Kidney International, Vol. 18 (1980), pp.
173 -1 78
Renal hemodynamics and volume homeostasis during
pregnancy in the rat
EDWARD A. ALEXANDER, SUSANNE CHURCHILL, and HOWARD H. BENGELE
The Thorndjke Memorial Laboratory, Renal Section, Boston City Hospital, and Departments of Medicine and
Physiology, Boston University School of Medicine, Boston, Massachusetts
The rat is used frequently as a model for normal
and abnormal pregnancy, as many of the alterations
in renal function and sodium metabolism found in
human pregnancy also occur in the rat. In addition,
the short gestational period of 3 weeks, a useful par-
allel of the three trimesters of human pregnancy,
makes this animal convenient for laboratory investi-
gations. Thus, it is appropriate to review the renal
hemodynamic and fluid volume changes that occur
during gestation in the rat. In this review, we have
included those experimental studies that we judged
to be most relevant to recent physiologic concepts.
Renal hemodynamics
There is abundant evidence that the GFR is in-
creased during human pregnancy, and this appears
to be true in rat pregnancy as well (Table 1). Lind-
heimer and Katz [1] performed careful inulin clear-
ance studies in anesthetized hydropenic term-preg-
nant rats and their virgin littermates. They found
the GFR to be 19% higher in the pregnant animals.
Sicinska, Bailie, and Rector [2] noted an increase of
42% in similarly performed studies. In anesthetized
rats receiving modest volume loads, both Mathews
and Taylor [3] and Lichton [4] found the GFR to be
about 29% greater than was that in control rats. Re-
cently, Davison and Lindheimer [5] and Churchill et
al (unpublished observations) found the GFR to be
significantly increased by 19 and 29%, respectively,
in unanesthetized rats at term. Thus, there appears
to be little question that GFR is increased in the rat
at or near term and that the increment is unaffected
by anesthesia.
There is controversy about when a significant in-
crease in GFR occurs in gestation. Some have
noted increments at 11 to 14 days [3, 6, 7] and even
as early as 5 to 6 days [6]. Lindheimer et al and
others [1, 4] could not find, however, significant in-
173
creases in anesthetized animals at 13 to 14 days or
in unanesthetized rats at 8 to 11 days [5] when they
compared them with virgin littermates.
The mechanism whereby GFR is increased in
pregnancy is unknown. Multiple possibilities exist.
Removal of the fetuses on day 14 did not affect GFR
at term, whereas removal of the entire uterus re-
turned filtration rate to control levels [3], suggesting
that the placenta or its products are important in the
GFR increment. Further studies of this phenome-
non have not been reported. Few studies that eval-
uate the effect on GFR of the specific hormonal
changes that occur during gestation are available.
Pregnancy levels of progesterone alone, however,
do not increase GFR in the rat [8]. In the recent
work on glomerular ultrafiltration forces in normal
rats by Brenner, Deen, and Robertson [9], the im-
portance of plasma protein concentration as a mod-
ulator of glomerular filtration was emphasized. Be-
cause plasma protein concentration is decreased
significantly at term [10, 11], it might be surmised
that this alteration is important for the increase in
GFR. In a preliminary report, Baylis [7] evaluated
renal hemodynamics at the whole kidney and neph-
ron level in gravid Münich-Wistar rats. She reports
an increase in plasma flow and a proportional rise in
GFR on gestational day 12, without a change in the
other determinants of ultrafiltration. Thus, the
plasma flow dependency of GFR was found in preg-
nant rats as well as in controls. She noted no
changes in plasma protein concentration, system-
ically or at the nephron level, thus excluding a de-
crease in colloid oncotic pressure as a determinant
Received for publication January 7, 1980
0085—2538/80/0018-0173 $01.20
© 1980 by the International Society of Nephrology
174
Table 1. Inulin clearance (mllmin) in pregnant rats at term
Volume load
Anesthetized rats
Mathews and Taylor [31
Lichton[4]
Katz and Lindheimer [23]
Sicinskaetal[2]
Lindheimer and Katz [I]
Unanesthetized rats
Davison and Lindheimer [5]
Churchill [131
a All pregnant groups were significantly higher than control animals except as noted below.
b This includes three separate groups that received 10 to 20% of the ECF as an acute isotonic saline load. No significant differences
were found between groups.
