INTRODUCTION — Developmental renal defects include (1) bilateral/unilateral renal agenesis, (2) renal hypodysplasia characterized by a reduction in the number of nephrons leading to a small overall kidney size and frequent dysplasia with or without cysts, and (3) multicystic dysplastic kidney (MCDK).

A kidney may be absent because it never developed (agenesis [probably rare]) or because of complete regression of a dysplastic kidney (aplasia/MCDK). In this topic, the term "renal agenesis" will be used to refer to absent kidneys resulting from either of these etiologies (figure 1).

Renal agenesis may be either unilateral or bilateral. Bilateral renal agenesis is incompatible with extrauterine life because prolonged absence of amniotic fluid results in pulmonary hypoplasia, leading to severe respiratory insufficiency at birth. The longest-surviving child lived 39 days [1]. Early serial amnioinfusion is under investigation as a potential life-saving intervention by pulmonary palliation, but only anecdotal information is available in human fetuses, and the procedure does not eliminate the need for renal transplantation for long-term survival.

This topic will discuss prenatal diagnosis of renal agenesis. An overview of congenital anomalies of the kidney and urinary tract (CAKUT) is available separately. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

EPIDEMIOLOGY — Prior to the widespread use of prenatal ultrasonography and the availability of legal pregnancy termination in the United States, the incidence of bilateral renal agenesis was approximately 1 in 4000 births and approximately 1 in 250 autopsies of stillbirths and infant deaths [2,3]. It is 2.5 times more common in males than in females [4].

The incidence of unilateral renal agenesis is approximately 1 in 3000 live births [5]. Some series have reported more affected males than females and more left-sided agenesis [5,6].

EMBRYOLOGY, PATHOGENESIS, AND RISK FACTORS — An absent kidney may be secondary to early involution of a multicystic dysplastic kidney (or dysplastic kidney) or to true renal agenesis (figure 1) [7]. Renal agenesis (and many other renal malformations) occurs when the ureteric bud fails to develop and thus fails to induce differentiation of the metanephrogenic mesenchyme to renal tubular epithelium. In vitro models reveal that, when the ureteric bud and metanephrogenic mesenchyme meet, the ureteric bud branches, and nephrons form within three to seven days; however, if they remain apart, nephrons do not form, and the mesenchymal tissue undergoes apoptosis. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Embryology'.)

Unilateral renal agenesis can be caused by mutations in many genes, such as RET (10q11.2), BMP4 (14q22-q23), FRAS1 (4q21.21), FREM1 (9p22.3), or UPK3A (22q13.31). Mutations in the RET, FGF20 (8p22), or ITGA8 (10p13) genes have been reported in bilateral renal agenesis.

Maternal clinical risk factors for bilateral renal agenesis include preexisting diabetes, a prepregnancy body mass index greater than 30 kg/m² (adjusted odds ratio [aOR] 1.92, 95% CI 1.00-3.67), smoking during the periconceptional period (aOR 2.09, 95% CI 1.08-4.03), and binge drinking during the second month of pregnancy (aOR 3.64, 95% CI 1.19-11.10) [8,9].

SONOGRAPHIC EVALUATION OF THE FETAL URINARY TRACT — A systematic approach to evaluating the fetal kidneys, adrenals, bladder, and amniotic fluid volume is of utmost importance in making a correct diagnosis of renal agenesis. American Institute of Ultrasound in Medicine (AIUM) guidelines for detailed obstetric ultrasound examinations between 12+0 and 13+6 weeks of gestation recommend visualization of the kidneys and bladder and color Doppler of the renal arteries and the umbilical arteries alongside the bladder [10].

Fetal kidneys and adrenal glands — The fetal kidneys are relatively hyperechoic in the first trimester and can be visualized at both sides of the lumbar spine starting at 10 to 12 weeks. Transverse and coronal views can be used for assessing their presence; the addition of color Doppler flow on the coronal view is useful for visualization of the renal arteries. A small amount of fluid in the renal pelvis is physiologic and is helpful in identifying the renal tissue (image 1A and image 1B and image 2A).

