Pulsed Doppler Ultrasonography of the Human Fetal Renal Artery

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The renal arteries arise directly from the aorta just below the projection of the 12th rib and below the superior mesenteric artery. The left renal artery is usually a little higher and longer than that on the right (Fig. 15.1). Close to the renal hilum the renal arteries divide into multiple branches with large ante- rior and posterior branches. These branches in turn divide into large segment arteries, which eventually terminate in arcuate arteries. The best way to assess the renal arteries is to find the abdominal aorta and the renal hilum using a coronal axis view. The renal arteries are usually seen arising from the lateral as- pect of the abdominal aorta. The superior artery is often difficult to visualize in the fetus compared to that in the adult, but the renal artery can be seen using a multipurpose midfrequency scanhead (3±

5 MHz). Respiratory or total body movement make it difficult to obtain an adequate duplex signal. With patience, experience, and perseverance, a Doppler examination of the renal artery can be performed successfully in about 90% of patients.

The abdominal aorta and fetal kidney should be localized first using a two-dimensional examination (Fig. 15.2). The Doppler cursor is placed in the area where the ultrasonographer suspects the renal artery to be, with the Doppler sample volume and Doppler

angle adjusted prior to turning on the Doppler instru- ment (Fig. 15.3) so Doppler ultrasound exposure is minimized. The power output should be decreased to about 50%±75% of its spatial peak temporal average (SPTA) specification. Even at this lower power output the Doppler signal is adequate to obtain echoes from the fetal renal artery. Color mapping is used last to confirm the two-dimensional impression that the Doppler signal is indeed coming from the renal artery and not from the fetal aorta (Fig. 15.4). The renal artery Doppler waveform has a characteristically high peak forward velocity and low but continuous forward flow during diastole that is easily differentiated from the adjacent fetal abdominal aorta.

Like any other Doppler examination, the renal velocity waveforms should be obtained during a period of fetal quiescence. The velocity waveforms should be recorded at a fast speed, with the lowest pass filter.

Using these guidelines, most ultrasonographers are able to obtain adequate Doppler waveforms from these small renal vessels. It is of the utmost importance to minimize Doppler and color exposure, as the safety of such techniques on human fetuses has not been fully evaluated [1].

Pulsed Doppler Ultrasonography of the Human Fetal Renal Artery

Jean-Claude Veille

Fig. 15.1. Fetal renal arteries. Note that the left renal artery is behind the renal vein and is longer than the right renal artery

Fig. 15.2. Two-dimensional examination of a fetus at 30 weeks' gestation. The fetal abdominal aorta is easily seen at the level of the left kidney. On careful inspection, the fetal renal artery is seen at its bifurcation with the aorta

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Doppler Principles and Hints

Flow is determined by a pressure difference between two points and by the resistance to flow within that structure. This relation is known as Poiseuille's law and has been mathematically described:

Q DP=R ;

where DP is the flow difference, and R is the flow resistance. The heart (pump) is the driving force behind generating the pressure difference, which in turn is the force behind fluid flow. The flow resistance is mostly determined by the length and radius of the vessel of interest, in this case the renal artery. In- creasing the length of the vessel increases the resistance, whereas doubling the radius of the vessel decreases resistance to blood flow by one-sixteenth of the original value [1]. Other than vessel size and pressure differences, the pulsatile nature of blood flow in the fetus results in expansion and contraction of the vessel, which in turn affects the Doppler waveform profile. Thus pulsatile flow in compliant vessels affects forward flow during systole and flow reversal during diastole.

When assessing Doppler flow of the fetal renal artery, attention must be given to whether flow is best described as plug flow or laminar flow [1]. At the im- mediate bifurcation of the renal artery with the abdominal aorta (i.e., at the entrance of the renal vessel), the flow of the blood is essentially constant across the vessel. Closer to the renal parenchyma, flow becomes more laminar and assumes a parabolic profile (i.e., maximum flow velocity is at the center of the vessel, whereas flow is almost zero at or close to the walls of the vessel). Hence depending on the posi- tion of the Doppler sample, the Doppler velocity pattern is affected.

The acute angle between the bifurcation of the abdominal aorta and the renal artery can significantly affect the renal blood flow profile. Theoretically, flow is turbulent at such sites and can result in a random, chaotic flow pattern of red blood cells [1]. Because these aberrant flow patterns can affect the final Dop- pler waveform profile, the fetal renal artery is sampled close to the renal parenchyma, keeping the Doppler sample within the lumen of the vessel (Fig. 15.3). A Doppler sample size of 1.5 mm is used and is adequate for most studies done on fetuses beyond 20±24 weeks.

Doppler measurement is angle-dependent. Thus it is important to keep the angle at or less 308 when ob- taining Doppler signals from the fetal renal artery.

Doppler angles of more than 308 could significantly affect the Doppler shift and thus the Doppler wave- Fig. 15.3. Doppler sample is placed on the area of the fe-

tal renal artery without turning the Doppler apparatus. It allows adjustment of the Doppler sample volume, the Dop- pler angle (which should be <308), and the location of the Doppler sample within the lumen of the ªpresumedº location of the fetal renal artery

Fig. 15.4. Color should be the last part of the fetal renal artery localization, not the first. Note the abdominal aorta and its bifurcation as it enters the pelvis. The fetal renal artery is seen bifurcating from the abdominal aorta and en- tering the renal parenchyma. The Doppler is finally turned on to display the returning signals either on the video monitor or recorded to allow analysis at a later time

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form signals. This point is even more important when using color-flow studies of the fetal renal artery. An angle of 808±908, for example, results in no Doppler shift, which in turn results in an inability to visualize color flow of the fetal renal artery. The Doppler angle is not critical, however, when assessing qualitative spectral indices, such as the pulsatility index (PI), resistance index (RI), or systolic/diastolic (S/D) ratio as the angle does not change the relation between the peak systolic and end-diastolic flows. To optimize vi- sualization of the fetal renal artery, Duplex ultrasound is used in order to combine real-time cross- sectional ultrasound images of the fetal renal artery and precisely locate the Doppler sample (Fig. 15.3).

