Toxaemia of Pregnancy, Acute Renal Failure

Contr. Nephrol., vol 25, pp. 132-136 (Karger, Basel 1981)

Metabolism of Uric Acid in Normal and

Pathologic Pregnancy
M. Beaufils, S. Uzan, R. DonSimoni, D. Brault and J.e. Colau
Service de Nephrologie (Prof. G. Richet), Service de Gynecologie-Obstetrique
(Prof. J. Salat-Baroux), Service Central de Biochimie (Prof. P. Laruel/e), H6pital
Tenon, Paris, France

It has been known for many years that serum uric acid (SUA) is increased in
so-called 'toxeamia of pregnancy'. Pollak and Nettles (1), 20 years ago, empha-
sized the parallelism between increase in SUA and the clinical severity of the dis-
ease on one hand and the importance of renal glomerular lesions on the other.
More recently, Redman et al. (2) have demonstrated that SUA is a very accurate
means of predicting fetal outcome in hypertensive pregnancies. In fact, determi-
nation of SUA is now widely accepted as an important parameter for following
high risk pregnancies.
If hyperuricemia is so closely linked with the fetal outcome, it is likely that
it is related to a critical pathophysiologic phenomenon. Therefore, it seems im-
portant to look at its mechanism. We do not intend to cover here the whole field
of uric acid metabolism in pregnancy, on which extensive reviews have been re-
cently published (3, 4). We shall only present some insights which we have found
by personal work in the last few years.

Metabolism of Uric Acid during Normal Pregnancy

From a population of 528 women, we obtained in our hospital the values

of SUA during normal pregnancies which are in keeping with most published re-
sults (3). The mean prepregnant value is 280 Mmol/!. At 26 weeks, it is 200 ± (SD)
50 Mmol/l, then progressively increases, reaching prepregnant values at 40
weeks. This decrease in SUA seems to be mostly accounted for by an increase in
uric acid clearance (from 9.25 ± 2.17 to 13.2 ± 4 ml/min), and an increase in
fractional excretion of this substance (from 9.02 ± 2 to 13.08 ± 1.77%).
The possible contribution of the fetal compartment is difficult to assess. We
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had the opportunity of following two successive pregnancies in a patient with

xanthine oxidase deficiency. Findings are indicated in table I. A significant pro-
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 Metabolism of Uric Acid in Normal and Pathologic Pregnancy 133

Table I. Evolution of serum uric acid, urinary uric acid and urinary oxypurines throughout
pregnancy and in early postpartum, in a patient with xanthine oxidase deficiency

Pregnancy, weeks Post partum

24 30 36 40 day I day 60

Serum uric acid, /lmol/I <20 80 ISO 150 60 <20

Unnary uric acid, mmol/day 0.35 0.80 0.15 0.03
Urinary oxypurines, /lmol/day 1,780 980 1,260 1,800

duction of uric acid occurred, allowing maternal SUA to reach subnormal values.
SUA measured in cord blood was 220 J.lmol, identical in arterial and venous
samples. Thus, it is unlikely that the fetus contributed significantly to the appear-
ance of SUA in the maternal compartment. The most likely hypothesis is that
xanthine oxidase activity was present in the placental tissue, allowing production
of uric acid from precursors.

Uric Acid Metabolism in Hypertensive Pregnancies

SUA values were compared during the third trimester in 47 normal pregnan-
cies, 184 pregnancies with hypertension, and 16 pregnancies with hypertension
and heavy proteinuria. Results are indicated in figure l. In spite of a high vari-
ability in all conditions, SUA is Significantly higher in hypertensive than in nor-
mal pregnancies, and the highest values are observed when heavy proteinuria is
present.
There is a good correlation between SUA and fractional excretion of uric
acid. Moreover, as shown in figure 2, variations in SUA are strongly correlated
with inverse variations in fractional excretion. There is also a strong positive cor-
relation between fractional excretions of uric acid and sodium.

Uric Acid Metabolism in Pregnancies with Major Intrauterine Growth

Retardation (IUCR)

As shown in figure 1, when IUGR was not associated with hypertension,

mean SUA, studied in 13 patients, was 289 ± 79 pmol/l, not significantly differ-
ent from values observed in normal pregnancies. Moreover, hyperuricemia (de-
fined as SUA> 350 pmol/l was present in 3 of 13 patients with IUGR without
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hypertension and in 12 of 16 patients with IUGR and hypertension (p < 0.01 by

X2 test).
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 Beaufils/Uzan/DonSimoni/Brault/Colau 134

***
4JO
AFE 'I,

..
ns

60 JOG
+50
**
'" 50 *** c5 2JG
"" *** E

~ LJ
E A SUA 'I,
1{ 40
....: .'.
-50 +50

rJ HT PE IJGR N HT PE IUGR
Serum UriC aCId -50 •
1 2

Fig. 1. Serum uric acid (SUA and plasma volume (PV) in normal pregnancies (N), hy-
pertensive pregnancies (HT), hypertension with heavy proteinuria (PE), and intrauterine
growth retardation without hypertension (UGR). Results are expressed as mean ± SD. ***
p < 0.001.
Fig. 2. Correlation between variations in SUA and variations in fractional excretion
(FE) of uric acid in individual patients. y = -1.294 X + 7.04, r = - 0.79, n = 23, p < 0.001.