Starting at 20 weeks, identification of the fetal kidneys requires stricter criteria than mere presence of tissue in the renal fossa. Renal corticomedullary differentiation is defined as a relatively hyperechoic cortex compared with the medulla and should be present starting at 20 weeks. Thus, presence of a kidney should be based on visualization of an echogenic reniform mass containing hypoechoic medullary pyramids circumferentially arranged beneath the renal cortical tissue (image 1A-D). After 20 weeks, cortical echogenicity evolves from a hyperechoic pattern during the second trimester to a hypoechogenic pattern in the third trimester with no fetus displaying cortical hyperechogenicity as compared with spleen or liver after 32 weeks [11].

The renal arteries can normally be seen on coronal views to exit from either side of the aorta, cranial to its bifurcation into the common iliac vessels. Pattern recognition of the renal artery and vein waveforms using pulsed Doppler should enable the sonologist to distinguish these vessels from other abdominal vessels.

Fetal adrenal glands can be consistently visualized at 11 to 13 weeks using transabdominal and transvaginal imaging [12]. The adrenal glands lie superior and medial to the kidney. The gland has an inverted "V" shape on longitudinal views and has an oval shape on transverse views. The ultrasound appearance is characterized by an echogenic central stripe representing the medulla and surrounding peripheral sonolucent rim representing the cortex.

Fetal bladder — The bladder can be visualized as early as 10 weeks of gestation. In one study, the bladder was always visualized when the crown rump length (CRL) was more than 67 mm, and in 91 percent of cases when the CRL was 38 to 67 mm [13]. The use of both transabdominal and transvaginal ultrasound enables bladder visualization in 98 percent of cases at 12 to 13 weeks [14].

Urine production starts at 9 weeks of gestation and increases significantly after 16 weeks. Fetal urine production is estimated to be approximately 7.3 mL/hour at 24 weeks of gestation, increasing to 71.4 mL/hour near term or approximately 300 mL/kg fetal weight/day [15].

The fetal bladder fills and empties approximately every 30 to 60 minutes. Therefore, the bladder should be observed for accumulation of urine over one hour before concluding that urine is not being produced. Persistent absence of the bladder at ≥16 weeks should be considered abnormal [16].

Furosemide should not be administered to the mother to stimulate fetal diuresis and bladder filling because the lack of bladder response may also be noted in cases with normal kidney function.

Color flow Doppler imaging of the pelvic umbilical arteries can be useful for demarcating the location of the bladder (image 3).

Retrograde filling of the bladder, such as in urogenital sinus anomalies, and midline urachal cysts may be misdiagnosed as normal renal urine production [17].

Amniotic fluid volume — The major nonspecific marker of bilateral renal agenesis is severely reduced or absent amniotic fluid. In early pregnancy, the movement of fluid across the amnion, fetal membranes, and chorionic plate is thought to be the dominant source of amniotic fluid. Fetal urine becomes the main source after approximately 16 weeks of gestation. Therefore, amniotic fluid volume in pregnancies complicated by renal agenesis might appear normal before 15 to 16 weeks, even though sharply reduced or absent amniotic fluid volume is the most prominent ultrasonic feature of this disorder after 15 to 16 weeks [17]. (See "Physiology of amniotic fluid volume regulation".)

The absence of fluid is not pathognomonic of bilateral renal agenesis; it can also be associated with severe fetal growth restriction, fetal demise, urinary outflow obstruction, and preterm prelabor rupture of membranes. Unilateral renal agenesis is associated with a normal volume of amniotic fluid unless the contralateral kidney is abnormal with complete obstruction.

PRENATAL DIAGNOSIS OF RENAL AGENESIS

Renal findings — The prenatal diagnosis of bilateral renal agenesis is based upon sonographic nonvisualization of the fetal kidneys, ureters, and bladder, accompanied by oligohydramnios (image 4). In two studies, the prenatal detection rate for bilateral renal agenesis/dysgenesis by ultrasound was reported to be 84 and 91 percent; the detection rate for unilateral renal agenesis was 59 and 80 percent [18,19].

