Novel erythropoiesis stimulating protein for treatment of anemia in chronic renal insufficiency

BACKGROUND: Novel erythropoiesis stimulating protein (NESP) is a glycoprotein with a threefold longer terminal half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to determine whether NESP is effective for the treatment of anemia at a reduced dosing frequency relative to rHuEPO in patients with chronic renal failure not yet on dialysis [chronic renal insufficiency (CRI)]. METHODS: This was a multicenter, randomized, open-label study. A total of 166 rHuEPO-naive patients with CRI were randomized in a 3:1 ratio to receive NESP (0.45 microg/kg once weekly) or rHuEPO (50 U/kg twice weekly) administered subcutaneously for up to 24 weeks. Dose adjustments were made as necessary to achieve a hemoglobin response, defined as an increase > or =1.0 g/dL from baseline and a concentration > or = 11.0 g/dL. RESULTS: During the 24-week treatment period, 93% (95% CI, 87 to 97%) of patients receiving NESP and 92% (95% CI, 78 to 98%) of patients receiving rHuEPO achieved a hemoglobin response. The median time to response was seven weeks (range of 3 to 25 weeks) in both groups. After correction of anemia, mean hemoglobin concentrations were maintained within the target range of 11.0 to 13.0 g/dL for the remainder of the 24-week treatment period. The safety profiles of NESP and rHuEPO were similar, and no antibodies were detected to either drug. CONCLUSIONS: These results demonstrate that NESP safely and effectively corrects and maintains hemoglobin concentrations at a reduced dosing frequency relative to rHuEPO in patients with CRI, providing a potential benefit to patients and health care providers.     

Treatment of anemia in chronic renal failure by a long-activing activator of erythropoiesis

THE INTEREST AND LIMITS OF ERYTHROPOIETIN: Chronic renal failure (CRF) is often associated with anemia, mainly because of insufficient renal synthesis of erythropoietin (EPO). This observation led in the early 1980 to the cloning of the complementary DNA coding for the EPO molecule, the large-scale production of a recombinant human EPO (rHuEPO), and its large utilisation in clinical practice. More than a decade after this outstanding research progress, the use of rHuEPO has literally transformed the treatment of anemia of CRF. The efficacy of rHuEPO is dose-dependent and corrects the anemia in the majority of the patients. However, its relative short plasma half-live (4-8 hours) requires repeated injections of the drug, usually two to three times a week. A LONG ACTING ANALOGUE: The novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of rHuEPO capable of stimulating erythropoiesis by the same mechanisms as the natural EPO. NESP possesses five N-linked oligosaccharide chains and two times more sialic acid residues than rHuEPO. The addition of these extra-carbohydrate chains gives NESP greater metabolic stability and a half-life 3.6 times longer than rHuEPO. THE PROPERTIES OF NESP: Numerous studies have shown that NESP normalized and maintained stable the hemoglobin concentration when administered once a week and even at the frequency of one injection every other week. The optimal and maintenance dose is 0.45 microgram/kg/week, either intravenously or subcutaneously. Adverse events are similar to those seen with rHuEPO, and no antibodies against NESP have been detected in over 1,500 patients treated with NESP for more than 1 year. IN CONCLUSION: This novel long acting activator of the erythropoiesis is efficient and safe for the treatment of anemia of IRC patients. Its prolonged half-life, the delay between injections, and the decrease in the frequency of dose changes might result in an advantage for the patients and the medical staff.     

Once weekly versus twice weekly subcutaneous administration of recombinant human erythropoietin in haemodialysis patients.

