephrine; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasoconstriction

This study investigated the hypothesis that a genetic predisposition to hypertension is involved in the etiology of the elevation in blood pressure induced by human recombinant erythropoietin (rHuEPO).. Blood pressure changes after 10 weeks of treatment with rHuEPO were compared between 26 patients with a positive family history of hypertension and 27 with a negative family history.. Mean blood pressure was significantly increased in patients with a positive family history of hypertension (+8.8 mm Hg, p < 0.001). In contrast, the change was not significant in those whose family history was negative (+1.8 mm Hg, not significant). The mean blood pressure of 14 of 26 patients with a positive family history of hypertension increased by more than 10%, whereas such an increase occurred in only 2 of 27 patients with a negative family history (p < 0.001). The two groups were similar in terms of the total dose of rHuEPO given, the degree to which their anemia improved, and their basal blood pressures.. It appears that hemodialysis patients with a positive family history of hypertension are susceptible to developing hypertension during treatment with rHuEPO.

Topics: Antihypertensive Agents; Blood Pressure; Body Weight; Causality; Confounding Factors, Epidemiologic; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Male; Medical History Taking; Middle Aged; Renal Dialysis; Weight Gain

The role of the submandibular salivary gland in erythropoiesis in the male mouse (MRC TO strain) was evaluated by subjecting mice without submandibular salivary glands (SX) and control (C) sham-operated mice to a variety of stimuli intended to stress the erythropoietic system. In SX mice, after removal of the submandibular glands at age 4 weeks and observation for 8 weeks, mean hematocrit was the same as in C mice, but mean body weight was less. Bilateral removal of the submandibular glands at age 6 weeks neither affected the rate of fall and subsequent recovery of hematocrit which followed treatment with phenylhydrazine (80 mg/kg intraperitoneally [i.p.] 9 days after operation) nor altered the rate of increase in hematocrit or change in body weight which occurred during hypobaric hypoxia (0.5 atm, > 23 hours/day) for 23 days. Mean (SEM) estimates of serum immunoreactive erythropoietin after 17 hours' continuous hypobaric (0.5 atm) exposure were not significantly different between SX [186 (30) mU/mL, n = 7] and C mice [232 (17) mU/mL, n = 7]. In mice given bilateral nephrectomies at age 6 weeks--2 weeks after SX or C surgery--and then both treated with phenylhydrazine (60 mg/kg i.p.) and exposed for 17 hours to hypobaric (0.5 atm) hypoxia, mean estimates of serum immunoreactive erythropoietin were 22.6 (10.6) mU/mL and 22.3 (5.4) mU/mL in SX (n = 5) and C (n = 5) mice. Results of the study do not support the premise that the submandibular salivary glands either contribute to the erythropoietic response or are a source of extrarenal erythropoietin.

Topics: Animals; Atmospheric Pressure; Body Weight; Erythropoiesis; Erythropoietin; Hematocrit; Hypoxia; Male; Mice; Phenylhydrazines; Submandibular Gland

Urea kinetic modeling (UKM) was carried out to evaluate the water control in patients undergoing long-term hemodialysis. In 21 patients on chronic dialysis, the results of two different determinations of the total body water, i.e. by the deuterium oxide (D2O) method and by UKM, were compared. A correlation was observed with Y = 0.98X + 5.9 (P less than 0.01, r = 0.91) for males and Y = 0.97X + 6.2 (P less than 0.01, r = 0.90) for females, indicating that UKM is useful for determining the total body water. In addition, the 21 patients were classified into two groups based on their ECG findings, and UKM was performed in the two groups for comparison. The values of the total body water were 68.5 +/- 4.0% and 68.6 +/- 6.2% of body weight, respectively, with no significant difference between them. However, the CTR was 50.2 +/- 2.8% and 46.2 +/- 4.4%, respectively. Thus, not only X-ray examinations but also UKM should be carried out to determine the standard weight (SW-DW) in the presence of cardiac dysfunction. Instructions for water control were given when the total body water exceeded 73% during the UKM measurements over 5 years, which allowed an optimal total body water to be maintained thereafter. The possible influence of erythropoietin (EPO) was also examined by performing UKM in 8 cases receiving EPO and 7 cases without EPO. No noticeable difference was observed between the two groups. 17 patients using a polyacrylonitrile (PAN) membrane were further divided into those with and those without EPO to evaluate the possible influence of the PAN membrane-EPO combination. As a result, no significant difference was demonstrated, suggesting that UKM can be satisfactorily performed under such conditions. In 11 patients on chronic dialysis, the levels of alpha-human atrial natriuretic peptide (alpha-hANP) were measured pre- and post-dialysis to examine the relationship between the change in alpha-hANP and rate of weight loss (%). A significant correlation was observed with Y = 12.8X + 5.1 (P less than 0.05, r = 0.68). In conclusion, UKM was found to be useful for evaluating the water control and for assessing the optimal dialysis in patients receiving long-term hemodialysis.

