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.     

Correction of anemia in patients on continuous ambulatory peritoneal dialysis with subcutaneous recombinant erythropoietin twice a week: a long-term study.

Subcutaneous recombinant human erythropoietin (rHuEPO) was given for 12 months twice weekly to 10 patients on continuous ambulatory peritoneal dialysis (CAPD) with anemia (hemoglobin less than 9.0 mg/dl). All patients responded to a median weekly dose of between 37.5 to 100 (mean 55 to 105) units/kg and reached a target hemoglobin of 10-12 mg/dl in a mean of 11.7 weeks (range 5-24). Serum iron, iron saturation and ferritin were significantly lower and serum potassium was significantly higher than the pre-treatment level from 1 month onwards. Five patients without pre-treatment iron overload required oral iron supplement and 3 required oral potassium-binding resin. No significant change in other serum biochemical parameters was observed. Blood pressure remained stable during the treatment period but additional or increased dosage of antihypertensive drugs was required in 5 patients. Peritoneal small solute clearance and ultrafiltration and residual renal clearance did not change significantly after correction of anemia. The incidence of peritonitis and exit site infection was similarly unaffected. One patient developed a severe headache which was not associated with hypertension and responded to withdrawal of rHuEPO treatment. Most of the remaining patients showed improvement in subjective well-being. It was concluded that the subcutaneous route twice a week is a safe, convenient and cost-effective way to administer rHuEPO to patients on CAPD.     

Pharmacokinetics and pharmacodynamics of subcutaneous and intraperitoneal administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis

The single-dose pharmacokinetics of 50 U/kg body weight of recombinant human erythropoietin (rHuEPO) given by either the subcutaneous (s.c.) or the intraperitoneal (i.p.) route were studied in 20 anemic patients maintained on continuous ambulatory peritoneal dialysis. Their baseline hemoglobin levels were less than 9 g/dl. The absorption of rHuEPO via the i.p. route was limited. The serum erythropoietin (EPO) level was only slightly elevated from a baseline value of 27 +/- 3 mU/l to a plateau of 36 +/- 4 mU/l at 12-24 hours. In comparison, after s.c. injection, a peak EPO level of 81 +/- 13 mU/l was obtained after 24 hours. The areas under the concentration-time curve from 0-24 hour were 803 +/- 67 and 1492 +/- 165 mU/l.h for the i.p. and s.c. group respectively (p less than 0.003). The same two groups of patients were then given rHuEPO by either the s.c. or the i.p. route over a period of 16 weeks. In the s.c. group, the hemoglobin increased significantly from 6.9 +/- 0.3 g/dl to 9.8 +/- 0.6 g/dl (p less than 0.004). The mean rHuEPO dosage was 84 +/- 9 U/kg body wt/week. In the i.p. group, despite relatively higher rHuEPO dosage (133 +/- 7 u/kg body wt/week), the hemoglobin level did not increase significantly (7.0 +/- 0.4 g/dl to 8.0 +/- 0.4 g/dl, p = 0.09). Subcutaneous administration of rHuEPO is effective and convenient for patients maintained on continuous ambulatory peritoneal dialysis.     

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.     

Erythropoietin and cardiocirculatory condition in aged patients with chronic renal failure

BACKGROUND/AIM: The clearest benefit of recombinant human erythropoietin (rHuEPO) in end-stage renal disease is a substantial reduction in transfusion dependency and an improved quality of life. In this report, we describe the efficacy of weekly subcutaneous administration of rHuEPO in 11 elderly patients with anemia secondary to chronic renal failure. METHODS: The role of rHuEPO therapy in increasing the patient's quality of life and in decreasing the hospitalization rates secondary to cardiac morbidity was verified in 11 elderly patients (age range between 66 and 85 years) with anemia due to chronic renal failure. The mean hemoglobin level at the beginning of the study was 8.2 +/- (SD) 0.7 g/dl, and the serum creatinine concentration was 4.8 +/- 1.36 mg/dl. The patients underwent baseline and annual echocardiography, in addition to an electrocardiogram. RESULTS: Most patients experienced a partial regression of left ventricular hypertrophy, and no congestive heart failure was documented. The mean hemoglobin level during rHuEPO therapy increased to 11.3 +/- 1.2 g/dl, while the mean serum creatinine concentration did not change significantly. CONCLUSIONS: Our results confirm that early anemia correction in aged chronic renal failure patients permits improvement of the quality of life, of exercise performance, and of cognitive functions. Reduced transfusion need and regression of left ventricular hypertrophy favor a minor incidence of cardiac morbidity and contribute to reduce health costs.     

