INTRODUCTION — A kidney may be absent because it never developed (agenesis), which is rare, or because of complete regression of a multicystic dysplastic, dysplastic, or hypoplastic kidney. In this topic the term "renal agenesis" will be used to refer to the absence of one or both kidneys as a result of any of these etiologies.
Renal agenesis may be either unilateral or bilateral. The prognosis of individuals with unilateral renal agenesis (URA) depends on the function of the contralateral kidney. Bilateral renal agenesis (BRA) is incompatible with extrauterine life beyond days to weeks because prolonged absence of amniotic fluid results in pulmonary hypoplasia, leading to severe respiratory insufficiency at birth.
Prenatal diagnosis of renal agenesis will be discussed here. 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)".)
●URA – The incidence of URA is approximately 1 in 2000 to 3000 births [1-3]. In a systematic review, 63 percent of subjects were male (odds ratio [OR] 1.67, 95% CI 1.49-1.87) and 52 percent of missing kidneys were on the left (OR 1.10, 95% CI 0.97-1.25) .
●BRA – The incidence of BRA is approximately 1 to 3 per 10,000 births [4,5], with a 2:1 male to female ratio .
PATHOGENESIS — An absent kidney may represent true renal agenesis or it may be secondary to early involution of a nonfunctioning multicystic dysplastic, dysplastic, or hypoplastic kidney (figure 1) .
True 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'.)
Genetic factors — The induction of ureteric buds from mesonephric mesenchymal tissue involves interactions between different genes, transcription factors, and growth factors. Pathogenic variants in the genes may affect different parts of the urologic and nonurologic systems during embryogenesis and thus can present with different phenotypes .
Over 40 genomic disorders and 50 genes have been implicated in syndromic or nonsyndromic forms of congenital anomalies of the kidney and the urinary tract (CAKUT). Approximately 6 to 20 percent of isolated CAKUT phenotypes underlying a solitary functioning kidney are caused by pathogenic variants in the HNF1B, PAX2, or DSTYK . Only four genes (ITGA8, GREB1L, GFRA1, and FGF20) have been confirmed to have a causal role in nonsyndromic BRA in humans. More is known about pathogenic variants in syndromic renal agenesis, including branchio-oto-renal syndrome (EYA1, SIX5), Fraser syndrome (FRAS1, FREM2, GRIP1), Pallister-Killian syndrome (GLI3) and Townes-Brock syndrome (SALL1) . (See "Renal hypodysplasia".)
SONOGRAPHIC EVALUATION OF THE FETAL URINARY TRACT
Timing and scope of examination — A systematic approach to evaluating the fetal kidneys, adrenals, bladder, and amniotic fluid volume is essential to distinguish normal from abnormal development and to diagnose renal abnormalities correctly. American Institute of Ultrasound in Medicine (AIUM) guidelines for detailed obstetric ultrasound examination recommend:
●12+0 to 13+6 weeks of gestation – Visualization of the kidneys and bladder and color Doppler of the renal arteries and the umbilical arteries alongside the bladder. A detailed obstetric ultrasound examination at this gestational age can detect some renal anomalies; however, performance and interpretation requires advanced training, knowledge, and imaging skills .
●≥14 weeks of gestation – Visualization of the kidneys, bladder, and adrenal glands plus color Doppler of the renal arteries and the umbilical arteries alongside the bladder .
Kidneys — 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 allow evaluation of both kidneys on a single image for comparison of side-to-side echogenicity, size, and morphology. Sagittal views are helpful when the collecting system is being evaluated or when the kidneys are not in their expected location. The addition of color Doppler flow on the transverse or 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).
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). Cortical echogenicity evolves from a hyperechoic pattern during the second trimester to a hypoechogenic pattern as compared with fetal liver or spleen in the third trimester. In one study of 156 fetal renal ultrasounds, the renal cortex was hyperechoic in 92 percent between 21 and 25 weeks but hypoechoic in 70 percent between 34 and 37 weeks; no fetus displayed cortical hyperechogenicity after 32 weeks .
