Introduction

Congenital kidney anomalies including those that cause urinary tract obstruction are the most common abnormalities discovered on screening antenatal ultrasounds and are the most common causes of long-term postnatal kidney problems in children. Perinatologists, neonatologists, and health care professionals caring for women with high-risk pregnancies and for preterm infants should therefore arm themselves with a working knowledge of kidney development, the effects of prenatal injury on the developing kidney, and the accuracy of antenatal assessments in predicting postnatal outcomes.

In this chapter we will review normal human kidney development with a focus on the events that occur around and after 20 weeks’ gestation. This midpoint in fetal life and in fetal kidney development is the time at which most screening antenatal ultrasounds are performed and at which decisions around continuation of the pregnancy are made. We will highlight the controversies and difficulties in accurately diagnosing urinary tract obstruction in the fetus, in determining the extent and clinical relevance, if any, of this obstruction, and the limited array of valid markers in the affected fetus that accurately predict postnatal outcome.

Definitions and Scope of Congenital Urinary Tract Obstruction

Congenital urinary tract obstruction (CUTO) refers to anomalies of the developing urinary tract resulting in obstruction to urinary flow. Obstruction can occur anywhere along the urinary tract from the urethra to the developing kidney calyces ( Box 21.1 ). Most commonly encountered and clinically significant are anomalies causing bladder outlet obstruction, which are predominant in male fetuses, and either due to a posterior urethral valve (PUV) or urethral atresia. Bladder outlet or lower urinary tract obstruction in females tends to be due to more complex anomalies such as developmental anomalies of the cloaca and in syndromes such as megacystis microcolon. CUTO due to PUV is the most common anomaly, occurring in approximately 1 : 3000 live male births, and is found exclusively in male fetuses. It is the most common cause of chronic kidney disease in young boys and the single most common cause for needing a kidney transplant.

The severity of kidney injury in cases with PUV is related to both the timing and the severity of the urethral obstruction. In some cases, bladder outlet obstruction is evident as early as 18 to 20 weeks’ gestation, at the time of the first screening antenatal ultrasound. In other cases, the obstruction is apparent only later in gestation in the third trimester and after 32 weeks’ gestation. Additionally, the severity of obstruction can vary from mild, going undetected until later in life, to severe, resulting in significant bilateral developmental kidney injury, oligohydramnios, and fetal death. The explanation for this variation in clinical phenotype is unknown. It may be related to a spectrum of alterations in the pattern of development of the urethra, including anterior fusion of the developing plicae of the prostatic and membranous urethra, lack of normal canalization of the urethra, or an anomaly in the insertion of the Wolffian duct. Other anomalies include urethral atresia, which is much less common, with a prevalence of 1 : 30,000 births. It may be seen in association with other urogenital anomalies and as part of a more extensive cloacal anomaly of development. Uretero-pelvic junction (UPJ) obstruction is the most common anatomical cause of hydronephrosis in the fetus and newborn, occurring in 1 : 500 to 1 : 2000 live births. The causes of UPJ obstruction are varied, including extrinsic compression of the ureter at the level of the junction of the kidney pelvis; however, most cases are intrinsic and result from abnormal ureteric development and in the surrounding muscular layers. As with PUV and urethral obstruction, most cases of ureteric obstruction are incomplete or partial, rendering predictions of postnatal outcome and decisions around the need for surgical correction difficult. Severe UPJ obstruction also results in significant developmental kidney injury, and in cases with bilateral involvement (20%–25%), results in significant fetal morbidity and mortality. Uretero-vesico junction (UVJ) obstruction also causes hydronephrosis that may be detectable in the developing fetus. It is less common than UPJ obstruction but, like UPJ obstruction, if severe and early, it can result in significant developmental kidney injury.

