© 1990 S. Karger AG, Basel 0250-8095/90/0105-040452.75/0
Am J Nephrol 1990;10:404-408
Experience with Low Dose Intravenous and Subcutaneous Administration of Recombinant Human Erythropoietin Lawrence P. McMahon, John K. Dawborn Renal Unit, Department of Medicine. Austin Hospital. Heidelberg, Victoria. Australia
Key Words. Erythropoietin, low dose, subcutaneous
Introduction Recombinant human erythropoietin (r-HuEPO) is well established as an effective treatment for the anaemia of chronic renal failure. Although there have been several reports of alternative methods of adminis tration [1-4], the optimal route and frequency remain undetermined. This is of some practical importance be cause of the cost of treatment and the logistic difficulties of intravenous (i.v.) administration, particularly in home haemodialysis or continuous ambulatory perito neal dialysis patients. We have studied a group of stable haemodialysis patients to assess the initial response to low dose subcutaneous (s.c.) and i.v. r-HuEPO.
Patients and Methods Six male and six female anaemic haemodialysis patients were studied for 14 weeks. Causes of renal failure were glomerulonephri tis in 6 patients, reflux nephropathy in 4. and SLE and renal vascu lar disease in 1 patient each. Seven patients were receiving single drug therapy for control of hypertension. Patients were divided into
two groups (A and B); there was no significant difference between groups for age, weight, years of either haemodialysis or prior trans plantation, or level of haemoglobin (table 1). Patients not re sponding to r-HuEPO (1 group A, 3 group B), with ferritin levels less than 500 pg/1 and/or a transferrin saturation of < 25% received an iron transfusion after 7 weeks of therapy. One patient (group A) received an iron transfusion within the first 2 weeks of treatment. No patient had evidence of aluminium toxicity or significant hyper parathyroidism (table 2). Group A was given 25 U/kg thrice per week i.v., and group B 25 U/kg twice per week s.c. At the end of 7 weeks, doses were doubled. Serum erythropoietin (EPO) levels were measured by radioimmu noassay (Incstar® ) in both groups before, and at regular intervals for 48 h after the first injection. Patients in both groups were given r-HuEPO (Eprex®. JanssenCilag) after haemodialysis. This was stored as a sterile solution in buffer between 2 and 8 °C. The ampoule concentration was 4,000 U/ml. Intravenous doses were diluted in 10 ml of normal saline and administered into the dialysis line close to the needle insertion over 5 min. Subcutaneous injections were delivered undiluted after warming the syringe to room temperature (20 °C). Blood pressure and weight were measured before and after each dialysis session. Haemoglobin, mean corpuscular volume, platelet and leukocyte count were measured weekly, and plasma potassium, urea, creati nine, and liver function tests measured every four weeks. Iron stud ies were assessed monthly. Fistula assessment monitoring (FAM) was performed in each patient prior to starting r-HuEPO.
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Abstract. Twelve stable haemodialysis patients were divided into two groups and given recombinant human erythropoietin (r-HuEPO) for 14 weeks either intravenously (i.v.) or subcutaneously (s.c.). Dosage was 25 units/kg either thrice (i.v.) or twice (s.c.) per week for 7 weeks, and then 50 units/kg for a further 7 weeks. Response to s.c. therapy was comparable to i.v. despite a 33% lower weekly dosage, and was significant at both 7 (i.v.: 1.1 ± 0.3, mean ± SEM, p = 0.02; s.c.: 0.8 ± 0.3 g/dl, p = 0.03) and 14 weeks (i.v.: 2.8 ± 0.5, p = 0.003; s.c.: 2.6 ± 0.6 g/dl, p = 0.009). A correlation was observed between response to r-HuEPO and initial ferritin levels (r = 0.63, p = 0.04). One patient required an increase in antihypertensive medication and there was one arteriovenous fistula thrombosis. Results suggest that overall s.c. therapy is as effective as i.v. therapy, and that a good response with few side effects can be obtained using relatively low doses of r-HuEPO.
Low Dose Intravenous and Subcutaneous Erythropoietin
405
Table 1. Clinical data before and after treatment with r-HuEPO Patient No.