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.     

Autologous blood transfusion with recombinant human erythropoietin in heart surgery--studies on the volume of preoperative donation and postoperative administration]

Recombinant human erythropoietin (rHuEPO) was administered to 42 elective heart surgery patients, and the volume of autologous blood donated within the preoperative short period and effects of improving anemia by postoperative rHuEPO administration were studied. rHuEPO (100 U/kg/day) and chondroitin sulfate-iron (40 mg/day) were given intravenously for preoperative 14 days, and each 400 ml of autologous blood was donated on the 14th and 4th day before operation. Reticulocytes increased significantly 3 days after administration (p less than 0.01). The hemoglobin level, 13.4 +/- 1.0 g/dl before the first donation, returned to 13.4 +/- 1.1 g/dl just before operation. 800 ml of autologous blood, needed for usual open heart surgery, may possibly have been donated within 14 days without making patients anemic by intravenous rHuEPO administration. For postoperative rHuEPO administration, the patients were divided into 3 groups: Group I (10 cases): given for 14 days, Group II (12 cases): for 7 days, Group III (20 cases): no administration. Reticulocytes decreased rapidly after termination of rHuEPO administration in each group, and on the 7th day after termination, they returned to the level before administration. The hemoglobin level in Group I was maintained after termination of rHuEPO, and was +2.2 +/- 1.1 g/dl on the 21st postoperative day compared with the level of 1st postoperative day. The hemoglobin level in Group II fell after termination and was +0.9 +/- 0.7 g/dl on the 21st day, this being comparable to the level of Group III. There were significant differences between Group I and II (p less than 0.05), and between Group I and III (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The evaluation of postdialysis L-carnitine administration and its effect on weekly requiring doses of rHuEPO in hemodialysis patients

BACKGROUND: In this study, our aim was to evaluate the effect of postdialysis administration of parenteral L-carnitine supplementations on hematological parameters and also on weekly requiring dose of the recombinant human erythropoietine (rHuEPO) in hemodialysis (HD) patients. MATERIAL AND METHODS: The stable 34 patients (17 male, 17 female) were enrolled in the study who were on rHuEPO therapy and a regular maintenance HD program at 5 h, three times a week with bicarbonate dialysate and with biocompatible membranes in HD Center of Medical Faculty Hospital in University of Dicle. rHuEPO was administered subcutanously at 80-120 U/kg/week. The patients were divided into two groups: Group 1, rHuEPO therapy (n=17) and Group 2, rHuEPO therapy + L-carnitine (n=17). L-carnitine (L-carnitine ampul, Santa Farma) 1 g was injected postdialysis intravenously via venous route of the dialytic set, three times a week. The patient's hemoglobin (Hgb), hematocrit (Hct), serum iron (Fe(+2)), total iron-binding capacity (TIBC), transferrin saturation index (TSI), and serum ferritin (Fer) levels were followed during the 16-week period. The weekly requiring doses of rHuEPO and hematological parameters of patients were recorded at the beginning of the study, at 8 weeks, and at 16 weeks of the study period. RESULTS: In group 1 (n=17, 13 female, four male), the mean age was 38.8 +/- 12.1 years, mean period time on HD therapy was 18.1 +/- 14.9 months, and mean Kt/V value was 1.48 +/- 0.28. In group 2 (n=17, 13 male, four female), the mean age was 48.1 +/- 15.4 years, mean period time on HD therapy was 34.4 +/- 23.0 months, and mean Kt/V value was 1.29 +/- 0.20. The hematological parameters of the groups were found as follows: in group 1, Hgb: 7.9-10.8 g/dl, Hct: 25.3-32.5%; in group 2, Hgb: 10.2-11.8 g/dl, Hct: 30.6-35.4%, respectively (p < 0.05). The target Hgb/Hct values were achieved at the end of the study in both groups. Both groups were the same according to their serum Fe(+2) markers (p > 0.05). But unlike serum Fe(+2) markers, there were significant differences on weekly requiring doses of rHuEPO therapy between groups. While in group 1, the mean weekly requiring dose of rHuEPO was 6529 U/week (120 U/kg/ week) at the beginning of the study, and maintenance weekly requiring dose of rHuEPO was 3588 U/week (66 U/kg/week) at the end of the study, in group 2, they were 4882 U/week (80 U/ kg/week), and 1705 U/week (28 U/kg/week), respectively. According to these values, the total reduction in weekly requiring dose of rHuEPO was 45% in group 1, and 65% in group 2; the net gain was 20% in group 2 (p < 0.05). CONCLUSIONS: If other factors related to anemia are excluded, the postdialysis parenteral L-carnitine therapy can be considered in selected stable patients, which may improve anemia and may reduce the weekly requiring dose of the rHuEPO and also be cost-effective.     

