Low-Dose Recombinant Human Erythropoietin Therapy in Chronic Hemodialysis Patients Don R. Duff, MD, Thomas A. Golper, MD, Rebecca S. Sloan, RN, Michael E. Brier, PhD, and George R. Aronoff, MD • To test the hypothesis that low-dose recombinant human erythropoietin (r-HuEpo) would be effective and safe therapy for the anemia of end-stage renal failure, we studied 37 chronic hemodialysis patients for 3 months before and 6 months after beginning treatment with r-HuEpo, 3,000 U, administered initially intravenously (IV) three times weekly. Hematocrit increased from a mean of 25.2 vol% into the target range (mean, 32.2 vol%, a 28% increase) by 4 months. Transfusion requirements were dramatically reduced. Eight patients (22%) had exacerbated or new development of hypertension, while in trials using higher doses this occurred in 35%. Vascular access thrombosis, dialyzer clotting, and seizures were not seen more frequently during r-HuEpo therapy. Dialyzer reuse was not affected. Low-dose r-HuEpo therapy is effective in most hemodialysis patients and may be associated with less adverse effects because of the slower increase in blood viscosity. As targets are reached, downward dosage adjustments need to be smaller when using an initial low-dose regimen. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Hemodialysis; erythropoietin; end-stage renal disease; anemia; vascular access; transfusions; hypertension.
R
ECOMBINANT human erythropoietin (r-HuEpo) corrects the anemia associated with end-stage renal disease. I -7 In addition, the rate of increase in hematocrit has been shown to be dose-dependent starting with doses as low as 15 U/kg body weight. 1-5,7 Although clinical trials report substantial increases in hemoglobin concentration and hematocrit with doses of 150 U / kg, we postulated that patients would also respond to lower doses with a more gradual increase in red blood cell (RBC) production and that the slower increase would diminish adverse effects reported with r-HuEpo. PATIENTS AND METHODS
Thirty-seven patients with end-stage renal disease maintained on in-center hemodialysis were monitored. Thirty-five patients completed 6 months of r-HuEpo treatment, and the remaining two patients died in the fourth month of therapy. The population included 17 women and 20 men, 23 black and 14 white, whose mean age was 53 ± 3 years (range, 9 to 73 years). The average time on dialysis was 4.7 years, with a range from 3 months to 12 years. The causes of renal failure included hypertension, 38%; diabetes mellitus, 22%; chronic glomerulonephritis, 19%; polycystic kidney disease, 8%; pyelonephritis, 3%: obstructive uropathy, 3%; and unknown, 8%. The patients were chosen to receive r-HuEpo if they met all of the following criteria: hematocrit less than 30 vol%, no
From the Departments of Medicine and Pharmacology, University of Louisville School of Medicine, Louisville, KY. Address reprint requests to Thomas A. Golper, MD, Kidney Disease Program, University of Louisville, 500 S Floyd St, Louisville, KY 40292. © 1991 by the National Kidney Foundation, Inc. 0272-6386/91/1801-0009$3.00/0 60
active seizure disorder or uncontrolled hypertension, a serum ferritin level of at least 100 JlgjL (100 ngjmL) before therapy, and their primary physician felt that they would benefit from a higher hematocrit.
Study Design The patients were observed for 3 months before receiving r-HuEpo and then for 6 months after therapy was begun. Initially, each patient received 3,000 U r-HuEpo directly into their venous return line at the end of dialysis thrice weekly. During the fourth or fifth month of treatment, 20 patients converted from the intravenous (IV) route to the subcutaneous route of administration at the same dosage. Throughout the study, doses were reduced by 12.5 to 25 U/kg if rapid hematocrit increases were observed or when patients reached their target hematocrit of 33 to 35 vol%. Hemoglobin and hematocrit, determined at all times by Coulter counter, were measured monthly or more frequently if indicated by a rapid change. A complete serum chemistry profile and ferritin levels were assessed monthly. Blood pressure was measured before and after each dialysis treatment with a mercury manometer. All blood transfusions, clotted dialyzers, thrombosed accesses, seizures, dry weight changes, interdialytic weight gains, and the exact dose and route of r-HuEpo administration were noted. The r-HuEpo was purchased from Amgen (Thousand Oaks, CA). Thirty-four patients dialyzed for 12 hours weekly, one for 9 hours, one for 13.5 hours, and one for 15 hours weekly, all on reused cellulosic dialyzers. Although not routinely employed, urea kinetic modeling was used in select circumstances. Heparin doses were empirically increased 25% with the initiation ofr-HuEpo; otherwise there were no planned changes in the chronic dialysis prescription. Serum ferritin levels were maintained above 100 JlgjL, as suggested by Van Wyck et al. 8 Patients were transfused when symptoms of anemia were noted. Data collected are presented as a mean ± SEM and compared by analysis of variance for repeated measures with a Newman-Keuls post test, Student's t test, linear regression, and by chi-square analysis. A probability less than 0.05 was considered significant.