Cause of renal failure
Haemoglobin g/dl
Length of haemodialysis years
Group A 1 2 3 4 5 6
glomerulonephritis SLE reflux nephritis reflux nephritis glomerulonephritis glomerulonephritis
7.7 6.6 6.2 4.2 7.2 5.6 (6.3 ± 0.5)
Group B 7 8 9 10 11 12
glomerulonephritis reflux nephritis reflux nephritis glomerulonephritis renovascular glomerulonephritis
6.6 8.6 4.8 4.6 9.5 4.3 (6.4 ± 0.9)
Time since transplantation years
Weight kg
Age years
Change in haemoglobin after 14 weeks, g/dl
1.5 4.5 2 6 4 3 (3.5± 0.7)
0 0 0 0 12 4 (2.7 ±2.0)
76 62 60 60.5 55 52 (61 ±3)
58 54 19 42 63 45 (47 ±6)
2.1 0.6 3.7 3.8 2.6 3.9
0 3 10 2 9 4.5 (4.8 ±1.6)
0 4 0 0 0.5 0(0.8 ±0.7)
82 84 62 53 90 49 (70±7)
66 56 28 40 61 44 (49 ±6)
0.9 0.6 3.2 4.5 2.7 3.8
The mean group values (+ SF.M) are given in parentheses.
Results There was a comparable rise in haemoglobin in both groups at 7 (i.v.: 1.1 ± 0.4, p = 0.02 vs. s.c.: 0.8 ± 0.3 g/dl, p = 0.03) and at 14 weeks (2.8 ± 0.5, p = 0.003 vs. 2.6 ± 0.6 g/dl, p = 0.009), with no significant difference between groups at either time (fig. 1). Peak levels of EPO after the first injection (i.v.: 450 ± 25 and s.c.: 53 ± 6 mU/ml) occurred within 30 min and at 20 h, respec tively. A poor early response (first 7 weeks) was observed in 5 patients with initial ferritin levels less than 500 pg/1. Three of these later responded to iron transfusion. Lack of response correlated with initial ferritin levels (r = 0.63. p = 0.04), and a similar but not significant correlation was observed with percentage transferrin saturation (r = 0.40, p = 0.22; fig. 2). In patients not requiring an iron transfusion after 7 weeks (n = 8) the higher dose of r-HuEPO also produced a greater increase in haemoglo bin (i.v.: 1.1 ± 0.4 vs. 2.1 ± 0.4; s.c.: 1.2 ± 0.3 vs. 2.1 ± 0.3) when the two periods were compared. At the end of the study an inadequate response ( < 2.0 g/dl rise in hae-
Table 2. Biochemical parameters prior to treatment with r-HuEPO Patient No.
Ferritin
Transferrin saturation %
Parathyroid hormone ng/ml
Aluminium pmol/l
Group A Ia 2h 3 4 5 6
25 253 2,100 806 468 873
12.3 21.3 95.2 42.5 65.8 47.4
3.0 1.9 13.1 21.8
0.7
0.5
< 0 .5 1.1 1.3 1.5
Group B 7h 8h 9 10*’ 11 12
171 312 1.840 161 1,801 683
16.1 20.8 87.5 25.0 97.0 41.7
0.8 3.8 3.9 14.2 34.9 19.6
0.5 0.9 0.6 1.2 1.6 < 0 .5
0.0
1.0
* Patient received iron transfusion within the first 10 days of treatment. b Patients receiving iron transfusion at 7 weeks of treatment.
moglobin) to r-HuEPO was seen in three patients (ta ble 1). In 1 patient this was associated with a prolonged pneumonic illness, and 2 patients (group B) subsequently responded to higher doses of r-HuEPO (350 U/kg/week) on completion of the trial.
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All patients gave informed consent and all completed the trial. One patient (group A) was hospitalized for 3 weeks for a pneumonic illness, and another (group B) for 3 days for arteriovenous fistula repair following thrombosis. Statistical significance was determined by Student’s paired and unpaired t test and by the Spearman correlation.