Optimal route and frequency of administration of recombinant human erythropoietin (rHuEPO) have not yet been determined. There is some evidence to suggest that subcutaneous administration of rHuEPO may be more effective than the intravenous route in reversing renal anemia. It is also unclear whether rHuEPO is more effective when given by a large intermittent dose or by more frequent multiple divided doses. We have compared the effect of twice weekly versus once weekly subcutaneous administration of rHuEPO in two groups of haemodialysis patients. At the end of 12 weeks of treatment with rHuEPO, the mean haemoglobin levels had risen from 6.9 +/- (SD) 0.7 to 8.9 +/- 1.3 g/dl in the once weekly group and from 7.2 +/- 1.0 to 9.3 +/- 1.6 g/dl in the twice weekly group. The average doses of rHuEPO used during the study were 127 +/- 6 and 115 +/- 18 U/kg body weight/week for the once weekly and twice weekly groups, respectively. Subcutaneous administration of low-dose rHuEPO is effective in reversing renal anaemia. Similar responses were obtained with once weekly and twice weekly regimens.     

Randomized trial of darbepoetin alfa for treatment of renal anemia at a reduced dose frequency compared with rHuEPO in dialysis patients

BACKGROUND: Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency. METHODS: A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment. RESULTS: The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected. CONCLUSIONS: Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.     

Once weekly versus twice weekly subcutaneous administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis.

Twice weekly subcutaneous (s.c.) administration of recombinant human erythropoietin (rHuEPO) is effective in reversing renal anemia in CAPD patients. However the optimal frequency of administration has not been established. It would be more convenient to give rHuEPO by once weekly rather than twice weekly injection. We have therefore compared the effect of twice weekly versus once weekly s.c. administration of rHuEPO. Two groups of 10 CAPD patients were given the same starting dose of s.c. rHuEPO (100 U/kg body wt/week) either as a single weekly dose or twice weekly in divided doses. The rHuEPO dosage was then adjusted according to the hematologic response. The aim was to increase hemoglobin levels by about 1 g/dl per month. The target hemoglobin was 10 g/dl. After 16 weeks of treatment with rHuEPO, the hemoglobin levels rose from 6.6 +/- 1.2 (mean +/- SD) to 10.1 +/- 1.1 g/dl in the once weekly group and from 6.4 +/- 0.8 to 10.2 +/- 1.1 g/dl in the twice weekly group. The average doses of rHuEPO used during the study were 84 +/- 16 and 88 +/- 15 U/kg body wt/wk for the once weekly and twice weekly groups respectively. Subcutaneous administration of low dose rHuEPO is effective in reversing renal anemia. Similar responses were obtained with once weekly and twice weekly regimens. It is therefore acceptable and convenient for patients to receive one weekly s.c. injection of rHuEPO for the treatment of renal anemia.     

Efficacy and safety of darbepoetin alfa for anemia in children with chronic kidney disease: a multicenter prospective study in Japan

Background

We evaluated the safety and efficacy of darbepoetin alfa (DA), an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia, in Japanese children with chronic kidney disease (CKD) on peritoneal dialysis (PD) and hemodialysis (HD), and not on dialysis (ND).

Methods

A total of 31 pediatric CKD patients (13 PD, 2 HD, and 16 ND) were enrolled. DA was administered bi-weekly intravenously (IV) or subcutaneously (SC) for PD or ND patients, and weekly IV for HD patients for 24 weeks. The target Hb was defined as 11.0 to ≤13.0 g/dl. In patients receiving rHuEPO, the initial DA dose was calculated at 1 μg DA for 200 IU rHuEPO. The initial DA dose for naïve patients was determined by body weight, and intended not to exceed 0.5 μg/kg per administration. For some PD or ND patients, the dosing frequency was subsequently changed to once every 4 weeks.

Results

Mean Hb values increased from 10.5 ± 1.1 to 11.1 ± 1.1 g/dl after 4 weeks of DA treatment. The target Hb was achieved in all patients, 64.5 % of whom maintained the value at completion of the study. Hb responses were similar between IV and SC. The dosing frequency was extended to once every 4 weeks in 37.9 % of PD or ND patients. Eighty-seven adverse events were noted in 27 (87.1 %) of 31 patients, none of which were associated with DA.

Conclusion

These results suggest that IV or SC administration of DA is an effective and safe treatment for renal anemia in Japanese children with CKD.     