These expansive duplex systems are difficult to oper- ate, as data acquisition is machine- and operator-dependent.

Although the diastolic flow of the fetal renal artery is a low-impedance/low-resistance flow, the diastolic flows are not as high as those observed in the umbilical artery. Diastolic flow of this vascular bed has always been present in normal fetuses at gestational ages of less than 16 weeks. Absent or reverse diastolic flows of this vascular bed in the fetus should be considered abnormal. It is imperative to keep the wall filter at a minimum to avoid causing artifacts that may have serious clinical implications. We elect to reduce the wall filter to 50 Hz during the Doppler acquisition in order to avoid this problem.

When this circulation is quantitatively assessed, in addition to the problems associated with signal acquisition it is important to understand the Doppler waveform. The Doppler spectrum is composed of a range of scattered velocities derived electronically using fast Fourier transformation. When tracing the Doppler curve for quantitative flow assessment, it is important to trace the sharpest part of the ascending and the descending part of the curve in order to avoid the inclusion of contaminated signals. This point is particularly important because quantitative determination of blood flow of such a small vessel as the fetal renal artery may easily be over- or underes- timated. Consistency when tracing the curve is therefore essential. To make analysis of the Doppler curve consistent, the returning Doppler signals should be as sharp and pure as possible.

Clinical Application: Fetal Renal Artery Doppler Assessment

The first report on noninvasive measurement of human circulation using ultrasound was published in 1977 by FitzGerald and Drumm [2]. Since then numerous pa- pers have emerged in the literature describing application of the technique to the study of maternal, placen-

tal, and fetal circulations [3±8]. With the introduction of duplex ultrasonography, fetal intracardiac [9] and regional [10±17] circulations have been assessed.

Pulsed-wave (PW) Doppler ultrasound is particularly well suited for studying the hemodynamics of the human fetus, as the associated techniques are noninvasive, well accepted by the patients, easily reproducible, and relatively safe for the human fetus.

Fetal Renal Doppler Imaging

Since the introduction of pulsed Doppler ultrasound to obstetrics, volume flow measurement of the central and the peripheral fetal circulation has been possible (Table 15.1). Previously most of the data on the actual measurement of the fetal circulation were acquired using invasive techniques, which obviously was not possible in human fetuses. Although volume flow measurements are not widely acceptable and are done only in high-risk pregnancies, a few investigators have given some insight on the normal and abnormal human fetal circulation. Pulsed Doppler requires ex- pensive equipment, is usually cumbersome, and has some inherent errors in volume flow [18]. Color flow imaging allows the operator to interrogate most of the fetal vascular beds including the fetal renal artery.

This vascular bed is usually easy to identify at its ori- gin, which is at a 908 angle from the abdominal aorta (Fig. 15.3) [11]. The pulsed Doppler range gate is placed in the renal artery with an angle close to zero.

This methodology is powerful but needs to be vali- dated. Using such technology, we were able to longitudinally follow normal fetuses in order to determine fetal vascular changes across gestation (Fig. 15.5).

Although these values changed with advancing gestation, the changes were not significant.

In one study, using color and pulsed Doppler ultrasonography, interobserver reliability of measurements in the fetal circulation was evaluated in 41 pregnancies of 25±39 weeks' gestation. Two observers recorded flow velocity waveforms from the middle cerebral and renal arteries for measurement of peak systolic, minimum diastolic, and mean velocities, PI, and RI. Intraclass correlation coefficient of reliability was calculated by analysis of variance. Substantial interobserver agreement was found for the pulsatility index and minimum diastolic velocity in both arteries. Therefore, these measurements have the great- est clinical applicability [19].

Renal Artery Doppler Studies in the Normal Fetus

Vyas et al. established reference ranges for the PI of the fetal renal artery in a cross-sectional study done on 114 human fetuses [11] between weeks 17 and 43

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of gestation. In the normal human fetus, impedance to flow in the renal artery decreased with advancing gestational age [11]. In more than 54% of these normal fetuses the renal artery had an absent end-diastolic Doppler velocity. A high-pass filter of 125 Hz was used which may have obstructed low levels of end-diastolic flow. Hecher et al. reported on duplex

Doppler ultrasonography in one normal human fetus studied at week 22 of gestation, seven fetuses studied between weeks 32 and 35, and 12 fetuses studied between weeks 36 and 40 [12]. They noted that end-diastolic flow was absent in four of the seven fetuses studied between weeks 32 and 35 (or 4 of 20 fetuses,

>20%) despite normal growth and normal amniotic Fig. 15.5a±c. Normal Doppler changes. a Longi- tudinal study of the fetal renal peak flow velocity (PFV) in normally grown fetuses across gestation.

