***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: STUDY OBJECTIVE To determine the effectiveness and safety of recombinant human erythropoietin ( rHuEpo ) . PATIENTS Hemodialysis patients ( 333 ) with uncomplicated anemia ( hematocrit less than 0.30 ) . All received rHuEpo intravenously , three times per week at 300 or 150 U/kg body weight , which was then reduced to 75 U/kg and adjusted to maintain the hematocrit at 0.35 + /- 0.03 ( SD ) . RESULTS The baseline hematocrit ( 0.223 + /- 0.002 ) increased to 0.35 , more than 0.06 over baseline within 12 weeks in 97.4 % of patients . Erythrocyte transfusions ( 1030 within the 6 months before rHuEpo therapy ) were eliminated in all patients within 2 months of therapy . Sixty-eight patients with iron overload had a 39 % reduction in serum ferritin levels after 6 months of therapy . The median maintenance dose of rHuEpo was 75 U/kg , three times per week ( range , 12.5 to 525 U/kg ) . Nonresponders had complicating causes for anemia , myelofibrosis , osteitis fibrosa , osteomyelitis , and acute or chronic blood loss . Adverse effects included myalgias , 5 % ; iron deficiency , 43 % ; increased blood pressure , 35 % ; and seizures , 5.4 % . The creatinine , potassium , and phosphate levels increased slightly but significantly . The platelet count increased slightly but there was no increase in clotting of vascular accesses . CONCLUSIONS The anemia of hemodialysis patients is corrected by rHuEpo result ing in the elimination of transfusions , reduction in iron overload , and improved quality of life . Iron stores and blood pressure must be monitored and treated to maintain the effectiveness of rHuEpo and to minimize the threat of hypertensive encephalopathy The investigators evaluated the impact of recombinant human erythropoietin ( r-HuEPO ) therapy on health-related quality of life ( HRQL ) in predialysis chronic renal disease patients with anemia . Eighty-three patients were entered into a r and omized , parallel-group , open-label clinical trial with follow-up evaluations over 48 weeks . Forty-three patients were assigned to r-HuEPO treatment , and 40 patients were assigned to an untreated control group .  Hematocrit levels were measured at baseline and monthly . HRQL was assessed at baseline and at weeks 16 , 32 , and 48 . The HRQL assessment included measures of physical function , energy , role function , health distress , cognitive function , social function , home management , sexual dysfunction , depression , and life satisfaction . Significant improvements in hematocrit levels were observed in the r-HuEPO-treated group ( P < 0.0001 ) , and no changes were seen in the untreated group . Correction of anemia ( hematocrit > or = 36 ) occurred in 79 % of r-HuEPO-treated patients and 0 % of control patients . Significant improvements in assessment s of energy ( P < 0.05 ) , physical function ( P < 0.05 ) , home management ( P < 0.05 ) , social activity ( P < 0.05 ) , and cognitive function ( P < 0.05 ) were found for the r-HuEPO-treated group . No changes were observed in the control group , except for a decrease in physical function ( P < 0.05 ) . Between-group differences favoring the r-HuEPO-treated group were found for energy ( P < 0.05 ) and physical functioning ( P < 0.05 ) . In patients receiving r-HuEPO , significant improvements were seen in hemotocrit levels , and these increases result ed in improvements in HRQL Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets . We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials . In the 4 month analysis , significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha . In unadjusted analyses , the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint ( death , myocardial infa rct ion , congestive heart failure or stroke ) . In adjusted models , high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with r and omization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose . Similar results were seen in the 9 month analysis . Our study demonstrates that patients achieving their target had better outcomes than those who did not ; and among subjects who achieved their r and omized target , no increased risk associated with the higher hemoglobin goal was detected . Prospect i ve studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin BACKGROUND In patients with end-stage renal disease , anemia develops as a result of erythropoietin deficiency , and recombinant human erythropoietin ( epoetin ) is prescribed to correct the anemia partially . We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis . METHODS We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis :  618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent , and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study . The median duration of treatment was 14 months . The primary end point was the length of time to death or a first nonfatal myocardial infa rct ion . RESULTS After 29 months , there were 183 deaths and 19 first nonfatal myocardial infa rct ions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infa rct ions among those in the low-hematocrit group ( risk ratio for the normal-hematocrit group as compared with the low-hematocrit group , 1.3 ; 95 percent confidence interval , 0.9 to 1.9 ) . Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary , the study was halted . The causes of death in the two groups were similar . The mortality rates decreased with increasing hematocrit values in both groups . The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group . CONCLUSIONS In patients with clinical ly evident congestive heart failure or ischemic heart disease who are receiving hemodialysis , administration of epoetin to raise their hematocrit to 42 percent is not recommended A r and omized , double-blind , placebo-controlled , multicenter trial was performed to assess the safety and efficacy of subcutaneous recombinant erythropoietin ( EPO ) in peritoneal dialysis patients . Seventy-eight patients were r and omized to receive EPO and 74 received placebo  during the first 12 wk . After this ,  placebo patients with hematocrit less than 32 % entered the EPO maintenance phase along with the initial EPO patients . Hematocrit rose significantly in the EPO group from 23.8 to 32 % after 6 wk , and this was sustained at 33.7 % at 12 wk . In the placebo group , the pre study hematocrit was 23.8 % as well , and no significant change in hematocrit occurred over 12 wk . Concomitant with the rise in hematocrit , transfusion requirements fell only in the EPO group . Eighty-eight percent of patients receiving EPO had their anemia ameliorated