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.     

Subcutaneous recombinant human erythropoietin in chronic renal allograft dysfunction

We investigated the efficacy and safety of subcutaneous recombinant human erythropoietin (rHuEpo) in 25 children with chronic renal allograft dysfunction (13 girls, 12 boys, mean age 15.8±4.2 years) for a treatment period of 9 – 162 (median 43) weeks. rHuEpo was started once weekly at a dose of 105±25 U/kg per week in 16 children, twice weekly at a dose of 175±70 U/kg per week in 6 children, and three times weekly at a dose of 270±28 U/kg per week in 3 children. The hematocrit increased in 21 children from 23.2%±3.1% to 33%±3.1% within 7.2±4.9 weeks at a mean rate of 1.98%/week. The hematocrit increase and rHuEpo starting dose were linearly related (delta hematocrit/week = 0.8+0.08 U/kg per week, r = 0.44, P <0.05). The maintenance dose was 74±23 (43 – 114) U/kg per week. Four children failed to reach the target hematocrit, most likely due to noncompliance. Seventeen recurrences of anemia (“anemic episodes”) during rHuEpo therapy were identified in 12 children, mostly associated with acute or insidious deteriorations in graft function. There was no acceleration of progression of graft dysfunction with rHuEpo treatment. We conclude that subcutaneous rHuEpo at a single weekly dose of 100 IU/kg per week is highly effective in children with chronic graft dysfunction. Children who appear to be rHuEpo resistant or experience rHuEpo-resistant episodes should be assessed for noncompliance, changes in graft function since the last dosage adjustment, and blood loss, such as seen in dysfunctional uterine bleeding in adolescent girls. Received February 13, 1997; received in revised form and accepted June 26, 1997     

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.     

The Beneficial Effect of Low Initial Dose and Gradual Increase of Erythropoietin Treatment in Hemodialysis Patients

Abstract: It is well known that the effects of human re-combinant erythropoietin (rHuEPO) are dose-dependent. However, when higher doses of rHuEPO are used, the frequency of the side effects also increases. The aim of our study was to analyze the hematologic parameters and blood pressure response in hemodialysis patients treated with low initial and gradually increased rHuEPO. Sixteen regular hemodialysis patients were treated with 3 times 20 U/kg/week of rHuEPO subcutaneously during the first month. Every fourth week the dose was increased by 3 times 20 U/kg/week if the hematocrit did not rise by 2%. If the elevation was 2% or more, the dose of the rHuEPO was not changed. Blood count and blood pressure were checked every week. The antihypertensive treatment was also reviewed weekly. The hematocrit increased significantly from the second week, and 11 patients achieved the target level (30%) between Weeks 8 and 24. Two patients reached the 30% hematocrit level between Weeks 2 and 8, and another 2 patients reached the target level between Weeks 25 and 28. There was 1 nonresponder. The average rHuEPO dose needed to achieve the target hematocrit was 56.3 U/kg/week. We did not observe significant changes in the mean arterial or diastolic blood pressure. It was necessary to increase the doses of anti-hypertensive drugs, namely nifedipine and captopril, to control blood pressure. Encephalopathy occurred in none of the cases. The low initial dose and the gradual increase of rHuEPO treatment were beneficial to the hemodialysis patients. Although the target hematocrit took longer to achieve, high blood pressure and encephalopathy were prevented by close monitoring and administration of suitable antihypertensive treatment.     

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.     

Safety and efficacy of erythropoietin in children with chronic renal failure

 A prospective randomized study of the use of recombinant human erythropoietin (rHuEPO) in children with chronic renal disease was conducted to assess dosing requirements and side effects. Forty-four children with chronic renal failure, aged 4 months to 21 years, were studied. Twenty-five patients were pre dialysis, 10 on peritoneal dialysis, and 9 on hemodialysis. Patients received either 150 U/kg per week or 450 U/kg per week divided thrice weekly of rHuEPO for 12 weeks or until target hemoglobin (Hb) was attained. Dose was then adjusted to maintain a normal Hb. Eighty-two percent of patients reached target Hb by 7.9±5.6 weeks (mean±SD); 95% of patients in the high-dose group and 66% in the low-dose group reached target Hb within 12 weeks. The overall median rHuEPO dose at target Hb was 150 U/kg per week. Hemodialysis patients tended to require more rHuEPO to maintain a normal Hb (median 250 U/kg per week). Transfusion requirements and panel-reactive antibody levels decreased during the 12 weeks. Iron deficiency and/or hypertension occurred in 30% of children. In conclusion, rHuEPO at 150 U/kg per week is safe and effective in treating anemia in children with chronic renal disease. Received: 12 March 1998 / Revised: 24 June 1998 / Accepted: 6 July 1998     