American Journal of Kidney Diseases, Vol XVIII, No 1 (July), 1991: pp 60-64
61
LOW-DOSE R-HUEPO IN HEMODIALYSIS PATIENTS
GRAMS/DL 11
~r-------------------------------~ro
10.5
10.5
45
45
10
10 9.5
UNITS/KG
11
EPOTHERAPVINITlATED
*
*
9
9.5
8.5
40
9
35
8.5
30
40
EPO THERAP'f INITIATED
35
*
8
8
25UL---L---L---L---L---L---L--~
-1
o
2
MONTHS
3
4
5
6
-2
7.5
Fig 1. Mean (±SEM) hemoglobin response to lowdose r-HuEpo. "Indicates that these values are different from the -2 through +1 month data at P < 0.05 level. By month 2 of therapy, the hemoglobin concentration had increased significantly, but in months 5 and 6, it appears to be declining.
RESULTS
The mean r-HuEpo dose was 45.7 ± 2.1 V/ kg, with a range of 23 to 83 V /kg. This amount was based on each patient receiving 3,000 V. Within 6 weeks of therapy, there was a significant increase in mean hematocrit and hemoglobin concentrations (Figs 1 and 2). This increase followed a linear pattern through the fourth treatment month. The mean hematocrit before treatment began was 25.2 vol% and increased to 32.2 vol% during the fourth month of treatment. The greatest change in the mean hematocrit occurred during the first 4 months, but never exceeded 12% of the preceding month's value. VOLUME % 34
34 32
-1
0
2
MONTHS
3
4
30
__--L25
5
6
Fig 3. Mean (±SEM) r-HuEpo dose each month for all patients. "Indicates these values differ from the data of zero through month 2 at P < 0.05 leVel. By month 4, major downward dose adjustments had been made as target hematocrits were achieved. In retrospect, this adjustment was excessive.
This upward trend in hematocrit and hemoglobin concentrations did not continue during the last 2 months of observation. As patients approached their target hematocrits of 33 to 35 vol%, r-HuEpo doses were decreased by 12.5 to 25 V/kg, to a mean of 33.2 ± 3.7 V/kg (Fig 3). Furthermore, by the fifth treatment month, 20 patients were receiving their r-HuEpo injections subcutaneously. Twenty-four of the 37 patients demonstrated an increase in their hematocrit of 6 vol% or greater (Fig 4). The magnitude of the response to therapy did not correlate with serum ferritin concentration or r-HuEpo dose. However, the patient who received 83 V/kg was a 77-year-old, 36-kg woman whose hematocrit increased from 23.2 to 34 vol% by the second treatment month and to 42 vol% by the third month. Four patients showed no change in their hematocrit during
EPO THERAPY INITIATED 30 28
#OFPTS
*
20 28
28
28
24
24
22U~L---.L'---0~--L---~2--~3--~4--~5---7 22
20
,.
,.
'0
'0
6
MONTHS
Fig 2. Mean (±SEM) hematocrit response to low-dose r-HuEpo. "Indicates that these values are different from the -2 through +1 month data at P < 0.05 level. The hematocrit response parallels the hemoglobin response. The drop-off in the last 2 months is thought to reflect an excessive dose reduction as targets were achieved, rather than iron deficiency.
-2 TO +2
3T05
IT010
>10
DELTA HCT RESPONSE
Fig 4. Frequency and magnitude of the hematocrit response to low-dose r-HuEpo. Two thirds of the patients demonstrated a hematocrit increase of at least 6 vol%.
62
DUFF ET AL
3O,-----==-------------~30
25
25
20
20
15
15
10
10
2
MONTHS
Fig 5. Transfusions before and during low-dose rHuEpo therapy. These data represent the total number of RBe units required for all 37 patients. By the third month of low-dose therapy, there appears to be a reduction in the total number of units transfused. Since transfusions were given for symptoms, a bias cannot be ruled out.
