Therapy of Renal Anemia in Children and Adolescents with Recombinant Human Erythropoietin (rHuEPO) Alfonso Campos, M.D. Eduardo H. Garin, M.D.
Summary: Eleven anemic children and adolescents with a median age of 14 years (range six months-20 years) on chronic hemodialysis were treated with recombinant human erythropoietin (rHuEPO) intravenously three times a week for an average of 9.2 months. After eight weeks of therapy, hematocrit rose from 20.3 ± 1.4% to 31.7 ± 0.7% (0.20 ± 0.01 to 0.31 ± 0.007, p ~~‘s;~~&dquo;i~~~~La~o~~~·x,:~~a~yaw~~~:a a~y~~~%,~~&dquo;; a&dquo;
>.~az~~r;‘~:E’~%s.>s’,~~.~>,F~aR~~,~%~ ;§.j. $g~._Qt jy~ ;x ,,; ;~ j .;,, ; , ~,Q.=.~, ;§Qj,£jQ,j£;q~.qq§~jjg$ifl§yfl.%Q£; t~,a, ~ ’
^
*
?= : .
.·
1, : g~°,_ _ ~aaa&dquo;
Serum iron and ferritin concentrations and total iron binding capacity were measured monthly. Vitamin B12 and folic acid concentrations were obtained every three months. To assess the adequacy of dialysis, urea kinetic studies according to the method described by Barth’ were performed before rHuEPO therapy, at the time of reaching target hematocrit, and at the end of the follow-up period. The formula Kt/V, where K dia=
lyzer
urea
time, and V
clearance,
t
=
dialysis
distribution volume was used for this purpose. The rHuEPO dose was increased by 25 u/kg if after four to six weeks of therapy the hematocrit had not increased by 4% to 6%. The dose of rHuEPO was decreased by 25 u/kg/dose when the target hematocrit level of 30% to 33% (0.300.33) was reached. At the initiation of rHuEPO therapy, three patients with serum ferritin concentrations < 100 gg/L (< 100 ng/ml) were begun on oral iron therapy (5 mg of elemental iron/kg/day). The use of rHuEPO for patients on hemodialysis had been previously approved by Tampa Gen=
urea
· . , .
, _
,
~~_ ’:%~ ~~~~~~~&dquo;~~ ~ ~.~~k~.ar~r~z.^sTs~:~~~saa; ~~l’i; ]/I_/~jll~~%~ll~/~~~~~~~~~,ii~~~. a
y~~~·’’a~ ~a~~,~s~~:~,T°~, ‘~ ~~3~
~
~;&dquo;
‘
,
r
F~
:° : ~ yaF~>egss,c~x’~aa^~~~~ ~s~~~s~sp~~,‘,^.·3a · ,axa~~~’~’>~s, .
,
~>
~
~’s~s~s;~~~U
~~
~ ~
p~~~tF.~~~~~y4 M’ ~ , r.Y ~~fra.ia ,~,~a
o-
~
:
.
/~
*Results
, are
~~ ,
~,.
xs‘
,.
8~>ic
~~~
..
v
&dquo;
a
’‘ez&dquo;:a., ~&dquo;ay,~a> s ,
...
_
k>aYl~r·,
~~a’‘>‘WoCe~,’s2 -,
,..
t. &dquo;
..
,
j&dquo; ,
given as rr1èa,ns;~ $tan~~{~,’e([br of t
a_
~IiLs7i,t(b,a ial~Lll,dM£t4~ patient who&dquo;did notr-èspond tf
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
95
maintain hematocrit within target range were 47.5 ± 4.49, 36 ± 3.8, and 48.5 ± 6.77 u/kg/dose at
three, six, and nine months of therFigure
1.
rHuEPO
on
Effect
of
reticulocyte count (open circles) and hematocrit (closed circles) levels. Results are expressed as means. Vertical line represents one standard error of the mean.
eral Hospital. All parents were informed regarding the use and potential risks and benefits of this medication.
Statistical analysis was performed one-way analysis of variance, randomized block assignment, and multiple &dquo;t&dquo; tests. Analysis of variand differences between ance
using
means were performed on the logarithms of the measured values.
