Low-dose Erythropoietin Research Articles

A STUDY OF THERAPEUTIC RESPONSE AND ADVERSE EFFECTS OF INTRAVENOUS ERYTHROPOIETIN VERSUS SUBCUTANEOUS ERYTHROPOIETIN ON HEMODIALYSIS PATIENTS IN THE DEPARTMENT OF NEPHROLOGY OF OHRC

Objective: To study the efficacy of intravenous erythropoietin and subcutaneous erythropoietin in hemodialysis patients who have persistent anemia despite correction of iron therapy and to measure the outcomes in terms of raise in haemoglobin concentration and adverse events in both the groups.Methods: After ethical committee approval the current study was conducted at the Department of Hemodialysis of Owasi Hospital and Research Centre, Hyderabad a period of 6 mo duration. 60 patients undergoing hemodialysis were recruited into out study who had haemoglobin less than 10.0 despite corrected iron levels. Patients were divided into two groups for intravenous administration and subcutaneous administration of alpha erythropoietin. Patients were stratified into three sub-groups of mild, moderate and severe anaemia. Therapeutic response was recorded in the form of monthly hemoglobin and hemoatocrit. Of the 30 patients in the subcutaneous group, erythropoietin was given to 19 males and 11 females, while intravenous erythropoietin was administered to 17 males and 13 females in the other 30 patients.Results: The mean hemoglobin level in the subcutaneous group was 5.16 at the commencement of the study and in the intravenous group the mean hemoglobin was 5.0. In the subcutaneous group, the mean rise in the hemoglobin was rapidly achieved in 3 mo duration when compared to the intravenous group. Mean Systolic Blood pressure was higher in the intravenous group when compared to the subcutaneous group. Spillage of the drug was minimal in subcutaneous group when compared to the intravenous group.Conclusion: After correction of the iron deficiency, low dose of erythropoietin subcutaneously promised to maintain expected hemoglobin level above 10 g/dL with no adverse events compared to intravenous erythropoietin. Erythropoitin alpha at a dose of 4000 IU was enough to achieve the therapeutic target of Hemoglobin>10.0 by administering subcutaneously accelerated hypertension was less when compared to Intravenous erythropieitn post dialysis. Hence we recommend to use erythropoietin subcutaneously rather than intravenously.

Ratlarda Deneysel Miyokard İnfarktüsünün Yaygınlığını Öngörmede EKG, Kardiyak Troponin T ve Yüksek Duyarlıklı C Reaktif Proteinin Önemi

Objective: To analyze the predictive value of ECG variables, cardiac troponin T (cTnT) and high-sensitive C reactive protein (hsCRP) levels in estimating the degree of experimental myocardial infarction in the living rats before euthanasia. Material and Methods: Permanent ligation of the left anterior descending coronary artery was performed to develop acute myocardial infarction in 4-month-old male Wistar rats (n=18). Saline (n=5), low-dose erythropoietin (5 000 U.kg−1, n=6) and high-dose erythropoietin (10 000 U.kg−1, n=7) were administered intraperitoneally after the ligation to obtain varying degree of infarction. ECG records were taken before (phase 1), at the end of (phase 2), and at 6 hours after the ligation (phase 3). cTnT and hsCRP levels were measured in phase 3. The size of infarct area was calculated with planimetry on a single midventricular slice stained with triphenyltetrazolium chloride. Results: The height of ST segment in phase 2, the Q/R and ST/R ratios measured in phase 3, and the Q/R ratio difference between phases 2 and 3 were found to be associated with the large infarct area. The cutoff values estimated for these variables were capable of predicting the presence of an infarct area ≥40%. cTnT and hsCRP levels were unsuccessful in estimating the size of infarction. Conclusion: The variables of a 3-lead ECG may have a predictive value in estimating the presence of large infarction before euthanasia. ST segment elevation may be significantly different as early as the first-half hour of coronary ligation. The levels of cTnT and hsCRP are not associated with the size of infarction, and do not have a predictive value.

