Pediatric Nephrology
Pediatr Nephrol (1990) 4:618-622 9 IPNA 1990
Original article Recombinant human erythropoietin therapy in children maintained by haemodialysis Susan P. A. Rigden l, Giovanni Montini 1, Max Morris 1, Kenneth G. A. Clark 2, George B. Haycock 1, Cyril Chantlerl, and Ronald C. HilP I Department of Paediatrics, Evelina Children's Hospital and 2 Department of Haematology,Guy's Hospital, London SE1 9RT, UK 3 Medical Department, Cilag Ltd, Saunderton, High Wycombe,Bucks, UK Received October 17, 1989; received after revision April 6; accepted April 10, 1990
Abstract. Six children (aged 3 years 11 months to 15 years 9 months) with end-stage renal failure and anaemia (mean haemoglobin 7.1 g/dl, range 6 . 3 - 7 . 7 g/dl) on thriceweekly haemodialysis were treated with recombinant human erythropoietin (rHuEPO), given as an intravenous bolus in an escalating dose regime after dialysis. All responded with an increase in reticulocyte count and haemoglobin concentration in a mean time of 11 weeks (range 9 - 1 3 weeks) and at a dose of 100 or 150 units/kg thrice weekly. The dose of rHuEPO was then adjusted to maintain the haemoglobin concentration within the lower half of the normal range for the child's age and sex. The mean haemoglobin after 12 weeks treatment was 10.9 g/dl (range 8.5-12.1 g/dl) and after 24 weeks, 10.5 g/dl (range 7.9-13.3 g/dl). Four children had no further need for blood transfusion and are thus no longer at risk of blood-borne infection, iron overload and serfsitisation to H L A histocompatibility antigens. Serum ferritin fell in the three patients with evidence of iron overload; the three with low or normal iron stores at the onset of treatment maintained erythropoiesis with oral iron supplementation. H L A antibodies decreased in all patients. The only serious complication encountered was thrombosis of vascular access in one child. No child became seriously hypertensive or developed cerebral symptoms. The benefits of rHuEPO therapy for children with end-stage renal failure are potentially considerable and with careful monitoring, the risks low.
Key words: Recombinant human erythropoietin End-stage renal failure - Haemodialysis - Anaemia - Iron overload - H L A antibodies
Offprint requests to: S. R A. Rigden, 9th Floor Guy's Tower,
Guy's Hospital, St. Thomas' Street, London SE1 9RT, UK
Introduction Anaemia is a major debilitating complication of end-stage renal disease. The pathophysiology of this anaemia is complex and may include shortened red-cell survival, inhibition of erythropoiesis by uraemic toxins, aluminium toxicity, iron and folate deficiency and blood loss on dialysis [1]. However the most important factor appears to be inadequate production of erythropoietin [2], and human erythropoietin derived from recombinant D N A (rHuEPO) has now been used in clinical trials to correct the anaemia of adult patients with end-stage renal failure maintained by chronic haemodialysis [3, 4]. Children with end-stage renal disease tend to be more anaemic than adult patients, and are more likely to be transfusion dependent [5] with the attendant risks of bloodborne infection, iron overload and sensitisation to H L A antigens [6], which may reduce the chance of subsequent successful renal transplantation. This study was designed to assess the efficacy and safety of rHuEPO therapy in children with end-stage renal failure maintained on chronic haemodialysis.
