Metabolic responses of the kidney in fetal sheep:

effect of acute and spontaneous hypoxemia

HARRIET S. IWAMOTO AND ABRAHAM M. RUDOLPH

Cardiovascular Research Institute and Departments of Pediatrics, Physiology, and Obstetrics,
Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143

IWAMOTO,HARRIET S.,AND ABRAHAM M. RUDOLPH. Met- consumption rates in the kidney under normoxemic and
abolic responses of the kidney in fetal sheep: effect of acute and hypoxemic conditions.
spontaneous hypoxemia. Am. J. Physiol. 249 (Renal Fluid Elec-
trolyte Physiol. 18): F836-F841,1985.-To examine the effects
of hypoxemia on carbohydrate and O2 consumption by the fetal METHODS
kidney, we inserted catheters into the descending aorta, inferior Animal preparation. We studied 14 fetal sheep with
vena cava, and left renal vein of 14 fetal sheep at 120-130 days
gestation. Three to nine days after surgery, nine fetuses had an known gestations of 124-133 days (term = 145 days).
arterial Pop of 22 t 2 mmHg and O2 content of 2.68 t 0.65 After a 24. to 48-h fast, low epidural anesthesia was
mM. In these fetuses, the kidneys consumed O2 (107 -I- 21 induced in the ewes by injecting 4 ml of 1% tetracaine
pm01 min-l
l 100 g-l, mean * SD) and lactate (14 A 9.6 prnol.
l
hydrochloride (Pontocaine HCl, Breon Laboratories,
min-’ 100 g-l) but produced glucose (5.6 t 6.5 pmol . min.
l New York, NY). Polyvinyl catheters (ID, 1.3 mm; OD,
100 g-l; 95% confidence limits, 0.62 and 10.5). When acute 2.3 mm) were inserted in the left maternal dorsalis pedis
hypoxemia was induced by decreasing maternal fractional in- artery and vein and passed centrally to lie in the inferior
spired O2 (FIN,) to 0.09, renal O2 consumption fell slightly (to vena cava and descending aorta. Ketamine hydrochloride
82 t 21 pmol min-’ 100 g-l), and there was net glucose uptake
n l

(Vetalar, Parke-Davis, Morris Plains, NJ) was adminis-

and net lactate release. A group of five fetuses was sponta-
neously hypoxemic 3-5 days after surgery and had an arterial
PO* of 14 t 2 mmHg and O2 content of 1.99 $- 0.51 mM. Renal
blood flow and O2 consumption were greater in these fetuses
than in the normoxemic fetuses. There was net lactate uptake
and no net flux of glucose across the renal circulation.
results demonstrate that renal metabolism of carbohydrate
altered by changes in fetal oxygenation.
carbohydrates; oxygen consumption; blood flow
IN NORMOXEMIC FETAL SHEEP, glucose metabolism ac-
counts for about half and lactate and amino acid metab-
olism account for most of the rest of the oxidative met-
abolic rate (2). We have shown that under normoxemic
conditions, in relation to tissue weight, the fetal kidney
consumes O2 at a rate comparable with that of the
gastrointestinal tract [but less than that of the heart,
brain, and liver (4, 5, l2)], consumes lactate, and pro-
duces small amounts of glucose (9). Hypoxemia alters
organ blood flow (3) and blood concentration of many
metabolic substrates (11) and thus may change the deliv-
ery rate of metabolic substrates to fetal organs as well as
change fetal organ metabolism. In this investigation, we
measured 02 consumption and carbohydrate metabolism
in the fetal kidney in response to acutely induced and
spontaneously occurring hypoxemia. We placed a non-
occlusive catheter in the left renal vein and measured
arteriovenous concentration differences across the renal
vascular bed. By simultaneously measuring renal blood
flow with the radionuclide-labeled microsphere tech-
nique, we were able to calculate 02, glucose, and lactate
F836
tered intravenously to the ewe in amounts of 50 mg at
IO-15-min intervals to maintain sedation; with any evi-
dence of restlessness, additional ketamine was adminis-
tered.
These Using aseptic procedures, we made a midline incision
is in the ventral abdomen of the ewe and exposed the
pregnant horn of the uterus. Catheters were placed into
the fetus as described previously (10). Briefly, both fetal
hindlimbs were exteriorized through a 7-lo-cm incision
and polyvinyl catheters (ID, 0.8 mm; OD, 1.2 mm) were
inserted into both pedal arteries and veins and passed
centrally to lie in the distal descending aorta and inferior
vena cava. The hindlimbs and lower portion of the fetal
trunk were then extracted to the level of the pubis.
Through a 2- to 3-cm midline abdominal incision just
above the pubis, a silicone rubber catheter (ID, 1.6 mm;
OD, 3.3 mm) was placed in the fetal bladder and secured
with a purse-string suture. A catheter was then placed
in the left renal vein of the fetus through a retroperito-
neal incision. The catheter, which comprised a 1.5cm
endpiece of a 20-gauge Teflon intravenous catheter (I.V.
Cath; ID, 0.56 mm; OD, 0.8 mm; Becton-Dickinson,
Rutherford, NJ) fitted into a 4-cm length of polyvinyl
catheter (ID, 0.8 mm; OD, 1.2 mm), was secured in place
with a 6-O silk suture in the adventitia of the vein. It was
then connected to a 40-cm length of polyvinyl catheter.
The muscle and skin of the fetal incision were sutured.
A catheter was placed in the amniotic fluid cavity for
the measurement of intrauterine pressure. The vascular
catheters were filled with heparin sodium solution (1,000
U/ml) and sealed. Kanamycin sulfate (600 mg) and pen-
icillin G (1 million units) were administered into the
0363-6127/85 $1.50 Copyright 0 1985 the American Physiological Society

Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.

 EFFECT OF HYPOXEMIA ON FETAL RENAL METABOLISM
maternal venous and amniotic cavity catheters on the
day of surgery and each day thereafter. After surgical
procedures were completed, the catheters were passed
through the abdominal wall to the ewe’s flank where they
were protected by a cloth pouch sewn to the skin. The
ewe’s abdomen was sutured in layers. The free end of the
bladder catheter was connected to the amniotic catheter,
allowing urine to flow into the amniotic cavity. The
animals were allowed to recover for 3-9 days after surgery
before any study was performed.
To ensure that blood sampled from the renal venous
catheter was not contaminated with blood from the in-
ferior vena cava, in a manner described previously (1-O),
we
. infused [ 14C]inulin (17 mCi/mmol, Amersham, Ar-
lin .gtonHeights, IL) into the inferior vena cava caudal
to the renal vein while obtaining simultaneous blood
samples from the descending aorta and renal vein under
normoxic and hypoxic conditions. If the 14C had appeared
first in the renal vein, the renal venous samples would
have been contaminated with inferior vena caval blood.
Experimental protocol. Nine fetuses were considered to
be normoxic (PO:! >19 mmHg) at the time 1of study and
were exposed to acute hypoxemia. Fetal vascular pres-
sures and heart rate were recorded continuously (Sta-
tham P23 IDb transdu cers and Beckman eight-channel
Dynograph direct-writing recorder). While the ewe was
breathing room air, blood samples were obtained simul-
taneously from the desce nding aorta, renal . vein, and
inferior ve na cava for the determination of Po2, pco2,
pH, hemoglobin concentration, blood O2 saturation, and
blood glucose and lactate concentrations. Fifteen-mi-
crometer-diameter radionuclide-labeled microspheres
were injected into the inferior vena cava while a reference
sample was obtained from the descending aorta for the
determination of blood flow distribution. The micro-
spheres injected were randomly chosen from a group of
microspheres labeled with either 153Gd 57Co, ‘14”In, 51Cr,
l13Sn, %Sr, g5Nb, 54Mn, or (j5Zn. Acute hypoxemia was
induced by giving the ewes a low-02 gas mixture to
breathe [ 14 liters of N2, 12 liters of air, and 1 liter of CO2
per minute; fractional inspired 02 (FIN,) = 0.091. Addi-
tional blood samples were obtained and d ifferently la-
beled microspheres were injected at 15 an d 40 min after
the induction of acute hypoxemia. After each set of blood
samples was obtained, an equivalent amount of donor
fetal blood was infused for replacem .ent. Five fetuses
were sponta neously hypoxemic ( arterial PO2 ~16 m .mHg)
at the time of the study. Three measureme nts of blood
constituents and blood flow distribution were made at
15-2O-min intervals as detailed above, but the ewes
breathed room air throughout the study.
Measurement and analysis of the data. At the end of
the studies, the ewe was anesthetized with an intravenous
injection of pentobarbital sodium and killed. The fetuses
were removed from the uterus. The left and right kidneys
and the lower portion of the fetal body below the second
intercostal space, excluding the abdominal organs, were
dissected, incinerated in an oven at 325°C for 48 h,
ground into a coarse powder, placed into plastic vials to
a uniform height of 3 cm, and counted for radioactivity
in a l,OOO-channel multichannel pulse-height analyzer
Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.
F837
(Norland, Fort Atkinson, WI). We calculated the specific
activity of each isotope within a sample using a least-
squares analysis (1). Blood flow to the kidneys was
calculated by dividing the number of counts in the kidney
by the counts in the refe rence sample and multiplying
by the withdrawal rate of the reference sample (8). Left