Efficacy and immunogenicity of novel erythropoietic agents and conventional rhEPO in rats with renal insufficiency

Recombinant human erythropoietin (rhEPO) is used to treat anemia in chronic renal insufficiency. Erythropoietin (EPO) immunogenicity can lead to EPO-resistant anemia. Conjugating proteins with polyethylene glycol (PEG) can prolong elimination half-life and diminish protein immunogenicity. We investigated the efficacy of new erythropoietic agents, synthesized by single (Ro 50-3821) and multiple (MIX) integrations of PEG and succinimidyl butanoic acid with rhEPO, in rats with chronic renal insufficiency. Sprague-Dawley rats with surgically induced renal insufficiency received Ro 50-3821 or MIX subcutaneously (s.c.) over 4-12 weeks compared to rhEPO and NaCl. Hemoglobin and antibody levels served as primary efficacy and safety variables. Dosing intervals and dose-response characteristics were investigated. Ro 50-3821 (2.5 microg/kg once weekly) increased hemoglobin levels by 7 g/dl after 4 weeks compared to 1 g/dl in NaCl controls (P<0.05). MIX (2.5 microg/kg once weekly) and rhEPO (0.25 microg/kg three times weekly) increased hemoglobin levels by 3 g/dl. Ro 50-3821 administered for 12 weeks (0.75 microg/kg once weekly) increased hemoglobin levels (from 13 to 19 g/dl) more effectively than rhEPO (0.75 microg/kg once weekly, decline from 13 to 11 g/dl, P<0.05). No antibodies against Ro 50-3821 were detected after 12 weeks of treatment. Antibodies against rhEPO were seen in 69% of animals (P<0.00001). Ro 50-3821 increased hemoglobin levels with once weekly s.c. dosing. Multiple pegylated EPO is less effective. In rats, rhEPO failed to increase hemoglobin levels with once weekly long-term dosing. Antibody formation following rhEPO may explain this finding. Therefore, Ro 50-3821 may provide important clinical advantages compared to unpegylated EPO. It can be administered in longer dosing intervals and has a lower risk of unfavorable immunological responses.     

Darbepoetin alfa once every 2 weeks for treatment of anemia in dialysis patients: a combined analysis of eight multicenter trials

AIM: Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa in a large cohort of dialysis patients. METHODS: Data were combined from eight similarly designed 24-week phase 3b European studies, in which patients receiving EPO alfa or beta once-weekly were converted to Q2W darbepoetin alfa. Darbepoetin alfa dosage was titrated to maintain hemoglobin (Hb) between 10 and 13 g/dl and efficacy was evaluated during a 4-week evaluation period. RESULTS: In the 1,101 patients assigned to Q2W darbepoetin alfa (i.v., n = 196, s.c., n = 905), mean (SD) Hb levels were 11.53 (0.77) g/dl at baseline and 11.35 (1.04) g/dl at evaluation (mean change in Hb -0.27 g/dl, 95% confidence interval 0.34, -0.20). Hb levels were maintained between 10 and 13 g/dl during evaluation in 85% of patients. Darbepoetin alfa doses were similar at baseline and evaluation, and the i.v. and s.c. routes were associated with similar efficacy and dose requirements. Darbepoetin alfa was well-tolerated. CONCLUSIONS: Q2W darbepoetin alfa is effective in maintaining Hb levels in dialysis patients switched from weekly rHuEPO, regardless of the route of administration and with no notable increase in the weekly equivalent dose.     

