ERYTHROPOIETIN 0889-8588/94 $0.00 + .

20

OF
RECOMBINANT
ERYTHROPOIETIN IN RENAL
DIALYSIS PATIENTS
Luis F. Gimenez, MD, and Paul J. Scheel, MD

The advent of erythropoietin (EPO) can be considered one of the

major advances over the past 10 years in the treatment of end-stage renal
disease (ESRD) patients who are receiving chronic maintenance dialysis.
Not only has it resulted in freedom from transfusion dependency and
elimination of the attendant risks, but also it has led to a significant
improvement in the quality of life these patients are able to achieve
within the physical and emotional limitations imposed by the multiple
metabolic abnormalities, concomitant medical problems of ESRD, and
the dialysis process itself.
In the pre-EPO era, the management of anemia in dialysis patients
was essentially palliative and consisted of periodic provision of blood
transfusions, avoidance of iron and folate deficiency, prevention of alu-
minum overload, correction of severe hyperparathyroidism, and use of
androgens. These strategies, however, afforded only limited and usually
transient success in ameliorating anemia, and androgenic therapy was
associated with substantial side effects (hyperlipidemia, acne, hirsutism,
voice changes, and so on).

EPO PHYSIOLOGY

EPO is a 165-amino-acid glycoprotein with a molecular weight of

30,400 daltons that is produced mainly by the kidney of adult mammals
(90%)44 and to a lesser extent (10%) by the liver. 29

From the Department of Medicine, Division of Nephrology, The Johns HoplGns University
School of Medicine (LFG, PJS); The Good Samaritan Hospital (LFG); and The Johns
Hopkins Hospital (LFG, PJS), Baltimore, Maryland

HEMATOLOGY /ONCOLOGY CLINICS OF NORTH AMERICA

VOLUME 8 • NUMBER 5 • OCTOBER 1994 913

914 GIMENEZ & SCHEEL

The precise site of production within the kidney has been identified
as the peritubular interstitial cells. 4s The principal stimulus for erythro-
poietin production is a decrease in oxygen delivery to these sites, which
occurs during states of anemia or hypoxemia. 20
The precise intracellular mechanisms whereby the EPO gene is stim-
ulated have been recently described. 4, 32 Once secreted, this hormone
stimulates bone marrow erythroid cells to develop into mature red cells?9
The end result of this process is a vigorous and early reticulocytosis that
occurs within a week of initiating therapy, leading eventually to an
increase in hemoglobin and hematocrit in a dose-dependent manner.
Purification of EPO was first reported in 1977.61 Through the use of
recombinant DNA technology,43 human erythropoietin was made avail-
able in vast quantities,19 allowing the conduction of animal and human
trials21 that culminated with FDA approval for use in dialysis patients by
June 1989.
It has been estimated that approximately 75% of the US hemodi-
alysis population are potential candidates for the use of EPO. 2s It has also
been shown that almost all (more than 95%) hemodialysis patients re-
spond to the hormone and are able to achieve a target hematocrit of 35%
within the first 12 weeks of treatment. 23

EPOTHERAPY

When a dose of 100 U /kg is administered intravenously to hemodi-

alysis patients at the end of dialysis, peak concentrations of 1000 to 2000
mU/mL are achieved, which drop rapidly over the next 1V2 to 2 days
with a half-life of 5 to 8 hours40 (Fig. 1). Although it is usually recom-
mended that EPO be given during the last 5 minutes of dialysis, we have
found no difference if it is given at the beginning (unpublished observa-
tions). It has been also shown that EPO is not dialyzable. IS
The median dose of EPO required to maintain a target hematocrit of
33% to 38% is 75 U /kg intravenously three times a week. However, 17%
of the patients will require more than 150 U /kg intravenously three
times weekly.23 The most likely explanation for this variability in dosing
required to attain the target hematocrit is the fact that there is more than
a 10-fold variation in steady-state plasma EPO levels at any given level
of anemia in ESRD patients. 31
Thus, based on this information, the most sensible approach is to
begin with a dose of 75 to 100 U /kg intravenously three times a week,
making the necessary adjustments every 2 to 6 weeks if the rise in
hematocrit is steady and not greater than 1% to 2% per week. If the rate
of increase exceeds this value, the dose should be decreased by 25%.
Conversely, if there is no response, the dose should be increased by 25%.
Dosage changes more frequently than every 4 weeks are not recom-
mended, because changes in effectiveness cannot be assessed over a
shorter time. The goal should be to achieve a target hematocrit by 10 to
12 weeks of therapy.23
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS P ATlENTS 915

5000

IIIIntravenous
1000 o Subcutaneous
fllntraperitoneal

500
E
:J
g
o0..
W
100

50

10

a 25 50 75
Time (hours)

Figure 1. Single-dose kinetics of rhEPO after IV, SC, and IP administration. Mean plasma
concentration-time curves after IV, SC (group I) or IP (group II) rHuEPO administration.