and right kidneys were counted separately to ensure that
microspheres were mixed adequately and that the renal
venous catheter did not obstruct blood flow.
Blood gases ‘and pH were determined on a Corning
model 175 blood gas analyzer (Corning Medical, Med-
field, MA). Hemoglobin concentration and blood O2 sat-
uration were determined on a Radiometer hemoximeter
(model OSM2, Copenhagen, Oakland, CA). O2 capacity
was calculated as the product of the hemoglobin concen-
tration and 1.35, and O2 content was calculated as the
product of 02 saturation and O2 capacity. The amount
of dissolved 02 was considered to be negligible. Blood
concentrations of glucose and lactate were measured in
duplicate samples by enzymatic methods (Sigma). The
intra-assay coefficient of variation for the glucose assay
was 1.0~l.4%, and the intra-assay coefficient of variation
for the lactate assay was 3.0-3.2%. Renal vascular re-
sistance was calculated by dividing the difference be-
tween descending aortic and renal venous pressure by
blood flow and expressed in units of mmHg/mlmin-’ l
100 g-l. O2 consumption by the kidney was calculated by
multiplying renal blood flow by the difference in blood
O2 contents in the descending aorta and renal vein and
expressed in units of pmol 02 min-’ 100 g-‘. Net renal
l l
glucose and lactate uptake or release were calculated by
multiplying renal blood flow by the difference in blood
glucose or lactate concentrations in the desce Inding aorta
and renal vein. Substrate-O2 quotient, the theoretical
fraction of total 02 consumption required to completely
metabolize a substrate to CO2 and H20, was calculated
as the arteriovenous substrate concentration divided by
the arteriovenous O2 content difference times a factor (6
for glucose, 3 for lactate; Ref. 2).
All values a re expressed as means t SD. The data
from the acute hypoxemia studi .es were analyzed by one-
way analysis of variance for repeated measures (20).
Con trast compar bisons were then used to determine which
means, at the indicated level of significance, were statis-
tically different from the means of the control value or
values. The relationships between 02 delivery and O2
consumpti .on, arterial and arteriovenous 02 con tent, and
arterial O2 content and renal O2 extraction were analyzed
by simple linear correlation. Differences between values
obtained from normoxemic and spontaneously hypox-
emit fetuses were assessed by the nonparametric Mann-
Whitney U test.
RESULTS
Chronic maintenance of the renal venous catheter did
not obstruct blood flow; under both normoxemic and
hypoxemic conditions, blood flows to the left and right
kidneys. were not significantly different (Table 1). The
blood sampled from the renal venous catheter was not
contaminated with inferior vena caval blood; in all in-
F838 H. S. IWAMOTO AND A. M. RUDOLPH

stances, as [ 14C]inulin was infused into the distal inferior TABLE 2. Effect of acute hypoxemia on renal 02
vena cava, 14C appeared first in the descending aorta and consumption
then in the renal vein (10).
Metabolism during normoxemia. Under normoxemic Normoxemia 40' Hypoxemia
conditions, the pH, Pco~, POT, hemoglobin concentration Sheep Oxygen con- Oxygen content,
and saturation, and O2 content of the blood in the de- No. tent, mM mM
scending aorta of the nine normoxemic fetuses were A A-V A A-V
within the range of expected values (Table 1). The body 2.37 0.60 127 76 1.01 0.60 159 95
weight of these fetuses was 2.99 t 0.56 kg. Renal 02 3.13 0.67 137 92 1.29 0.64 102 65
delivery was 453 t 160 prnol. min-’ 100 g-l, 02 extrac-
l 3.89 0.58 199 115 1.83 0.81 139 113
tion was 25 t 7%, and 02 consumption was 107 t 21 1.68 0.54 141 76 0.66 0.27 274 74
pmol. mix? 100 g-l (Tables 1 and 2). 2.10 0.57 207 118 1.18 0.46 180 83
2.80 0.60 193 116 1.00 0.62 87 54
l