Effect of weekly or successive iron supplementation on erythropoietin doses in patients receiving hemodialysis

AIMS: To conduct a 3-month prospective study to determine the optimal way for intravenous iron supplementation in hemodialysis (HD) patients with resistance to recombinant human erythropoietin (rHuEPO) therapy due to deficient iron storage. METHODS: Thirty-five HD patients with iron deficiency were divided into three groups: (1) patients receiving an intravenous infusion of 40 mg of iron during the first ten HD sessions (n = 12); (2) patients receiving 40 mg of iron injected once a week for 10 weeks (n = 12), and (3) patients without any iron supplementation (n = 11). The rHuEPO dosage was adjusted to maintain hemoglobin levels >10.0 g/dl, and the degree of anemia was assessed 3 months later. RESULTS: In group 1, the hemoglobin levels were significantly increased after 4 weeks and remained increased until the end of the study (p < 0.01). In group 2, the hemoglobin levels were gradually increased until the end of the study (p < 0.01). There was no difference in the final hemoglobin values between both groups. The rHuEPO dosage was significantly decreased from 131 +/- 18 to 90 +/- 17 U/kg/week in group 1 (p < 0.01), but could not be changed in group 2 during the observation period despite a similar elevation of the serum ferritin level. In group 3, the rHuEPO doses were rather increased at the end of the study (p < 0.05). CONCLUSION: Aggressive iron supplementation for the short term may be effective to restore rHuEPO hyporesponsiveness in HD patients with functional iron deficiency.     

Efficacy prospective study of different frequencies of Epo administration by i.v. and s.c. routes in renal replacement therapy patients.

BACKGROUND: The problem of pure red cell aplasia (PRCA) prompted nephrologists to revert to a wider intravenous (i.v.) utilization of erythropoeitin (Epo). Once weekly i.v. Epo administration has been suggested to be as effective as the twice/thrice weekly i.v. dose. The aim of the present study was to test whether once weekly i.v. Epo administration is equally as cost-effective as once weekly subcutaneous (s.c.) and 2-3 times weekly i.v. administration. METHODS: We prospectively studied 41 patients (23 males, aged 28-82 years), on renal replacement therapy for 18-286 months, stabilized on twice or thrice weekly s.c. Epo-alpha (basal). The patients were treated for three consecutive 6 month periods with once weekly s.c. (OWSC), once weekly i.v. (OWIV) and twice/thrice weekly i.v. (TWIV) Epo-alpha. The initial dose for each period was equal to the final dose of the previous one; when necessary, the dose was adjusted according to DOQY guidelines. Iron, folic acid and vitamin B(12) supplementations were given throughout all the study periods. At the end of each of the four study periods, the following parameters were evaluated: haemoglobin, haematocrit, hypochromic red blood cells (RBCs), iron, serum ferritin, transferrin, folate, vitamin B(12), C-reactive protein (CRP), Kt/V, parathyroid hormone (PTH) and weekly dose of Epo-alpha. RESULTS: Thirty-three out of 41 enrolled patients completed the study (there were five deaths, two renal transplants and one transfer). No significant changes were observed as regards iron, serum ferritin, transferrin, folate, vitamin B(12), CRP, Kt/V or PTH level. Haemoglobin levels were not different at the end of the basal (11.7+/-1.21), OWSC (11.8+/-0.86) and TWIV (12.1+/-1.04) periods, while significantly lower levels were observed after the OWIV period (11.0+/-0.97, P<0.01). Weekly Epo consumption (Epo U/week/kg body weight/g haemoglobin) was: basal 11.57+/-5.96; OWSC 10.22+/-4.53; OWIV 15.99+/-7.7*(a); and TWIV 11.89+/-6.3*(a) (*P<0.01 vs basal; (a)P<0.01 vs OWSC). CONCLUSIONS: From our results, the OWIV schedule seems to have less efficacy in the control of anaemia of chronic renal failure patients on dialysis treatment than either OWSC or TWIV schedules.     