treatment, despite receiving an equivalent mean dose of 47.5 U/kg (range, 37 to 51 U/kg). Only one of these four patients had no apparent reason to explain the failure to respond to r-HuEpo therapy. The persistent anemia of the other three patients was attributed to significant blood loss associated with dialysis or to surgery. There was a significant decrease in the number of blood transfusions needed in the study population after the initiation of r-HuEpo (Fig 5). Sixteen of 37 patients required blood transfusions before rHuEpo therapy. They were transfused a total of 55 U packed RBC in the 3 months preceding rHuEpo, an average of 0.49 U per patient per month. In the first treatment month, six patients received 12 U. However, after the first treatment month, the total population's transfusion requirement was that three different patients were transfused 9 U, representing a ratio of 0.05 U per patient per month. Two of these three patients had originally responded to r-HuEpo and the transfusions were administered to correct acute blood losses. Most patients required some form of iron therapy to maintain a serum ferritin concentration greater than 100 J.lg/L. There was a slight decrease in the group's mean ferritin level after the initiation of r-HuEpo. However, there was no further change in serum ferritin after the first month of treatment. Twenty-seven percent of our patients required IV iron dextran during r-HuEpo therapy, administered when serum ferritin concentrations fell below 100 J.lg/L, while receiving
orally administered iron or if patients could not tolerate oral iron. Three frequently transfused patients, who had received 21 U blood in the 3 months before starting r-HuEpo therapy, had serum ferritin concentrations exceeding 1,000 J.lg/L. None of these three received any transfusions after 4 weeks of r-HuEpo therapy. No therapeutic phlebotomies were performed. During therapy, serum ferritin concentration increased in one patient, decreased in another, and was unchanged in the third. Interdialytic weight gains were similar before (3.1 kg) and during (3.2 kg) r-HuEpo treatment. Blood pressure measured before or after each dialysis treatment was not significantly altered by r-HuEpo therapy (predialysis, Fig 6). Twentyfour patients were receiving oral antihypertensive drugs at the initiation ofr-HuEpo therapy. Three of these required an increase in the doses of their antihypertensive medications. Eight of the 37 patients receiving r-HuEpo demonstrated at least a 10 mm Hg increase in mean blood pressure before dialysis. Six were already receiving antihypertensive medications and three of these required additional medication. The two patients not receiving antihypertensive medications and whose blood pressure increased by at least 10 mm Hg still did not require antihypertensive treatment. Seven of these eight patients whose blood pressure increased also demonstrated at least a 6 vol% increase in hematocrit to a mean of 28.5 ± 1.3. Twenty-three patients whose blood pressure did not change, but whose hematocrit inmmHg
mmHg
'55
155
'50
'50
SYSTOLIC
""
'35
'3() '25
'20
t
"5 -- 135
,3() '25
EPO THERAPY INITIATED
115 110
'00
os
'20
110
j
,OS
,,, '05 '00 95
DIASTOLIC '"os ~t--~ __ ~ __ ~--~--~--~--~--~ : '"
90
75 70
75
'-:---'---'---'---'----'----'-----'----~ -2
70
MONTHS
Fig 6. Systolic and diastolic (±SEM) blood pressure response to low-dose r-HuEpo at start of dialysis. Predialysis systolic and diastolic blood pressure did not significantly change during the period of observation. The highest pressures were in the last 2 months, when hematocrits had decreased (see Fig 2).
LOW-DOSE R-HUEPO IN HEMODIALYSIS PATIENTS
creased at least 6 vol%, had a mean hematocrit at 6 months of 30.6 ± 1.0. There was no increased incidence of vascular access thrombosis or hemodialyzer clotting in our patients during therapy with r-HuEpo. In the 3 months preceding therapy, there were six thrombosed hemodialysis accesses for an average of two thromboses per month for the 37 patients. For the 6 months ofr-HuEpo therapy, there were 12 episodes of thrombosed vascular accesses, also an average of two thromboses per month for the entire study population. Similar results were observed regarding hemodialyzer clotting. Only two dialyzers clotted in the 3 months preceding therapy, compared with three clotted dialyzers over the 6-month period during treatment with erythropoietin. All patients who received r-HuEpo had their heparin doses increased by 25% at the onset of therapy. There was no change in the number of reuses for each dialyzer during treatment with erythropoietin. Seizures were uncommon in the study population. Only one patient experienced an isolated seizure during the 6 months ofr-HuEpo therapy. This seizure occurred during the third month of treatment. Comparing the 6 months of r-HuEpo therapy with the 3-month baseline data, the adequacy of dialysis appeared unchanged. As shown in Table 1, the concentrations of blood urea nitrogen (BUN), creatinine, phosphorus, albumin, and potassium were not different during treatment with erythropoietin.
63
DISCUSSION
Recombinant erythropoietin is effective in treating the anemia associated with end-stage renal disease. I -7 The doses used in the Phase III Multicenter Trials were considerably larger than those used in our study. Eschbach et al demonstrated that the rate, but not the magnitude, of increase in hematocrit is dose-dependent. lOur data support this concept. Target hematocrits can be achieved with lower erythropoietin doses in most patients with end-stage renal failure. The increase in hematocrit to predetermined target levels requires a longer duration of therapy and should be achieved unless precluded by shortened RBC survival. Consistent results were noted from a German multicenter trial wherein 40 U /kg was administered to 29 patients. Four patients demonstrated no response and 17 patients demonstrated a reduced response, defined as a hematocrit increase ofless than 10 vol%.4,5 Our data and the German study show that most in-center hemodialysis patients will respond to low-dose erythropoietin with either a frank increase in hematocrit or a reduction in transfusion requirements. Since transfusion indications in our study were the appearance of anemic symptoms, there may have been a subjective bias against transfusion once treatment with r-HuEpo was begun. The development or exacerbation of hypertension has been noted to occur in up to 35% of all subjects where hematocrit has been increased with erythropoietin therapy.6,7,9 This increase in
Table 1. Mean (±SEM) Serum Chemistries in 37 Chronic Hemodialysis Patients Before and During Low-Dose r-HuEPO Therapy Month
Parameter
BUN mmolJL urea (mg/dL) Creatinine I'mol/L (mg/dL) Potassium mEq/L Phosphate mmol/L (mg/dL) Albumin g/dL
-2
0
+2
+4
+6
26.3 ± 1 .1 (73 ± 3)
25.1 ± 1.3 (73± 3)
26.2 ± 1.3 (73±4)
24.6 ± 1 .1 (69 ± 3)
22.9 ± 1.0 (64 ± 3)
1167 ± 62 (13.2 ± 7. )
1105 ± 62 (12.5 ± .7)
1096 ± 53 (12.4 ± .6)
1016 ± 53 (11 .5 ± 6).