●Renal arteries — 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. However, in keeping with the ALARA principle (as low as reasonably achievable), fetal abdominal Doppler should only be performed when there is an indication, such as for a detailed second-trimester anatomical examination or nonvisualization of a kidney.
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 . The use of both transabdominal and transvaginal ultrasound enables bladder visualization in 98 percent of cases at 12 to 13 weeks .
●Umbilical arteries – The left and right umbilical arteries run alongside the left and right lateral borders of the bladder. Color flow Doppler imaging of the pelvic umbilical arteries thus can be useful for demarcating the location of the bladder (image 3).
●Urine — In most of the first trimester, amniotic fluid AF is likely derived from the embryonic surface of the placenta, transport from the maternal compartment across the amnion (transmembranous pathway), and secretions from the surface of the body of the embryo. 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 .
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 is abnormal .
Furosemide should not be administered to the mother to facilitate diagnosis of renal agenesis. Early studies reported increased diuresis in both normally grown and growth-restricted fetuses at 32 to 40 weeks after maternal administration of 60 mg furosemide and concluded that failure to see the bladder after one to two hours of administration establishes the absence of renal function. However, more recent small case series/case reports demonstrated that growth-restricted fetuses and fetuses with renal abnormalities may not respond to furosemide challenges due to late response, earlier gestational age, and/or placental dysfunction [18,19].
Adrenal glands — Fetal adrenal glands can be visualized as early as 11 to 13 weeks using transabdominal and transvaginal imaging in centers of excellence in fetal imaging . 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.
PRENATAL PRESENTATION AND DIAGNOSIS
●URA – The prenatal diagnosis of URA is based upon sonographic nonvisualization of one kidney and depends on accurately excluding the presence of a second kidney in the renal fossa or an ectopic location (image 4). URA is most commonly identified in the third trimester when the lack of visualization of the kidney is more readily apparent. Only a small proportion of URA (2.4 percent) is diagnosed at a first-trimester ultrasound scan  and it often remains unsuspected and missed in the second trimester since the amniotic fluid and bladder volume are normal. In a study that reported results of a French registry of URA between 1995 and 2013, the sensitivity of prenatal diagnosis improved overtime (from 54.2 percent in 1995 to 1997 to 95.8 percent in 2010 to 2013) .
An empty renal fossa warrants a detailed search for an ectopic kidney location or a dysplastic kidney. Of note, the adrenal will still be present in the renal fossa, but will have a more linear shape (the "lying down adrenal") in about half of fetuses. 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 5), horseshoe kidney was the final diagnosis in 6 percent, and 5 percent had crossed fused ectopic kidney . Intrathoracic renal ectopia can rarely occur with intact diaphragm, and with eventration of the diaphragm, or congenital diaphragmatic hernia .
An empty renal fossa also warrants careful examination of the contralateral kidney, which undergoes compensatory enlargement in all cases that can be seen on ultrasound starting at 20 weeks [24,25]. Hypertrophy of the contralateral kidney has been defined as a renal length >95th percentile for gestational age and a ratio of the anteroposterior to transverse diameter more than 0.9, which, in a study of 12 cases of URA, differentiated all cases of true renal agenesis from renal ectopy . 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 .
●BRA – The prenatal diagnosis of BRA is based upon sonographic nonvisualization of the fetal kidneys, ureters, and bladder, accompanied by oligohydramnios (after 16 weeks) (image 2B). Approximately 85 to 90 percent of cases are diagnosed prenatally [28,29].
Only a small proportion of BRA (15.4 percent) is diagnosed at a first-trimester ultrasound scan  since at that early gestational age the amniotic fluid volume primarily depends on osmosis from maternal plasma and is not dependent on the kidneys. Prenatal diagnosis is typically made at the routine fetal anatomic sonographic survey performed at 18 to 22 weeks of gestation when the amniotic fluid is largely derived from renal urine production, and therefore will be low or absent with BRA.
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 but not definitive evidence of renal agenesis (image 2A-B) [30,31]. 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 BRA and in one of eight fetuses with URA with a contralateral atrophic multicystic kidney on postmortem examination . Three fetuses had only one renal artery imaged; two of these had URA 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.