Efficacy and tolerance of treatment with recombinant-human erythropoietin in chronic renal failure (pre-dialysis) patients

Recombinant-human erythropoietin (r-HuEPO) was administered to 24 anaemic pre-dialysis patients with end-stage renal disease. R-HuEPO was injected i.v. three times weekly during the first two months (correction phase). Fixed dosages of 50 U/kg, 100 U/kg, and 150 U/kg were used, and each dose group consisted of eight patients. During the subsequent six months r-HuEPO was given once weekly and the dose was adjusted to maintain a stable haemoglobin value (maintenance phase). The mean +/- SD haemoglobin increased from 9.3 +/- 0.6 to 11.1 +/- 1.3 g/dl with 50 U/kg, from 7.9 +/- 1.4 to 11.8 +/- 1.7 g/dl with 100 U/kg and from 8.4 +/- 1.0 to 12.1 +/- 1.1 g/dl with 150 U/kg of r-HuEPO. The two highest dose groups showed a marked reticulocytosis and a transient thrombocytosis. During the maintenance phase haemoglobin remained stable (11.9 +/- 1.1 g/dl) at a mean dose of 199 +/- 139 U/kg of r-HuEPO per week. Blood pressure did not increase, but in nine of eighteen previously hypertensive patients antihypertensive medication was increased. One hypertensive patient developed seizures. No accelerated progression of renal failure could be demonstrated. All patients reported an improved sense of well-being. R-HuEPO is an important new therapeutic agent for the treatment of anaemia of end-stage renal failure that is also effective in pre-dialysis patients.     

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.     

Pilot study of the optimum hematocrit for patients in the predialysis stage after renal transplantation

Anemia is a common complication in patients with chronic kidney diseases including posttransplant patients. Guidelines for the treatment of anemia in chronic kidney disease published by NHF-K/DOQI recommend the target hemoglobin and hematocrit (Hb and Ht) levels to be in the 11 to 12 g/dL and 33% to 36% ranges, respectively, which are somewhat higher than those recommended in Japan (Ht = 30%). However, these guidelines were established mainly from the data on hemodialysis patients with only limited information available as to the impact of anemia control in posttransplant patients. The aim of the present study was to evaluate cardiac function and quality of life (QOL) when the Ht was raised to about 36% by administration of recombinant-human-erythropoietin (rHuEPO) to patients with mild impairment of renal function (s-Cre < 2.0 mg/dL) after renal transplantation. Twenty-five patients were analyzed for cardiac function, blood data, and QOL in a prospective study encompassing 8 months of rHuEPO treatment. Using a once weekly subcutaneous dose of 6000 IU of Epoetin-beta, the Ht became 33% to 36% and Hb was 11 to 12 g/dL. Among the cardiac function tests, left ventricular end-diastolic diameter and left ventricular mass index decreased significantly. QOL did not show any significant changes after administration of rHuEPO. In conclusion, we demonstrated a potential benefit of using rHuEPO to maintain the Hb between 11 and 12 g/dL and the Ht between 33% and 36% in posttransplant patients with regard to the prevention of cardiovascular complications. Further study is required to establish the benefits of correcting anemia by rHuEPO on the outcome of posttransplant patients.     

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.     

Recombinant human erythropoietin dosage in children undergoing hemodialysis and continuous ambulatory peritoneal dialysis