There is a slight but nonsignificant increase in PFVwith advancing age. b Longitudinal study of the systolic-to-diastolic (S/D) ratio in normal fetuses across gestation. There is no significant change in the S/D ratio of the fetal renal artery as gestation advances. c Longitudinal study of the time velocity integral (TVI) (area under the curve) in normal fetuses across gestation. TVI progressively increases with advancing gestation

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fluid [12]. In a longitudinal study of 22 normal human fetuses using color PW Doppler, Veille et al.

found that all of the normal fetuses had end-diastolic velocities [20]. Although additional studies may be needed to clarify this issue, absent end-diastolic flow velocities of the fetal renal artery should be considered suspicious for fetal hypoxia especially if oligohydramnios is documented.

With the availability of color Doppler and, more recently, power angiography, the fetal central and peripheral circulation can be assessed. In one study describing the development of uteroplacental and fetal blood flow during the third trimester in 393 uncomplicated pregnancies with uncomplicated term delivery, maximum systolic, mean and maximum end-diastolic velocity after correcting the angle were studied in a cross-sectional study. Quantiles such as quantitative Doppler indices for the maximum systolic, mean time averaged maximum velocity (TAMX), and maximum end-diastolic velocity were calculated and published. Certain conclusions can be drawn as a result of these studies:

1. Resistance to the blood flow in the maternal por- tion of the placenta does not change during the third trimester.

2. Resistance to the blood flow on the fetal side of the placenta decreases up to week 42 of gestation.

3. Cerebral vascular resistance decreases constantly up to gestational week 42.

4. Vascular resistance to the blood flow of the kidney decreases only slightly during the third trimester [21].

Using the same technology, we evaluated longitudinally the renal circulation from late gestation to the first year of life in order to understand fundamental changes within this vascular bed as the fetus adapts to major circulatory changes occurring during this time period. Sixteen healthy human fetuses were studied during the last trimester of pregnancy, within 2 days of birth, at 6 weeks, at 6 months, and at 1 year. Using noninvasive color pulsed Doppler, blood flow velocities of the renal artery, the tricuspid and mitral valves in the fetus, and in the ascending aorta in the newborn/infants were obtained at each study period. Diameters of these respective areas were also obtained. Total cardiac output and renal blood flow were calculated using the time velocity integral, the area of the structure of interest, and heart rate. We found:

1. Renal artery dimensions, time velocity integral, peak flow velocity, S/D ratio, and absolute volume blood flow (RVBF) were all significantly correlated with advancing gestational age.

2. RVBF relative to body weight and percent RVBF were not.

3. In spite of an overall increase in renal blood flow, flow to the kidney appears to be constant during the time period of this study.

4. Most of the ªmaturationalº changes that occur within this vascular bed appear to be related to changes within the vascular resistance and the renal artery diameter [22].

Konje et al. used color angiography to longitudinally quantify blood flow volume in renal arteries during gestation. They followed 81 appropriately grown fetuses from 24 to 38 weeks of gestation (Table 15.1).

When flow was adjusted to the estimated fetal weight, there was an initial and significant fall in the blood flow in all the vessels to a minimal level at 30 weeks of gestation. Blood flow rose thereafter until term.

The ratios of flow volume in the ascending aorta to those in the other vessels increased with gestation, with the highest ratio being that between the ascending aorta and the renal arteries [23].

Andriani et al. measured the renal RI, an estimate of renal vascular resistance, from the last trimester of pregnancy to the sixth month of life in a large series of healthy subjects. Ninety-three subjects were studied, 32 were fetuses in the last trimester of pregnancy (group 1) and 61 were children, 30 aged 0±1 month, 20 aged 1±3 months and 11 aged 3±6 months. All subjects underwent color Doppler ultrasonography and the RI of the renal artery was measured for each kidney (Table 15.2). The RI was very high in the ªfetalº group but decreased noticeably during the first 6 months of life, reaching values similar to those in adults after the third month. The variability in RI continuously declined with age and there were no sta- tistically significant differences between the left and right kidneys [24].

Maternal meal ingestion has been found to increase fetal renal blood flow. In a cross-over study, fetal Doppler studies of the umbilical, middle cerebral, and renal arteries and the descending aorta were first performed during the fasting state and repeated in the fed state. Maternal meal state did not significantly change the PI of either the umbilical artery (n=20), the middle cerebral artery (n=19), or the descending aorta (n=15). The PI of the fetal renal artery de-

Table 15.1. Change in flow volume in middle cerebral artery, ascending aorta, and renal artery of appropriate-for- gestational-age fetuses

Vessel 24weeks

(mm/min) 38 weeks (mm/min) Middle cerebral artery 39Ô19 140Ô64 Ascending aorta 216Ô77.6 937.4Ô292.5

Renal artery 27.5Ô16.8 80.3Ô57.3

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creased significantly after maternal meal ingestion in normally grown fetuses during late pregnancy (n=14) (fasting=2.36Ô0.16 versus fed=2.09Ô0.33;

P=0.021). These authors postulated that the decrease in the resistance may be associated with increased fetal urine production after maternal meals [25].

Renal Artery Doppler Studies in IUGR Fetuses

Using duplex Doppler ultrasound and a low wall filter (50 Hz), Veille and Kanaan could not demonstrate absent end-diastolic flow of the fetal renal artery in a group of asymmetric fetuses who were suffering intrauterine growth restriction (IUGR) [13]. The PI in the IUGR fetuses was significantly higher than in normally grown fetuses. Among the IUGR group, fetuses with signs of hypoxia had an even higher S/D ratio than the fetuses without signs of hypoxia [13].

These investigators suggested that local mechanisms are operational in the fetal kidneys that may in turn influence renal blood flow.