The diagnosis is typically made at the routine sonographic fetal anatomic survey performed at 18 to 20 weeks of gestation. A small proportion of bilateral renal agenesis (15.4 percent) and unilateral renal agenesis (2.4 percent) can be diagnosed by the first-trimester scan [20].

Unilateral renal agenesis is more difficult to diagnose since amniotic fluid and bladder volume are normal; the diagnosis depends on accurately excluding the presence of a second kidney in the renal fossa or an ectopic location (image 5). Unilateral renal agenesis cases may be missed in 21 percent of cases unless a third-trimester scan is performed.

An empty renal fossa warrants a detailed search for an ectopic kidney location or a dysplastic kidney. In one study, renal agenesis accounted for only 40 percent of empty renal fossae; 49 percent of the cases had an ectopic kidney in the pelvis (image 6), horseshoe kidney was the final diagnosis in 6 percent, and 5 percent had crossed fused ectopic kidney [21].

Intrathoracic renal ectopia can rarely occur with intact diaphragm, and with eventration of the diaphragm, or congenital diaphragmatic hernia [22].

In unilateral renal agenesis, compensatory enlargement, usually defined as renal length >95^th percentile for gestational age, occurs in all cases and can be seen on ultrasound starting at 20 weeks [23]. Thus, an enlarged kidney contralateral to an empty renal fossa supports the diagnosis of unilateral renal agenesis or in utero dysplasia of the other kidney [24]. In one study, the compensatory hypertrophy of the contralateral kidney was defined as a ratio of the anteroposterior to transverse diameter more than 0.9; this cutoff differentiated all cases of true renal agenesis from renal ectopy [25]. One group described a unique growth pattern of the solitary kidney, steeper during the second than the third trimester and independent of the normative data [26].

Color flow Doppler — Color flow Doppler imaging of the renal arteries should be performed when the kidneys are not visualized. Failure to image renal vessels with color flow Doppler using appropriately low gain settings is suggestive, although not definitive evidence, of renal agenesis (image 2A-B) [27,28]. By comparison, color flow Doppler demonstration of renal vessels confirmed by waveform analysis verifies the presence of renal tissue. In a study that correlated prenatal color imaging with postnatal evaluation, absent renal blood flow was noted in seven of eight fetuses with bilateral renal agenesis and in one of eight fetuses with unilateral agenesis with contralateral atrophic multicystic kidney on postmortem examination [29]. Three fetuses had only one renal artery imaged; two of these had unilateral agenesis and one had a multicystic dysplastic kidney on postnatal evaluation. The presence of both kidneys was confirmed postnatally in all 22 fetuses in whom both renal arteries were identified prenatally.

Adrenal gland findings — The adrenal gland or bowel may fill in the empty renal fossa and mimic renal tissue if appropriate care is not taken in cases with renal agenesis or renal ectopy. The adrenal gland has an echogenic medulla with a relatively hypoechoic cortex and is normally V or Y shaped. In half of the cases with an empty renal fossa, the adrenal gland appears flattened on parasagittal images and fills the renal fossa, named "lying down sign" [30].

Bladder findings — A filling and emptying fetal bladder is the best indicator of fetal urine production. Nonvisualization of the fetal bladder combined with oligohydramnios indicates severe pathology and can occur secondary to a prerenal or renal etiology [31]. Prerenal cases are associated with severe placental insufficiency and resultant fetal growth restriction with abnormal umbilical artery Doppler indices. Preterm prelabor membrane rupture should be ruled out as it can mimic renal pathology in cases with oligohydramnios. Renal causes of an empty bladder include bilateral renal agenesis, unilateral renal agenesis with contralateral severe renal dysplasia or multicystic kidney, bilateral renal dysplasia, or bilateral medullary cystic kidney disease (MCKD). Cloacal and bladder exstrophy may present with renal agenesis or nonfunctional kidney abnormalities that may lead to oligohydramnios and should be considered in the differential diagnosis.

