**4. Fetal kidneys**

136 From Preconception to Postpartum

Fig. 3. The Hourly Fetal Urine Production Rate (HFUPR) estimation was based on the increase

The filling and emptying dynamics of the fetal urinary bladder have been investigated in detail. The mean time for the bladder-filling phase was 25 minutes (range 7-43 minutes) and

Gestational age (weeks) Maximum volumes (mL) HFUPR (mL/hour) 20 1 5 21 2 6 22 2 7 23 3 8 24 4 9 25 5 10 26 6 11 27 7 13 28 9 14 29 10 16 30 11 18 31 13 20 32 14 22 33 16 25 34 18 27 35 20 30 36 22 33 37 24 37 38 27 41 39 30 46 40 32 51

(Rabinowitz R, Peters MT, Vyas S, Campbell S, Nicolaides KH. Measurement of fetal urine production

gestational ages were calculated by the author according to formulas in the reference article.

in normal pregnancy by real-time ultrasonography. Am J Obstet Gynecol 1989;161(5):1264-6) Table 1. The maximum bladder volumes before emptying and HFUPR at different

in bladder volume during a filling phase and extrapolated to a time span of one hour.

it was not significantly influenced by gestational age (Rabinowitz et al., 1989).

In a human 2D ultrasound study comprising IUGR and AGA fetuses, the volume of fetal kidneys, as well as the urine production rate, was estimated (Deutinger et al., 1987). In IUGR fetuses, both the volume of the kidneys and the HFUPR were significantly reduced when compared with the AGA fetuses. In agreement with this study, the growth of fetal kidneys was significantly slower in Small for Gestational Age (SGA) vs. AGA fetuses when it came to the anterio-posterior diameter and transverse circumference of the kidneys (Konje et al., 1997). This divergence was most marked after 26 weeks of gestation.

The fetal kidneys gradually increase in volume with gestational age (Hansmann, 1985). Renal weight as an autopsy finding is, however, often compromised and associated with a coefficient of variation as large as 50%, due to oedema and passive venous engorgement. Renal functional capacity depends on the number of nephrons, but no known relationship exists between renal weight and the number of glomeruli (Hinchliffe et al., 1991). For many years, estimates of glomerular numbers have therefore been derived using a variety of methods (Bendtsen and Nyengaard, 1989). Unfortunately, these methods have been shown to have some degrees of bias. However, a new stereological dissector technique permits the direct, unbiased estimation of glomerular numbers (Hinchliffe et al., 1992). This new dissector method was used to estimate the number of nephrons in fetuses. The number was 15,000 per kidney in human fetuses at 15 gestational weeks and between 740,000 and 1,060,000 at term.

The total number of nephrons was estimated in a comparative investigation of six IUGR stillbirths of known gestational age with controls comprising eleven stillbirths with a birth weight greater than the 10th percentile (prenatal period) and eight liveborn IUGR infants, who died within a year of birth, with a control group of seven appropriately grown infants who also died within a year of birth (postnatal period). The number of nephrons for five of the six IUGR stillborn children and all the growth-retarded children who died within one year was significantly reduced compared with the controls (Hinchliffe et al., 1992). Moreover, in animal models, growth restriction has been associated with a reduced number of nephrons (Bauer et al., 2002; Bauer et al., 2003). It has been suggested that the mechanism underlying the reduced number of nephrons in IUGR fetuses is increased apoptosis due to changes in the levels of apoptosis-related proteins (Pham et al., 2003). 

Renal Function and Urine Production in the Compromised Fetus 139

Calculated bladder volumes cannot be validated in living human fetuses, as the true fetal urinary bladder volumes are not known. The reliability of the estimated bladder dimensions, on the other hand, has been evaluated using the 2D ultrasound technique (Fagerquist et al., 2001; Fagerquist et al., 2003; Fagerquist et al., 2002). The calculation of the measurement error was based on the variability in repeated estimations of identical bladder volumes. Standard deviation (SD) was used because the variation was normally distributed. Furthermore, there was a linear relationship between bladder volume and the measurement error, which has been thoroughly documented in three previous studies (Fagerquist et al., 2001; Fagerquist et al., 2003; Fagerquist et al., 2002). This is a prerequisite for using a linear

Fig. 4. The SD was calculated when estimating the bladder volume of 120 fetuses. Different methods were used and this gave rise to 222 relationships between SD and bladder volume. The maximum and minimum bladder volumes were 80.5 mL and 0.1 mL respectively. The

and

distribution of the SDs supports a linear relationship (correlation coefficient 0.36).

**6. Methods for estimating the volume of the fetal urinary bladder** 

regression function (Skrepnek, 2005).

#### **4.1 Renal artery flow velocity and urine production in fetuses with hypoxemia**

The HFUPR was determined by 2D ultrasound immediately before cordocentesis for blood gas analysis in 27 Small for Gestational Age (SGA) and 101 AGA fetuses (Nicolaides et al., 1990). The HFUPR was reduced in the group of SGA fetuses in comparison with AGA fetuses. Furthermore, the reduction in urine production for the SGA fetuses was correlated with the degree of fetal hypoxemia, while the degree of fetal hypoxemia did not correlate with the degree of fetal smallness.

Several studies demonstrate associations between increased impedance in the fetal renal arteries and factors suggestive of compromised fetal conditions and, in some studies, also reduced urine production rates (Mikovic et al., 2003; Miura, 1991; Stigter et al., 2001; Vyas et al., 1989). In one study, the renal artery flow-velocity wave forms were examined in normal and hypoxemic human fetuses (Vyas et al., 1989). The Pulsatility Index (PI), which is peak systolic velocity minus end diastolic velocity over mean velocity, was higher in SGA than in AGA fetuses. Furthermore, using cordocentesis in the SGA fetuses, a significant, direct correlation was found between blood oxygen deficit and increased renal artery PI (Vyas et al., 1989). Moreover, in a study of 35 IUGR fetuses, the PI in the fetal renal arteries was significantly increased (Mikovic et al., 2003). In studies of fetal urine production, it was demonstrated that the PI in the renal artery was higher in IUGR than in AGA fetuses and that it displayed a negative correlation with the urine production rate and the amniotic fluid volume (Miura, 1991). In spite of varying results regarding the PI in fetal renal arteries (Silver et al., 2003; Stigter et al., 2001), the data suggest that, in fetal hypoxemia, there is a redistribution of blood flow, with a decrease in renal blood perfusion and a decrease in HFUPR. These findings may be important, as it would be of great clinical interest to detect whether or not a particular fetus with growth restriction is further compromised.