4.7 ± .1
4.8± .2
5.1 ±.1
5.1 ±.1
4.9 ± .1
2.1 ± .2 (6.4 ± .4)
2.1 ±.2 (6.6 ± 5. )
2.3 ± .1 (7.3 ± 4. )
2.2 ±.1 (6.7 ± 4. )
1.9 ± .1 (5.9 ± 3).
3.8 ±.1
4.0 ±.1
3.9 ±.1
3.9 ± .1
4.0 ±.1
990 ± 53 (11.2 ± .6)
64
DUFF ET AL
blood pressure is believed to be secondary to the greater blood viscosity that accompanies increasing hematocrits. Other work suggests that the correction of anemia causes an increase in peripheral resistance through direct arteriolar vasoconstriction. 9,10 Our data may suggest that the more gradual increase in hematocrit seen with the lower r-HuEpo doses does not cause an increase in blood pressure. The incidence of thrombosed vascular accesses and dialyzer clotting, and the number of dialyzer reuses, were not changed during r-HuEpo treatment. In anticipation of these potential problems, heparin doses were empirically increased by 25% at the initiation of erythropoietin therapy. This action may explain the low incidence of these occurrences during our study. Seizures were rarely seen either before or during r-HuEpo therapy. Adequacy of dialysis as measured by monthly serum chemistries did not change during our period of observation. In the Phase III Trials, there was a slight increase in serum potassium and phosphate concentrations. 6 Our data may differ because the level of hematocrit achieved in our study was less than that observed in these trials. Our observations show that much smaller adjustments in r-HuEpo doses are indicated when using low-dose therapy than previously reported using higher doses. 6 In the Phase III Trials, stable hematocrits were achieved by adjusting the thrice
weekly dose in 12.5- to 25-U/kg increments. Decreasing the r-HuEpo dose by this amount in our study resulted in a rapid decrease in hematocrit in many patients and may explain the decrease in mean hematocrit seen during the final months of our observations (Figs 1 and 3). It is possible that iron deficiency may have developed, but this was not likely, since supplements were administered parenterally and serum ferritin did not decline. Thus, when using the lower doses of rHuEpo described here, we recommend reducing the dose by only 5 to 10 U /kg as target hematocrit is approached. We conclude that low-dose r-HuEpo is effective in treating the anemia of many patients with end-stage renal failure. The rate of hematocrit increase is slower than that observed with higher doses. However, since an occasional patient demonstrated a rapid increase in hematocrit, twice monthly hematocrit determinations seems prudent. In general, this more gradual increase in hematocrit may result in less adverse effects. As target hematocrits are reached with low-dose therapy, smaller dose adjustments should be made to avoid precipitous decrements in the hematocrit. ACKNOWLEDGMENT The authors thank the patients and staff of the Dialysis Unit of the University of Louisville Kidney Disease Program for their cooperation during this investigation.