Role of diagnostic amnioinfusion — The absence of amniotic fluid sharply diminishes the sonographer's ability to examine the presence and structure of the fetal kidneys. Impaired visualization is further exacerbated by crowding of the fetal extremities adjacent to the torso. Poor visualization of fetal anatomy due to absence of amniotic fluid is the main obstacle to accurate diagnosis of bilateral renal agenesis.

Diagnostic amnioinfusion has been used to surmount this limitation. As an example, one study reported successful fluid replacement was possible in 95 percent of diagnostic procedures and suspected fetal anomalies were confirmed in 27/30 patients; the diagnosis of bilateral renal agenesis was excluded in three fetuses after amnioinfusion [32]. However, it is not clear whether amnioinfusion improves the diagnostic accuracy for bilateral agenesis when a careful color Doppler examination of the renal artery has been performed. The procedure for amnioinfusion and its role in management to improve outcome are described separately. (See "Amnioinfusion", section on 'Transabdominal approach' and 'Pregnancy outcome and obstetric management' below.)

Role of magnetic resonance imaging — On T2-weighted magnetic resonance imaging (MRI), renal agenesis is characterized by the absence (signal void) of both the normal bright urine signal isointense to maternal fat within the renal pelvis and bladder and the less intense signal of the renal parenchyma.

The contribution of fetal MRI to the diagnosis of renal agenesis remains unclear [33,34]. In one study, fetal MRI helped to demonstrate an ectopic, hypotrophic, or horseshoe kidney in cases with suspected renal agenesis on ultrasound [35].

Differential diagnosis — True renal agenesis, severe renal hypoplasia, and cystic dysplasia with subsequent atrophy (renal dysplasia defined as a renal remnant and ureter without normal renal histology) all lead to the same clinical presentation, but distinguishing these entities can be difficult both on ultrasound examination and at autopsy [36]. With true agenesis, the kidney and ureter are absent with no detectable rudiment. In contrast, atrophy of a previously hypoplastic, dysplastic, or multicystic kidney leaves a rudimentary kidney and ureter. Ultrasound examination can only distinguish between renal agenesis and atrophy if serial studies are performed and the early studies show the presence of the now atrophic kidney.

ASSOCIATED ABNORMALITIES

Structural and genetic abnormalities — Bilateral renal agenesis is associated with other structural abnormalities in over 50 percent of cases. Most abnormalities involve the cardiac, central nervous, urogenital, and skeletal systems.

Among cases of unilateral renal agenesis, urological anomalies occur in 30 to 70 percent of cases [5,6,37-39]. The most common anomalies are vesicoureteral reflux (28 to 41 percent), ureterovesical junction obstruction (11 to 18 percent), and ureteropelvic junction obstruction (6 to 7 percent). The remaining 30 to 50 percent of cases have structural malformations of the heart (eg, septal defects), gastrointestinal tract (eg, anal atresia), genital, or skeletal systems.

The incidence of a single umbilical artery is increased with unilateral renal agenesis. With true unilateral agenesis, the ureter and the ipsilateral bladder hemitrigone are absent. The embryonic insult that results in unilateral renal agenesis may involve not only the ureteral bud, but also other mesonephric duct derivatives, including the seminal vesicles, vas deferens, and epididymis. The absence of the vas deferens is the most frequent genital anomaly in males with renal agenesis and can be bilateral even if the renal agenesis is unilateral. One-third of males with bilateral congenital absence of the vas deferens have unilateral renal agenesis.

Bilateral and unilateral renal agenesis have been associated with the following:

●22q11.2 deletion syndrome – 22q deletion syndrome is a contiguous gene deletion syndrome with de novo mutations in 90 percent and autosomal dominant inheritance. It is characterized by conotruncal cardiac malformations, congenital diaphragmatic hernia, tracheoesophageal fistula/esophageal atresia/laryngeal web, polydactyly, craniosynostosis, polymicrogyria, renal anomalies, facial dysmorphology, and palatal abnormalities. Renal abnormalities are noted in one-third of the patients and usually are in the form of agenesis, hypoplasia, or dysplasia. Prevalence is 1 in 3000 to 6000 live births. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis".)