Effect of hyperparathyroidism on response to erythropoietin in children on dialysis

The response to recombinant human erythropoietin (rHuEPO), 50 units/kg thrice weekly, was studied prospectively in 17 children and adolescents with end-stage renal disease who were either transfusion dependent or had hematocrits <25%. For convenience, rHuEPO was given intravenously to 12 hemodialysis (HD) patients and subcutaneously to 5 peritoneal dialysis (PD) patients. Blood pressure, hematocrit, iron indices, and serum potassium, calcium, phosphorus, alkaline phosphatase, urea nitrogen, and intact parathyroid hormone (PTH) were monitored serially. When serum ferritin was <100 ng/ml during therapy, 6 patients received iron supplementation. rHuEPO therapy eliminated frequent transfusions in all patients; 11 of 17 patients reached the target hematocrit of 30% – 33% by week 16 of rHuEPO, 50 units/kg thrice weekly. The 5 PD patients treated subcutaneously reached target at week 6±1; 6 HD patients treated intravenously reached target at week 11±3; 6 additional HD patients never reached target at this dose; 5 of 6 had pre-rHuEPO serum PTH levels >400 pg/ml, significantly higher than those of the other patients (P <0.005); 3 of 6 later reached a hematocrit of 30% – 33% after the rHuEPO dose was increased to 120 – 130 units/kg thrice weekly. We conclude that most pediatric dialysis patients can be treated successfully with rHuEPO, 50 units/kg thrice weekly, unless the serum PTH concentration is markedly elevated, in which case a higher dose is likely to be needed. Received May 8, 1997; received in revised form September 16, 1997; accepted September 19, 1997     

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.     

Low-dose erythropoietin is effective and safe in children on continuous ambulatory peritoneal dialysis

Hypertension is one of the most important complications of erythropoietin (rHuEPO) therapy in dialysis patients. In this study, the effect of two different dosage regiments of subcutaneous rHuEPO on blood pressure [BP] was evaluated in 20 anemic children on continuous ambulatory peritoneal dialysis (CAPD). Patients were randomized to receive rHuEPO 50 U/kg, either once a week (group 1, 50 U/kg per week) or three times a week (group 2, 150 U/kg per week). At the beginning of the study, 8 patients in group 1 and 8 patients in group 2 were on antihypertensive therapy. In group 1, the hematocrit increased gradually and significantly from 18.98%±1.79% to 30.1%±1.62% after 6 months, while in group 2 it rapidly increased from 19.53%±1.86% to 32.4%±1.11% after 3 months. A significant increase in the mean arterial BP was observed in group 2. Antihypertensive therapy had to be increased in all of the 8 previously hypertensive patients and had to be initiated in 1 of the 2 originally normotensive patients in the same group. None of the patients in group 1 required a change in antihypertensive medication. We conclude that during treatment with rHuEPO pre-existing hypertension and the dose of rHuEPO are the most important risk factors for the development or worsening of hypertension in children on CAPD, and gradual elevation of hematocrit by low-dose rHuEPO avoids the development of severe hypertension. Received December 11, 1995; received in revised form September 16, 1996; accepted September 19, 1996     

Intravenous ascorbic acid administration for erythropoietin-hyporesponsive anemia in iron loaded hemodialysis patients