Lower Erythropoietin Doses and Medicare Payment Reform

Lower Erythropoietin Doses and Medicare Payment Reform

Anti-inflammatory effect of erythropoietin on hepatic ischemia reperfusion injury in fatty liver rats

Objective To explore the anti-inflammatory effect of erythropoietin (EPO) on hepatic ischemia reperfusion (IR) injury in fatty liver rats. Methods A total of 100 male SD rats were fed with high-fat diet for 12 weeks. After the model was successfully established, the fatty liver rats were randomly divided into sham-operation (SHAM), the ischemia-reperfusion (IR) and EPO preconditioning group. Se-rum ALT and AST as well as hepatic histopathological changes were measured. Xanthine oxidase method was used to detect the liver tissue SOD. Thiobarbituric acid method was used to detect the MDA. Enzyme-linked immunosorbent adsorption assay (ELISA) was used to detect the plasma tumor necrosis factor alpha (TNF-α) and interleukin 1 (IL-1). Results In the EPO preconditioning groups the swelling hepatocytes was observed, but the inflammatory cell infiltration was significantly decreased and no necrosis of hepatocytes was found. ALT and AST in the EPO preconditioning groups were significantly lower than those in IR group (P EPO-2 >EPO-3 (P<0.05); but the values of SOD in the EPO groups were: EPO-1<EPO-2<EPO-3 (P<0.05). Conclusions EPO preconditioning has a protective effect against hepatic IR injury in fatty liver rats, possibly through inhibiting the inflammatory reaction to prevent the IR injury. The anti-inflammatory effect of high-dose EPO is better than that of low-dose EPO. Key words: Erythropoietin; Ischemia reperfusion injury; Fatty liver; Oxidative stress; Inflammatory reaction

The Effect Of Erythropoietin Administration In Experimental Burns Wound Healing: An Animal Study

Background: The hematopoietic growth factor erythropoietin (EPO) attracts attention due to its all-tissue-protective pleiotropic properties. The purpose of this study is to investigate the effect of EPO in experimental burn wounds healing.&#x0D; Methods: Fifteen healthy Sprague-Dawley, strain of Rattus Novergicus weighing 300-350 grams, were prepared to achieve deep dermal burns. Animals were randomized to receive either low-dose EPO injection (600 IU/mL), high-dose EPO injection (3000 IU/mL) or nothing (control group). After 14 days of observations, quantitative and qualitative assessments of wound healing was determined.&#x0D; Results: The size of the wound area and re-epithelialization rate percentage was determined on Day-0, Day-5, Day-10, and Day-14. The average of raw surface areas measurement (p value: 0.012 in day-5; 0.009 in day-10 and 0.000 in day-14) and healing percentage of the lesions (p value: 0.011 in day-5; 0.016 in day-10 and 0.010 in day-14) were significantly best in the low-dose EPO grup compared to the control group and high-dose EPO grup. The histopathology evaluation revealed that the highest score for for re-epithelialization, granulation tissue and neo-angiogenesis were achieved by the low-dose EPO injection group than in both control and high-dose EPO injection groups.&#x0D; Conclusion: In this animal study using Sprague-Dawley rats, Recombinant Human EPO (rHuEPO) injection administration prompted the evidences of improved re-epithelialization and wound healing process of the skin caused by deep dermal burns. These findings may lead to a new therapeutic approach to improve the clinical outcomes for the management of burns wound healing.

Efficacy and safety of erythrocytapheresis and low-dose erythropoietin for treatment of hemochromatosis.

The aim of this study was to determine retrospectively the efficacy of combined therapy using erythropoietin (EPO) and erythrocytapheresis (EA) in patients with hereditary hemochromatosis (HH) who did not tolerate phlebotomy. Twenty patients (age range, 43-74 years) with genetically confirmed HH had received low-dose EPO (4,000 IU) in accordance to the patient's hemoglobin levels between each EA session. Laboratory parameters including hemoglobin, ferritin, transferrin, and iron were measured at regular intervals. Anemia did not occur in a single patient and no serious side effects were observed. Combined treatment with EPO and EA was well tolerated, and all 18 patients who suffered from fatigue prior to therapy recovered. Median ferritin values were 678.5 ng/L before treatment and 145 ng/L after treatment. EA in combination with EPO is safe and effective in treating patients with HH. Prospective studies comparing this therapeutic option to phlebotomy are warranted. J. Clin. Apheresis 32:170-174, 2017. © 2016 Wiley Periodicals, Inc.

Erythropoietin improves cardiac wasting and outcomes in a rat model of liver cancer cachexia

BackgroundErythropoietin 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. MethodsWistar 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. ResultsTumor-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). ConclusionsOverall, 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.