●Fraser syndrome is an autosomal recessive disorder characterized by renal agenesis, laryngeal atresia or webs, cryptophthalmos, and syndactyly. Prevalence is 1:200,000 live births. (See "Renal hypodysplasia", section on 'Genetic disorders'.)

●Otocephaly is a rare malformation characterized by agnathia or mandibular hypoplasia, melotia (anteromedial malposition of ears), microstomia, aglossia or microglossia, and renal agenesis. Holoprosencephaly and situs inversus are other abnormalities seen in some cases. Prevalence is less than 1 in 70,000 live births.

●Cat-eye syndrome (coloboma of iris-anal atresia syndrome) is a disorder that is characterized by a fissure in the iris of the eye, preauricular skin tags, and the absence of an anal opening. Other abnormalities may include heart defects and renal agenesis, hypoplasia, or dysplasia. Most patients have a de novo small supernumerary marker chromosome with partial tetrasomy of 22pter-22q11. Prevalence is 1 to 9 in 100,000 live births. (See "Congenital cytogenetic abnormalities", section on '47,+inv dup(22)(q11)'.)

●Melnick-Fraser syndrome (branchio-oto-renal syndrome) is an autosomal dominant disorder characterized by preauricular pits, malformations of the outer, middle, and inner ear associated with mixed hearing loss, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Prevalence is 1 in 40,000 live births.

●VACTERL association – Vertebral anomalies, Anal atresia, Cardiac defects, TE fistula (tracheoesophageal fistula), Renal defects, Limb defects and isolated anomalies of the cardiovascular, skeletal, and central nervous systems [36,40].

In fetuses with VACTERL association, 52 percent have a structural renal abnormality, and unilateral renal agenesis comprised one-third of the cases [41]. There is a wide range of manifestation of VACTERL associations. Prevalence is 1 in 10,000 to 40,000 newborns.

●Caudal dysplasia syndrome (CDS) or caudal regression is associated with hypoplastic lower extremities, fused iliac wings, lumbosacral vertebrae anomalies with absent sacral vertebrae in severe cases, closed neural tube defect with tethered cord and lipoma, and renal agenesis. Prevalence is 1.0 to 2.5 per 100,000 live births and is 200 times higher in diabetics. (See "Closed spinal dysraphism: Pathogenesis and types", section on 'Caudal regression or sacral agenesis'.)

●Sirenomelia is characterized by a single lower extremity, absent sacrum, urogenital anomalies, and imperforate anus. Abnormally formed lower limbs with varying degrees of fusion are the major feature of sirenomelia, whereas maldeveloped lower limbs without fusion are found in association with caudal dysgenesis. A review of nine CDS and six sirenomelia cases revealed that 22 percent of the CDS and 66 percent of the sirenomelia cases were associated with bilateral renal agenesis [42]. Prevalence is 1 in 60,000 live births.

●Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome – Since the wolffian and müllerian ducts are contiguous, müllerian abnormalities are common in females with renal agenesis. Septate uterus is relatively common and can be associated with renal agenesis. MRKH affects at least 1 of 4500 females and had been considered a sporadic anomaly with suggestion of autosomal dominant inheritance in some cases. Congenital absence of the upper vagina and uterus is the prime feature of the disease. MRKH is generally divided into two subtypes: MRKH type 1 (57 percent), in which only the upper vagina, cervix, and uterus are affected, and MRKH type 2 (43 percent), which is associated with additional malformations generally affecting the renal and skeletal systems. MRKH type 2 also includes müllerian renal cervical somite (MURCS) characterized by cervicothoracic defects. Of all the MRKH cases, 47 percent are associated with unilateral renal agenesis. Another study reported that the urinary tract anomalies are seen in 40 percent, including unilateral renal agenesis (21 percent), pelvic kidney, horseshoe kidney, and ureteric duplication. Spinal anomalies have been reported in 10 to 12 percent of cases and include wedge, supernumerary, or asymmetric and rudimentary vertebral bodies [43]. (See "Congenital anomalies of the hymen and vagina", section on 'Vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome)'.)