Arterial glucose concentration was 0.928 t 0.258mM 2.33 0.84 150 126 0.77 0.41 249 102
(Table 3). In one animal, glucose concentration in the 2.81 0.53 208 110 1.61 0.54 172 93
renal vein was the same as that in the descending aorta, 3.00 0.92 146 134 1.51 0.37 163 60
but in the eight other animals glucose concentration was
Mean 2.68 0.65 165 107 1.21' 0.52 166 82
greater in the renal vein, indicating net glucose produc- *SD k0.65 to.14 k30 *21 to.39 k0.16 zk58 k21
tion. In these fetuses, the net amount of glucose produced
A, concentration in the descending aorta; A-V, concentration differ-
by the kidneys ranged from 0.58 to 19.68prnol mine1 l

ence between the descending aorta and renal vein. Blood flow is
100 g-’ (Table 3). expressed as ml. min-’ 100 g-’ and O2 consumption (7$02) is expressed
l

Arterial lactate concentration was 1.53 t 0.32 mM as pm01 . min-’ -100 g-‘. * Significantly different from normoxemia, P
(Table 4). In all animals, there was net lactate uptake by < 0.05.
the kidney at a mean rate of 13.77t 9.16 pmolmin-’ l

100 g-l. The mean lactate-to-O2 ratio was 0.43,suggest- TABLE 3. Effect of acute hypoxemia on glucose flux
ing that lactate metabolism accounted for 43% of renal across the renal vascular bed
O2 consumption under normoxemic conditions.
Metabolism during acute hypoxemia. Acute hypoxemia Normoxemia 40' Hypoxemia
increased mean arterial pressure significantly from a Sheep
Glucose, mM Glucose, mM
No.
control value of 48 t 3.9 to 57 t 6.2 mmHg (P < 0.005) A A-V
VG VG
A A-V
but had no significant effect on fetal heart rate (control,
177 t 17 beats/min; hypoxemia, 172 t 15 beats/min), 1.12 0 0 1.29 0.020 3.18
0.938 -0.017 -2.33 1.118 0.024 2.45
renal blood flow, or calculated renal vascular resistance 1.143 -0.100 -19.68 1.317 0.124 17.19
after 15 or 40 min of hypoxemia (Table 1). Arterial pH, 0.749 -0.018 -2.53 0.846 0.05 13.68
Po2 Pco~, and O2 content and blood saturation all de- 0.784 -0.028 -5.81 1.249 0.047 8.48
creased significantly (Table 1). 1.415 -0.041 -7.90 1.69 0.118 10.26
Renal O2 consumption was 107 t 21 ~molomin-l~ 100 0.577 -0.004 -0.60 0.913 -0.004 -0.99
0.747 -0.051 -10.61 0.878 -0.014 -2.40
0.880 -0.004 -0.58 0.931 -0.010 -1.63

TABLE 1. Effect of hypoxemia on arterial blood pH Mean 0.928 -0.019 -5.56 1.137" 0.039 5.581*
and gases and renal 02 delivery and 02 extraction tSD k0.258 to.032 t6.43 k0.278 ~0.052 k7.117
A, concentration in the descending aorta; A-V, concentration differ-
Acute Spontaneous ence between the descending aorta and renal vein. Glucose flux (Vo) is
Normoxemia* Hypoxemia* Hypoxemiaf expressed as prnol min-’ 100 g-? * Significantly different from nor-
l l

moxemia value, P < 0.05.