Results Baseline and follow-up laboratory data are summarized in Table 1. Ten of eleven patients responded to rHuEPO, reaching the target hematocrit between one and two was
months of therapy. This goal achieved at the dose of 62.5 ±
5.6 u/kg/dose (mean ± SEM, range 50-75). Failure to reach the target hematocrit occurred in one infant who has required a gradual increase of rHuEPO every four to six weeks to a current dose of 275
count and hematocrit levels is shown in Figure 1. An increase in the reticulocyte count was seen after one week of rHuEPO with levels peaking in two to three weeks. The increase in reticulocyte
ulocyte
followed by an average hematocrit increase of 3% every two weeks. Upon reaching the target hematocrit, the dose of rHuEPO was decreased in the ten patients who responded to the treatment. To keep the hematocrit within target range, six of these patients required further decreases of the rHuEPO dose in the following three months. However, at six months of therapy, a decrease in the reticulocyte count was observed prompting an increase of the rHuEPO dose. Excluding the only child that did not respond to rHuEPO, the dose requirements to count was
u/kg/dose. This infant is receiving phenobarbital therapy and has no clinical or radiographic evidence of renal osteodystrophy. Although this is the only patient who continues to require periodic blood transfusions, her transfusion
re-
quirements have decreased from 75 ml/kg/month to 10 ml/kg/ month. The effect of rHuEPO
96
on
retic-
2. Effect of rHuEPO onn individual serum ferritin levels.
Figure
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
apy respectively (Table 1). At present, with the exception of the nonresponsive patient, maintenance doses of rHuEPO range from 25-75 u/kg/dose, given three times a week. Ferritin concentrations decreased in ten of eleven patients (Figure 2). Four patients were begun on oral iron therapy (5 mg elemental iron/kg/day) as serum ferritin dropped below 100 gg/L (100 ng/ml) after three months of rHuEPO therapy. Three patients with initially high serum ferritin
concentrations (915-1,275 Jlg/L) also experienced a decrease in their levels. Folate and vitamin B12 levels remained normal in all patients. With correction of the anemia, all patients experienced a subjective increase in appetite and energy level. After three months of rHuEPO therapy, the TSF and MAMC increased by 15% ± 4.2% and 5% ± 1.4%, respectively (mean ± SEM), and thereafter remained
stationary. Administration of rHuEPO no serious immediate adverse side effects. The effects of rHuEPO therapy on mean arterial pressure (MAP), urea kinetics, and heparin requirements during dialysis are shown in Table 2. As a caused
Discussion
group, there were no significant changes in the MAP after three months of therapy. However, two patients whose hypertension had previously been under control required an increase in antihypertensive medication to maintain a blood pressure below the 95th percentile for age. Two other patients were started
antihypertensive therapy
on
as
their blood pressures rose from the 50th and 75th percentile to above the 95th percentile for age. The development or worsening of hypertension occurred within the first two months of rHuEPO
therapy. Antihypertensive regiincluded calcium channel blockers and angiotensin converting enzyme inhibitors. During rHuEPO therapy, no significant changes were noted in urea kinetic modeling paramemens
(Kt/V) or heparin require(Table 2).
ters
ments
One patient’s vascular graft clotted three months after initiation of rHuEPO therapy. This occurred in association with a hematocrit of 34% and the development of hypotension at the end of dialysis.
