Eur J Pediatr (1992) 151 : 540-542
European Journal of
Pediatrics
9 Springer-Verlag1992
Intraperitoneal administration of recombinant human erythropoietin in children on continuous ambulatory peritoneal dialysis R. E. Reddingius, C.H. Schr6der, and L. A. H. Monnens Department of Paediatrics, Sint Radboud University Hospital, P.O.B. 9101, NL-6500 HB Nijmegen, The Netherlands Received July 12, 1991 / Accepted in revised form December 12, 1991
Abstract. In 16 children treated by continuous ambulatory peritoneal dialysis ( C A P D ) recombinant human erythropoietin was administered intraperitoneally for the treatment of renal anaemia. The m e a n treatment period was 8.3 months. Mean haemoglobin values increased from 4.9 retool/1 at start of therapy to 6.2 after 6 months. While 11 out of 16 children needed a total of 22 transfusions during the 6 months prior to therapy, no transfusions were needed after initiation of therapy. Patients started with a dose of 300 units/kg per week. After 6 months of therapy, the m e a n dose was 370 and after 12 months 279 units/kg per week. No major sideeffects were observed. The incidence of peritonitis was not increased. We conclude that intraperitoneal administration of erythropoietin is effective in the treatment of renal anaemia in children treated by C A P D . Key words: C A P D - Children - Erythropoietin - Intraperitoneal administration
(lmmol/1 = 16g/1). Between November 1988 and May 1990 16 children, 11 boys and 5 girls, entered the study. Median age of these children was 4.1 years (range 0.8-16.5). The children had been treated by CAPD for a mean period of 20.5 months (range 2.5-70 months). In the 6 months prior to therapy 11 out of 16 patients required a total of 22 transfusions. All patients started with a weekly dose of 300 units recombinant human erythropoietin (Recormon, Boehringer Mannheim GmbH, Almere, The Netherlands) per kilogram body weight. Three times per week erythropoietin was given in 20 ml/kg of dialysis fluid (Dianeal 1.36%, Baxter Inc., Deerfield, IL, USA) overnight in a 10-12-hour dwell period. The parents injected erythropoietin in the bags themselves. Before starting treatment the parents were carefully trained by a member of the nursing staff. A strictly aseptic technique was used. Dummy ampoules containing saline were used for teaching dissolving of the drug and injecting it into the dialysis bag. Training took about lh, and was repeated if the parents or the instructing nurse were not certain about the familiarity with the procedure. The target haemoglobin level was 6.5-7.0 mmol/1. Dosage was adjusted every 2 months. As long as the target level was not reached, erythropoietin dosage was increased by 75 units/kg per week. Dosage was decreased by 75 units if the haemoglobin concentration exceeded 7.0mmol/1. Haemoglobin, haematocrit and reticular cell counts were assessed every 2 weeks. Serum ferritin levels and transferrin saturation were assessed every 2 months.
Introduction Intravenous and subcutaneous administration of erythropoietin has proven to be an effective treatment modality for renal anaemia in dialysis patients. In adult continuous ambulatory peritoneal dialysis (CAPD)-patients erythropoietin is usually administered subcutaneously. Since injections create a considerable psychological distress in young children treated by C A P D , intraperitoneal administration of erythropoietin would be preferable. We studied the effect of intraperitoneal erythropoietin in a group of children treated by C A P D .
Patients and methods The study population consisted of children treated by CAPD for at least 2 months with mean haemoglobin values below 5.8mmol/1 Offprint requests to: R. E. Reddingius Abbreviation: CAPD = continuous ambulatory peritoneal dia-
lysis
Results The patients were treated for a period of 3-12 months. At the end of the study period six patients had been treated for a period of 12 months, 5 between 6 and 12 months and 5 for less than 6 months. In all patients haemoglobin values increased after start of therapy. Mean haemoglobin level was 4.9mmol/1 at start of therapy, 5.8 after 3 months, 6.2 after 6 months, and 6.7 after 12 months (Fig. 1). The highest reticulocyte counts of up to 67/thousand were seen in the 1st month of therapy. No patient required blood transfusions after start of therapy. Mean erythropoietin dosage is depicted in Fig. 2. After 6 months of therapy the highest doses of erythropoietin were given. A t that m o m e n t the m e a n dose was 370 (range 244-482) units/kg per week. After 12 months of therapy the m e a n dose was 279 (range 175-417). This reduction was not due to patient selection because the m e a n dose in patients who were treated for 12 months was also 370 units/kg per week after 6 months of therapy. Oral iron therapy (ferrous chloride) was started
541
8 ....Hb .....(mmol/l) ......................................................................................Discussion .....................................................................