An important consideration in the antenatal assessment of a fetus with CUTO is the potential association with other anomalies either within or outside the urinary tract, due either to a genetic syndrome where the gene mutation affects multiple sites along the urinary tract or other organ systems, or to a field defect where multiple systems are affected during development. Collectively these are referred to as CAKUT ( c ongenital a nomalies of the k idney and u rinary t ract). The precise number of CAKUT cases that are due to genetic mutations is unknown; however new generation sequencing approaches have identified new gene mutations in up to 23% of cases with multiple malformations and in 15% of individuals with isolated urinary tract anomalies.

Antenatal Diagnosis of Congenital Urinary Tract Obstruction

The hallmark diagnostic test for urinary tract obstruction in the fetus is the identification of hydronephrosis by imaging studies. Most cases of CUTO are identified by second trimester screening ultrasound. Fetal hydronephrosis is found in approximately 1% to 5% of all pregnancies screened routinely by antenatal ultrasound. However, not all antenatal hydronephrosis (ANH) is due to urinary tract obstruction. In fact, the majority of cases with antenatally diagnosed hydronephrosis (50%–70% of cases) have transient or functional hydronephrosis that resolves spontaneously over time with no intervention. In a meta-analysis of a large number of pregnancies screened with antenatal ultrasounds (104,572), only 1.6% had documented postnatal urinary tract pathology. Importantly, in cases of documented ANH, increasing severity of hydronephrosis, as defined by an increase in antero-posterior diameter (APD) of the renal pelvis, increased the likelihood of finding postnatal pathology, and in particular, an obstructive urinary tract condition. Of the obstructive conditions, UPJ obstruction was the most common, occurring in 54.3% of cases with severe ANH (as defined as an APD > 15 mm in the third trimester), PUV occurred in 5.3%, while other causes of ureteric obstruction were seen in 5.3% of the cases. The severity of ANH, therefore, is an important determinant of the likelihood of postnatal pathology. It can be used in a standardized care plan to help direct antenatal consultation and immediate postnatal investigation and follow-up ( Fig. 21.1 ). In particular, in cases of an isolated unilateral ANH, even in severe cases, a postnatal ultrasound before 1 month of age would be indicated to confirm the antenatal findings. In moderate to severe cases, further staged testing would be performed to evaluate the severity of obstruction, associated urinary tract anomalies, and the need for surgical consultation and intervention. While there is experimental evidence in animal models that supports the benefit of relieving obstruction on longer-term kidney function, the indications and timing for this surgery in human fetuses are unclear and controversial. Clinical indications for surgical intervention in the postnatal period include progression of hydronephrosis on ultrasound, differential kidney function less than 40% on nuclear renogram, a drop in differential function of more than 10% on consecutive scans, or clinical complications such as febrile urinary tract infection or pain. Both the severity of hydronephrosis and the loss of function in the hydronephrotic kidney are predictive of the likelihood of requiring surgery.

Clinical pathway for postnatal imaging of antenatally detected hydronephrosis (ANH). In mild, moderate, and unilateral severe ANH detected in the second or third trimester, follow-up ultrasound (US) imaging should be performed in the first month after birth. Subsequent specialist referrals will depend on the severity of hydronephrosis at that point. In situations where the hydronephrosis is severe and bilateral, where the contralateral kidney is abnormal, or where there are features of posterior urethral valves (PUV), specialist referral is recommended prior to delivery and also immediately after birth. Postnatal imaging should be performed prior to discharge from hospital.

(Adapted from van den Brekel A. Postnatal investigation of antenatally detected hydronephrosis. UBC Faculty of Medicine series: This Changed My Practice, 2015. http://thischangedmypractice.com/postnatal-investigation-hydronephrosis/ .)

Fetuses in which the hydronephrosis on screening antenatal ultrasound is bilateral and severe on at least one side, where there is a solitary kidney with hydronephrosis, where there is unilateral hydronephrosis and an abnormal contralateral kidney, or where there are features of bladder outlet obstruction are at risk for the complications of kidney failure. These situations therefore require antenatal consultation with a maternal fetal specialist, pediatric nephrologist, and/or pediatric urologist (see Fig. 21.1 ).

