Prenatal sonographic diagnosis of cystic kidney disease

INTRODUCTION — 

Congenital cystic kidney disease is one of the major causes of end-stage kidney disease in children and adults. The clinical presentation may become apparent in the fetus or child, or may be delayed to adulthood. These disorders have a wide spectrum of outcomes depending on whether there is unilateral or bilateral involvement, contralateral disease or compensatory hypertrophy in unilateral cases, other organ involvement, and the extent of kidney damage determined by characteristics of the syndrome complex, if any.

In children, a larger proportion of kidney cysts are due to genetic diseases as compared with adults. A monogenic disease is identified in 50 to 70 percent of cases with two or more kidney cysts and/or increased cortical echogenicity. In cases with extrarenal anomalies, the risk of a chromosomal anomaly is increased. Genetic pathology is less common for solitary cysts with normal kidney parenchyma and in isolated unilateral multicystic dysplastic kidney (MCDK) or cystic dysplasia [1,2].

Ultrasound is the most common imaging method for diagnosis of fetal kidney cystic diseases. Congenital cystic kidney diseases that can be diagnosed by prenatal ultrasound examination will be reviewed here. The diagnosis, clinical manifestations, and prognosis of kidney cysts and cystic disorders in children are discussed separately, including:

●(See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

●(See "Kidney cystic diseases in children".)

●(See "Autosomal dominant polycystic kidney disease (ADPKD) in children".)

●(See "Autosomal recessive polycystic kidney disease in children".)

ULTRASOUND CHARACTERISTICS OF FETAL CYSTIC KIDNEY DISEASE — 

Fetal cystic kidney disease is characterized by small or large cysts the cortex, medulla, or both, representing dilated tubules, glomerular cystic dilation, or real cysts. However, the cysts are not always visible on fetal ultrasound. Instead, the main finding is often large hyperechogenic kidneys secondary to the interfaces created by microscopic cysts and dilated tubules and to interstitial fibrosis and inflammation [3].

Ultrasound examination of fetuses with cystic kidney changes and/or hyperechogenic kidneys includes assessment of [4]:

●Kidney echogenicity – To assess for hyperechogenicity, cortical echogenicity is compared with the liver and spleen and medullar echogenicity is compared with cortical echogenicity. In one study of normal fetuses serially examined after 20 weeks, cortical echogenicity evolved from a hyperechoic pattern as compared with liver and spleen during the early second trimester to a hypoechogenic pattern in the third trimester, with no fetus displaying cortical hyperechogenicity after 32 weeks [5]. At 21 to 25 weeks, the most frequent pattern (present in 92 percent) was hyperechogenicity of the kidney cortex, whereas hypoechogenicity was the most common pattern at 34 to 37 weeks (present in 70 percent). A hypoechoic medulla compared with the renal cortex was present in all cases.

●Cyst location – The location of cysts (ie, medulla, cortex, or both), which may be helpful in different diagnosis.

●Kidney size and contour – Maximal midsagittal length, width, and depth at the level of the hilum should be measured, and kidney volume should be calculated using 2D or 3D imaging [6,7]. These measurements are compared with population standards. Echogenic kidneys less than four standard deviation above the mean without cysts and with normal amniotic fluid volume may represent a variant of normal [8]. Absence of reniform shape with multiple cysts is consistent with multicystic dysplasia.

●Corticomedullary differentiation (CMD) – The absence of CMD and increased or reversed CMD are concerning for a fetal kidney pathology [9].

●Amniotic fluid volume – In the second half of pregnancy, amniotic fluid volume is produced by fetal kidneys and lungs [10]. As such, normal amniotic fluid volume is the best predictor of normal fetal kidney function. Oligohydramnios is a marker of impaired fetal kidney function, but has several other etiologies. (See "Oligohydramnios: Etiology, diagnosis, and management in singleton gestations".)

CLASSIFICATION — 

Several classification systems for congenital cystic kidney disease have been proposed, considering the pathologic, clinical, and genetic features of these disorders [11]. For prenatal ultrasound imaging purposes, fetal cystic kidney disease may be classified as hyperechogenic or cystic.

●Hyperechogenic kidneys due to nonvisualizable small cysts, so called "polycystic kidneys," usually have a syndromic etiology:

•Autosomal recessive polycystic kidney disease

•Autosomal dominant polycystic kidney disease

•Kidney cysts seen with other syndromes (glomerulocystic and medullary cystic dysplasia/ nephronophthisis)

●Cystic kidney disorders presenting with visible renal cysts:

•Multicystic kidneys

•Obstructive cystic kidney dysplasia

•Cystic kidney tumors

•Simple renal cysts

DIAGNOSTIC EVALUATION — 

The work-up of fetal hyperechogenic kidneys and/or cystic kidneys includes:

●A thorough fetal anatomic survey

●Review of the family's genetic history (pedigree)

●Ultrasound examination of the kidneys of the parents, grandparents, and siblings of the fetus

●Genetic counseling and fetal genetic testing via fetal karyotype or chromosomal microarray (copy number variants) or molecular genetic investigation for monogenic disease depending on the nature of the kidney abnormality, extrarenal abnormalities, and family history [12].

