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Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, and University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75231
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We measured blood erythropoietin
(EPO) concentration, arterial O2 saturation
(SaO2), and urine PO2 in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h
at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood
flow (Doppler) and Hb were determined at sea level and after 6 h
at each altitude (n = 24) to calculate renal
O2 delivery. EPO increased significantly after 6 h at
all altitudes and continued to increase after 24 h at 2,454 and
2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied
markedly among individuals, ranging from 
41 to 400% after 24 h
at 2,800 m. Similar to EPO, urine PO2 decreased after 6 h at all altitudes and returned to baseline by 24 h
at the two lowest altitudes but remained decreased at the two highest altitudes. Urine PO2 was closely related to EPO
via a curvilinear relationship (r2 = 0.99),
although also with prominent individual variability. Renal blood flow
remained unchanged at all altitudes. SaO2 decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit
statistically significant, relationships between EPO and SaO2 (r = 0.41, P < 0.05) and no significant relationship with renal O2
delivery. These data suggest that 1) the altitude-induced increase in EPO is "dose" dependent: altitudes 
2,100-2,500 m appear to be a threshold for stimulating sustained EPO release in most
subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in
the erythropoietic response to altitude that is only partially
explained by "upstream" physiological factors such as those
reflecting O2 delivery to EPO-producing tissues.
high altitude; ventilatory acclimatization; urine PO2; renal blood flow
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WHEN MAMMALS ARE EXPOSED to high-altitude hypoxia, they exhibit certain physiological responses, such as the production of erythropoietin (EPO), which triggers an increase in red cell mass and Hb concentration (7, 10, 11, 35). This hematologic acclimatization response facilitates the restoration of normal blood O2 content and improves tissue oxygenation, despite lowered arterial PO2 (PaO2). The concentration of EPO in blood increases ~90-120 min after reduction of the inspiratory PO2 (5), rises progressively during the first 24-48 h, and then declines toward baseline over days to weeks (1, 28).
The role of EPO in the polycythemia induced by field and simulated (hypobaric chamber) altitude has been studied extensively in humans (1, 28, 29) and animals (12, 15). However, most studies were conducted at high altitudes (>4,000-6,000 m) (15, 21, 28, 29). Cross-sectional studies show a curvilinear relationship between PaO2 and red cell mass, with no increase until PaO2 decreases below 70 Torr, and arterial O2 saturation (SaO2) begins to decrease prominently (35). However, whether sea level natives will experience stimulated erythropoiesis in response to lower altitudes is unknown. This question is particularly important to certain populations such as endurance athletes who travel to moderate altitude for training purposes (17, 31), as well as the millions of people exposed to moderate altitude during occupational and/or recreational activities (23).
The EPO-producing site in response to hypoxia is primarily the kidney (20), although extrarenal sensing mechanisms also have been postulated in experimental animals (30). It is assumed that a change in the delivery of O2 to renal tissue is a key factor for stimulating EPO production at altitude. However, this assumption has not been demonstrated directly in human studies. Renal O2 delivery is regulated not only by renal blood flow (RBF) and arterial O2 content (CaO2), but also by hemodynamics (such as cardiac output) and the affinity of Hb for O2 (35). Ultimately, it is the difference between renal O2 delivery and renal O2 utilization that determines O2 content of the kidney cells, which is not necessarily linearly related to arterial oxyhemoglobin saturation.
In the present study, we hypothesized that there would be a threshold "dose" of altitude exposure that would be required for sustained EPO release and that the magnitude of the response would be based on variability in known physiological parameters. To test this hypothesis, we measured blood EPO, urine PO2 as an index of renal tissue PO2, RBF, and SaO2 in 48 subjects at sea level and at four levels of simulated altitude.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Forty-eight young, healthy subjects (32 men and 16 women, 21 ± 2.5 yr, 61.3 ± 10.4 kg, 170 ± 12 cm) volunteered to take part in the study. All subjects received written and verbal explanations of the experiment before giving consent. The Institutional Review Boards of the University of Texas Southwestern Medical Center and Presbyterian Hospital of Dallas approved the study.
