The Effect of Altitude on Dosing and Response to

Erythropoietin in ESRD
M. Alan Brookhart,* Sebastian Schneeweiss,* Jerry Avorn,* Brian D. Bradbury,

Kenneth J. Rothman,*

Michael Fischer,* Jyotsna Mehta,* and Wolfgang C. Winkelmayer*

*Division of Pharmacoepidemiology and Pharmacoeconomics and

Renal Division, Department of Medicine,
Brigham and Womens Hospital & Harvard Medical School, Boston, Massachusetts;

Department of Epidemiology,
Amgen, Inc, Thousand Oaks, California; and

RTI Health Solutions, Research Triangle Park, North Carolina
ABSTRACT
For poorly understood reasons, patients with end-stage renal disease (ESRD) differ substantially in their
response to treatment with recombinant erythropoietin (EPO). Because hypoxia influences many of the
biologic pathways involved in erythropoiesis, the altitude at which a patient lives may affect the
dose-response relationship of EPO. In this retrospective cohort study, clinical data from 341,737 incident
hemodialysis patients registered in the U.S. Renal Data System were combined with elevation data from
the U.S. Geological Survey to address this question. Higher altitude was associated with smaller EPO
doses and higher hematocrit levels. For example, compared with patients at sea level, patients living
above 6000 ft received 19% less EPO (12.9 versus 15.9 thousand units/wk) but had hematocrit levels 1.1
points higher (35.7% versus 34.6%). These associations were found within subgroups defined by sex,
race, age, calendar time, cause of ESRD, and dialysis center profit status, and persisted after adjustment
for various potential confounding factors. Furthermore, resistance to EPO decreased with elevation. Our
results suggest that ESRD patients living at high altitude either increase endogenous EPO production or
respond better to endogenous and exogenous EPO.
J Am Soc Nephrol 19: 13891395, 2008. doi: 10.1681/ASN.2007111181
Patients with chronic kidney disease (CKD), in-
cluding those with end-stage renal disease (ESRD)
produce insufficient amounts of renal erythropoie-
tin to maintain normal hemoglobin levels. The pri-
mary treatment for the anemia caused by CKD is
human recombinant erythropoietin (EPO). Treat-
ment with EPO has been shown to increase hemat-
ocrit levels and reduce the need for blood transfu-
sions in CKD patients with anemia.
13
However,
managing EPO therapy is complicated because of
the great within- and between-person variability in
the erythropoietic response to EPO.
4,5
The within-
person variability in response leads to fluctuating
hemoglobin levels, which may adversely affect pa-
tient outcomes.
610
An improved understanding of
factors that influence EPO responsiveness could
lead to greater hemoglobin control and thus safer
and more effective anemia management strategies
for CKD patients.
The mechanisms underlying EPO response are
complex, however, as exogenous EPO and admin-
istered iron promote red blood cell production
through an intricate cascade of physiologic re-
sponses to the tissue hypoxia caused by anemia. In
healthy people, lowered oxygen tension in the cell
leads to increased production of endogenous EPO
and regulation of various pathways involved with
iron metabolism.
11
In patients with CKD, the pro-
Received November 9, 2007. Accepted January 11, 2008.
Published online ahead of print. Publication date available at
www.jasn.org.
Correspondence: Dr. M. Alan Brookhart, Division of Pharmaco-
epidemiology and Pharmacoeconomics, Brigham and Womens
Hospital/Harvard Medical School, 1620 Tremont Street, Suite
3030, Boston, MA 02120. Phone: 617-278-0937; Fax: 617-232-
8602; E-mail: [email protected]
Copyright 2008 by the American Society of Nephrology
CLINICAL EPIDEMIOLOGY
www.jasn.org
J Am Soc Nephrol 19: 13891395, 2008 ISSN : 1046-6673/1907-1389 1389
duction of endogenous EPO decreases with the loss of kidney
function; therefore, the biologic response to hypoxia is altered
in CKD.
One factor that may illuminate the interrelations of the
many factors involved with EPO response is the altitude at
which a patient lives. At higher altitudes, patients are exposed
to a lower partial pressure of oxygen; thus, altitude can influ-
ence tissue hypoxia (similar to anemia) and the array of phys-
iologic responses to hypoxia involved in erythropoiesis. In this
study, we sought to determine whether altitude affects either
EPO dose requirements or treatment response among a large
cohort of ESRD patients on hemodialysis in the United States.