6
f
~
6
~
7
.....................................................................................................................................................
....
i 3
0
i 6
i 9
time(months)
f 12
Fig. t. Blood haemoglobin levels during treatment with erythropoietin. Values are given as means _+ 1 standard deviation, n, number of patients studied
EPO (U/kg/week) ....................................................................................................................................................................
500-,
3~176
0
. . . . . . . .
3
6
9 12 time(months)
Fig.2. Dosage of erythropoietin during the treatment period. Values are given as means _+ 1 standard deviation, n, number of patients studied
when serum ferritin levels were below 100 gg/1. Only 4 out of 16 patients required iron therapy. In 11 patients who were treated for at least 6 months, we compared serum ferritin levels and transferrin saturation at the start of therapy to levels after 6 months of therapy. The geometric mean of the serum ferritin level was 221 gg/1 prior to start of therapy and 129 gg/1 after 6 months of therapy (Wilcoxon P < 0.01). Transferrin saturation was 0.37 + 0,15 before start of therapy and 0.30 + 0.10 after 6 months of therapy (not significant). In the study period a total of nine episodes of peritonitis occurred. The incidence of peritonitis was thus one every 14.7 patient months. A relationship between erythropoietin administration and peritonitis was suspected in one case only. In this child peritonitis occurred immediately after start of erythropoietin therapy. Ten out of 16 children did not suffer from peritonitis during the study period. In the 3 years before the study was performed (1987-1989) in our centre 28 peritonitis episodes were observed in 501 patient months (one episode every 17.9 patient months). The spectrum of the micro-organisms cultured did not change after introduction of erythropoietin.
Most children treated with haemodialysis are treated with intravenous erythropoietin at the end of dialysis, giving good results [1, 3, 19]. Good results have also been obtained with the intravenous treatment of children undergoing CAPD or continuous cycling peritoneal dialysis [1, 18]; this mode of therapy, however, is not practical. Subcutaneous administration of erythropoietin has been advocated since good therapeutic results have been obtained in several groups of patients with anaemia due to renal disease [1, 5, 14, 20, 23]. However, in young children treated by CAPD, subcutaneous injections will generally result in a struggle between the child and his/ her parents. The administration of medication has been reported to contribute considerably to pm:ental stress experiences [8]. For children treated by CAPD, intraperitoneal administration may be considered and has been advocated in the literature [6]. The amount of absorption of erythropoietin is, however, a point of discussion. In rabbits, an almost complete absorption from the peritoneal cavity was found [2]. In humans only a very limited absorption was observed [4, 12, 13]. Controversial results were obtained in therapeutic studies with intraperitoneal erythropoietin [6, 9, 10, 12]. Since the absorption of erythropoietin was assumed to be inversely correlated with the quantity of dialysis fluid used for instillation, it was decided to halve the amount of dialysis fluid [2]. It was not chosen to instill the erythropoietin undiluted, since this would implicate that the patient would not be dialysed for a period of 12 h, Since erythropoietin will be mainly absorbed by the lymphatics, and lymphatic absorption has been reported to be higher in children than in adults [15], a sufficient absorption was expected and established (unpublished observations). There are no unanimous data on the dosages needed for the treatment with erythropoietin. In a large study on intravenous administration