They received acute isotonic saline load equal to 5% body wt.
of the elevated filtration rate. In view of the failure
of others to find an increase of plasma flow at term
[1, 3, 5], however (see below), the determinants of
ultrafiltration must be different late in pregnancy or
these findings may be peculiar to the Münich-Wis-
tar strain. Future studies exploring the components
of glomerular ultrafiltration should help clarify the
mechanisms by which filtration increases during
pregnancy.
Renal plasma flow has been estimated by PAH
clearance by Mathews and Taylor [3], Lindheimer
and Katz [1], and Davison and Lindheimer [5], and
in none of these studies was there any significant
difference between term-pregnant and control rats.
On day 14, however, PAH clearance was signifi-
cantly elevated in the study of Mathews and Taylor
[3] but not in that of Lindheimer and Katz [1]. Re-
cently, Baylis, using the inulin extraction technique
[7], provided preliminary data demonstrating an in-
crease in renal plasma flow at day 12. Thus, con-
trary to measurements in the human where renal
plasma flow is elevated at term, in the rat renal
plasma flow is rarely found to be increased. In the
one study that evaluated intrarenal blood flow dis-
tribution by using microspheres, no alterations
were noted in pregnancy [8].
Volume control
Cumulative sodium retention has been demon-
strated conclusively during pregnancy in the rat.
Lichton [12] found that about 88% of the sodium
retained occurred during the final 2 weeks of preg-
nancy, and 65% during the last week alone. Kirksey
and Pike [10] measured sodium balance during the
final 2 weeks of gestation on what they considered
to be low-sodium (0.014 mEq/g of food), normal-so-
dium (0.064 mEqlg), and high-sodium (0.55 mEq/g)
Alexander et al
Control Pregnanta
Yes 1.64 1.93
Yes 1.92 2.48
Yes 2.64 to 321b 2.84 to 373b
Yes 2.84 3.40a
No 2.14 3.03
No 2.08 2.47
No 2.39 2.80
No 2.56 3.30
diets. Urinary sodium excretion was 40%, 50%, and
90% of that ingested, but nonpregnant control rats
excreted 95 to 99% of their intake on these diets. In
sodium-balance studies in our laboratory [13], we
found that rats on a sodium diet of 0.19 mEq/g ex-
creted 71% of the amount ingested during the final 2
weeks of pregnancy. Significant retention occurred,
however, only during week 3. Thus, it appears that
fractional sodium retention is dependent on the
amount of dietary sodium that is provided. The rela-
tionship between the amount of sodium in the diet
and the fractional excretion of sodium is displayed
in Fig. 1. Total absolute retention for the last 2
weeks of pregnancy in these three studies [10, 12,
13] was comparable when sodium was not restrict-
ed, and it was about 6 to 10 mEq. The salt avidity of
pregnant rats has been well documented. When al-
lowed free access to hypertonic saline, pregnant
rats drank three times as much as they did before
conception. This avidity drops dramatically post-
partum [14]. Furthermore, when pregnant rats were
placed on a salt-deficient diet and provided with ei-
ther saline or water to drink, they drank far more
saline than did pregnant rats ingesting a normal-salt
diet [15]. Thus, it appears that during gestation rats
can modulate both the amount of sodium they in-
gest and the amount excreted so that sufficient so-
dium is available to supply the needs of gestation.
When dietary sodium is severely restricted, how-
ever, so that the needs of the products of concep-
tion cannot be met, there appears to be a reduction
in the number of fetuses per pregnancy, and those
fetuses born are smaller in weight [10].
The distribution of this retained sodium has also
been examined. Lindheimer and Katz [1] measured
the volume of distribution of inulin as a measure of
extracellular fluid (ECF) space at 14 and 20 days of
 Renal hemodynamics and volume homeostasis
100 .
x
a,
C S
75
C x
0
a, . E
C,
as 50 X
E
-C
0 x
-o 25 $
a,
0,
C
1'
0 0.1 0.2 0.3 0,4 0.5
Dietary sodium, mEq/g of food
Fig. 1. Relationship between dietary sodium and fraction of in-
gested sodium excreted in the urine. Data were obtained from
Refs. 10, 13, 35, and 36. X's denote values that combine weeks 2
and 3 of pregnancy; closed circles (.), week 3 of pregnancy.