Vyas and Campbell found that 64% of small-for- gestational-age (SGA) human fetuses had a PI higher than the 90th percentile confidence interval of the reference range for gestation (Fig. 15.6) [15]. They found no association between the change in PI and a

change in umbilical cord PO2 concentration. In this group of SGA fetuses, 20 of 48 (42%) had oligohydramnios. The PI of 16 of 20 fetuses with oligohydramnios (80%) were above the 95th percentile of their normal reference range [15]. The authors concluded that as the impedance to fetal renal blood flow increases, which indicates a higher PI, it is associated with a decrease in fetal urine production.

In a prospective longitudinal study, the changes within the fetal renal circulation were assessed by Doppler sonography in preterm severely growth-restricted fetuses during the period of gradual deterioration prior to delivery; the relationship between Doppler measurements, amniotic fluid index, birth weight, and fetal condition at birth were examined.

Sixteen preterm growth-restricted fetuses between 26 and 35 weeks of gestational age were studied. Serial Doppler measurements were made of the renal artery, umbilical artery, middle cerebral artery, and ductus venosus. The PI in the renal artery did not show any correlation with cord blood pH, birth weight, or amniotic fluid index corrected for gestational age (Delta/

SDAFI). Peak systolic velocities in the renal artery showed a significant reduction with time (n=7, P<0.05) and a significant correlation with venous cord pH at delivery (n=12, r=0.84, P<0.001), Delta/

SDAFI (n=16, r=0.67, P<0.01), and birth weight (n=16, r=0.61, P<0.02). Birth weight correlated significantly with Delta/SDAFI (n=15, r=0.57, P<0.05), PI values of the middle cerebral artery (n=15, r=

±0.61, P<0.02), and PI values of the ductus venosus (n=16, r=0.55, P<0.05). Delta/SDAFI correlated significantly with pulsatility index values of the ductus venosus (n=15, r=0.51, P<0.05) and arterial cord pH values at delivery (n=8, r=0.78, P<0.05). These authors concluded that a progressive redistribution of the circulation occurs with deterioration of the fetal condition in the growth-restricted preterm fetus as reflected by changes in peak systolic velocities, but not by changes in pulsatility values of the fetal renal artery waveforms [26].

Doppler has been used to test the hypothesis that infants exhibiting catch-up growth as an indicator of IUGR have a higher incidence of predelivery abnormal Doppler results. In total, 196 women with singleton pregnancies at high risk of IUGR were followed up for postnatal catch-up growth during the first 7 months. Forty-six of the 196 infants demonstrated catch-up growth and were therefore classified as growth restricted; 85% of this group had had abnormal Doppler results prior to delivery, compared with 14% of the normal growth group. The authors concluded that Doppler appears to distinguish IUGR (as defined by catch-up growth) from normal growth more successfully in infants with an average birth weight ratio than in infants with a low birth weight Table 15.2. Resistance index (RI) of the renal artery in nor-

mal fetuses and children

Age group Number RI

Fetuses (3rd trimester) 32 0.67±0.88

0±1 month 30 0.57±0.90

1±3 months 20 0.60±0.84

3±6 months 11 0.65±0.75

Fig. 15.6. The 5th, 50th, and 90th percentiles for the fetal renal artery pulsatility index (PI) and gestational age. Sixty- four percent of small-for-gestational age fetuses had a PI above the 90th percentile. (Reprinted from [15] with permission)

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ratio and is a better predictor of IUGR than SGA [27].

In another study, the renal volume in fetuses with IUGR fetuses was 31% (95% CI, 20%±40%), which was less than the renal volume obtained in the group of non-IUGR fetuses after adjusting for gestational age. The ratio of renal volume to estimated fetal weight was 15% (95% CI, 1%±26%), which was less than the same ratio in the non-IUGR fetuses. No differences were seen in the renal artery Doppler measurements. These authors concluded that IUGR appears to be associated with a decrease in fetal renal volume. Because renal volume is a likely proxy for nephron number, this study supports the hypothesis that IUGR may be linked to congenital oligonephro- pathy and potentially to hypertension in later life and other related vascular diseases [28].

Some authors have determined the fetal blood flow redistribution and the amount of amniotic fluid in appropriate-for-gestational-age (AGA) fetuses and growth-restricted fetuses. In one study, Yoshimura determined the blood flow velocity waveforms of the umbilical artery, descending aorta, middle cerebral artery, renal artery, and uterine artery using pulsed Doppler ultrasonography in 100 AGA fetuses and 39 growth-restricted fetuses. The PI values and the amount of amniotic fluid were compared between the two groups. The PI values of the umbilical artery and renal artery were significantly higher in AGA fetuses with oligohydramnios than in fetuses with an adequate amount of amniotic fluid. The PI values of the umbilical artery and renal artery were significantly higher and the PI of the middle cerebral artery was significantly lower in growth-restricted fetuses with oligohydramnios than in fetuses with an adequate amount of amniotic fluid. Furthermore, there was a significant negative correlation between the PI value of the renal artery and the vertical diameter of amniotic fluid, and between the PI value of the renal artery and the amniotic fluid index. The PI value of the renal artery was related to the amount of amniotic fluid in growth-restricted fetuses, and the same relationship was demonstrated in AGA fetuses [29].

Arduini and Rizzo reported on the renal blood flow velocity waveforms of 114 IUGR fetuses and 97 postterm fetuses [16]. They found that the IUGR fetuses had a higher PI than a group of normally grown fetuses especially if there was oligohydramnios. Interestingly, postterm fetuses had PIs similar to those of normal term fetuses. In the postterm fetuses there was no correlation between the amount of amniotic fluid and the fetal renal PI values. To explain these apparent discrepancies, the authors suggested that the etiology of the oligohydramnios could have different mechanisms in these two subsets of fetuses.