and seizures. Watkins et als compared the efficacy of 50 to 150 u/kg/dose of rHuEPO. Each treatment group included patients on hemodialysis, peritoneal dialysis, and predialysis in renal failure. Nine patients on hemodialysis received rHuEPO intravenously and all others subcuta-
We conclude from this study that rHuEPO is safe and effective and is recommended as treatment for the anemia of children and adolescents on hemodialysis. Ten of eleven patients responded to the mean dose of 62.5 u/kg three times a week, reaching the target hematocrit within two months. While similar hemoglobin levels have been achieved in children on hemodialysis with higher rHuEPO dosages (97 ± 3, 100, and 150 u/kg/ dose) ,6-S our data clearly demonstrate that a lower dose is
neously. Contrary to our findings, of their patients on 50 u/kg/dose reached the target hemoglobin level in up to 21 weeks of therapy. Their data are difficult to analyze since they are only preliminary and presented in abstract form. An obvious explanation for
equally effective. Preliminary data from a double-blind study in pediatric hemodialysis patients also demonstrated the effectiveness of this lower dose.l° In adults, Eschbach et al4 demonstrated the response to rHuEPO to be dose-dependent and predictable above 15 u/kg/ dose. At the highest dose of 500 u/kg, the average hematocrit doubled within four to five weeks. We believe that in children receiving hemodialysis, the rapid response associated with high rHuEPO doses should be avoided to minimize problems with hypertension
this difference is not apparent. While there are no previous reports on maintenance doses of rHuEPO for pediatric hemodialysis patients, our results demonstrate that once the target hematocrit has been reached, rHuEPO in the dose range of 25-75 u/kg given three times per week was effective over a seven-month period to maintain the desired hematocrit. Once the target hematocrit was reached, we arbitrarily chose to decrease the rHuEPO dose. However, this was followed by a decrease in the reticulocyte
none
TabM ’-
~ ~‘
©-i’,>ig ,~/ § ,£l
’
.. ’ ,
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’
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and folt
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
97
count
which
prompted
a
subse-
quent increase to a higher rHuEPO dose. It is possible that the initial rHuEPO dose may not need to be reduced once the target hematocrit is reached. Work is ongoing to determine the optimal route and frequency of rHuEPO administration. Preliminary studies in adult hemodialysis patients comparing subcutaneous and intravenous use have shown conflicting results. Some studies have demonstrated that subcutaneous administration provides faster correction of the anemia at a lower rHuEPO dose.ll,12 Others have found no such advantages. 13,14 There are no similar studies in pediatric hemodialysis patients. We believe that in these patients, rHuEPO given intravenously at the end of dialysis assures compliance with the drug and is a painless and practical route for rHuEPO administration. Correction of the anemia was associated with a subjective increase in appetite and energy level. Others have demonstrated an objective improvement in exercise tolerance after anemia correction with rHuEP0.15 Our patients’ nutritional status also improved as documented by higher TSF and MAMC measurements. The elimination of blood transfusions is a major advantage of rHuEPO therapy for hemodialysis patients who now have a lower risk of exposure to infectious agents and the development of cytotoxic antibodies. Transfusions were uniformly required in all our patients before erythropoietin therapy. Only one patient still receives periodic blood transfusions, though her need has decreased markedly. This patient is a 12-month-old who does not have any evidence of iron deficiency, aluminum toxicity, occult gastrointestinal blood loss, or radiographic evidence of renal os-
98
teodystrophy. Continuously elereticulocyte counts suggest a
vated bone
marrow
response
to
rHuEPO, but the persistence of the anemia could be due to chronic blood loss in the dialyzer. An age-dependent response to rHuEPO has been reported in a preliminary study,&dquo; so it is possible that infants and young children may require higher rHuEPO doses. rHuEPO therapy has some potentially adverse effects. Hypertension is the most common side effect observed in adults on hemodialysis.4,17 Correction of the anemia probably causes a decrease in peripheral dilation and an increase in total peripheral resis-
leading
hypertension. patients in this study (36%) required adjustment tance
to
Four of the eleven
initiation of antihypertensive therapy as the anemia was corrected. Our observations are comparable to the 27% incidence of hypertension noted in the European multicenter study of rHuEPO therapy for children on hemodialor
ysis.’ Hypertensive encephalopain any of our the blood and pressure patients was controlled with a combination of calcium channel blockers and angiotensin converting enzyme inhibitors. Discontinuance of eryth-
thy
did
not occur
ropoietin
therapy
was
not
necessary. Thrombosis of the vascular access has been reported to occur in up to 15% of adults and 10% of children on dialysis treated with rHuEPO.6,lS,19 It has been suggested that vascular thrombosis may be due to increased blood viscosity or that correction of the anemia may shorten the prolonged bleeding time in uremic patients.&dquo;’ In this study, thrombo-occlusion of the graft occurred in one of the eleven patients. As the risk of thrombosis is not defined in pedi-
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
atric hemodialysis patients, the single thrombotic event could have occurred by chance. For the overall group, there was also a tendency toward an increase in the heparin dose during dialysis. Preliminary data by Watkins et als showed in-
creased heparin requirements in one third of their patients. Thus, to minimize the risk of thrombosis in rHuEPO-treated children, it is advisable to monitor the ACT closely and to avoid hypotension and overcorrection of the anemia.