Fetal magnetic resonance imaging (MRI) can be helpful for identifying extrarenal anomalies in cases with oligohydramnios; alternatively, sonographic visualization can be improved by a diagnostic amnioinfusion.

DIFFERENTIAL DIAGNOSIS

Hyperechogenic kidneys/polycystic kidneys — Uniformly hyperechogenic fetal kidneys without visible macrocysts are a common incidental finding on obstetric ultrasound examination. It is essential to differentiate significant kidney disease from normal variants, which are characterized by normal kidney size, moderately bright cortex, visible corticomedullary differentiation (after 20 weeks of gestation), normal bladder size, and normal amniotic fluid volume [9,13]. Since nephrogenesis is not completed until the third trimester until 32 to 36 weeks, serial scans can decrease the possibility of a false-positive initial diagnosis [10,14]. In general, isolated normal or slightly increased kidney size and normal amniotic fluid volume predict a good outcome [8,15]. However, prenatal ultrasound alone cannot predict etiology or long-term outcome in the absence of family history, postmortem, or postnatal data. Diagnosis of an associated anomaly may be more helpful than the imaging characteristics and pinpoint a syndromic etiology [9].

The ultrasonographic differential diagnosis of enlarged fetal hyperechogenic kidneys and/or cystic kidneys, includes:

●Autosomal recessive polycystic kidney disease (ARPKD) – Significantly enlarged kidneys with reniform shape, loss of corticomedullary differentiation, subcortical hypoechoic rim, cysts (if visible) predominantly in the medulla, reduced amniotic fluid volume.

●Autosomal dominant polycystic kidney disease (ADPKD) – Kidneys moderately enlarged, amniotic fluid volume usually normal, increased corticomedullary differentiation, cysts (if visible) usually in cortical location, but rarely presents in the prenatal period, generally in the third trimester.

●Obstructive dysplasia – Hyperechogenic kidneys, cortical cysts with or without dilated upper or lower urinary tract.

●Multicystic dysplasia – Usually unilateral, reniform shape not preserved, kidney enlarged by randomly distributed large size cysts that do not connect, without normal renal parenchyma.

●Syndromes that present with hyperechogenic kidneys and/or kidney cysts – These are often differentiated by the associated anomalies. In one study, the final diagnosis in 93 fetuses presenting with hyperechogenic kidneys who went on to develop nephropathy was ARPKD (33 percent), ADPKD (30 percent), Bardet-Biedl syndrome (12 percent), Meckel-Gruber syndrome (10 percent), Ivemark II syndrome (6 percent), trisomy 18 (5 percent), Jarcho-Levin syndrome (spondylothoracic dysplasia; 1/93), Beemer syndrome (narrow ribs, micromelia, with or without polydactyly; 1/93), and Meckel-like syndrome (1/93) [9]. Another case series of 98 fetuses with bilateral polycystic kidneys reported the three most common diagnoses were ARPKD (53.1 percent), Meckel-Gruber syndrome (17.3 percent), and ADPKD (2 percent); other diagnoses included Joubert, Jeune, McKusick-Kaufman, and Bardet-Biedl syndromes, overgrowth syndromes, Mainzer-Saldino syndrome, and renal tubular dysgenesis [16].

Most of the hereditary cystic kidney diseases are due to primary ciliopathies. Primary ciliopathies are secondary to single gene variants that lead to abnormal ciliary formation or function. The cumulative prevalence of primary ciliopathies is 1:2000. The primary or "immobile" cilium is a microtubule base organelle that extends from the cell surface and transduce molecular signals from the extracellular environment, acting as "antennae" for the cell. Primary cilia is present in almost all vertebrate cells including the nephron tubule and collecting ducts where they contribute to the flow of the urine and, indirectly, to its composition and osmolality. Ciliopathies share clinical features with a considerable genetic and phenotypic overlap. They commonly present with cystic changes in the kidneys, hepatobiliary disease, pancreatic cysts or dysplasia, cerebellar abnormalities, retinal degeneration, colobomas of the retina and iris, polydactyly, abnormal bone growth, and obesity [17]. ADPKD, ARPKD, and nephronophthisis are the most common causes and mainly present with hepatorenal system findings. However, ADPKD rarely presents in the prenatal period. Other ciliopathies involve multiorgan systems.

Autosomal dominant polycystic kidney disease

Overview

●Epidemiology – ADPKD is the most common inherited kidney cystic disease with an incidence at birth of 1:400 to 1000 [18]. However, it rarely presents in utero (<1 percent of cases) or in the neonatal period with ultrasound changes. The typical age of clinical onset is in the third to fifth decade of life.