Magnetic resonance imaging — The contribution of fetal magnetic resonance imaging (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 .
On T2-weighted images, renal agenesis is characterized by the absence 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.
Ultrasound with diagnostic amnioinfusion — The absence of amniotic fluid in BRA may diminish 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 BRA.
Amnioinfusion has historically been used to surmount this limitation. A study in 1991 reported successful fluid replacement in 95 percent of diagnostic procedures and confirmation of suspected fetal anomalies in 27 out of 30 patients; the diagnosis of BRA was excluded in three fetuses after amnioinfusion . However, improved image resolution and use of renal artery Doppler examination has diminished the role of amnioinfusion, which is rarely needed with contemporary imaging. The procedure for amnioinfusion and its role (investigational only at this time) in management to improve outcome are described separately. (See "Amnioinfusion", section on 'Transabdominal approach' and 'Pregnancy management and parental counseling' below.)
Differential diagnosis and diagnostic pitfalls
●True renal agenesis versus severe renal hypoplasia or multicystic dysplasia with subsequent atrophy all lead to the same clinical presentation (nonvisualized kidney(s)). Distinguishing these entities can be difficult both on ultrasound examination and at autopsy . With true renal agenesis, the ipsilateral ureter and bladder trigone are absent with no detectable rudiment. By comparison, 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 showed the presence of a subsequently atrophic kidney.
●Retrograde filling of the bladder in persistent cloaca and midline urachal cysts may be misdiagnosed as a normal bladder filled by normal renal urine production .
●Ectopic kidney in the pelvis or, rarely, in the thorax, may be misinterpreted as renal agenesis.
●The adrenal glands occupy the renal fossa with or without the lying down sign in URA and BRA and can be mistaken for a kidney.
●Nonvisualization of the fetal bladder combined with oligohydramnios indicates severe pathology that may be caused by a prerenal, renal, or unrelated etiology .
•Prerenal cases are associated with severe placental insufficiency and resultant fetal growth restriction, often with abnormal umbilical artery Doppler indices.
•Renal causes of an empty bladder with oligohydramnios include BRA; URA with contralateral severe renal obstruction, renal dysplasia, or multicystic kidney; bilateral renal dysplasia or severe obstruction; or bilateral cystic kidney disease. In addition, 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.
•Preterm prelabor membrane rupture should be ruled out as it can mimic renal pathology in cases with oligohydramnios. A filling and emptying fetal bladder is the best indicator of fetal urine production, but the examination must allow sufficient time for the bladder to fill (at least 30 to 60 minutes).
●Severely reduced or absent amniotic fluid is the major nonspecific marker of BRA. However, the absence of fluid is not pathognomonic of BRA as it is also associated with preterm prelabor rupture of membranes, severe fetal growth restriction, fetal demise, and urinary outflow obstruction. URA may be associated with oligohydramnios if the contralateral kidney is abnormal.
SYNDROMES, ASSOCIATIONS, AND SEQUENCES IN WHICH RENAL AGENESIS MAY BE PRESENT
Overview of associated anomalies
●URA is associated with urologic or nonurologic anomalies in 30 to 70 percent of cases [1,2,40-42].
The most common urologic anomalies are vesicoureteral reflux (19 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 nonurologic structural malformations (heart, gastrointestinal tract, reproductive tract, and/or skeletal systems) with/without single umbilical artery or can be classified as an association, sequence, or syndrome. (See 'Specific disorders' below.)
●BRA is associated with other structural abnormalities in over 50 percent of cases. Most abnormalities involve the cardiac, central nervous, urogenital, and/or skeletal systems.
●22q11.2 deletion syndrome is a contiguous gene deletion syndrome with de novo mutations in 90 percent and subsequent autosomal dominant inheritance. Ten percent are inherited from a parent who may or may not have phenotypic features given the wide presentation of this syndrome. The syndrome is associated with 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".)