Except for a preliminary report no significant increase in hypertension among pediatric hemodialysis patients receiving
in which
rHuEPO
was
noted,&dquo;
no
con-
trolled study in pediatric patients has evaluated the relationship berHuEPO and hypertension thrombosis. However, a statistically significant increase in hypertension and graft-clotting in the rHuEPO-treated group was found in a randomized, double-blind, multicenter trial involving 118 adult hemodialysis patients.2° Correction of anemia may decrease plasma volume and decrease the dialyzer clearance leading to underdialysis in rHuEPO-treated patients.21 We could not demonstrate any change in urea dialysis efficiency in our population. Similarly, Watkins et als reported no demonstrable change. These observations are consistent with the data that urea clearance is not altered by a change in the hematocrit.22 Ferritin concentrations decreased in all the patients that responded to rHuEPO, and as a corollary, patients with iron overload had a reduction of iron stores associated with erythropoietin therapy. The ferritin concentration failed to decrease in the patient who continued to require periodic blood transfusions. Low ferritin concentrations developed tween or
in five of the
eight patients who adequate baseline iron stores. These changes occurred in the first
Acknowledgments
11.
The authors thank the pediatric nurses of the University of South Florida and Tampa General Hospital for providing care for the patients, and Mrs. Peggy DeSousa for typing the manuscript.
Bensarab A, Vlasses P, Caro J, et al. Subcutaneous administration of recombinant human erythropoietin for treatment of ESRD anemia. Kidney Int.
12.
Muirhead N, Wong C. Erythropoietin for anemia in high risk hemodialysis patients: comparison of IV and SC ad-
had
months of rHuEPO administration when the target hematocrit was being reached. Based on these data, we suggest that unless patients are iron overloaded, they should receive iron supplementation during the initial phase of rHuEPO treatment. In addition, patients who before rHuEPO administration are iron depleted should be started on iron therapy concomitantly with rHuEPO. As iron depletion develops in most children during rHuEPO administration, and oral compliance with iron therapy may be questionable, we recommend that their iron stores be monitored closely. We used ferritin concentrations to assess adequacy of iron stores. However, serum ferritin alone may not be sufficient to guide the need for exogenous iron treatment since infection and inflammatory disease may decrease the release of iron to the circulation. In patients who appear to have adequate iron stores but do not respond to rHuEPO, measurement of serum iron/total iron binding capacity may be more appropriate. In summary, rHuEPO is safe and effective and should be considered as the treatment of choice for anemia in children and adolescents on hemodialysis, as it essentially eliminates the need for periodic blood transfusions. This is accomplished without significant changes in dialysis efficiency or two
dialysis
stores
are
reduced,
most
13.
Meisl F, Mauker W, Loibl V, et al. No therapeutic or economic advantage of erythropoietin application by the subcutaneous route. Int. Kidney
14.
Blank
15.
Montini G, Zacchello
REFERENCES 1.
Fischer JW, Nelson PK, Beckman B, et al. Kidney control of erythropoietin production. In: Dunn MJ, ed. Renal Endocrinology. Baltimore, MD. William and
1990;37:311.
Wilkins; 1983: 142-180. 2.
3.
4.
5.
Immunobiology. 1986;172:213-224. Eschbach JW, Egrie JC, Downing MR, et
N Engl J Med. 1987;316:73-78. Sinai-Trieman L, Salusky IB, Use
6.
Fine RN. recombinant in children un-
of subcutaneous
human
erythropoietin
dergoing continuous cycling peritoneal J Pediatr. 1989;114:550-554. dialysis. Scigalla P. Therapy of renal anemia with rHuEPO in children. First results of
European multicenter study. Kidney Int. 1990;37:244 (abstract). 7.
Gonzalez R, Rajpoot D, Pomerantz et al. Efficacy of recombinant human erythropoietin (EPO) in children with anemia of end Res.
stage renal disease. Pediatr
1990;27:329A (abstract).
8.
Watkins SL, Hickman RO, Avner ED. Dosage and efficacy of erythropoietin in pediatric renal patients. Pediatr Res.
9.
Barth RH,
1990;27:341A (abstract).
10.
Berlyne
GM.
kinetic
M, Bosch JP. rHuEPO route of administration and dosage in hemodialysis. J Am Soc Nephr. 1990;1:395 (abstract).
Shoemaker C, Rudendorf R, et al. Isolation and characterization of genomic and cDNA clones of human erythropoietin. Nature. 1985;313:806810. Egrie JC, Strickland TW, Lane J, et al. Characterization and biological effects of recombinant human erythropoietin.