Intravenous ascorbic acid administration (IVAA) could override recombinant human erythropoietin (rHuEPO) resistance in hemodialysis patients with iron overload. We investigated the hematopoietic response to IVAA in iron-overloaded hemodialysis patients. We included 36 patients whose ferritin levels were higher than 500 microg/L and who needed more than 100 U/kg/week of rHuEPO. The study included an initial phase (500 mg IVAA twice weekly was administered to all of the patients for 8 weeks) and a maintenance phase (patient groups were formed; Group 1 received IVAA 500 mg/week for 8 weeks and Group 2 received no therapy). We observed a significant increase in hematocrit and transferrin saturation and a decrease in the percentage of hypochromic red cells and ferritin levels at the end of the initial phase. The total weekly-required rHuEpo dose and rHuEpo/hemoglobin also fell significantly after the initial phase. The response remained stable in patient groups during the maintenance phase. In 6 nonresponders, the hypochromic red cells were <10%. In conclusion, IVAA effectively overrides rHuEPO resistance in iron-overloaded hemodialysis patients.     

Effect of lidocaine on the hematopoietic properties of recombinant human erythropoietin in the uremic rat

Subcutaneous injections of recombinant human erythropoietin (rHuEPO) produce considerable pain which can result in noncompliance. As a prelude to an investigation of the possible use of local anesthetics as additives to subcutaneous rHuEPO, we examined the effect of the addition of lidocaine on the erythropoietic properties of rHuEPO. Two weeks after 5/6 nephrectomy, 22 rats were randomly assigned to the following groups: normal saline, rHuEPO, lidocaine, and rHuEPO plus lidocaine. Injections were given three times a week for 2 weeks. No change in hematocrit was observed in the saline and lidocaine groups. The hematocrit of the rHuEPO rats increased from 44.5±1.4% (mean±SD) to 61.6±2.1% (P<0.0005), and that of the rHuEPO plus lidocaine group from 42.8±4.3% to 63.9±3.0% (P<0.005), with no difference between the groups. We conclude that the combination of rHuEPO plus lidocaine is as effective as rHuEPO alone in increasing the hematocrit of rats with chronic renal failure.     

Complete switch to darbepoetin in a hemodialysis unit

AIMS: In March 2003, our hemodialysis unit switched all patients from subcutaneous (s.c.) rHuEPO to intravenous (i.v.) darbepoetin. The primary outcome was to assess the efficacy of i.v. darbepoetin to maintain target serum hemoglobin (Hb) compared to s.c. rHuEPO. Secondary outcomes were to evaluate the manufacturer's recommend guidelines for conversion of rHuEPO to darbepoetin, and to assess the cost implications of darbepoetin therapy. METHODS: This was an 18-month open-label observational study of 95 hemodialysis patients. At the time of the switch to darbepoetin (baseline), data were collected retrospectively for six months and prospectively for 12 months, at three-month intervals. The first six months of darbepoetin therapy was considered a dose titration phase, thus, data were analyzed comparing two six-month periods: (-) six months to baseline (rHuEPO phase) and (+) 6-12 months (darbepoetin phase). Doses were titrated to a target Hb of 120-135 g/l. RESULTS: There was no significant difference in Hb between phases at any time point. Mean Hb ranged from 119.6-121.5 g/l for rHuEPO and 121.9-123.4 g/l for darbepoetin. The median darbepoetin dose remained stable throughout the analysis at 30 microg/week while the median dose of rHuEPO rose from 8,000 U/week at minus six months to 9,000 U/week at baseline. Median 12-month cost savings associated with the administration of darbepoetin were estimated at 212,000 dollars. The recommended darbepoetin dose from the manufacturer's conversion table was deemed too low for baseline rHuEPO doses above 17,000 U/week. A more simplified dose conversion nomogram was created. CONCLUSION: Darbepoetin was able to maintain similar serum Hb levels compared to rHuEPO at a substantially reduced cost.     