●Natural history – ADPKD is characterized by the slow development (over decades) of large spherical cystic dilation in the nephron, although the initial differentiation to nephrons and the collecting system is normal. The kidney pathology is focal with areas of abnormal nephrons scattered among areas of normal nephrons. The tubule wall, which is lined by a single layer of epithelial cells, expands, and then rapidly closes off from the tubule of origin as true cysts. This is different from ARPKD in which cysts are derived from collecting tubules and remain connected to the nephron of origin [19]. Initially, cysts may be localized to the distal nephron and the collecting duct; in later stages, they are spread to both the cortex and medulla. As the cysts enlarge, they severely compromise the functional integrity of the remaining normal parenchyma. Approximately 50 percent of ADPKD patients will progress to end-stage kidney disease, requiring transplant or dialysis by late middle age. The kidney manifestations, ex utero diagnosis, course of this disorder in children, and treatment are discussed elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children" and "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)

●Extrarenal abnormalities – Extrarenal abnormalities include cysts in other organs, such as the liver, seminal vesicles (in males), pancreas, and arachnoid membrane. There also may be noncystic abnormalities, such as intracranial and coronary artery aneurysms and dolichoectasia, aortic root dilation and aneurysms, mitral valve prolapse, and abdominal wall hernias [20]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

Fetal findings

●Kidneys – Due to slow progression of the disease, the minor changes, if any, are usually missed in the prenatal period. Cases with prenatal presentation are characterized by moderately enlarged kidneys (1 to 2 standard deviations above the mean size) with a hyperechogenic cortex [21]). The medulla can be hypoechogenic or less commonly hyperechogenic in prenatally diagnosed cases; [21]. Very rarely, one kidney may be larger than the other, suggesting unilateral disease.

Some early prenatal forms of ADPKD may mimic ARPKD and can present with increased cortical echogenicity, decreased corticomedullary differentiation, multiple medullary cysts, and decreased amniotic fluid [22]. Ultrasound evaluation of the parents' kidneys may be useful for differential diagnosis. If either parent has ADPKD, the finding of enlarged echogenic fetal kidneys with or without cysts strongly supports the diagnosis of ADPKD. Absence of cysts in the parents (particularly if they are >30 years of age) suggests ARPKD.

However, it is important to note that in 5 to 10 percent of patients, ADPKD result from de novo variants (see 'Genetics' below). In addition, a normal ultrasound in a fetus at risk provides no reassurance of absence of ADPKD because of the variability in ultrasound findings and late presentation of this disorder.

●Amniotic fluid volume – Amniotic fluid volume is usually normal since normal nephrons are present. In a report of 27 prenatally diagnosed cases, amniotic fluid volume was normal in 89 percent, slightly diminished in 7 percent, and increased initially, but with secondary normalization in one case (4 percent) [21].

●Associated abnormalities – Associated structural abnormalities, such as cysts in the liver and pancreas (see 'Overview' above), have not been identified prenatally.

Genetics — Most cases (approximately 90 to 95 percent) are inherited as an autosomal dominant trait with complete penetrance. The disease is genetically heterogeneous, with two major genes encoding plasma membrane-spanning polycystin 1 and polycystin 2, PKD1 (16.p13.3; approximately 78 percent families) and PKD2 (4p21; approximately 15 percent), and a rare third locus, GANAB (11q12.3; approximately 0.3 percent) [23]. The polycystins regulate tubular and vascular development in the kidneys and other organs (liver, brain, heart, and pancreas) and interact to increase the flow of calcium through a cation channel formed in plasma membranes. Variants of PKD1 are more common than variants of PKD2,are likely to be associated with more kidney cysts, and lead to earlier development of kidney insufficiency (on average 20 years earlier) [18]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)

The family history for ADPKD is negative in 10 to 15 percent of patients due to de novo mutations in 5 percent, mild PKD2 cases, nontruncating PKD1 variants, or unavailability of parental records [24]. If fetal ADPKD is suspected and not known to be inherited in the family, then the parents should undergo ultrasound evaluation of their kidneys and liver, as kidney compromise may not occur until later in life. (See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis".)

Confirmation of the diagnosis is possible by molecular DNA studies of fetal samples obtained by amniocentesis or chorionic villus sampling. Direct DNA sequencing of PKD1 and PKD2 detects pathogenic variants in up to 91 percent of cases. [25]. The potential of next-generation sequencing (NGS) technologies for high-throughput screening of both PKD1 and PKD2 has been demonstrated [26,27]. (See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis", section on 'Establishing the diagnosis of ADPKD'.)

Prognosis — Kidney function is preserved and the amniotic fluid volume remains normal in most prenatal cases, but prenatal presentation may be associated with more rapid postnatal progression of the disease [28,29]. A study of 26 children with a mean follow-up of 76 months reported hypertension in five, proteinuria in two and chronic kidney disease in two [29]. A high proportion of siblings developed early kidney cysts. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children", section on 'Outcome'.)

Autosomal recessive polycystic kidney disease

Overview

●Epidemiology – Autosomal recessive polycystic kidney disease (ARPKD) occurs in 1:20,000 live births, which corresponds to a 1:70 carrier frequency in nonisolated populations. Fetal death or neonatal death may occur due to oligohydramnios and lung hypoplasia [19].

●Classification – ARPKD has been subclassified into perinatal, neonatal, infantile, and juvenile types. Kidney involvement is more common in cases with perinatal presentation, whereas liver involvement is more typical of later diagnosis of ARPKD.