●VACTERL association refers to 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. In fetuses with VACTERL association, 52 percent have a structural renal abnormality, and URA comprises one-third of the cases . There is a wide range of manifestation of VACTERL associations. Prevalence is 1 in 10,000 to 40,000 newborns.
●Fraser syndrome is an autosomal recessive disorder characterized by renal agenesis, laryngeal atresia or webs, ambiguous genitalia, 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 BRA. Prevalence is 1 in 40,000 live births.
●Townes-Brocks syndrome (TBS; anus-hand-ear syndrome) is an autosomal-dominant disorder characterized by imperforate anus or anal stenosis, overfolded superior helices, microtia, and thumb malformations such as preaxial polydactyly, triphalangeal thumbs, and hypoplastic thumbs without hypoplasia of the radius. Minor features include foot, cardiac, and renal abnormalities in 42 percent, including renal agenesis. Prevalence is 1 in 200,000 live births. TBS is caused by the heterozygous variant of the SALL1 gene. De novo mutations account for 50 percent of cases. SALL1 is an essential organogenesis regulator for urological, renal, limb, ear, brain, and liver development .
●Caudal regression (or sacral agenesis) is a congenital anomaly involving the lower sacral and coccygeal spine due to defective secondary neurulation and 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. Associated anomalies develop in urogenital, anorectal, respiratory, and cardiac areas. Because complex anomalies of different systems are frequently associated, caudal regression is a component of various syndromes, including VACTERL, OEIS (omphalocele, cloacal exstrophy, imperforate anus, spinal defects), and the Currarino triad (caudal agenesis, presacral mass, anorectal anomalies) . Prevalence is 1 to 2.5 per 100,000 live births and is 200 times higher in patients with diabetes. Most cases seem sporadic without a genetic association. (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 regression. A review of nine caudal regression and six sirenomelia cases revealed that 22 percent of the caudal regression and 66 percent of the sirenomelia cases were associated with BRA . Prevalence is 1 in 60,000 live births.
●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 in the midtrimester 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)".)
●The following syndromes are not typically diagnosed prenatally, but parental counseling may be important for assessment of their presence at or prior to puberty and earlier with suggestive findings. Due to common embryological pathways, over 30 percent of patients with URA have an associated müllerian anomaly.
•Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome affects 1 in 4500 females and refers to congenital absence of the upper vagina with variable uterine development. MRKH is mostly a sporadic anomaly. Autosomal dominant inheritance with reduced penetrance is seen in familial cases. Oligogenic and polygenic inheritance and recurrent aberrations in chromosomal regions 1q21.1, 16p11.2, 17q12, and 22q11.21 are reported.
Type II MRKH comprises approximately half of the cases and is associated with extragenital malformations including URA, ectopy, renal hypoplasia, horseshoe kidneys, and hydronephrosis in 30 to 40 percent of cases; malformations of the spine, such as Klippel-Feil anomaly or scoliosis, occur in 10 to 40 percent of cases. MURCS association (ie, müllerian hypoplasia, renal agenesis, cervicothoracic somite dysplasia) is the most severe form of MRKH II and characterized by müllerian aplasia, renal agenesis, and cervical somite dysplasia . (See "Congenital anomalies of the hymen and vagina", section on 'Vaginal agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome)'.)
•Obstructed hemivagina and ipsilateral renal anomaly syndrome (OHVIRA) is characterized by the triad of didelphys uterus, obstructed hemivagina, and ipsilateral renal agenesis. Prenatal diagnosis has not been reported; however, a case was diagnosed at fetal autopsy .
•Kallmann syndrome is a congenital form of hypogonadotropic hypogonadism characterized by hypo- or anosmia and lack of testicular development and amenorrhea and the absence of secondary sexual characteristics by puberty. Typical diagnosis occurs when a child fails to begin puberty. Prevalence is 1 in 48,000 individuals. Cleft palate and lip, hypodontia, cleft hand or foot, central hearing impairment, mirror movements of the hands (synkinesis), and ataxia are often present. The majority of cases are sporadic. More than 30 pathogenic variants are reported with autosomal dominant, autosomal recessive, or X-linked inheritance, as well as digenic or oligogenic models. KAL1 is the most common pathogenic variant, located on Xp22.3 and encoding anosmin-1, which participates in GnRH neuron adhesion, axonal migration, and organogenesis . Renal agenesis occurs in 30 percent of cases with KAL1 . (See "Isolated gonadotropin-releasing hormone deficiency (idiopathic hypogonadotropic hypogonadism)", section on 'Anosmic form of IHH (Kallmann syndrome [KS])'.)
