Prenatal sonographic diagnosis of cystic kidney disease

INTRODUCTION — Cystic kidney disease is one of the major causes of end-stage kidney disease in children and adults. Congenital cystic kidney diseases may become clinically apparent in the fetus, child, or adult. 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".)

PRENATAL DIAGNOSIS OF CYSTIC KIDNEY DISEASE — Fetal cystic kidney disease is characterized by small or large cysts and kidney hyperechogenicity on ultrasound examination; however, many times, the cysts are not visible and the main finding is hyperechogenic kidneys. Kidney cystic structures can be localized to the cortex, medulla, or both, and may represent dilated tubules, glomerular cystic dilation, or real cysts. Kidney hyperechogenicity is secondary to the numerous interfaces created by microscopic cysts and dilated tubules and to interstitial fibrosis and inflammation [3].

To assess 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 [4]. 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.

Ultrasound examination of fetuses with cystic kidney changes or hyperechogenic kidneys also includes assessment of [5]:

●Kidney size – 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].

●Corticomedullary differentiation (CMD) – The absence of CMD and increased or reversed CMD are concerning for a fetal kidney pathology [9]. Normal CMD is defined as a relatively hyperechoic cortex compared with the medulla. CMD can be visualized starting at 15 to 16 weeks and becomes more prominent at 20 weeks [10].

●Amniotic fluid volume – In the second half of pregnancy, amniotic fluid volume is produced by fetal kidneys and lungs [10]. Therefore, 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 clinical purposes, it is useful to classify cystic kidney diseases that present in the fetus in the following way:

●Hereditary disorders

•Autosomal recessive polycystic kidney disease

•Autosomal dominant polycystic kidney disease

•Hepatocyte nuclear factor-1-beta (HNF1B) nephropathy

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

●Nonhereditary disorders

•Kidney dysplasia

-Multicystic kidney disease

-Obstructive cystic kidney dysplasia

•Nondysplastic nonhereditary kidney cysts

-Kidney cystic tumors

-Simple kidney cysts

DIAGNOSTIC EVALUATION — The work-up of fetal hyperechogenic kidneys with or without kidney cysts 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

●Fetal genetic testing

The risk for an abnormal fetal karyotype or pathogenic copy number variants, which can be diagnosed by chromosomal microarray, should be discussed with the patient. Other appropriate genetic testing, including molecular genetic investigation for monogenic disease, are discussed depending on the nature of the kidney abnormality, extrarenal abnormalities, and family history.

DIFFERENTIAL DIAGNOSIS — Uniformly echogenic 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 [9,12]. Since nephrogenesis is not completed until the third trimester until 32 to 36 weeks, an early diagnosis may be a false-positive result [10,13]. Serial scans can be helpful to assess the amniotic fluid volume and the appearance of the kidneys over time in such cases. In general, isolated normal or slightly increased kidney size and normal amniotic fluid volume predict a good outcome [8,14]. 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 malformation may be more helpful than the cystic characteristics and pinpoint a syndromic etiology [9].

The ultrasonographic differential diagnosis of enlarged hyperechogenic kidneys, with or without cysts, 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 present] usually in cortical location, but rarely presents in the prenatal period).

●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 are 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 [15].

Fetal magnetic resonance imaging (MRI) can be helpful for identifying extrarenal anomalies in cases with oligohydramnios and to rule out sacrococcygeal teratoma in cases of a pelvic ectopic multicystic dysplastic kidney. Fetal MRI can also help in differentiating ARPKD from congenital kidney cystic diseases without medullary involvement. For example, in one study, MRI of two fetuses with enlarged hyperechoic kidneys showed localized medullary hyperintense lesions suggesting ARPKD in one fetus and medullary cystic dysplasia in the other fetus with Jeune's syndrome [16].

HEREDITARY DISORDERS — Most of the hereditary cystic kidney diseases are due to primary ciliopathies. Autosomal dominant polycystic kidney disease (ADPKD) is the most common ciliopathy in this group of disorders. The prevalence of these inherited disorders is approximately 1:2000 [17].