REFERENCES I. Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Eng! J Med 316:73-78, 1987 2. Winearls CG, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 2:1175-1178,1986 3. Bommer J, Alexiou C, Muller-Buhl U, et al: Recombinant human erythropoietin therapy in haemodialysis patients: Dose determination and clinical experience. Nephrol Dial Transplant 2:238-242, 1987 4. Bommer J, Kugel M, Schoeppe W, et al: Dose-related effects of recombinant human erythropoietin on erythropoiesis: Results of a multi-center trial in patients with end-stage renal disease. Contrib Nephrol 66:85-93, 1988 5. Kuhn K, Nonnast-Daniel. B, Grutzmacher P, et al: Analysis of initial resistance of erythropoiesis to treatment
with recombinant human erythropoietin: Results of a multicenter trial in patients with end-stage renal disease. Contrib NephroI66:94-103, 1988 6. Eschbach JW, Abdulhadi MH, Browne JK, et al: Recombinant human erythropoietin in anemic patients with endstage renal disease: Results of a phase III multicenter clinical trial. Ann Intern Med III :992-1000, 1989 7. Canaud B, Polito-Bouloux C, Garred U, et al: Recombinant human erythropoietin: 18 months experience in hemodialysis patients. Am J Kidney Dis 15:169-175, 1990 8. Van Wyck DB, Stivelman JC, Ruiz J, et al: Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 35:712-716,1989 9. Schaefer RM, Leschke M, Strauer BE, et al: Blood rheology and hypertension in hemodialysis patients treated with erythropoietin. Am J Nephrol 8:449-453, 1988 10. Neff MS, Kim KE, Persoff.M, et al: Hemodynamics of uremic anemia. Circulation 18:876-883, 1971
R
ECOMBINANT human erythropoietin (r-HuEpo) corrects the anemia associated with end-stage renal disease. I -7 In addition, the rate of increase in hematocrit has been shown to be dose-dependent starting with doses as low as 15 U/kg body weight. 1-5,7 Although clinical trials report substantial increases in hemoglobin concentration and hematocrit with doses of 150 U / kg, we postulated that patients would also respond to lower doses with a more gradual increase in red blood cell (RBC) production and that the slower increase would diminish adverse effects reported with r-HuEpo. PATIENTS AND METHODS
Thirty-seven patients with end-stage renal disease maintained on in-center hemodialysis were monitored. Thirty-five patients completed 6 months of r-HuEpo treatment, and the remaining two patients died in the fourth month of therapy. The population included 17 women and 20 men, 23 black and 14 white, whose mean age was 53 ± 3 years (range, 9 to 73 years). The average time on dialysis was 4.7 years, with a range from 3 months to 12 years. The causes of renal failure included hypertension, 38%; diabetes mellitus, 22%; chronic glomerulonephritis, 19%; polycystic kidney disease, 8%; pyelonephritis, 3%: obstructive uropathy, 3%; and unknown, 8%. The patients were chosen to receive r-HuEpo if they met all of the following criteria: hematocrit less than 30 vol%, no
From the Departments of Medicine and Pharmacology, University of Louisville School of Medicine, Louisville, KY. Address reprint requests to Thomas A. Golper, MD, Kidney Disease Program, University of Louisville, 500 S Floyd St, Louisville, KY 40292. © 1991 by the National Kidney Foundation, Inc. 0272-6386/91/1801-0009$3.00/0 60
active seizure disorder or uncontrolled hypertension, a serum ferritin level of at least 100 JlgjL (100 ngjmL) before therapy, and their primary physician felt that they would benefit from a higher hematocrit.
Study Design The patients were observed for 3 months before receiving r-HuEpo and then for 6 months after therapy was begun. Initially, each patient received 3,000 U r-HuEpo directly into their venous return line at the end of dialysis thrice weekly. During the fourth or fifth month of treatment, 20 patients converted from the intravenous (IV) route to the subcutaneous route of administration at the same dosage. Throughout the study, doses were reduced by 12.5 to 25 U/kg if rapid hematocrit increases were observed or when patients reached their target hematocrit of 33 to 35 vol%. Hemoglobin and hematocrit, determined at all times by Coulter counter, were measured monthly or more frequently if indicated by a rapid change. A complete serum chemistry profile and ferritin levels were assessed monthly. Blood pressure was measured before and after each dialysis treatment with a mercury manometer. All blood transfusions, clotted dialyzers, thrombosed accesses, seizures, dry weight changes, interdialytic weight gains, and the exact dose and route of r-HuEpo administration were noted. The r-HuEpo was purchased from Amgen (Thousand Oaks, CA). Thirty-four patients dialyzed for 12 hours weekly, one for 9 hours, one for 13.5 hours, and one for 15 hours weekly, all on reused cellulosic dialyzers. Although not routinely employed, urea kinetic modeling was used in select circumstances. Heparin doses were empirically increased 25% with the initiation ofr-HuEpo; otherwise there were no planned changes in the chronic dialysis prescription. Serum ferritin levels were maintained above 100 JlgjL, as suggested by Van Wyck et al. 8 Patients were transfused when symptoms of anemia were noted. Data collected are presented as a mean ± SEM and compared by analysis of variance for repeated measures with a Newman-Keuls post test, Student's t test, linear regression, and by chi-square analysis. A probability less than 0.05 was considered significant.
American Journal of Kidney Diseases, Vol XVIII, No 1 (July), 1991: pp 60-64
61
LOW-DOSE R-HUEPO IN HEMODIALYSIS PATIENTS
GRAMS/DL 11
~r-------------------------------~ro
10.5
10.5
45
45
10
10 9.5
UNITS/KG
11
EPOTHERAPVINITlATED
*
*
9
9.5
8.5
40
9
35
8.5
30
40
EPO THERAP'f INITIATED
35
*
8
8
25UL---L---L---L---L---L---L--~
-1
o
2
MONTHS
3
4
5
6
-2
7.5
Fig 1. Mean (±SEM) hemoglobin response to lowdose r-HuEpo. "Indicates that these values are different from the -2 through +1 month data at P < 0.05 level. By month 2 of therapy, the hemoglobin concentration had increased significantly, but in months 5 and 6, it appears to be declining.