There is no consensus as to the optimal hematocrit level to be

achieved, because the oxygen demands are different for each patient,
especially if age and level of physical activity are considered. Although
several studies have shown improvement in quality of life,59 cardiovas-
cular status,33.88 and cognitive fundion65 at hematocrits of 30% to 32%,
whether higher hematocrits will further enhance the beneficial effects
without the undue risk of side effects remains to be seen.
It is important to ensure that, before initiating therapy, the patient
has adequate iron stores, is not losing blood surreptitiously (from the GI
tract), is free of infection or tumor, and that the blood pressure is well
controlled on a stable drug
EPO is sold in the States in vials 2000, 3000, 5000,
and 10,000 units vial. Each vial contains the drug prepared in a
sterile buffered to which serum albumin (0.25%) has been added
in an attempt to minimize to plastic dialysis

involves not
916 GIMENEZ & SCHEEL

Blood pressure readings are done with every dialysis treatment; a

complete blood cell count should be requested on a weekly basis until
the target hematocrit is reached and thereafter (maintenance phase) it is
monitored twice a month. Iron profiles should be checked on a monthly
basis until the hematocrit reaches target, and during the maintenance
phase every 3 months unless there is evidence of evolving iron defi-
ciency. If this occurs, a thorough investigation should be done to find
and correct the cause, adjusting the iron replacement therapy using the
intravenous route if necessary. This is not only good medical practice
but also cost-effective, because it prevents the waste of EPO incurred
when used in patients whose iron stores are inadequate to support an
effective and sustained erythropoietic response.
Finally, because the adequacy of dialysis may be altered during EPO
therapy by either lack of compliance with diet (improved appetite)52 or
changes in solute clearance related to a higher plasma viscosity/8 blood
urea nitrogen, creatinine, potassium, and/or urea kinetics should be
closely monitored to make the necessary adjustments to the dialysis
prescription.

Factors Affecting Uremia in Dialysis Patients

The etiology of anemia in chronic dialysis patients is multifactorial,

with erythropoietin lack playing a major role, but additional factors are
also important. These include hemolysis, either acute (as in systemic
lupus erythematosus, sickle cell disease, vasculitis) or chronic (as in
hypersplenism, uremic toxins); iron deficiency related to chronic blood
loss associated with the dialysis procedure50 or occult gastrointestinal
blood 10ss74; osteitis fibrosa cystica secondary to severe hyperparathy-
roidism; folate deficiency due to loss of this water-soluble vitamin
through the dialyzer, compounded by inadequate oral intake due to
restricted intake of folate-rich foods; infection; aluminum overload that
is toxic to erythroid function; and the presence of uremic inhibitors of
erythropoiesis (Table 1).

Use of EPO in Peritoneal Dialysis

Patients on maintenance peritoneal dialysis in either of its two most

used modalities (continuous ambulatory peritoneal dialysis or continu-

Table 1. ANEMIA IN DIALYSIS PATIENTS

EPO deficiency Blood loss
Hemolysis Folate deficiency
acute Osteitis fibrosa cystica
chronic Infection
Iron deficiency Aluminum overload
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS PATIENTS

hematocrit than do
the need for
these
and benefits as do their
treated with EPa. the
subcutaneous route
dialysis
achieve the same response as patients?O The
likely reasons for this difference include the fact that patients on contin-
uous dialysis, unlike hemodialysis patients, are
not subjected to blood loss with the dialysis treatment itself, and
also that the kinetics of EPa clearance when it is administered
subcutaneously differ from the with intravenous administration.
Although the peak plasma concentration following subcutaneous
administration is only 10% of that achieved when given intravenously,
the increase is gradual, taking 12 to 24 hours to peak.
plasma levels remain at 36 hours and stay higher than following
intravenous delivery for up to 72 hours owing to slow continuous ab-
sorption from the subcutaneous site. 40 The intraperitoneal route
has also been studied but has been shown to be less effective than the
subcutaneous or intravenous routes. 57

Resistance to EPO

The multifactorial etiology of the anemia in dialysis patients should

alert the clinician to look for other contributing factors (Table 2) that
could explain why a patient may fail to respond initially or why a
who is initially responsive later develops "resistance" to the drug.
The most frequent cause of resistance is iron deficiency, which can
be related to either lack of compliance with oral supplements or occult
blood loss, usually through the gastrointestinal tract but also through the
extracorporeal dialysis circuit with each treatment. 50 Patients treated con-
comitantly with chelating agents such as deferoxamine for aluminum
overload will suffer a rapid depletion of iron as well.1
Clinical parameters that are useful in monitoring iron stores nonin-
vasively are the serum ferritin level (which should be greater than 100
mg/mL) and transferrin which is a measure of the amount of