Darbepoetin alfa: a new therapeutic agent for renal anemia

Darbepoetin alfa is a super-sialylated analog of human erythropoietin that has a longer circulating half-life in vivo compared to both native and recombinant hormone. It has the same mechanism of action as erythropoietin, stimulating the same surface membrane receptor and triggering the same intracellular chain of events. An extra two N-linked carbohydrate chains, however, gives darbepoetin alfa greater metabolic stability in vivo, and its terminal half-life after intravenous administration is approximately three times longer than for intravenous erythropoietin. This in turn allows injections of the drug to be given less frequently, and studies have shown that once-weekly and once-every-other-week dosing can maintain the hemoglobin concentration in patients with renal anemia. The recommended starting dose for darbepoetin alfa is 0.45 microg/kg once weekly for both IV and SC administration, with subsequent titration based on the hemoglobin concentration. The adverse event profile is very similar to that seen with rHuEPO, and no antibodies have been detected in several thousand patients exposed to the drug, some of whom have been treated for up to five years now. Following a clinical research program that began in November 1996, darbepoetin alfa was finally approved by the European Commission in June 201, and by the FDA in September 201.     

Pharmacokinetics of recombinant human erythropoietin applied subcutaneously to children with chronic renal failure

The single-dose pharmacokinetics of recombinant human erythropoietin (rHuEPO) given SC was investigated in 20 patients aged 7–20 years at different stages of chronic renal failure. In a pilot study we confirmed the lower bioavailability of the drug in 2 children when given SC compared with the IV route (24% and 43%, respectively). Following administration of 4,000 units/m², rHuEPO SC effective serum erythropoietin concentrations increased from a mean baseline level (±SD) of 23±13 units/l to a mean peak concentration of 265±123 units/l, which was reached after 14.3±9.4 h, followed by a slow decline until baseline values were attained at 72 h. Mean residence time was 30±9 h and mean elimination half-time 14.3±7 h. The single-dose kinetics of SC rHuEPO in children with different degrees of renal failure are comparable to those in adult patients. Possibly, the higher efficacy of SC rHuEPO in patients with renal anaemia compared with IV rHuEPO is related to its prolonged action.     

Treatment of acute postoperative anemia with recombinant human erythropoietin

Risks inherent in the administration of blood products have increased efforts to avoid homologous transfusion. Although this has increased interest in autologous transfusion and intraoperative salvage, little attention has been focused on efforts to enhance endogenous erythropoiesis as a method of minimizing exposure to homologous blood. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study is to evaluate the effect of rHuEPO, administered postoperatively, on a model of acute blood loss. Eleven adult male baboons were randomized into two groups. All animals underwent a laparotomy and an exchange transfusion, with 6% hetastarch, to a final hematocrit of 15%. Group I (N = 6) received 1,000 units/kg of recombinant human erythropoietin daily for the first 14 postoperative days. Group II (N = 5) received an equivalent volume of placebo. All animals were given supplemental vitamin B12, folate and 200% of shed iron, as iron dextran IV, after exchange transfusion. Response was observed for a period of 35 days. All animals survived the protocol. There were no adverse reactions to rHuEPO or surgical complications. The hematocrits were similar between groups at baseline and after exchange transfusion. The maximal rate of erythropoiesis was significantly faster in the rHuEPO group (2.1 vs. 1.3%/day; p less than 0.01). The time required to return to hematocrits of 30% (9.9 vs. 17.4 days, p less than 0.001) and to baseline hematocrits (11.9 vs. 32.1 days, p less than 0.01) were both significantly shorter in the rHuEPO group. The data show that rHuEPO accelerates the recovery from anemia in the postoperative setting. Acceleration of erythropoiesis represents another alternative to homologous transfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

RBC improved survival due to recombinant human erythropoietin explains effectiveness of less frequent, low dose subcutaneous therapy.

