J Am Soc Nephrol 13: 1412–1414, 2002
Anemia Management in Chronic Kidney Disease: Role of
Factors Affecting Epoetin Responsiveness
JOSEPH W. ESCHBACH
Minor & James Medical, Seattle, Washington.
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
The article by Coladonato et al., “Trends in Anemia Management
among US Hemodialysis Patients,” (1) notes an encouraging
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/15/2023
increase in mean hematocrit levels from 31.1% to 34.1% between
1994 and 1998, an increase into the target range (33 to 36%)
recommended by the 1997 and 2000 DOQI Anemia Work Groups
of the National Kidney Foundation (2,3). On the other hand, the
authors claim in this analysis of up to 7660 hemodialysis patients
that this rise in hematocrit was associated with a disproportionate
increase in recombinant erythropoietin (epoetin) dosing, suggest-
ing that there were factors blunting the response to epoetin. The
implication of the authors is that American nephrologists are not
using epoetin in an effective and optimal manner.
Part of their analysis is based on an imprecise understanding of
the action of epoetin, and part of their analysis is relevant, but their
translation of this information into improved therapy is less clear.
In the thirteen years since the US Food and Drug Administra-
tion approved epoetin for clinical use, the mean hematocrit of
ESRD patients has gradually increased from ⬍30% to ⬎34%.
The achievement of these favorable results has required increasing
amounts of epoetin (1,4). On the one hand, there is a biologic need
for more hormone to attain higher hematocrit levels; on the other
hand, there are factors that can blunt the response to epoetin and
therefore increase epoetin usage.
Coladonato et al. (1) noted that a 17.2% increase in epoetin
dose was needed to increase the hematocrit 9.7% from 31.1%
to 34.1%. The authors consider this a disproportionate increase
in epoetin and attempt to verify this by using a nonphysiologic
term, “EPO Resistant Index”. The ERI is defined as the aver-
age weekly dose of epoetin divided by the mean hematocrit.
Because the ERI increased in association with the increased
hematocrit, the authors assume that there are nonbiologic fac-
tors to explain the increased epoetin requirements. The reason
this is not a physiologic term is that at least three studies have
shown that it requires approximately two times the dose of
epoetin to increase the hematocrit of 30 to 33% to 40 to 42%
(5–7). If the ERI were physiologic, doubling the epoetin dose
should result in a hematocrit of 60%!
There is a broad range of response to epoetin, both in ESRD
and normal subjects (8). Although there is a dose response
“curve” with epoetin (9), there is also a wide individual range of
Correspondence to Dr. Joseph W. Eschbach, Minor & James Medical, 515
Minor Ave., Seattle, WA 98104. Phone: 206-386-9500; Fax: 206-389-9605;
E-mail: jweschbach@aol.com
1046-6673/1305-1412
Journal of the American Society of Nephrology
Copyright © 2002 by the American Society of Nephrology
DOI: 10.1097/01.ASN.0000016440.52271.F7
response to a fixed dose of epoetin (10). In the first US multicenter
study of iron-replete hemodialysis patients, 15 U/kg to ⱖ150 U/kg
of intravenous epoetin three times a week were needed to maintain a
hematocrit of 32 to 38%. This variable response was also noted in
clinical trials with epoetin in which the percent of patients reaching
target hematocrit was a function of the starting dose of epoetin (11).
Only 25% of patients reached target with 25 U/kg three times a week
versus 96% treated with ⱖ150 U/kg three times a week. The increase
in epoetin dosage was logarithmic, not linear, to achieve these results.
Nevertheless, despite the nonlinear and biologically variable
responses to either native or exogenous erythropoietin, Colado-
nato et al. (1) have defined variable factors that influence epoetin
responsiveness and its associated hematocrit response. Male gen-
der, more years on dialysis, older age, higher urea reduction ratio
(URR) and transferrin saturation, use of intravenous iron, and
lower serum ferritin were noted to be favorably associated with
higher hematocrit levels. It was also noted that those patients
achieving higher hematocrit values tended to require less epoetin.
In addition, increasing weight, URR, and transferrin saturation,
male gender, diabetes mellitus, and older age were associated with
significantly lower epoetin doses. Although some of these vari-
ables may be biologic, others can influence the management of
anemia in ESRD patients, such as iron deficiency.
Patients with hematocrit levels ⬎33% required less epoetin.
However, the data depict only the converse: higher doses of
epoetin were required below a hematocrit of 33%, with no further
decrease in epoetin requirements at hematocrit levels ⬎33%.
