Kidney International, Vol. 31 (1987), pp.

1181—1185

Renal handling of calcium in the early newborn period

SHARON R. SIEGEL and ANTHONY HADEED

Department of Pediatrics, University of California Medical Center, Los Angeles, California, USA

Renal handling of calcium in the early newborn period. Urinary the history and Dubowitz score [9], and only AGA infants were
calcium excretion was studied in two matched groups of 28 clinical- included. Fluid and electrolyte requirements were determined
ly—well preterm and fuilterm infants between 24 and 48 hours of life. In
the developmental period from 28 to 40 weeks gestation, urinary for each infant by the physician responsible for the primary
care, and were subject to some variation. The rate of intrave-
calcium excretion was positively correlated to the gestational age (r =
nous fluid administration was controlled with the use of an
0.583, P < 0.01), serum calcium levels (r = 0.512, P < 0.01), the rate of
glomerular ifitration (r = 0.715, P < 0.001), and urinary cyclic AMP infusion pump, and for those fed orally, a prescribed volume of
excretion (r = 0.717, P < 0.001). Urinary calcium excretion was formula every three or four hours were given either by gavage
independent of sodium and calcium intake, and urinary sodium and
phosphate excretion. The mean fractional total calcium excretion and or by nipple feeding.
fractional ionized calcium excretion in babies 32 weeks was <1.0%, During the study a pediatric urine collector (PUC) was
compared to >2.5% for sodium. Serum calcium levels were positively attached to each infant, and the first voided specimen was timed
correlated with gestational age (r = 0.803, P < 0.001), and serum and discarded. A second PUC was applied and all urine
phosphate levels (r = 0.85, P < 0.001). Whole blood ionized calcium specimens were collected and combined for creatinine, cal-
levels were positively correlated to gestational age (r = 0.625, P <
0.001), and serum total calcium levels (r = 0.440, P < 0.05). The cium, phosphate, sodium, and cyclic AMP in Group I, between
newborn kidney in babies 32 weeks gestation, did not have impaired 24 and 48 hours of age. The bladder was manually pressed after
conservation of calcium as for sodium; and neither sodium nor calcium the collection of the last specimen, but additional urine was not
intake appeared to affect urinary calcium excretion in the well newborn obtained by this maneuver in any infant. Blood samples were
infant. Probably neither excess excretion of calcium nor serum phos-
phate levels contribute to early neonatal hypocalcemia. drawn at the end of the urine collection period for creatinine,
calcium, phosphate, and sodium in Group 1. In Group 2 only
whole—blood ionized calcium and serum total calcium were
measured along with serum and urine creatinine.
Early neonatal hypocalcemia occurs in premature infants, Creatinine was determined by the method of Folin and Wu
and a decline in plasma calcium in most fuliterm infants, in the [10], sodium by flame photometry, and phosphate by the
first 48 hours of life [1—3]. Renal salt wasting in babies less than method of Fiske and Subbarow [11]. Calcium was measured by
32 weeks gestation [4, 5] can contribute to the development of atomic absorption spectrophotometry [12], and ionized calcium
hyponatremia [6, 7]. Brown and Sternaka [8] have shown that by flow through ion electrodes [13, 14]. Urinary cyclic 3',
sodium intake can affect urinary calcium excretion via urinary 5'-adenosine monophosphate (cAMP) was determined by ra-
sodium excretion, which is positively related to urinary calcium dioimmunoassay [15]. GFR was determined by creatinine clear-
excretion; and urinary sodium and calcium excretion are nega- ance (Ccr). Fractional excretion of sodium (FENa), total calcium
tively related to serum calcium levels, in seriously ill, hypocal- (FEa total), and ionized calcium (FEca ionized) were calculated as
cemic preterm infants. The purpose of this study was to
determine in clinically—well preterm and fuliterm infants: 1) CNa and Cca total and CCa ionized
whether there is impaired reabsorption of calcium which can x 100.
contribute to early neonatal hypocalcemia, 2) the relationship of
Cr
urinary calcium excretion to calcium intake and serum calcium Institutional approval was obtained from the committee for
levels, and 3) the relationship of urinary calcium excretion to human protection, and informed consent was given by the
sodium intake and urinary sodium excretion. parents. Statistics were determined by linear regression analy-
sis and Student's t-test.
Methods
Two groups of 28 matched infants ranging in gestational ages Results
from 28 to 40 weeks were studied between 24 and 48 hours of
The fluid, sodium, and calcium intake is shown in Table 1.
age. The Apgar score was greater than 7 at five minutes, and
The intake was calculated from birth until the end of the urine
infants were clinically well. The gestational age was assessed by
collection, and expressed as intake per 24 hours.
Figure 1 shows that both urinary calcium excretion (gImin)
and serum calcium levels (mgIlOO ml) were directly related to
Received for publication November 20, 1984 gestational age, r = 0.583, P < 0.01, and r = 0.803, P < 0.001,
and in revised form June 16 and November 10, 1986 respectively. Figure 2 shows that whole blood ionized calcium
© 1987 by the International Society of Nephrology levels were positively correlated to gestational age, r = 0.625, P