Effectiveness of less frequent, once weekly, low dose subcutaneous recombinant human erythropoietin (rHuEPO) in maintaining 35% hematocrit in patients with chronic renal failure, predialysis and ESRD receiving dialysis, is dependent on rHuEPO induced prolonged RBC survival. One year of weekly rHuEPO doses to 7 patients originally part of the National Cooperative Protocol were evaluated for a total of 372 weeks for an average of 53 weeks per patient. The original 8 to 12 week dosage was directed by protocol for units per dose at 3 doses per week (4 IV, 3 subcutaneous). Thereafter, all doses were subcutaneous. Units/dose and doses/week were titrated to keep hematocrit at 35-38%. Dosage reduction of rHuEPO was determined by two investigators at the time of each examination. Statistical correlation was performed on effect of rHuEPO on 51Cr T1/2 RBC survival changes and changes of rHuEPO weekly doses. Patients evaluated at specific time points in the study were compared to themselves as their own controls by paired t-test analysis. The long-term increased RBC count correlated with prolonged RBC survival by 51Cr T1/2 rather than reticulocytosis. A relatively increased ease of sustaining the target hematocrit of 35% was demonstrated from the 8th week to 1 year. Thirty-two percent of the expanded RBC mass was older at 12 weeks and 22% was older at 1 year. rHuEPO dosage was reduced to 27% at weeks 8-12, to 21% at weeks 20-24, and to 38% at 1 year corresponding to prolonged RBC survival. 51Cr T1/2 increased from 21.6 days control to 28.6 days at 12 weeks and 26.3 days at 1 year.(ABSTRACT TRUNCATED AT 250 WORDS)     

Erythropoietin treatment in children with renal failure

 Erythropoietin (EPO) treatment dramatically changes the life of a child with end-stage renal disease. The administration of recombinant human (rHu)EPO is beneficial and safe in the predialysis period, during hemodialysis or peritoneal dialysis, and after renal transplantation. The goal of hemoglobin correction should be the level at which normal quality of life is possible without adverse events: in children this is usually 10–11 g/dl. rHuEPO is administered once to twice a week subcutaneously to children before dialysis, during peritoneal dialysis, and after transplantation. There is no real benefit of intraperitoneal administration. In children on hemodialysis two to three times a week IV administration is preferred. Among the many reasons for non-response to rHuEPO, iron deficiency (absolute or functional), infections, and hyperparathyroidism are the most common in the pediatric renal patient. Hypertension is the most-frequent side effect of rHuEPO treatment and needs careful monitoring. Iron should be supplemented orally or IV. No significant beneficial effect of rHuEPO on growth has been demonstrated. However, the association with recombinant human growth hormone therapy is not detrimental in children. Received: 4 May 1998 / Revised: 31 July 1998 / Accepted: 31 July 1998     

Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients.

Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (Epoetin) which has an increased terminal half-life in animal models. The aim of this study was to extend these observations to humans. Using a double-blind, randomized, cross-over design, the single-dose pharmacokinetics of Epoetin alfa (100 U/kg) and an equivalent peptide mass of NESP were compared following intravenous bolus in 11 stable peritoneal dialysis patients. This was followed by an open-label study to determine the single-dose pharmacokinetics of an equivalent peptide mass of NESP by subcutaneous injection in six of these patients. The mean terminal half-life for intravenous NESP was threefold longer than for intravenous Epoetin (25.3 versus 8.5 h), a difference of 16.8 h (95% confidence interval, 9.4 to 24.2 h, P = 0.0008). The area under the serum concentration-time curve was significantly greater for NESP (291.0 +/- 7.6 ng x h per ml versus 131.9 +/- 8.3 ng x h per ml; mean +/- SEM; P < 0.0005), and clearance was significantly lower (1.6 +/- 0.3 ml/h per kg versus 4.0 +/- 0.3 ml/h per kg; mean +/- SEM; P < 0.0005). The volume of distribution was similar for NESP and Epoetin (52.4 +/- 2.0 ml/kg versus 48.7 +/-2.1 ml/kg; mean +/-SEM). The mean terminal half-life for subcutaneous NESP was 48.8 h. The peak concentration of subcutaneous NESP was approximately 10% of that following intravenous administration, and bioavailability was approximately 37% by the subcutaneous route. The longer half-life of NESP is likely to confer a clinical advantage over Epoetin by allowing less frequent dosing in patients treated for anemia.     