Possible Explanations for Reduced Fractional Excretion of Uric Acid

during Pregnancy

The main hypotheses to be investigated are (1) hyperlactatemia, (2) hypo-

volemia, (3) angiotensin II, (4) antidiuretic hormone, (5) other hormones?
The role of excess lactate released by the ischemic placenta, and acting as a
competitive inhibitor of uric acid transport in kidney tubules has been advocated
by several authors (5). Fadel et al. (6) have shown that there is no correlation be-
tween serum lactate and fractional excretion of uric acid in hypertensive preg-
nancies. In their study, mean serum lactate was slightly lower in hypertensive
than in normal pregnancies. Intravenous infusion of lactate however, caused the
same impairment of uric acid clearance in both normal and hypertensives. This
study cast serious doubt on the supposed role of blood lactate in hyperuricemia.
We could confirm Fadel's data, with those of Allart (7). SUA and serum lactate
were measured in 44 pregnant patients. Although mean SUA was significantly
higher in hypertensive patients, there was no significant difference in blood lac-
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tate. Moreover, there was no difference in blood lactate between normouricemic

and hyperuricemic patients.
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 Metabolism of Uric Acid in Normal and Pathologic Pregnancy 135

1:: 4-
+ 50 E

-50 -25 +25 +50 ..

200 300 400
-50 SUA, ~mol!ml
3 4

Fig. 3. Correlation between variations in SUA and variations in plasma volume in indi-
vidual hypertensive pregnant women. y = -1.555 X + 2.429, r = - 0.74, n = 43, P < 0.001.
Fig. 4. Correlation between SUA and plasma renin activity (PRA) in hypertensive preg-
nant women. y = -18.65 X + 7.395, r = -0.65, n = 15, p < 0.01.

Reduced plasma volume is a well-known feature in hypertensive pregnancies

(8). We measured plasma volume, using the Evans blue dilution method, in 47
women with normal pregnancy, 180 women with hypertensive pregnancy, 16
women with hypertension and proteinuria, and 13 women with IUGR without
hypertension. Results are shown in figure I. Plasma volume was significantly
lowered in hypertensive pregnancies, especially when proteinuria was present,
and in IUGR. In hypertensive pregnancies there was a fairly good negative corre-
lation between SUA and plasma volume. In 43 patients, sequential measurements
could be made. As shown in figure 3, there was a highly significant negative cor-
relation between changes in plasma volume and changes in SUA in individual pa-
tients. Thus, it is likely that hypovolemia plays a significant role in the decrease
of uric acid clearance in hypertensive pregnant women.
It must be remembered, however, that SUA is not significantly increased in
IUGR, in spite of striking hypovolemia. Thus, decrease of uric acid clearance as
a nonspecific renal response to hypovolemia is not an ominous phenomenon. It
is either specific or at least sensitized by hypertension. Thus, the question raised
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is that of a common denominator between hypertension and the renal response

to hypovolemia.
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 Beaufils/Uzan/DonSimoni/Brault/Colau 136

The renin-angiotensin system: Ferris and Gorden (9) have shown that angio-
tensin II decreases fractional excretion of uric acid, regardless of the variations in
glomerular fIltration rate. Thus, angiotensin II could be the common denomina-
tor postulated above. Therefore, we measured plasma renin activity in 15 patients.
The results are shown in figure 4. There is a significant negative correlation be-
tween plasma renin activity and SUA. The implications of this remain to be de-
termined and more cases are needed to confirm this correlation. It is however
very unlikely that angiotensin II may have been responsible for hyperuricemia,
since the correlation is negative.
In summary, variations of SUA in pregnancy are mostly accounted for by
variations in tubular transport of uric acid. The reduction in uric acid clearance
observed in hypertensive pregnancies cannot be explained by hyperlactatemia. It
is correlated with hypovolemia, at least in hypertensive patients. This correlation
seems to be lost in IUGR without hypertension, pointing to a mechanism specif-
ic of hypertension. This does not seem to be angiotensin. Further studies are
needed to elucidate this point.

References

2 Pollak, V.E.; Nettles, J.B.: The kidney in toxemia of pregnancy. Medicine, Baltimore
39:469~526(1960).
2 Redman, C.W.G.; Beilin, L.J.; Bonnar, J.; Wilkinson, R.H.: Plasma urate measurements
in predicting fetal death in hypertensive pregnancy. Lancet i: 1370~1373 (1976).
3 Dunlop, W.; Davidson, J.M.: The effect of normal pregnancy upon the renal handling
of uric acid. J. Obstet. Gynaec. Br. Commonw. 84: 13~21 (1977).
4 Hill, L.M.: Metabolism of uric acid in normal and toxemic pregnancy. Mayo Clin. Proc.
53: 743~751 (1978).
5 Handlers, J .S.: The role of lactic acid in the reduced excretion of uric acid in toxemia
of pregnancy. J. clin. Invest. 39: l526~1530 (1960).
6 Fadel, H.E.; Northrop, G.; Misenhimer, H.R.: Hyperuricemia in preeclampsia. Am. J.
Obstet. Gynec. 125: 640~647 (1976).
7 Allart, J.P.: Dosage de l'acide lactique dans l'hypertension gravidique; these Paris
(1979).
8 Chesley, L.c.: Plasma and red cell volumes during pregnancy. Am. J. Obstet. Gynec.
112: 440-450 (1972).
9 Ferris, T.F.; Gorden, P.: Effect of angiotensin and norepinephrine upon urate clearance
in man. Am. J. Med. 44: 359~365 (1968).
137.132.123.69 - 3/25/2017 6:56:13 PM

M. Beaufils, MD, Service de Nephrologie, Hopital Tenon, 4 rue de la Chine,

F-75020 Paris (France)
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