RESULTS
We identified 341,737 ESRD patients who initiated hemodial-
ysis between 1995 and 2004 and who met the study entry re-
quirements. The median elevation of patients in the sample
was 407 feet, and 7487 (2.2%) patients lived above 4000 ft. To
depict the geographic distribution of elevations inhabited by
patients, we mapped the median elevation of patients by
county in the lower 48 states (Figure 1). Besides a few counties
in the Appalachian Mountains, the median elevation for coun-
ties east of the Mississippi was below2000 ft. The counties with
median patient elevations over 6000 ft were found in New
Mexico, Arizona, Nevada, Colorado, California, and Wyo-
ming. There were 61 patients in Colorado and California who
lived over 9500 ft.
Table 1 presents the characteristics of the sample stratified
by elevation group. Race was imbalanced across elevation
groups. In the lowest elevation group, 40% of patients were of
black race, but this percentage decreased with elevation to only
5%inthe over 6000 ft group. Inthe lowest elevationgroup, less
than 1% of the patients in the study identified themselves as
American Indian, but 30% did in the highest elevation group.
The percentage of patients in the oldest age group generally
decreased with elevation (21% down to 15%). The percentage
of patients with hypertension as the reported cause ESRD also
decreased with elevation(28%downto 10%), whereas the per-
centage of patients with diabetes as the reported cause of ESRD
increasedwithelevation(46%upto61%). Patients inthe high-
est elevation group had slightly worse kidney function at initi-
ation of dialysis than patients in the lowest elevation group
(mean glomerular filtration rate 7.8 versus 8.4) and slightly
lower serum albumin levels (3.0 versus 3.2). Compared with
patients in the lowest elevation group, fewer patients in the
highest elevation group were treated at for-profit dialysis cen-
ters (71% versus 77%).
Hematocrit increased with elevation within each time pe-
riod studied (Figure 2A), and hematocrit levels in the highest
elevation group were sharply higher for all time periods. Mean
weekly EPO use (U/wk) decreased with elevation within each
time period studied (Figure 2B). The trends persisted within
subgroups definedby sex, race, age, cause of ESRD, anddialysis
profit center status (data not presented). EPO resistance de-
creased with elevation across the entire study population (Fig-
ure 2C).
In Table 2, we report average hemat-
ocrit, EPOuse, and EPOresistance by el-
evation group and the least-square
means from the regression analysis. The
least-square means mirror the graphs
and reveal decreasing EPO use, increas-
ing hematocrit levels, and decreasing
EPOresistance withincreasing elevation.
Statistical adjustments slightly attenu-
ated the differences between the EPO
dose in the highest and lowest elevation
groups (Table 2) but had no effect on the
difference in hematocrit levels between
elevation groups.
In Table 3, we present least-squares
means of baseline hematocrit levels,
change in hematocrit levels from base-
line to the index month, and index EPO
dose among patients who did not receive
EPO before starting dialysis. This table
reveals baseline hematocrit levels in-
creasing with altitude, the change in he-
matocrit relatively flat across elevation
groups, and index EPO doses decreasing
with elevation.
In the sensitivity analysis, in which we
Not Represented in Study
2000-3999 ft.
<250 ft.
4000-5999 ft.
250-1999 ft.
6000+ ft.
Figure 1. Map of average county-level elevation of patients in study cohort.
CLINICAL EPIDEMIOLOGY www.jasn.org
1390 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 13891395, 2008
required that patients have no hospitalizations during the in-
dex month, the results were substantively unchanged.
DISCUSSION
In our study of a very large cohort of ESRD patients on main-
tenance hemodialysis, we found that increasing altitude was
associated with modestly lower exogenous EPO use, but with
higher achieved hematocrit levels. We also found that EPO
resistance decreased monotonically with elevation. These asso-
ciations existed within subgroups defined by sex, race, age,
calendar time, and dialysis center profit status and were not
greatly affected by multivariable adjustments for many poten-
tial confounding factors. It is known that healthy people living
at highaltitude have higher average hematocrit levels thanpeo-
ple living at sea level; therefore, dialysis providers at high alti-
tude may target higher hematocrit levels in their patients. It is
interesting, however, that these higher hematocrit levels are
achieved using substantially less EPO.