PH 7.36t0.02 7.34+0.02$ 7.33+0.05$
POT, mmHg 22,t2 13+2$ 14&2$
Pco~, mmHg 50t4 45+3$ 47*5 g-l during normoxemia and 82 t 21 prnol. min-’ . 100 g-l
Hemoglobin, g/dI 8.6k1.4 9.5+1.4$ 10.2+0.7$ during acute hypoxemia; there was no significant statis-
Blood saturation, % 51*7 38-e10$ 32+7$ tical difference between these two values. When values
O2 content, mM 2.68k0.65 1.21+0.39$ 1.99+0.51$
Renal blood flow, of 02 delivery and 02 consumption were compared, how-
ml. min-’ -100 g-’ ever, there was a significant positive linear relationship
Total 165k30 166k58 28Ok80$ (Fig. lA; correlation coefficient r = 0.66, P C 0.05). The
Left 167t33 169k61 266+79$ relationship between renal blood flow and arterial 02
Right 164t33 163k58 292+83$ content during acute hypoxemia was not significant (Fig.
Renal vascular 0.3OkO.06 0.38kO.14 0.20+0.05$
resistance, lB), but renal 02 extraction increased significantly as
mmHg/ml . min-’ l
arterial 02 content decreased (Fig. 1C; correlation coef-
100 g body wt-’ ficient r = -0.80, P < 0.05). During acute hypoxemia,
O2 delivery, pmol
l 453k160 194&62$ 5051fr102 arterial glucose concentration increased to 1.14 t 0.28
min-’ 100 g-’
l

O2 extraction, % 25k7 45+12$ 2928 mM and net glucose flux changed from net glucose
O2 consumption, pm01 l 107k21 82*21 138*35$ release to net glucose uptake (Table 3). Arterial lactate
min”. 100 g-’ concentration also increased, and lactate flux changed
Values are means t SE. * n = 9. t 15 measurements in 5 fe- from net lactate uptake to net lactate release (Table 4).
tuses. $ Significantly different from normoxemia, P < 0.05. Metabolism during spontaneous hypoxemia. A group of

Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.

EFFECT OF HYPOXEMIA ON FETAL RENAL METABOLISM F839

TABLE 4. Effect of acute hypoxemia on lactate flux (49 t 4 mmHg) were not significantly different from
across the renal vascular bed normoxemic fetuses, but the hemoglobin concentration
and renal blood flow were greater and renal vascular
Normoxemia 40’ Hypoxemia resistance was less (Table 1). Renal O2 delivery was not
Sheep different in the two groups, but renal 02 consumption
Lactate, mM Lactate, mM
No.
A-V
VL
A A-V
VL was significantly greater in the spontaneously hypoxemic
A
fetuses (Table 1). Unlike the situation in acutely hypox-
2.04 0.190 24.16 5.56 -0.09 -14.31 emit fetuses, in the spontaneously hypoxemic fetuses
1.80 0.232 31.74 4.34 -0.60 -61.36
4.046 0.044 6.10 renal O2 consumption was not related to 02 delivery (Fig.
1.214 0.09 17.71
1.437 0.085 11.95 6.468 -0.132 -36.13 lo), O2 extraction was not related to arterial 02 content
1.402 0.08 16.59 6.699 -0.084 -15.15 (Fig. W), and renal blood flow increased significantly as
1.724 0.023 4.43 7.309 -0.111 -9.65 arterial 02 content decreased (Fig. 1E; correlation coef-
0.974 0.037 5.56 3.074 -0.368 -91.45 ficient r = -0.65, P < 0.05).
1.480 0.023 4.79 2.651 0.213 36.58
1.704 0.048 6.99 4.094 0.045 7.31 Arterial glucose concentration in these fetuses was 0.91
t 0.32 mM and the arteriovenous concentration differ-
Mean 1.531 0.090 13.77 4.916' -0.120 -19.78* ence for glucose (-0.031 t 0.072 mM) was not signifi-
*SD kO.324 kO.074 t9.61 k1.659 kO.240 k38.52 cantly different from zero. Arterial lactate concentration
A, concentration in the descending aorta; A-V, concentration differ- was 3.94 t 3.10 mM, greater than in the normoxemic
ence between the descending aorta and renal vein. Lactate flux (Vi) is fetuses (P c O.OOl),and there was net uptake of lactate
expressed as pmol min-’
l 100 g-'. * Significantly
l different from nor-
at a rate of 21.35 t 31.79 ~molmin-‘= 100 g-' (95%
moxemia, P < 0.05.
confidence limits, 3.12 and 39.58). The mean lactate-to-
ACUTE SPONTANEOUS
O2 ratio was 0.44, suggesting that lactate metabolism
accounted for 44% of renal O2 consumption in these
spontaneously hypoxemic fetuses.