Detailed ultrasound examination of the fetal urinary tract detects the majority of obstructive kidney anomalies, particularly when performed by an experienced operator. Fetal magnetic resonance imaging (MRI) can complement ultrasound studies by providing a more comprehensive assessment of the fetal urinary tract, which may be indicated in complex syndromes, associated CAKUT, or pregnancies with severe oligohydramnios and pulmonary hypoplasia. However, predictive values of MRI for CUTO are lacking and further prospective, comparative studies in larger patient populations are needed to justify the inherent cost, and in the newborn infant, the need for sedation with MRI studies.

Postnatal Outcomes of Antenatally Diagnosed Congenital Urinary Tract Obstruction

An understanding of the postnatal outcomes of the various conditions associated with fetal urinary tract obstruction is required to direct further antenatal counseling, investigation, consultation, and intervention. As discussed in the previous sections, the postnatal outcome of mild hydronephrosis is excellent and in most cases there is complete resolution of the antenatal findings, as seen in up to 97% of cases in a large prospective observational cohort. Therefore, in the face of an otherwise normal fetus, the hydronephrosis can be further evaluated with postnatal ultrasound imaging within the first month after birth.

Moderate to severe unilateral hydronephrosis, on the other hand, is often indicative of underlying pathology, the most likely being UPJ obstruction. Isolated unilateral UPJ obstruction diagnosed in the fetus is not associated with increased morbidity or mortality and ultimately with impaired postnatal and long-term global kidney function or chronic kidney disease and therefore there is no immediate need for antenatal intervention. However, UPJ obstruction does impact single-unit differential function and long-term outcome in the affected kidney. In prospective follow-up studies of children diagnosed with unilateral ANH and postnatal UPJ obstruction, in cases that were initially monitored and managed conservatively, over 50% required surgery for declining function in the affected kidney and in almost 90% of those who had more severe degrees of hydronephrosis.

Conditions that may affect fetal health and outcomes are those that involve both kidneys, including bilateral ANH, unilateral ANH with an affected contralateral kidney, or bladder outlet obstruction. The likelihood that the condition will be life-threatening to the fetus and will significantly impact postnatal outcome is directly related to the severity of the obstruction and the extent of injury caused to the developing kidney, that is, the degree of developmental kidney injury. The challenge is to accurately estimate the extent of this injury. These estimates will inform decisions around the continuation of the pregnancy and, potentially, decisions about intervention within the antenatal or immediate postnatal period.

The Effects of Urinary Tract Obstruction on the Developing Kidney

Urinary tract obstruction during fetal life disrupts normal kidney development. This consists of the acquisition and development of new nephrons, the functional units of the kidney, of morphogenesis, the enlargement and growth of the existing kidney structures, and of segment-specific differentiation or the development of the specific and unique functions of the kidney. Active nephrogenesis begins at about 6 to 8 weeks’ gestation and continues through to 36 weeks. New nephron formation results from a reciprocal induction of the ureteric duct and the pluripotent cells of the metanephric mesenchyme, derived from the embryonic mesoderm layer. During that time the human fetus acquires the full complement of approximately 600,000 to 1 million nephrons. The initiation of glomerular filtration begins with vascularization of the developing glomeruli at about 8 to 10 weeks’ gestation, resulting in the production of fetal urine. Over the course of gestation, the full complement of glomeruli are acquired, the nephron undergoes segmental differentiation, and the nephrons grow and extend to eventually form a well-demarcated cortex and medulla region.

The acquisition of renal function also occurs during fetal gestation and mirrors the morphologic changes. Glomerular filtration begins with vascularization of the kidney and glomeruli, with the development and regulation of renal blood and plasma flow, and with the de novo expression of protein and ion transporters through the length of the nephron. The fetal kidney develops the capacity to dilute urine through the regulated reabsorption of minerals such as Na ⁺ , K ⁺ , Cl ⁻ , and the capacity to concentrate the urine through the reabsorption of water through the development of water channels under the influence of the circulating hormone vasopressin.