Endotoxin-free dialysate improves response to erythropoietin in hemodialysis patients

BACKGROUND/AIMS: Inflammatory process induced by endotoxin is one of the causes of resistance to recombinant human erythropoietin (rHuEPO) in hemodialysis patients. Thus dialysate contaminated with endotoxin may diminish response to rHuEPO. We investigated whether dose of rHuEPO could be reduced with endotoxin-free ultrafiltered dialysate. METHODS: Twenty-seven chronic hemodialysis patients receiving rHuEPO were studied. The patients did not have known causes of anemia other than chronic renal failure. An endotoxin-cut polyethylene ultrafilter was installed into the dialysate fluid circuit. Hematocrit and dose of rHuEPO were monitored before and after installation. Dose of rHuEPO was adjusted to keep hematocrit at about 30%. Endotoxin concentration of dialysate was measured by commercial limulus test (Endospecy. RESULTS: After installation of ultrafilter, dialysate endotoxin concentration decreased from >100 to <1.0 endotoxin units/liter (EU/l). Dose of rHuEPO decreased from 90.0 U/kg/week (median) to 57.3 U/kg/week (p < 0.05) and hematocrit increased from 30.3% (median) to 32.2% (p = 0.03) after 5 months of installation of ultrafilter. The running cost of the ultrafilter corresponded to only 4% of the cost of spared rHuEPO. CONCLUSIONS: Ultrafiltered endotoxin-free dialysate caused significant reduction in dose of rHuEPO to keep target hematocrit level. Endotoxin-cut ultrafilter was beneficial to hemodialysis patients in medical and in economical aspects.     

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.     

The effect of epoetin dose on hematocrit

Nearly all dialysis patients receive epoetin therapy to treat anemia. Using the United States Renal Data System, we monitored the 14,001 patients aged 65 and older who started dialysis and epoetin treatment in 2003-2004. We estimated the dose-response relationship for the average epoetin dose and hematocrit during a 3-month initiation and subsequent 3-month maintenance phase using a marginal structural model to adjust for measured time-dependent confounding by indication. During the initiation phase, an S-shaped dose-response relationship for average weekly epoetin dose and hematocrit response was found. Average hematocrit levels rose as the epoetin dose was increased from 9,000 to approximately 22,500 units per week. At higher doses, the effect of increasing epoetin was minimal with average hematocrit levels plateauing at 38.5%, but this was less evident in the maintenance phase. Among patients who reached this phase, doses required to maintain the hematocrit level were lower than those required to achieve similar hematocrit levels in the initiation phase. The dose-response curve found in our study suggests that published recommendations for starting dose are appropriate, and a starting dose of 7,500-15,000 units per week can maintain the hematocrit level in the desired target range of 33-36%.     

Significance of parenteral iron administration for HCV-positive hemodialysis patients

BACKGROUND: It is well recognized that parenteral iron administration is recommended for hemodialysis (HD) patients treated with rHuEPO. On the other hand, hepatic iron concentration increases in chronic hepatitis C, and iron reduction improves serum transaminase levels in these patients. METHODS: We compared the rHuEPO doses with hematological parameters in HCV-positive (n = 7) and HCV-negative (n = 32) HD patients when parenteral low-dose iron was administered for one year (target ferritin level: 200-300 ng/ml, target hematocrit level: 30-33%). RESULTS: None of the parameters was significantly different between the groups at the start of the study. One year later, levels of hematocrit and serum ferritin significantly increased compared with those at the start in each group (HCV-positive group: 28.0 +/- 2.7-->31.3 +/- 1.5%, p < 0.01, 119.3 +/- 171.9-->303.3 +/- 77.7 ng/ml, p < 0.05, respectively, HCV-negative group: 26.8 +/- 2.2-->30.0 +/- 3.5%, p < 0.01, 69.8 +/- 100.5-->278.4 +/- 66.4 ng/ml, p < 0.01, respectively). Serum transaminase levels were not significantly different between the start and end points in the HCV-positive group, but 2 patients showed an increase in these levels. In the HCV-negative group, the rHuEPO dose at the end point was significantly reduced compared with that at the start (4,875 +/- 2,089-->4,031 +/- 2,203 IU/W, p < 0.05). In the HCV-positive group, however, it was difficult to reduce the rHuEPO dose in order to maintain the target hematocrit level (4,071 +/- 1,134-->3,857 +/- 1,464 IU/W, NS). CONCLUSION: We suggested that rHuEPO should be used together with parenteral iron administration, even in HCV-positive HD patients, because it is safe at low doses under careful observation.     

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.