Jacobs K,
al. Correction of the anemia of endstage renal disease with recombinant human erythropoietin. Results of a combined Phase I and II clinical trial.
patients
will require iron therapy. Our treatment protocol was somewhat arbitrary and alterations based upon subsequent studies may be in order in the future.
J Am Soc Nephr. 1990 ; 1 :404 ministration. (abstract) .
heparin requirements. Hypertension may worsen or develop in some patients within the first two months of treatment. Because iron
1990;37:236 (abstract).
Simplified apmodelling. Kid-
proach
to urea
ney Int.
1988;33:216 (abstract).
Harmon W. Double-blind placebo control study of the use of epoietin alfa (EPO) in pediatric hemodialysis
Jabs K,
patients. J Am Soc Nephr. 1990;1:400 (ab-
G, Baraldi E, et al.
Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodi16.
alysis. J Pediatr. 1990; 117:556-560. Scigalla P. Does recombinant human erythropoietin (rHuEPO) influence the linear growth of children with end stage renal disease? J Am Soc Nephr.
1990; 1:406 (abstract). 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. 1989; 111:992-1000. 18. Nonnast-Daniel B, Creutzig A, Khn K, et al. Effect of treatment with recombinant human erythropoietin on peripheral hemodynamics and oxygenation. Contrib Nephrol. 1988;66:185-194. 19. Weinarts CG, Pippard MJ, Downing MR, Oliver DO, et al. Effects on human erythropoietin derived from recombinant DNA on the anemia of patients maintained by chronic hemodialysis. Lancet. 1986;2:1175-1178. 20. Canadian Erythropoietin Study Group. The clinical effects and side-effects of recombinant human erythropoietin in anemic patients on chronic hemodialysis. Kidney Int. 1990;37:278 (abstract). 21. Shinaberger JH, Miller JH, Gardner PW. Disadvantages and risks of normal hematocrit hemodialysis. Kidney Int. 17.
1989;35:264 (abstract). 22.
Cheung AK, Alford MF, Wilson MM, et al. Urea movement across erythrocyte membrane during artificial kidney treatment. Kidney Int. 1983 ;23 :866-869.
stract) .
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
99
Summary: Eleven anemic children and adolescents with a median age of 14 years (range six months-20 years) on chronic hemodialysis were treated with recombinant human erythropoietin (rHuEPO) intravenously three times a week for an average of 9.2 months. After eight weeks of therapy, hematocrit rose from 20.3 ± 1.4% to 31.7 ± 0.7% (0.20 ± 0.01 to 0.31 ± 0.007, p ~~‘s;~~&dquo;i~~~~La~o~~~·x,:~~a~yaw~~~:a a~y~~~%,~~&dquo;; a&dquo;
>.~az~~r;‘~:E’~%s.>s’,~~.~>,F~aR~~,~%~ ;§.j. $g~._Qt jy~ ;x ,,; ;~ j .;,, ; , ~,Q.=.~, ;§Qj,£jQ,j£;q~.qq§~jjg$ifl§yfl.%Q£; t~,a, ~ ’
^
*
?= : .
.·
1, : g~°,_ _ ~aaa&dquo;
Serum iron and ferritin concentrations and total iron binding capacity were measured monthly. Vitamin B12 and folic acid concentrations were obtained every three months. To assess the adequacy of dialysis, urea kinetic studies according to the method described by Barth’ were performed before rHuEPO therapy, at the time of reaching target hematocrit, and at the end of the follow-up period. The formula Kt/V, where K dia=
lyzer
urea
time, and V
clearance,
t
=
dialysis
distribution volume was used for this purpose. The rHuEPO dose was increased by 25 u/kg if after four to six weeks of therapy the hematocrit had not increased by 4% to 6%. The dose of rHuEPO was decreased by 25 u/kg/dose when the target hematocrit level of 30% to 33% (0.300.33) was reached. At the initiation of rHuEPO therapy, three patients with serum ferritin concentrations < 100 gg/L (< 100 ng/ml) were begun on oral iron therapy (5 mg of elemental iron/kg/day). The use of rHuEPO for patients on hemodialysis had been previously approved by Tampa Gen=
urea
· . , .
, _
,
~~_ ’:%~ ~~~~~~~&dquo;~~ ~ ~.~~k~.ar~r~z.^sTs~:~~~saa; ~~l’i; ]/I_/~jll~~%~ll~/~~~~~~~~~,ii~~~. a
y~~~·’’a~ ~a~~,~s~~:~,T°~, ‘~ ~~3~
~
~;&dquo;
‘
,
r
F~
:° : ~ yaF~>egss,c~x’~aa^~~~~ ~s~~~s~sp~~,‘,^.·3a · ,axa~~~’~’>~s, .