Physiological and pharmacodynamic considerations for route of EPO administration

Three intertwined issues--effectiveness, dosage, and route of administration--dominate discussion about recombinant human erythropoietin (rHuEPO). The major biological effect of rHuEPO is to regulate the number of committed erythroid precursors and to cause them to mature into erythrocytes. The constant presence of rHuEPO is critical to the sustenance, multiplication, and differentiation of committed erythroid progenitors that otherwise undergo apoptosis and die before they reach maturity. The route for rHuEPO administration influences the plasma concentration-time profiles. The erythropoietic response is not dependent on the peak concentration of rHuEPO achieved but on the duration of time that rHuEPO levels are maintained above a critical concentration. High levels immediately after intravenous doses are unnecessary to either induce or to sustain erythropoiesis. During the period of relative rHuEPO deficiency that invariably follows intravenous administration, committed but still rHuEPO-dependent cells undergo apoptosis and die in the bone marrow. The subcutaneous route sustains rHuEPO levels above basal levels in the interdialytic period, prevents death of rHuEPO-dependent cells, and results in more efficient and more sustained erythropoiesis. Areas under active investigation include modifications of the parent hormone and novel delivery systems that decrease elimination and maximize the residence time of rHuEPO in the circulation.     

Effect of recombinant human erythropoietin on synthesis of methylguanidine in uraemic patients on haemodialysis or continuous ambulatory peritoneal dialysis

The effect of recombinant human erythropoietin (rHuEPO) on synthesis of methylguanidine was studied in 6 uraemic patients on haemodialysis and 5 uraemic patients on continuous ambulatory peritoneal dialysis (CAPD). The Two groups of patients were started on a 24-week course of thrice weekly 1500 IU of rHuEPO by the intravenous route. Serum methylguanidine level and methylguanidine/creatinine ratio were comparable in these groups. In the two groups no significant differences were observed in these measurements comparing the pretreatment values with those 4, 8, 12 or 24 weeks after starting rHuEPO administration. During rHuEPO therapy, serum methylguanidine levels and methylguanidine/creatinine ratio showed no considerable difference between the two groups. These findings suggest that administration of rHuEPO does not alter methylguanidine synthesis in uraemic patients on haemodialysis and CAPD.     

Perioperative recombinant human erythropoietin

The risks of transfusion-associated infectious disease have made increased efforts to avoid homologous transfusion imperative. Little attention has been focused on efforts to accelerate erythropoiesis as a method of reducing homologous blood use. Recombinant human erythropoietin (rHuEPO) has been shown to enhance erythropoiesis. The purpose of this study was to evaluate the effects of perioperative rHuEPO administration on postoperative erythropoiesis. Fifteen baboons were divided into three groups of five each. Group I received no rHuEPO. Group II received five daily preoperative doses of rHuEPO (1000 U/kg). Group III received five daily preoperative doses and 14 daily postoperative doses of rHuEPO (1000 U/kg). All animals underwent a laparotomy followed by an exchange transfusion to a final hematocrit of 15%. The time in days required to recover to hematocrits of 20% was significantly shorter in both groups that received preoperative doses of rHuEPO when compared with that of controls (3.3 vs 5.7 days, p less than 0.01). The recovery times to hematocrits of 25%, 30%, and baseline levels were all significantly shorter in the group that received both preoperative and postoperative doses of rHuEPO. The data show that perioperative dosage of rHuEPO significantly accelerates postoperative erythropoiesis. Perioperative administration of rHuEPO may reduce the requirements for homologous transfusion.     