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406
Fig. 1. Weekly changes in haemoglobin in groups A and B after treatment with either intravenous (o) or subcutaneous (•) r-HuEPO. Fig. 2. Correlation between change in haemoglobin and initial ferritin levels and percentage transferrin saturation during the first 7 weeks of treatment (n = 11). o = Intravenous; • = subcutaneous.
Table 3. Blood pressure before and after treatment Blood pressure, mm Hg ----------------------------------------------------------before after
Antihypertensive therapy prior to r-HuEPO
160/85 165/80 120/70 160/90 140/80 130/90
170/90 140/90 130/80 150/90 140/80 140/95
+ +
180/85 140/85 135/70 160/70 110/70 160/80
175/80 150/90 140/85 160/70 140/70 145/75
+
-
+ -
+a t -
+
a Patient required increased anti-hypertensive treatment during the study.
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Mean diastolic blood pressure rose significantly in group A from 83 ± 3 mm Hg before treatment to 88 ± 2.5 (p = 0.04) afterwards. There was no rise in diastolic blood pressure in group B (post-treatment diastolic blood pressure 78 ± 3), nor in systolic blood pressure or weight in either group. A rise in blood pressure (> 5 mm Hg) was seen in 6 patients (4 group A and 2 group B; table 3). Three of these (2 group A) were already on treatment for hypertension, and 1 required an increase in medication during the study. 4 patients known to be hypertensive (1 group A and 3 group B) did not demonstrate an increase in blood pressure during the study. Percentage transferrin saturation (i.v.: 47.4 ± 12.3 vs. s.c.: 48.0 ± 14.5) and ferritin levels (754 ± 300 vs. 828 ± 323 pg/1) did not differ between groups at the start of treatment (table 2). During the study there was a significant fall in both parameters in those patients (n = 7) not requiring an iron transfusion (percentage transfer rin saturation: 68.1 ± 8.3 vs. 47.7 ± 9.1, p = 0.007;
407
Low Dose Intravenous and Subcutaneous Erythropoietin
Discussion Separate studies [1,2] have claimed that despite rela tively poor bioavailability (approximately 20%) s.c. ad ministration of r-HuEPO is more effective than i.v. in maintaining haemoglobin levels. This study demon strates that the s.c. route is as efficient in increasing hae moglobin at both the relatively low dosage regimens used. As in other studies [5-7], haemoglobin rose more quickly when the dosage was increased. It has been sug gested [ 1] that the reason for the improved response with s.c. treatment is the more prolonged, if modestly ele vated, serum EPO levels (72-96 h) compared with the peaks and troughs associated with i.v. treatment. An adequate response was demonstrated in 9 pa tients. Two patients did not respond to s.c. treatment except at much higher doses. It is recognized that a pro portion of patients do require much higher doses of r-HuEPO to obtain a response [5, 6, 8]. Apart from these patients being among the heaviest in their group, no other factors were identified to explain their lack of response. Serum levels of EPO after their first injection were similar to other patients in the group. Sufficient iron stores (ferritin levels of 500 pg/i or transferrin saturation of 25%) were required for an opti mal response as has been found by others [5, 9, 10]. Five patients in the study required an iron transfusion, de spite being on oral ferrous sulphate (325 mg, three per day) from the start of the study. Four of the five had unpleasant side effects to the parenteral iron, including muscle and joint aches and pains, diarrhoea and, in 1 patient, transient thrombocytopaenia (75 X 109/l). Such symptoms were controlled in subsequent transfusions by concurrent therapy with oral prednisolone. Complications were minimal. Fistula thrombosis oc curred in a stenosed fistula which was more than 10
years old, and which required reconstructive surgery. A rise in blood pressure was more common in patients receiving i.v. r-HuEPO, though only 1 required an in crease in medication. Increased blood pressure with treatment is well recognized, and is usually more com mon in patients who are already hypertensive [7, 11, 12]. In our study 50% of patients whose blood pressure increased were known previously to be hypertensive. Also 4 patients (3 group B) already receiving anti-hyper tensive therapy showed no change in blood pressure dur ing the study. Post-dialysis body weight did not alter in any patient during treatment making volume-dependent hypertension unlikely, and so far there are no studies to support a direct pressor effect of r-HuEPO. Rather the converse has been demonstrated [13]. The failure of group B to show a rise in blood pressure may be related to the small patient numbers or an additional benefit of s.c. therapy. To simplify management and reduce costs, it would be reasonable to start treatment with r-HuEPO at a dose of 50 U/kg twice a week s.c., increasing the dose in the small proportion of patients who do not respond.