,
~>
~
~’s~s~s;~~~U
~~
~ ~
p~~~tF.~~~~~y4 M’ ~ , r.Y ~~fra.ia ,~,~a
o-
~
:
.
/~
*Results
, are
~~ ,
~,.
xs‘
,.
8~>ic
~~~
..
v
&dquo;
a
’‘ez&dquo;:a., ~&dquo;ay,~a> s ,
...
_
k>aYl~r·,
~~a’‘>‘WoCe~,’s2 -,
,..
t. &dquo;
..
,
j&dquo; ,
given as rr1èa,ns;~ $tan~~{~,’e([br of t
a_
~IiLs7i,t(b,a ial~Lll,dM£t4~ patient who&dquo;did notr-èspond tf
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
95
maintain hematocrit within target range were 47.5 ± 4.49, 36 ± 3.8, and 48.5 ± 6.77 u/kg/dose at
three, six, and nine months of therFigure
1.
rHuEPO
on
Effect
of
reticulocyte count (open circles) and hematocrit (closed circles) levels. Results are expressed as means. Vertical line represents one standard error of the mean.
eral Hospital. All parents were informed regarding the use and potential risks and benefits of this medication.
Statistical analysis was performed one-way analysis of variance, randomized block assignment, and multiple &dquo;t&dquo; tests. Analysis of variand differences between ance
using
means were performed on the logarithms of the measured values.
Results Baseline and follow-up laboratory data are summarized in Table 1. Ten of eleven patients responded to rHuEPO, reaching the target hematocrit between one and two was
months of therapy. This goal achieved at the dose of 62.5 ±
5.6 u/kg/dose (mean ± SEM, range 50-75). Failure to reach the target hematocrit occurred in one infant who has required a gradual increase of rHuEPO every four to six weeks to a current dose of 275
count and hematocrit levels is shown in Figure 1. An increase in the reticulocyte count was seen after one week of rHuEPO with levels peaking in two to three weeks. The increase in reticulocyte
ulocyte
followed by an average hematocrit increase of 3% every two weeks. Upon reaching the target hematocrit, the dose of rHuEPO was decreased in the ten patients who responded to the treatment. To keep the hematocrit within target range, six of these patients required further decreases of the rHuEPO dose in the following three months. However, at six months of therapy, a decrease in the reticulocyte count was observed prompting an increase of the rHuEPO dose. Excluding the only child that did not respond to rHuEPO, the dose requirements to count was
u/kg/dose. This infant is receiving phenobarbital therapy and has no clinical or radiographic evidence of renal osteodystrophy. Although this is the only patient who continues to require periodic blood transfusions, her transfusion
re-
quirements have decreased from 75 ml/kg/month to 10 ml/kg/ month. The effect of rHuEPO
96
on
retic-
2. Effect of rHuEPO onn individual serum ferritin levels.
Figure
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
apy respectively (Table 1). At present, with the exception of the nonresponsive patient, maintenance doses of rHuEPO range from 25-75 u/kg/dose, given three times a week. Ferritin concentrations decreased in ten of eleven patients (Figure 2). Four patients were begun on oral iron therapy (5 mg elemental iron/kg/day) as serum ferritin dropped below 100 gg/L (100 ng/ml) after three months of rHuEPO therapy. Three patients with initially high serum ferritin
concentrations (915-1,275 Jlg/L) also experienced a decrease in their levels. Folate and vitamin B12 levels remained normal in all patients. With correction of the anemia, all patients experienced a subjective increase in appetite and energy level. After three months of rHuEPO therapy, the TSF and MAMC increased by 15% ± 4.2% and 5% ± 1.4%, respectively (mean ± SEM), and thereafter remained
stationary. Administration of rHuEPO no serious immediate adverse side effects. The effects of rHuEPO therapy on mean arterial pressure (MAP), urea kinetics, and heparin requirements during dialysis are shown in Table 2. As a caused
Discussion
group, there were no significant changes in the MAP after three months of therapy. However, two patients whose hypertension had previously been under control required an increase in antihypertensive medication to maintain a blood pressure below the 95th percentile for age. Two other patients were started
antihypertensive therapy
on
as
their blood pressures rose from the 50th and 75th percentile to above the 95th percentile for age. The development or worsening of hypertension occurred within the first two months of rHuEPO
therapy. Antihypertensive regiincluded calcium channel blockers and angiotensin converting enzyme inhibitors. During rHuEPO therapy, no significant changes were noted in urea kinetic modeling paramemens
(Kt/V) or heparin require(Table 2).