There may be several explanations for this observation. Patients
with lower hematocrit levels often have been infected or have had
surgery, leading to an inflammatory block and therefore epoetin
hyporesponsiveness. Nephrologists are evidently using more epo-
etin to try to improve the hematocrit in this setting. On the other
hand, absolute or functional iron deficiency may also be contrib-
uting to this “extra” use of epoetin. In Coladonato et al. (1), ⬍60%
of patients were getting intravenous iron if their transferrin satu-
ration (Tsat) was ⬍20%. As a result, 6 to 8.5% of patients had
absolute iron deficiency (Tsat, ⬍20%; serum ferritin, ⬍100 ng/
ml); 40 to 50% of those with hematocrit values ⬍33% had either
functional iron deficiency and/or inflammation, because they had
Tsat values of ⬍20% in association with normal serum ferritin levels.
Unfortunately, the authors neither discuss functional iron deficiency,
a condition that will occur in every epoetin-treated patient unless
adequate iron reserves are maintained and/or replenished with intra-
venous iron, nor do they attempt to separate inflammatory block from
functional iron deficiency. This is important because intravenous iron
is needed for the latter and is not effective in the former condition.
More of the patients with hematocrit values ⬎33% were re-
ceiving intravenous iron than patients with lower values. Unfor-
 J Am Soc Nephrol 13: 1412–1414, 2002
tunately, the use of intravenous iron continues to be controversial;
therefore, many patients are denied adequate iron stores to meet
the need for optimal epoetin-induced erythropoiesis. When the
only intravenous iron preparation available for use in the United
States was iron dextran, the 1:150 occurrence of anaphylaxis
restricted its use. There are now two safer forms of intravenous
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
iron available: iron gluconate and iron sucrose, which are not
associated with dextran-induced anaphylaxis and which should
increase the use of intravenous iron. Like any intravenous product,
iron must be given for specific indications and iron status must be
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/15/2023
monitored regularly. In Seattle, the DOQI guidelines for intrave-
nous iron administration have been followed for the past 5 yr (2).
Tsat and serum ferritin are measured every 3 mo, and intravenous
iron is not given if the Tsat or the serum ferritin exceed 50% or
800 ng/ml, respectively. Five percent of patients transiently ex-
ceed these limits. The mean Tsat and serum ferritin levels were 30
⫾ 13% and 389 ⫾ 307 ng/ml, respectively, in June 2001, asso-
ciated with a hematocrit of 35.9 ⫾ 3.7% and an epoetin dose of
193 ⫾ 245 U/kg per wk for 988 patients (12). This indicated that
by maintaining adequate iron stores by weekly intravenous iron
doses of 15 to 125 mg of iron gluconate the mean hematocrit was
greater and was achieved with less epoetin than that reported by
Coladonato et al. (1) for 1998. Higher hematocrits can only be
achieved without inappropriately higher epoetin doses if iron
replacement is given on a regular basis (i.e., weekly or biweekly)
to replace the repetitive dialyzer blood losses and to prevent
functional iron deficiency. The observation by Coladonato et al.
(1) that the use of intravenous iron was inversely proportional to
the hematocrit and directly proportional to the epoetin dose con-
flicts with their later statement that intravenous iron use is associated
with higher epoetin doses and higher hematocrit levels. More epoetin
is needed to achieve higher hematocrit levels, and more iron will also
be needed, but it is unlikely that the extra iron will prevent the need
for more epoetin. More iron will be needed to maintain a higher
hematocrit because iron losses from whole blood dialyzer residual
increases as a function of more red blood cells in that residual.
The observation that heavier patients require less epoetin to
Figure 1. Distribution of normal hemoglobin values for healthy men and women with superimposed recommended target hemoglobin level for
patients with chronic kidney disease. Adapted by A. Besarab with permission from reference 21.
Anemia Management in CKD 1413
achieve similar hematocrit levels as occurs with less heavy pa-
tients is intriguing. This also applies to Seattle dialysis patients
(12). Either more epoetin is given to less heavy patients to attain
the target hematocrit or heavier patients are more sensitive to the
effect of epoetin. However, improving nutrition and increasing the
weight of obviously undernourished patients should help reduce
epoetin requirements. It is unfortunate that the authors purposely
did not analyze serum albumin levels and its relationship to the
other variables analyzed. They correctly note that a low serum
albumin has a strong association with higher epoetin doses. How-
ever, the relationship among weight, gender, albumin levels, nu-
trition, and epoetin responsiveness is not clear. In Seattle, as also
reported by Coladonato et al. (1), men required less epoetin than
women, but men also had significantly higher serum albumin (bcp
method) levels. Serum albumin levels also decreased in both
genders as epoetin doses increased (12). The decrease in albumin
levels as a function of increasing epoetin doses could be the result
of inflammation/malnutrition, or it could be biological, but the
lower albumin levels observed in women compared with men is
unlikely to be solely the result of inflammation or malnutrition.