RESULTS
The mean r-HuEpo dose was 45.7 ± 2.1 V/ kg, with a range of 23 to 83 V /kg. This amount was based on each patient receiving 3,000 V. Within 6 weeks of therapy, there was a significant increase in mean hematocrit and hemoglobin concentrations (Figs 1 and 2). This increase followed a linear pattern through the fourth treatment month. The mean hematocrit before treatment began was 25.2 vol% and increased to 32.2 vol% during the fourth month of treatment. The greatest change in the mean hematocrit occurred during the first 4 months, but never exceeded 12% of the preceding month's value. VOLUME % 34
34 32
-1
0
2
MONTHS
3
4
30
__--L25
5
6
Fig 3. Mean (±SEM) r-HuEpo dose each month for all patients. "Indicates these values differ from the data of zero through month 2 at P < 0.05 leVel. By month 4, major downward dose adjustments had been made as target hematocrits were achieved. In retrospect, this adjustment was excessive.
This upward trend in hematocrit and hemoglobin concentrations did not continue during the last 2 months of observation. As patients approached their target hematocrits of 33 to 35 vol%, r-HuEpo doses were decreased by 12.5 to 25 V/kg, to a mean of 33.2 ± 3.7 V/kg (Fig 3). Furthermore, by the fifth treatment month, 20 patients were receiving their r-HuEpo injections subcutaneously. Twenty-four of the 37 patients demonstrated an increase in their hematocrit of 6 vol% or greater (Fig 4). The magnitude of the response to therapy did not correlate with serum ferritin concentration or r-HuEpo dose. However, the patient who received 83 V/kg was a 77-year-old, 36-kg woman whose hematocrit increased from 23.2 to 34 vol% by the second treatment month and to 42 vol% by the third month. Four patients showed no change in their hematocrit during
EPO THERAPY INITIATED 30 28
#OFPTS
*
20 28
28
28
24
24
22U~L---.L'---0~--L---~2--~3--~4--~5---7 22
20
,.
,.
'0
'0
6
MONTHS
Fig 2. Mean (±SEM) hematocrit response to low-dose r-HuEpo. "Indicates that these values are different from the -2 through +1 month data at P < 0.05 level. The hematocrit response parallels the hemoglobin response. The drop-off in the last 2 months is thought to reflect an excessive dose reduction as targets were achieved, rather than iron deficiency.
-2 TO +2
3T05
IT010
>10
DELTA HCT RESPONSE
Fig 4. Frequency and magnitude of the hematocrit response to low-dose r-HuEpo. Two thirds of the patients demonstrated a hematocrit increase of at least 6 vol%.
62
DUFF ET AL
3O,-----==-------------~30
25
25
20
20
15
15
10
10
2
MONTHS
Fig 5. Transfusions before and during low-dose rHuEpo therapy. These data represent the total number of RBe units required for all 37 patients. By the third month of low-dose therapy, there appears to be a reduction in the total number of units transfused. Since transfusions were given for symptoms, a bias cannot be ruled out.
treatment, despite receiving an equivalent mean dose of 47.5 U/kg (range, 37 to 51 U/kg). Only one of these four patients had no apparent reason to explain the failure to respond to r-HuEpo therapy. The persistent anemia of the other three patients was attributed to significant blood loss associated with dialysis or to surgery. There was a significant decrease in the number of blood transfusions needed in the study population after the initiation of r-HuEpo (Fig 5). Sixteen of 37 patients required blood transfusions before rHuEpo therapy. They were transfused a total of 55 U packed RBC in the 3 months preceding rHuEpo, an average of 0.49 U per patient per month. In the first treatment month, six patients received 12 U. However, after the first treatment month, the total population's transfusion requirement was that three different patients were transfused 9 U, representing a ratio of 0.05 U per patient per month. Two of these three patients had originally responded to r-HuEpo and the transfusions were administered to correct acute blood losses. Most patients required some form of iron therapy to maintain a serum ferritin concentration greater than 100 J.lg/L. There was a slight decrease in the group's mean ferritin level after the initiation of r-HuEpo. However, there was no further change in serum ferritin after the first month of treatment. Twenty-seven percent of our patients required IV iron dextran during r-HuEpo therapy, administered when serum ferritin concentrations fell below 100 J.lg/L, while receiving