Patients and methods Six children with end-stage renal failure were studied; all were clinically stable and had been maintained by thrice weekly hospital haemodialysis for at least 3 months. Signed informed consent was obtained from their parents and, if appropriate, from the children. The study was approved by the hospital ethical committee.Patient details are snmmarisedin Table i. No child had any other cause for anaemia, any systemic disease that might mask a response to rHuEPO, uncontrolled hypertension, severe secondary hyperparathyroidism, evidence of aluminium toxicity, liver dysfunction, hepatitis B or human immunodeficiency virus infection. Pregnancy was excluded in the post-pubertal female patient. The trial was designed as an open-label non-randomised study with an escalating dose regime. After a 2-week placebo period during which only the diluent was given and base line data were collected, rHuEPO was commenced in a dose of 10 units/kg thrice weekly, given as an intravenous bolus at the end of dialysis. The children were admitted for 24 h following administration of the first dose for monitoring of vital signs (temperature, blood pressure, pulse and respiration rates). There-
619
Table 1. Patient details on entry to the study Patient no,
Age (years, months)
Sex
Weight (kg)
Dialysis access
Anephric
Serum ferritin (pog/l)
Transfusion Failed requirement transplants previous 6 months
HLA panel reactivity (%)
1
14,10
M
44.3
a-v
No
1792
2
1
83
2
8,9
M
24,3
a-v
No
185
1
1
93
3
3,11
M
16,2
Goretex graft
Yes
278
5
2
100
4
4,9
M
14,3
Haemocath Goretex graft
No
739
3
3
98
5
15,9
F
33,2
a-v
No
9
2
1
100
6
14,4
F
30,7
a-v
No
1325
4
3
82
a-v, Arteriovenous fistula
after each dose was administered at the completion of dialysis and vital signs were measured before and 60 min after injection of the rHuEPO. Following 2 weeks therapy at 10 units/kg, the dose was increased at 2-weekly intervals to 25 units/kg, 50 units/kg and 100 units/kg. The dose was further increased to 150 units/kg after 3 weeks if necessary. Each increase in dose required that no toxic effects were observed at the previous step and that the haemoglobin concentration had not risen more than 2 g/dl above the mean value of the six observations obtained during the placebo period of the study. Target haemoglobin was defined as a haemoglobin value between the mean and 2 SD below the mean for age and sex [7]. Once the target haemoglobin level was reached, the dose of rHuEPO was titrated to maintain the haemoglobin within the target range. Blood counts, including reticulocyte counts, were performed before each dialysis. Plasma potassium and urea were measured before each dialysis and a biochemical profile (urea, electrolytes, creatinine, glucose, calcium, phosphate, alkaline phosphatase, total protein, albumin, bilirubin, aspartate aminotransferase, 7-glutamyl transferase, urate) was performed weekly. Iron status was assessed by monthly determinations of serum ferritin and 3-monthly measurements of serum iron and total
iron-binding capacity. HLA antibodies were assessed at monthly intervals by testing serum samples against panels of lymphocytes from 66 random donors [6], All children had their blood pressure checked twice daily at home by their parents, who were instructed to telephone the children's dialysis unit if the 97th eentile value for systolic blood pressure for age [8] was exceeded. Echocardiograms, ECGs and (in children more than 5 years of age) exercise tolerance tests using a modified Bruce treadmill protocol [9] were performed prior to commencing rHuEPO therapy and within 4 weeks of achieving the target haemoglobin level.
Results A l l c h i l d r e n r e s p o n d e d t o r H u E P O t h e r a p y w i t h a n increase in reticulocyte count and haemoglobin concentrat i o n ( T a b l e 2; F i g s . 1, 2). T a r g e t h a e m o g l o b i n w a s a c h i e v e d i n a m e a n t i m e o f 11 w e e k s ( r a n g e 9 - 13 w e e k s )
Table 2. Effect of recombinant human erythropoietin treatment on haemoglobin, reticulocyte response, HLA antibodies, iron status and biochemistry Baseline