Topics: Acrylic Resins; Adult; Atrial Natriuretic Factor; Body Water; Body Weight; Deuterium; Deuterium Oxide; Erythropoietin; Female; Humans; Male; Membranes, Artificial; Middle Aged; Renal Dialysis; Time Factors; Urea; Water

Pathophysiological and therapeutic properties of anemia in rats with adjuvant-induced arthritis (AA) were investigated. Both anemia and chronic inflammation were induced in rats by a single injection of Freund's complete adjuvant. This study confirmed other earlier data that these anemic rats with AA had reduced serum iron levels and that the anemia was characterized as mild, non-progressive, hypochromic, microcytic. In addition, our studies showed that these anemic rats had slightly but significantly enhanced erythropoietin titers, but not renal failure; there was no significant difference in blood urea nitrogen and creatinine levels in anemic and normal groups. The anemia in rats with AA was improved by recombinant human erythropoietin (r-HuEPO) at 30 and 100 U/kg/day, given i.v. for 5 days. In contrast, iron-chondroitin-sulfate colloid (10 mg/kg/day, i.v. for 5 days) failed to improve the anemia and to enhance the effects of r-HuEPO. These data suggest that anemia in rats with adjuvant-induced arthritis is distinguished, pathophysiologically and therapeutically, from iron deficiency anemia, hemolytic anemia, and renal anemia.

Topics: Anemia, Hypochromic; Animals; Arthritis, Experimental; Body Weight; Chondroitin Sulfates; Colloids; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Iron; Rats; Rats, Inbred Lew; Recombinant Proteins

Nutritional status was assessed in 25 anemic hemodialysis patients before and during erythropoietin treatment. Nutritional assessment included regular blood chemistry determinations, anthropometric measurements, analysis of protein content in skeletal muscle, and estimation of daily protein intake from protein catabolic rate determinations (using urea kinetic modelling) and dialysis efficiency for urea. These measurements were done immediately prior to erythropoietin treatment, after anemia correction and after one year of maintenance erythropoietin treatment. Both relative body weights and subcutaneous fat stores were low at the start, but increased significantly (p less than 0.05) during the study. Sixteen of the 25 patients gained weight and eight patients lost weight. The patients with weight gain had at the start of the study low weight indices (body weight 89.9 +/- 7.6% of ideal body weight, body mass index 20.6 +/- 1.6), significantly (p less than 0.005) lower than the patients with weight loss. Although protein malnutrition was not obvious from arm anthropometrics, alkali soluble protein/DNA ratio or from serum albumin determinations, ASP/DNA ratio, increased in three of five patients investigated after one year on erythropoietin treatment. Neither protein catabolic rate nor dialysis efficiency changed significantly during the study. We conclude that anemia correction with erythropoietin has a positive effect on malnutrition in hemodialysis patients. In patients with underweight, an adjustment of fat stores was initially observed, followed possibly by an improvement in muscle protein content.

Topics: Adult; Anemia; Anthropometry; Body Mass Index; Body Weight; Combined Modality Therapy; Drug Evaluation; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Muscles; Nutrition Assessment; Recombinant Proteins; Renal Dialysis

Very high concentrations of erythropoietin (epo), in clonogenic cultures, result in reduced production of neutrophils, and fetal progenitors are more sensitive to this effect of epo than are those of adults. However, the significance of this observation is unclear because no evidence of reduced neutrophil production has been presented following administration of recombinant epo to human or animal subjects. In the present study we injected newborn rats, beginning on the first day of life, with 20, 200, or 2,000 U epo/kg body weight, and measured serum epo concentrations after 2, 8, 24, or 48 hours. After selecting a dose that resulted in serum concentrations greater than 1,000 mU/mL (a concentration that resulted in down-modulation of neutrophil production from neonatal rat progenitors in vitro) other newborn rats were treated for 3 days with that dose (1,000 U epo/kg) or a vehicle control. Administration of epo resulted in increased hematocrits (P less than .001), reticulocyte counts (P less than .001), normoblasts/femur (P less than .05), and normoblasts/spleen (P less than .001). Recipients of epo also had more erythroid colony-forming units (CFU-E) (P less than .001) and higher CFU-E tritiated thymidine suicide rates (P less than .01) than did controls. However, femurs and spleens of epo recipients contained fewer postmitotic neutrophils (femur, P less than .01; spleen, P less than .01), proliferative neutrophils (femur, P less than .01; spleen, P less than .02), granulocyte-macrophage colony-forming units (CFU-GM) (P less than .005), and lower CFU-GM tritiated thymidine suicide rates (P less than .01). Seven and nine days after twice-daily administration of 2,000 U epo/kg, blood neutrophil concentrations had diminished (P less than .05). Thus, administration of high doses of recombinant epo to newborn rats resulted in diminished neutrophil production accompanying accelerated erythropoiesis.