pregnancy. They found that the ECF as a fraction of
nonconceptus body weight was significantly in-
creased only at 20 days. Churchill, Bengele, and Al-
exander [16] repeated these studies and found a
small but significant increment at 14 days and an
increase comparable to the data of Lindheimer and
Katz [1] at term (Fig. 2). In both these studies, ECF
space was found to be about 25% of nonconceptus
body weight whereas in nonpregnant animals it was
about 20% of body weight. Both of these studies
contrast sharply with that of Lichton, Rasa, and
Hugh [17], who found no change in absolute inulin
space at term and an actual decrease when this was
expressed as a percentage of nonconceptus body
weight.
Lichton found all of the additional retained so-
dium in the uterus and its contents [12]. Our studies
[13] are at variance with Lichton's data because we
found only about 60% of the retained sodium within
the fetuses, placentas, and amniotic fluid. Because
extracellular fluid expansion has been documented
in the dam [1, 16], it seems highly likely that the
retained sodium is shared by the mother and the
products of conception.
Accepting the fact that pregnant rats are in signif-
icant positive sodium balance, how is this additional
sodium retention achieved by the kidney? The regu-
lation of sodium involves an extensive system of in-
terdependent variables and overlapping regulatory
responses. Simply said, sodium excretion depends
on the difference between the amount of sodium fil-
tered and the amount reabsorbed. In pregnancy, as
was discussed above, GFR is increased sufficiently
so that the amount of filtered sodium is increased
175
C
0
C
.0
'0
C
C
C
0.6
Non- 14 21 Non- 14 21
pregnant Day Day pregnant Day Day
Fig. 2. Extracellular fluid volume measured by inulin distribution
and nonconceptus body weight in pregnant and nonpregnant
rats. (Reprinted by permission of Am J Physiol [16])
even though plasma sodium concentration regularly
decreases [1]. In nonpregnant animals, substantial
evidence indicates, however, that changes in the fil-
tered load of sodium do not necessarily lead to con-
comitant changes in sodium excretion in the final
urine [18]. Rather, adjustments take place along the
nephron that compensate for such variations in fil-
tered sodium. Thus, changes in GFR are followed
by parallel changes in absolute sodium reabsorp-
tion. When the increment in filtered load is accom-
panied by an acute [19-21] or chronic expansion of
ECF volume [22], however, the increment in abso-
lute reabsorption is blunted, and sodium excretion
increases. But in pregnancy, a condition in which
both the filtered load of sodium and the ECF vol-
ume are increased chronically, absolute tubular
reabsorption is not blunted and sodium excretion is
not increased [1]. When acute saline loading is su-
perimposed on the chronic expansion of pregnancy,
however, the natriuretic response of pregnant rats
is not different from that of control animals [23]. It
appears, therefore, that during pregnancy a new
ECF fluid volume setting is attained, and any addi-
tional sodium infusion is excreted normally.
What accounts for this failure to decrease tubular
sodium reabsorption in the face of an expanded
ECF? There is much evidence that sodium reab-
sorption in the proximal tubule varies with pen-
tubular oncotic pressure, such that a decrease in on-
cotic pressure leads to a decrease in reabsorption
[24]. In pregnancy, circulating serum protein con-
centrations are decreased at term when sodium
reabsorption is most avid. Thus, it appears unlikely
that penitubular oncotic factors contribute to so-
176 Alexander et
dium retention. If single nephron hemodynamics
are similar, however, to those of the whole kidney
at term, nephron filtration fraction will be markedly
elevated, possibly producing an increase in pen-
tubular oncotic pressure and thus an increase in
proximal reabsorption. All this remains highly spec-
ulative until more data from direct evaluation of
proximal reabsorption and peritubular factors are
available.
We recently completed a group of superficial
nephron micropuncture studies in hydropenic term
rats in which we attempted to define a specific neph-
ron locus of increased sodium reabsorption [16]. No
differences in fractional or absolute tubular sodium
reabsorption were found comparing pregnant and
nonpregnant rats when the filtered load of sodium in
the pregnant group was reduced to that of the non-
pregnant group. Thus, it appears that glomerulo-
tubular balance was present, and the increment in
absolute sodium reabsorption can be accounted for
by the increment in filtered load. How glomerulo-
tubular balance persists in animals that have a
markedly increased ECF volume has not yet been
clarified.