●Aneuploidy

•In one series of 682 fetuses with renal defects who were karyotyped, the overall incidence of chromosomal abnormalities was 13 percent [44]. The incidence of aneuploidy was 5 percent in isolated bilateral renal agenesis, but there were no cases of aneuploidy in the three fetuses with isolated unilateral renal agenesis. The incidence of karyotypic abnormalities with unilateral or bilateral renal agenesis and multiple anomalies was 33 and 40 percent, respectively. The pattern of chromosomal abnormalities, but not the frequency, was related to the type of renal defect; the risk of chromosomal anomalies was similar for unilateral or bilateral involvement, mild or moderate or severe hydronephrosis, renal agenesis, oligohydramnios or normal amniotic fluid volume. In moderate/severe hydronephrosis, renal agenesis and multicystic dysplasia, trisomy 13 and 18 were the most common abnormalities.

•Another study included 95 cases of bilateral renal agenesis, of which 91 percent were diagnosed prenatally [18]. Chromosomal abnormalities were present in 8.1 percent of cases. The prenatal detection rate for unilateral renal agenesis was 62 percent and 25 percent had chromosomal abnormalities; however, 94 percent of these cases had multiple malformations.

Potter sequence — Potter sequence is a historical term that was used to define the typical appearance of a fetus or neonate exposed to severely decreased or absent amniotic fluid secondary to renal disease. Typically, this syndrome is characterized at birth by pulmonary hypoplasia, limb deformations (altered positioning of hands and feet, clubbed feet, hip dislocation), and flattened facies. It results from external compression of the fetus, limitation of fetal movement, and alteration in the dynamics of lung liquid movement due to severe oligohydramnios. Potter sequence can also be seen in infants with normal kidneys with prolonged leakage of amniotic fluid or rarely with severe fetal growth restriction; thus, it is not pathognomonic of renal anomalies. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

PREGNANCY OUTCOME AND OBSTETRIC MANAGEMENT — Bilateral renal agenesis is incompatible with extrauterine life because prolonged absence of amniotic fluid results in pulmonary hypoplasia leading to severe respiratory insufficiency at birth. Fetuses can survive in utero since the placenta is responsible for fetal oxygenation and excretion of wastes; nevertheless, there is a higher rate of fetal loss that is probably related to cord compression. As many as 33 percent of fetuses with bilateral renal agenesis die in utero [45].

Patients who opt for pregnancy termination should be encouraged to consent to autopsy for definitive diagnosis. A nondestructive method of pregnancy termination is desirable for this reason.

In unilateral renal agenesis, a thorough sonographic examination should be performed to look for additional structural defects, especially of the vertebrae, gastrointestinal system, heart, limbs, and reproductive tract, although many reproductive tract anomalies are difficult or impossible to detect with prenatal ultrasound.

Genetic testing by chromosomal microarray analysis (CMA) should be offered prenatally. It is well-established that CMA will provide additional information over karyotype in approximately 6 to 7 percent of pregnancies when the fetus has an anomaly identified on ultrasound. The American College of Obstetricians and Gynecologists recommends CMA as the first tier test in the diagnostic evaluation of fetal structural anomalies [46]. Abnormal CMA is reported in 2.5 to 10.5 percent of isolated unilateral renal agenesis [47,48]. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)

Molecular testing via targeted CAKUT panels or whole exome sequencing is an option that may be available at a research or clinical laboratory. These tests are most useful if other organ systems are affected or multiple affected pregnancies have occurred with the same phenotype, suggesting a genetic etiology.

There are no fetal indications for early delivery.

Investigative role of therapeutic amnioinfusion — It has been proposed that early serial amnioinfusion is a potential life-saving intervention for some affected fetuses. In animal models, restoration of amniotic fluid through an intraamniotic catheter prevents pulmonary hypoplasia [49]. However, only anecdotal information is available in human fetuses, and the procedure does not eliminate the need for renal transplantation for long-term survival [50].