Acknowledgement We thank the Pharmacists and Nursing Staff of the Renal Units. Austin and Repatriation Hospitals for their assistance, and JanssenCilag Australia for supply of r-HuEPO. Dr. McMahon is supported by an Australian Kidney Foundation Research Grant.
References 1 Macdougall IC, Neubert P, Coles GA, Roberts DE, Dharmasena AD, Williams JD: Pharmacokinetics of recombinant human erythropoietin in patients or. continuous ambulatory peritoneal dialysis. Lancet 1989;i:425. 2 Bommer J, Ritz E, Weinrich T, Bommer G, Ziegler T: Subcuta neous erythropoietin. Lancet I988;ii:406. 3 Boughton KJ, Abels RI, Rudnick SA: Subcutaneous erythropoi etin. Lancet 1988;ii:684. 4 Danielson BG. Salmonson T, Wikström B: Treatment of anaemia of chronic renal failure with recombinant human eryth ropoietin. Comparison between intravenous and subcutaneous administration: in Erythropoietin Literature. Uppsala. Sweden. Janssen-Cilag, 1989. 5 Eschbach JW. Egrie JC. Downing MR. Browne JK. Adamson JW: Correction of the anaemia of endstage renal disease with recombinant human erythropoietin. N Engl J Med 1987;316: 73-78. 6 Bommer J, Alexiou C, Müller-Bühl U, Eifert J. Ritz E: Recom binant human erythropoietin therapy in haemodialysis patients - dose determination and clinical experience. Nephrol Dial Transplant 1987;2:238-242.
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ferritin: 1,224 ± 221 vs. 981 ± 270, p = 0.003; data not shown); there was also a small rise in platelet count (193 ± 20 vs. 242 ± 11 X 109/1, p = 0.006). White cell count (5.9 ± 0.7 vs. 6.8 ± 0.6 X 109/l, p = 0.08), mean cor puscular volume (92.1 ± 0.9 vs. 94.7 ± 1.4 fl, p = 0.06), and plasma urea, creatinine, and potassium did not alter significantly with treatment (data not shown). One patient (group A) required a small increase in antihypertensive medications. There was one throm bosed arteriovenous fistula (group B; previous FAM assessment had suggested an arterial stenosis). No other side effects were reported.
McMahon/Dawbom
408
12 Deschodt G, Granollcras C, Alsabadani B, Branger B, Koch KM, Shaldon S: Changes in cardiac output, blood pressure and peripheral resistance following treatment of renal anaemia by recombinant human erythropoietin (abstract). Nephrol Dial Transplant 1988:3:494. 13 Bund SJ, Hcagcrty A, Edmunds M, Walls J: Erythropoietin does not induce vasoconstriction directly in human subcutaneous resistance arterioles. Nephron 1989;53:173.
Received: January 26, 1990 Accepted: April 20, 1990 Lawrence P. McMahon Renal Unit Austin Hospital Heidelberg, Vic. 3084 (Australia)
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7 Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM: Effect of human erythropoietin derived from recom binant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;ii: 1175—1178. 8 Casati S, Passerini P, Campise MR, Graziani G, Cesana B, Perisic M, Ponticelli C: Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having hae modialysis. Br Med J 1987;ii: 1017—1020. 9 Van Wyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA: Iron status in patients receiving erythropoietin for dialysis-associated anaemia. Kidney Int 1989;35:712-716. 10 Macdougall IC, Hutton RD, Cahill I, Coles GA, Williams JD: Poor response to treatment of renal anaemia with erythropoietin corrected by giving iron intravenously. Br Med J 1989;ii: 157158. 11 Raine AEG: Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin thera py. Lancet 1988;i:97—99.