DISCUSSION
In this study, acute hypoxemia did not change renal
QCOO blood flow. This finding conflicts with previous reports
oxY~oeiverytlJmol/min/1oog)
by Cohn et al. (3) and Peeters et al. (18). The sheep in
this study were approximately the same age as those used
by Cohn et al. (3), but the hypoxic stimulus used by
Cohn et al. (FIN, = 0.06) was slightly greater than that
used in this study (FIQ = 0.09). This may in part be
responsible for the discrepancy between the results of
00 I 2 3 o- I 2 3 4
the two studies. Peeters and colleagues defined a curvi-
linear relationship between arterial 02 content and renal
blood flow such that renal blood flow did not decrease
significantly until arterial 02 content decreased to l-l.5
mM. However, individual values of renal blood flow in
their study were quite variable in the low range of arterial
o&40& I 2 3 I 2 3 O2 contents, and not all values conformed to the calcu-
Arterial oxygen content hM1 lated curvilinear relationship. The data presented in Fig.
FIG. 1. Relationships of O2 delivery and arterial 02 content to renal 1B and the data of Peeters and colleagues do not appear
O2 consumption, blood flow, and 02 extraction in normoxemic (A), to differ significantly; thus there may be no conflict
acutely hypoxemic (A), and spontaneously hypoxemic (0) fetal sheep. between the results of these two studies. The results of
In normoxemic fetuses made acutely hypoxemic, renal 02 consumption the present study do not differ from those of Millard et
decreased as O2 delivery decreased (r = 0.66, P < 0.005) (A), arterial
O2 content and renal blood flow were not related (B), and renal 02
al. (l5), who found in fetal sheep that a decrease in
extraction increased as arterial 02 content decreased (r = -0.80, P < arterial POP from a mean value of 20 to 13 mmHg did
0.001) (C). In spontaneously hypoxemic fetuses, 02 delivery and renal not change renal blood flow significantly, but a further
O2 consumption were not related (D), renal blood flow increased as decrease to 9 mmHg did decrease renal blood flow. In-
arterial O2 content decreased (r = -0.65, P < 0.01) (E), and 02 hibition of prostaglandin synthesis reduced renal blood
extraction was not related to arterial O2 content (F).
flow markedly during hypoxemia, suggesting that pros-
taglandins play a role in maintaining renal blood flow.
five fetuses had an arterial Pop of 14 t 2 mmHg and O2 Since prostaglandin production and influence on the
content of 1.99 t 0.51 mM (significantly less than nor- circulation in the kidney increases in stressful situations
moxemic fetuses; Table 1) at the time of study and were (14), prostaglandin-mediated vasodilation may be re-
considered to be spontaneously hypoxemic. The mecha- sponsible for the higher renal blood flow in the sponta-
nism for this is unknown, but these fetuses were not neously hypoxemic fetuses.
growth retarded, since their body weight was 2.71t 0.56 In response to hypoxemia, renal 02 consumption was
kg. The arterial PCO~ and pH and arterial blood pressure maintained. In acutely hypoxemic fetuses, renal 02 ex-

Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.