Protocol. Each week, for a total of 4 wk, the subjects spent 24 h in a decompression chamber at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m (612, 590, 564, and 538 Torr barometric pressure, respectively) in pseudo-random and balanced order (ultimately, order was 2,454, 2,800, 2,085, and 1,780 m). The last altitude was fixed a priori at 1,780 m to minimize any effect of the chamber exposures on subsequent experiments conducted in the field. For comfort, only 12 subjects were in the chamber during any 24-h exposure. The temperature (25 ± 0.5°C), humidity (28 ± 1%), and CO2 concentration (0.07 ± 0.02%) in the chamber were carefully controlled.
EPO concentration. EPO concentration was measured at sea level (before decompression) and after 6 and 24 h at each simulated altitude. For logistical reasons, in half of the subjects, EPO was measured in plasma by radioimmunoassy (Ramco, Houston, TX), and in the other half, it was determined in serum with an enzyme-linked immunosorbent assay kit (Human EPO Quantikine IVD, catalog no. DEP00, R & D Systems) (2). On one set of 72 samples, EPO concentration was assayed in plasma and serum with these respective kits to determine the relationship between the two methods. The plasma and serum EPO values were tightly correlated with a regression coefficient of 0.96, a slope of 1.0, and an intercept of 2.7 (i.e., plasma values were 2.7 mU/ml higher than serum values in a systematic fashion but varied together in a 1:1 relationship). To minimize any influence of this difference between the two methods for calculating percent changes in EPO, all serum values were adjusted by this offset (2.7) to make them equivalent to the plasma measurements. Hb was measured by a CO-oximeter (Instrumentation Laboratories).
Urinary PO2. Urine samples were collected anaerobically at sea level and after 6 and 24 h at each simulated altitude with the use of the following procedure. 1) Each subject voided to empty his/her bladder. 2) After the first void, each subject drank 500 ml of a hypotonic sports drink (Gatorade). 3) About 30 min after drinking the Gatorade, subjects voided through an external catheter to a vinyl bag, with care taken to avoid exposure to air. For men, this was achieved with a standard "condom"-style catheter (C. R. Bard). For women, an external collection device developed for use in space was employed (Medpoint, Chicago, IL). This procedure produced a urine flow rate of 5-10 ml/min. 4) Immediately after collection, the urine samples were drawn into a 2-ml syringe and placed immediately on ice. The urine PO2 was analyzed with a blood-gas analyzer (Instrumentation Laboratories).
RBF. RBF was measured in 24 subjects (16 men and 8 women) at sea level and after 6 h of each altitude exposure by using Doppler ultrasonography (22, 36). A color Doppler ultrasound scanner (model HDI 5000, Advanced Technology Laboratory, Bothel, WA) was used for examination. After the flow in internal vessels was identified with color Doppler ultrasonography, a sample volume was positioned in the renal artery or its first branch. The sample volume was placed in exactly the same position for each determination (based on a scout image during the first measurement), and the Doppler velocity was corrected for the angle of insonation. Volumetric flow was calculated by multiplying the area of the insonated blood vessel by the time-averaged mean velocity over at least three consecutive beats. Renal O2 delivery was calculated from the product of RBF and CaO2 [CaO2 = Hb (g/dl) × SaO2 (%) × 1.36 (ml O2/g)].
SaO2. SaO2 was estimated by pulse oximetry (model 3700, Ohmeda) at sea level and after 6 and 24 h at each simulated altitude.
Statistical analysis. Values are means ± SE. Sea level values (baseline) were taken from the mean values of four measurements, which were made immediately before each simulated altitude exposure. The EPO, urine PO2, and SaO2 data at different altitudes and times were analyzed by means of a two-way (repeated-measure) analysis of variance. The Newman-Keuls post hoc test was used for multiple comparisons between variables. Linear regression analysis and correlation coefficients were used to assess the relationships between variables. Comparison and correlation were considered significant when P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EPO.
EPO was 14.3 ± 0.8 mU/ml at sea level; it increased significantly
after 6 h at all four simulated altitudes and then declined slightly after 24 h at 1,780 and 2,085 m. In contrast to the two lowest altitudes, mean EPO concentration continued to increase significantly after 24 h at 2,454 and 2,800 m (Fig.
1A). There was marked
individual variability in EPO release at all altitudes (Fig.