Am J Nephrol 1990;10:404-408
Experience with Low Dose Intravenous and Subcutaneous Administration of Recombinant Human Erythropoietin Lawrence P. McMahon, John K. Dawborn Renal Unit, Department of Medicine. Austin Hospital. Heidelberg, Victoria. Australia
Key Words. Erythropoietin, low dose, subcutaneous
Introduction Recombinant human erythropoietin (r-HuEPO) is well established as an effective treatment for the anaemia of chronic renal failure. Although there have been several reports of alternative methods of adminis tration [1-4], the optimal route and frequency remain undetermined. This is of some practical importance be cause of the cost of treatment and the logistic difficulties of intravenous (i.v.) administration, particularly in home haemodialysis or continuous ambulatory perito neal dialysis patients. We have studied a group of stable haemodialysis patients to assess the initial response to low dose subcutaneous (s.c.) and i.v. r-HuEPO.
Patients and Methods Six male and six female anaemic haemodialysis patients were studied for 14 weeks. Causes of renal failure were glomerulonephri tis in 6 patients, reflux nephropathy in 4. and SLE and renal vascu lar disease in 1 patient each. Seven patients were receiving single drug therapy for control of hypertension. Patients were divided into
two groups (A and B); there was no significant difference between groups for age, weight, years of either haemodialysis or prior trans plantation, or level of haemoglobin (table 1). Patients not re sponding to r-HuEPO (1 group A, 3 group B), with ferritin levels less than 500 pg/1 and/or a transferrin saturation of < 25% received an iron transfusion after 7 weeks of therapy. One patient (group A) received an iron transfusion within the first 2 weeks of treatment. No patient had evidence of aluminium toxicity or significant hyper parathyroidism (table 2). Group A was given 25 U/kg thrice per week i.v., and group B 25 U/kg twice per week s.c. At the end of 7 weeks, doses were doubled. Serum erythropoietin (EPO) levels were measured by radioimmu noassay (Incstar® ) in both groups before, and at regular intervals for 48 h after the first injection. Patients in both groups were given r-HuEPO (Eprex®. JanssenCilag) after haemodialysis. This was stored as a sterile solution in buffer between 2 and 8 °C. The ampoule concentration was 4,000 U/ml. Intravenous doses were diluted in 10 ml of normal saline and administered into the dialysis line close to the needle insertion over 5 min. Subcutaneous injections were delivered undiluted after warming the syringe to room temperature (20 °C). Blood pressure and weight were measured before and after each dialysis session. Haemoglobin, mean corpuscular volume, platelet and leukocyte count were measured weekly, and plasma potassium, urea, creati nine, and liver function tests measured every four weeks. Iron stud ies were assessed monthly. Fistula assessment monitoring (FAM) was performed in each patient prior to starting r-HuEPO.
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Abstract. Twelve stable haemodialysis patients were divided into two groups and given recombinant human erythropoietin (r-HuEPO) for 14 weeks either intravenously (i.v.) or subcutaneously (s.c.). Dosage was 25 units/kg either thrice (i.v.) or twice (s.c.) per week for 7 weeks, and then 50 units/kg for a further 7 weeks. Response to s.c. therapy was comparable to i.v. despite a 33% lower weekly dosage, and was significant at both 7 (i.v.: 1.1 ± 0.3, mean ± SEM, p = 0.02; s.c.: 0.8 ± 0.3 g/dl, p = 0.03) and 14 weeks (i.v.: 2.8 ± 0.5, p = 0.003; s.c.: 2.6 ± 0.6 g/dl, p = 0.009). A correlation was observed between response to r-HuEPO and initial ferritin levels (r = 0.63, p = 0.04). One patient required an increase in antihypertensive medication and there was one arteriovenous fistula thrombosis. Results suggest that overall s.c. therapy is as effective as i.v. therapy, and that a good response with few side effects can be obtained using relatively low doses of r-HuEPO.
Low Dose Intravenous and Subcutaneous Erythropoietin
405
Table 1. Clinical data before and after treatment with r-HuEPO Patient No.