PREGNANCY MANAGEMENT AND PARENTAL COUNSELING
Unilateral renal agenesis
•Imaging – A detailed anatomical ultrasound examination and fetal echocardiogram should be performed in pregnancies with URA to evaluate for associated structural malformations.
•Pedigree – A full family history should be obtained, given the association between URA and a variety of heritable conditions. (See 'Syndromes, associations, and sequences in which renal agenesis may be present' above.)
-Diagnostic testing via amniocentesis or chorionic villus sampling should be offered. Microarray analysis provides additional information over G-banded karyotype in approximately 6 percent for a fetus with a structural anomaly and in 1 percent without a structural anomaly . Abnormal microarray is reported in 2.5 to 14.5 percent of isolated URA [52,53]. A study of 522 pediatric patients with renal hypodysplasia and renal agenesis reported copy number variants (CNVs) in 14.5 percent of isolated cases and 22.5 percent of individuals with multiple malformations. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. A majority of the known CNV disorders had documented associations with developmental delay or neuropsychiatric diseases . (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)
-Molecular testing via targeted congenital anomalies of the kidney and the urinary tract (CAKUT) panels or exome sequencing is an option if microarray is nondiagnostic. These tests are most useful if other organ systems are affected or multiple affected pregnancies have occurred, suggesting a genetic etiology. Parents should be aware that even with sequencing-based testing prenatally, further genomic testing may be informative postnatally if additional phenotypic findings are noted in the newborn or later in the child.
●Prenatal care – URA alone is not an indication for antenatal fetal surveillance or early delivery. URA with other urological or other system abnormalities should be followed by serial examinations for assessment of fetal growth and amniotic fluid volume.
●Prognosis – A congenital solitary functioning kidney is mostly the consequence of either URA or medullary cystic kidney disease (MCKD). These children are at risk of hypertension, proteinuria, and kidney function loss. The data regarding the magnitude of the risk remain controversial, with kidney injury rates ranging from 6 to 60 percent at age 15 and limited studies in adulthood. The renal damage has been attributed to the increase in glomerular filtration per nephron (fewer nephrons are present) and secondary increases in glomerular hypertension that leads to glomerulosclerosis . Postnatal renal function in URA depends on adequate intrauterine and postnatal compensatory growth [24,27,56]. Absence of contralateral compensatory hypertrophy and presence of ipsilateral CAKUT are independent risk factors for the development of renal insufficiency in children with a solitary functioning kidney .
A systematic review of 43 studies including 2864 patients with prenatal and/or postnatal diagnosis of URA reported CAKUT in 32 percent (of which vesicoureteral reflux was most frequent and was seen in 24 percent of patients), extrarenal anomalies in 31 percent, hypertension in 16 percent, and micro-albuminuria in 21 percent. Ten percent of patients had a glomerular filtration rate (GFR) <60 mL/min/1.73 m² .
In children with congenital solitary kidney, blood pressure, kidney function, and ultrasound should be monitored, with the frequency dependent on the presence of risk factors. They should also be assessed for associated reproductive system anomalies such as obstructed hemivagina and ipsilateral renal anomaly (OHVIRA), Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, and absence of vas deferens in males, as appropriate. Historically, most pediatric urologists recommended that children with a solitary kidney avoid contact sports. The risk of kidney loss resulting from trauma is less than 1 percent, thus this recommendation is no longer valid [58,59].