in adult haemodialysis patients a median weekly dose of 200 units/kg was adequate [21]. Subcutaneous administration generally allows lower dosages: the literature provides data ranging form 84 to 120 units/kg per week for adult patients during the maintenance phase [12, 14]. In a paediatric study the mean dose needed was 210 units/kg per week [20]. Larger doses are needed if erythropoietin is applied intraperitoneally. Frenken et al. used a maintenance dose of 216 units/kg per week in adult patients [6], whereas our study needed 279 units/kg per week in children after 1 year of treatment. The time from start of treatment to achievement of target range was about 9 months in our study (see Fig. 1). This is relatively long, but acceptable since no blood transfusions were necessary after start of erythropoietin therapy. Contamination is a risk if medication is added to the dialysis fluid. Indeed, a high incidence of peritonitis in strong association with erythropoietin administration has been reported in children as well as in adults [16, 17]. We believe, however, on the basis of the results presented in this study, that careful training of the parents
542 can minimise the risk of peritonitis. T h e peritonitis incidence in the study population was one every 14.7 patient months, which is low w h e n c o m p a r e d with literature data of paediatric series and is similar to o u r experience in previous years [7, 11]. O t h e r side-effects of the t h e r a p y were only of m i n o r importance. Seizures were not observed in our patients. H y p e r t e n s i o n was not a m a j o r p r o b l e m in o u r population, although two children n e e d e d m i n o r adjustment of their antihypertensive medication. O n l y 4 out of the 16 patients n e e d e d iron supplementation. This is low c o m p a r e d to the literature [22]. The explanation is the iron o v e r l o a d present in most children at the start of erythropoietin t h e r a p y due to multiple blood transfusions. In the future, when erythropoietin will be started before transfusions are n e e d e d , m o s t patients will require iron supplements. In conclusion, since the incidence of peritonitis is not increased and the training p r o c e d u r e is not very costly or timeconsuming, intraperitoneal administration of erythropoietin is the preferred m o d e of t r e a t m e n t in y o u n g children on C A P D . The advantages with respect to patient and p a r e n t acceptance will c o m p e n s a t e for the s o m e w h a t higher costs.
Acknowledgement. Boehringer Mannheim GmbH, Almere, The
8. 9. 10.
11. 12.
13.
14.
15.
Netherlands is gratefully acknowledged for supplying recombinant human erythropoietin (Recormon). 16. References
1. Alexander SR (1991) Pediatric uses of recombinant human erythropoietin: the outlook in 1991. Am J Kidney Dis 18 : 4253 2. Bargman JM, Breborowicz A, Rodela H, Sombolos K, Oreopoulos DG (1988) Intraperitoneal administration of recombinant human erythropoietin in uremic animals. Perit Dial Int 8 : 249-252 3. Bianchetti MG, H~immertli I, Roduit C, Neuhaus TJ, Leumann EP, Oetliker OH (1990) Epoetin alfa in anaemic children or adolescents on regular dialysis. Eur J Pediatr 150 : 509512 4. Boelaert JR, Schurgers ML, Matthys EG, et al (1989) Comparative pharmacokinetics of recombinant erythropoietin administered by the intravenous, and intraperitoneal routes in continuous ambulatory peritoneal dialysis (CAPD) patients. Perit Dial Int 9 : 95-98 5. Canaud B, Polito-Bouloux C, Garred LJ, et al (1990) Recombinant human erythropoietin; 18 months' experience in hemodialysis patients. Am J Kidney Dis 15 : 169-175 6. Frenken LAM, Coppens PJW, Tiggeler RGWL, Koene RAP (1989) Intraperitoneal erythropoietin. Lancet I: 962 7. Howard RL, Millspaugh J, Teitelbaum I (1990) Adult and pediatric peritonitis rates in a home dialysis program: Corn-
17.
18.
19. 20. 21.
22. 23.