1181
1182 Siegel and Hadeed

Table 1. Dietary intake for groups 1 and 2, respectively 6'

Intake 28—32 Weeks 33—37 Weeks 38—40 Weeks r= 0.625
P< .001
Fluid 67.11 69.26 53.78
ml/kg/24 hr
69.56 71.31 58.68

Sodium 2.38 1.21 0.87

.,I 5. .
mEq/kg/24 hr
2.21 1.30 0.91 E
E .
Calcium
mg/kg/24 hr
25.32 30.69 38.76
0 •• •
26.41 32.11 37.84
(0
0 .
(0
N
C
Data are M and 0
SEM.
0
0
.0
A 0
-c 3-
.E .80
r=0.583 S
P<.001 S

is
C
o .60

0x
2
E .40 28 30 32 34 36 38 40
0
10
• S Gestational age, weeks
1)
.20 S Fig. 2. Whole blood ionized calcium levels are directly related to
C gestational age, r = 0.625, P < 0.001.

0
= 0.440
P< 0.05
B r= 0.803
P< .001

I, 9
11
0
01
0
00
E 00
E7 0

U
to 0 0
E 7

'5 0 U
Co
U
E 5. 0
3 I I I I to
(1)
28 30 32 34 36 38 40
Gestationat age, weeks
2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0
Fig. 1. Urinary calcium excretion is directly related to gestational age, Whole blood ionized calcium, mg/born!
P <0.01, A; and serum calcium levels are directly related to gestational
age, p < .00!, B, between 24 and 48 hours of life. Fig. 3. Whole blood ionized calcium levels are directly related to serum
total calcium, r = 0.440, P <0.05.

<0.001; and Figure 3 shows that whole blood ionized calcium than 2.5%. Figure 5 shows that urinary calcium excretion was
levels were directly related to serum total calcium, r = 0.440, P unrelated to urinary sodium excretion, r = 0.052.
<0.05. Urinary calcium excretion was unrelated to urinary phos-
Figure 4 shows that neither sodium, R = 0.044, nor calcium phate excretion, r = 0.041 (Fig. 6). Serum calcium levels (Fig.
intake, r = 0.341, affected urinary calcium excretion. Table 2 6) were positively related to the serum phosphate levels, r =
shows that mean fractional total calcium excretion and ionized 0.850, P < 0.001.
calcium excretion was less than 1.0% in babies 32 weeks Urinary calcium excretion was directly related to urinary
gestation, while mean fractional sodium excretion was greater cyclic AMP, r = 0.717, P < 0.001, (Fig. 7).
 Renal handling of calcium in the newborn 1183