●Recurrence risk – The recurrence risk depends on whether a parent has a congenital solitary kidney. Some cases of URA result from in utero regression of multicystic dysplastic kidneys [7,60]. These fetuses 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. A study on individuals with solitary functioning kidney reported urogenital anomaly risk of 7 percent for offspring, 4 percent for parents, and 2.5 percent for siblings . The incidence of BRA in offspring was 0.8 percent. Concordance for type of anomaly in affected relatives was 50 percent. The study results may have underestimated the risk as it was a questionnaire design and not all of the relatives had renal imaging.
Other studies that evaluated first-degree relatives of patients with CAKUT with renal imaging reported a 4 to 6 percent risk of CAKUT in first-degree relatives and 7.9 to 14.4 percent risk in families. In one study, familial renal agenesis was found in three of the five families of index cases with renal agenesis [61-64].
●Counseling – The prognosis for URA should be discussed. For URA with additional anomalies and findings suggestive of a syndrome, counseling should be directed by these findings. Parental and sibling imaging is recommended due to the increased risk of CAKUT in the family. Fetal ultrasound is recommended for future pregnancies in which the mother or their partner has a congenital solitary kidney .
Additional information on postnatal evaluation, care, and prognosis of URA is available separately. (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)", section on 'Unilateral renal agenesis'.)
Bilateral renal agenesis
●Genomic testing – Genomic testing should be offered for fetal BRA . Chorionic villus sampling for microarray is possible in cases with anhydramnios where amniocentesis is difficult. There is limited information on the yield of microarray in BRA. One study reported the diagnostic yield was 25 percent (two of eight BRA cases, and one of the two cases was isolated) . If nondiagnostic, molecular testing via targeted CAKUT panels or exome sequencing is an option. These tests are most useful if other organ systems are affected or multiple affected pregnancies have occurred, suggesting a genetic etiology.
●Prognosis – Prenatally diagnosed isolated BRA is associated with 100 percent lethality without intervention. Except for a single case study using serial amnioinfusion, there has been no other case of survival following dialysis and transplantation documented in BRA . 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 BRA die in utero .
The major determinant of postnatal mortality in BRA is pulmonary hypoplasia, which develops secondary to anhydramnios. Inclusion of complex BRA with associated anomalies without adequate or no information on prenatal imaging findings and cases with renal dysgenesis and abnormally developed kidneys with BRA make interpretation of natural course of isolated true BRA difficult [4,68]. One case of discordant BRA in a monoamniotic twin pregnancy with pulmonary function because of the normal urine production of the cotwin, and another case of BRA with normal pulmonary function attributed to coexisting duodenal atresia were reported; albeit, both died prior to transplant at two months and age 4, while on peritoneal dialysis, respectively. The former had normal imaging until delivery and the second case had no prenatal imaging information [69,70]. In cases where there is evidence of isolated renal abnormalities rather than BRA with development of anhydramnios after 20 to 22 weeks, parents should be counseled that there may be rare survivors with long-term peritoneal dialysis until large enough for a renal transplant.
Early serial therapeutic 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 . (See 'Investigative role of therapeutic amnioinfusion' below.)
●Prenatal care and counseling
•Patients with affected pregnancies may opt for pregnancy termination or continue the pregnancy and plan for palliative neonatal care. In live-born cases with BRA, a postnatal renal/bladder ultrasound confirms the diagnosis. Patients who opt for pregnancy termination should be encouraged to consent to autopsy (including genetic evaluation) for definitive diagnosis. A nondestructive method of pregnancy termination is desirable for this reason.
•It is probably worthwhile to evaluate for the presence of both maternal kidneys and the absence of gross renal defects at the time of prenatal ultrasound, as this can be accomplished quickly and without additional expense. Screening an asymptomatic father and siblings of the fetus should be considered (discussed below). Approximately 9 to 14 percent of first-degree relatives of patients with BRA, bilateral severe dysgenesis, or agenesis of one kidney and dysgenesis of the other will have renal abnormalities (most often URA but also duplicated collecting systems) [72,73].
•In cases of BRA with early severe oligohydramnios, antenatal surveillance and early delivery will not change the expected rate of fetal or neonatal demise. Due to lack of ability to improve survival, BRA is not an indication for antenatal fetal surveillance or early delivery.