Aldosterone has been suggested frequently as
being a major factor in the enhanced reabsorption of
sodium in pregnancy, because plasma levels of this
mineralocorticoid are elevated during gestation in
humans [25, 26] and in some, but not all, animal
species studied [27—31]. It has been postulated that
aldosterone is elevated to counteract the possible
natriuretic factors that occur during normal preg-
nancy, such as increased filtration rate, decreased
plasma protein concentration, and increased circu-
lating progesterone, a known mineralocorticoid an-
tagonist. There is no direct evidence, however,
demonstrating that the sodium retention of preg-
nancy is mediated by aldosterone in the rat or other
species.
Two studies of in vitro incubation of adrenal
glands from pregnant rats suggest that aldosterone
production is elevated at term. Khokhar and Pike
[32] found a doubling of aldosterone production be-
tween day 1 and 18 of pregnancy in rats ingesting a
sodium diet of 0.317 mEq/g of food. This increase
was sustained until term. In sodium-restricted rats,
this value increased fourfold by day 18 but dropped
to the same value as sodium-replete animals by
term. In a similar type study, Schneider and Mul-
row 133] observed a 1.6-fold rise in aldosterone pro-
duction by the incubated adrenal glands when term
animals were compared with nonpregnant controls.
Both groups of rats ingested a diet containing 0.1
al
mEq of sodium per gram of food. In this study, the
authors were unable to achieve a further increase in
hormone production by decreasing the salt content
of the diet, suggesting that the first diet may have, in
fact, been inadequate and that aldosterone produc-
tion was already maximal.
There are only two reports of plasma aldosterone
levels in rat pregnancy. Using the double-isotope
derivative technique, Whipp et al [30] found a two-
fold to threefold elevation in whole blood aldos-
terone levels at term. When both control and preg-
nant rats were placed on saline, only the aldoster-
one concentrations in the pregnant rats decreased.
The authors suggested that aldosterone concentra-
tion fell to control levels in the pregnant rats on sa-
line because their regular diet (0.1 mEq of sodium
per gram of food) was salt deficient. We measured
aldosterone levels by radioimmunoassay (radioim-
munoassay performed by Dr. J. Melby, Boston
University Medical Center) in pregnant animals in-
gesting a sodium diet of 0.2 mEq/g of food. The
measured plasma concentrations were actually
somewhat lower than were the values obtained in
nonpregnant, female control rats [31]. Caution must
be exercised, however, in interpreting plasma al-
dosterone data because there is such wide variation
among individual animals, methods of aldosterone
analysis, and dietary intake. In addition, high
plasma levels do not necessarily reflect an actual ef-
fect on the target organ.
Some recently obtained data from our laboratory
may be more pertinent to the importance of aldos-
terone in gestational sodium conservation. We per-
formed daily sodium balance studies on pregnant
rats receiving spironolactone [11] or after total adre-
nalectomy [31]. Both groups were in marked posi-
tive sodium balance, which was not significantly
different from that found in untreated or unoperated
pregnant animals. Thus, it appears that aldosterone
is not necessary for the sodium retention that oc-
curs during gestation in the rat. Although aldoster-
one may not be the primary stimulus for renal con-
servation of sodium during rat pregnancy, this hor-
mone may continue to help modulate sodium
homeostasis, albeit at a new body volume setting.
Many other factors may be important in the regu-
lation of sodium excretion during pregnancy,
though none have been studied specifically. From
experiments in dogs it has been suggested that es-
trogens may be important [34]. The dosages used,
however, were pharmacologic, and thus further
confirmation of this idea is needed. No studies in
the rat are available. Other potential factors in-
 Renal hemodynamics and volume homeostasis
dude, in part, the autonomic nervous system, the
so-called "natriuretic hormone," and other circula-
tory substances such as the placenta hormones,
prostaglandins, kinins, vasopressin, and oxytocin.
The role of these factors in pregnancy awaits exper-
imental testing.