A .80 r= —0.052

60 S
.70
r= 0.341 • .
.60

E 30
E
C.,
S S
'
0
a)
.50

0 15 (a
xa).
E S
0
0 P —— I C.,
S

. ..
S
a)
a)
C' .30
>_
B a)
0
4i C
.20
. S
Q
•%SS •
• .
00 .10 • S

0
000 1.0 1.5 2.0 2.5 3.0 3.5 5.0

oO 00 Urinary sodium excretion, Eq/min

Fig. 5. Urinary calcium excretion is note related to urinary sodium

I I excretion.
0 5 10 15 20 25 30
Urinary calcium excretion, mg/kg/24 hr

Fig. 4. Neither sodium nor calcium intake is related to urinary calcium

excretion.
Table 2. Fractional calcium and sodium excretion between
24 and 48 hours of age
Fractional excretion 28—32 Weeks 33—37 Weeks 38—40 Weeks
% Calcium excretion
0.41
Total calcium
Calcium excretion 0.79
Ionized calcium
Sodium excretion 2.70
Data are M and SEM.
Urinary calcium excretion was positively correlated to crc-
atinine clearance, r = 0.715, P < 0.001, (Fig. 8).
Discussion
Figures 1, 2, and 3 show the relationship of gestational age to
neonatal calcium levels. Both total calcium, as shown by Tsang
et al [16], and ionized calcium which controls its biological
activity, are positively related to gestational age. Total and
ionized calcium levels are positively correlated, as previously
shown by Venkataranan et al [17]. In addition, Figure 1, shows
that lower gestational—age infants excreted less calcium
(g/min) on a similar calcium intake (Table 1). Expressing
calcium excretion per body weight, the babies of lowest gesta-
tional age (28 to 32 weeks) did not excrete any more calcium
than those of higher preterm gestational age (33 to 37 weeks) or reabsorption of calcium and sodium occur simultaneously at the
fullterm (38 to 40 weeks), 18.29 3.61 (M and SEM), 16.35
2.16, and 16.52 2.85 mg/kg124 hr, respectively. This suggests
that the lower gestational age babies (28 to 32 weeks) who are
prone to early neonatal hypocalcemia do not excrete more
urinary calcium than the higher gestational—age babies.
Brown and Sternaka [8] have previously shown than in
hypocalcemic preterm infants with multiple illnesses (RDS,
seizures, pneumothorax, hematuria and proteinuria [possible
0.23 0.16
varying degrees of renal failure, although not stated], hypoten-
0.60 0.36 sion, of which 23% died), sodium intake was positively related
to calcium excretion, while calcium intake was unrelated to
0.52 0.19 urinary calcium excretion. Also, they showed that sodium and
calcium excretion were negatively related to serum calcium
levels. Our data (Fig. 4) shows that neither sodium nor calcium
intake appeared to affect urinary calcium excretion in the
newborn. The relative lack of influence of calcium intake on
calcium excretion has previously been shown in normal adults
[181. Our data, in contrast to Brown's, shows that urinary
calcium excretion (g/min), r = 0.512, P < 0.01, or per body
weight (mg/kg/24 hr), r = 0.362, P < 0.05, is positively related
to the serum calcium levels in the newborn, so that infants with
lower serum calcium levels excreted less urinary calcium. We
were dealing with well newborn infants in contrast to the very
sick infants in Brown's study. Since the relationship between
sodium and calcium excretion and intake could have been
altered by variables as hypoxemia, acidosis, respiratory dis-
tress, hypotension with decreased renal perfusion, present in
these sick babies, the opposing results in our study population
cannot be compared.
Micropuncture studies have demonstrated that renal tubular
 /
1184 Siegel and Hadeed

A .80 r 0.717
P < 0.001
.80

..
r= —0.041 .70
S
C
.2 .60 .60
a)
x
E .40 S c .50
.2
. S
a)

.2: . .. S
S
' S 0
.40
E
S
I

400 500 700 900

.30 .
100 200 300
a) $
C
Urinary phosphate excretion, mmol/min
B .20 S
S
*
r = 0.850 OcP
o
. S
P< 0.001 °
.10

E
E 7
C.)
25 50 75 100 150 200 250
a)
C.)