The efficacy of erythropoietin (EPO) in 11 children on hemodialysis (HD) and 8 on continuous ambulatory peritoneal dialysis (CAPD) (mean age 11.8 years) was compared. The initial EPO dose was 50 U/kg s.c. once a week; the time of observation was 24 weeks. In the CAPD group, the mean hemoglobin (Hb) level increased from 7.7±0.2 to 11.2±0.6 g/dl (P< 0.001) and hematocrit (Hct) from 22.3±1.0 to 32.6±1.4% (P<0.001), while in the HD group the mean Hb rose from 7.7±0.6 to 9.3±0.8 g/dl (P<0.001) and mean Hct from 22.7±2.3 to 27.6±2.8% (P<0.001) after 12 weeks of observation. An increase in Hb to over 10 g/dl was obtained in 87.5% of children on CAPD but in only 10% on HD after 8 weeks of EPO treatment. After 12 weeks of treatment, all children on CAPD had the target Hb level of more than 10 g/dl, while 7 children on HD required increased doses of EPO (100 U/kg per week). We conclude that the EPO dose of 50 U/kg given s.c. once a week is effective for children with anemia on CAPD but is insufficient for children on HD. Received June 17, 1996; received in revised form January 24, 1997; accepted March 4, 1997     

Novel erythropoiesis stimulating protein

Novel erythropoiesis stimulating protein (NESP) is a hyperglycosylated analogue of recombinant human erythropoietin (rHuEPO) that stimulates erythropoiesis by the same mechanism as the native hormone. The addition of two extra carbohydrate chains, however, gives NESP greater metabolic stability in vivo, and its terminal half-life after IV administration is three-fold longer than for IV rHuEPO. This allows injections of both IV and SC NESP to be given less frequently, and indeed studies have shown that once-weekly, and even once every other week, dosing can maintain the hemoglobin concentration in patients treated for renal anemia. The optimum starting dose is 0.45 microg/kg once weekly via the IV and SC routes of administration. Adverse effects are very similar to those seen with rHuEPO, and no antibodies have been detected in over 1,500 patients exposed to NESP thus far. NESP therefore represents a triumph for drug synthesis by recombinant DNA technology, and we can look to the future of this new therapeutic agent with much hope and expectation.     

Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients.

BACKGROUND: Darbepoetin alfa is a unique molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its approximately 3-fold longer half-life and greater biological activity than recombinant human erythropoietin (rHuEpo), darbepoetin alfa maintains effective haemoglobin control at extended dose intervals compared with rHuEpo. This study assessed the efficacy and safety of unit doses of darbepoetin alfa for the treatment of renal anaemia. METHODS: In this multicentre, prospective, open-label study, 1502 dialysis subjects maintained on stable rHuEpo treatment were switched to darbepoetin alfa at extended dose intervals by the same route of administration as previous rHuEpo therapy [intravenous (i.v.), n = 900 or subcutaneous (s.c.), n = 602]. Subjects receiving rHuEpo two (n = 408, 27%) or three times (n = 884, 59%) a week were switched to darbepoetin alfa once a week, and those receiving rHuEpo once a week (n = 210, 14%) were switched to darbepoetin alfa once every 2 weeks. The unit doses of darbepoetin alfa (10-150 microg) were titrated to maintain haemoglobin concentrations of 10-13 g/dl for 24 weeks. RESULTS: Haemoglobin concentrations were maintained effectively in subjects regardless of whether they received darbepoetin alfa once a week or once every 2 weeks. The overall mean change in haemoglobin from baseline to the evaluation period (weeks 21-24) was +0.10 g/dl [95% confidence interval (CI) 0.04+/- 0.17]. The mean haemoglobin concentration increased by 0.19 g/dl (95% CI 0.11+/-0.27) in subjects receiving i.v. darbepoetin alfa, and was unchanged (-0.02 g/dl; 95% CI -0.12 to 0.07) in patients treated with s.c. darbepoetin alfa. Subjects with baseline haemoglobin < 11 g/dl experienced a clinically relevant increase in mean haemoglobin concentration of 0.67 g/dl (95% CI 0.56+/-0.77) from baseline to the evaluation period. The mean weekly i.v. and s.c. darbepoetin alfa dosage requirements during the evaluation period were 19.9 microg/week (95% CI 19.02+/-20.87) and 21.6 microg/week (95% CI 20.36+/- 22.94), respectively. Darbepoetin alfa was well tolerated and the safety profile was consistent with previous trials with darbepoetin alfa in dialysis subjects. CONCLUSIONS: Treating renal anaemia with darbepoetin alfa administered at extended dose intervals is both effective and well tolerated. Moreover, administration of darbepoetin alfa by both the i.v. and s.c. route is associated with stable haemoglobin concentrations.