●In a single case report, serial amnioinfusion was associated with the birth of a preterm neonate (29 weeks) with appropriate lung volume and no stigmata of Potter sequence [51]. At nine months of age, she was meeting her gestational age-adjusted milestones and growing appropriately on daily home peritoneal dialysis, with plans for renal transplantation at 12 to 24 months of age. However, most of her first nine months of life was spent in the hospital due to problems related to prematurity and/or dialysis.

●In another report of eight cases from a single institution, serial amnioinfusion through an intraamniotic catheter restored amniotic fluid volume to normal in all cases with an average delivery interval of 64 days (range 9 to 96 days). There was one death due to pulmonary hypoplasia and another due to unrecognized laryngeal web. The remaining six cases did not have pulmonary hypoplasia [52]. A follow-up publication from this center reported the outcome of eight cases of bilateral renal agenesis with serial amnioinfusion [53]. There were six neonatal deaths and two survivors beyond 30 days; however, both newborns died of sepsis on dialysis. There were no survivors to transplantation.

More information is needed about complication rates (eg, abruption, infection, preterm birth) and short- and long-term outcomes, including quality of life, before this procedure can be considered a reasonable intervention for treatment of bilateral renal agenesis and, until then, should be offered only as approved innovation or research [50,54]. A multidisciplinary group has reviewed the ethical considerations of this intervention and guided the development of a prospective trial to evaluate amnioinfusion in this setting [55]. A multicenter study, the Renal Anhydramnios Fetal Therapy (RAFT) trial, has begun at Mayo Clinic and Johns Hopkins Hospital, with the support from North American Fetal Therapy Network. RAFT is a nonrandomized trial that aims to assess the efficacy of serial amnioinfusions started no later than 26 weeks in early renal anhydramnios cases. The primary outcome is survival to successful dialysis as compared with the patients who declined the intervention [56-58].

COUNSELING

Bilateral renal agenesis — Most cases of bilateral agenesis are sporadic. However, genetic factors play a role in the pathogenesis, and multifactorial inheritance is a likely explanation, although the precise method of genetic inheritance is unknown. X-linked, autosomal recessive, autosomal dominant inheritance has also been described. In one series of 199 cases, seven siblings were known to be affected [59]. Twenty to 36 percent of bilateral renal agenesis is associated with familial inheritance; the genetic mechanism may be autosomal dominant inheritance with incomplete penetrance and variable expression. The risk of recurrence is reported as 3 to 6 percent but may reach 8 percent in cases associated with multiple congenital abnormalities [60,61]. Fetal ultrasound evaluation as early as 12 to 14 weeks of gestation, but traditionally at 16 to 20 weeks of a subsequent pregnancy, is the only way to determine whether the fetus is affected.

Approximately 9 to 14 percent of first-degree relatives of patients with bilateral renal agenesis, bilateral severe dysgenesis, or agenesis of one kidney and dysgenesis of the other have renal abnormalities, most often unilateral renal agenesis, but also duplicated collecting systems [61,62]. It is probably worthwhile to evaluate for the presence of both kidneys and the absence of gross renal defects in the mother at the time of prenatal ultrasound, as this can be accomplished quickly and without additional expense. The value of screening other asymptomatic family members should be considered.

Unilateral renal agenesis — Some cases of unilateral renal agenesis result from in utero regression of multicystic dysplastic kidneys [7,63]. These patients have an ipsilateral blind ending ureter. Because renal agenesis, hypoplasia, and cystic dysplasia have been reported in the same syndromes, the same families, and occasionally even the same individual, they can, when unilateral, be included together under the heading of congenital solitary kidney.

The minimal estimate of empiric risk to offspring of individuals with congenital solitary kidney is 7 percent for congenital solitary kidney and 1 percent for bilateral renal agenesis. Ultrasound examination is recommended to check for urogenital anomalies in first-degree relatives. Prenatal diagnosis by ultrasound is recommended for pregnancies in which the patient or her partner has a congenital solitary kidney [36].