•In cases with mixed renal disorders (renal agenesis of one kidney, multicystic kidney of the other) and late oligohydramnios when there may be potential for relatively normal pulmonary function, antenatal surveillance and early delivery for nonreassuring fetal testing may be considered in advanced fetal care centers since there may be rare survivors in this group. (See "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations", section on 'Prenatal care'.)
•Patients should be informed that most cases of BRA are sporadic, but 20 to 36 percent are associated with familial inheritance; the genetic mechanism may be autosomal dominant inheritance with incomplete penetrance and variable expression. X-linked and autosomal recessive inheritance have also been described. In nonfamilial nonsyndromic cases, genetic factors still appear to play a role in the pathogenesis, and multifactorial inheritance is the likely explanation, although the precise method of genetic inheritance is unknown.
The risk of recurrence is reported to be 3 to 6 percent but may reach 8 percent in cases associated with multiple congenital abnormalities [72,74]. If the affected proband is associated with a specific genetic syndrome, genetic diagnosis can inform recurrence risk, and if present, preimplantation genetic testing for the disorder or prenatal diagnostic testing are available. 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 in the absence of known genetically identifiable etiology.
Investigative role of therapeutic amnioinfusion — Early serial therapeutic amnioinfusion has been proposed as a potentially life-saving intervention for some fetuses with BRA. In animal models, restoration of amniotic fluid through an intraamniotic catheter prevented pulmonary hypoplasia . However, only anecdotal information is available in human fetuses, and the procedure does not eliminate the need for renal transplantation for long-term survival .
●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 . 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 . A follow-up publication from this center reported the outcome of eight cases of BRA with serial amnioinfusion . 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 BRA and, until then, should be offered only as approved innovation or research [68,76]. 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 . 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 [4,80,81].
SUMMARY AND RECOMMENDATIONS
●Definition – Renal agenesis refers to congenital absence of the kidney and ureter, which may be either unilateral (URA) or bilateral (BRA). A kidney and ureter may be absent because they never developed (which is rare) or because of complete regression of a multicystic dysplastic, dysplastic, or hypoplastic kidney. (See 'Introduction' above.)
●Prenatal diagnosis (see 'Sonography' above)
•The diagnosis of BRA is based upon sonographic nonvisualization of the fetal kidneys, ureters, and bladder, accompanied by oligohydramnios, usually after 16 weeks of gestation. Failure to image the renal arteries with color flow Doppler (using appropriately low gain settings) supports the diagnosis, but is not definitive evidence of renal agenesis (URA or BRA) (image 2A-B).
•URA 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.
●Differential diagnosis and diagnostic pitfalls – Nonvisualization of the fetal bladder combined with oligohydramnios/anhydramnios indicates severe pathology and can occur secondary to a prerenal etiology (eg, preterm prelabor membrane rupture, fetal growth restriction) or a renal etiology (BRA, URA with contralateral severe renal dysplasia or multicystic kidney disease, bilateral renal dysplasia, or bilateral 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 'Differential diagnosis and diagnostic pitfalls' above.)
●Postdiagnostic evaluation – For pregnancies with URA, a thorough examination (including echocardiography) for other structural anomalies should be performed. Genetic testing with microarray should be offered. If nondiagnostic, molecular testing via targeted congenital anomalies of the kidney and the urinary tract (CAKUT) panels or exome sequencing is an option and most useful if other organ systems are affected or multiple affected pregnancies have occurred with the same phenotype. (See 'Syndromes, associations, and sequences in which renal agenesis may be present' above and 'Pregnancy management and parental counseling' above.)
•Evaluation of family members – We suggest renal ultrasound examination of first-degree relatives of fetuses with BRA or URA to check for congenital renal anomalies. (See 'Pregnancy management and parental counseling' above.)