Darbepoetin-alfa treatment of anemia secondary to chronic renal failure in dialysis patients: Results of a French multicenter study

Darbepoetin alfa is a unique genetically engineered glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). The objective of this study was to determine if darbepoetin alfa administered at a reduced dosing frequency relative to the prior rHuEpo regimen is an effective and safe alternative for treating renal anemia in patients undergoing dialysis. A total of 1,008 French hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (i.v., N = 217) or subcutaneous (s.c., N = 791) route were switched to darbepoetin alfa given by the same route of administration at a reduced dosing frequency. Patients receiving rHuEPO once weekly (N = 248, 25%) were switched to darbepoetin alfa every two weeks, and those receiving rHuEPO two or three times weekly (N = 760, 75%) were switched to darbepoetin alfa once weekly. The doses of darbepoetin alfa were titrated to maintain hemoglobin concentration in the target range of 10.0 to 13.0 g/dl for up to 24 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period (weeks 21-24). Adjusted (for covariates that might influence hemoglobin response) mean change in hemoglobin from baseline to the evaluation period was not clinically significant: +0.11 g/dl (95% CI: -0.30; 0.52). An i.v./s.c. dose ratio of 0.96 (95% CI: 0.86; 1.06) at evaluation confirms previous findings that darbepoetin alfa dose requirements were not different for the s.c. and i.v. routes. At the end of the evaluation period, more than 98% of patients successfully maintained hemoglobin within the target range and at their darbepoetin alfa assigned dosing frequency. Darbepoetin alfa was well tolerated with a safety profile consistent with that observed in previous darbepoetin alfa studies. Darbepoetin alfa administered at a reduced dosing frequency relative to the prior rHuEpo regimen effectively maintains hemoglobin in the target range in dialysis patients with renal anemia.     

Neuroprotective potential of erythropoietin and darbepoetin alfa in an experimental model of sciatic nerve injury. Laboratory investigation

OBJECT: The objectives of this study were to examine whether the systemic administration of recombinant human erythropoietin (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery in a rat model of sciatic nerve injury, and to compare the effects of these agents in the model. METHODS: Thirty male Sprague-Dawley rats received a crush injury to the left sciatic nerve and subsequently underwent either placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. RESULTS: Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment and improving compound muscle action potentials following nerve injury. Darbepoetin alfa, however, shortened the duration of peripheral nerve recovery'and facilitated recovery from the neurological and electrophysiological impairment following crush injury significantly better than rHuEPO. Examination of the footprint length factor data revealed that darbepoetin alfa-treated animals recovered preinjury function by postoperative Day 10, 4 days earlier than animals treated with rHuEPO and 11 days earlier than animals treated with placebo. CONCLUSIONS: These results suggest that recovery of neurological function in a model of peripheral nerve injury is more rapid with weekly administration of darbepoetin alfa than with daily rHuEPO treatment. Agents that facilitate nerve regeneration have the potential to limit the extent of motor endplate loss and muscle atrophy. The administration of EPO in its long-lasting recombinant forms affords significant neuroprotection in peripheral nerve injury models and may hold promise for future clinical applications.     

Effects of intravenous ascorbic acid on erythropoiesis and quality of life in unselected hemodialysis patients