Treatment 12th week
24th week a
Haemoglobin (g/dl)b
7.1 (6.3 -7.7)
10.9 (8.5-12.1)
10.5 (7.9-13.3)
Reticulocytes absolute ( x 109/1)b
46.6 (21.0-63.0)
133.0 (86.0-197.0)
82.0 (43.0-125.0)
1.9 (0.7 -2.9)
4.0 (1.9-7.5)
2.2 (1.1 - 3.1)
HLA antibodies~ (% panel reactivity)
93 +7.8
71 + 16.0"
59_+5.1"*
Ferritin (p.g/1)b iron-loaded patients (nos. 1, 4, 6)
1285 (739-1792)
574 (418-745)
707 (424- 891)
157 (9 - 278)
57 (18 - 99)
(45 - 75)
4.1 _+0.7
4.2_+0.6***
4.2_+0.8***
% count
Non-loaded patients (nos. 2, 3, 5) Potassium (mmol/l)c Urea (mmol/l)o
15.7_+7.5
14.6_+7.9"**
14.7-2-_6.4"**
Creatinine (gmol/1)c
779 •
823-+ 311"**
783-+250"**
* P
Pediatr Nephrol (1990) 4:618-622 9 IPNA 1990
Original article Recombinant human erythropoietin therapy in children maintained by haemodialysis Susan P. A. Rigden l, Giovanni Montini 1, Max Morris 1, Kenneth G. A. Clark 2, George B. Haycock 1, Cyril Chantlerl, and Ronald C. HilP I Department of Paediatrics, Evelina Children's Hospital and 2 Department of Haematology,Guy's Hospital, London SE1 9RT, UK 3 Medical Department, Cilag Ltd, Saunderton, High Wycombe,Bucks, UK Received October 17, 1989; received after revision April 6; accepted April 10, 1990
Abstract. Six children (aged 3 years 11 months to 15 years 9 months) with end-stage renal failure and anaemia (mean haemoglobin 7.1 g/dl, range 6 . 3 - 7 . 7 g/dl) on thriceweekly haemodialysis were treated with recombinant human erythropoietin (rHuEPO), given as an intravenous bolus in an escalating dose regime after dialysis. All responded with an increase in reticulocyte count and haemoglobin concentration in a mean time of 11 weeks (range 9 - 1 3 weeks) and at a dose of 100 or 150 units/kg thrice weekly. The dose of rHuEPO was then adjusted to maintain the haemoglobin concentration within the lower half of the normal range for the child's age and sex. The mean haemoglobin after 12 weeks treatment was 10.9 g/dl (range 8.5-12.1 g/dl) and after 24 weeks, 10.5 g/dl (range 7.9-13.3 g/dl). Four children had no further need for blood transfusion and are thus no longer at risk of blood-borne infection, iron overload and serfsitisation to H L A histocompatibility antigens. Serum ferritin fell in the three patients with evidence of iron overload; the three with low or normal iron stores at the onset of treatment maintained erythropoiesis with oral iron supplementation. H L A antibodies decreased in all patients. The only serious complication encountered was thrombosis of vascular access in one child. No child became seriously hypertensive or developed cerebral symptoms. The benefits of rHuEPO therapy for children with end-stage renal failure are potentially considerable and with careful monitoring, the risks low.
Key words: Recombinant human erythropoietin End-stage renal failure - Haemodialysis - Anaemia - Iron overload - H L A antibodies
Offprint requests to: S. R A. Rigden, 9th Floor Guy's Tower,
Guy's Hospital, St. Thomas' Street, London SE1 9RT, UK
Introduction Anaemia is a major debilitating complication of end-stage renal disease. The pathophysiology of this anaemia is complex and may include shortened red-cell survival, inhibition of erythropoiesis by uraemic toxins, aluminium toxicity, iron and folate deficiency and blood loss on dialysis [1]. However the most important factor appears to be inadequate production of erythropoietin [2], and human erythropoietin derived from recombinant D N A (rHuEPO) has now been used in clinical trials to correct the anaemia of adult patients with end-stage renal failure maintained by chronic haemodialysis [3, 4]. Children with end-stage renal disease tend to be more anaemic than adult patients, and are more likely to be transfusion dependent [5] with the attendant risks of bloodborne infection, iron overload and sensitisation to H L A antigens [6], which may reduce the chance of subsequent successful renal transplantation. This study was designed to assess the efficacy and safety of rHuEPO therapy in children with end-stage renal failure maintained on chronic haemodialysis.