●Pregnancy management – BRA and URA are not indications for antenatal fetal surveillance or early delivery. In cases of BRA with mixed renal disorders (renal agenesis of one kidney, multicystic kidney of the other) and late oligohydramnios when there may be potential for relatively normal pulmonary function, antenatal surveillance and early delivery for nonreassuring fetal testing may be considered in advanced fetal care centers since there may be rare survivors in this group. (See 'Pregnancy management and parental counseling' above.)
●Recurrence risk – Most cases of BRA are sporadic; the risk of recurrence is 3 to 6 percent, but may reach 8 percent in cases associated with multiple congenital abnormalities. (See 'Bilateral renal agenesis' above.)
The recurrence risk of URA depends on whether a parent has a congenital solitary kidney, and recurrence may include BRA. (See 'Unilateral renal agenesis' above.)
●Prognosis – In the absence of in utero intervention, BRA is always fatal in the newborn period. The prognosis for patients with URA is excellent (in the absence of other major structural abnormalities); however, some data suggest an increased risk of renal dysfunction, proteinuria, and hypertension, and a high risk for dialysis. (See 'Unilateral renal agenesis' above.)
1 : Congenital unilateral renal agenesis: Prevalence, prenatal diagnosis, associated anomalies. Data from two birth-defect registries.
5 : Fetuses and infants with congenital urinary system anomalies: correlation between prenatal ultrasound and postmortem findings.
8 : Prenatal genetic considerations of congenital anomalies of the kidney and urinary tract (CAKUT).
9 : Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney.
11 : AIUM Practice Parameter for the Performance of Detailed Diagnostic Obstetric Ultrasound Examinations Between 12 Weeks 0 Days and 13 Weeks 6 Days.
12 : AIUM Practice Parameter for the Performance of Detailed Second- and Third-Trimester Diagnostic Obstetric Ultrasound Examinations.
15 : Assessment of fetal anatomy at 12 to 13 weeks of gestation by transabdominal and transvaginal sonography.
21 : Diagnosis of fetal non-chromosomal abnormalities on routine ultrasound examination at 11-13 weeks' gestation.
26 : Measurement of compensatory hyperplasia of the contralateral kidney: usefulness for differential diagnosis of fetal unilateral empty renal fossa.
28 : Prenatal detection of congenital renal malformations by fetal ultrasonographic examination: an analysis of 709,030 births in 12 European countries.
30 : Fetal renal artery flow velocity waveforms in the presence of congenital renal tract anomalies.
32 : Accuracy of prenatal diagnosis of renal agenesis with color flow imaging in severe second-trimester oligohydramnios.
34 : Complementary role of magnetic resonance imaging after ultrasound examination in assessing fetal renal agenesis: a case report.
44 : Adult diagnosis of Townes-Brocks syndrome with renal failure: Two related cases and review of literature.
53 : Detection of copy number disorders associated with congenital anomalies of the kidney and urinary tract in fetuses via single nucleotide polymorphism arrays.
55 : Clinical Management of Children with a Congenital Solitary Functioning Kidney: Overview and Recommendations.
58 : Attitudes of pediatric urologists regarding sports participation by children with a solitary kidney.
61 : The significance of early second-trimester sonographic detection of minor fetal renal anomalies.
62 : Screening of renal anomalies in first-degree relatives of children diagnosed with non-syndromic congenital anomalies of kidney and urinary tract.
63 : Screening for Renal and Urinary Tract Anomalies in Asymptomatic First Degree Relatives of Children with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
64 : The Frequency of Familial Congenital Anomalies of the Kidney and Urinary Tract: Should We Screen Asymptomatic First-Degree Relatives Using Urinary Tract Ultrasonography?
65 : Association of prenatal renal ultrasound abnormalities with pathogenic copy number variants in a large Chinese cohort.
75 : Serial amnioinfusions prevent fetal pulmonary hypoplasia in a large animal model of oligohydramnios.
77 : Use of an Amnioport to Maintain Amniotic Fluid Volume in Fetuses with Oligohydramnios Secondary to Lower Urinary Tract Obstruction or Fetal Renal Anomalies.
78 : Contemporary Outcomes of Patients with Isolated Bilateral Renal Agenesis with and without Fetal Intervention.
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