Topics: Animals; Animals, Newborn; Body Weight; Cell Cycle; Erythropoiesis; Erythropoietin; Femur; Hematopoietic Stem Cells; Leukocyte Count; Neutrophils; Rats; Rats, Inbred Strains; Spleen

Adult female Wistar rats were injected with 125 mg/kg b.w. of human methemoglobin (M-Hb) in order to induce a first episode of hemodynamically-mediated acute renal failure (HMARF). Eleven days after the injection of M-Hb, other groups of rats received another equal dose of the drug in order to induce a second episode of HMARF. Evaluation of renal function, histopathology studies, and determinations of plasma and kidney erythropoietin (Epo) titers by radioimmunoassay in normoxic and hypoxic conditions were performed 1, 2, 3, 5 and 10 days after M-Hb administration. Treatment induced transient increases in plasma urea concentration, fractional sodium excretion, and urine volume, and significant depression in urine osmolality. In every case, the maximal effect of the first injection of M-Hb on the individual parameters was always greater than that of the second injection, and observed on the 5th post-injection day. Histologic sections showed interstitial cellular infiltration, desquamation of the proximal tubular epithelium and collapse or dilation of the tubular lumen. Treatment with M-Hb depressed Epo titers in both kidney homogenates and plasma in normoxic as well as hypoxic rats. Here again, the effect of the first injection of the drug was higher than that of the second one. These observations indicate that there is a negative correlation between kidney tubule injury and Epo production in normoxic and hypoxic conditions. The findings give support to the concept that Epo production is related to proximal tubular function.

Topics: Acute Kidney Injury; Analysis of Variance; Animals; Body Weight; Erythropoietin; Female; Kidney Tubules; Methemoglobin; Organ Size; Oxygen; Rats; Rats, Inbred Strains

Erythrocytes in anemic rats with adjuvant arthritis (AA) were less deformable compared with normal rats. Swelling of the spleen was noticed in anemic rats with AA. The treatment of anemic rats with recombinant human erythropoietin (r-HuEPO; 30 and 100 U/kg, i.v., for 5 days) resulted in a normalization of both the anemia and erythrocyte deformability. It is suggested that erythrocytes with reduced deformability may be sequestered by endothelial slits of the spleen, which may play a causative role in the anemia in rats with AA.

Topics: Anemia; Animals; Arthritis, Experimental; Body Weight; Erythrocyte Deformability; Erythropoiesis; Erythropoietin; Female; Organ Size; Rats; Recombinant Proteins

Recombinant human erythropoietin (rHu-EPO) was given during 12 to 20 months in 15 long term haemodialysis anaemic (mean Hb: 6.6 +/- 1 g/dl) patients who required no blood transfusion. Patients over 65, or with severe arterial disease or with uncontrolled hypertension were not included in this trial. Correction of anaemia (mean Hb 12.1 +/- 0.6 g/dl) was achieved in all patients and maintained all along the study. An improved sense of wellbeing and increased exercise tolerance were reported by all patients. Appropriate maintenance dosage of rHu-EPO was 74 +/- 6 U/kg i.v. twice weekly. High dose oral and/or intravenous iron therapy was necessary in the absence of previous marked iron overload. One retinal venous thrombosis was the sole severe side-effect encountered. A slight but significant increase of blood pressure was observed with the need of intensifying previous anti-hypertensive therapy in one patient and of starting one in one another. Fine adjustment of the dry weight was necessary to maintain blood pressure in the normal range. Heparin requirements increased in the majority of patients because of hollow fibre clotting but there was no evidence of decreased efficacy of dialysis. In two patients clotting of arteriovenous fistula was not obviously related to the rHu-EPO treatment.