One possible explanation for our results is that ESRD pa-
tients at higher altitudes produce more endogenous EPO than
comparable patients living at sea level and thus need less exog-
enous EPO. This could happen if some renal or extrarenal EPO
production capacity is unused at low elevation. Supportive of
this hypothesis are reports documenting that ESRD patients
increase EPO production in response to acute hypoxic stress,
suchas pulmonary dysfunctionor bloodloss.
1214
It is less clear
whether EPO levels in ESRD patients would respond to the
mild hypoxia induced by moderate increases in elevation. Bos-
man et al. found that patients with CKD were able to mount a
weak EPO response to 5 h of hypobaric hypoxia equivalent to
approximately 13,000 ft above sea level.
15
A similar study by
Quick et al. found no EPO response in ESRD patients exposed
to 3 h of hypobaric hypoxia equivalent to approximately
15,000 ft above sea level.
16
It is possible, however, that long-
term exposure to hypoxia may elicit an EPO response greater
than what was observed in short-duration hypobaric experi-
ments.
An alternative explanation for our findings is that patients
at higher altitude respond more efficiently to EPO than pa-
tients at lower altitudes. This hypothesis has biologic plausibil-
ity, as the hypoxia inducible factor (HIF) that regulates EPO
expression is known to be involved in the transcription of
other proteins participating in erythropoiesis. For example,
HIF is known to regulate iron metabolism by controlling ex-
pression of transferrin, involved with iron transport, trans-
ferrin receptor (TfR), involved with cellular iron uptake, and
hepcidin, which affects both intestinal iron absorption and re-
lease of iron by macrophages.
1720
Consistent with the hypoth-
esis that EPO response is enhanced at high altitude is a study
finding that levels of soluble transferrin receptor (STfR), a
measure of TfR expression, were increased under hypobaric
hypoxia
21
and another study reporting that STfR levels pre-
Table 1. Baseline characteristics of subjects in sample, by elevation group
<250 ft
N (%) or
mean (SE)
250 to 1999 ft
N (%) or
mean (SE)
2000 to 3999 ft
N (%) or
mean (SE)
4000 to 5999 ft
N (%) or
mean (SE)
>6000 ft
N (%) or
mean (SE)
N 140,350 184,578 9320 5934 1555
Male gender 72,024 (51.3%) 94,595 (51.3%) 4941 (53.0%) 3172 (53.5%) 780 (50.2%)
Age, years
18 374 (0.3%) 454 (0.3%) 30 (0.3%) 24 (0.4%) 10 (0.6%)
1839 10,954 (7.8%) 13,669 (7.4%) 649 (7.0%) 496 (8.4%) 117 (7.5%)
4059 38,423 (27.4%) 47,259 (25.6%) 2700 (29.0%) 1701 (28.7%) 417 (26.8%)
6075 59,107 (42.1%) 80,012 (43.4%) 4115 (44.2%) 2660(44.8%) 767 (49.3%)
75 29,466 (21.0%) 40,754 (22.1%) 1770 (19.0%) 1032 (17.4%) 240 (15.4%)
Race
white 68,443 (48.8%) 114,431 (62.0%) 7475 (80.2%) 4321 (72.8%) 926 (59.6%)
black 55,978 (39.9%) 57,405 (31.1%) 774 (8.3%) 416 (7.0%) 82 (5.3%)
American Indian 714 (0.5%) 3070 (1.7%) 676 (7.3%) 862 (14.5%) 478 (30.7%)
GFR (estimated) 8.4 (0.01) 8.8 (0.01) 8.9 (0.04) 8.2 (0.05) 7.8 (0.08)
Serum albumin 3.17 (0.002) 3.16 (0.002) 3.10 (0.007) 3.10 (0.012) 3.00 (0.023)
Cause of ESRD
hypertension 39,104 (27.9%) 47,970 (26.0%) 1599 (17.2%) 767 (12.9%) 158 (10.2%)
diabetes 64,433 (45.9%) 86,019 (46.6%) 5275 (56.6%) 3298 (55.6%) 945 (60.8%)
glomerulonephritis 13,625 (9.7%) 18,575 (10.1%) 908 (9.7%) 789 (13.3%) 184 (11.8%)
History of MI 10,329 (7.4%) 16,290 (8.8%) 694 (7.5%) 510 (8.6%) 133 (8.6%)
History of cancer 5970 (4.3%) 9625 (5.2%) 405 (4.4%) 228 (3.8%) 58 (3.7%)
History of CHF 43,706 (31.1%) 60,574 (32.8%) 2903 (31.2%) 1568 (26.4%) 485 (31.2%)
Weight (kg) 72.4 (0.06) 75.3 (0.05) 72.1 (0.23) 74.6 (0.26) 70.7 (0.46)
Iron administered during index month 75,801 (54.0%) 103,101 (55.9%) 4694 (50.4%) 2944 (49.6%) 737 (47.4%)
Treated at for-profit center 107,933 (76.9%) 134,401 (72.8%) 7156 (76.8%) 4055 (68.3%) 1096 (70.5%)
CHF, congestive heart failure; GFR, glomerular filtration rate; ESRD, end-stage renal disease; MI, myocardial infarction.