They speculated that the oligohydramnios in the

IUGR fetuses was related to changes in intrarenal vascular resistance [16], and in postterm fetuses it was related to changes in tubular reabsorption.

Mari et al. [17] found that among four human fetuses affected by asymmetric IUGR who had oligohydramnios and abnormal fetal renal artery velocimetry the perinatal mortality was high (three of four), con- firming the findings of Veille and Kanaan [13].

Thus most of the published studies on fetal renal artery waveforms support the concept that IUGR fetuses with oligohydramnios have a PI above the established values for the 95th percentile (Fig. 15.7).

The combination of IUGR, oligohydramnios, and elevated PI of the fetal renal artery seems to be associated with an increase in perinatal morbidity and mortality. These Doppler studies support an intrarenal increase in impedance, which in turn affects renal perfusion and urine production.

Akita et al. evaluated renal blood flow in 102 normal human fetuses between weeks 20 and 40 of gestation and compared these normative results to those of 11 IUGR fetuses with normal amniotic fluid, 15 fetuses with oligohydramnios, and 10 IUGR fetuses with oligohydramnios [30]. Color duplex PW Doppler ultrasound was used to evaluate the fetal renal artery.

The ascending aorta and pulmonary arteries were evaluated at the same time. Akita et al. concluded that the kidneys of IUGR fetuses with oligohydramnios were poorly perfused because of a decrease in stroke volume, which was found to be associated with these fetuses [30].

Although a prerenal etiology for oligohydramnios is always possible, human and animal data strongly suggest that the human kidney is capable of modify- ing intrarenal resistances according to alterations in the in utero environment. Evidence obtained from fetal renal arteries of guinea pigs, for example, suggests that the fetal circulation exhibits heterogeneity in

Fig. 15.7. Confidence intervals for a group of normal fetuses. This graph and the one in Fig. 15.6 are comparable and point to an elevated pulsatility index (PI) of the fetal renal artery. (Reprinted from [16] with permission)

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response to hypoxia [31]. Hypoxia caused the fetal carotids to contract, whereas the same degree of hypoxia caused the fetal renal arteries to relax. In vivo studies suggest that the same vessel responds differ- ently within its length. For example, the proximal carotid of the fetal guinea pig constricts, whereas the distal carotid relaxes under the same hypoxic conditions [31].

Such regional differences are supported by observations in the fetal circulation of normal human fetuses. Normal women during the third trimester of pregnancy were asked to inhale a gas mixture con- taining 3% CO2 [32]. The responses of the umbilical, middle cerebral, and renal arteries were analyzed before and during the 15-min CO2 challenge. A significant decrease in the S/D velocity ratio occurred in the fetal middle cerebral artery but not in the fetal renal artery or the umbilical artery [32]. The authors concluded that human fetal vessels can selectively vary their resistance with the same stimulus, support- ing the vascular differences previously reported for guinea pigs.

One study looked at two groups of pregnancies resulting in intrauterine chronic hypoxia in the third trimester. Group 1 comprised 120 pregnant women with pregnancy-associated hypertension and/or proteinuria. Group 2 consisted of 87 pregnancies with IUGR. Both study groups included pregnant women in the third trimester. Hyperechogenic renal medullae were detected in 15 out of 120 cases with pregnancy- associated hypertension and/or proteinuria, and in 22 fetuses of the 87 pregnancies involving IUGR [33].

Fetal renal hyperechogenicity appears to be an indicator of fetal arterial circulatory depression, correlated with pathological changes in the RI for the fetal renal arteries. The fetal renal arterial blood flow RI was significantly lower in hyperechogenic cases. The authors concluded that these findings may represent an indication of subsequent intrauterine and neonatal complications. In such fetuses cesarean section was increased because of intrauterine hypoxia. In those with fetal renal hyperechogenicity there was an increase in fetal distress (43%), admission to a neonatal intensive care unit (51%), and an increase in perinatal mortality (5.4%, as compared with 0.8%±1.0% in the normal population). They concluded that a de- tailed ultrasound and Doppler examination of renal parenchyma and arteries may be a useful method prenatally to diagnosis fetal reduced renal perfusion [33].

Fetal Renal Artery Doppler Studies and Postterm Pregnancy

Arduini and Rizzo reported on the PI of 97 patients with gestational ages of more than 42 weeks [16].

They found no significant differences in the fetal renal artery PIs for postdate pregnancies when compared to a group of normal fetuses studied between weeks 40 and 42 of gestation, even when these postterm pregnancies had decreased amniotic fluid volume. In a study done on 50 patients with prolonged pregnancies Veille et al. found that the S/D ratio was significantly higher in prolonged pregnancies complicated by oligohydramnios [34]. These authors also found a significant negative correlation between the amniotic fluid index and the fetal renal S/D ratio [34]. Animal and human data indicate and support the notion that moderate to severe hypoxia significantly affects renal blood flow and renal vascular impedance [35, 36]. Since the introduction of the color Doppler technique, small vessels such as the fetal renal arteries can be effectively studied. With technical improvement and standardization of the pulsed Dop- pler acquisition, studies using such noninvasive methods contribute to our understanding of fetal regional circulation during normal and abnormal development.

The amniotic fluid decreases with advancing gestation in the face of an increase in cardiac output and an increase in renal perfusion. The etiology of oligohydramnios in normally grown fetuses who are born postterm has been studied using Doppler velocimetry.