Topics: Adult; Anemia; Body Weight; Drug Evaluation; Erythropoietin; Female; Humans; Hypertension, Renal; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retinal Vein Occlusion

Our present study was undertaken to determine the serum erythropoietin concentration (radioimmunoassay), hematocrit, red cell mass, and body weight of mice exposed to hypoxia in a hypobaric chamber (0.42 atm, 22 h/day) for 14 days and during the 10 posthypoxic days at ambient pressure to clarify the correlation of the red cell mass and erythropoietin production during hypoxia. The mean serum erythropoietin titer was 326.23 +/- 77.04 mU/ml after 2 days, reached the highest level after 3 days (452.2 +/- 114.5 mU/ml), then gradually declined to a level of 36.5 +/- 11.4 mU/ml after 14 days of hypoxia, and was undetectable during the 10-day posthypoxic period. The hematocrit values were significantly increased from 41.09 +/- 0.50% at day 0 to 51.65 +/- 1.08% after 3 days and to 72.20 +/- 1.53% after 14 days of hypoxia. The red cell mass (calculated from initial body weight) increased from 3.24 +/- 0.1 ml/100 g at day 0 to 7.32 +/- 0.46 ml/100 g after 14 days of hypoxia and declined to 6.66 +/- 0.53 ml/100 g at the end of the 10-day posthypoxic period. The mice lost weight while they were in the hypobaric chamber and showed a significant increase in body weight during the 10-day posthypoxic period. These studies support the concept that chronic intermittent hypoxia causes an early increase, followed by a rapid decline, in erythropoietin production, which is correlated with the gradual increase in red cell mass.

Topics: Animals; Atmospheric Pressure; Body Weight; Erythrocyte Volume; Erythropoietin; Female; Hematocrit; Hypoxia; Mice; Polycythemia

Stimulation of erythropoiesis during growth is necessary to ensure proportionality between erythrocyte mass and body mass. However, the way by which erythrocyte formation is adapted to body growth is still unknown. Growth arrest in hypophysectomized rats is accompanied by decreased erythropoiesis. We have, therefore, examined whether insulin-like growth factor I (IGF-I), the mediator of growth hormone effects on body growth, is able to restore erythropoiesis in these animals. Subcutaneous infusions of 120 micrograms of recombinant human IGF-I per day in hypophysectomized rats led to increases in body weight, 59Fe incorporation into erythrocytes, and the number of reticulocytes that were similar to increases caused by infusions of 28 milliunits of human growth hormone per day. Body weight gain and 59Fe incorporation were linearly correlated. Like growth hormone, IGF-I also caused a significant rise in serum erythropoietin concentrations. However, the stimulatory effect on erythropoiesis occurred before serum erythropoietin levels had risen. These results demonstrate that IGF-I mediates the stimulatory effect of growth hormone on erythropoiesis in vivo and thus further support the somatomedin concept. They also show that IGF-I can stimulate erythropoiesis in an endocrine manner, and they suggest two possible routes of action: a direct one and an indirect one by means of enhanced erythropoietin production.

Topics: Animals; Body Weight; Erythrocyte Count; Erythropoiesis; Erythropoietin; Growth Hormone; Hematocrit; Hypophysectomy; Insulin-Like Growth Factor I; Male; Rats; Recombinant Proteins; Reticulocytes; Somatomedins

Adult female Wistar rats were injected with 1 mg/kg body weight of uranyl nitrate (UN). Evaluation of renal function, histopathology studies, and determination of plasma erythropoietin (Ep) titers after exposure to 456 mb for 16 h were performed at 1, 2, 7, 10, 15, and 21 days after drug injection. Plasma urea and creatinine concentrations markedly increased during the first seven days after injection, reaching maximal values on day 7 and decreasing thereafter. Significant increases in urine volume and significant depressions in urine osmolality also were observed; both alterations were most marked on day 7 after injection. A coagulative necrosis of the epithelium of proximal convoluted tubules, desquamation of the necrotic cells, and dilation or collapse of the tubular lumen were observed; the lesions were more marked on day 7. Plasma Ep levels in UN-treated rats exposed to hypobaria were markedly lower than in noninjected controls similarly exposed. Measurements were performed one, two, and seven days after UN injection, with maximal depression observed on day 7. These observations indicate that there is a correlation between the extent of both tubule damage and degree of renal dysfunction and plasma Ep production during exposure to hypoxia in UN-treated rats. This suggests that the renal Ep component is derived primarily from tubular cells.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Body Weight; Calcinosis; Erythropoietin; Feeding Behavior; Female; Organ Size; Oxygen; Rats; Time Factors; Uranyl Nitrate; Water-Electrolyte Balance

Over the first three months of continuous ambulatory peritoneal dialysis (CAPD) the level of hemoglobin (Hb) rises significantly in most patients. To elucidate this further we studied the hematological response over 3 months of 8, previously non-transfused new patients treated with CAPD. Mean Hb rose by +2.78 g/dl (P less than 0.02). Mean RCM rose by 284 ml (37.7%) (P less than 0.05) and 3.7 ml/kg (29.6%) (P less than 0.05). PV fell relative to BW only, by -8.6 ml/kg (P less than 0.05). There was no significant change in serum vitamin B12 or folate concentrations or evidence of hemolysis. Plasma ferritin fell in all patients, but hematological changes of iron deficiency appeared in only one. Bio-assayable erythropoietin (EPO) levels were generally in the normal range, but inappropriately low for the degree of anemia. EPO did not change significantly apart from in two patients, one with polycystic disease. These results indicate that over the initial 3 months of therapy the majority of CAPD patients have a rise in Hb, due mainly to a rise in RCM, unrelated to changes in serum EPO level.