The induction of nephrogenesis, the transition of progenitor mesenchymal cells to differentiated epithelia, and the differentiated maturation of tubular segments are all events initiated and orchestrated by a precise temporal and spatial expression of a hierarchy of genes and the proteins they encode. The fundamental importance of this expression occurs early in the development of the mammalian kidney, as early as the mesonephros stage of development where genes responsible for axial orientation and kidney cell determination are expressed. The process of induction of directed gene expression occurs throughout fetal life and into the postnatal period, where genetically directed kidney tubule cell growth and differentiation continue to occur.

While the specifics of gene expression are beyond the scope of this discussion, in principle, a disruption in the normal pattern of kidney development gene expression can result in abnormally formed kidneys that function abnormally. A number of in utero events may be responsible for this disruption, including in utero exposure to toxins, gene mutations, hypoxia, protein restriction, preterm birth, and intrauterine growth restriction, among others ( Fig. 21.2 ). In the case of monogenic mutations, the severity of the phenotype depends on the hierarchical importance of the gene, as downstream genes controlling a multitude of essential developmental processes are also likely to be affected. More often, the developmental kidney defect is part of a polygenic disorder and is associated with a number of other phenotypic malformations.

Antenatal factors that influence fetal kidney outcomes. Urinary tract obstruction, in addition to a number of other antenatal insults, can affect long-term kidney outcome in the fetus. Severe obstruction disrupts normal nephrogenesis, resulting in a decrease in nephron endowment and consequent predisposition to chronic kidney disease.

Fetal urinary tract obstruction, like gene mutations or in utero exposure to toxins, also affects normal kidney development when it occurs during the critical stages of nephrogenesis. In addition to hydronephrosis, significant obstruction results in renal hypodysplasia (RHD), characterized by a reduction in the normal parenchyma; disrupted architecture, often with reduced formation of the medulla; a reduction in the number of glomeruli; cystic transformation of the glomeruli and tubules along the full length of the nephron; remodeling of the developing collecting ducts; and marked expansion and fibrosis of the kidney interstitium. Mechanistically, obstruction to urinary flow disrupts the normal induction of nephrons, leading to a glomerular deficit and abnormally formed glomeruli, a proximal tubular deficit and alteration in segment-determining genes, and a remodeling of the collecting duct with alteration in the normal cell populations. In addition, obstruction of urinary flow in both the proximal tubule and the collecting duct causes a phenotypic change in the epithelia, with the formation of peritubular smooth muscle collars, remodeling of the pericyte and peritubular capillary network, and recruitment and expansion of the interstitial fibroblast population.

The Effects of Urinary Tract Obstruction on Fetal Kidney Function

Given its effects on the normal development of kidney architecture, urinary tract obstruction in the fetus impacts both fetal and postnatal kidney function. However, kidney function in the fetus is difficult to determine, given developmental changes over gestation, the complexity and array of functional changes, the interposition of the placenta, and the technical and ethical limitations of studying and sampling fetal blood and urine. Our knowledge of normal human fetal kidney function has been extrapolated from experimental animal models, postnatal observations in preterm human infants, and from histopathologic analyses of human fetal kidneys. Unlike in the newborn infant, the effects of obstruction on kidney function at specific times of fetal evaluation have not been well described. Most routine antenatal screening ultrasounds occur at 18 to 20 weeks’ gestation; significant urinary tract obstruction at that time manifests as hydronephrosis, hydroureters, and bladder and urethral anomalies. While these effects on kidney anatomy are easily appreciated, their effects on actual “real-time” kidney function may be difficult to measure.