Primary ciliopathies are secondary to single gene variants that lead to defective proteins and abnormal ciliary formation or function. The cumulative prevalence of primary ciliopathies is 1:2000. The primary cilium or "immobile" cilium is a microtubule base organelle that extends from the cell surface and is present in almost all vertebrate cells. The cilia transduce molecular signals from the extracellular environment, acting as "antennae" for the cell. Primary cilia can be found in the nephron tubule and in the 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. Primary cilia are found on the surface of almost every mammalian cell type. As such, ciliopathies often involve multiple organ systems. 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 [18]. ADPKD, ARPKD, and nephronophthisis are the most common causes and mainly present with hepatorenal system findings. Other ciliopathies involve multiorgan systems.

As such, differential diagnosis depends on the location of kidney involvement typical of the disease, family history, and associated anomalies [15].

Autosomal dominant polycystic kidney disease

Overview

●Epidemiology – ADPKD is the most common inherited kidney cystic disease. The estimated incidence at birth is 1:400 to 1000 deliveries [19]. ADPKD 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 all parts of 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 [20]. 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 [21]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

Fetal findings

●Kidneys – Typically, the kidneys appear normal prenatally. The rare prenatal presentation of ADPKD is characterized by moderately enlarged kidneys (1 to 2 standard deviations above the mean size for gestational age) with a hyperechogenic cortex (25 of 27 cases [93 percent] in one series [22]). The medulla can be hypoechogenic or hyperechogenic. A hypoechogenic medulla resulting in increased corticomedullary differentiation was reported in 20 of 26 (77 percent) prenatally diagnosed cases; absent or decreased corticomedullary differentiation with hyperechoic medulla was less frequent [22]. Cysts are seen in approximately 15 percent of prenatal cases and are usually in the cortex. Very rarely, one kidney may be larger than the other, suggesting unilateral disease.

The ultrasonographic appearance of the kidneys may not allow certain differentiation of autosomal recessive from autosomal dominant disease [23]. ARPKD kidneys in utero are markedly enlarged (4 to 15 standard deviations above the mean), hyperechoic, and display "decreased" corticomedullary differentiation because of the hyperechoic medulla. By comparison, ADPKD kidneys in utero tend to be moderately enlarged with a hyperechoic cortex and relatively hypoechoic medulla causing "increased" corticomedullary differentiation [24]. However, ADPKD can mimic ARPKD and can present with increased cortical echogenicity, decreased corticomedullary differentiation, multiple medullary cysts, and decreased amniotic fluid [25].

Ultrasound evaluation of the parents' kidneys may be useful for differential diagnosis. If either parent has ADPKD, the finding of enlarged echogenic kidneys with or without cysts in the fetus strongly supports the diagnosis. Absence of cysts in the parents (particularly if they are >30 years of age) suggests ARPKD rather than ADPKD.

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; this is an important distinction from ARPKD. 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) [22].

●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) [26]. 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) [19]. (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 [27]. 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. [28]. The potential of next-generation sequencing (NGS) technologies for high-throughput screening of both PKD1 and PKD2 has been demonstrated [29,30]. (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 presentation prenatally may be associated with more rapid postnatal progression of the disease [31,32]. In one study, 43 percent of patients diagnosed prenatally died within the first year of life, 3 percent developed kidney failure by age 3 years, and 67 percent developed hypertension [32]. Another study of 26 children with a mean follow-up of 76 months reported a more favorable prognosis [32]. In this study, 19 children were asymptomatic, 5 had hypertension, 2 had proteinuria, and 2 had chronic kidney insufficiency. 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) is a rare disorder, occurring in 1:20,000 live births, which corresponds to a 1:70 carrier frequency in nonisolated populations. Fetal death may occur because of severe oligohydramnios, and neonatal death may occur because of lung hypoplasia due to oligohydramnios and thoracic compression by the large kidneys [20].

●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 [33]. 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.