Older age and longer duration of dialysis were noted to be
associated with higher hematocrit and/or better epoetin respon-
siveness. Before the availability of epoetin, it had been observed
that patients over time had a tendency to increase their hematocrit
(13). Whether this was the result of more native erythropoietin
secretion from the liver and/or remnant kidneys or the result of the
presence of other erythroid growth factors, such as insulin-like
growth factor-1 (14), is not known. Epoetin-treated ESRD pa-
tients occasionally develop normal hematocrit levels and no
longer require epoetin therapy, confirming that native erythropoi-
esis may improve with time in some patients.
Only 12% of patients received their epoetin subcutaneously.
Those patients required 11% less epoetin to maintain the same
hematocrit as achieved with intravenous dosing. It has been
known for over 12 yr that epoetin given subcutaneously is more
effective for the majority of patients than if given intravenously.
The cost implications of this are significant. If an additional 12%
 1414 Journal of the American Society of Nephrology
of patients were to use epoetin subcutaneously, this would amount
to a savings of ⬎$110,000,000 on the basis of the one billion
dollar expenditure for epoetin in 1999 (15). Unfortunately, there is
a negative cost incentive to reduce the amount of epoetin admin-
istered because dialysis centers rely on the “profits” achieved
from Medicare-reimbursed payments. Ideally, every patient re-
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
ceiving an erythropoietin preparation before beginning dialysis
should continue with subcutaneous injections.
One encouraging observation from Coladonato et al. (1) is
that the percent of patients achieving hematocrit levels ⬎36%
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/15/2023
has increased from ⬍10% to ⬎30% between 1994 and 1998.
Nephrologists are realizing that patients not only feel better at
these closer-to-normal levels, but there have been no signifi-
cant side effects with this improved hematologic state. In view
of the increasing number of studies now showing even superior
functional, survival, and quality-of-life status at a normal he-
matocrit, (16 –20), the day will come when governmental re-
imbursement mechanisms will allow our patients with chronic
kidney disease to enjoy the same hematocrit/hemoglobin val-
ues as normal subjects, adjusted for gender, as seen in Figure
1. It is inevitable that more epoetin will be needed to achieve
this goal, but it is imperative that every effort be made to
optimize the effectiveness of epoetin to minimize its cost
burden. Maintaining optimal iron balance, improving nutrition,
which includes optimal dialysis, minimizing the chances for
infection (e.g., avoiding central catheters), and administering
the hormone subcutaneously will all help to achieve this goal.
References
1. Coladonato JA, Frankenfield DL, Reddan D, Klassen P, Szczech L,
Johnson CA, Owen Jr WF: Trends in anemia management among U.S.
hemodialysis patients. J Amer Soc Nephrol 13: 1288-1295, 2002
2. NKF-DOQI: Clinical Practice Guidelines for the Treatment of
Anemia of Chronic Renal Failure. New York, National Kidney
Foundation, 1997, pp 29-47
3. NKF-K/DOQI: Clinical Practice Guidelines for the Treatment of
Anemia of Chronic Kidney Disease. New York, National Kidney
Foundation, 2001, pp 33-49
4. Cotter DJ, Thamer M, Kimmel PL, Sadler JH: Secular trends in
recombinant erythropoietin therapy among the U.S. hemodialysis
population: 1990 –1996. Kidney Int 54: 2129 –2139, 1998
5. Eschbach JW, Glenny R, Robertson T, Guthrie M, Rader B, Evans R,
Chandler W, Easterling T, Denney J, Schneider G: Normalizing the
Hematocrit (Hct) in hemodialysis patients (HDP) with Epo improves
quality of life (q/l) and is safe. J Am Soc Nephrol 4: 425, 1993
6. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Oka-
moto DM, Schwab SJ, Goodkin DA: The effects of normal versus low
treated hematocrit values in hemodialysis patients with cardiac disease
with erythropoietin. N Engl J Med. 339: 584–590, 1998
7. Foley RN, Parfrey PS, Morgan J, Barre PE, Campbell P, Cartier P,
Coyle D, Fine A, Handa P, Kingma I, Lau CY, Levin A, Men-
delssohn D, Muirhead N, Murphy B, Plante RK, Posen G, Wells
GA: Effect of hemoglobin levels in hemodialysis patients with
asympotomatic cardiomyopathy. Kidney Int 58: 1325–1335, 2000
8. Eschbach JW, Haley NR, Egrie JC, Adamson JW: A comparison
of the responses to recombinant human erythropoietin in normal
and uremic subjects. Kidney Int 43: 407– 416, 1992
See related article, “Trends in Anemia Management among U.S. Hemodialysis Patients,” on pages 1288 –1295.