orally administered iron or if patients could not tolerate oral iron. Three frequently transfused patients, who had received 21 U blood in the 3 months before starting r-HuEpo therapy, had serum ferritin concentrations exceeding 1,000 J.lg/L. None of these three received any transfusions after 4 weeks of r-HuEpo therapy. No therapeutic phlebotomies were performed. During therapy, serum ferritin concentration increased in one patient, decreased in another, and was unchanged in the third. Interdialytic weight gains were similar before (3.1 kg) and during (3.2 kg) r-HuEpo treatment. Blood pressure measured before or after each dialysis treatment was not significantly altered by r-HuEpo therapy (predialysis, Fig 6). Twentyfour patients were receiving oral antihypertensive drugs at the initiation ofr-HuEpo therapy. Three of these required an increase in the doses of their antihypertensive medications. Eight of the 37 patients receiving r-HuEpo demonstrated at least a 10 mm Hg increase in mean blood pressure before dialysis. Six were already receiving antihypertensive medications and three of these required additional medication. The two patients not receiving antihypertensive medications and whose blood pressure increased by at least 10 mm Hg still did not require antihypertensive treatment. Seven of these eight patients whose blood pressure increased also demonstrated at least a 6 vol% increase in hematocrit to a mean of 28.5 ± 1.3. Twenty-three patients whose blood pressure did not change, but whose hematocrit inmmHg
mmHg
'55
155
'50
'50
SYSTOLIC
""
'35
'3() '25
'20
t
"5 -- 135
,3() '25
EPO THERAPY INITIATED
115 110
'00
os
'20
110
j
,OS
,,, '05 '00 95
DIASTOLIC '"os ~t--~ __ ~ __ ~--~--~--~--~--~ : '"
90
75 70
75
'-:---'---'---'---'----'----'-----'----~ -2
70
MONTHS
Fig 6. Systolic and diastolic (±SEM) blood pressure response to low-dose r-HuEpo at start of dialysis. Predialysis systolic and diastolic blood pressure did not significantly change during the period of observation. The highest pressures were in the last 2 months, when hematocrits had decreased (see Fig 2).
LOW-DOSE R-HUEPO IN HEMODIALYSIS PATIENTS
creased at least 6 vol%, had a mean hematocrit at 6 months of 30.6 ± 1.0. There was no increased incidence of vascular access thrombosis or hemodialyzer clotting in our patients during therapy with r-HuEpo. In the 3 months preceding therapy, there were six thrombosed hemodialysis accesses for an average of two thromboses per month for the 37 patients. For the 6 months ofr-HuEpo therapy, there were 12 episodes of thrombosed vascular accesses, also an average of two thromboses per month for the entire study population. Similar results were observed regarding hemodialyzer clotting. Only two dialyzers clotted in the 3 months preceding therapy, compared with three clotted dialyzers over the 6-month period during treatment with erythropoietin. All patients who received r-HuEpo had their heparin doses increased by 25% at the onset of therapy. There was no change in the number of reuses for each dialyzer during treatment with erythropoietin. Seizures were uncommon in the study population. Only one patient experienced an isolated seizure during the 6 months ofr-HuEpo therapy. This seizure occurred during the third month of treatment. Comparing the 6 months of r-HuEpo therapy with the 3-month baseline data, the adequacy of dialysis appeared unchanged. As shown in Table 1, the concentrations of blood urea nitrogen (BUN), creatinine, phosphorus, albumin, and potassium were not different during treatment with erythropoietin.
63
DISCUSSION
Recombinant erythropoietin is effective in treating the anemia associated with end-stage renal disease. I -7 The doses used in the Phase III Multicenter Trials were considerably larger than those used in our study. Eschbach et al demonstrated that the rate, but not the magnitude, of increase in hematocrit is dose-dependent. lOur data support this concept. Target hematocrits can be achieved with lower erythropoietin doses in most patients with end-stage renal failure. The increase in hematocrit to predetermined target levels requires a longer duration of therapy and should be achieved unless precluded by shortened RBC survival. Consistent results were noted from a German multicenter trial wherein 40 U /kg was administered to 29 patients. Four patients demonstrated no response and 17 patients demonstrated a reduced response, defined as a hematocrit increase ofless than 10 vol%.4,5 Our data and the German study show that most in-center hemodialysis patients will respond to low-dose erythropoietin with either a frank increase in hematocrit or a reduction in transfusion requirements. Since transfusion indications in our study were the appearance of anemic symptoms, there may have been a subjective bias against transfusion once treatment with r-HuEpo was begun. The development or exacerbation of hypertension has been noted to occur in up to 35% of all subjects where hematocrit has been increased with erythropoietin therapy.6,7,9 This increase in
Table 1. Mean (±SEM) Serum Chemistries in 37 Chronic Hemodialysis Patients Before and During Low-Dose r-HuEPO Therapy Month
Parameter
BUN mmolJL urea (mg/dL) Creatinine I'mol/L (mg/dL) Potassium mEq/L Phosphate mmol/L (mg/dL) Albumin g/dL
-2
0
+2
+4
+6
26.3 ± 1 .1 (73 ± 3)
25.1 ± 1.3 (73± 3)
26.2 ± 1.3 (73±4)
24.6 ± 1 .1 (69 ± 3)
22.9 ± 1.0 (64 ± 3)
1167 ± 62 (13.2 ± 7. )
1105 ± 62 (12.5 ± .7)
1096 ± 53 (12.4 ± .6)
1016 ± 53 (11 .5 ± 6).