DZIP1L encodes a ciliary TZ protein (DZIP1L, DAZ interacting protein 1-like) that localizes to centrioles and the distal end of basal bodies and is required in regulating transformation zone integrity. Clinical manifestations in individuals with DZIP1L variants present prenatally or in early childhood and appear to be associated with a moderate course [34]. For example, in one series of seven affected individuals, all had enlarged hyperechogenic kidneys and arterial hypertension; four progressed to end-stage kidney disease between 12 and 26 years of age and three others had normal kidney function at ages 9, 13, and 15 years [35]. (See "Autosomal recessive polycystic kidney disease in children", section on 'Pathogenesis'.)

HNF1B variants have been reported to be the most common cause for bilateral fetal kidney hyperechogenicity. In a study of 62 pregnancies with bilateral hyperechoic kidneys, HNF1B variants were found in 29 percent of cases [36]. HNF1B is a transcription factor encoded by the TCF2 gene and is involved in the early development of the kidney, intestine, pancreas, liver, and genital tract. HNF1B acts as a transcription factor for several cystic kidney disease genes including PKHD1 and PKD2. Variants in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, maturity-onset diabetes of the young type 5, electrolyte abnormalities, and genital malformations. While many HNF1B fetuses display normal or slightly enlarged echogenic kidneys often with bilateral cortical cysts and normal amniotic fluid volume, others may present with oligo- or anhydramnios and massively enlarged polycystic kidneys (>+3 standard deviations) that mimic ARPKD. Polyhydramnios is also reported and has been attributed to polyuria. Cortical or diffuse kidney cysts may accompany prenatal presentation and develop in more than 90 percent of cases in the postnatal period. Less frequently, HNF1B variants may present prenatally with cystic kidney dysplasia, kidney agenesis, pelvicalyceal dilation, and multicystic dysplastic kidney (MCDK) [36,37].

HNF1B is inherited in an autosomal dominant fashion in 50 percent of affected individuals, with large variability in expressivity and penetrance. De novo variants comprise the remaining 50 percent. Pathogenic variants in the coding region or splice sites of HNF1B comprise 50 percent of cases while the remaining have large deletions that include HNF1B and several other genes on 17q12. Patients with a large genomic rearrangement in 17q12 are much more frequently affected by cognitive impairment, seizures, and other neurodevelopmental disorders [34].

The phenotype of ARPKD can also be mimicked by either dominant or recessive variants in PKD1 and PKD2, the genes usually causing ADPKD. Early presentation of ADPKD prenatally or in childhood can be as high as 2 to 5 percent. It is important to image the parents and obtain a family history; however, the family history may not be helpful in cases with de novo mutations of ADPKD1 and ADPKD2 (approximately 15 to 20 percent) and recessive inheritance of incompletely penetrant hypomorphic mutations in PKD1 and PKD2 [34].

●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 outer kidney cortex remains normal since there are no tubules in this area. 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 [38]. 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, ie, with no corticomedullary differentiation. When bilateral, significantly enlarged echogenic kidneys, a small or absent bladder, and oligohydramnios are seen, ARPKD is the most likely etiology; however, a precise prenatal diagnosis cannot be made with certainty by ultrasound alone.

The sonographic features of ARPKD can appear anytime during gestation. Elongated hyperechogenic kidneys with normal transverse and anteroposterior diameters may be the only ultrasound finding before the third trimester [39]. Serial ultrasound examinations with measurement of kidney dimensions that confirm progressive enlargement and reduction in amniotic fluid volume help establish the diagnosis. Molecular testing can also confirm the diagnosis, which is particularly important before 24 weeks of gestation when the diagnosis is less certain.

The kidney size is typically 4 to 15 standard deviations above the mean size for gestational age [40]. Due to the large kidney size, the abdominal circumference is larger than expected for gestational age.

Late in pregnancy, isolated macroscopic cysts less than 10 mm in size are visible in the medulla in one-third of cases. One review reported cysts in 60 percent of ARPKD cases and 37 percent of ADPKD cases [15]. 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 [40]. Pyramidal hyperechogenicity resembling medullary nephrocalcinosis (calcium deposits) with reversal of corticomedullary differentiation has also been reported [41]. This finding is important since there are very few other causes of reversed corticomedullary differentiation. By comparison, in children and adults, kidney enlargement is less prominent, and a hypoechoic outer cortical rim with reversed corticomedullary differentiation, medullary macrocysts, or echoic nonshadowing foci in the medulla are usually seen [12].