ters
ments
One patient’s vascular graft clotted three months after initiation of rHuEPO therapy. This occurred in association with a hematocrit of 34% and the development of hypotension at the end of dialysis.
and seizures. Watkins et als compared the efficacy of 50 to 150 u/kg/dose of rHuEPO. Each treatment group included patients on hemodialysis, peritoneal dialysis, and predialysis in renal failure. Nine patients on hemodialysis received rHuEPO intravenously and all others subcuta-
We conclude from this study that rHuEPO is safe and effective and is recommended as treatment for the anemia of children and adolescents on hemodialysis. Ten of eleven patients responded to the mean dose of 62.5 u/kg three times a week, reaching the target hematocrit within two months. While similar hemoglobin levels have been achieved in children on hemodialysis with higher rHuEPO dosages (97 ± 3, 100, and 150 u/kg/ dose) ,6-S our data clearly demonstrate that a lower dose is
neously. Contrary to our findings, of their patients on 50 u/kg/dose reached the target hemoglobin level in up to 21 weeks of therapy. Their data are difficult to analyze since they are only preliminary and presented in abstract form. An obvious explanation for
equally effective. Preliminary data from a double-blind study in pediatric hemodialysis patients also demonstrated the effectiveness of this lower dose.l° In adults, Eschbach et al4 demonstrated the response to rHuEPO to be dose-dependent and predictable above 15 u/kg/ dose. At the highest dose of 500 u/kg, the average hematocrit doubled within four to five weeks. We believe that in children receiving hemodialysis, the rapid response associated with high rHuEPO doses should be avoided to minimize problems with hypertension
this difference is not apparent. While there are no previous reports on maintenance doses of rHuEPO for pediatric hemodialysis patients, our results demonstrate that once the target hematocrit has been reached, rHuEPO in the dose range of 25-75 u/kg given three times per week was effective over a seven-month period to maintain the desired hematocrit. Once the target hematocrit was reached, we arbitrarily chose to decrease the rHuEPO dose. However, this was followed by a decrease in the reticulocyte
none
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97
count
which
prompted
a
subse-
quent increase to a higher rHuEPO dose. It is possible that the initial rHuEPO dose may not need to be reduced once the target hematocrit is reached. Work is ongoing to determine the optimal route and frequency of rHuEPO administration. Preliminary studies in adult hemodialysis patients comparing subcutaneous and intravenous use have shown conflicting results. Some studies have demonstrated that subcutaneous administration provides faster correction of the anemia at a lower rHuEPO dose.ll,12 Others have found no such advantages. 13,14 There are no similar studies in pediatric hemodialysis patients. We believe that in these patients, rHuEPO given intravenously at the end of dialysis assures compliance with the drug and is a painless and practical route for rHuEPO administration. Correction of the anemia was associated with a subjective increase in appetite and energy level. Others have demonstrated an objective improvement in exercise tolerance after anemia correction with rHuEP0.15 Our patients’ nutritional status also improved as documented by higher TSF and MAMC measurements. The elimination of blood transfusions is a major advantage of rHuEPO therapy for hemodialysis patients who now have a lower risk of exposure to infectious agents and the development of cytotoxic antibodies. Transfusions were uniformly required in all our patients before erythropoietin therapy. Only one patient still receives periodic blood transfusions, though her need has decreased markedly. This patient is a 12-month-old who does not have any evidence of iron deficiency, aluminum toxicity, occult gastrointestinal blood loss, or radiographic evidence of renal os-
98
teodystrophy. Continuously elereticulocyte counts suggest a
vated bone
marrow
response
to
rHuEPO, but the persistence of the anemia could be due to chronic blood loss in the dialyzer. An age-dependent response to rHuEPO has been reported in a preliminary study,&dquo; so it is possible that infants and young children may require higher rHuEPO doses. rHuEPO therapy has some potentially adverse effects. Hypertension is the most common side effect observed in adults on hemodialysis.4,17 Correction of the anemia probably causes a decrease in peripheral dilation and an increase in total peripheral resis-
leading
hypertension. patients in this study (36%) required adjustment tance
to
Four of the eleven