CLINICAL EPIDEMIOLOGY www.jasn.org
J Am Soc Nephrol 19: 13891395, 2008
Altitude and Erythropoietin in ESRD 1391
dicted response to EPOtherapy among treatment-na ve ESRD
patients.
22
It has also been reported that pharmacologic stabi-
lization of HIF improves iron utilization.
23
If the expression of
other proteins involved with erythropoiesis increases with al-
titude in ESRD, endogenous or exogenous EPO may encoun-
ter a more activated system of hypoxia response in patients
who live at higher elevations.
Our analysis of patients who did not receive EPO before
starting dialysis found that patients at higher elevation start
EPO treatment with higher hematocrit levels. This could be
caused by either greater endogenous
EPO production or increased response
to endogenous EPO. However, the ob-
servation that patients at high altitude
experience a similar increase in hemato-
crit from baseline to the index month
while requiring less exogenous EPO
strongly suggests that EPO response is
increased at high elevation.
We have conceptualized altitude as a
variable that is related to EPO require-
ments only throughits effect onhypoxia-
regulated pathways involved with eryth-
ropoiesis. However, the distributions of
several variables were imbalanced across
elevation groups, suggesting that our re-
sults could be distorted by unmeasured
factors. Racial groups in particular were
strongly imbalanced, with most Ameri-
can Indians living at high elevation and
most black patients living at sea level.
Cause of ESRD, weight, age, and dialysis
profit status were also associated with al-
titude. Nevertheless, when we looked at
the associations between elevation and
both EPO use and hematocrit levels in
subgroups defined by sex, race, age, cal-
endar time, and dialysis profit center sta-
tus, the same associations were found.
Furthermore, multivariable adjustments
for an array of clinical and demographic
factors did not materially affect our esti-
mates. The robustness of our analysis to
restriction and adjustment suggests that
our findings are not likely to be the result
solely of unmeasured confounding fac-
tors.
Further research with more detailed
data could help us better understand the
biologic processes underlying our find-
ings. For example, measurements of en-
dogenous EPO levels in patients who
have not yet begun EPO therapy could
indicate whether endogenous EPO pro-
duction was up-regulated at altitude.
More granular longitudinal data onbothEPOandironadmin-
istration with repeated measures of ferritin and transferrin sat-
uration could be examined to determine whether the interre-
lations between these factors depended on altitude.
Furthermore, data including additional variables associated
with EPO response, such as current albumin levels and vascu-
lar access type, could help rule out unmeasured confounding
as an explanation of these associations.
Given the current concerns about the safety of EPO and
persistent questions about optimal hemoglobin targets and
2000-3999 ft.
<250 ft.
4000-5999 ft.
250-1999 ft.
6000+ ft.
Elevation Group
EPO Dose (U/Week) / Hematocrit
0.50 0.45 0.40 0.35 0.30 0.25
1995-1996 1997-1998 1999-2000 2001-2002 2003-2004
E
P
O

D
o
s
e

(
1
,
0
0
0

U
/
W
e
e
k
)
19
17
15
13
11
9
7
5
H
e
m
a
t
o
c
r
i
t
38
37
36
35
34
33
32
31
A.
B.
C.
1995-1996 1997-1998 1999-2000 2001-2002 2003-2004
Figure 2. (A) Average hematocrit by elevation group and time period. (B) Average EPO
dose by elevation group and time period. (C) EPO resistance (EPO dose/hematocrit) by
elevation group.
CLINICAL EPIDEMIOLOGY www.jasn.org
1392 Journal of the American Society of Nephrology J Am Soc Nephrol 19: 13891395, 2008
dosing algorithms, the results of the present study raise impor-
tant clinical questions. If patients respond better to EPO at
high altitude, it is natural to speculate about whether hemoglo-
bin levels could be normalized at high altitude with a decreased
risk of adverse events. Furthermore, the possibility that EPO
may be more effective at high altitude raises the question of
whether the increased effectiveness could be duplicated at
lower elevations. HIF-stabilizing agents, currently under re-
search, mimic the physiologic effects of hypoxia. Future re-
search examining the use of these compounds in combination
with EPO therapy may provide useful clinical and scientific
informationabout the process of erythropoiesis andthe factors
governing EPO treatment response.
