Weeks Of Erythropoietin Treatment Research Articles

2007-P: Age-Dependent Metabolic Response to Erythropoietin in Mice

Erythropoietin (EPO), the cytokine required for erythrocyte production, regulates glucose homeostasis and fat mass accumulation in animal models. For example, young (5-6 weeks) mice on high fat diet (HFD) treated with EPO for 5 weeks show a dose dependent increase in hematocrit and reduction in fat mass accumulation/weight gain. To assess potential age and sex dependent EPO metabolic response, C57/Bl6 mice beginning at 3 months, 4 months or 6 months of age were fed normal chow (NC) or high fat diet (HFD) and treated with EPO or saline for up to 6 weeks. After 3 weeks of EPO treatment, all mice exhibited the expected increase in hematocrit (hct up to 70%) that was accompanied by an improvement in glucose tolerance. Body weight gain was unchanged in the 3-month groups, while the 4- and 6-month males on HFD showed a reduced gain in body weight with 3-weeks of EPO treatment. Since earlier studies suggested an increased reduction in fat mass with extended EPO treatment, EPO treatment was continued for three more weeks. At 6 weeks EPO treatment, body weight gain was not affected in the 3-month groups on NC or HFD but was reduced in the 4- and 6-month groups on HFD in male and female mice. These differences in weight gain appear to be due to differences in fat accumulation. However, after 6 weeks EPO treatment, about 66% of the 3-month group, 70% of the 4-month group showed reduced hematocrit below baseline to low as 22% in the 3-month group and 11% in the 4-month group. Mice with the lowest hct showed the greatest impairment in glucose tolerance. In the 6-month group on HFD, EPO treatment for 6 weeks decreased body weight in both males and females. However, hct decreased in all 6-month mice treated with EPO for 6 weeks, falling as low as 15% and the improved glucose tolerance with EPO treatment seen at 3 weeks was no longer apparent. These data suggest an age dependent immune response at 6 weeks of human EPO treatment in mice and production of anti-human EPO antibodies with the potential to also reduce erythropoiesis and glucose tolerance associated with endogenous EPO. Disclosure H. Rogers: None. C.T. Noguchi: None. Funding National Institutes of Health

Erythropoietin enhances whole body lipid oxidation during prolonged exercise in humans.

Animal studies have suggested that erythropoietin, besides its well-known hematopoietic effects, can modulate metabolism and prevent fat accumulation. We investigated the effects of repeated injections of recombinant human erythropoietin (EPO) on the balance of substrate oxidation during aerobic exercise in humans. Twelve healthy aerobically trained males received subcutaneously either moderate dose of EPO (50 U/kg, EPO) or saline injections (NaCl 0.9 %, control) three times a week for 4 weeks. Body weight, % fat, maximal aerobic capacity, and substrate utilization during exercise were assessed before and after treatment, while hemoglobin and hematocrit were monitored regularly during the treatment. Carbohydrate and fat oxidation were evaluated via indirect calorimetry, during a submaximal exercise performed at 75 % of the participants' maximal aerobic capacity (V̇(O2max)) for 60 min. Results showed that 4 weeks of EPO treatment significantly enhanced fat oxidation (+56 % in EPO versus -9 % in control) during exercise, independent of its effects on hematological parameters or V̇(O2max). This study shows that EPO can modulate substrate utilization during exercise, leading to enhanced fat utilization and lower use of carbohydrates. This opens new research directions exploring whether systemic EPO levels, in physiological conditions, participate to the modulation of fat oxidation.

Determinants of Red Cell Distribution Width (RDW) in Cardiorenal Patients: RDW is Not Related to Erythropoietin Resistance

BackgroundStudies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. Methods and ResultsIn the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = −0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = −0.48, P < .001, and transferrin saturation, r = −0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. ConclusionsEPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

Beyond erythropoiesis: The anti-inflammatory effects of erythropoietin

See article by Li et al. [4] (pages 684–694) in this issue. Erythropoietin (EPO) is a 30.4-kDa glycoprotein essential for red blood cell production. In adults, EPO is produced primarily in the kidney via an oxygen-sensing mechanism and stimulates erythroid progenitors in the bone marrow to increase red blood cell mass. In addition to its role in erythropoiesis, EPO has been shown to protect against ischemic injury in several organs including the heart. In various animal models, administration of EPO reduces infarct size and improves cardiac function following myocardial ischemia and reperfusion (I/R). The protective effects have been observed regardless of whether EPO was administered before ischemia, at the onset of ischemia, or at reperfusion [1,2]. The protective effects of EPO are also seen in chronic models of myocardial infarction (MI). In this regard, treatment of EPO before or immediately after coronary artery ligation decreases cardiac remodeling and improves myocardial function. Interestingly, a single dose of EPO (3000 IU/kg, i.p.) immediately after induction of MI improved cardiac function measured 8 weeks later. The therapeutic relevance of EPO was further demonstrated by van der Meer et al., who showed that EPO treatment started 3 weeks after MI improved cardiac function in a rat model of heart failure [3]. Consistent with this finding, in a report in this issue of Cardiovascular Research , EPO was started 6 weeks after induction of MI when heart failure was fully established in mice. Four weeks of EPO treatment diminished left … * Tel.: +1 519 685 8300x55443; fax: +1 519 685 8341. Email address: qfeng{at}uwo.ca