E
Urinary cAMP excretion, pmol/min
5 0
a)
(I,
Fig. 7. Urinary calcium excretion is directly related to urinary cyclic
AMP excretion, P < 0.001.
3
0.5 1.0 1.5 2.0 2.5 3.0 .80
r = 0.715
Serum phosphate, mmol/lOOml P< 0.001
Fig.6. Urinary calcium excretion is unrelated to urinary phosphate
excretion, A; serum calcium levels are related to serum phosphate .70
levels, B, P < 0.001, between 24 and 48 hours of life.
.60

proximal nephron sites [191 and respond similarly to alteration

of extracellular fluid volume [20]. The bulk of proximal calcium .50

transport is passive but sodium dependent, although a portion is

active and also sodium dependent, the energy presumably
deriving from Na and KtATPase. Little is known of the
.40 .
E
mechanism of calcium transport in the distal nephron, but it is U
a) S
clear that there may be major independent, active transport o .30
processes [21] for sodium and calcium. It is not clear whether
there is also a significant sodium—dependent calcium transport.
a)
C
• ..
S
Postnatally, the newborn undergoes an isotonic contraction of .20
•
• S S •
his extracellular fluid volume [22]. Table 2 shows that the mean
fractional total calcium excretion and ionized calcium excretion .10 S
in infants 32 weeks gestation as less than 1.0%, while mean
fractional sodium excretion was greater than 2.5%. More than
99% reabsorption of both calcium and sodium would be ex- 0 —.— . , , ,,
pected in the growing preterm 32 weeks gestation on the 0.5 1.0 1.5 2.0 3.0 4.0 5.0
intake shown in Table 1. However, a mean of greater than 99% Creatinine clearance, mi/mm
is present only for calcium transport in these babies. Figure 5 Fig. 8. Urinary calcium excretion is directly related to creatinine
shows that urinary sodium excretion is unrelated to urinary clearance, P < .001.
calcium excretion. These data suggest that there is not a close
association between calcium and sodium transport in the im-
mature developing kidney. but significant correlation. Figure 6 shows that serum calcium
Tsang et al [16] showed that hyperphosphatemia was associ- levels are positively related to serum phosphate levels, so that
ated with low serum calcium levels in normal preterm and low calcium levels are positively related to low serum phos-
fullterm babies only at 48 hours of age, r = 0.3, P < 0.05, a low phate levels in normal infants between 24 and 48 hours of life.
 Renal handling of calcium in the newborn
Therefore, increased endogenous phosphate probably does not
contribute to neonatal hypocalcemia under 48 hours of age.
As an incidental finding, we noted that urinary cAMP is
strongly related to urinary calcium excretion (Fig. 7). We
previously found no relationship between urinary cAMP and
urinary phosphate excretion [23] in the early newborn period;
urinary cAMP is unrelated to urinary sodium excretion, r =
0.027, in these infants. Urinary cAMP has an almost identical
linear relationship to GFR (Car), r 0.95, P < 0.001, in these
infants, also shown previously [23]. The same strong correla-
tion of urinary calcium excretion to urinary cAMP, r = 0.71, P
<0.001 (Fig. 7), may reflect the almost identical relationship of
urinary cAMP to C1. Stonestreet, Bell and Oh [24] have shown
that endogenous creatinine clearance represents a good estima-
tion of GFR (inulin clearance) in very low gestational—age
infants.
Urinary calcium excretion in the adult is the reflection of the
immediate relationship between the rates of glomerular filtra-
tion and tubular reabsorption [21]. Since Figure 8 shows that
urinary calcium excretion is positively correlated to creatinine
clearance; urinary calcium excretion in the newborn may also
reflect a similar immediate relationship between the rates of
glomerular filtration and tubular reabsorption.
Reprint requests to Sharon R. Siegel, M.D., 15501 Azzure Court, Los
Angeles, California 90077, USA.
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