2) but generally consistent responses
among individuals (i.e., those individuals with the greatest responses
to the lowest altitudes had the greatest responses to the highest
altitudes). For example, the coefficient of variation (standard
deviation/mean) for the percent change from baseline after 24 h at
2,800 m was 0.83.
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Urine PO2.
Changes in urine PO2 are shown in Fig.
1C. The mean value of urine PO2 at
sea level was 84.7 ± 1.7 Torr; similar to the pattern for EPO, it
decreased after 6 h at all altitudes and returned rapidly to near
baseline by 24 h at 1,780 and 2,085 m but remained lower at 2,454 and 2,800 m. There was a highly significant curvilinear (2nd-order
regression) relationship between the mean values for urine
PO2 and EPO by 24 h at all four simulated
altitudes (r2 = 0.992; Fig.
3). When examined on an individual basis,
the median r2 for this relationship was 0.87 (range 0.11-1.00).
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SaO2.
SaO2 at sea level was 98.1 ± 0.4%, decreased
slightly but significantly after 6 h at 1,780 and 2,085 m (1.1 and
1.6%, respectively), and decreased to a greater extent at 2,454 and
2,800 m (4.8 and 5.4%, respectively). It returned to baseline by
24 h at the two lowest altitudes but remained significantly
reduced at the two highest altitudes (Fig. 1B). The
magnitude of desaturation from sea level after 24 h at each
simulated altitude (
SaO2) was correlated to the
degree of the increase in EPO (EPO) rise
(r2 = 0.17, P < 0.05; Fig.
4). Thus the change in
SaO2 accounted for <20% of the variability in EPO
concentration.
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RBF.
RBF values are shown in Table 1. There
was no significant difference in RBF at 6 h compared with sea
level values at all simulated altitudes. When SaO2 and
Hb were factored in (i.e., renal O2 delivery), there was no
significant influence of renal O2 delivery on EPO release
at these moderate altitudes.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal findings of this study include the observation that short-term, sustained EPO production occurs at moderate altitude once a threshold of 2,100-2,500 m is crossed. Below this altitude, changes in EPO are modest and not sustained after 24 h of exposure in the majority of individuals. Moreover, EPO production at altitude is marked by substantial interindividual variability, governed by "upstream" factors related to renal parenchymal PO2, as well as other undetermined mechanisms, presumably related to transcriptional regulation of EPO by renal tissue hypoxia.
Optimal threshold altitude for EPO release. EPO is a glycoprotein hormone that regulates proliferation and differentiation of erythroid cells. Its production is markedly enhanced by reductions in CaO2 mediated by anemia or hypoxia (6, 20) and certain metals such as cobalt and nickel (37). A number of physiological studies demonstrated that the concentration of EPO is substantially increased after high-altitude exposure and then gradually declines toward baseline within the first few days to weeks of exposure (21, 28, 29).
However, most studies examining the erythropoietic effect of altitude have used much higher altitudes (and, therefore, more severe hypoxia) than reported in the present study, generally >4,000 m. In contrast, the majority of occupational and recreational exposures occur at more moderate altitudes, between 2,000 and 3,000 m (23). Some populations, such as endurance athletes, routinely travel to moderate altitudes with a goal to improve sea level performance via altitude-induced erythrocytosis (17). However, cross-sectional studies by Weil et al. (35) demonstrated that an erythropoietic response to hypoxia is not achieved until PaO2 decreases to ~65-70 Torr (corresponding to an altitude of 2,500-3,000 m in sedentary individuals); red cell mass and PaO2 are linearly correlated when altitude-induced hypoxemia becomes more severe. Whether such a threshold is present in sea level natives ascending to moderate altitude is uncertain. Previous studies at moderate altitudes have consistently demonstrated an increase in EPO of a magnitude similar to that observed in the present study in response to real or simulated altitude (normobaric or hypobaric hypoxia) of ~2,500 m (2, 4, 5, 9, 14, 17). One study (5) compared the acute (5.5 h) effect of 3,000 vs. 4,000 m in a hypobaric chamber and demonstrated a more rapid rate of rise and a proportionately greater increase in EPO at the higher altitude. The present study extends these previous observations by demonstrating what appears to be a threshold, rather than a continuous linear relationship, at lower altitudes. Specifically, the EPO levels at the two lowest altitudes increased modestly (24-30%), peaking at 6 h after exposure; in contrast, EPO