initiation of antihypertensive therapy as the anemia was corrected. Our observations are comparable to the 27% incidence of hypertension noted in the European multicenter study of rHuEPO therapy for children on hemodialor
ysis.’ Hypertensive encephalopain any of our the blood and pressure patients was controlled with a combination of calcium channel blockers and angiotensin converting enzyme inhibitors. Discontinuance of eryth-
thy
did
not occur
ropoietin
therapy
was
not
necessary. Thrombosis of the vascular access has been reported to occur in up to 15% of adults and 10% of children on dialysis treated with rHuEPO.6,lS,19 It has been suggested that vascular thrombosis may be due to increased blood viscosity or that correction of the anemia may shorten the prolonged bleeding time in uremic patients.&dquo;’ In this study, thrombo-occlusion of the graft occurred in one of the eleven patients. As the risk of thrombosis is not defined in pedi-
Downloaded from cpj.sagepub.com at The University of Iowa Libraries on June 27, 2015
atric hemodialysis patients, the single thrombotic event could have occurred by chance. For the overall group, there was also a tendency toward an increase in the heparin dose during dialysis. Preliminary data by Watkins et als showed in-
creased heparin requirements in one third of their patients. Thus, to minimize the risk of thrombosis in rHuEPO-treated children, it is advisable to monitor the ACT closely and to avoid hypotension and overcorrection of the anemia.
Except for a preliminary report no significant increase in hypertension among pediatric hemodialysis patients receiving
in which
rHuEPO
was
noted,&dquo;
no
con-
trolled study in pediatric patients has evaluated the relationship berHuEPO and hypertension thrombosis. However, a statistically significant increase in hypertension and graft-clotting in the rHuEPO-treated group was found in a randomized, double-blind, multicenter trial involving 118 adult hemodialysis patients.2° Correction of anemia may decrease plasma volume and decrease the dialyzer clearance leading to underdialysis in rHuEPO-treated patients.21 We could not demonstrate any change in urea dialysis efficiency in our population. Similarly, Watkins et als reported no demonstrable change. These observations are consistent with the data that urea clearance is not altered by a change in the hematocrit.22 Ferritin concentrations decreased in all the patients that responded to rHuEPO, and as a corollary, patients with iron overload had a reduction of iron stores associated with erythropoietin therapy. The ferritin concentration failed to decrease in the patient who continued to require periodic blood transfusions. Low ferritin concentrations developed tween or
in five of the
eight patients who adequate baseline iron stores. These changes occurred in the first
Acknowledgments
11.
The authors thank the pediatric nurses of the University of South Florida and Tampa General Hospital for providing care for the patients, and Mrs. Peggy DeSousa for typing the manuscript.
Bensarab A, Vlasses P, Caro J, et al. Subcutaneous administration of recombinant human erythropoietin for treatment of ESRD anemia. Kidney Int.
12.
Muirhead N, Wong C. Erythropoietin for anemia in high risk hemodialysis patients: comparison of IV and SC ad-
had
months of rHuEPO administration when the target hematocrit was being reached. Based on these data, we suggest that unless patients are iron overloaded, they should receive iron supplementation during the initial phase of rHuEPO treatment. In addition, patients who before rHuEPO administration are iron depleted should be started on iron therapy concomitantly with rHuEPO. As iron depletion develops in most children during rHuEPO administration, and oral compliance with iron therapy may be questionable, we recommend that their iron stores be monitored closely. We used ferritin concentrations to assess adequacy of iron stores. However, serum ferritin alone may not be sufficient to guide the need for exogenous iron treatment since infection and inflammatory disease may decrease the release of iron to the circulation. In patients who appear to have adequate iron stores but do not respond to rHuEPO, measurement of serum iron/total iron binding capacity may be more appropriate. In summary, rHuEPO is safe and effective and should be considered as the treatment of choice for anemia in children and adolescents on hemodialysis, as it essentially eliminates the need for periodic blood transfusions. This is accomplished without significant changes in dialysis efficiency or two
dialysis
stores
are
reduced,
most
13.
Meisl F, Mauker W, Loibl V, et al. No therapeutic or economic advantage of erythropoietin application by the subcutaneous route. Int. Kidney
14.
Blank
15.
Montini G, Zacchello
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