Cause of renal failure
Haemoglobin g/dl
Length of haemodialysis years
Group A 1 2 3 4 5 6
glomerulonephritis SLE reflux nephritis reflux nephritis glomerulonephritis glomerulonephritis
7.7 6.6 6.2 4.2 7.2 5.6 (6.3 ± 0.5)
Group B 7 8 9 10 11 12
glomerulonephritis reflux nephritis reflux nephritis glomerulonephritis renovascular glomerulonephritis
6.6 8.6 4.8 4.6 9.5 4.3 (6.4 ± 0.9)
Time since transplantation years
Weight kg
Age years
Change in haemoglobin after 14 weeks, g/dl
1.5 4.5 2 6 4 3 (3.5± 0.7)
0 0 0 0 12 4 (2.7 ±2.0)
76 62 60 60.5 55 52 (61 ±3)
58 54 19 42 63 45 (47 ±6)
2.1 0.6 3.7 3.8 2.6 3.9
0 3 10 2 9 4.5 (4.8 ±1.6)
0 4 0 0 0.5 0(0.8 ±0.7)
82 84 62 53 90 49 (70±7)
66 56 28 40 61 44 (49 ±6)
0.9 0.6 3.2 4.5 2.7 3.8
The mean group values (+ SF.M) are given in parentheses.
Results There was a comparable rise in haemoglobin in both groups at 7 (i.v.: 1.1 ± 0.4, p = 0.02 vs. s.c.: 0.8 ± 0.3 g/dl, p = 0.03) and at 14 weeks (2.8 ± 0.5, p = 0.003 vs. 2.6 ± 0.6 g/dl, p = 0.009), with no significant difference between groups at either time (fig. 1). Peak levels of EPO after the first injection (i.v.: 450 ± 25 and s.c.: 53 ± 6 mU/ml) occurred within 30 min and at 20 h, respec tively. A poor early response (first 7 weeks) was observed in 5 patients with initial ferritin levels less than 500 pg/1. Three of these later responded to iron transfusion. Lack of response correlated with initial ferritin levels (r = 0.63. p = 0.04), and a similar but not significant correlation was observed with percentage transferrin saturation (r = 0.40, p = 0.22; fig. 2). In patients not requiring an iron transfusion after 7 weeks (n = 8) the higher dose of r-HuEPO also produced a greater increase in haemoglo bin (i.v.: 1.1 ± 0.4 vs. 2.1 ± 0.4; s.c.: 1.2 ± 0.3 vs. 2.1 ± 0.3) when the two periods were compared. At the end of the study an inadequate response ( < 2.0 g/dl rise in hae-
Table 2. Biochemical parameters prior to treatment with r-HuEPO Patient No.
Ferritin
Transferrin saturation %
Parathyroid hormone ng/ml
Aluminium pmol/l
Group A Ia 2h 3 4 5 6
25 253 2,100 806 468 873
12.3 21.3 95.2 42.5 65.8 47.4
3.0 1.9 13.1 21.8
0.7
0.5
< 0 .5 1.1 1.3 1.5
Group B 7h 8h 9 10*’ 11 12
171 312 1.840 161 1,801 683
16.1 20.8 87.5 25.0 97.0 41.7
0.8 3.8 3.9 14.2 34.9 19.6
0.5 0.9 0.6 1.2 1.6 < 0 .5
0.0
1.0
* Patient received iron transfusion within the first 10 days of treatment. b Patients receiving iron transfusion at 7 weeks of treatment.
moglobin) to r-HuEPO was seen in three patients (ta ble 1). In 1 patient this was associated with a prolonged pneumonic illness, and 2 patients (group B) subsequently responded to higher doses of r-HuEPO (350 U/kg/week) on completion of the trial.
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All patients gave informed consent and all completed the trial. One patient (group A) was hospitalized for 3 weeks for a pneumonic illness, and another (group B) for 3 days for arteriovenous fistula repair following thrombosis. Statistical significance was determined by Student’s paired and unpaired t test and by the Spearman correlation.
McMahon/Dawborn
406
Fig. 1. Weekly changes in haemoglobin in groups A and B after treatment with either intravenous (o) or subcutaneous (•) r-HuEPO. Fig. 2. Correlation between change in haemoglobin and initial ferritin levels and percentage transferrin saturation during the first 7 weeks of treatment (n = 11). o = Intravenous; • = subcutaneous.