Summary. We believe that in pregnant rats, GFR
is elevated at term, whereas renal plasma flow ap-
pears not to be increased. The mechanism for this
increment is unclear, as is the specific time during
gestation when renal hemodynamics increase. Rats
increase their salt appetite and significantly positive
sodium balance occurs, which is most pronounced
during the last week of gestation. The retained so-
dium is distributed in part to the products of con-
ception and in part to the mother, particularly in in-
creasing her extracellular fluid volume. Although
chronic volume expansion is present, absolute
tubular sodium reabsorption remains elevated. The
mechanism for this elevated tubular reabsorption
appears not to be related to aldosterone because re-
duction or inhibition of this mineralocorticoid does
not affect sodium balance significantly.
Acknowledgments
The research was supported by National Insti-
tutes of Health Grant HL 17458. Mrs. M. Shea gave
secretarial assistance.
Reprint requests to Dr. E. A. Alexander, Thorndike Memorial
Laboratory, Boston City Hospital, 818 Harrison Avenue, Bos-
ton, Massachusetts 02118, USA
References
1. LINDHEIMER MD, KATZ Al: Kidney function in the preg-
nant rat. J Lab Clin Med 78:633—641, 1971
2. SICINSKA J, BAILIE MD, RECTOR FC JR: Effects of angioten-
sin on blood pressure and renal function in pregnant and
non-pregnant rats. Nephron 8:375—381, 1971
3. MATTHEWS BF, TAYLOR DW: Effects of pregnancy on inulin
and para-aminohippurate clearances in the anaesthetized
rat. J Physiol 15 1:385—389, 1960
4. LICHTON U: Urinary excretion of water, sodium, and total
solutes by the pregnant rat. Am J Physiol 204:563—567, 1963
5. DAVISON JM, LINDHEIMER MD: Changes in renal haemody-
namics and kidney weight during pregnancy in the unanaes-
thetised rat. JPhysiol 301:129—136, 1979
6. ATHERTON JC, PIRIE SC: Effects of pregnancy on glomeru-
lar filtration rate and sodium reabsorption in the rat kidney.
J Physio/ 273:82P—83P, 1977
7. BAYLIS C: The mechanism of increased glomerular filtration
rate during pregnancy in the rat. J Physiol 295: 1OIP, 1979
8. LINDHEIMER MD, KOEPI'EN B, KATZ Al: Renal function in
normal and hypertensive pregnant rats, in Hypertension in
Pregnancy, edited by LINDHEIMER MD, KATZ Al, ZUSPAN
FP, New York, John Wiley and Sons, 1976, pp. 217-227
9. BRENNER BM, DEEN WM, ROBERTSON CR: Determinants of
glomerular filtration rate. Ann Rev Physiol 39:9-18, 1976
177
10. KIRKSEY A, PIKE RL: Some effects of high and low sodium
intakes during pregnancy in the rat. J Nutr 77:33—42, 1962
11. CHURCHILL SE, BENGELE HH, ALEXANDER EA: Sodium
retention and the role of aldosterone in the pregnant rat.
Physiologist 22:19, 1979
12. LIcHroN Ii: Salt saving in the pregnant rat. Am J Physiol
201:765—768, 1961
13. CHURCHILL SE: Sodium homeostasis in pregnancy in the
rat. Ph.D. Thesis, Boston University Medical School, 1979
14. BARELARE B, RICHTER CP: Increased sodium chloride appe-
tite in pregnant rats. Am J Physiol 121:185—188, 1938
15. PIKE RL, YAO C: Increased sodium chloride appetite during
pregnancy in the rat. J Nutr 101:169-176, 1971
16. CHURCHILL SE, BENGELE HH, ALEXANDER EA: Sodium
balance during pregnancy in the rat. Am J Physiol 239:R 143-
R148, 1980
17. LICHTON Ii, RASA AP, HUGH J: Effects of vasopressin and
spironolactone on excretion of water and solutes by the
pregnant rat. Am J Physiol 214:1468-1474, 1968
18. LINDHEIMER MD, LALONE RC, LEVINSKY NG: Evidence
that an acute increase in glomerular filtration has little effect
on sodium excretion in the dog unless extracellular volume
is expanded. J Clin Invest 46:256—265, 1967
19. BRENNER BM, DAUGHARTY TM, UEKI IF, TROY JL: Quan-
titative assessment of proximal tubule function in single
nephrons of the rat kidney. Am J Physiol 220:2058-2067,
1971
20. DAUGHARTY TM, UEKI IF, NICHOLAS DP, BRENNER BM:
Comparative renal effects of isoncotic and colloid-free vol-
ume expansion in the rat. Am J Physiol 222:225—235, 1972
21. KNOX FG, SCHNEIDER EG, WILLIS LR, STRANDHOY JW,
OTT CE: Effect of volume expansion on sodium excretion in
the presence and absence of increased delivery from superfi-
cial proximal tubules. J C/in Invest 52:1642—1646, 1973
22. DAUGHARTY TM, UEKI IF, NICHOLAS DP, BRENNER BM:
Renal response to chronic intravenous salt loading in the rat.