Recently, Oz obtained the RI of the renal and umbilical artery Doppler velocimetry in 147 singleton postterm fetuses (287 days or more of gestation) [37]. The renal artery RI was significantly higher in cases with oligohydramnios [RI: mean (Ô standard error) = 0.8843 Ô0.11 versus 0.8601Ô0.05, P£0.05]). A renal artery Doppler end-diastolic velocity below the mean for gestation significantly increases the risk of oligohydramnios. These authors concluded that an elevated renal artery Doppler RI was more predictive of oligohydramnios than the umbilical RI. They went on to speculate that a reduced renal artery end-diastolic velocity suggests an increase in arterial impedance and that this may be an important factor in the development of oligohydramnios in prolonged pregnancies [37].

We previously noted that postterm fetuses with oligohydramnios and evidence of fetal acidosis had a significant increase in the RI of the fetal renal artery when compared to a group of fetuses that were also postterm and had oligohydramnios [38]. Scott et al.

[39] had similar findings, that the PI of the renal artery was higher in normally grown fetuses with oligohydramnios when compared to those with normal amniotic fluid. These investigators also found that those fetuses who were growth restricted and had oligohydramnios had significant PI values of the fetal renal arteries.

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Fetal Renal Artery Doppler Studies and Intravascular Transfusion

Animal data indicate that renal blood flow is increased during the first hour after volume expansion with maternal whole blood [35]. Mari et al. evaluated the PI of the renal artery waveform from nine anemic fetuses before and after intravascular transfusion [36]. The PI of the fetal renal artery decreased within the first 2 h after intravascular transfusion. The authors speculated that these observed changes represented a fall in renal vascular resistance to accommo- date and eliminate the excess infused fluid. Such decreases in the PI have also been reported immediately after intravascular transfusion [37].

Fetal Renal Artery Doppler Studies and Maternal Drug Intake

Indomethacin

Indomethacin has been found useful for the treatment of preterm labor and in women whose pregnancies are complicated by polyhydramnios [40]. Treat- ment in utero may cause premature ductal closure, tricuspid insufficiency, and pulmonary hypertension [41]. Such potentially serious complications have significantly reduced its routine use in obstetrics.

Indomethacin has been found to cause a significant increase in fetal renal vascular resistance and a decrease in renal blood flow [42]. Using PW Doppler ultrasound Mari et al. studied the fetal renal blood flow velocity waveforms in 17 fetuses prior to and 24 h after maternal intake of indomethacin [43]. They found no significant differences in the PI values before and during indomethacin therapy [43]. These authors speculated that the decrease in urine production observed in the fetus during maternal intake of indomethacin was vasopressin-mediated and not secondary to increases in renal vascular resistance. This important observation must be confirmed by additional studies.

Van Bel et al. studied the effect of a single dose of intravenous indomethacin on renal blood flow velocity waveforms. Using color PW Doppler imaging on 15 premature infants, they found that a single dose of intravenous indomethacin led to a sharp decrease in peak systolic and temporal mean flow velocities [44].

These effects were maximal 10 min after the indomethacin dosing.

Aspirin

Aspirin, a potent antiinflammatory drug, has been shown to inhibit the biosynthesis and release of prostaglandins, even in low dosage. This observation led many researchers to speculate that the ingestion of

daily low-dose aspirin may result in a decrease in the incidence of preeclampsia and fetal growth restriction, and that it may improve pregnancy outcome in women with positive lupus anticoagulant and anti- cardiolipin antibodies [45, 46].

Veille et al. studied the effect of prolonged maternal ingestion of low-dose aspirin on the fetal renal circulation [47]. They could demonstrate no significant hemodynamic changes in the fetal renal Doppler waveforms in fetuses chronically exposed to low-dose aspirin compared to a group of fetuses not exposed to such medication. Thus the prolonged use of low- dose aspirin in the human fetus does not seem to significantly affect fetal renal circulation.

Ritodrine

The effects of intravenous ritodrine infusion on the fetal renal artery waveforms of eight singletons were assessed by Rasanen [48]. The fetal renal artery waveforms were examined prior to ritodrine and after 2.5 h of infusion. Ritodrine decreased the Doppler waveform indices of the renal arteries, suggesting a decrease in vascular resistance of these vessels [48].

Angiotensin-Converting Enzyme Inhibitors

The angiotensin-converting enzyme (ACE) inhibitors have been used to treat hypertensive disorders during pregnancy. Such treatment can severely and some- times definitively impair renal function in the fetus, leading to postnatal anuria [49]. Evidence from the published literature suggests that the primary mecha- nism by which ACE inhibitors affect development of the fetal kidney is through decreasing the renal blood flow [50] and their interference between the renin-angiotensin system and the prostaglandins.

Table 15.3 shows the effects of maternal medication on fetal renal blood flow.

Table 15.3. Effects of maternal medication on fetal renal blood flow

Maternal drugs Effect on fetal

renal artery Reference ACE inhibitors Decrease in PI Martin RA [50]

Aspirin No change Veille JC [47]

Betamethasone No change in PI Edwards A [51]

Cyclooxygenase-2

inhibitor No change Holmes RP [52]

Ibuprofen No change Romagnoli C

Indomethacin PI is increased [53]Kang NS [54]

Intravaginal

Misoprostol No change Wang Z [55]

Ritrodrine No change Rasanen J [48]

Terbutaline No change Kramer WB [56]

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Fetal Renal Artery and Fetal Anomalies Renal Agenesis

Pregnancies associated with early oligohydramnios have a poor prognosis. The fetal anatomy is particularly difficult to assess because the acoustic window is notoriously poor. In cases of bilateral renal agenesis, the fetal renal arteries are absent.