Topics: Adult; Body Weight; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Folic Acid; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Plasma Volume; Vitamin B 12

Renal cell carcinoma tissues from two patients, one with and one without erythrocytosis, were successfully transplanted into athymic nude mice. Transplantations of the erythrocytic tumor through six successive generations of nude mice produced a significant (P less than 0.001) elevation in mean hematocrit from 36.5 +/- 2.1% (range 32-42%) to 53.7 +/- 5.1% (range 40-63%), in comparison with a non-erythrocytic tumor which showed a progressive fall in hematocrit from 46.5 +/- 2.0% (range 41-50%) to 36.8 +/- 1.6% (range 33-40%). Non-grafted control nude mice maintained stable hematocrit levels from an initial level of 45 +/- 0.5% to 46.5 +/- 1.2% when studied over the same time interval. Similarly red cell mass values in the mice transplanted with the erythrocytic tumor (5.04 +/- 1.85 ml/100 g) were considerably higher than in both the non-grafted nude mice (3.39 +/- 0.81 ml/100 g) and the non-erythrocytic tumor-grafted mice (3.8 +/- 0.3 ml/100 g) after 6 generations of transplants. Plasma erythropoietin levels in the erythrocytic tumor-grafted mice (169.4 +/- 83.1 mU/ml) were significantly (P less than 0.02) higher than in the non-grafted controls (22.2 +/- 9.5 mU/ml), and furthermore the erythropoietin levels in the tumor extracts were significantly (P less than 0.02) higher in the tumors from erythrocytic mice (range 54.7 to 234.6 mU/g tumor) than in the tumors from non-erythrocytic mice (range 0.3 to 1.9 mU/g tumor). In vitro monolayer cultures of these tumors confirmed the higher erythropoietin levels in the erythrocytic renal carcinoma (138 mU/ml) as compared with culture media of non-erythrocytic tumors (15-91 mU/ml) using the fetal mouse liver assay (59Fe incorp. into heme). The present studies indicate autonomous erythropoietin production by human renal cell carcinomas both in vivo in nude mice and in vitro in tissue cultures.

Topics: Animals; Body Weight; Culture Techniques; Erythropoietin; Female; Hematocrit; Humans; Kidney Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Neoplasm Transplantation; Polycythemia; Radioimmunoassay

Plasma erythropoietin concentrations were studied in 11 preterm appropriate for gestational age infants at the age of 3-14 weeks. Their birth weights ranged from 860-1 690 g. Erythropoietin was measured by a cell culture technique. Significant concentrations of erythropoietin was detected in 18 out of 29 samples, at all stages of the early anemia. The highest levels were found at 3-9 weeks. Individual erythropoietin values did not correlate with hemoglobin concentrations, hematocrit levels or 'corrected' reticulocyte counts, nor did the 'corrected' reticulocyte count correlate with hemoglobin or hematocrit. The lack of correlation with hemoglobin concentration most likely reflects the importance of other factors as well as the hemoglobin in determining the oxygenation status of the infant. A significant positive correlation (r = 0.60, p less than 0.01) was found between erythropoietin concentration and weight gain in the preceding week. The study shows that small preterm infants are capable of erythropoietin production during their early anemia, and indicates that the hormone plays a role in the regulation of erythropoiesis also at this time of life.

Topics: Anemia, Neonatal; Body Weight; Erythrocyte Count; Erythropoietin; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Reticulocytes

In order to test the hypothesis that the early cessation of erythropoietin (Ep) production during hypobaric hypoxia is induced by lowered food intake, we have compared the plasma Ep titer of rats after exposure to continuous hypoxia (42.6 kPa = 7000 m altitude) for 4 days with that in fed or fasted rats after exposure to discontinuous hypoxia. We found that plasma Ep was rather low after 4 days of continuous hypoxia. However, the Ep titer significantly rose again, when rats were maintained normoxic for 18 h and then exposed to repeated hypoxia for 6 h. Because this was also found in rats which were deprived of food during the normoxic interval and the second hypoxic period, we conclude that the fall of the Ep titer during continuous hypoxia is not primarily due to reduced food intake. In addition, our findings show that fasting per se lowers the Ep-response to hypoxia in normal rats but not exhypoxic rats.