parison of continuous ambulatory and continuous cycling peritoneal dialysis. Am J Kidney Dis 16 : 469-472 Hulstijn-Dirkmaat I (1989) Continuous ambulatory peritoneal dialysis in children and family stress. Int J Adolesc Med Health 4 : 19-25 Icardi A, Paoletti E, Molinelli G (1990) Efficacy of recombinant erythropoietin after subcutaneous or intraperitoneal administration to patients on CAPD. Adv Perit Dial 6 : 292-295 Lai KN, Lui SF, Leurtg JCK, Law E, Nicholls MG (1991) Effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin on blood pressure and vasoactive hormones in patients on continuous ambulatory peritoneal dialysis. Nephron 57 : 394-400 Levy M, Balfe JW, Geary DF, Fryer-Keene SP, Bannatyne RM (1989) Peritonitis in children undergoing dialysis. Child Nephrol Urol 9 : 253-258 Lui SF, Chung WWM, Leung CB, Chan K, Lai KN (1990) Pharmacokinetics and pharmacodynamics of subcutaneous and intraperitoneal administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Clin Nephrol 33:47-51 MacDougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, Williams JD (1989) Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet I: 425-427 MacDougatl IC, Davies ME, Hutton RD, et al (1990) The treatment of renal anaemia in CAPD patients with recombinant human erythropoietin. Nephrol Dial Transplant 5:950955 Mactier RA, Khanna R, Moore H, Russ J, Nolph KD, Groshong T (1988) Kinetics of peritoneal dialysis in children: Role of lymphatics. Kidney Int 34 : 82-88 Miranda B, Selgas R, Rinon C, et al (1990) Treatment of the anemia with human recombinant erythropoietin in CAPD patients. Adv Perit Dial 6 : 296-301 Mtiller-Wiefel DE, Bosch A, Feist K, Bier V, Scharer K (1989) Erythropoietin (EPO) treatment in pediatric patients with renal anemia: application forms, dosage and response. Proc IPNA $5-03 Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J, Scigalla P (1990) One year's experience with recombinant erythropoietin in children undergoing continuous ambulatory or cycling peritoneal dialysis. Pediatr Nephrol 4 : 498-500 Scigalla P, Bonzel KE, Bulla M, et al (1989) Therapy of renal anemia with recombinant human erythropoietin in children with end-stage renal disease. Contr Nephrol 76: 227-241 Sinai-Trieman L, Salusky IB, Fine RN (1989) Use of subcutaneous recombinant erythropoietin in children undergoing continuous cycling peritoneal dialysis. J Pediatr 114:550-554 Sundal E, Kaeser U (1989) Correction of anaemia or chronic renal failure with recombinant human erythropoietin: safety and efficacy of one year's treatment in a European multicentre study of 150 haemodialysis-dependent patients. Nephrol Dial Transplant 4: 979-987 Van Wyck DB, Stievelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA (1989) Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 35 : 712-716 Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL (1990) Treatment of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 89 : 432-435
European Journal of
Pediatrics
9 Springer-Verlag1992
Intraperitoneal administration of recombinant human erythropoietin in children on continuous ambulatory peritoneal dialysis R. E. Reddingius, C.H. Schr6der, and L. A. H. Monnens Department of Paediatrics, Sint Radboud University Hospital, P.O.B. 9101, NL-6500 HB Nijmegen, The Netherlands Received July 12, 1991 / Accepted in revised form December 12, 1991
Abstract. In 16 children treated by continuous ambulatory peritoneal dialysis ( C A P D ) recombinant human erythropoietin was administered intraperitoneally for the treatment of renal anaemia. The m e a n treatment period was 8.3 months. Mean haemoglobin values increased from 4.9 retool/1 at start of therapy to 6.2 after 6 months. While 11 out of 16 children needed a total of 22 transfusions during the 6 months prior to therapy, no transfusions were needed after initiation of therapy. Patients started with a dose of 300 units/kg per week. After 6 months of therapy, the m e a n dose was 370 and after 12 months 279 units/kg per week. No major sideeffects were observed. The incidence of peritonitis was not increased. We conclude that intraperitoneal administration of erythropoietin is effective in the treatment of renal anaemia in children treated by C A P D . Key words: C A P D - Children - Erythropoietin - Intraperitoneal administration
(lmmol/1 = 16g/1). Between November 1988 and May 1990 16 children, 11 boys and 5 girls, entered the study. Median age of these children was 4.1 years (range 0.8-16.5). The children had been treated by CAPD for a mean period of 20.5 months (range 2.5-70 months). In the 6 months prior to therapy 11 out of 16 patients required a total of 22 transfusions. All patients started with a weekly dose of 300 units recombinant human erythropoietin (Recormon, Boehringer Mannheim GmbH, Almere, The Netherlands) per kilogram body weight. Three times per week erythropoietin was given in 20 ml/kg of dialysis fluid (Dianeal 1.36%, Baxter Inc., Deerfield, IL, USA) overnight in a 10-12-hour dwell period. The parents injected erythropoietin in the bags themselves. Before starting treatment the parents were carefully trained by a member of the nursing staff. A strictly aseptic technique was used. Dummy ampoules containing saline were used for teaching dissolving of the drug and injecting it into the dialysis bag. Training took about lh, and was repeated if the parents or the instructing nurse were not certain about the familiarity with the procedure. The target haemoglobin level was 6.5-7.0 mmol/1. Dosage was adjusted every 2 months. As long as the target level was not reached, erythropoietin dosage was increased by 75 units/kg per week. Dosage was decreased by 75 units if the haemoglobin concentration exceeded 7.0mmol/1. Haemoglobin, haematocrit and reticular cell counts were assessed every 2 weeks. Serum ferritin levels and transferrin saturation were assessed every 2 months.