We identified a case of absent renal arteries using color Doppler transvaginal ultrasonography in a fetus with severe oligohydramnios. This 18-week pregnancy was complicated by severe oligohydramnios. Abdom- inal ultrasonography was not adequate to evaluate the fetal anatomy, including the presence or absence of kidneys. Using a transvaginal color Doppler ultrasound technique, the abdominal aorta was identified but the renal arteries were not. The fetus subse- quently died in utero, and postmortem examination confirmed the ultrasonic finding of bilateral renal agenesis (Fig. 15.8).

MarÉl et al. reported similar findings in a group of 14 fetuses during the second trimester in which there was oligohydramnios and a strong suspicion of renal agenesis on ultrasound recordings. Using a col- or ultrasound technique, the renal arteries were properly identified in six of eight cases, in which normal kidneys were found at postmortem examination. In all six cases of complete renal agenesis proved at au- topsy they could not properly identify the renal artery [57].

It is of utmost importance to recognize that the presence or absence of color is angle-dependent. If

the Doppler signal is perpendicular to the flow of blood, there is no Doppler shift and therefore no col- or. Thus an erroneous diagnosis could easily be made if this Doppler principle is violated.

Pyelectasis

Fetal pyelectasis may affect renal blood flow. In one study, Kara et al. compared the RIs in the fetal interlobar renal arteries (IRAs) of third-trimester fetuses with or without pelvicaliceal dilatation of up to 10 mm with those of full-term healthy infants [58].

They studied three groups according to the antero- posterior diameter of the renal pelvic dilatation:

group 1, no dilatation; group 2, 1±5-mm dilatation, and group 3, 6±10-mm dilatation. The IRA of both kidneys were obtained in 139 of the fetuses (Table 15.4). The RI in the fetal IRA did not differ in fetuses with and without renal pelvic dilatation of up to 10 mm. The authors concluded that an increase in the RI of fetuses that have a mild degree of pyelectasis should be investigated further for possible renal pathology.

Color Doppler Ultrasonography and Fetal Renal Obstruction

Bates and Irving reported on color Doppler imaging of the fetal renal artery in 29 fetuses who had either unilateral or bilateral significant urinary tract dilatation [59]. Although they initially hypothesized that fetal renal obstruction could be detected by analysis of the Doppler waveforms, their study failed to confirm any abnormality of the PI in these fetuses.

Fetuses with hydronephrosis secondary to a ureteropelvic junction (UPJ) obstruction were followed up after birth. Using a uroradiology database (1994 through 1999) Rooks and Lebowitz identified children who had a surgically corrected UPJ obstruction from intrinsic and extrinsic causes. These authors identified 100 who had symptomatic UPJ obstruction and who were treated with surgery. In 11 of these cases (11 %), the obstruction was caused by a crossing vessel. Extrinsic UPJ obstruction caused by a vessel is an uncommon cause of obstruction when all patients are considered, but fetal color Doppler should be included in all cases of UPJ obstruction found on pre- natal sonography [60].

Fig. 15.8. Transvaginal color ultrasonogram of an 18-week fetus with severe oligohydramnios and for whom the trans- abdominal scan was not informative. This transvaginal col- or ultrasound scan showed the abdominal aorta and the absence of fetal renal arteries, strongly suggesting bilateral renal agenesis. The postmortem examination confirmed the ultrasound diagnosis

Table 15.4. Resistance index (RI) in fetuses with and without renal pelvic dilatation [58]

Group 1

No dilatation Group 2

1±5 mm Group 3

6±10 mm

Number 172 98 47

RI-XÔSD 0.81Ô0.09 0.80Ô0.07 0.80Ô0.06

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Multicystic Fetal Kidneys

The diagnosis of multicystic kidney in utero can be made with reasonable reliability with real-time sonography. However, a cystic hydronephrotic kidney may be difficult to distinguish from a multicystic kidney, ne- cessitating postnatal renography. Gill et al. reported their observations of Doppler waveform variation in cystic fetal kidneys [61]. Five consecutive fetuses with a unilateral cystic kidney and one with a unilateral hydronephrotic duplex kidney and cystic upper moiety were evaluated in utero with color Doppler renal sonography. The Doppler signal on serial ultrasound was consistently absent in the ipsilateral cystic kidney, while normal renal artery Doppler waveforms with a systolic and diastolic component were obtained from the contralateral and unaffected moieties. Postnatal renography confirmed nonfunction in all cystic moieties.

The hydronephrotic noncystic moiety of the duplex kidney showed a normal Doppler waveform and good function. Thus absence of renal artery Doppler waveforms in fetal cystic kidneys correlates with renal nonfunction suggesting that fetal Doppler sonography could be an additional tool to diagnose confidently a multicystic kidney in utero [61].

Fetal Artery Waveforms and Meckel Syndrome

Hata et al. reported on the results of PW Doppler examination of the fetal renal artery of a 21-week-old fetus affected by occipital encephalocele and polycystic dys- plastic kidneys [62]. PW Doppler sonography showed an increase in the diastolic component of the velocity

waveform of the renal artery, causing the PI to be significantly lower than in normal fetuses. They speculated that this increase in renal ªperfusionº was prob- ably an expression of the enlarged kidney mass [62].