Erythropoietin delivered via intra-arterial infusion reduces endoplasmic reticulum stress in brain microvessels of rats following cerebral ischemia and reperfusion.

Local infusion of low dose erythropoietin (EPO) alleviates cerebral ischemia and reperfusion (I/R) injury in rats; however, the underlying molecular mechanisms are still unclear. The present study investigated the effect of low dose EPO treatment on I/R-induced endoplasmic reticulum (ER) stress in brain tissue and isolated microvessels in rodents. Sprague-Dawley rats were subjected to 2 h ischemia/24 h reperfusion by middle cerebral artery (MCA) occlusion, then administered fluorescein isothiocyanate-labeled EPO via MCA infusion (MCAI) or subcutaneous injection (SI) to compare the efficiency of two modes of delivery. Neurobehavioral deficits and infarct volume, and the expression of ER stress-associated proteins and apoptosis in brain tissue or isolated microvessels, as well as the transcriptional activity of 16 factors involved in ER stress and the unfolded protein response in brain tissue was asscessed. A higher EPO level in cerebrospinal fluid and brain tissue was observed in rats treated with EPO by MCAI (800 IU/kg) than by SI (5000 IU/kg). Moreover, neurobehavioral deficits and infarct volume were reduced in rats treated with EPO by MCAI and salubrinal. EPO suppressed the expression of ER stress signals glucose-regulated protein 78, activating transcription factor (ATF) 6α, and CCAAT enhancer-binding protein homologous protein (CHOP), as well as that of the pro-apoptotic protein caspase-3 in brain microvessels, and decreased the number of CHOP-positive, apoptotic neurons. EPO treatment also reduced the transcriptional activities of CHOP, forkhead box protein O1, and ATF4. These results provide evidence that low dose EPO treatment via MCAI provides neuroprotection following acute ischemic stroke by inhibiting the ER stress response.

Erythropoietin Stimulates Bone Resorption Via Direct Activation of the Monocytic Lineage and Via Increased RANKL Production By B Cells and Osteoblasts

The negative effect of hypoxia on bone metabolism is well established but its mechanism of action is not fully understood. Hypoxia triggers the production of erythropoietin (EPO), a hormone most recognized for its hematopoietic function. An increasing number of roles unrelated to red blood cell production have been attributed to EPO, many of which are mediated by non-erythroid cells. In light of the controversy on the effect of increased serum levels of EPO on the skeleton, we investigated here the effect of the hormone on bone metabolism using EPO overexpressing (Tg6), and EPO-administered adult mice. In these models, the increase in EPO levels is similar to its physiologic increase at high altitude without the confounding direct effect of hypoxia on bone cells. Using microcomputed tomography, histology and serum markers we found that high EPO levels result in a severe trabecular bone loss (-32 to -61% decrease in bone density in Tg6 and EPO-injected animals, respectively; p<0.05 versus their respective controls throughout), due to increased bone resorption (+28 to +18% in TRAP5b serum levels) and reduced bone formation rate (-19 to -74%). This bone loss consisted of reduced trabecular number, but not thickness, with no effect on the cortical bone compartment. A similar bone response was observed with high and low doses of EPO, with no difference between intermittent and continuous administration modes. Using flow cytometry analysis and specific cell surface markers, we found that EPO (both overexpression and injection) targets the monocytic lineage by increasing the number of CD115+CD265- monocytes/macrophages by 43 and 57% (p<0.05), CD115+ CD265+ pre-osteoclasts by 2 and 4-fold (p=0.02) and mature osteoclasts (TRAP positive) by 64 and 88% (p<0.05, Figure 1A) in bones, compared to WT and diluent controls, respectively.EPO has direct stimulatory effects in vitro on both macrophages and preosteoclasts thus coupling immune and skeletal systems, Activation of purified BM-derived macrophages with EPO, led to a 33% increase (p=0.01) in phagocytosis of 5T33 multiple myeloma cells. EPO strongly stimulated osteoclastogenesis (TRAP staining, Figure 1B) and pit resorption (measured in calcium-phosphate-coated wells) in a cell-autonomous manner. Furthermore, our data indicate that EPO receptor (EPO-R) signaling in osteoclast precursors involves the Jak2 and PI3K pathways, but is independent of the MAPK/MEK pathway. In addition to the direct effect of EPO on monocyte derived cells, high EPO also led to a 1.6 fold (p=0.03) increase in the transcript levels of the osteoclastogenic cytokine RANKL in total bone marrow. Notably, the major sources of RANKL are B cells and osteoblasts, and our data indicate that both cell types express EPO-R, suggesting that they are direct targets of EPO. Accordingly we found an EPO-related increase in membrane bound RANKL on B cells (1.8-fold, p=0.0003) and osteoblasts (1.16-fold, p=0.001) isolated from bone marrow (Figure 1C). To test whether EPO-R on osteoblasts also mediates the attenuation of bone formation, we treated isolated osteoblasts with EPO. However, EPO treatment in vitro did not inhibit osteoblast differentiation and activity, as demonstrated by RT-qPCR of marker genes and mineralization assays.Taken together, these findings demonstrate that EPO strongly regulates bone mass by stimulating osteoclastogenesis and attenuating bone formation. The osteoclastogenic action of EPO is mediated both directly by EPO-R on the monocytic lineage and indirectly via EPO-R signaling on B cells and osteoblasts. Regarding bone formation, the negative effect of EPO on bone formation rate in vivo was not reproduced in isolated cells, thus implying the involvement of cells beyond the osteoblastic lineage. We also propose a new mechanism for hypoxia-induced bone loss that involves EPO action on monocytic, B cell and osteoblastic lineages. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Pre-Transplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin.