F840 H. S. IWAMOTO AND A. M. RUDOLPH

traction increased from 25 to 45%. This increase in 02 glucose release to net glucose uptake and from net lactate
extraction in response to decreased 02 delivery is similar uptake to net lactate release. These changes may reflect
to the response of the musculoskeletal system (Mayman, changes in certain metabolic pathways. In hypoxia, gly-
Iwamoto, and Rudolph, unpublished observations) and colysis is accelerated due to an increase in the activity of
gastrointestinal tract (18). In response to hypoxemia, phosphofructokinase (17), which could result in an in-
however, blood flow to the musculoskeletal system and crease in lactate production and a decrease in glucose
gastrointestinal tract dec reased, as did O2 consumption. production. This is consistent with our observed changes
In the kidney, renal 0 2 consumption was maintained in net substrate flux. The changes in renal metabolism
probably because blood flow did not decrease. In spon- may also reflect changes in intrarenal blood flow distri-
taneously hypoxemic fetuses, 02 consumption was in- bution. Katz et al. (13) have reported that acute asphyxia
creased probably due to the increase in blood flow. The resulting from uterine artery constriction preferentially
reasons for this are unclear; perhaps the kidney plays a decreased blood flow to the outer renal cortex. In this
role in the response to hypoxemia. Acute hypoxemia area of the adult cat kidney, glucose is both produced via
alters renal excretion of solutes and water (19), increases gluconeogenesis and utilized via glycolysis resulting in
renal output of renin and prostaglandins (19, Iwamoto net glucose production, whereas in the corticomedullary
and Rudolph, unpublished observations), and may in- portion of the kidney gluconeogenesis and glycolysis
crease renal output of erythropoietin (21, 22). These or result in net glucose utilization (6). If there were such
other as yet undefined changes in renal function may be regional differences in glucose metabolism in the fetal
important in the fetal response to hypoxemia. sheep kidney as in the adult cat kidney, a decrease in
In normoxemic fetuses, we have shown that lactate blood flow to the outer renal cortex with acute hypoxemia
was I take In up by the kidn .eys at a rate which accounted would shun .t blood flow away from an area of net glucose
for 43% of the oxidative me tabol ism. This percentage, production to an area of net glucose consumption, and
obtained by calculating the lactate-to-O2 quotient (2), is this could account for the changes we observed in glucose
based on the assumption that lactate taken up is com- flux across the renal vascular bed.
pletely oxidized to CO2 and H20 and may be an overes- In the fetus in which hypoxemia occurred sponta-
timate of the actual amount of lactate oxidized by the neously, there was net uptake of lactate at a rate com-
kidneys. We have also shown that there was net glucose parable with normoxic fetuses but no net uptake or
production by the fetal kidneys and have preliminary release of glucose. In these fetuses, there may have been
evidence that a portion of this glucose is derived from lactate oxidation and formation of glucose from lactate.
lactate (Gleason, Iwam oto, and Rudolph, unpublished The glucose produced may have been totally consumed
observa tions). W hereas some lactate may be oxidized within the kidney, resulting in no net release. To accu-
directly as substrate, some is converted to glucose either rately assess rena .l metabolism in spo ntaneously and
directly through gluconeogenic pathways or possibly in- acutely hypox .emic fetuses, more studies are necessa .ry.
directly through initial formation of glycogen and sub-
sequent release of glucose-6-phosphate (7, 16). The net
amount of glucose produced by the kidney, estimated by We gratefully acknowledge the skillful technical assistance of Chris-
tine Roman, Carol Eisenberger, Bruce Payne, and Carl McWatters
the Fick principle to be equal to l-2% of total umbilical that made the completion of this project possible.
uptake (2), may be an underestimate of total renal glu- This work was supported in part by Public Health Service Grant
cose production. Conceivably, glucose formed in one area HD-17618 and Individual National Research Service Award HL-06125
of the kidney can be used as substrate in another area; awarded to Dr. Iwamoto.
it would be impossible to measure total renal glucose This work was presented in part at the 30th Annual Meeting of the
Society for Gynecological Investigation, Washington, DC, March 1983.
production using Fick methodology alone.
Acute hypoxemia altered renal metabolism from net Received 4 February 1985; accepted in final form 21 June 1985.