Table 3. Blood pressure before and after treatment Blood pressure, mm Hg ----------------------------------------------------------before after
Antihypertensive therapy prior to r-HuEPO
160/85 165/80 120/70 160/90 140/80 130/90
170/90 140/90 130/80 150/90 140/80 140/95
+ +
180/85 140/85 135/70 160/70 110/70 160/80
175/80 150/90 140/85 160/70 140/70 145/75
+
-
+ -
+a t -
+
a Patient required increased anti-hypertensive treatment during the study.
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Mean diastolic blood pressure rose significantly in group A from 83 ± 3 mm Hg before treatment to 88 ± 2.5 (p = 0.04) afterwards. There was no rise in diastolic blood pressure in group B (post-treatment diastolic blood pressure 78 ± 3), nor in systolic blood pressure or weight in either group. A rise in blood pressure (> 5 mm Hg) was seen in 6 patients (4 group A and 2 group B; table 3). Three of these (2 group A) were already on treatment for hypertension, and 1 required an increase in medication during the study. 4 patients known to be hypertensive (1 group A and 3 group B) did not demonstrate an increase in blood pressure during the study. Percentage transferrin saturation (i.v.: 47.4 ± 12.3 vs. s.c.: 48.0 ± 14.5) and ferritin levels (754 ± 300 vs. 828 ± 323 pg/1) did not differ between groups at the start of treatment (table 2). During the study there was a significant fall in both parameters in those patients (n = 7) not requiring an iron transfusion (percentage transfer rin saturation: 68.1 ± 8.3 vs. 47.7 ± 9.1, p = 0.007;
407
Low Dose Intravenous and Subcutaneous Erythropoietin
Discussion Separate studies [1,2] have claimed that despite rela tively poor bioavailability (approximately 20%) s.c. ad ministration of r-HuEPO is more effective than i.v. in maintaining haemoglobin levels. This study demon strates that the s.c. route is as efficient in increasing hae moglobin at both the relatively low dosage regimens used. As in other studies [5-7], haemoglobin rose more quickly when the dosage was increased. It has been sug gested [ 1] that the reason for the improved response with s.c. treatment is the more prolonged, if modestly ele vated, serum EPO levels (72-96 h) compared with the peaks and troughs associated with i.v. treatment. An adequate response was demonstrated in 9 pa tients. Two patients did not respond to s.c. treatment except at much higher doses. It is recognized that a pro portion of patients do require much higher doses of r-HuEPO to obtain a response [5, 6, 8]. Apart from these patients being among the heaviest in their group, no other factors were identified to explain their lack of response. Serum levels of EPO after their first injection were similar to other patients in the group. Sufficient iron stores (ferritin levels of 500 pg/i or transferrin saturation of 25%) were required for an opti mal response as has been found by others [5, 9, 10]. Five patients in the study required an iron transfusion, de spite being on oral ferrous sulphate (325 mg, three per day) from the start of the study. Four of the five had unpleasant side effects to the parenteral iron, including muscle and joint aches and pains, diarrhoea and, in 1 patient, transient thrombocytopaenia (75 X 109/l). Such symptoms were controlled in subsequent transfusions by concurrent therapy with oral prednisolone. Complications were minimal. Fistula thrombosis oc curred in a stenosed fistula which was more than 10
years old, and which required reconstructive surgery. A rise in blood pressure was more common in patients receiving i.v. r-HuEPO, though only 1 required an in crease in medication. Increased blood pressure with treatment is well recognized, and is usually more com mon in patients who are already hypertensive [7, 11, 12]. In our study 50% of patients whose blood pressure increased were known previously to be hypertensive. Also 4 patients (3 group B) already receiving anti-hyper tensive therapy showed no change in blood pressure dur ing the study. Post-dialysis body weight did not alter in any patient during treatment making volume-dependent hypertension unlikely, and so far there are no studies to support a direct pressor effect of r-HuEPO. Rather the converse has been demonstrated [13]. The failure of group B to show a rise in blood pressure may be related to the small patient numbers or an additional benefit of s.c. therapy. To simplify management and reduce costs, it would be reasonable to start treatment with r-HuEPO at a dose of 50 U/kg twice a week s.c., increasing the dose in the small proportion of patients who do not respond.