Pre-Transplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin.

Brief communication (Original). Correlation of glycated albumin with self blood glucose monitoring in diabetic patients on hemodialysis taking erythropoietin

Abstract Background: Serum glycated albumin (GA) is a marker of glycemic control in diabetic renal patients, but studies were limited by the use of few random glucose values to define glycemic control. Objectives: To determine whether GA correlated with self blood glucose monitoring is better than HbA1c in hemodialyzed diabetic patients taking erythropoietin. Methods: This was a cross-sectional study of diabetic patients on hemodialysis with and without erythropoietin. GA was measured by ELISA and HbA1c by ion-exchange HPLC. GA was reported as the GA/albumin ratio where albumin was measured using bromocresol green. The average capillary blood glucose level over the preceding three months (CBG) was calculated from self-reported daily prebreakfast, prelunch, and prebed glucose meter readings. Results: Thirty-four patients were recruited; 18 were taking erythropoietin (6000 units per week) and 16 had never received erythropoietin. HbA1c correlated poorly with CBG in patients taking erythropoietin (r = -0.014, P = 0.96) compared with patients without erythropoietin (r = 0.579, P = 0.02). The correlation of GA/albumin ratio with CBG in the erythropoietin group (r = 0.612, P = 0.007) was similar to the nonerythropoietin group (r = 0.854, P &lt; 0.001). The slope for HbA1c versus CBG was 2.8-fold greater in patients without erythropoietin compared with those taking erythropoietin. There was no significant difference in the slopes for GA/albumin ratio versus CBG between the two patient groups (P &gt; 0.05). Conclusion: In diabetic patients on hemodialysis and taking low doses of erythropoietin, GA/albumin is a better marker of glycemic control than HbA1c.

Multiple low doses of erythropoietin delay the proliferation of hepatocytes but promote liver function in a rat model of subtotal hepatectomy

The impact of various doses of erythropoietin (EPO) on liver regeneration after partial hepatectomy (PH) in different animal models is still under debate. We investigated the impact of low doses of EPO on liver regeneration in a rat model of subtotal hepatectomy. We established a 90 % PH rat model with perioperative injections of low-dose EPO (1,000 IU/kg). We analyzed survival and hepatocyte proliferation in animals treated with or without EPO and assessed liver function by blood ammonia measurement and the indocyanine green 15-min retention test. Low doses of EPO treatment improved the survival of rats after 90 % PH. Unexpectedly, during the first 24 h after the operation, liver regeneration in the EPO-treated rats was inhibited. DNA synthesis, cell proliferation, and the expression of cyclins and p-STAT3 peaked 48 h after PH, which was delayed by about 24 h vs. the control rats. Furthermore, EPO treatment increased the serum level of IL-6 and protected the hepatocytes from apoptosis. Low doses of EPO do not stimulate early hepatocyte proliferation in the regenerating liver, but contribute to liver protection by inducing IL-6 and inhibiting apoptosis.

