Results

The median value of Ucreat in the neonates (7060 μmol/l, range 680–19300) differed significantly (p< 0.0001) from that of older children (1961 μmol/l, range 260–9970) (fig 1). These numbers also show that the scatter of the creatinine values at birth was far greater than at a later age (figs 1-3). The mean Ucreat:osmolality ratio of the neonates was 19.7 μmol/mOsm/kg/H₂O (range 7.9–40.5) and 5.2 (range 2.7–17.6) for the older children (p<0.0001) (fig 2). No significant differences were found between the sexes. There was, however, a significant difference (p<0.001) for both Ucreat and Ucreat:osmolality values between the two urine samples in the neonates, with the highest values found in the first urine sample (fig 3A). For those aged between 1 month and 3 years of age, both urine values were comparable and remained remarkably stable (figs 1 to3B).

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Box plot of urinary creatinine excretion values (Ucreat) in 48 healthy neonates and four additional groups of older children. Data are given as medians and range. Difference between neonates and other children was highly significant (p<0.0001).

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Box plot of urinary creatinine:osmolality ratios in 48 healthy neonates and four additional groups of older children. Data are given as median and range. Difference between neonates and other children was highly significant (p<0.0001).

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Box plots of urinary creatinine:osmolality ratios in two urine samples of healthy neonates (2 to 4 days apart) (A) and four additional groups of older children 7 days apart (B). Data are given as median and range. Difference between first and second urine samples in the neonates was significant (p<0.001). No significant differences between the values in the two urine samples were found in the older children (p=0.98).

Discussion

The production of creatinine is related to total lean body mass, which generally does not change within relatively short periods of time.11 12 When serum creatinine concentrations are constant, the glomerular filtration rate (GFR) is stable and tubular secretion and reabsorption of creatinine (in health at most ages) is minimal, the rate of elimination of creatinine from the body does not fluctuate very much. This steady state is the rationale for using the Ucreat concentration as a reference standard for the chemical analysis of a spot urine.13 The urinary solute:creatinine ratio was therefore considered to be a rather useful and reliable tool both in children and adults, as well as non-invasive, convenient, sensitive and relatively inexpensive.1-5

Our study set out to ask whether the Ucreat is indeed stable in the early neonatal period. The results clearly show that this is not the case. The mean Ucreat concentration was significantly higher in neonates than in older children (fig 1). This difference remained almost unchanged when the Ucreat concentration values were corrected for changes in urine dilution and concentration by factoring Ucreat by Uosm (fig 2). More important, however, is the great scatter in the Ucreat:osmolality ratio values during the first week of life and the significant fall in these values within 48 hours (fig 3A). This contrasts with the picture seen in older children and adults. The latter also tend to have a large scatter in Ucreat due to wide variability in urinary volumes. At that age the influence of volume changes can be minimised after factoring the Ucreat data with Uosm. Recently Moore et al 14proposed a validation of this approach for the screening of albuminuria in spot urine samples of adult patients with correction by the specific gravity of the urine sample. As shown by us, these forms of corrections are, however, not valid in the immediate newborn period. A similar impression was reported by Karlsson et al 15 when studying urinary protein excretion in neonates.

We would have preferred to compare the reported spot urine results with normal data obtained by complete, timed urine collections. This would have been the ultimate proof of our assertion that Ucreat is an unreliable reference value in the early newborn period. This would, however, have required bladder catheterisation of healthy neonates, which could obviously not be undertaken. Given these ethical constraints, the correction of Ucreat by Uosm was the only practical alternative.

The scatter of Ucreat can not be explained by differences in lean body mass, because all the babies were healthy, full term newborns with birthweights appropriate for their gestational ages. Other lines of evidence may, however, shed light on our findings. It has to be remembered that creatinine is a small compound (radius 0.5 nm; molecular weight 113 Daltons) which easily passes the placental barrier. During the first days of extrauterine life the baby’s serum creatinine concentrations therefore largely represent those of the mother. This changes rapidly after birth with neonatal serum creatinine values more or less stabilising within 1 to 3 weeks, depending on gestational age.16-18 During postnatal anabolic growth muscle mass will increase, thus adding to changes in serum creatinine concentrations and urinary excretion of creatinine. Obviously, the tubular delivery and handling of creatinine also undergo rapid developmental changes, mainly due to the postnatal increase in GFR, which almost doubles within two weeks of birth in term neonates, with a slightly slower change in premature infants.19-21 Tubular handling of creatinine in healthy neonates is also different from that in older, more “mature” individuals. In the very young, and in particular in premature neonates (human infants, newborn rabbits, piglets) creatinine seems to undergo tubular reabsorption. This is probably due to “back-leak” of creatinine across the highly permeable “immature” luminal and basolateral tubular structures.22

The striking variations in urinary creatinine excretion in healthy neonates may even be exaggerated when dealing with sick full term babies, and even more so with premature infants, when hypoxaemia and circulatory failure will affect normal maturational changes in GFR.23-27

Whatever the pathophysiological explanation for the changes in Ucreat in the very young, it is very clear that the above observations undermine one of the basic assumptions for the chemical evaluation of spot urine samples in the early neonatal period: the constancy of Ucreat. We therefore conclude that factoring the urine solute concentration by Ucreat does not improve the reliability of random, spot urine examinations in the early neonatal period.