The development of normal fetal kidney function involves the acquisition of normal glomerular numbers that determine normal fetal glomerular filtration rate (GFR), of mechanisms that regulate this fetal GFR, and of fetal kidney tubular function, that are responsible for the establishment and maintenance of Na ⁺ , H ₂ O, and acid-base balance.

Development of glomeruli, the glomerular vasculature, and the glomerular filtration barrier occurs between 8 and 36 weeks’ gestation in humans. Fetal GFR increases steadily over this time, reflecting new nephron development, an increase in the number of glomeruli, and, most importantly, an increase in glomerular surface area. After the completion of nephrogenesis, GFR rapidly increases during the later stages of gestation, due in part to the enlargement of the glomeruli and filtration area with increase in body mass of the fetus, and to renal blood redistribution and recruitment of the outer cortical nephrons ( Fig. 21.3 ). While the absolute creatinine clearance (a standard measure of kidney function) for a 20 weeks’ gestation fetus is estimated to be less than 1 mL/min, over the subsequent period of nephrogenesis, and at term, the GFR increases approximately fivefold to 4 to 5 mL/min ( Fig. 21.4 ).

Relationship between fetal glomerular filtration rate (GFR) and fetal kidney weight and gestational age. Pattern of change in GFR and persistence of the nephrogenic zone of the human fetal kidney cortex. As the gestational age increases, the nephrogenic zone decreases and disappears by 36 weeks’ gestation. This is associated with a corresponding increase in GFR as reflected by creatinine clearance. Data from 205 neonates, N ranging from 7 to 26 in each group at different gestational ages.

(Reproduced with permission from Trnka P, Hiatt MJ, Tarantal AF, Matsell DG. Congenital urinary tract obstruction: defining markers of developmental kidney injury. Pediatr Res. 2012;72:446-454.)

Increase in fetal glomerular filtration rate (GFR) during gestation. Creatinine clearance was calculated from fetal urine and blood sample values during fetal life and in preterm infants, and used as a surrogate measure of fetal GFR. In both the fetus (lighter dots, upper line) and in the preterm infant (darker dots, lower line), creatinine clearance increased with increasing gestational age.

(Reproduced with permission from Haycock GB. Development of glomerular filtration and tubular sodium reabsorption in the human fetus and newborn. Br J Urol. 1998;81 Suppl 2:33-38.)

In addition to being due to an increase in the number of functional glomeruli, the increase in fetal GFR also results from developmental changes in the variables that determine single nephron function: an increase in mean arterial pressure, which increases glomerular capillary hydrostatic pressure ; an increase in renal blood flow ; and a decrease in renal vascular resistance. In turn, regulators of normal fetal GFR physiology also undergo maturational changes during fetal life, including an upregulation of the components of the renin-angiotensin system, which controls systemic blood pressure by maintaining systemic and renal vascular resistance ; the sympathetic nervous system, which increases renal vascular resistance, preferentially increasing the afferent arteriolar tone of the fetal glomerulus and decreasing GFR ; and endothelin, prostaglandins (PGE2, PGD2, and PGI2), and nitric oxide, which are important fetal kidney vasoregulators.

As the fetal kidney develops glomerular function it also acquires complex, differentiated, segment-specific tubular function. Fetal kidneys are unable to fully dilute and concentrate urine. Urine concentrating ability increases with increasing gestational age, reflecting the fetal kidney’s increased responsiveness to antidiuretic hormone, water channel development, and renal medullary maturation. Important changes also occur in sodium transport. Urinary sodium losses, as reflected by the fractional excretion of sodium (FENa), decrease with increasing gestational age and fetal kidney maturity. The FENa in term infants is less than 1%, while in preterm and small-for-gestational-age infants it approaches 2.4%, being higher in more preterm infants ( Fig. 21.5 ). Likewise, a number of maturational changes occur in sodium handling in the developing fetal kidney, including an increase in the abundance of sodium transporters (Na-K-ATPase, NHE3 exchanger, Na-K-2Cl cotransporter, and the ENaC channel), enhanced paracellular transport, increased responsiveness to circulating hormones, and a postnatal decrease in circulating atrial natriuretic peptide. The capacity of the fetal kidney to regulate acid-base balance is less than in the adult kidney, but increases with gestational age. In the proximal tubule, the expression of the sodium transporters NHE3, Na-K-ATPase, and type IV carbonic anhydrase increase with kidney maturation. Similarly, the fetal kidney has a reduced ability to secrete both organic and inorganic acids. In the fetal cortical collecting duct, the intercalated cell population, in particular the alpha-intercalated cells responsible for acid excretion, is significantly reduced compared to the postnatal kidney.