Human Choriogonadotropin and Epoetin Alfa in Acute Ischemic Stroke Patients (REGENESIS-LED Trial)

Preclinical studies suggest that growth factors in the early days after stroke improve final outcome. A prior study found three doses of human choriogonadotropin alfa followed by three doses of erythropoietin to be safe after stroke in humans. A proof of concept trial (REGENESIS) was initiated but placed on regulatory hold during review of an erythropoietin neuroprotective trial. Due to financial constraints, the trial was largely moved to India, using lower erythropoietin doses, as the REGENESIS-LED trial. Entry criteria included National Institutes of Health Stroke Scale 8-20, supratentorial ischemic stroke, and 24-48 h poststroke at start of therapy. Patients were randomized to three QOD doses of subcutaneous human choriogonadotropin alfa followed by three QD doses of intravenous erythropoietin (three escalating dose cohorts, 4000-20,000 IU/dose) vs. placebo. Primary outcomes were safety and neurological recovery. The study was halted early by the sponsor after 96 enrollees. There was no significant difference across treatment groups in the proportion of patients experiencing death, serious adverse events, or any adverse event. There was no significant difference in National Institutes of Health Stroke Scale score change from baseline to Day 90 between placebo and active treatment, whether active cohorts were analyzed together or separately, and no exploratory secondary measure of neurological recovery showed a significant difference between groups. Administration of human choriogonadotropin alfa followed by erythropoietin is safe after a new ischemic stroke. At the doses studied, placebo and active groups did not differ significantly in neurological recovery. Study limitations, such as the use of multiple assessors, differences in rehabilitation care, and being underpowered to show efficacy, are discussed.

Pretransplant HbA1c Is a Useful Predictor for the Development of New-Onset Diabetes in Renal Transplant Recipients Receiving No or Low-Dose Erythropoietin.

Aims. To evaluate the predictive power of pretransplant HbA1c for new-onset diabetes after transplantation (NODAT) in kidney transplant candidates, who had several predispositions for fluctuated HbA1c levels. Methods. We performed a retrospective study of 119 patients without diabetes who received kidney transplantation between March 2000 and January 2012. Univariate and multivariate logistic regression analyses were used to investigate the association of several parameters with NODAT. Predictive discrimination of HbA1c was assessed using a receiver-operating characteristic curve. Results. Seventeen patients (14.3%) developed NODAT within 1 year of transplantation. Univariate logistic regression analysis revealed that recipient age, gender, and HbA1c were predictors of NODAT. In the multivariate analysis, the association between pretransplant HbA1c and NODAT development did not reach statistical significance (P = 0.07). To avoid the strong influence of high-dose erythropoietin on HbA1c levels, we performed subgroup analyses on 85 patients receiving no or low-dose (≤6000 IU/week) erythropoietin. HbA1c was again an independent predictor for NODAT. Receiver-operating characteristic analysis revealed a cut-off value of 5.2% with an optimal sensitivity of 64% and specificity of 78% for predicting NODAT. Conclusions. Our results reveal that the pretransplant HbA1c level is a useful predictor for NODAT in patients receiving no or low-dose erythropoietin.

Erythropoietin Accelerates Fracture Healing an Experimental Animal Study

Aim: The efficacy of erythropoietin (EPO) on wound healing has been shown before. There islimited data about the efficacy of EPO on fracture healing. In this study, the efficacy of EPO onclosed forearm fracture healing is searched by an experimental model. Material and method: Twenty eight rats were picked randomly and divided into EPO andControl groups. On the first day, fracture was performed on the right ulna and radius of all rats.500 U/kg daily low dose EPO was administered for each rat in EPO group and the same volumeof isotonic sodium chloride solution was given intraperitoneally in the control group for fivedays. Seven rats from each group were sacrificed at the end of the first week; the others weresacrificed at the end of the third week. Results: At the end of the first week and third week, bone healing scores of EPO group issignificantly higher than the control group according to the histological, clinic and radiologicanalysis. Conclusion: EPO could have positive effects on healing of forearm fracture on rats in acuteand subacute period. Low dose EPO may be a new protective agent against delayed union ornonunion in the risk population to go or not to go to surgical treatment