J Am Soc Nephrol 13: 1412–1414, 2002
9. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson
JW: Correction of the anemia of end-stage renal disease with
recombinant human erythropoietin: Results of a combined phase
I and II clinical trial. N Engl J Med 316: 73–78, 1987
10. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing
MR, Egrie JC, Evans RW, Friedman EA, Graber SE, Haley NR,
Korbet S, Krantz SB, Lundin AP, Nissenson AR, Ogden DA,
Paganini EP, Rader B, Rutsky EA, Stivelman J, Stone WJ, Teschan
P, Van Stone JC, Van Wyck DB, Zuckerman K, Adamson JW:
Recombinant human erythropoietin in anemic patients with end-
stage renal disease. Ann Intern Med 111: 992–1000, 1989
11. Eschbach JW, Adamson JW: Anemia in renal disease. In: Dis-
eases of the Kidney, 5th ed., edited by Schrier RW, Gottschalk
CW, Boston, Little Brown and Company. 1993, pp 2743–2758
12. Eschbach JW, Varma A, Stivelman JC: Is it time for a paradigm
shift? Is erythropoetin deficiency still the main cause of renal
anaemia? Nephrol Dial Transplant 2002, in press
13. Eschbach JW, Adamson JW, Cook JD: Disorders of red blood
cell production in uremia. Arch Int Med 170; 126: 812– 815
14. Brox AG, Zhang F, Guyda H, Gagnon RF: Subtherapeutic eryth-
ropoietin and insulin-like growth fator-1 correct the anemia of
chronic renal failure in the mouse. Kidney Int 50: 937–943, 1996
15. Collins AJ, Kasiske B, Herzog C, Chen S-C, Everson S, Constantini
E, Grimm R, McBean M, Xue J, Chavers B, Keane W, Matas A,
Manning W, Louis T, Ma J, Pan W, Liu J, Li S, Roberts T, Dalleska
F, Snyder J, Ebben J, Frazier E, Sheets D, Johnson R, Li S, Dunning
S, Gilbertson D, St. Peter W, Frederick P, Eggers P, Agodoa W:
Excerpts from the United States Renal Data System 2001 Annual
Data Report: Atlas of end-stage renal disease in the United States.
Am J Kidney Dis 38[Suppl 3]: S183, 2001
16. Collins AJ, Li S, St. Peter W, Ebben J, Roberts TG, Ma JZ,
Manning W: Death, hospitalization, and economic associations
among incident hemodialysis patients with hematocrit values of
36 to 39%: J Am So Nephrol 12: 2465–2473, 2001
17. McMahon LP, McKenna MJ, Sangkabutra T, Mason K, Sostaric
S, Skiknner SL, Burge C, Murphy B, Crankshaw D: Physical
performance and associated electrolyte changes after haemoglo-
bin normalization: A comparative study in haemodialysis pa-
tients. Nephrol Dial Transplant 14: 1182–1187, 1999
18. Pickett JL, Theberge DC, Brown WS, Schweitzer SU, Nissenson
AR: Normalizaing hematocrit in dialysis patients improves brain
function. Am J Kidney Dis 33: 1122–1130, 1999
19. Benz RL, Pressman MR, Hovick ET, Peterson DD: A prelimi-
nary study on the effects of correction of anemia with recombi-
nant human erythropoietin therapy on sleep, sleep disorders, and
daytime sleepiness in hemodialhysis patients (the SLEEPO
study). Am J Kidney Dis 34: 1089 –1095, 1999
20. Hayashi T, Suzuki A, Shoji T, Togawa M, Okada N, Tsubakihara
Y, Imai E, Hori M: Cardiovascular effect of normalizing the
hematocrit level during erythropoietin therapy in predialysis pa-
tients with chronic renal failure. Am J Kidney Dis 35: 250 –256,
2000
21. Dallman PR, Looker AC, Johnson CL, Carroll M: Influence of
age on laboratory criteria for the diagnosis of iron deficiency
anemia and iron deficiency in infants and children. In: Iron
Nutrition in Health and Diseases, edited by L Hallberg, Asp
N-G, London, John Libbey & Co., 1996, pp 65–74