increased more prominently (77-92%) at the two highest altitudes, with a continued increase after 24 h at 2,500 and 2,800 m (Fig. 1A). These observations suggest that altitudes >2,100-2,500 m appear to be required for stimulating sustained EPO release. The mechanism of this differential response is likely to include the greater oxyhemoglobin desaturation that occurs as the PO2 falls to the steep portion of the oxyhemoglobin dissociation curve. Thus the EPO levels at all altitudes paralleled the changes in SaO2; the magnitude of desaturation at altitude was correlated to the degree of the increase in EPO, suggesting that there may be an inadequate hypoxic stimulus for the production of EPO at <2,100 m. However, the strength of this relationship was relatively weak, with a correlation coefficient, albeit statistically significant, of only 0.42. Part of this weak relationship may be explained by the fact that the changes in SaO2, among the different altitudes and at each altitude, compared with control were very small. For example, mean SaO2 values fell by <1% at 1,780 m, which was statistically significant as a group effect but within the limits of precision of the pulse oximeter for any individual measurement. In this regard, it is remarkable that such clear differences in EPO levels occurred, despite relatively small differences in SaO2. The relationship between SaO2 and EPO, particularly at the earliest time point, may be further complicated by the fact that the rate of EPO production in response to altitude-induced hypoxia is likely to be variable depending on the absolute degree of hypoxia achieved (5). One additional confounding factor may be that the renovascular bed autoregulates sufficiently to maintain adequate renal O2 delivery, despite systemic hypoxia. In the present study, RBF after 6 h of exposure to simulated high altitude was not significantly different from RBF at sea level. Moreover, EPO levels at all simulated altitudes were not correlated with renal O2 delivery, incorporating measures of RBF and CaO2. These data suggest that, within the limits of our methodology to detect changes in RBF, renal O2 delivery, by itself, is not a strong determinant of EPO production in humans, as has been demonstrated in animal studies (25).Urine PO2 as an estimate of renal tissue PO2. However, renal O2 delivery reflects only one side of the equation: ultimately, renal parenchymal PO2, a function of renal O2 delivery minus renal O2 utilization, appears to be the essential determinant of EPO production (11, 37). Thus renal vein or urine PO2 as an estimate of renal tissue PO2 may be a better marker of the stimulus for EPO release than SaO2 or renal O2 delivery (24). To our knowledge, this is the first study to measure urine PO2 in humans at different altitude exposures, although other investigators have demonstrated increases in urine PO2 during increases in PO2 mediated by hyperoxia (13, 18, 27). Moreover, graded reductions in RBF lead to similarly graded reductions in urinary PO2, confirming the dependence of urine PO2 on renal O2 availability (13). According to the concept of countercurrent gas diffusion (27), urine PO2 in the collecting ducts is lower than the venous PO2. The estimated renal venous PO2 at sea level is ~70-80 Torr in humans (27) and 50-60 Torr in rats (24). Renal tissue EPO and plasma EPO in rats have been correlated to renal venous PO2 during exposure to chronic hypoxia in a curvilinear relationship similar to that observed in humans in the present study (24).
A number of technical issues must be considered in the interpretation of measurements of urinary PO2. First, it should be recognized that the kidney is not uniform in its oxygenation, with gradations of PO2 from the outer cortex to the inner medulla (16). Moreover, urine PO2 is sensitive to hydration state, with most (16, 26), but not all (18), studies showing an increase in urine PO2 with increasing degrees of hydration and/or urine flow rates. Conversely, if urine flow rates are too low, i.e., <3 ml/min, there is significant uptake of O2 in the walls of the ureters and bladder, reducing bladder PO2 compared with renal pelvic PO2 (27); flow rates of5 ml/min
are necessary to ensure that urethral collections reflect the
PO2 from the renal pelvis (27).
Finally, a prominent water diuresis (26) or saline loading (18) can influence the results by increasing or decreasing
urine PO2, respectively. Fortunately, when
hydration status is carefully controlled and urine flow rates are
neither too low nor too high, urine PO2 is very
reproducible in any given subject from day to day and is a reasonable
reflection of renal medullary oxygenation (8, 18, 26). In
the present study, baseline sea level measurements of urine
PO2 were reproducible from week to week and
similar to data reported by other investigators (8).