Changes in sodium excretion in the developing kidney. At birth, urinary sodium losses, measured by the fractional excretion of sodium (FENa), decrease with increasing gestational age. For example, the FENa is significantly higher in the infant born between 1000 and 1500 g (lightest red line) than in the term infant (black line). In the preterm and low-birth-weight infant, the fractional excretion of sodium decreases after birth and by 2 to 3 weeks approaches that of the term infant.

(Modified from Bueva A, Guignard JP. Renal function in preterm neonates. Pediatr Res. 1994;36:572-577.)

The precise effects of obstruction on these various elements of normal kidney function in the human fetus have not been described, but can be extrapolated from observations in infants born with urinary tract obstruction, particularly those born preterm, from autopsy specimens of fetuses with severe bladder outlet obstruction, and from experimental animal models. In a large cohort of children with RHD and small kidneys, PUV was responsible for approximately 30% of the cases, while other forms of CAKUT, including cases of hydronephrosis, were responsible for another 25%. Similarly in children with PUV, approximately 75% have been shown to have at least one small kidney when evaluated postnatally. These observations support the experimental evidence that urinary tract obstruction results in a nephron deficit, which translates into a decrease in fetal GFR and predisposes to postnatal progression of chronic kidney disease. While in experimental animals the expression of regulatory factors of GFR is altered, with persistent fetal expression of renin in the microvasculature, activation of the RAS, and downregulation of eNOS in the obstructed developing kidney, similar studies in human fetuses are lacking.

In human and nonhuman primate fetuses, urinary tract obstruction causes substantial collecting duct tubular injury and has a particular effect on collecting duct development and postnatal function. This is reflected in collecting duct epithelial remodeling noted in early fetal life, with a dropout of normal intercalated cell populations evident by late gestation. Similarly, proximal tubule epithelial cell injury has been reported with abundant cell death in obstructed developing rat kidneys. The functional consequences of these injuries on tubular function are difficult to quantify in the fetus. However in newborn infants, affected by severe PUV, particularly those born preterm, alterations in kidney function are commonly seen, including a decrease in GFR, and tubular abnormalities including polyuria (due to a defect in concentrating ability), urinary salt wasting (due to a decrease in tubular Na ⁺ reabsorption), and metabolic acidosis (due to an altered expression in collecting duct intercalated cell expression).

The Measurement of Fetal Kidney Function

The evaluation of fetal kidney function is complex, imperfect, and controversial. Precise evaluation of fetal kidney function, however, would enable an estimate of the severity of injury at the time of evaluation and help with further discussions around immediate and postnatal prognosis. Estimates of fetal kidney health and function include imaging studies, fetal blood and urine sample estimates of fetal GFR, and amniotic fluid (AF) sampling, including the concentrations of analytes, fluid volumes, and fetal urine flow rates.