Erythropoietin and Platelet Function

There is ample evidence that indeed, erythropoietin regulates platelets. It also regulates megakaryocytes which produce platelets. Endothelial cells, blood clotting, and calcium (Ca ++ ) which regulates blood pressure are also regulated. A number of diseases and clinical conditions may be favorably treated by erythropoietin therapy as listed below. Uremia, aplastic anemia, refractory anemia, myelodysplastic syndrome, bone marrow transplants, post-hepatitic aplastic anemia, extremely low birth weight infants, uremic thromboembolism, hemodialysis and thrombocytopenia patients are benefited from erythropoietin therapy. Erythropoietin does not support platelet production during antiviral therapy. The response to erythropoietin is dose dependent both in men and in mice and rats. If high dose of recombinant human erythropoietin is used, it will stimulate platelet production, which is a transient effect. Expanded erythropoiesis exerts a negative impact on platelet production. Secondary thrombocytopenia was not related to splenic pooling, and its very slow correction after cessation of erythropoietin therapy was not compatible with changes in platelet survival. Rather, it is consistent with stem cell competition between erythroid and megakaryocytic development. Low dose erythropoietin administration improved platelet adhesion/aggregation and ameliorated prolongation of bleeding time in chronic renal failure rats. Long-term erythropoietin (150 U/kg, twice weekly for 6 weeks) administration led to Ca ++ levels normalization. Detailed studies revealed that improved Ca ++ signaling with erythropoietin is associated with increased Ca ++ uptake and expanded Ca ++ stores in platelets.

Low-dose erythropoietin alleviates the chronic fibrosis of kidney in mice models of renal ischemia-reperfusion injury

Objective To evaluate the possible mechanism of low-dose erythropoietin (EPO) alleviating renal interstitial fibrosis after ischemia-reperfusion injury (IRI).Methods Renal interstitial fibrosis was induced by unilateral renal IRI in mice.Mice were randomly divided into three groups:sham-operated,ischemic control and low-dose EPO treatment.They were sacrificed at 28th day after operation.The kidneys were taken for pathological analysis.The expression of laminin (LN),fibronectin (FN) and transforming growth factor-β1 (TGF-β1) in the kidneys was detected by using immunohistochemistry,and TGF-β1 by Western blotting.Results There was remarkable renal interstitial fibrosis in the control group as compared to the EPO group.The levels of LN,FN,and TGF-β1 mRNA and protein were significantly reduced in the EPO group (3.60 ± 0.46,3.85 ± 0.44,3.44 ± 0.52,0.77 ± 0.05) compared to the control group (4.39±0.54,4.99±0.22,4.33 ±0.29,0.91 ±0.04).Conclusion The results suggested low-dose EPO can reduce the accumulation of extracellular matrix through regulating TGF-β1 expression,thereby alleviating renal interstitial ftbrosis and protecting the kidney. Key words: Erythropoietin; Renal ischemia; Reperfusion injury; Tubulointerstitial fibrosis

Effects of erythropoietin on osteoblast proliferation and function

The purposes of this study were to investigate the effects of erythropoietin (EPO) on the proliferation and function of human osteoblast cells (hFOB 1.19) cultured in vitro and to explore the underlying molecular mechanisms to provide a theoretical foundation for clinical applications of EPO in oral implant and restoration therapies. Cultured hFOB 1.19 cells were treated with high and low doses of EPO. Changes in cell viability after 24 and 48 h of treatment were evaluated with the Mosmann tetrazolium assay. Changes in cell proliferation after 48 h of EPO treatment were measured by bromodeoxyuridine (BrdU) labeling, and changes in alkaline phosphatase (ALP) activity were determined by a specific assay. The effects of EPO on osteocalcin secretion were determined with the enzyme-linked immunosorbent assay, and changes in the protein expression of osteoprotegerin (OPG), osteopontin (OPN) and receptor activator of NF-κB ligand (RANKL) were assayed by western blot. The effects of EPO treatment on the levels of the EPO receptor (EPOR), phosphorylated Jak2 (P-Jak2) and phosphorylated Stat3 (P-Stat3) in hFOB 1.19 cells were evaluated in conjunction with a Jak2/Stat3 inhibitor. After 24 h of EPO treatment, hFOB 1.19 cells showed increased cell viability compared with the blank control group (p < 0.05). After 48 h, cell viability and growth were further improved relative to controls, with a significant increase observed for viability (p < 0.05). A significant increase in the proportion of BrdU-labeled proliferating cells was observed in the high-dose EPO group (p < 0.05), and EPO-treated cells also showed enhanced ALP activity (p < 0.05). There were no statistically significant differences in osteocalcin secretion between groups after 48 h of EPO treatment (p > 0.05); however, increased secretion was observed in EPO-treated cells after 96 h of treatment (p < 0.05). EPO treatment significantly promoted OPG and OPN expression (p < 0.05) while significantly inhibiting RANKL expression (p < 0.01). EPO treatment also significantly upregulated the levels of EPOR, P-Jak2 and P-Stat3 in hFOB 1.19 cells (p < 0.01); these effects were abrogated by co-treatment with a Jak2/Stat3 inhibitor (AG490) (p < 0.01). EPO significantly stimulated osteoblast proliferation and differentiation. The underlying molecular mechanism is associated with the ability of EPO to promote ALP activity, osteocalcin secretion and OPG and OPN expression and to inhibit RANKL expression in osteoblasts. This mechanism appears to be mediated by the Jak2/Stat3 pathway.