by Week 12 of the study . There was a wide range of dosage requirements during the maintenance phase , ranging from 8,000 U thrice weekly to 4,000 U every other week . Adverse events after EPO were similar to those seen in hemodialysis patients given this agent , with hypertension developing or worsening in 55 % of EPO patients during the initial 12 wk of therapy . Blood pressure was more likely to rise in patients with hypertension before receiving EPO . EPO is safe and effective in peritoneal dialysis patients , as it is in hemodialysis patients . Other than a rise in blood pressure , which is manageable with antihypertensives and ultrafiltration with dialysis , no serious side effects are seen . The optimal target hematocrit , effects of anemia improvement on quality of life , and end-organ ( heart , brain ) effects of anemia improvement in this patient population require further study OBJECTIVE --To determine whether recombinant human erythropoietin improves the quality of life and exercise capacity of anaemic patients receiving haemodialysis . DESIGN --A double blind , r and omised , placebo controlled study . SETTING --Eight Canadian university haemodialysis centres . PATIENTS --118 Patients receiving haemodialysis aged 18 - 75 with haemoglobin concentrations less than 90 g/l , no causes of anaemia other than erythropoietin deficiency , and no other serious diseases . INTERVENTIONS -- Patients were r and omised to three groups to receive placebo ( n = 40 ) , erythropoietin to achieve a haemoglobin concentration of 95 - 110 g/l ( n = 40 ) , or erythropoietin to achieve a haemoglobin concentration of 115 - 130 g/l ( n = 38 ) . Erythropoietin was given intravenously thrice weekly , initially at 100 units/kg/dose . The dose was subsequently adjusted to achieve the target haemoglobin concentration . All patients with a serum ferritin concentration less than 250 micrograms/l received oral or intravenous iron for one month before the study and as necessary throughout the trial . MAIN OUTCOME MEASURES --Scores obtained with kidney disease question naire , sickness impact profile , and time trade off technique ; and results of six minute walk test and modified Naughton stress test . RESULTS --The mean ( SD ) haemoglobin concentration at six months was 74 ( 12 ) g/l in patients given placebo , 102 ( 10 ) g/l in those in the low erythropoietin group , and 117 ( 17 ) g/l in those in the high erythropoietin group . Compared with the placebo group , patients treated with erythropoietin had a significant improvement in their scores for fatigue , physical symptoms , relationships , and depression on the kidney disease question naire and in the global and physical scores on the sickness impact profile . The distance walked in the stress test increased in the group treated with erythropoietin , but there was no improvement in the six minute walk test , psychosocial scores on the sickness impact profile , or time trade off scores . There was no significant difference in the improvement in quality of life or exercise capacity between the two groups taking erythropoietin . Patients taking erythropoietin had a significantly increased diastolic blood pressure despite an increase in either the dose or number of antihypertensive drugs used . Eleven of 78 patients treated with erythropoietin had their sites of access clotted compared with only one of 40 patients given placebo . CONCLUSIONS -- Patients receiving erythropoietin were appreciably less fatigued , complained of less severe physical symptoms , and had moderate improvements in exercise tolerance and depression compared with patients not receiving erythropoietin . At the doses used in this trial there was a higher incidence of hypertension and clotting of the vascular access in patients treated with erythropoietin We studied the mechanism of erythropoietin (EPO)-induced  hypertension ( HTN ) in rats with chronic renal failure ( CRF ) . After partial nephrectomy , rats were r and omized into four groups . Group A received EPO , 150 U/kg , two times weekly for 6 wk to prevent anemia ; group B received placebo injections and became anemic ; group C received EPO but was kept anemic by dietary iron deficiency ; and group D received placebo and regular transfusions to match hematocrit ( Hct ) in group A. Blood pressure ( BP ) , Hct , platelet cytosolic calcium ( [Ca2+]i ) and magnesium concentration , and pressor and vasodilatory responses were determined . By design , Hct in groups A and D were comparable and significantly greater ( P < 0.01 ) than in groups B and C. Despite divergent Hct values , the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy . EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals . EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization , angiotensin II or alpha 1-agonist , methoxamine in vitro , or the pressor response to angiotensin II in 
    Output:
    
Early reports ( 46 ) described sustained increases in hemoglobin levels accompanied by improvements in exercise tolerance , quality of life , and cognitive functioning , with relatively few adverse events .
For persons without substantial erythropoietin resistance , smaller epoetin doses will increase erythrocyte production and prolong erythrocyte life , whereas for persons with erythropoietin resistance , supraphysiologic doses of epoetin may be required to approach hemoglobin targets .
Erythropoietin has effects beyond erythrocytosis , including hemoglobin-independent hypertension ( 8) and angiogenesis ( 9 ) , which are probably promoted by exogenous nonphysiologic administration .
This well-executed meta- analysis mostly confirms earlier findings , showing that higher hemoglobin targets are associated with fewer transfusions but increase hypertension , access thrombosis , and stroke .
In the CESG trial , substantial benefits to quality of life and physical performance were associated with the 2 higher hemoglobin targets , although outcome measures did not differ between the 2 treatment groups .
What we definitively know is limited : Targeting hemoglobin levels greater than 130 g/L with epoetin or darbepoetin is probably more harmful than beneficial for most persons .
Critical questions remain : Is there a lower hemoglobin limit above which most patients derive a benefit with epoetin therapy , and what is that level ?
Is there a subset of persons who feel better with higher hemoglobin levels for whom higher levels should be targeted ?
Would risk be reduced if other agents , including iron , were increasingly used instead of high-dose erythropoietin or darbepoetin ?
Is low-dose ESA therapy safe ?