Acknowledgement We thank the Pharmacists and Nursing Staff of the Renal Units. Austin and Repatriation Hospitals for their assistance, and JanssenCilag Australia for supply of r-HuEPO. Dr. McMahon is supported by an Australian Kidney Foundation Research Grant.
References 1 Macdougall IC, Neubert P, Coles GA, Roberts DE, Dharmasena AD, Williams JD: Pharmacokinetics of recombinant human erythropoietin in patients or. continuous ambulatory peritoneal dialysis. Lancet 1989;i:425. 2 Bommer J, Ritz E, Weinrich T, Bommer G, Ziegler T: Subcuta neous erythropoietin. Lancet I988;ii:406. 3 Boughton KJ, Abels RI, Rudnick SA: Subcutaneous erythropoi etin. Lancet 1988;ii:684. 4 Danielson BG. Salmonson T, Wikström B: Treatment of anaemia of chronic renal failure with recombinant human eryth ropoietin. Comparison between intravenous and subcutaneous administration: in Erythropoietin Literature. Uppsala. Sweden. Janssen-Cilag, 1989. 5 Eschbach JW. Egrie JC. Downing MR. Browne JK. Adamson JW: Correction of the anaemia of endstage renal disease with recombinant human erythropoietin. N Engl J Med 1987;316: 73-78. 6 Bommer J, Alexiou C, Müller-Bühl U, Eifert J. Ritz E: Recom binant human erythropoietin therapy in haemodialysis patients - dose determination and clinical experience. Nephrol Dial Transplant 1987;2:238-242.
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ferritin: 1,224 ± 221 vs. 981 ± 270, p = 0.003; data not shown); there was also a small rise in platelet count (193 ± 20 vs. 242 ± 11 X 109/1, p = 0.006). White cell count (5.9 ± 0.7 vs. 6.8 ± 0.6 X 109/l, p = 0.08), mean cor puscular volume (92.1 ± 0.9 vs. 94.7 ± 1.4 fl, p = 0.06), and plasma urea, creatinine, and potassium did not alter significantly with treatment (data not shown). One patient (group A) required a small increase in antihypertensive medications. There was one throm bosed arteriovenous fistula (group B; previous FAM assessment had suggested an arterial stenosis). No other side effects were reported.
McMahon/Dawbom
408
12 Deschodt G, Granollcras C, Alsabadani B, Branger B, Koch KM, Shaldon S: Changes in cardiac output, blood pressure and peripheral resistance following treatment of renal anaemia by recombinant human erythropoietin (abstract). Nephrol Dial Transplant 1988:3:494. 13 Bund SJ, Hcagcrty A, Edmunds M, Walls J: Erythropoietin does not induce vasoconstriction directly in human subcutaneous resistance arterioles. Nephron 1989;53:173.
Received: January 26, 1990 Accepted: April 20, 1990 Lawrence P. McMahon Renal Unit Austin Hospital Heidelberg, Vic. 3084 (Australia)
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7 Winearls CG, Oliver DO, Pippard MJ, Reid C, Downing MR, Cotes PM: Effect of human erythropoietin derived from recom binant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 1986;ii: 1175—1178. 8 Casati S, Passerini P, Campise MR, Graziani G, Cesana B, Perisic M, Ponticelli C: Benefits and risks of protracted treatment with human recombinant erythropoietin in patients having hae modialysis. Br Med J 1987;ii: 1017—1020. 9 Van Wyck DB, Stivelman JC, Ruiz J, Kirlin LF, Katz MA, Ogden DA: Iron status in patients receiving erythropoietin for dialysis-associated anaemia. Kidney Int 1989;35:712-716. 10 Macdougall IC, Hutton RD, Cahill I, Coles GA, Williams JD: Poor response to treatment of renal anaemia with erythropoietin corrected by giving iron intravenously. Br Med J 1989;ii: 157158. 11 Raine AEG: Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: implications of erythropoietin thera py. Lancet 1988;i:97—99.