Table 2. ERYTHROPOIETIN RESISTANCE

Iron deficiency Infection
dietary noncompliance Chronic inflammatory processes
blood loss Hemolysis
concomitant cheialing therapy Inadequate EPO dosing
Severe hyperparathyroidism Splenomegaly
Aluminum overload Thalassemia trait
918 GIMENEZ & SCHEEL

iron being delivered to the reticuloendothelial system for utilization and

should be greater than 20%.21
The presence of microcytosis, although suggestive of iron deficiency,
is not diagnostically selective in the dialysis population because micro-
cytosis can be seen in aluminum toxicity.83
It is important to recognize that the absorption of oral iron supple-
ments is decreased if they are taken with phosphate binders or antacids. 36
Severe hyperparathyroidism may affect hematopoiesis by two mech-
anisms: direct inhibition by parathyroid hormone6o and replacement of
bone marrow tissue by fibrosis. 72 Correction of hyperparathyroidism has
been associated with an improved erythropoietic response. 3
As discussed earlier, aluminum overburden is manifested by micro-
cytosis on peripheral smear and also by resistance to EPO. This probably
occurs by enzymatic interference with heme synthesis58 or by impaired
iron utilization.86
After iron deficiency, infections and inflammation constitute the se-
cond most common cause of EPO failure. 22 Infection interferes with the
transfer of iron from the reticuloendothelial system to transferrin,13 and
thus with an effective hematopoietic response to EPO. This should al-
ways be remembered when assessing patients who are "resistant" to the
drug, because it may be the first clinical manifestation of ongoing occult
infection.62,80 Also, chronic inflammatory processes such as connective
tissue disorders are associated with hyporesponsiveness to EPO. 38
Hemolysis should be considered whenever a patient has clinical
evidence of ongoing, underlying illnesses such as active systemic lupus
erythematosus, vasculitis, sickle cell anemia, and glucose-6-phosphate
dehydrogenase deficiency. Rarely, hemolysis can occur due to inade-
quate water treatment within the dialysis unit leading to contamination
of the dialysate with copper53 or chloramines.64 Dialysis equipment mal-
function, such as an overheating of dialysate/ hypertonic dialysate, or
kinking of the dialysis tubing, can also produce acute severe hemolysis. 56
Finally, inadequate EPO dosing should always be considered after
the preceding causes have been excluded.

Side Effects of EPO

Although side effects have been reported with the use of EPO (Table
3), these rarely lead to discontinuation of the therapy, with an overall
discontinuation rate of less than 3% in eight studies of 920 patients. 85

Table 3. SIDE EFFECTS OF ERYTHROPOIETIN

Hypertension Thrombosis of vascular access
Hypertensive encephalopathy/seizures Pain at injection site (SO)
Flu-like syndrome Decreased dialysiS efficiency
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS PATIENTS 919

Hypertension
The overall incidence of hypertension has been reported to be 33%
in four major clinical trials. 71 Possible risk factors associated with a higher
likelihood of developing hypertension include the presence of chronic
renal failure and a genetic predisposition for hypertension,42 because
normal volunteers6 and patients with multiple myeloma,51 AIDS,28 or
rheumatoid arthritis69 who received EPG did not develop an increase in
blood pressure. Also, patients with severe pre-existing anemia are at
higher risk for developing hypertension?1
The lack of correlation observed between mean blood pressure levels
and achieved hematocrifl does not support the hypothesis that hyper-
tension occurring during EPG therapy is a direct effect of an increase in
hematocrit. Because anemic ESRD patients have a high cardiac output
with a decreased peripheral vascular resistance/3 correction of the ane-
mia is associated with a gradual decrease in cardiac output, increase in
peripheral vascular resistance,39 and an increase in whole blood viscos-
ity,47 all of which are believed to be responsible for the elevation of mean
arterial pressure.
Gther contributing factors may playa role, such as EPG-induced
mobilization of vascular smooth muscle cytosolic calcium,76 an increase
in endothelin/2 and an increase in sympathetic nervous activity.
Hypertensive encephalopathy with seizures were of particular con-
cern in the early clinical trials, with a reported incidence of 5.4% in the
United States23 and 3.3% in Europe. 82 Clinically, these patients presented
with a rapid increase in blood pressure with prodromal headaches, vis-
ual disturbances, drowsiness, nausea, and vomiting, followed by gener-
alized seizures. 18 Most episodes occurred during the first 3 months of
therapy, when cardiovascular and hemodynamic parameters were
changing quickly.24
Special attention should be paid to patients who have a past history
of seizures or underlying central nervous system pathoiogYZ7 that may
predispose them to the development of this complication. Fortunately,
lowering the dose or discontinuing EPG and optimizing the antihyper-
tensive regimen or the patient's estimated "dry weight" early on will
substantially decrease the risk of hypertensive crisis or hypertensive
encephalopathy.
Approximately 5% of patients will develop a flu-like illness,23 char-
acterized by myalgias, bone pains, low-grade temperature, and diapho-
resis that begins 2 hours after receiving the drug and lasts for 12 hours.
This reaction usually remits after 2 weeks of therapyB2 with the use of
anti-inflammatory drugs75 or by lowering the rate of EPG infusion. 5
The improvement of uremic bleeding diathesis in dialYSis patients
receiving EPG has been invoked as a predisposing factor for an observed
higher incidence of vascular access81 or dialyzerl l clotting. However,
whether this is real is debatable, because Esbach's multicenter study did
not show a significantly higher risk of access clotting in patients receiv-
ing EPG when compared with placebo-treated individuals,z3 Further-
more, patients at a higher risk for clotting their vascular access usually
920 GIMENEZ & SCHEEL