CONCISE METHODS
Data
We obtained data from the U.S. Renal Data System (USRDS) and the
U.S. Geological Survey (USGS). The USRDS contains detaileddata onall
patients inMedicares ESRDprogram, includinginformationcollectedat
dialysis initiation (reported on the Medical Evidence Form, CMS-2728),
describing demographics, primary cause of ESRD, clinical data (e.g.,
weight), and certain laboratory measurements (e.g., serum albumin and
hematocrit levels). In addition, the USRDS contains all Medicare Part A
and B claims that include information on diagnoses and procedures re-
corded for all hospitalizations and outpatient visits. The USRDS also
contains claims for total monthly EPO doses, reported with the final
hematocrit level recorded during the month.
From USGS data, we obtained a list of 137,061 U.S. cities along
with their state and county Federal Information Processing Standards
code, and elevation. We also obtained a list of U.S. zip codes with their
primary city and the average elevation of the county, as reported by
the USGS. We then matched the zip code data to the USGS city ele-
vation data using city name, and the county and state Federal Infor-
mation Processing Standards code. This allowed us to assign to each
zip code the elevation of its primary city. For zip codes that could not
be matched to a city in the USGS data, we set the elevation equal to the
average elevation in the county. Altitudes for each patient were ob-
tained using the zip code for their primary residence (assessed during
the index month) as reported in the USRDS data.
The study investigators obtained Data Use Agreements from the
National Institute of Digestive and Diabetes and Kidney Diseases. The
Brigham and Womens Hospital Institutional Review Board ap-
proved this research.
Patient Selection
From the USRDS standard analytic files, we selected all patients
who initiated hemodialysis treatment between January 1, 1995 and
December 31, 2004. We excluded all patients who did not survive
to 9 mo after entry into the ESRD program. Follow-up began at the
start of the 9th month. For each patient, the EPO dose and the
hematocrit level were recorded for the first month during fol-
low-up (the index month) in which a patient received EPO and
spent less than 5 d in the hospital. Patients were dropped if they
switched to peritoneal dialysis, received a transplant before the
index month, or reached the 15th month without having received
an eligible EPO administration. We converted the total EPO ad-
ministered during the index month into units per week (U/wk). To
compute units per week, we first computed units per day by divid-
Table 2. Unadjusted and adjusted mean achieved hematocrit, EPO dose (U/week), and EPO resistance by elevation
group with 95% confidence intervals
Elevation Group
Hematocrit
(unadjusted)
Hematocrit
(adjusted
a
)
Weekly EPO Dose
(1000 U/week) (unadjusted)
Weekly EPO Dose
(1000 U/week) (adjusted
a
)
EPO Resistance
(adjusted
a
)
250 ft 34.6 (34.634.6) 34.3 (34.334.4) 15.9 (15.916.0) 17.0 (16.817.3) 0.52 (0.510.52)
2501999 ft 34.6 (34.634.6) 34.3 (34.234.4) 15.3 (15.315.4) 16.3 (16.116.6) 0.50 (0.490.51)
20003999 ft 34.8 (34.834.9) 34.5 (34.434.6) 13.7 (13.414.0) 15.1 (14.715.4) 0.46 (0.440.47)
40005999 ft 35.2 (35.135.3) 34.9 (34.835.0) 13.1 (12.813.5) 14.6 (14.215.0) 0.44 (0.420.45)
6000 ft 35.7 (35.535.9) 35.4 (35.235.7) 12.9 (12.213.6) 14.7 (14.015.4) 0.44 (0.410.46)
a
Adjusted for age, sex, race, weight, calendar year, estimated glomerular filtration rate at baseline, cause of ESRD, profit status of treating center, history of
myocardial infarction, history of congestive heart failure, history of cancer, and concurrent iron administration. Adjusted means are least-squares means that use
the fitted regression to compute a mean for each elevation group standardized to the population distribution of covariates included in the regression model.