●Natural history – The clinical manifestations, management, and outcome of ARPKD are discussed elsewhere. (See "Autosomal recessive polycystic kidney disease in children".)

●Genetics – ARPKD is caused by variants in the polycystic kidney and hepatic disease gene (PKHD1) on chromosome 6p, which encodes the protein fibrocystin/polyductin. Fibrocystin is normally expressed in the primary cilia and the basal body of kidney and bile duct epithelial cells. Its exact function is not known; however, fibrocystin likely acts as a membrane receptor, interacting with extracellular protein ligands and transducing intracellular signals to the nucleus involved in collecting duct and biliary differentiation [30]. ARPKD can also be caused by other variants, including the DAZ interacting zinc finger protein 1-like gene (DZIP1L), and can be mimicked by variants in the hepatocyte nuclear factor-1beta (HNF1B) gene and PKD1 and PKD2 genes.

Clinical manifestations in individuals with DZIP1L variants present prenatally or in early childhood and appear to be associated with a moderate course [31]. (See "Autosomal recessive polycystic kidney disease in children", section on 'Pathogenesis'.)

●Pathology – Kidney pathology in ARPKD is characterized by nonobstructive dilatation or ectasia of the collecting tubules located in the medulla, resulting in microcysts up to 2 mm in diameter. The cysts may expand into the cortex in severe cases. The severity of the kidney disease is proportional to the percentage of nephrons affected by cysts and is correlated with the severity of the PKHD1 variants [32]. All affected individuals have some degree of liver involvement with biliary dysgenesis and hepatic fibrosis. The pathology and pathogenesis of ARPKD are discussed in detail elsewhere. (See "Autosomal recessive polycystic kidney disease in children".)

Fetal findings

●Kidneys – The predominant prenatal ultrasound feature of ARPKD is uniform, massive enlargement of the kidneys with preservation of the reniform shape (image 1A-B) with diffuse hyperechogenicity of both cortex and medulla, with no corticomedullary differentiation. The kidney size is typically 4 to 15 standard deviations above the mean size for gestational age [33]. Due to the large kidney size, the abdominal circumference is larger than expected for gestational age.

ARPKD is the most likely etiology when bilateral, significantly enlarged echogenic kidneys, a small or absent bladder, and oligohydramnios are seen; however, a precise prenatal diagnosis cannot be made with certainty by ultrasound alone.

Late in pregnancy, isolated macroscopic cysts less than 10 mm in size are visible in the medulla in one-third of cases. Since there are no collecting ducts/tubules in the cortex, a normal relatively hypoechoic cortical rim can help in differential diagnosis in favor of ARPKD [16,33].

Pyramidal hyperechogenicity resembling medullary nephrocalcinosis (calcium deposits) with reversal of corticomedullary differentiation has also been reported in prenatally diagnosed cases of ARPKD [34]. This finding is important since there are very few other causes of reversed corticomedullary differentiation.

●Amniotic fluid volume – The massive enlargement of the kidneys is often associated with oligohydramnios and a small or absent bladder due to the drastic reduction in urine production. The prognosis is better in cases where amniotic fluid volume is preserved until late gestation [33].

●Associated anomalies – Associated liver disease is not evident on prenatal ultrasound. In a small series of six patients, prenatal MRI revealed intrahepatic bile duct ectasia in 84 percent [35].

Genetics — PKHD1 is a large gene extending over a 500-kilobase genomic segment on chromosome 6p12. Direct variant analysis has been reported to detect 85 percent of cases [36]. A wide range of variants and high frequency of compound heterozygotes make the prediction of phenotype challenging.

Targeted NGS panels including ADPKD-associated genotypes and other mimickers are recommended for a complete differential diagnosis of the ARPKD-related phenotype [37]. Molecular genetic testing is discussed in detail separately. (See "Autosomal recessive polycystic kidney disease in children", section on 'Molecular genetic testing'.)

Asymptomatic siblings of affected children should be evaluated for hepatic fibrosis and kidney lesions. (See "Autosomal recessive polycystic kidney disease in children", section on 'Genetic counseling'.)

Obstetric management of ADPKD and ARPKD — Follow-up in pregnancy involves assessment of the kidneys and amniotic fluid volume every two weeks. Cases with early-onset oligohydramnios are not candidates for serial amnioinfusions, as in the Renal Anhydramnios Fetal Therapy (RAFT) trial [38], due to associated comorbidities [38]. No published data are available regarding the impact of preterm birth on the course of polycystic kidney disease. As such, early delivery for potential benefit of early dialysis should be weighed against potential harms from prematurity and the lack of data regarding benefit. The American College of Obstetricians and Gynecologists consider isolated or otherwise uncomplicated oligohydramnios (defined as maximum fluid pocket less than two centimeters) an indication for delivery at 36+0 to 37+6 weeks [39]. The benefit of late antenatal corticosteroids in cases with major fetal anomalies has not been studied.