Quantitation of Fetal Renal Blood Flow

To date, one of the most valuable uses of duplex ultrasound has been for quantitation of stroke volume and cardiac output [63±68]. Doppler ultrasonography estimates the average of all the blood velocities across a vascular structure. If the size of the vascular structure can be measured and assumed to be circular, the area can be calculated. The product of the time velocity integral (TVI), the cross-sectional area of the vascular structure (A), and the heart rate (HR) has been shown to represent the volume of blood flow moving through that structure. The PW Doppler waveform also reflects ventricular contractility.

Flow TVI A HR

Analysis of the upward swing of the initial part of the curve has been correlated with ventricular systolic function. Stated another way, the time from the begin- ning of the Doppler curve to the peak of the curve can be measured and correlates with systolic ventricular performance [66]. Thus Doppler sonography is able not only to quantify blood flow through individual vascular structures but also to assess ventricular contractility. A typical Doppler waveform is shown in Fig. 15.9.

Volume estimates obtained using Doppler techniques have been shown to correlate well with both the Fick and thermodilution methods for estimating

Fig. 15.9. Fetal human renal artery has high peak systolic velocity and low end-diastolic velocity, resulting in a high systolic/diastolic ratio and pulsatility index. The time velocity integral (TVI) is shown in the hatched area.

The TVI is multiplied by the area of the renal artery to estimate the renal blood flow

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cardiac output in children and adults. The variability in measuring the TVI is low. Most of the errors when quantifying blood flow lie in proper determination of the cross-sectional area of the structure of interest, which has been reported to have a 7%±16% variability. Thus a small error when estimating the vessel diameter can result in a significant error in the calculated areas and therefore in the assessment of blood flow. Averaging multiple measurements can decrease these errors.

Color Doppler ultrasonography has greatly en- hanced the ability to visualize blood flowing through these small vessels and thus has increased the preci- sion of determining the size of the vessel. Although color may help visualize and identify small vessels, it is important to keep in mind that color output must be adjusted to the type of flow being analyzed (low flow versus high flow). A high color output may result in a color ªspillº from the borders of the vessel, which causes overestimation of the vessel size (alias- ing) (Fig. 15.10).

Visser et al., using color PW Doppler techniques, quantified renal blood flow in 22 preterm and 29 term healthy neonates [67]. The gestational age of these newborns varied between 24 weeks and term, with a range of weights between 1000 and 5000 g.

The mean renal artery blood flow was 21Ô5 ml

´min^±1´kg^±1, which represented 16.1% of the cardiac output. This value is higher than what was previously reported for fetal lambs in which fetal renal blood flow is about 2%±3% of the combined cardiac output [68]. Validation of such instrumentation in human fetuses is impossible for obvious reasons. Veille et al.

compared invasive blood flow measurements of the fetal lambrenal artery using PW Doppler ultrasound obtained directly from a Doppler probe placed

around the artery (Transonic, Ithaca NY). They performed 36 simultaneous blood flow measurements using both invasive and noninvasive techniques. The PW Doppler ultrasound blood flow (noninvasive) and transit time ultrasound (invasive) blood flow estima- tions correlated well (r²=0.73) [69] (Fig. 15.11). The preliminary data therefore suggest that color PW Doppler ultrasonography can reliably quantify fetal renal blood flow.

Veille et al. presented data from the quantitative assessment of 24 normal human fetuses longitudinally followed during pregnancy. They used a color PW Doppler ultrasound technique to localize and measure the size of the fetal renal artery just beyond its bifurcation from the abdominal aorta. Their preliminary data indicate that there is a progressive, significant increase in fetal renal blood flow with advancing gestational age, but that the percent of the combined cardiac output perfusing the human kidneys remains constant throughout gestation at about 5%±8% [20]. Longitudinal studies carried out to year one showed that the absolute renal blood flow to the kidneys increased but the relative renal blood flow did not [70].

Fetal Renal Blood Flow and Polyhydramnios

Rosnes et al. compared fetal cardiac and renal blood flow in euhydramnic and idiopathic polyhydramnic fetuses. Doppler waveforms were recorded from the Fig. 15.10. ªColor spillº, which can occur if the color set-

tings are not set properly. The sizes of the abdominal aorta and the fetal renal artery are over-estimated if the color edges are considered indicative of vessel size

Fig. 15.11. Simultaneous invasive and noninvasive blood flow measurements in fetal lambs. Pulsed Doppler ultrasound blood flow (noninvasive) and transit time ultrasound (invasive) blood flow correlated well. (Reprinted from [69], with permission)

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renal artery at the renal hilus and just below the tricuspid and mitral valves. Fetuses with idiopathic polyhydramnios had reduced total cardiac output, decreased right ventricular output, decreased renal blood flow, decreased renal diameter and decreased percent renal perfusion compared to euhydramnic control fetuses [71]. They suggested that in fetuses with polyhydramnios, renal perfusion was not the primary cause for the polyhydramnios.

In summary, with the improvements in ultrasound techniques, color PW Doppler ultrasonography can be applied to qualify and quantify fetal regional blood flow in normal and abnormal human fetuses.

These noninvasive methods may reveal how fetal renal blood flow is affected in fetuses with growth ab- normalities, certain renal diseases, or oligohydramnios or during maternal intake of certain medica- tions. A complete understanding of the distribution of renal blood flow in fetuses at risk for asymmetric IUGR may lead to an earlier diagnosis of such patho- logic conditions, which may permit early intervention. Such intervention may then decrease the morbidity and mortality associated with IUGR fetuses.

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