Effect of ethnicity on erythropoietin therapy response for hemodialysis patients: A retrospective study

Anemia is a common feature in chronic kidney disease patients due to deficiency of erythropoietin (EPO). Diseased kidneys are unable to produce EPO, which enhances red blood cell production from the bone marrow. Recombinant human EPO in hemodialysis patients was introduced with perfect outcomes as a hormonal substitutive treatment. Some ethnic minority groups have high prevalence of anemia associated with chronic kidney diseases. The aim of this study is to evaluate the differences between African Caribbeans and Caucasians' EPO therapy response with regard to hemoglobin (Hb), some factors affecting it and some comorbid conditions. A retrospective study for 6 months of 100 patients on hemodialysis was conducted on two ethnic minorities groups; 46 patients were African Caribbean and 54 patients were Caucasian, who received EPO therapy at once or three times weekly dose at the Hanbury Dialysis Unit of Royal London Hospital. There were three types of EPO therapy used: Aranesp, Mircera and Neorecormon. Forty-six patients were African Caribbean and 54 patients were Caucasian. There were 63.4% of patients treated by Aranesp while 13% were given Mircera; 22.8% of the sample used Neorecorman. It was shown that the chosen comorbid conditions had higher percentage in the African Caribbeans than in Caucasians. Diabetic and/or hypertensive patients are almost double the patient numbers. In addition, sickle cell anemia is only present in African Caribbeans. There were 43.5% of African Caribbeans and 81.1% of Caucasians who met the standards of Hb level. There was no significant difference between African Caribbeans and Caucasians regarding parathyroid hormone, c-reactive protein, B12, mean corpuscular volume, ferritin, and folate. In this study, there was a significant difference in the Hb levels between African Caribbean and Caucasian groups. Sixty percent of African Caribbeans had mean Hb less than normal levels. However, they received lower EPO dose than Caucasians. As a result, this may affect the whole treatment and therapy which may lead to anemic complications.

Neuroprotective effect of erythropoietin on nandrolone decanoate-induced brain injury in rats

Anabolic–androgenic steroids (AAS) are used in the medical treatment of many disorders. Erythropoietin (EPO) is a hematopoietic cytokine that has anti-apoptotic, anti-oxidative, and anti-inflammatory effects. The aim of the present study is to investigate the neuroprotective effects of EPO in the hippocampus, parietal cortex and prefrontal cortex, in brain damage due to nandrolone decanoate. 35 Wistar male rats were randomly divided into: (1) control group, (2) sham group, (3) nandrolone decanoate group (ND, intramuscular, 10mg/(kgweek), 8 weeks), (4) ND+low dose EPO treated group (ND+L-EPO) and (5) ND+high dose EPO treated group (ND+H-EPO). EPO was administrated by intraperitoneal injection at a dose of 100U/(kgday) for L-EPO treatment and at a dose of 500U/(kgday) for H-EPO treatment during 8 weeks. The number of neurons of CA1, CA2, CA3 and dentate gyrus of hippocampus, parietal cortex and prefrontal cortex were significantly less in the ND group compared with the control group. Treatment with H-EPO significantly preserved the number of neurons in hippocampus when compared with ND administrated. Besides, H-EPO treatment decreased the number of TUNEL-positive and active caspase-3 positive cells and MDA levels and increased GPx levels when compared to ND group. In conclusion, abuse of AAS causes reduction in the number of neurons in hippocampus, parietal cortex and prefrontal cortex regions and increases oxidative damage and therefore H-EPO may be useful as a neuroprotective agent in brain injury.