Topics: Animals; Body Weight; Eating; Erythropoietin; Fasting; Hypoxia; Male; Rats; Rats, Inbred Strains

Plasma erythropoietin (erythropoiesis stimulating factor(s), ESF), PCV and body weight were measured in normal mice from birth until the age of 70 d. Low but detectable ESF activity was present at birth, following by undetectable levels 12-48 h after birth. Thereafter the ESF level rapidly increased. Peak levels were obtained 15-20 d after birth. During the same phase an increased growth velocity occurred, coincident with decreased PCV levels. A fall to undetectable levels in plasma ESF activity coincided with decelleration of growth 40-50 d after birth. In small litters (four pups per litter) growth velocity and PCV levels were significantly higher than in large litters (16 pups per litter) 8 and 15 d after birth. The plasma ESF activity, however, did not differ between the two groups. Prohibiting suckling for a period of 16 h did not change the plasma ESF level. The hypothesis is put forward that growth directly or indirectly stimulates ESF production.

Topics: Animals; Body Weight; Erythropoietin; Female; Growth; Hematocrit; Litter Size; Mice; Pregnancy

The effect of erythropoietin on anemia was studied in anephric rats undergoing peritoneal dialysis. Both the number of bone marrow red cell precursors and plasma iron turnover were markedly depressed in untreated peritoneally dialyzed anephric animals when compared to peritoneally dialyzed sham-operated control rats. Anephric rats receiving 2 U of erythropoietin per day for 12 days had greater than threefold more bone marrow red cell precursors and a twofold larger plasma iron turnover than did the saline injected anephric rats. There was no significant difference in either bone marrow red cell precursors or plasma iron turnover in the erythropoietin-treated anephric rats when compared to the nonuremic controls. Although the rats receiving erythropoietin for 12 days had a significantly higher hematocrit (29.5%) than the saline injected uremic rats did (19.0%), the hematocrit was significantly lower than that found in nonuremic control animals, either receiving erythropoietin (48.1%) or not receiving erythropoietin (41.6%). Our data suggests that erythropoietin is potentially a useful agent for the treatment of anemia of chronic renal failure.

Topics: Anemia; Animals; Blood Urea Nitrogen; Body Weight; Bone Marrow; Bone Marrow Cells; Erythropoietin; Hematocrit; Iron; Kidney Failure, Chronic; Male; Nephrectomy; Peritoneal Dialysis; Rats

Topics: Animals; Body Weight; Erythropoietin; Male; Nutritional Physiological Phenomena; Parenteral Nutrition; Parenteral Nutrition, Total; Rats

Current concepts of the pathogenesis of anemia in uremic animals are derived mainly from the results of studies performed either in vitro or in bilaterally nephrectomized animals. These data may not be applicable to the situation which exists in more chronically uremic animals. In 1932, Chanutin and Ferris showed that removal of five-sixths of the renal mass caused rats to become uremic and to remain so for a prolonged period of time. Rats made uremic in this manner were utilized as models for studying the pathogenesis of the anemia of uremia. Removeal of five-sixths of the renal mass of rats caused their BUNs to rise to over 100 mg/100 ml and to remain at this level for over 3 wk. The hematocrits of these uremic rats fell from 42% to approximately 30% in 3 wk. Erythropoietin (Ep) production immediately fell to a barely detectable level postoperatively and did not increase significantly in 3 wk, although the renal remnant hypertrophied. Extrarenal Ep production also remained at a low level and did not increase during the 3-wk observation period. The response of plethoric uremic rats to 2 units of Ep was as great (in some experiments greater) as that of sham-operated ones. A surprising finding was that plethoric uremic rats, injected with saline rather than with Ep, incorporated more 59Fe into their red blood cells than did sham-operated ones. This finding suggested that in uremic rats erythropoiesis was less markedly suppressed by plethora than it was in non-uremic rats.

Topics: Anemia; Animals; Blood Urea Nitrogen; Blood Volume; Body Weight; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Injections, Subcutaneous; Iron Radioisotopes; Nephrectomy; Rats; Uremia

A transplantable rat pheochromocytoma in New England Deaconess Hospital (NEDH) was first described by WARREN in 1972. It is characterized by the documented association with systolic hypertension and the known presence of increased urinary metanephrines and vanilmadelic acid in tumor-bearing animals. The present report describes features of the transplantable tumor, our laboratories have noted, in five tumor transplantations starting in 1974. Tumor-bearing animals survive 49 +/- 5 days and die much sooner than aging, non-tumor-bearing litter mates. Gross measurements confirm the rapid growth of the primary tumor, although at autopsy, histologically proven metastatic foci are rarely seen. Polycythemia with or without increased erythropoietin (ESF) levels were not detected. Electronmicroscopic studies confirmed the presence in tumor tissue of the previously described intracytoplasmic granules. Further studies on this endocrine-associated transplantable tumor are warranted and feasible.