Cesarean birth due to abdominal dystocia for massively enlarged kidneys and birth at a facility with level IV neonatal intensive care capacity should be discussed with parents. Given the high perinatal mortality and need for hemodialysis and kidney transplant in survivors of ARPKD, clinicians should have a detailed discussion with parents regarding their preferences regarding aggressive perinatal treatment.

Prognosis — Fetuses with very large kidneys and severe oligohydramnios are likely to have a poor outcome due to pulmonary hypoplasia. When amniotic fluid volume remains normal and the kidneys are moderately enlarged, the likelihood of survival is higher.

Age at diagnosis impacts the age at end-stage kidney disease and survival in ARPKD: perinatal type survives hours, neonatal type survives months, infantile type survives up to 10 years, and juvenile type survives decades. When there is a presumptive diagnosis of ARPKD, neonatal mortality of 30 to 40 percent due to pulmonary hypoplasia has been reported. Parents should be counseled regarding pregnancy termination due to reduced life expectancy of affected offspring. However, if pulmonary hypoplasia is not life threatening, dialysis and kidney transplantation can prolong survival. One-year survival rates of 92 to 95 percent have been reported in patients who survive the first month of life [40]. In a long-term follow-up study up to age 10 years, the survival rate was 82 percent and survivors had complications including end-stage kidney disease (29 percent), hypertension (75 percent), and sequelae of congenital hepatic fibrosis and portal hypertension (44 percent) [41]. Long-term pulmonary function appears to be good in those who did not require mechanical ventilation in the newborn period [42,43]. (See "Autosomal recessive polycystic kidney disease in children", section on 'Outcome'.)

Kidney cysts seen with other syndromes — Many syndromes present prenatally with hyperechogenic cystic kidneys. The distinction between glomerulocystic kidney disease, medullary cystic kidney disease, and nephronophthisis is complex and requires examination of kidney histopathology; however, there are some differentiating sonographic features that can aid in prenatal diagnosis.

Differential diagnosis includes, but not limited to:

●Oral-facial-digital syndrome type 1 (OFD1) – OFD1 is associated with dysfunction of primary cilia and is characterized by oral, facial, and digital anomalies as well as polycystic kidneys. Prenatal findings include median cleft lip or palate, hypertelorism, micrognathia, brachydactyly, syndactyly, clinodactyly of the fifth finger, duplicated great toe, preaxial or postaxial polydactyly, intracerebral cysts, agenesis of the corpus callosum, and cerebellar agenesis with or without Dandy-Walker malformation. Prevalence is 1:50,000 to 1:250,000. As inheritance is dominant X-linked, OFD1 is usually lethal in utero for males and thus predominantly affects females. OFD1 gene variants cause OFD syndrome type 1 and encode a protein located in the centrosome and basal body of primary cilia, suggesting that OFD syndromes are ciliopathies [44]. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Syndromic cases'.)

●Short rib-polydactyly syndromes (SRPS) – SRPS types I-IV are rare lethal skeletal ciliopathies with a female predominance and autosomal recessive inheritance. Findings include median cleft lip or palate, narrow thorax with short ribs, severe micromelia, polydactyly, and small cerebellar vermis with multicystic kidneys. (See "Approach to prenatal diagnosis of life-limiting skeletal dysplasias", section on 'Skeletal ciliopathies'.)

●Trisomy 18 – Kidney cortical cysts can be seen in 17 percent of the fetuses with trisomy 18. Other kidney abnormalities include duplication of the collecting system, horseshoe kidney, and hydronephrosis [45]. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome'.)

●Trisomy 13 – Kidney cortical cysts are noted in one-third of fetuses with trisomy 13, and hydronephrosis is seen in 21 percent [45]. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 13 syndrome'.)

●Tuberous sclerosis complex – Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas in various organ systems of the body. Findings include facial angiofibromas, ungual fibromas, cortical tubers, GCKD, angiolipomas in the kidney, and cardiac rhabdomyomas. Fetal MRI may be helpful to identify kidney and brain manifestations [46]. Prevalence is 1:5800, and inheritance is autosomal dominant, but two-thirds of cases result from a de novo variant.

Kidney cysts are observed in 14 to 33 percent of patients with TSC. The kidney cysts are usually single or multiple small lesions and rarely symptomatic. Less commonly, TSC coexists with polycystic kidney disease. In these cases, the kidney cysts are multiple, large, and frequently symptomatic in the postnatal period. The TSC2 locus is adjacent to PKD1 leading to presentation of both phenotypes (TSC2/PKD1 contiguous gene syndrome) [47]. (See "Tuberous sclerosis complex: Clinical features".)

●Jeune syndrome (asphyxiating thoracic dysplasia) – Jeune syndrome is a primary ciliary skeletal disorder. Findings include marked thoracic hypoplasia with short ribs, micromelia, facial dysmorphism, polydactyly, brachydactyly, variable anomalies of the kidney (glomerular and tubular cysts that may progress to tubular atrophy), pancreas, retina, and liver. It is frequently lethal in infancy, but some patients survive into adolescence or adulthood. Prevalence is 1:126,000, and inheritance is autosomal recessive [48]. (See "Approach to prenatal diagnosis of life-limiting skeletal dysplasias".)