have pre-existing problems such as venous stenosis. s A recent Canadian

study found that the probability of vascular access thrombosis may be
higher for artificial grafts as compared with native arteriovenous fistu-
las. 16 Therefore, some clinicians recommend the use of aspirin (one tablet
a day) for those patients at risk, who are on EPO, based on the fact that
EPO-induced increase in platelet aggregability is reversed by aspirin.s4
However, no clinical trials have been done to substantiate this conten-
tion.
Pain at the subcutaneous injection site has been reported in up to
one third of the patients receiving the drug via this route. It has been
ascribed to the fact that the solution in which EPO is contained has a pH
of 6.9 because of the citric acid added as a preservative.
The observation that EPO-treated patients developed an increase in
pre dialysis serum potassium, creatinine, and phosphorus23 and the fact
that solute clearance is decreased with an increased hematocrif has led
to the recommendation that the patients' dialysis prescription should be
monitored closely to prevent underdialysis over the long term. The ra-
tionale used to explain the decreased solute clearance involves the fact
that as hematocrit increases, there is an associated elevation in blood
viscosity with a drop in the proportion of plasma water. Because solute
clearance occurring from plasma water depends on the rate of flow, a
change in flow of plasma water will result in changes in the rate of solute
removal. An additional factor that may also playa role in explaining the
worsening biochemical profile observed in these patients is an increase
in solute intake related to improved appetite. 52 Therefore, it follows that
dietary counseling should always be recommended to address this prob-
lem.
Although not all reports consistently show a solute clearance drop,
it is important to remember that the solutes usually measured clinically
(creatinine, blood urea nitrogen, and phosphorus) are only indirect mark-
ers for other putative unmeasured "uremic toxins" that may be as or
more important for the control of uremic syndrome.

Beneficial Effects of EPO

One of the most immediate and tangible clinical benefits seen in

these patients has been the virtual elimination of transfusion dependency
(Table 4). Whereas before EPO therapy up to 25% of dialysis patients
were transfusion-dependent, after EPO became available the need for
this therapy has no longer been necessary, except for acute and usually
unavoidable problems such as gastrointestinal bleeding, blood loss due
to surgery, or severe infections.
The United States phase IV multicenter clinical trial reported that
the rate of blood transfusions dropped from 0.3 units per patient per
month to 0.1 unit per patient per month. 66 The risks of blood transfu-
sions-namely, transmission of viral illnesses such as AIDS, hepatitis,
and cytomegalovirus-have also been virtually eliminated. Additionally,
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS PATIENTS 921

Table 4. BENEFICIAL EFFECTS OF ERYTHROPOIETIN

Hematologic
elimination of transfusion dependency
decrease in anti HLA antibodies
therapy for post-transfusional hemosiderosis
improved hemostasis
Cardiovascular
reduction in left ventricular hypertrophy
improved aerobic exercise capacity
improvement in symptomatic angina
Immunologic
improved cell-mediated immunity
improved response to hepatitis B vaccine
Psychosocial
improved cognitive function
improved quality of life
Miscellaneous
improvement in diabetic gastroparesis
improvement in uremic pruritus

a decrease in levels of anti-HLA antibodies (PRA, or panel reactive anti-

bodies) has been reported with cessation of blood transfusions. 34 This is
an important issue for patients who are expecting a renal transplant,
because high levels of anti-HLA antibodies have been associated with a
poor outcome of the transplant. 14
Post-transfusional hemosiderosis, a side effect of repeated blood
transfusions, can be treated by recurrent phlebotomy in these patients
while keeping their hematocrits within target range with EPO. 46 This has
resulted in improved organ function (liver, heart, pancreas) as the tissue
iron is removed, as well as a drop in the increased susceptibility to
infections reported in this subpopulation of dialysis patients.9 As stated
elsewhere in this article, EPO therapy has been shown to improve he-
mostasis, decreasing the risk of bleeding in dialysis patients. This may
be related to an observed increase in platelets and aggregability,84 in-
creased plasma viscosity,47 increased fibrinogen levels,I° and improve-
ment in factor VIn function. 41