Topics: Animals; Body Weight; Erythropoietin; Female; Kidney; Male; Neoplasm Transplantation; Neoplasms, Experimental; Pheochromocytoma; Rats; Transplantation, Homologous

In mice hypoxic hypoxia (0.5 atm.) results in a severe and persistent thrombocytopenia with a rapid decline in the platelet count between the fifth and ninth days of hypoxia, after which platelet counts level off at about half their normal value. The thrombocytopenia is not due to the associated polycythemia, splenomegaly, or increased blood volume. There is no significant change in platelet counts of mice made polycythemic by daily injections of 6 units of erythropoietin. Fifteen days of hyperbaria (3 atm.) has no effect on the platelet count of otherwise normal mice. Since there is only a slight decline in platelet count during the first 5 days of hypoxia, the persistent thrombocytopenia appears to be due to either a decreased rate of production of platelets or a structural or metabolic defect in platelets produced under conditions of hypoxia.

Topics: Animals; Blood Cell Count; Blood Platelets; Blood Transfusion; Blood Volume; Body Weight; Erythropoietin; Female; Hematocrit; Hyperbaric Oxygenation; Hypoxia; Mice; Mice, Inbred C3H; Organ Size; Polycythemia; Spleen; Splenectomy; Thrombocytopenia

Exposing mice to an atmospheric pressure of 300 mm Hg for 16 d caused a variety of hematologic effects. Hematocrit increased rapidly in the first 8 d of exposure and slowly in the second 8 d. Reticulocyte counts rose above normal, peaked on Day 8, and then fell rapidly toward the control level. Macrocytic erythrocytes, formed during exposure, remained macrocytic after the termination of exposure and after the loss of their reticulum. The posthypoxic mice proved sensitive for erythropoietin bioassay. Mice injected with normal dog serum showed a significantly higher incorporation of 59Fe than control mice injected with physiologic saline. A reduction of the duration of exposure to 10 d resulted in only a slight decrease in the sensitivity of the mouse bioassay system. However, a 16-d exposure at a pressure of 360 mm Hg resulted in considerably less sensitive bioassay animals.

Topics: Animals; Atmospheric Pressure; Biological Assay; Body Weight; Dogs; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematocrit; Hypoxia; Mice; Mice, Inbred ICR; Reticulocytes; Time Factors

Topics: Administration, Oral; Anemia, Hypochromic; Animals; Ascorbic Acid; Biological Transport; Body Weight; Diet; Erythropoietin; Female; Genetic Linkage; Hematocrit; Hemorrhage; Hypoxia; Injections, Intraperitoneal; Intestinal Absorption; Iron; Iron Radioisotopes; Male; Mice; Mice, Inbred Strains; Phenobarbital; Sex Chromosomes; Statistics as Topic

Atrial thrombosis is a common lesion in female Taconic Swiss mice fed a high-fat (28%), low-protein (8%), hypolipotropic diet for 10 wk or longer. After the third week of such feeding the mice studied here were injected with either erythropoietin, washed, packed red blood cells, lysed red blood cells, plasma or physiological saline.In mice receiving injections of lysed red cells, plasma or saline, respectively 75, 54 and 82% of those surviving for 10 wk had developed atrial thrombosis. Hematocrits were 9.3% or below in these groups. Hematocrits were maintained at an average of 33.0% in the erythropoietin group and 32.4% in the transfused (packed erythrocytes) group. Only one of the erythropoietin injected animals and none of the transfused animals developed atrial thrombosis. The evidence indicates that the anemia induced by the experimental diet results from lack of erythropoietin production or activity and that the hypoxia of anemia plays a role in the development of atrial thrombosis.