●Zellweger syndrome (cerebrohepatorenal syndrome) – Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum that present with several ciliopathy-related features. It is one of the peroxisomal biogenesis disorders with autosomal recessive inheritance. The characteristic manifestations include craniofacial abnormalities, severe hypotonia, hepatomegaly, liver dysfunction with prolonged jaundice, polycystic kidneys or kidney cortical cysts, epiphyseal stippling, and neuronal migration defects. It is a rare disorder, with prevalence less than 1:50,000. Lifespan is usually less than one year [49].(See "Peroxisomal disorders", section on 'Zellweger spectrum disorders'.)

●Ivemark II syndrome – Ivemark II syndrome, also referred to as the renal-pancreatic dysplasia sequence, includes polycystic kidneys or kidney cortical cysts, enlarged pancreas, pancreatic cysts, liver anomalies, absent or undeveloped spleen, heart anomalies, dilated bile ducts, and dilated pancreatic ducts [50]. This is a rare autosomal recessive syndrome, usually diagnosed on autopsy after a stillbirth, neonatal, or infant death.

●Meckel-Gruber syndrome – Meckel-Gruber syndrome is a ciliopathy characterized by occipital encephalocele, bilateral polycystic kidneys with medullary cysts, and postaxial polydactyly. Prevalence is 1:32,500 to 40,000 and inheritance is autosomal recessive. In early pregnancy, medullary cysts with mottled appearance of the medulla and a relatively hyperechoic cortex without cysts are seen. In late pregnancy, the kidney is diffusely involved with both medullary and cortical cysts [51]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Meckel-Gruber syndrome'.)

●Bardet-Biedl syndrome (BBS) – BBS is an autosomal recessive ciliopathy that displays retinal dystrophy, truncal obesity, polydactyly, cognitive impairment, urogenital anomalies, and kidney abnormalities as primary clinical features. Prenatal ultrasound findings include moderately enlarged hyperechogenic kidneys with absent corticomedullary differentiation, medullary cysts, normal amniotic fluid volume, postaxial polydactyly, and hypogonadism. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in the absence of familial history of ARPKD. However, a study of 74 cases reported polydactyly was missed by prenatal ultrasound in 55 percent of the cases [52]. Prevalence is 1:125,000 to 160,000.

●Beckwith-Wiedemann syndrome (BWS) – BWS is the most common epigenetic overgrowth and cancer predisposition disorder. It is characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (eg, Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and kidney abnormalities (eg, medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Prenatal findings include macroglossia, macrosomia, omphalocele, hemihyperplasia, enlarged kidneys, kidney cysts, polyhydramnios, placental mesenchymal dysplasia and liver enlargement. Prevalence is approximately 1:10,340 births. It is an imprinting disorder, occurring sporadically in 85 percent of cases and by familial transmission in 15 percent of cases. A negative result on molecular testing of blood may not rule out BWS due to mosaicism [53]. (See "Beckwith-Wiedemann syndrome".)

●Joubert syndrome – Joubert syndrome is an autosomal recessive ciliopathy characterized by cerebellar vermis hypoplasia (demonstrated as the molar tooth sign on MRI), polydactyly, hypotonia, congenital liver fibrosis, developmental delay, retinal dystrophy, ocular coloboma, abnormal eye movements, and kidney involvement. Kidney findings include cystic dysplasia or nephronophthisis (tubulointerstitial nephritis and cysts at the corticomedullary junction) with normal-sized hyperechoic kidneys without corticomedullary differentiation. The prevalence is 1.7:100,000 in the age range of 0 to 19 years [54]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)

Cystic kidneys

Multicystic dysplastic kidney

Overview — MCDK is a severe form of kidney dysplasia in which the kidney consists of multiple noncommunicating cysts of various sizes separated by dysplastic parenchyma (image 2A-B). Primitive nephrons filled with urine are the basis of the multiple cysts, which are seen initially at the periphery of the kidney. The kidney is enlarged, and the overall shape is abnormal. The affected kidney is nonfunctional and may undergo involution, mostly after birth, when the cysts shrink from absence of urine production. Prenatal involution may be difficult to differentiate from renal agenesis. (See "Renal agenesis: Prenatal diagnosis".)

Most cases of MCDK are unilateral [55]. The prevalence is 1:4300 births, with the left kidney and males slightly more often affected. The prevalence of bilateral MCDK is 1:10,000 live births [56], but it is more likely to be associated with syndromes, field defects, neural tube defects, and other anomalies than unilateral MCDK [55].

Fetal findings

●Kidneys – The classic presentation of MCDK is a multiloculated unilateral abdominal mass consisting of multiple noncommunicating thin-walled cysts that are distributed randomly. No normal kidney tissue is apparent on ultrasound. The appearance of multiple large cysts in the paravertebral area has been likened to a cluster of grapes. The kidney is usually enlarged with an irregular, non-reniform outline and no visible kidney pelvis in early pregnancy, but may further enlarge or, less commonly, may shrink as pregnancy progresses. Shrinkage in severe bilateral cases may mimic renal agenesis. The ureter is atretic or absent. The renal artery is small or absent in MCDK, and the Doppler waveform, when present, is markedly abnormal with reduced systolic peak and absent diastolic flow.