Screening ultrasound during the second trimester of pregnancy identifies most cases of severe CUTO. Occasionally, the obstruction becomes clinically significant in later stages of pregnancy. Most cases of significant upper and lower urinary tract obstruction affecting one or both kidneys are associated with hydronephrosis. Lower tract obstruction, and in particular bladder outlet obstruction, can also result in posterior urethral dilatation (keyhole sign) and bladder involvement with a distended thick-walled bladder. The ultrasound findings of significant obstruction are correlated with the underlying histopathologic changes. Increased echogenicity of the affected kidneys reflects parenchymal disruption, a poorly defined cortico-medullary border reflects abnormal kidney architecture and underdevelopment or hypoplasia of the renal medulla, and cystic changes reflect tubular dilatation and cystic transformation of the injured developing tubules. All of these ultrasound findings are indicative of abnormal kidney development resulting from the effects of obstruction to urinary flow in the developing kidney.

While radiologic imaging of the fetal kidney is an imperfect measure of kidney function, direct measurement of fetal GFR would be an ideal determinant. However, estimating fetal GFR is technically challenging given the need for fetal blood sampling. Consequently, there are limited normative data in uncomplicated pregnancies. In humans, fetal GFR has been estimated as early as 20 weeks’ gestation. Fetal blood levels of β ₂ -microglobulin, the light chain of the class I major histocompatibility antigens, have been used to estimate fetal GFR. Fetuses with urinary tract obstruction have been shown to have higher serum levels than those without obstruction, reflecting a decrease in urinary clearance as a result of kidney injury, and β ₂ -microglobulin is a better predictor of postnatal kidney function than either α ₁ -microglobulin or cystatin C. In a cohort of fetuses with urinary tract malformations including urinary tract obstruction, a fetal serum β ₂ -microglobulin above the cutoff of 5.6 mg/L had a sensitivity of 80%, a specificity of 98.6%, a positive predictive value of 88.9%, and a negative predictive value of 97.1% for postnatal renal failure. The usefulness of β ₂ -microglobulin is hampered by the lack of robust normative data, resulting from sampling of a small number of patients, by measurements at different stages of gestation, and by variable measures of outcome.

More commonly, the concentrations of fetal urine electrolytes have been used in the antenatal evaluation of fetal kidney function in fetuses identified with significant lower urinary tract obstruction. In the developing fetal kidney, the ability to reabsorb electrolytes such as Na ⁺ , Cl ⁻ , Ca ²⁺ , and water increases with increasing gestational age. In the cases of kidney injury that occurs during kidney development, this tubular reabsorption is presumably impaired, resulting in higher than normal urinary concentrations. Fetal urinary values have been correlated with clinical outcomes, kidney histology, and postnatal kidney function. Significant kidney injury resulting in impaired postnatal function is associated with high fetal concentrations of electrolytes (high specificity, low false positive rate), but these electrolyte findings have low sensitivity to predict outcome (high false-negative rate). A recent comprehensive systematic review of the published studies of fetal urine analysis revealed that there is currently no individual analyte or threshold which, as a diagnostic test, can accurately predict postnatal renal function. The studies reviewed were hampered by selection bias, by small numbers, by variation in the thresholds of the most widely investigated analytes, and by lack of correlation with gestational age. The value of fetal urine, fetal blood, or AF cystatin C levels in assessing fetal kidney function is unknown. During normal pregnancy, AF cystatin C levels decrease with increasing gestational age, but are increased in pregnancies associated with fetal uropathy.

Fetal urinary flow rates and AF volume have also been used as indirect measures of fetal GFR during the second half of pregnancy and can be calculated from changes in fetal bladder volumes on repeat ultrasound examinations over time. In the early fetal period, most of the AF is produced by the amnion, placenta, and umbilical cord. AF volume increases from approximately 25 mL at 10 weeks’ gestation to approximately 400 mL at 20 weeks’ gestation when fetal kidneys become the main source, although the total volume of AF can vary substantially. By 28 weeks’ gestation, AF volume reaches a plateau of approximately 800 mL until term, with a slight decline postterm. Any impairment of fetal kidney function, including urinary tract obstruction, will manifest as oligohydramnios from mid-trimester onwards; however, this is a coarse estimation of absolute fetal GFR with poor correlation with actual GFR.