In our study, the urine PO2 was significantly
decreased by 6 h at all altitudes and then rapidly returned to
near baseline by 24 h at the two lowest altitudes and remained
significantly low at the two highest altitudes (Fig. 1C),
closely paralleling the changes in arterial oxyhemoglobin saturation.
The threshold above and below 2,100 m that was clearly evident in EPO
and SaO2, even at the first time point (6 h), was not
manifest until 24 h for the urine PO2
data. Although we cannot determine with certainty the mechanism for
this differential response, we speculate that the different time
courses of ventilatory acclimatization, neurohumoral activation, and
renal metabolic compensation may be at least partly responsible for
this inconsistency. The very small differences among the altitudes
studied and the resultant experimental noise may also be playing a role
at this early stage, before the overall response becomes more complete
after a full 24 h of exposure.
We suspect, but cannot prove, that the short-term acclimatization
response (primarily ventilatory acclimatization) appears to restore
renal tissue oxygenation rapidly and restrain the rise in EPO at the
lowest altitudes. For example, we did not measure ventilation or
end-tidal CO2 concentrations and thus have only indirect
evidence that ventilatory acclimatization occurred at these low
altitudes. However, we can say that although the magnitude of the
hypoxia (as estimated from SaO2) experienced at the
lowest altitudes was modest, the consistent decrease in urine
PO2 and subsequent rise in EPO provide
compelling evidence that this hypoxia was physiologically significant
at all altitudes and likely to stimulate peripheral chemoreceptors.
Most dramatically, on average, changes in urine
PO2 were strictly proportional to EPO levels at
all four altitudes (r2 = 0.992). This
strong, possibly deterministic, relationship supports the hypothesis
that renal tissue PO2 is an essential factor
for determining EPO production in humans at high altitude.
Individual variability of EPO production.
Despite this tight relationship for the mean group data, the individual
relationships between urine PO2 and EPO were
highly variable (Fig. 3). Moreover, EPO levels in response to
short-term simulated altitude exposure demonstrated marked
interindividual variability, ranging from 41 to 400% after
24 h of exposure to 2,800 m (Fig. 2). Intriguingly, the EPO
response was generally consistent among individuals; i.e., those
individuals with the greatest response to the lowest altitudes had the
greatest response to the highest altitudes. Some insight into possible
mechanisms for this variability may be found in a recent animal study
in which blood EPO and renal tissue EPO in response to acute or chronic hypoxic exposure were dramatically different in two rat strains, suggesting that genetic factors may be involved in the regulation of
the EPO response (24). In this study, the curvilinear
relationship between renal tissue PO2 and EPO,
as well as a marked difference between strains in the transcription of
mRNA for EPO in response to a given renal tissue
PO2, argued strongly for transcriptional regulation of EPO synthesis at altitude and was remarkably similar to
the data found in the present study in humans.
(33), a major
transcription factor that binds to the human EPO gene 3'-flanking
region and initiates transcriptional activation of the EPO gene in the
hypoxic cells of the kidneys (34). In light of these
observations, we speculate that these transcriptional and
posttranscriptional mechanisms for governing the regulation of EPO gene
expression may be playing a substantial role in the observed individual variability.
In summary, we conclude that short-term, sustained EPO production in
response to simulated altitude has a clear threshold: altitudes
>2,100-2,500 m are required to stimulate a sustained increase in
group EPO concentrations over 24 h. Despite this population effect, EPO production at altitude is marked by substantial
interindividual variability, with some individuals exhibiting ~100%
increases in EPO levels to exposures of 1,780 m, whereas others did not increase EPO levels in response to 2,805 m. This variability appears to
be governed by upstream factors related to renal parenchymal PO2, as well as by other undetermined
mechanisms, presumably related to transcriptional regulation of EPO by
renal tissue hypoxia.
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. D. Levine, Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas, 7232 Greenville Ave., Suite 435, Dallas, TX 75231 (E-mail: benjaminlevine{at}texashealth.org).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published November 30, 2001;10.1152/japplphysiol.00684.2001
Received 2 July 2001; accepted in final form 6 November 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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