Rare cases of Wilms tumor, multilocular cyst, or cystic mesoblastic nephroma can present in a similar manner to MCDK. From its ultrasound appearance, MCDK may also be confused with severe hydronephrosis; however, the cysts do not communicate in MCDK while they do with hydronephrosis. The kidney parenchyma can still be seen with hydronephrosis but is not seen in MCDK.

Occasionally, only a portion of the kidney is affected. This is called segmental MCDK and is seen in 4 percent of MCDK cases. Most cases occur in the upper pole of a duplex kidney and often involute spontaneously without significant complication [13,57]. Parenchymal tissue between the cysts is often hyperechogenic. MCDK can also occur in horseshoe kidney or in an ectopic kidney [58].

●Amniotic fluid volume – Amniotic fluid volume is normal with unilateral disease. Bilateral disease results in absent urine production, absence of bladder filling, and severe oligohydramnios that leads to pulmonary hypoplasia.

●Associated anomalies – In one review, MCDK was associated with other renal and extrarenal malformations in 29 percent and chromosomal abnormalities and syndromes in 7 percent of cases [59]. Kidney anomalies (ipsilateral or contralateral) are the most common associated anomalies, most often vesicoureteral reflux and obstruction of the ureteropelvic junction. Contralateral renal agenesis is seen in 15 percent. Compensatory hypertrophy may be seen in the contralateral kidney and indicates better outcome. The most common extrarenal abnormalities are heart abnormalities, esophageal or intestinal atresia, spinal abnormalities, and VACTERL association [55]. The risk of aneuploidy is reported as high as 14 percent. Aneuploidy and extrarenal anomalies are much less common in isolated unilateral MCDK [60-62].

Genetics — Referral to genetic counseling should be offered, and counseling should include discussion of inherited conditions and diagnostic testing by amniocentesis or chorionic villus sampling (CVS) [60,63,64]. In addition to aneuploidy risk, pathogenic copy number variants were reported in up to 13.5 to 16.7 percent, including some cases of unilateral isolated MCDK [65,66]. Gene panel testing or exome sequencing should be considered in cases with associated abnormalities or family history suggesting a specific syndrome.

Obstetric management — A thorough fetal survey should be performed to assess for additional structural anomalies that could suggest another disorder or a specific syndrome. Careful examination of the contralateral kidney is important in determining the prognosis. In unilateral disease, conservative management with periodic ultrasound assessment is sufficient.

Prognosis — Children with isolated unilateral MCDK with a normal contralateral kidney have good long-term outcomes with normal kidney function, infrequent urinary tract infections, and compensatory contralateral kidney hypertrophy. Routine removal of the multicystic kidney is no longer recommended because the long-term risks of hypertension and infection are low and the risk of malignancy is not increased [67]. More than 50 percent of the affected kidneys will atrophy and disappear over a period of ten years, obviating the issue of prophylactic surgical removal. (See "Kidney cystic diseases in children", section on 'Multicystic dysplastic kidney'.)

Infants with complex disease, bilateral MCDK, or contralateral urological abnormalities have a high incidence of chronic kidney insufficiency or failure. The prognosis is poor in bilateral disease with anhydramnios. The option of pregnancy termination should be discussed in these cases.

Obstructive renal cystic dysplasia — ORD occurs secondary to fetal urinary tract obstruction or vesicoureteral reflux. The kidneys are hyperechogenic, with or without subcapsular cysts. The kidney size may be normal with preserved corticomedullary differentiation, or diffusely hyperechoic with small subcortical cysts, megacystis, and dilated ureters. Serial sonograms may document the delayed visibility of kidney cysts and/or reduction in size of an initially enlarged kidney with compensatory hypertrophy of the contralateral kidney [13].

The mild form of ORD is associated with partial lower tract obstruction. Severe ORD with complete lower tract obstruction (urethral atresia, posterior ureteral valve) is characterized by marked cystic dysplasia with increased corticomedullary differentiation. Segmental ORD occurs in a duplex kidney and is typically confined to the upper moiety [13]. (See "Kidney cystic diseases in children", section on 'Nonhereditary: Cystic dysplasia'.)

ORD can also be seen in prune-belly syndrome, which consists of a distended abdomen with redundant skin and defective abdominal wall musculature, accompanied by megacystis, megaureters, hydronephrotic dysplastic kidneys, and bilateral cryptorchidism. (See "Prune-belly syndrome".)

Cystic kidney tumors — Kidney tumors of infancy are usually solid; if there is a cystic component, differential diagnosis should include cystic congenital mesoblastic nephroma, cystic nephroma, lymphangioma, cystic partially differentiated nephroblastoma (CPDN), adrenal hemorrhage, clear cell sarcoma (formerly called "anaplastic subtype of Wilms"), and cystic renal cell carcinoma [13,68]. Wilms tumor may contain cysts, which are caused by hemorrhage and necrosis. Cystic nephroma and CPDN are characterized by a solitary, well circumscribed, multiseptated mass of noncommunicating locules with thin septations. Lymphangiomas are characterized by septations. Ossifying kidney tumor of infancy can also present as multilocular cystic masses; however, most cases have minor nodular solid components associated with the cystic components [69].