●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. Pulmonary hypoplasia can occur when oligohydramnios is present early in gestation. The prognosis is better in cases where amniotic fluid volume is preserved [40].

●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 [42].

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 [43]. 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 [44]. 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. 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 [45]. 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 and thoracic compression. 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. Classically, survival in ARPKD has been predicted based on time of presentation: 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 [46]. 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) [47]. Long-term pulmonary function appears to be good in those who did not require mechanical ventilation in the newborn period [48,49]. (See "Autosomal recessive polycystic kidney disease in children", section on 'Outcome'.)

HNF1B-related nephropathy — Heterozygous mutations in the gene located at 17q12 that encodes the transcription factor hepatocyte nuclear factor-1-beta (HNF1B) represent the most common monogenic cause of developmental kidney disease. These HNF1B variants are a common cause for bilateral fetal kidney hyperechogenicity. The major differential diagnoses in these cases are ARPKD and ADPKD. In a study of 62 pregnancies with bilateral hyperechogenic kidneys, HNF1B variants were found in 29 percent of cases [36].

HNF1B, also known as transcription factor-2 (TCF2) is involved in the early development of the kidney, intestine, pancreas, liver, and genital tract and acts as a transcription factor for several cystic kidney disease genes, including PKHD1 and PKD2. As such, variants in HNF1B lead to a multisystemic presentation with congenital anomalies of the kidney and urinary tract, pancreas atrophy, maturity-onset diabetes of the young (MODY) type 5, electrolyte abnormalities, and genital malformations. While many HNF1B variants display are associated with normal or slightly enlarged echogenic kidneys and normal amniotic fluid volume, others may present with oligo- or anhydramnios and massively enlarged polycystic kidneys (>+3 standard deviations) that mimic ARPKD. Polyhydramnios is also reported and has been attributed to polyuria. Cortical or diffuse kidney cysts may accompany prenatal presentation and develop in more than 90 percent of cases in the postnatal period. Less frequently, HNF1B variants may present prenatally with cystic kidney dysplasia, hypoplasia, renal agenesis, pelvicalyceal dilation, multicystic dysplastic kidney (MCDK), horseshoe, and duplex kidneys; and collecting system abnormalities [36,37]. A slow progressive decline in kidney function and a 16 percent risk of end-stage kidney disease in the long term is reported for cases with HNF1B nephropathy [50].

HNF1B is inherited in an autosomal dominant fashion with 50 percent recurrence risk for affected individuals but large variability in expressivity and penetrance. The prevalence of spontaneous HNF1B deletion is as high as 50 percent. Pathogenic variants in the coding region or splice sites of HNF1B comprise 50 percent of cases while the remaining have large deletions that include HNF1B and several other genes on 17q12. Microarray can identify large size or whole gene deletions and molecular methods should be sought for the remaining types.

Kidney cysts seen with other syndromes — Many syndromes present with hyperechogenic cystic kidneys with some evident in the prenatal period. The distinction between the glomerulocystic, medullary cystic dysplasia, nephronophthisis/medullary cystic dysplasia complex requires examination of kidney histopathology.

Glomerulocystic kidney disease — Glomerulocystic kidney disease (GCKD) is characterized by cysts resulting from dilation of Bowman's space. At least 5 percent of the glomeruli are involved. Subcapsular cysts are diagnostic but not always present. These cysts do not become very large; thus, the kidney size tends to remain moderately enlarged (2 to 8 standard deviations above the mean for gestational age). The kidneys appear hyperechogenic with loss of corticomedullary differentiation.

Differential diagnosis includes:

●ADPKD glomerulocystic type – The cysts in ADPKD are initially isolated and located in the cortex [23]. Prevalence is 1:400 to 1000 and family history reveals autosomal dominant inheritance, as described above.