Cardiovascular Effects
The presence of left ventricular hypertrophy usually seen in dialysis
patients has been associated with poor prognosis over the long term.
Anemia78 and hypertension87 have both been implicated in its genesis. It
has been shown that the correction of anemia by EPO has led to a
reversal of left ventricular hypertrophy as assessed by echo cardiographic
criteria. 33 This effect has been ascribed to the reduction in peripheral
demand for blood due to the increased red cell mass with its associated
improvement in oxygen-carrying capacity.
The aerobic work capacity in dialysis patients improved significantly
with the correction of anemia,5s which takes place within the first 3
months of EPO therapy. Although this beneficial effect has been related
922 GIMENEZ & SCHEEL

to an increase in peak oxygen uptake, aerobic work capacity still remains

at 65% of predicted for age in these patients,55 with an overall improve-
ment out of proportion to the degree of increase observed in hemoglobin
levels (18% versus 58%).67 Thus, additional factors such as an underlying
muscle inability to extract oxygen have been invoked to explain this
discrepancy.67 Improvement in symptomatic ischemic heart disease with
improved exercise tolerance have also been reported,35,88 which is related
to an improved oxygen delivery to the myocardial muscle.

Immunologic Effects
Improved cell-mediated immunitr8 and immunogenic response to
hepatitis B vaccination77 have also been reported among dialysis patients
treated with EPO. An improvement in pruritus associated with a de-
crease in plasma histamine levels following EPOGEN therapy has also
been reported. 17

Psychosocial Effects
Among the most prominent beneficial effects associated with EPO
therapy is an improvement in cognitive function,54 with an increased
ability to remained focused, which in turn translates into increased so-
cialization and improved ability in carrying out the activities of daily
living. It has been shown that by correcting the anemia, there is a de-
crease in cerebral blood flow in dialysis patients,37 which perhaps results
in decreased delivery of uremic toxins to the brain and a lower intracra-
nial pressure.
It is now well established that EPO has resulted in a significant
improvement in the quality of life in dialysis patients as assessed by a
variety of standardized criteria and testing. 26 Categories evaluated and
reported as improved include functional ability, perceived health status,
ability to carry out activities of daily living, mood, appetite, sexual func-
tioning, sleep, self-esteem, and socialization.
Unfortunately, the improvements reported in quality of life (and
cognitive function) have failed to lead to better vocational rehabilitation
potential with improved employment status and increased economic
productivity in these patients.

ACKNOWLEDGMENT
The authors wish to express their appreciation for the secretarial assistance of Kathy
Thompson in the preparation of this manuscript.

References

1. Ambrus eM, Anthone S, Desh Pande G, et al: Removal of iron with immobilized
deferrioxamine. Transactions of the American Society of Artificial Internal Organs
33:749, 1987
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS PATIENTS 923