Postnatal renal function depends on adequate intrauterine and postnatal compensatory growth [23,26,64]. Absence of contralateral compensatory hypertrophy in patients with multicystic dysplastic kidneys is a risk factor for future renal insufficiency and occurs in approximately 4 percent of patients [65]. Associated ipsilateral CAKUT is another independent risk factor for the development of renal injury in children with a solitary functioning kidney [66].

Proteinuria, hypertension, and renal insufficiency appear to be more common later in life in unilateral agenesis. A systematic review of 43 studies with a total number of 2864 patients reported associated CAKUT in 32 percent (of which vesicoureteral reflux was most frequent and was seen in 24 percent of patients), extra-renal anomalies in 31 percent, hypertension in 16 percent, and micro-albuminuria in 21 percent. Ten percent of patients had a GFR <60 mL/min/1.73 m² [6]. The long-term renal complications can be explained by the hyperfiltration hypothesis that associates renal mass reduction leading to a vicious cycle of compensatory glomerular hyperfiltration. In the long run, glomerular hyperfiltration may result in renal injury [67].

Historically, most pediatric urologists recommended that children with a solitary kidney avoid contact sports. However, since the risk of kidney loss resulting from trauma is less than 1 percent, this recommendation does not appear to be evidenced based and needs reevaluation [68,69].

Additional information on postnatal evaluation, care, and prognosis of unilateral renal agenesis is available separately. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Unitlateral renal agenesis'.)

SUMMARY AND RECOMMENDATIONS

●Renal agenesis refers to congenital absence of the kidney and ureter, which may be either unilateral or bilateral. Renal hypoplasia and dysplasia can also lead to absence of the kidney and are commonly referred to as renal agenesis. In the absence of in utero intervention, bilateral renal agenesis is always fatal in the newborn period. (See 'Introduction' above.)

●The diagnosis of bilateral renal agenesis is based upon sonographic nonvisualization of the fetal kidneys, ureters, and bladder, accompanied by oligohydramnios, usually after 16 weeks of gestation. Unilateral renal agenesis is more difficult to diagnose and depends upon accurately excluding the presence of a second kidney in the renal fossa or in an ectopic location. (See 'Sonographic evaluation of the fetal urinary tract' above.)

●Nonvisualization of the fetal bladder combined with oligohydramnios indicates severe pathology and can occur secondary to a prerenal etiology, such as preterm prelabor membrane rupture or fetal growth restriction, or to a renal etiology, including bilateral renal agenesis, unilateral renal agenesis with contralateral severe renal dysplasia or multicystic kidney, bilateral renal dysplasia, or bilateral medullary cystic kidney disease. Cloacal and bladder exstrophy may present with renal agenesis or nonfunctional kidney abnormalities that may lead to oligohydramnios and should be considered in the differential diagnosis. (See 'Bladder findings' above.)

●Renal agenesis is associated with an increased risk of other structural abnormalities, copy number variants, single gene disorders, and chromosomal abnormalities. (See 'Associated abnormalities' above.)

●For pregnancies with unilateral renal agenesis, a thorough examination for other structural defects (especially of the reproductive tract) should be performed. If additional anomalies are detected, there is an increased risk of chromosomal abnormality; amniocentesis to determine the fetal karyotype should be offered. There are no fetal indications for early delivery. (See 'Pregnancy outcome and obstetric management' above.)

●Most cases of bilateral renal agenesis are sporadic. The risk of recurrence of bilateral renal agenesis is 3 to 6 percent, but may reach 8 percent in cases associated with multiple congenital abnormalities. Approximately 9 to 14 percent of first-degree relatives of patients with bilateral renal agenesis or dysgenesis have renal abnormalities. (See 'Bilateral renal agenesis' above.)

●We suggest renal ultrasound examination to screen parents and siblings of infants born with agenesis or dysgenesis of both kidneys or with agenesis of one kidney and dysgenesis of the other, given the heritable nature of these defects. (See 'Counseling' above.)

●The prognosis for patients with unilateral renal agenesis is reported as excellent; however, some data suggest an increased risk of renal dysfunction, proteinuria, and hypertension, and a high risk for dialysis. (See 'Unilateral renal agenesis' above.)