Simple renal cysts — Simple kidney cysts with otherwise normal findings can be identified by ultrasonography early in gestation, but in contrast to multicystic disease, the majority of simple cysts resolve during pregnancy without any sequelae [70]. The differential diagnosis includes dilated dysplastic upper pole with a duplicated collecting system, segmental multicystic dysplastic kidney, adrenal or splenic cyst, or a cystic tumor. Polycystic kidney disease can present with a single cyst in some cases [1].

SUMMARY AND RECOMMENDATIONS

●Definition – Fetal cystic kidney disease is one of the major causes of end-stage kidney disease in children and adults. It is characterized by small or large cysts and/or kidney hyperechogenicity on ultrasound examination. (See 'Introduction' above and 'Ultrasound characteristics of fetal cystic kidney disease' above.)

●Prenatal evaluation – Prenatal diagnostic evaluation includes a family and genetic history and sonographic assessment of fetal cortical and medullary echogenicity and corticomedullary differentiation, amniotic fluid volume, and detailed anatomical examination for associated anomalies. (See 'Diagnostic evaluation' above.)

•A monogenic disease is identified in 50 to 70 percent of cases with two or more kidney cysts and/or increased cortical echogenicity. In cases with extrarenal anomalies, the risk of a genetic anomaly is increased. Genetic pathology is less common for solitary cysts with normal kidney parenchyma and in isolated unilateral multicystic dysplastic kidney (MCDK) or cystic dysplasia.

•Bilateral hyperechogenic, so called "polycystic" kidneys in a fetus should prompt investigation of the kidneys in the rest of the family.

•Prenatal ultrasound alone should not be expected to predict etiology or long-term outcome in the absence of family history or postmortem or postnatal data. In general, normal or slightly increased kidney size and normal amniotic fluid volume indicate a good outcome. (See 'Differential diagnosis' above.)

●Ultrasonographic differential diagnosis of fetal renal cystic disease

•Hyperechogenic kidneys/polycystic kidneys – These kidneys contain small nonvisualizable cysts that result in kidney enlargement and hyperechogenicity with changes in corticomedullary differentiation. Many of these cases can be syndromic. Although prenatal renal findings cannot differentiate the etiology, associated abnormalities, genetic counseling, and testing may be helpful. Prenatal presentation is most common with ARPKD.

-Autosomal recessive polycystic kidney disease (ARPKD) – Findings include significantly enlarged kidneys with reniform shape, loss of corticomedullary differentiation, subcortical hypoechoic rim, cysts (if visible) predominantly in the medulla, reduced amniotic fluid volume. (See 'Autosomal recessive polycystic kidney disease' above.)

-Autosomal dominant polycystic kidney disease (ADPKD) – Rare presentation in 1 to 2 percent of cases prenatally. Findings include moderately enlarged kidneys, usually normal amniotic fluid volume, increased corticomedullary differentiation, cysts (if visible) usually in cortical location. (See 'Autosomal dominant polycystic kidney disease' above.)

-Other syndromes that present with hyperechogenic kidneys and/or kidney cysts may be differentiated by the associated anomalies and genetic testing. (See 'Kidney cysts seen with other syndromes' above.)

•Cystic kidneys

-Multicystic dysplasia – Findings include usually unilateral pathology in which the kidney is enlarged by randomly distributed large size cysts that do not connect, the reniform shape is not preserved, and normal renal parenchyma is lacking. Differential includes hydronephrosis (communicating cystic structures represent pelvicalyceal dilation), and cystic tumors. Reflux and obstruction of the ureteropelvic junction are common in the contralateral kidney. Genetic testing should be offered in all cases due to aneuploidy risk (more common if associated anomalies and bilateral presentation) and up to 16 percent risk of pathological copy number variants on microarray. (See 'Multicystic dysplastic kidney' above.)

-Obstructive renal cystic dysplasia due to lower urinary tract obstruction, reflux, or prune belly syndrome – Findings include megacystis with thickened bladder walls and dilated ureters and hyperechogenic kidneys with or without subcapsular cysts. The kidney size may be normal with preserved corticomedullary differentiation or diffusely hyperechoic with small subcortical cysts in severe cases. (See 'Obstructive renal cystic dysplasia' above.)

-Cystic renal tumors/masses with a cystic component – These include cystic congenital mesoblastic nephroma, cystic nephroma, lymphangioma, cystic partially differentiated nephroblastoma, adrenal hemorrhage, clear cell sarcoma, hemorrhage in Wilms tumor, and cystic renal cell carcinoma. (See 'Cystic kidney tumors' above.)

-Simple kidney cysts – These cysts usually resolve. Differential diagnosis includes dilated dysplastic upper pole with a duplicated collecting system, segmental MCDK, adrenal or splenic cyst, or a cystic tumor. Polycystic kidney disease can present with a single cyst in some cases. (See 'Simple renal cysts' above.)