Table 3. Adjusted mean baseline hematocrit, change in hematocrit from baseline, and EPO dose (U/week) by elevation
group, among treatment naive patients with 95% confidence intervals
Elevation
Group
Baseline Hematocrit
(adjusted
a
)
Change In Hematocrit
(adjusted
a
)
Weekly EPO Dose (1000 U/week)
(adjusted
a
)
250 ft 27.3 (27.227.5) 7.0 (6.97.2) 16.8 (16.617.1)
2501999 ft 27.4 (27.327.5) 7.0 (6.87.1) 16.0 (15.716.3)
20003999 ft 27.5 (27.427.7) 7.0 (6.87.2) 15.0 (14.515.4)
40005999 ft 28.0 (27.728.2) 6.8 (6.57.0) 14.4 (13.915.0)
6000 ft 28.3 (27.928.7) 6.9 (6.37.4) 14.2 (13.215.3)
a
Change in hematocrit achieved hematocrit baseline hematocrit. Adjusted means are least-squares means that use the fitted regression to compute a
mean for each elevation group standardized to the population distribution of covariates included in the regression model. The covariates included in the model
were age, race, sex, weight, calendar year, estimated glomerular filtration rate at initiation of dialysis, cause of ESRD, profit status of treating center, history of
myocardial infarction, history of congestive heart failure, history of cancer, and concurrent iron administration.
CLINICAL EPIDEMIOLOGY www.jasn.org
J Am Soc Nephrol 19: 13891395, 2008
Altitude and Erythropoietin in ESRD 1393
ing the total units of EPO administered during the month by the
days in the month minus the time the patient spent in hospital
during the month (EPO exposure captured in the USRDS is almost
entirely exposure from outpatient treatment at a dialysis facility.)
Statistical Analysis
We classified all patients into four groups based on the elevation
above sea level of their zip code of residence: 250 ft, 250 to 1999
ft, 2000 to 3999 ft, 4000 to 5999 ft, and 6000 ft. To depict the
geographic distribution of the elevations, we computed the me-
dian elevation of patients in each county and displayed it on a map.
We calculated means and frequencies of patient characteristics by
elevation group, and graphed the average hematocrit and EPO
dose during the index month across elevation groups. We also
explored the associations among altitude, hematocrit, and EPO
dose in subgroups defined by sex, race, age, calendar time, cause of
ESRD, and dialysis profit center status. We computed a measure of
EPO resistance that was defined to be a patients EPO dose in the
index month divided by the hematocrit level reported to Centers
for Medicare and Medicaid Services during that month. We plot-
ted EPOresistance and 95%confidence intervals for each elevation
group.
To adjust for possible confounding of the association between
elevation and achieved hematocrit, EPO dose requirement, and
EPO resistance, we fit multivariable linear regression models of
hematocrit, EPO dose, EPO resistance that included: age, sex, race,
calendar year, weight, primary recorded cause of ESRD (diabetes,
hypertension, glomerulonephritis, other), history of cancer, his-
tory of myocardial infarction, co-administration of iron, and
whether or not the EPO received during the index month was
administered at a for-profit dialysis center. These regression mod-
els were used to compute a population-averaged (least-squares)
mean and 95% confidence interval for each elevation group. This
approach uses the fitted regression model to estimate a mean EPO
dose and hematocrit value for each elevation group standardized
to the distribution of covariates observed in the overall popula-
tion. In a secondary analysis, we estimated least-squares means of
hematocrit levels measured at entry into the ESRD program (base-
line hematocrit), change in hematocrit from baseline to the index
month, and EPO administered during index month among pa-
tients who did not receive EPO before entry into the ESRD pro-
gram. In a sensitivity analysis, we redefined the index month to be
the first month during follow-up in which a patient received EPO
and had no hospitalizations.
All statistical analyses were performed in SAS, version 9.1.
24
ACKNOWLEDGMENTS
The authors thank Drs. Allan Collins and David Gilbertson at U.S.
Renal Data System for helpful comments and Jessica Agnew-Blais
for manuscript preparation. M.A.B. was supported by a career
development award from the National Institute on Aging (AG-
027400).
DISCLOSURES
M.A.B. and W.C.W. receive salary support from Amgen for an unrelated
research project. B.D.B. is an employee of Amgen. S.S. has consulted with
Research Triangle Institute on a project funded by Amgen.
Data reported herein were supplied by the U.S. Renal Data System. Inter-
pretation and reporting of these data are the responsibility of the authors and
in no way should be seen as official policy or interpretation of the U.S. govern-
ment.
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