Assessment of renal function in fetuses with lower urinary tract obstruction


Introduction

Fetal lower urinary tract obstruction (LUTO) or congenital bladder outlet obstruction has an incidence of 2.2/10,000 pregnancies and is usually diagnosed in late first or early second trimester of pregnancy with the characteristic findings of dilated fetal bladder, dilated proximal ureter, and renal hydronephrosis.

LUTO represents a spectrum of congenital anomalies with the principal etiology differing according to fetal sex and additional structural anomalies. If the affected fetus is male, the principal etiology is typically posterior urethral valves (PUVs), which has accounted for approximately half of cases presenting with LUTO in some case series ; prune belly syndrome or urethral atresia are other important additional causes. Female fetuses with LUTO are significantly less common and are more likely to be associated with complex etiology such as cloacal plate anomaly or monogenic megacystic microcolon syndrome.

Embryology and amniotic fluid homeostasis

Within the developing embryo, the renal tract develops from three overlapping sequential systems: the pronephros, the mesonephros, and the metanephros. These all derive from a specialized area of intermediate mesoderm: the urogenital ridge. Interaction between the ureteric bud (an outpouching of the mesonephros), the metanephros, and the metanephric blastema forms the developing kidney and excretory and collecting system by 11–12 weeks’ gestation, at which point fetal urine production begins. Up to 20 weeks’ gestation, the embryonic ureter undergoes a repeated branching process, forming the collecting system of the kidneys, renal pelvis, calyces, and collecting ducts. At this gestation, fetal urine has a low protein content and absence of glucose and phosphorus, suggesting that glomerular protein filtration is mature and tubular reabsorption is taking place.

The fetal renal system continues to mature through the third trimester with further induction of the mesenchyme by epithelial ureteric structures. Renal tubular reabsorption of sodium and β 2 -microglobulin and secretion of calcium increase during the second half of pregnancy. Finally, from 30 weeks onward, a progressive increase is observed in fetal urinary elimination of the nitrogen compounds: urea, creatinine, and ammonia.

In the first trimester, amniotic fluid is secreted by the placenta and membranes with water and solutes freely traversing fetal skin. During the second trimester, the fetal skin becomes impermeable to further diffusion through keratinization. As a result, from approximately 16 weeks amniotic fluid is almost exclusively produced through fetal urination, which progressively increases until, by term, a fetus can produce on average from 750 to 1000 mL of urine per day. Amniotic fluid is removed primarily through fetal swallowing, which has been seen to occur from 16 weeks’ gestation and increases up to the ingestion of 200 to 450 mL of amniotic fluid per day at full term. Fluid may also be eliminated via the fetal respiratory tract with term inspiratory flow rates of 200 mL/kg per day, although as alveolar phospholipid secretions can be found within the amniotic fluid, there remains uncertainty as to whether the fetal respiratory tract remains a net contributor or remover of amniotic fluid in utero. Finally, oncotic forces across the fetal membranes and placenta can also lead to reabsorption of amniotic fluid.

Natural history of lower urinary tract obstruction

The natural history of untreated LUTO is dependent upon the presence of severe oligohydramnios and associated pulmonary hypoplasia. When such features exist, cases demonstrate high mortality and morbidity rates, with up to 30% of survivors requiring renal replacement therapy. ,

Prenatal diagnosis of lower urinary tract obstruction

Imaging

Ultrasound and the classic lower urinary tract obstruction triad

Suspicion of congenital LUTO (congenital bladder neck obstruction) often arises in the first trimester from ultrasound evidence of an enlarged bladder. Fetal megacystis has been defined by a longitudinal bladder diameter of greater than 7 mm, prior to 14 weeks’ gestation, or a failure of bladder emptying during a 45-minute duration ultrasound scan in the second and third trimesters. However, megacystis is not always associated with LUTO and may be associated with spontaneous resolution, therefore serial ultrasonography is essential to confirm the diagnosis. Diagnostic confirmation occurs with the observation on prenatal ultrasound of a “classic” triad: dilated posterior urethra (so-called keyhole sign), urinary bladder enlargement, and hydronephrosis. However, even when defining this triad using strict criteria, specificity is low with up to 23% false-positive rate reported. Diagnostic accuracy can be improved with the use of clinical scoring systems. Within these scoring systems, fetal sex, ureteral size, degree of bladder distension, presence of severe oligo- or anhydramnios, and gestational age at diagnosis are key variables. These systems will be described in further detail in the “Antenatal Predictors of Postnatal Renal Function” section later in this chapter.

Recently, a clinical LUTO diagnostic score has been developed to replace the classic “ultrasound triad” for prenatal diagnosis of LUTO. This clinical LUTO score was developed in a retrospective cohort study in the Netherlands, which used a multivariate analysis of a 7-year data set including 124 cases of LUTO. The scoring system ( Table 1.1 ) includes five variables—fetal sex, degree of bladder distension, ureteral size, oligo- or anhydramnios, and gestational age at referral. Using these five variables, the scoring system discriminates LUTO from nonobstructive megacystis with superior accuracy to the classic “ultrasound triad” (area under the curve [AUC] of 0.84 vs. AUC = 0.63, P = .07). Indeed, in this staging system, a clinical LUTO score of 9.5 predicts LUTO with 78% sensitivity and 79% specificity, which corresponds to a 96% positive predictive value and 36% negative predictive value. The major strength of this study is that it mandated confirmation of the postnatal diagnosis. The authors found bladder volume showed better accuracy than longitudinal bladder diameter, which thus far has been the routine measurement for ascertaining megacystis. A bladder volume of greater than 35 cm 3 is reported as the optimal predictor of LUTO diagnosis (AUC = 0.66 with 0.6–0.8 confidence interval [CI], P = .03). Fetal hydronephrosis, renal cortical appearance, and keyhole sign performed poorly in the stepwise model compared with the five variables preserved for inclusion.

TABLE 1.1
Clinical Scoring System for Diagnosis of Fetal Lower Urinary Tract Obstruction
Adapted from Fontanella F, Duin LK, Adama van Scheltema PN, et al. Prenatal diagnosis of LUTO: improving diagnostic accuracy. Ultrasound Obstet Gynecol . 2018;52(6):739–743. doi:10.1002/uog.18990
Ultrasound Features Score
Bladder volume > 35 cm 3 or urinary ascites 4
Anhydramnios or oligohydramnios (DVP < 5th centile) 4
Male sex 4
Diagnosis before 26 weeks of gestation 4
Enlarged ureter (>7 mm diameter) 1.3 per mm above 7 mm Total ≥ 9.5 has 96% positive predictive value for LUTO
LUTO , lower urinary tract obstruction, DVP , Deepest Vertical Pool.

Fetal cystoscopy and MRI

Fetal cystoscopy is a tool to improve diagnostic accuracy in LUTO (simultaneous to its role in fetal intervention) that is now well recognized. This technique enables accurate prenatal diagnosis of PUV, urethral stenosis, and urethral atresia, with a high sensitivity and specificity for PUV. However, it is associated with significant risks of pregnancy loss.

In utero fetal MRI may be used as a diagnostic adjunct to ultrasound for many prenatal conditions. The use of this technique to improve diagnostic accuracy in LUTO may be helpful, in selected cases, to distinguish cloacal plate anomaly and megacystic microcolon syndrome. Models using imaging combination of ultrasound and MRI have been demonstrated in the literature ; however, these have yet to arrive in routine clinical practice.

Role of genetic testing in prenatal LUTO diagnosis

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