4.7 ± .1
4.8± .2
5.1 ±.1
5.1 ±.1
4.9 ± .1
2.1 ± .2 (6.4 ± .4)
2.1 ±.2 (6.6 ± 5. )
2.3 ± .1 (7.3 ± 4. )
2.2 ±.1 (6.7 ± 4. )
1.9 ± .1 (5.9 ± 3).
3.8 ±.1
4.0 ±.1
3.9 ±.1
3.9 ± .1
4.0 ±.1
990 ± 53 (11.2 ± .6)
64
DUFF ET AL
blood pressure is believed to be secondary to the greater blood viscosity that accompanies increasing hematocrits. Other work suggests that the correction of anemia causes an increase in peripheral resistance through direct arteriolar vasoconstriction. 9,10 Our data may suggest that the more gradual increase in hematocrit seen with the lower r-HuEpo doses does not cause an increase in blood pressure. The incidence of thrombosed vascular accesses and dialyzer clotting, and the number of dialyzer reuses, were not changed during r-HuEpo treatment. In anticipation of these potential problems, heparin doses were empirically increased by 25% at the initiation of erythropoietin therapy. This action may explain the low incidence of these occurrences during our study. Seizures were rarely seen either before or during r-HuEpo therapy. Adequacy of dialysis as measured by monthly serum chemistries did not change during our period of observation. In the Phase III Trials, there was a slight increase in serum potassium and phosphate concentrations. 6 Our data may differ because the level of hematocrit achieved in our study was less than that observed in these trials. Our observations show that much smaller adjustments in r-HuEpo doses are indicated when using low-dose therapy than previously reported using higher doses. 6 In the Phase III Trials, stable hematocrits were achieved by adjusting the thrice
weekly dose in 12.5- to 25-U/kg increments. Decreasing the r-HuEpo dose by this amount in our study resulted in a rapid decrease in hematocrit in many patients and may explain the decrease in mean hematocrit seen during the final months of our observations (Figs 1 and 3). It is possible that iron deficiency may have developed, but this was not likely, since supplements were administered parenterally and serum ferritin did not decline. Thus, when using the lower doses of rHuEpo described here, we recommend reducing the dose by only 5 to 10 U /kg as target hematocrit is approached. We conclude that low-dose r-HuEpo is effective in treating the anemia of many patients with end-stage renal failure. The rate of hematocrit increase is slower than that observed with higher doses. However, since an occasional patient demonstrated a rapid increase in hematocrit, twice monthly hematocrit determinations seems prudent. In general, this more gradual increase in hematocrit may result in less adverse effects. As target hematocrits are reached with low-dose therapy, smaller dose adjustments should be made to avoid precipitous decrements in the hematocrit. ACKNOWLEDGMENT The authors thank the patients and staff of the Dialysis Unit of the University of Louisville Kidney Disease Program for their cooperation during this investigation.
REFERENCES I. Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. N Eng! J Med 316:73-78, 1987 2. Winearls CG, Oliver DO, Pippard MJ, et al: Effect of human erythropoietin derived from recombinant DNA on the anaemia of patients maintained by chronic haemodialysis. Lancet 2:1175-1178,1986 3. Bommer J, Alexiou C, Muller-Buhl U, et al: Recombinant human erythropoietin therapy in haemodialysis patients: Dose determination and clinical experience. Nephrol Dial Transplant 2:238-242, 1987 4. Bommer J, Kugel M, Schoeppe W, et al: Dose-related effects of recombinant human erythropoietin on erythropoiesis: Results of a multi-center trial in patients with end-stage renal disease. Contrib Nephrol 66:85-93, 1988 5. Kuhn K, Nonnast-Daniel. B, Grutzmacher P, et al: Analysis of initial resistance of erythropoiesis to treatment
with recombinant human erythropoietin: Results of a multicenter trial in patients with end-stage renal disease. Contrib NephroI66:94-103, 1988 6. Eschbach JW, Abdulhadi MH, Browne JK, et al: Recombinant human erythropoietin in anemic patients with endstage renal disease: Results of a phase III multicenter clinical trial. Ann Intern Med III :992-1000, 1989 7. Canaud B, Polito-Bouloux C, Garred U, et al: Recombinant human erythropoietin: 18 months experience in hemodialysis patients. Am J Kidney Dis 15:169-175, 1990 8. Van Wyck DB, Stivelman JC, Ruiz J, et al: Iron status in patients receiving erythropoietin for dialysis-associated anemia. Kidney Int 35:712-716,1989 9. Schaefer RM, Leschke M, Strauer BE, et al: Blood rheology and hypertension in hemodialysis patients treated with erythropoietin. Am J Nephrol 8:449-453, 1988 10. Neff MS, Kim KE, Persoff.M, et al: Hemodynamics of uremic anemia. Circulation 18:876-883, 1971