2. Babb AL, Popoich RP, Farrell Te, et al: The effect of erythrocyte mass transfer rates on
solute clearance measurements during hemodialysis. Proc EDTA 9:303,1972
3. Barbour GL: Effect of parathyroidectomy on anemia in chronic renal failure. Arch
Intern Med l39:889, 1979
4. Beck J, Weinmann R, Caro J: Characterization of the hypoxia responsive enhancer in
the human erythropoietin gene shows presence of hypoxia inducible 120 kd nuclear
DNA-binding protein in erythropoietin producing and non producing cells. Blood
82:704,1993
5. Bennett WM: Side effects of erythropoietin therapy. Am J Kidney Dis 18(Suppl 1):84,
1991
6. Berglund B, Ekblom B: Effect of recombinant human erythropoietin treatment on blood
pressure and some hematological parameters in healthy men. J Intern Med 229:125,
1991
7. Berkes SL, Kahn SI, Chazan JA, et al: Prolonged hemolysis from overheated dialysate
Ann Intern Med 83:363, 1975
8. Besarab A, Girone JF, Erslev A, et al: Recent developments in the anemia of chronic
renal failure. Seminars in Dialysis 2:87,1989
9. Boelaert JR, Daneels RF, Shurgers ML, et al: Iron overload in hemodialysis patients
increases the risk of bacteremia: A prospective study. Nephrol Dial Transplant 5:l30,
1990
10. Brunner R, Steffen HM, Pollok M, et al: Blood rheology in hemodialysis patients treated
with recombinant human erythropoietin. Contrib Nephrol 76:306, 1988
11. Canadian Erythropoietin Study Group: Association between recombinant human eryth-
ropoietin and quality of life and exercise capacity of patients receiving hemodialysis.
Br Med J 300:573, 1990
12. Carlini R, Obialo CR, Rothstein M: Intravenous erythropoietin (rHuEPO) administra-
tion increases plasma endothelin and blood pressure in hemodialysis patients. Am J
Hypertens 6:103, 1993
l3. Carwright GE: The anemia of chronic disorders. Semin HematoI3:351, 1966
14. Cecka JM, Cho L: Sensitization. In Terasaki P (ed): Clinical Transplants. Los Angeles,
UCLA Tissue Typing Laboratory, 1988, p 365
15. Cheung AK, Hohnholt M, Leypoldt JK, et al: Hemodialysis membrane biocompatibility:
The case of erythropoietin. Blood Purif 9:153,1991
16. Churchil DN, Muirhead N, Goldstein M, et al: Probability of thrombosis of vascular
access among hemodialysis patients treated with recombinant human erythropoietin. J
Am Soc NephroI4:1809, 1994
17. Demarchi S, Cecchin E, Villalta D, et al: Relief of pruritus and decreases in plasma
histamine concentrations during erythropoietin therapy in patients with uremia. N Engl
J Med 326:969, 1992
18. Edmunds ME, Walls J, Tucker B, et al: Seizures in haemodialysis patients treated with
recombinant human erythropoietin. Nephrol Dial Transplant 4:1065, 1989
19. Egrie Je, Strickland TW, Lane J, et al: Characterization and biological effects of recom-
binant human erythropoietin. Immunobiology 172:2l3, 1986
20. Erslev AJ: Erythropoietin. N Engl J Med 324:l339, 1991
21. Esbach JW: The anemia of chronic renal failure: Pathophysiology and the effects of
recombinant erythropoietin. Kidney Int 35:134,1989
22. Esbach JW: Erythropoietin 1991-an overview. Am J Kidney Dis 18(Suppl1):3, 1991
23. Esbach JW, Abdulhadi MH Browne JK, et al: Recombinant human erythropoietin in
anemic patients with end stage renal disease. Ann Intern Med 111:992, 1989
24. Esbach JW, Adamson JW: Guidelines for recombinant human erythropoietin therapy.
Am J Kidney Dis 14(Suppll):2, 1989
25. Esbach JW, Adamson JW: Modern aspects of the pathophysiology of renal anemia.
Contrib Nephrol 66:63, 1988
26. Evans RW: Recombinant human erythropoietin and the quality of life of end-stage
renal disease patients: A comparative analysis. Am JKidney Dis 18(Suppl1):62, 1991
27. Faulds D, Sorkin EM: Epoetin (recombinant human erythropoietin): A review of its
pharmacokinetic properties and therapeutic potential in anemia and the stimulation of
erythropoiesis. Drugs 38:863,1989
28. Fischl M, Galpin JE, Levine JD, et al: Recombinant human erythropoietin for patients
with AIDS treated with zidovudine. N Engl J Med 322:1488,1990
924 GIMENEZ & SCHEEL