Patients and methods Six children with end-stage renal failure were studied; all were clinically stable and had been maintained by thrice weekly hospital haemodialysis for at least 3 months. Signed informed consent was obtained from their parents and, if appropriate, from the children. The study was approved by the hospital ethical committee.Patient details are snmmarisedin Table i. No child had any other cause for anaemia, any systemic disease that might mask a response to rHuEPO, uncontrolled hypertension, severe secondary hyperparathyroidism, evidence of aluminium toxicity, liver dysfunction, hepatitis B or human immunodeficiency virus infection. Pregnancy was excluded in the post-pubertal female patient. The trial was designed as an open-label non-randomised study with an escalating dose regime. After a 2-week placebo period during which only the diluent was given and base line data were collected, rHuEPO was commenced in a dose of 10 units/kg thrice weekly, given as an intravenous bolus at the end of dialysis. The children were admitted for 24 h following administration of the first dose for monitoring of vital signs (temperature, blood pressure, pulse and respiration rates). There-
619
Table 1. Patient details on entry to the study Patient no,
Age (years, months)
Sex
Weight (kg)
Dialysis access
Anephric
Serum ferritin (pog/l)
Transfusion Failed requirement transplants previous 6 months
HLA panel reactivity (%)
1
14,10
M
44.3
a-v
No
1792
2
1
83
2
8,9
M
24,3
a-v
No
185
1
1
93
3
3,11
M
16,2
Goretex graft
Yes
278
5
2
100
4
4,9
M
14,3
Haemocath Goretex graft
No
739
3
3
98
5
15,9
F
33,2
a-v
No
9
2
1
100
6
14,4
F
30,7
a-v
No
1325
4
3
82
a-v, Arteriovenous fistula
after each dose was administered at the completion of dialysis and vital signs were measured before and 60 min after injection of the rHuEPO. Following 2 weeks therapy at 10 units/kg, the dose was increased at 2-weekly intervals to 25 units/kg, 50 units/kg and 100 units/kg. The dose was further increased to 150 units/kg after 3 weeks if necessary. Each increase in dose required that no toxic effects were observed at the previous step and that the haemoglobin concentration had not risen more than 2 g/dl above the mean value of the six observations obtained during the placebo period of the study. Target haemoglobin was defined as a haemoglobin value between the mean and 2 SD below the mean for age and sex [7]. Once the target haemoglobin level was reached, the dose of rHuEPO was titrated to maintain the haemoglobin within the target range. Blood counts, including reticulocyte counts, were performed before each dialysis. Plasma potassium and urea were measured before each dialysis and a biochemical profile (urea, electrolytes, creatinine, glucose, calcium, phosphate, alkaline phosphatase, total protein, albumin, bilirubin, aspartate aminotransferase, 7-glutamyl transferase, urate) was performed weekly. Iron status was assessed by monthly determinations of serum ferritin and 3-monthly measurements of serum iron and total
iron-binding capacity. HLA antibodies were assessed at monthly intervals by testing serum samples against panels of lymphocytes from 66 random donors [6], All children had their blood pressure checked twice daily at home by their parents, who were instructed to telephone the children's dialysis unit if the 97th eentile value for systolic blood pressure for age [8] was exceeded. Echocardiograms, ECGs and (in children more than 5 years of age) exercise tolerance tests using a modified Bruce treadmill protocol [9] were performed prior to commencing rHuEPO therapy and within 4 weeks of achieving the target haemoglobin level.
Results A l l c h i l d r e n r e s p o n d e d t o r H u E P O t h e r a p y w i t h a n increase in reticulocyte count and haemoglobin concentrat i o n ( T a b l e 2; F i g s . 1, 2). T a r g e t h a e m o g l o b i n w a s a c h i e v e d i n a m e a n t i m e o f 11 w e e k s ( r a n g e 9 - 13 w e e k s )
Table 2. Effect of recombinant human erythropoietin treatment on haemoglobin, reticulocyte response, HLA antibodies, iron status and biochemistry Baseline
Treatment 12th week
24th week a
Haemoglobin (g/dl)b
7.1 (6.3 -7.7)
10.9 (8.5-12.1)
10.5 (7.9-13.3)
Reticulocytes absolute ( x 109/1)b
46.6 (21.0-63.0)
133.0 (86.0-197.0)
82.0 (43.0-125.0)
1.9 (0.7 -2.9)
4.0 (1.9-7.5)
2.2 (1.1 - 3.1)
HLA antibodies~ (% panel reactivity)
93 +7.8
71 + 16.0"
59_+5.1"*
Ferritin (p.g/1)b iron-loaded patients (nos. 1, 4, 6)
1285 (739-1792)
574 (418-745)
707 (424- 891)
157 (9 - 278)
57 (18 - 99)
(45 - 75)
4.1 _+0.7
4.2_+0.6***
4.2_+0.8***
% count
Non-loaded patients (nos. 2, 3, 5) Potassium (mmol/l)c Urea (mmol/l)o
15.7_+7.5
14.6_+7.9"**
14.7-2-_6.4"**
Creatinine (gmol/1)c
779 •
823-+ 311"**
783-+250"**
* P