Introduction Intravenous and subcutaneous administration of erythropoietin has proven to be an effective treatment modality for renal anaemia in dialysis patients. In adult continuous ambulatory peritoneal dialysis (CAPD)-patients erythropoietin is usually administered subcutaneously. Since injections create a considerable psychological distress in young children treated by C A P D , intraperitoneal administration of erythropoietin would be preferable. We studied the effect of intraperitoneal erythropoietin in a group of children treated by C A P D .
Patients and methods The study population consisted of children treated by CAPD for at least 2 months with mean haemoglobin values below 5.8mmol/1 Offprint requests to: R. E. Reddingius Abbreviation: CAPD = continuous ambulatory peritoneal dia-
lysis
Results The patients were treated for a period of 3-12 months. At the end of the study period six patients had been treated for a period of 12 months, 5 between 6 and 12 months and 5 for less than 6 months. In all patients haemoglobin values increased after start of therapy. Mean haemoglobin level was 4.9mmol/1 at start of therapy, 5.8 after 3 months, 6.2 after 6 months, and 6.7 after 12 months (Fig. 1). The highest reticulocyte counts of up to 67/thousand were seen in the 1st month of therapy. No patient required blood transfusions after start of therapy. Mean erythropoietin dosage is depicted in Fig. 2. After 6 months of therapy the highest doses of erythropoietin were given. A t that m o m e n t the m e a n dose was 370 (range 244-482) units/kg per week. After 12 months of therapy the m e a n dose was 279 (range 175-417). This reduction was not due to patient selection because the m e a n dose in patients who were treated for 12 months was also 370 units/kg per week after 6 months of therapy. Oral iron therapy (ferrous chloride) was started
541
8 ....Hb .....(mmol/l) ......................................................................................Discussion .....................................................................
6
f
~
6
~
7
.....................................................................................................................................................
....
i 3
0
i 6
i 9
time(months)
f 12
Fig. t. Blood haemoglobin levels during treatment with erythropoietin. Values are given as means _+ 1 standard deviation, n, number of patients studied
EPO (U/kg/week) ....................................................................................................................................................................
500-,
3~176
0
. . . . . . . .
3
6
9 12 time(months)
Fig.2. Dosage of erythropoietin during the treatment period. Values are given as means _+ 1 standard deviation, n, number of patients studied
when serum ferritin levels were below 100 gg/1. Only 4 out of 16 patients required iron therapy. In 11 patients who were treated for at least 6 months, we compared serum ferritin levels and transferrin saturation at the start of therapy to levels after 6 months of therapy. The geometric mean of the serum ferritin level was 221 gg/1 prior to start of therapy and 129 gg/1 after 6 months of therapy (Wilcoxon P < 0.01). Transferrin saturation was 0.37 + 0,15 before start of therapy and 0.30 + 0.10 after 6 months of therapy (not significant). In the study period a total of nine episodes of peritonitis occurred. The incidence of peritonitis was thus one every 14.7 patient months. A relationship between erythropoietin administration and peritonitis was suspected in one case only. In this child peritonitis occurred immediately after start of erythropoietin therapy. Ten out of 16 children did not suffer from peritonitis during the study period. In the 3 years before the study was performed (1987-1989) in our centre 28 peritonitis episodes were observed in 501 patient months (one episode every 17.9 patient months). The spectrum of the micro-organisms cultured did not change after introduction of erythropoietin.