29. Fried W: The liver as a source of extrarenal erythropoietin production. Blood 40:671,
1973
30. Fritschka E, Neumayer H-H, Seddighi S, et al: Effects of erythropoietin on parameters
of sympathetic nervous activity in patients undergoing chronic hemodialysis. Br J Clin
PharmacoI30:1355,1990
31. Gimenez LF, Watson AI, Spivak JL: Serum immunoreactive erythropoietin in patients
with end stage renal disease. Prog Clin Bioi Res 352:493,1990
32. Goldberg MA, Dunning SP, Bunn HF: Regulation of the erythropoietin gene: Evidence
that the oxygen serum is a heme protein. Science 242:1412,1988
33. Goldberg N, Lundin AP, Delano B, et al: Changes in left ventricular size, wall thickness
and function in anemic patients treated with recombinant human erythropoietin. Am
Heart J 124:424, 1992
34. Grimm De, Sinai-Trieman L, Sekiya NM: Effects of recombinant human erythropoietin
in HLA sensitization and cell mediated immunity. Kidney Int 38:12,1990
35. Hase H, Immamuray Y, Nakanura R, et al: Effects of rHuEPO therapy or exercise
capacity in hemodialysis patients with coronary artery disease. Jpn Circ J 57:131,1993
36. Hillman RS: Hematopoietic agents: Growth factors, minerals and vitamins. In Good-
man A, Rail TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics.
Pergamon Press, 1990, pp 1277
37. Hirakata H, Yao H, Osato S, et al: CBF and oxygen metabolism in hemodialysis pa-
tients: Effects of anemia with recombinant human EPO. Am J PhysioI262:F737, 1992
38. Hochberg Me, Arnold CM, Hogans BB, et al: Serum immunoreactive erythropoietin in
rheumatoid arthritis: Impaired response to anemia. Arthritis Rheum 31:1318, 1988
39. Hori K, Onoyama K, Iseki K, et al: Hemodynamics and volume changes by recombinant
human erythropoietin (rHuEPO) in the treatment of anemic hemodialysis patients. Clin
NephroI33:293, 1990
40. Hughes RT, Cotes PM, Oliver DO, et al: Correction of the Anaemia of Chronic Renal
Failure with Erythropoietin: Pharmacokinetic Studies in Patients on Haemodialysis and
C.A.P.D. Contributions in Nephrology 76:122-131,1989
41. Huraib S, al-Momen AK, Gader AM, et al: Effect of recombinant human erythropoietin
(r-HuEPO) on the hemostatic system in chronic hemodialysis patients. Clin Nephol
36:252,1991
42. Ishimitsu T, Tsukada H, Ogawa Y, et al: Genetic predisposition to hypertension facili-
tates blood pressure elevation in hemodialysis patients treated with erythropoietin. Am
J Med 94:401, 1993
43. Jacobs K, Shoemaker e, Rudersdorf R, et al: Isolation and characterization of genomic
and DNA clones of human erythropoietin. Nature 313:806, 1985
44. Jelkmann W: Renal erythropoietin: Properties and production. Rev Physiol Biochem
PharmacoI104:140, 1986
45. Lacombe C, Da Silva JL, Bruneval P, et al: Peritubular cells are the site of erythropoietin
synthesis in the morine hypoxic kidney. J Clin Invest 81:620, 1988
46. Lazarus JM, Hakim RM, Newell J: Recombinant human erythropoietin and phlebotomy
in the treatment of iron overload in chronic hemodialysis patients. Am J Kidney Dis
16:101, 1990
47. Lerche D, Schmidt R, Zoellner K, et al: Rheology in whole blood and in red blood cells
under recombinant human erythropoietin therapy. Contrib Nephrol 76:299, 1989
48. Lim VS, Flanigan MI, Kangman J: Effect of hematocrit on solute removal during high
efficiency hemodialysis. Kidney Int 37:1557,1990
49. Lindblad AS, Nolph KD: Hematocrit values in the CAPDjCCPD population: A report
of the National CAPD Registry. Perit Dial Int 10:275, 1990
50. Lindsay RM, Burton JA, Dargie HI, et al: Dialyzer blood loss. Clin Nephrol1:24, 1973
51. Ludwig H, Fritz E, Kotzmann H, et al: Erythropoietin treatment of anemia associated
with multiple myeloma. N Engl J Med 322:1693, 1990
52. Lundin AP: Quality of life: Subjective and objective improvements with recombinant
human erythropoietin therapy. Semin Nephrol (Suppl1)9:22, 1989
53. Manzler AD, Schreiner AW: Copper-induced acute hemolytic anemia. A new compli-
cation of hemodialysis. Ann Intern Med 73:609, 1970
54. Marsh JT, Brown WS, Wolcott D, et al: rHuEPO treatment improves brain and cognitive
function of anemic dialysis patients. Kidney Int 39:155,1991
 RECOMBINANT ERYTHROPOIETIN IN RENAL DIALYSIS PATIENTS 925