Topics: Anemia; Animals; Blood Transfusion; Body Weight; Diet; Dietary Fats; Erythrocytes; Erythropoietin; Female; Heart Atria; Heart Diseases; Hematocrit; Injections, Intraperitoneal; Mice; Plasma; Reticulocytes; Sodium Chloride; Thrombosis

Topics: Aging; Anemia; Animal Nutritional Physiological Phenomena; Animals; Animals, Newborn; Body Weight; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Hypoxia; Iron; Rabbits; Weaning

During the study of an inbred strain of Wistar rats which spontaneously develop hypertension when they reach a weight of approximately 150 g, it was found that these animals also develop an erythrocytosis. A significant increase in red cell count was observed in spontaneously hypertensive (SH) rats (8-11 x 10(6) RBC/mm(3)) when compared with normotensive rats (6-7 x 10(6) RBC/mm(3)) of the same strain. This increase in red cell count paralleled the increase in body weight and the rise in blood pressure. Since the plasma volume, as measured with labeled albumin was normal, there was an absolute increase in red cells. The hematocrit and hemoglobin content of the blood measured in SH rats were only slightly greater than those found in normotensive rats. However, the mean cell volume (MCV) of the red cells in the SH rats was 45-47 mu(3) as compared with 51-53 mu(3) in normotensive rats.A fourfold increase in 24 hr (59)Fe incorporation into the red cells was found in the SH rats when compared with normotensive controls. The bone marrow of the SH rats showed erythroid hyperplasia. When the SH rats were treated with alpha-methyldopa (Aldomet 200 mg/kg daily, i.p.) the red cell count fell in parallel with the drop in blood pressure. No change in red cell count or blood pressure was observed in normotensive rats treated in the same manner. The erythropoietin titer was high in SH rats, and was undetectable in normotensive rats. These observations suggest a direct relationship between the hypertension and the erythrocytosis mediated by erythropoietin; both are genetically controlled.

Topics: Animals; Blood Pressure; Blood Pressure Determination; Body Weight; Cell Survival; Chromium Isotopes; Dihydroxyphenylalanine; Erythrocyte Count; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Hypertension; Hypertension, Renal; Iron; Iron Isotopes; Leukocyte Count; Male; Plasma Volume; Polycythemia; Rats; Rats, Inbred Strains; Serum Albumin, Radio-Iodinated

Topics: Anemia; Animals; Body Weight; DNA; Erythropoiesis; Erythropoietin; Fetus; Heme; Hemoglobins; Iron; Liver; Mice; Mice, Inbred Strains; Reticulocytes; RNA; Rodent Diseases; Thymidine

Topics: Body Weight; Chromatography, DEAE-Cellulose; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Filtration; Hemoglobinuria, Paroxysmal; Humans; Hydrogen-Ion Concentration; Iron Isotopes; Male; Membranes, Artificial; Methods; Multiple Myeloma; Urine

Topics: Animals; Body Weight; Depression, Chemical; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematologic Diseases; Hyperemia; Immune Sera; Iron; Iron Isotopes; Rats

Topics: Animals; Blood Pressure; Blood Volume; Body Weight; Diet, Sodium-Restricted; Erythropoietin; Hematocrit; Hypertension, Renal; Hypoxia; Juxtaglomerular Apparatus; Male; Nephrectomy; Rats; Renin; Reticulocytes

Topics: Animals; Biological Assay; Blood Volume; Body Weight; Cobalt; Erythropoietin; Female; Hypoxia; Iron Isotopes; Kidney; Nephrectomy; Rats; Testosterone

Topics: Animals; Body Weight; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Dactinomycin; Erythrocytes; Erythropoiesis; Erythropoietin; Injections, Intravenous; Injections, Subcutaneous; Iron Isotopes; Mice

Topics: Animals; Blood Transfusion; Body Weight; Erythrocyte Count; Erythropoiesis; Erythropoietin; Germ-Free Life; Hematocrit; Hemoglobins; Iron Isotopes; Leukocyte Count; Mice; Stimulation, Chemical

Topics: Androgens; Animals; Body Weight; Erythropoiesis; Erythropoietin; Female; Hypertrophy; Hypoxia; Iron Isotopes; Kidney; Organ Size; Rats; Testosterone

Topics: Adult; Aged; Altitude; Arteries; Blood Gas Analysis; Blood Pressure; Body Weight; Bone Marrow Cells; Carbon Dioxide; Colorado; Culture Techniques; Erythropoietin; Female; Hematocrit; Humans; Hydrogen-Ion Concentration; Hypertension; Hypoxia; Male; Middle Aged; Obesity; Oxygen; Oxygen Inhalation Therapy; Partial Pressure; Polycythemia; Posture; Respiratory Function Tests

Topics: Animals; Biological Assay; Body Weight; Dogs; Erythropoietin; Female; Hematocrit; Iron Isotopes; Kidney; Male; Organ Size; Regional Blood Flow; Renal Artery

Topics: Adolescent; Adult; Anemia, Aplastic; Bilirubin; Blood Platelets; Body Weight; Bone Marrow Examination; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Iron; Leukocyte Count; Methandrostenolone; Neutrophils; Prednisone; Reticulocytes