J Cliii Invest 52:21—31, 1973
23. KATZ Al, LINDHEIMER MD: Renal handling of acute sodium
loads in pregnancy. Am J Physiol 225:696-699, 1973
24. BRENNER BM, TROY JL, DAUGHARTY TM: On the mecha-
nism of inhibition in fluid reabsorption by the renal proximal
tubule of the volume-expanded rat. J C/in Invest 50:15%-
1602, 1971
25. SMEATON TC, ANDERSEN GJ, FULTON DS: Study of al-
dosterone levels in plasma during pregnancy. J C/in Endo-
crinol Metab 44:1—7, 1977
26. WEINBERGER MH, KRAMER NJ, PETERSON LP, CLEARY
RE, YOUNG PCM: Sequential changes in the renin-angioten-
sin-aldosterone systems in normal and abnormal human
pregnancy, in Hypertension in Pregnancy, edited by LIND-
HEIMER MD, KATZ Al, ZUSPAN FP, New York, Wiley and
Sons, 1976, pp. 251-261
27. ROBB CA, DAVIS JO, JOHNSON JA, BLAINE EH, SCHNEIDER
EG, BAUMBER JS: Mechanisms regulating the renal excre-
tion of sodium during pregnancy. J C/in Invest 49:871-880, 1970
28. WINTOUR EM, BLAIR-WEST JR, BROWN EH, COGHLAN JP,
DENTON DA, NELSON 3, ODDIE CJ, SCOGGINS BA, WHIPP
GT, WRIGHT RD: The effect of pregnancy on mineralo- and
gluco-corticoid secretion in the sheep. C/in Exp Pharmacol
Physiol 3:331—342, 1976
29. WINTOUR EM, KNOBIL E, SC0GGIN5 BA, SKINNER SL,
COGHLAN JP: The renin-aldosterone systems in the pregnant
rhesus monkey (Macaca mulatta). C/in Exp Pharmacol
Physiol 1:167—170, 1974
178 Alexander et a!
30. WHIPP GT, COGHLAN JP, SHULKES AA, SKINNER SL, WIN-
TOUR EM: Regulation of aldosterone in the rat effect of
oestrous cycle, pregnancy, and sodium status. Aust J Exp
Biol 56:545—551, 1978
31. CHURCHILL SE, BENGELE HH, DALE SL, MELBYJC, ALEX-
ANDER EA: Plasma aldosterone in the pregnant rat. Clin Res
27:249A, 1979
32. KHOKHAR SA, PIKE RL: Aldosterone producing capacity of
adrenal glands cf sodium-restricted pregnant rats. J Nutr
103:1126—1130, 1973
33. SCHNEIDER 0, MULROW PJ: Regulation of aldosterone pro-
duction during pregnancy in the rat. Endocrinology 92:1208—
1215, 1973
34. JOHNSON JA, DAVIS JO: The effect of estrogens on renal so-
dium excretion in the dog, in Hypertension in Pregnancy,
edited by LINDHEIMER MD, KATZ Al, ZUSPAN FP, New
York, Wiley and Sons, 1976, pp. 239-248
35. PIKE RL, GURSKY DS: Further evidence of deleterious ef-
fects produced by sodium restriction during pregnancy. Am
J Clin Nutr 23:883-889, 1970
36. WARDLAW JM, PIKE RL: Some effects of high and low so-
dium intakes during pregnancy in the rat: IV. Granulation of
renal juxtaglomerular cells and zona glomerulosa width. J
Nutr 80:355—363, 1963