55. G, Thum H, Cada E, et al: Working capacity is increased following recombinant

human erythropoietin treatment. Kidney Int 34:525, 1988
56. McCarthy S, Callahant, Sweet S: Hemolytic reactions (HR) mechanically induced by
kinked hemodialysis lines [abstract]. Asaio Abstracts, 1993, p 75
57. McDougall Ie, Roberts DE, Neubert P, et al: Pharmacokinetics of intravenous, intra-
peritoneal and subcutaneous recombinant erythropoietin in patients on CAPD. Contrib
Nephrol 76:112,1989
58. McGonigle RJ, Parsons V: Aluminum induced anemia in hemodialysis patients. Neph-
ron 39:1, 1985
59. McMahon LP, Dawborn JK: Subjective quality of life assessment in hemodialysis pa-
tients at different levels of hemoglobin following use of recombinant human erythro-
poietin. Am J Nephrol 12:162, 1992
60. Meytes D, Bogin E, Ma A, et al: Effect of parathyroid hormone on erythropoiesis. J Clin
Invest 67:1263,1981
61. Miyake T, Kung CKH, Goldwasser E: Purification of human erythropoietin. J Bioi Chem
252:5558,1977
62. Muirhead N, Hodsman AB: Occult infection and resistance anemia to rHuEPO therapy
in renal failure. Nephrol Dial Transplant 5:232, 1990
63. Neff MS, Kim KE, Persoff M, et al: Hemodynamics of uremic anemia. Circulation
43:876, 1971
64. Neilan BA, Ehlers SM, Kolpin CF, et al: Prevention of chloramine-reduced hemolysis in
dialyzed patients. Clin NephroI10:105, 1975
65. Nissenson AR: Epoetin and cognitive function. Am JKidney Dis 20(Suppl1):21, 1992
66. Nissenson AR: National Cooperative rHu Erythropoietin Study in patients with chronic
renal failure: A phase IV multicenter study. Am J Kidney Dis 18(SuppI1):24, 1991
67. Painter P, Moore GE: The impact of recombinant human erythropoietin on exercise
capacity in hemodialysis patients. Advances in Renal Replacement Therapy 1:55, 1994
68. Palekar S, Singh AB, Sing M, et al: The effects of erythropoietin in cell mediated
immunity [abstract]. J Am Soc NeproI1:565, 1990
69. Pincus T, Olsen NJ, Russell J, et al: Multicenter study of recombinant human erythro-
poietin in correction of anemia in rheumatoid arthritis. Am J Med 89:161,1990
70. Piraino B, Johnston JR: The use of subcutaneous erythropoietin in CAPD patients. Clin
NephroI33:200, 1990
71. Raine AEG, Simon DR: Effects of erythropoietin in blood pressure. Am J Kidney Dis
18(Suppl1):76,1991
72. Rao DS, Shih M-S, Mohini R: Effect of serum parathyroid hormone and bone marrow
fibrosis on the response to erythropoietin in uremia. N Engl J Med 328:171, 1993
73. Santiago Ge, Rao TKS, Laird M: Effect of dialysis therapy of the hematopoietic system:
The National Cooperative Dialysis Study. Kidney Int 23(Suppl13):S95, 1983
74. Sawelson S, Akmal M, Gadallah M, et al: Incidence and cause of gastrointestinal
bleeding in uremic, hemodialysis (HD) and continuous ambulatory peritoneal dialysis
(CAPD) patients [abstract]. Kidney Int 37:244,1990
75. Schaefer RM, Horl WH, Massry SG: Treatment of renal anemia with recombinant
human erythropoietin. Am J Nephrol 9:353, 1989
76. SchiffI H: Correlation of blood pressure in end stage renal disease with platelet cytosolic
free calcium concentration during treatment of renal anemia with recombinant human
erythropoietin. Int J Artif Organs 15:343, 1992
77. Sennesael JJ, Van Der Niepen P, Verbeelen DL: Treatment with recombinant human
erythropoietin increases antibody titers after hepatitis B vaccination in dialysis patients.
Kidney Int 40:121, 1991
78. Silberberg J, Rahal D, Patton R, et al: Role of anemia in the pathogenesis of left
ventricular hypertrophy in end stage renal failure. Am J CardioI64:222, 1989
79. Spivak J: The mechanism of action of erythropoietin. International Journal of Cell
Cloning 4:139,1986
80. Spivak JL, Barnes De, Fuchs E, et al: Serum immunoreactive erythropoietin in HIV
infected patients. JAMA 261:3104,1989
81. Subota JT: Recombinant human erythropoietin in patients with anemia due to end
stage renal disease. Contrib Nephrol 76:166,1989
82. Sundal E, Kaeser U: Correction of anemia of chronic renal failure with recombinant
926 GIMENEZ & SCHEEL

human erythropoietin: Safety and efficacy of one year's treatment in a European mul-
ticentre study of 150 haemodialysis-dependent patients. Nephrol Dial Transplant 4:979,
1989
83. Swartz R, Dombrowski J, Burnatowska-Hledin M, et al: Microcytic anemia in dialysis
patients: Reversible marker of aluminum toxicity. Am J Kidney Dis 9:217, 1987
84. Taylor JE, Henderson IS, Stewart WK, et al: Erythropoietin and spontaneous platelet
aggregation in hemodialysis patients. Lancet 338:1361,1991
85. Thompson JR: Treatment of anemia in dialysis subjects. In Hemich WL (ed): Principles
and Practice of Dialysis. Baltimore, Williams & Wilkins, 1993, p 297
86. Trapp GA: Plasma aluminum is bound to transferrin. Life Sci 33:311, 1983
87. Watson AI, Whelton PK, Gimenez LF, et al: The effect of verapamil on dialysis patients
with left ventricular hypertrophy. Am J Hypertens 4:303,1986
88. Wizemann V, Kaufmann J, Kramer W: The effect of erythropoietin on ischemia toler-
ance in anemic hemodialysis patients with confirmed coronary artery disease. Nephron
62:161, 1992

Address reprint requests to

Luis F. Gimenez, MD
Division of Nephrology
The Johns Hopkins University
School of Medicine
Ross 958, 720 Rutland Avenue
Baltimore, MD 21205