Interaction between Erythropoietin and Peripheral Polymorphonuclear Leukocytes in Continuous Ambulatory Dialysis Patients

The effect of erythropoietin (EPO) on the oxidative stress (OS) and inflammation caused by polymorphonuclear leukocytes (PMNLs) in end-stage renal failure patients undergoing continuous ambulatory peritoneal dialysis (CAPD) was investigated in vivo and in vitro. The studies were performed on isolated PMNLs from peripheral blood of CAPD patients before and following 6 weeks of EPO treatment and from healthy controls. OS was expressed by the rate of superoxide release from phorbol 12-myristate 13-acetate (PMA) stimulated isolated PMNLs and the inflammatory state was evaluated by PMNL counts of the enrolled subjects. Following 6 weeks of EPO treatment in CAPD patients, both the rate of superoxide release from PMNLs and PMNL counts fell significantly when compared with the pretreatment values. In vitro incubation of PMNLs from CAPD patients with increasing amounts of EPO displayed a significant reduction in their rates of superoxide release. EPO, by direct interaction with PMNLs, attenuated their primed state, causing reduction in oxidative stress and inflammation.

Erythropoietin Treatment of Postural Hypotension in Anemic Type 1 Diabetic Patients With Autonomic Neuropathy

Postural hypotension (PH) is a feature of autonomic failure that may result from various causes and can be very difficult to treat. Recently, we and others (1, 2, 3) have shown that some patients with severe symptomatic autonomic neuropathy from type 1 diabetes (type 1 DAN) have a normocytic anemia associated with erythropoietin (EPO) deficiency. The treatment of these patients with EPO rapidly corrects their anemia (1) and improves their overall well-being. Preliminary observations by Hoeldtke et al. (3) of the effect of a maximum of 9 weeks of EPO treatment on blood pressure (BP) demonstrated a positive response in four cases of PH in type 1 DAN patients, but evaluation of BP was limited to only two to three readings before and after EPO treatment. These results stimulated the present study, in which we investigated the effect of EPO treatment for 3 months on supine and standing BP in four anemic EPO-deficient type 1 DAN patients. The patients were treated with recombinant human EPO (25 IU/kg s.c. thrice weekly). All four patients were women (48, 41, 30, and 30 years of age with a duration of diabetes of 13, 24, 19, and 11 years, respectively) and each had normocytic anemia with inappropriately low serum EPO levels. The known causes of anemia were excluded. All of the patients included in the study had pronounced symptomatic PH and at least one other symptom of autonomic neuropathy. …

Interaction between Erythropoietin and Peripheral Polymorphonuclear Leukocytes in Hemodialysis Patients

The effect of erythropoietin (EPO) on the oxidative stress and inflammation caused by polymorphonuclear leukocytes (PMNLs) in chronic hemodialysis (HD) patients was investigated in vivo and in vitro. The studies were performed on isolated PMNLs from peripheral blood of healthy controls and HD patients before and following 6 weeks of EPO treatment. The oxidative stress was expressed by the rate of superoxide release from phorbol 12-myristate 13-acetate stimulated PMNLs, and the inflammatory state was evaluated by in vitro PMNL survival, in addition to white blood cell and PMNL counts of the enrolled subjects. Following 6 weeks of EPO treatment, in HD patients, the rate of superoxide release from PMNLs as well as WBC and PMNL counts fell significantly when compared with the pretreatment values. PMNLs from HD patients and healthy controls incubated in vitro with increasing amounts of EPO displayed a significant reduction in their rates of superoxide release and a significant improvement in survival. We have concluded that EPO interacts with PMNLs, attenuating their primed state in HD patients, thus reducing oxidative stress and the extent of inflammation. To the best of our knowledge, this attenuation of the primed state of PMNLs by EPO is a new finding.

Short-term effect of erythropoietin on T-cell mitogenic proliferation in chronic renal failure patients.

Uremic patients undergoing hemodialysis (HD) are known to be highly susceptible to infections. Recent data indicate that in addition to its well-known stimulating effects on red cell production, erythropoietin (EPO) may also have immunomodulating properties. The aim of this study was to examine the effect of EPO on lectin-induced T-lymphocyte transformation in uremic patients, as part of its effect on the immune response. Sixteen HD patients and 20 age- and sex-matched healthy controls were compared before and after 6 and 20 weeks of EPO treatment. T lymphocytes were analyzed for their mitogenic activity following treatment with phytohemagglutinin (PHA), concanavalin A (CON A) and anti-CD3 by measuring 3H-thymidine incorporation. HD patients showed reduced mitogenic responses to all mitogens tested, compared to healthy controls. During the 6 weeks of EPO administration, a significant increase in T-lymphocyte activity could be demonstrated following exposure to all three mitogens (PHA, from 32 +/- 2 to 45 +/- 8; CON A, from 11 +/- 3 to 25 +/- 9; anti-CD3, from 11 +/- 3 to 22 +/- 5, means +/- SD). This increase was augmented after 5 months of EPO treatment. We conclude therefore that EPO improves in vitro T-cell mitogenic proliferation, even after short periods of treatment.