REFERENCES

1. BAER, R. W., B. D. PAYNE, E. D. VERRIER, G. J. VLAHAKES, D. lyte Physiol. 3): F415-F423, 1978.
MOLODOWITCH, P. N. UHLIG, AND J. I. E. HOFFMAN. Increased 7. HEMS, D. A., P. D. WHITTON, AND E. A. TAYLOR. Glycogen
number of myocardial blood flow measurements with radionuclide- synthesis in the perfused liver of the starved rat. Biochem. J. 129:
labeled microspheres. Am. J. Physiol. 246 (Heart Circ. Physiol. 15): 529-538,1972.
H418-H434,1984. 8. HEYMANN, M. A., B. D. PAYNE, J. I. E. HOFFMAN, AND A. M.
2. BATTAGLIA, F. C., AND G. MESCHIA. Principle substrates of fetal RUDOLPH. Blood flow measurements with radionuclide-labeled
metabolism. Physiol. Rev. 58: 499-527, 1978. particles. Prog. Cardiovasc. Dis. 20: 55-79, 1977.
3. COHN, H. E., E. J. SACKS, M. A. HEYMANN, AND A. M. RUDOLPH. 9. IWAMOTO, H. S., W. OH, AND A. M. RUDOLPH. Renal metabolism
Cardiovascular responses to hypoxemia and acidemia in fetal in fetal and newborn sheep. In: Physiologic Development of the
lambs. Am. J. Obstet. Gynecol. 120: 817-824, 1974. Fetus and Newborn, edited by C. T. Jones. London: Academic,
4. EDELSTONE, D. I., AND I. R. HOLZMAN. Fetal intestinal oxygen 1985, p. 37-40.
consumption at various levels of oxygenation. Am. J. Physiol. 242 10. IWAMOTO, H. S., AND A. M. RUDOLPH. Chronic renal venous
(Heart Circ. Physiol. 11): H50-H54, 1982. catheterization in fetal sheep. Am. J. Physiol. 245 (Heart Circ.
5. FISHER, D. J., M. A. HEYMANN, AND A. M. RUDOLPH. Fetal Physiol. 14): H524-H527, 1983.
myocardial oxygen and carbohydrate consumption during acutely 11. JONES, C. T. The development of some metabolic responses to
induced hypoxemia. Am. J. Physiol. 242 (Heart Circ. Physiol. 11): hypoxia in the foetal sheep. J. Physiol. Land. 265: 743-762, 1977.
H657-H661,1982. 12. JONES, M. D., R. E. SHELDON, L. L. PEETERS, G. MESCHIA, F. C.
6. FRIEDMAN, P. A., AND J. TORRETTI. Regional glucose metabolism BATTAGLIA, AND E. L. MAKOWSKI. Fetal cerebral oxygen con-
in the cat kidney in vivo. Am. J. Physiol. 234 (Renal Fluid Electra- sumption at different levels of oxygenation. J. Appl. Physiol. 43:

Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.

EFFECT OF HYPOXEMIA ON FETAL RENAL METABOLISM F841
1080-1084,1977. 18. PEETERS, L. L. H., R. E. SHELDON, M. D. JONES JR., E L.
13. KATZ, M. J., H. YAFFE, B. S. BLOCK, AND J. T. PARER. Alterations MAKOWSKI, AND G. MESCHIA. Blood flow to fetal organs as a
of intrarenal blood flow during asphyxia in the sheep fetus (Ab- function of arterial oxygen content. Am. J. Obstet. Gynecol. 135:
stract). Abstracts 30th Annu. Meet. Sot. Gynecol. Invest., Washing- 637-646,1979.
ton, DC, 1983, p. 301. 19. ROBILLARD, J. E., R. E. WEITZMAN, L. BURMEISTER, AND F. G.
14. MCGIFF, J. C. Prostaglandins, prostacyclin and thromboxanes. SMITH, JR. Developmental aspects of the renal response to hypox-
Annu. Rev. Phurmacol. Toxicol. 21: 479409, 1981. emia in the lamb fetus. Circ. Res. 48: 128-138, 1981.
15. MILLARD, R. W., H. BAIG, AND S. F. VATNER. Prostaglandin 20. WINER, B. J. Statistical Principles in Experimental Design (2nd
control of the renal circulation in response to hypoxemia in the edition). New York: McGraw-Hill, 1971.
fetal lamb in utero. Circ. Res. 45: 172-179, 1979. 21. ZANJANI, E. D., J. L. ASCENSAO, P. B. MCGLAVE, M. BANISADRE,
16. NEWGARD, C. B., L. J. HIRSCH, D. W. FOSTER, AND J. D. Mc- AND R. C. ASH. Studies on the liver to kidney switch of erythro-
GARRY. Studies on the mechanism by which exogenous glucose is poietin production. J. Clin. Invest. 67: 1183-1188, 1981.
converted into liver glycogen in the rat. J. Bill. Chem. 258: 8046- 22. ZANJANI, E. D., E. 0. HORGER III, A. S. GORDON, L. N. CANTOR,
8052,1983. AND D. L. HUTCHINSON. Erythropoietin production in the fetal
17. NEWSHOLME, E. A., AND C. M. START. Regulation in Metabolism. lamb. J. Lab. Clin. Med. 74: 782-788, 1969.
New York: Wiley, 1973.

Downloaded from www.physiology.org/journal/ajprenal at Tulane University (129.081.226.078) on February 15, 2019.