BACKGROUND: Intravenous ascorbic acid (IVAA) administration is reported to enhance erythropoiesis in hemodialysis (HD) patients with functional iron deficiency. We explored the effects of IVAA on erythropoiesis and health-related quality of life (HRQOL) in unselected HD patients. METHODS: Sixty-one HD patients were divided into two groups; 30 patients received 100 mg of IVAA (IVAA group) and 31 patients did not (control group) after each dialysis session. Hematocrit (Hct), reticulocyte hemoglobin content, transferrin saturation, ferritin, weekly recombinant human erythropoietin (rHuEPO) dosage, weekly intravenous iron (IVFE) dosage, and MOS Short Form 36 (SF-36) scale scores were measured at baseline and after 6 months of treatment. RESULTS: Mean changes in Hct in the IVAA and control groups were -0.5 and -0.6 mg/dL, respectively, while mean changes in SF-36 scale scores were: physical functioning -1.6 in the IVAA group and 0.38 in the controls; role physical (RP) 3.8 and 9.4; bodily pain 9.7 and 0.81; general health perception 3.7 and -0.68; vitality 4.3 and -7.5; social functioning 2.7 and 0.43; role emotional (RE) 6.9 and 4.9; mental health 3.6 and -1.7. The IVAA group showed significantly higher adverse events (chest pain: n=1, nausea: n=2 and fatigue: n=2) compared to the controls (no event). CONCLUSIONS: The beneficial effects of IVAA on erythropoiesis and HRQOL were not demonstrated in unselected HD patients. Indication of IVAA for HD patients leaves room for further study.     

The efficacy of once weekly compared with two or three times weekly subcutaneous epoetin beta: results from a randomized controlled multicentre trial. Swedish Study Group.

BACKGROUND: Anaemia in haemodialysis patients can be effectively treated with erythropoietin. We investigated whether subcutaneous (SC) epoetin ss administered once weekly was as effective as the same weekly dosage given in two to three divided doses. METHODS: One hundred and fifty-eight patients (delivered Kt/V >1.0, where K=dialyser-renal urea clearance, t=dialysis time and V=filtration volume, obtained by urea kinetic modelling) were randomized to treatment with SC epoetin beta either once weekly (n=118), or to their original dosage two or three times weekly (control group, n=40) for 24 weeks. All patients received intravenous iron supplementation when necessary. RESULTS: Eight-eight patients in the once weekly group and 30 patients in the control group were treated for at least 16 weeks and are included in the analysis. Stable haemoglobin levels were maintained without epoetin dose increases in 73% of patients in both groups. Mean haemoglobin levels at randomization and after 16 and 24 weeks were 11.4, 11.1 and 11.1 g/dl, respectively, in the once weekly group compared with 11.2, 11.3 and 11.2 g/dl, respectively, in the control group. The mean weekly epoetin beta dosages at randomization and after 16 and 24 weeks were 102, 103 and 106 IU/kg bodyweight, respectively, in the once weekly group compared with 109, 109 and 115 IU/kg bodyweight, respectively, in the control group. No statistically significant between-group differences were apparent for changes in haemoglobin levels or epoetin beta dosages at week 24. CONCLUSIONS: Once weekly SC administration of epoetin beta is as safe and effective in maintaining haemoglobin levels in stable haemodialysis patients as two or three times weekly administration of the same total dose. By using the once weekly regimen, patients can avoid up to 104 injections per year. This would reduce clinic time for patients who do not self administer, and may also encourage self-administration and improve overall compliance.     

Subcutaneous use of erythropoietin in heart surgery.

The effect of subcutaneous administration of recombinant human erythropoietin (rHuEPO) in ameliorating anemia resulting from autologous blood donation was compared with intravenous administration of rHuEPO. Forty patients undergoing coronary artery bypass procedures were divided into three groups. Group I (12 patients) received intravenous administration of rHuEPO (100 U.kg-1.day-1) and intravenous iron preparations for 14 days before operation; group II (14 patients) had subcutaneous administration of rHuEPO (600 U/kg) on preoperative days 14 and 7 and oral iron preparations for 14 days; and group III (14 patients) received oral iron preparations alone and served as the controls. Each patient predonated 800 mL of blood in the 2 weeks before operation. The reticulocyte count increased significantly in groups I and II (p less than 0.01), but little in group III. The hemoglobin level just before operation was higher in groups I (p less than 0.01) and II (p less than 0.05) compared with group III. Four patients (29%) in group III required homologous blood transfusion versus none in groups I and II (p less than 0.05). Subcutaneous administration of rHuEPO once a week was as effective as daily intravenous administration. Preoperative autologous blood donation can be performed over a short period on an outpatient basis with subcutaneous administration of rHuEPO.