Most children treated with haemodialysis are treated with intravenous erythropoietin at the end of dialysis, giving good results [1, 3, 19]. Good results have also been obtained with the intravenous treatment of children undergoing CAPD or continuous cycling peritoneal dialysis [1, 18]; this mode of therapy, however, is not practical. Subcutaneous administration of erythropoietin has been advocated since good therapeutic results have been obtained in several groups of patients with anaemia due to renal disease [1, 5, 14, 20, 23]. However, in young children treated by CAPD, subcutaneous injections will generally result in a struggle between the child and his/ her parents. The administration of medication has been reported to contribute considerably to pm:ental stress experiences [8]. For children treated by CAPD, intraperitoneal administration may be considered and has been advocated in the literature [6]. The amount of absorption of erythropoietin is, however, a point of discussion. In rabbits, an almost complete absorption from the peritoneal cavity was found [2]. In humans only a very limited absorption was observed [4, 12, 13]. Controversial results were obtained in therapeutic studies with intraperitoneal erythropoietin [6, 9, 10, 12]. Since the absorption of erythropoietin was assumed to be inversely correlated with the quantity of dialysis fluid used for instillation, it was decided to halve the amount of dialysis fluid [2]. It was not chosen to instill the erythropoietin undiluted, since this would implicate that the patient would not be dialysed for a period of 12 h, Since erythropoietin will be mainly absorbed by the lymphatics, and lymphatic absorption has been reported to be higher in children than in adults [15], a sufficient absorption was expected and established (unpublished observations). There are no unanimous data on the dosages needed for the treatment with erythropoietin. In a large study on intravenous administration in adult haemodialysis patients a median weekly dose of 200 units/kg was adequate [21]. Subcutaneous administration generally allows lower dosages: the literature provides data ranging form 84 to 120 units/kg per week for adult patients during the maintenance phase [12, 14]. In a paediatric study the mean dose needed was 210 units/kg per week [20]. Larger doses are needed if erythropoietin is applied intraperitoneally. Frenken et al. used a maintenance dose of 216 units/kg per week in adult patients [6], whereas our study needed 279 units/kg per week in children after 1 year of treatment. The time from start of treatment to achievement of target range was about 9 months in our study (see Fig. 1). This is relatively long, but acceptable since no blood transfusions were necessary after start of erythropoietin therapy. Contamination is a risk if medication is added to the dialysis fluid. Indeed, a high incidence of peritonitis in strong association with erythropoietin administration has been reported in children as well as in adults [16, 17]. We believe, however, on the basis of the results presented in this study, that careful training of the parents
542 can minimise the risk of peritonitis. T h e peritonitis incidence in the study population was one every 14.7 patient months, which is low w h e n c o m p a r e d with literature data of paediatric series and is similar to o u r experience in previous years [7, 11]. O t h e r side-effects of the t h e r a p y were only of m i n o r importance. Seizures were not observed in our patients. H y p e r t e n s i o n was not a m a j o r p r o b l e m in o u r population, although two children n e e d e d m i n o r adjustment of their antihypertensive medication. O n l y 4 out of the 16 patients n e e d e d iron supplementation. This is low c o m p a r e d to the literature [22]. The explanation is the iron o v e r l o a d present in most children at the start of erythropoietin t h e r a p y due to multiple blood transfusions. In the future, when erythropoietin will be started before transfusions are n e e d e d , m o s t patients will require iron supplements. In conclusion, since the incidence of peritonitis is not increased and the training p r o c e d u r e is not very costly or timeconsuming, intraperitoneal administration of erythropoietin is the preferred m o d e of t r e a t m e n t in y o u n g children on C A P D . The advantages with respect to patient and p a r e n t acceptance will c o m p e n s a t e for the s o m e w h a t higher costs.
Acknowledgement. Boehringer Mannheim GmbH, Almere, The
8. 9. 10.
11. 12.
13.
14.
15.
Netherlands is gratefully acknowledged for supplying recombinant human erythropoietin (Recormon). 16. References
1. Alexander SR (1991) Pediatric uses of recombinant human erythropoietin: the outlook in 1991. Am J Kidney Dis 18 : 4253 2. Bargman JM, Breborowicz A, Rodela H, Sombolos K, Oreopoulos DG (1988) Intraperitoneal administration of recombinant human erythropoietin in uremic animals. Perit Dial Int 8 : 249-252 3. Bianchetti MG, H~immertli I, Roduit C, Neuhaus TJ, Leumann EP, Oetliker OH (1990) Epoetin alfa in anaemic children or adolescents on regular dialysis. Eur J Pediatr 150 : 509512 4. Boelaert JR, Schurgers ML, Matthys EG, et al (1989) Comparative pharmacokinetics of recombinant erythropoietin administered by the intravenous, and intraperitoneal routes in continuous ambulatory peritoneal dialysis (CAPD) patients. Perit Dial Int 9 : 95-98 5. Canaud B, Polito-Bouloux C, Garred LJ, et al (1990) Recombinant human erythropoietin; 18 months' experience in hemodialysis patients. Am J Kidney Dis 15 : 169-175 6. Frenken LAM, Coppens PJW, Tiggeler RGWL, Koene RAP (1989) Intraperitoneal erythropoietin. Lancet I: 962 7. Howard RL, Millspaugh J, Teitelbaum I (1990) Adult and pediatric peritonitis rates in a home dialysis program: Corn-
17.
18.
19. 20. 21.
22. 23.
parison of continuous ambulatory and continuous cycling peritoneal dialysis. Am J Kidney Dis 16 : 469-472 Hulstijn-Dirkmaat I (1989) Continuous ambulatory peritoneal dialysis in children and family stress. Int J Adolesc Med Health 4 : 19-25 Icardi A, Paoletti E, Molinelli G (1990) Efficacy of recombinant erythropoietin after subcutaneous or intraperitoneal administration to patients on CAPD. Adv Perit Dial 6 : 292-295 Lai KN, Lui SF, Leurtg JCK, Law E, Nicholls MG (1991) Effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin on blood pressure and vasoactive hormones in patients on continuous ambulatory peritoneal dialysis. Nephron 57 : 394-400 Levy M, Balfe JW, Geary DF, Fryer-Keene SP, Bannatyne RM (1989) Peritonitis in children undergoing dialysis. Child Nephrol Urol 9 : 253-258 Lui SF, Chung WWM, Leung CB, Chan K, Lai KN (1990) Pharmacokinetics and pharmacodynamics of subcutaneous and intraperitoneal administration of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Clin Nephrol 33:47-51 MacDougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, Williams JD (1989) Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet I: 425-427 MacDougatl IC, Davies ME, Hutton RD, et al (1990) The treatment of renal anaemia in CAPD patients with recombinant human erythropoietin. Nephrol Dial Transplant 5:950955 Mactier RA, Khanna R, Moore H, Russ J, Nolph KD, Groshong T (1988) Kinetics of peritoneal dialysis in children: Role of lymphatics. Kidney Int 34 : 82-88 Miranda B, Selgas R, Rinon C, et al (1990) Treatment of the anemia with human recombinant erythropoietin in CAPD patients. Adv Perit Dial 6 : 296-301 Mtiller-Wiefel DE, Bosch A, Feist K, Bier V, Scharer K (1989) Erythropoietin (EPO) treatment in pediatric patients with renal anemia: application forms, dosage and response. Proc IPNA $5-03 Offner G, Hoyer PF, Latta K, Winkler L, Brodehl J, Scigalla P (1990) One year's experience with recombinant erythropoietin in children undergoing continuous ambulatory or cycling peritoneal dialysis. Pediatr Nephrol 4 : 498-500 Scigalla P, Bonzel KE, Bulla M, et al (1989) Therapy of renal anemia with recombinant human erythropoietin in children with end-stage renal disease. Contr Nephrol 76: 227-241 Sinai-Trieman L, Salusky IB, Fine RN (1989) Use of subcutaneous recombinant erythropoietin in children undergoing continuous cycling peritoneal dialysis. J Pediatr 114:550-554 Sundal E, Kaeser U (1989) Correction of anaemia or chronic renal failure with recombinant human erythropoietin: safety and efficacy of one year's treatment in a European multicentre study of 150 haemodialysis-dependent patients. Nephrol Dial Transplant 4: 979-987 Van Wyck DB, Stievelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA (1989) Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 35 : 712-716 Watson AJ, Gimenez LF, Cotton S, Walser M, Spivak JL (1990) Treatment of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 89 : 432-435