●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 [51]. (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 the lethal (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 [52]. (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 [52]. (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 [53]. 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) [54]. (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 [55]. (See "Approach to prenatal diagnosis of the lethal (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 [56].(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 [57]. This is a rare autosomal recessive syndrome, usually diagnosed on autopsy after a stillbirth, neonatal, or infant death.

Medullary cystic dysplasia/nephronophthisis — Medullary cystic dysplasia is characterized by tubular cysts that present later in life. Nephronophthisis is an autosomal recessive disorder characterized by tubular distention and cysts at the corticomedullary junction, tubulointerstitial nephritis, and glomerulosclerosis that progresses to terminal kidney failure during the second decade (juvenile form) or before age of five years (infantile form). Prenatal diagnosis of isolated nephronophthisis has not been reported. However, 10 to 20 percent of nephronophthisis cases are syndromic and include Joubert, Bardet-Biedel, and Jeune syndromes, among the others. Differential diagnosis includes:

●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 [58]. (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 [59]. 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 [60]. (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 [61]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)

NONHEREDITARY DISORDERS

Kidney dysplasia

●Epidemiology – Dysplastic kidneys are common malformations affecting up to 2 to 4 in 1000 births. They are part of the spectrum of Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT). (See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)

●Pathology – Kidney dysplasia is a continuum that has many subtypes, ranging from hypoplasia to agenesis to massive cystic kidneys, and is the leading etiology of end stage kidney disease in children. It is characterized by structural disorganization of the kidney tissue, poorly branched/differentiated nephrons and collecting ducts, increased stroma, and, occasionally, cysts and metaplastic tissues, such as cartilage. Kidney dysplasia originates from abnormal interaction between the ureteral bud and metanephric blastema.

●Etiology/genetics – Dysplastic kidneys may occur randomly or secondary to genetic defects, lower urinary tract obstruction (obstructive dysplasia [ORD]), or teratogen exposure [62]. Approximately 10 percent of affected fetuses have a family history of significant kidney/urinary tract malformation. Monogenic causes include variants in individual genes, such as TCF2/hepatocyte nuclear factor-1-beta (HNF1B), PAX2, and uroplakins. Compound heterozygote variants in several kidney/urinary tract developmental genes have also been reported [62-64].

The TCF2 gene encodes the protein HNF1B, which is involved in early kidney and pancreas development. HNF1B is an essential transcription factor that regulates the development and function of epithelia in the kidney, liver, pancreas, and genitourinary tract. In the embryonic kidney, HNF1B is required for ureteric bud branching, initiation of nephrogenesis, and nephron segmentation. In the adult kidney, HNF1B controls the expression of genes required for intrarenal metabolism and solute transport by tubular epithelial cells. Tubular abnormalities observed in HNF1B nephropathy include hyperuricemia with or without gout, hypokalemia, hypomagnesemia, and polyuria [65], as well as maturity-onset diabetes of the young type 5, genital tract abnormalities, and liver and intestinal abnormalities [66].

PAX2 is a central nephrogenic molecule involved in the outgrowth and branching of the ureteric bud and is also expressed during the development of the eye, ear, and nervous system, as well as the urogenital tract. PAX2 is involved in approximately half of the patients with autosomal-dominant renal-coloboma syndrome characterized by ocular and kidney malformations. Uroplakins are cell membrane proteins distributed in the apical surface of the urothelium.

NEK8 variants are associated with severe kidney cystic dysplasia [67]. NEK8 is a major gene for kidney dysplasia and belongs to a protein complex defining the inversin compartment of the cilium. It is a negative regulator of the Hippo signaling pathway, which controls organ growth by controlling the balance between cell proliferation and cell cycle arrest through the phosphorylation state and nuclear shuttling of transcriptional cofactors YAP/TAZ. NEK8 missense and loss-of-function variants have different effects on nuclear YAP imbalance in the Hippo pathway.

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 [68]. 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 [69], but it is more likely to be associated with syndromes, field defects, neural tube defects, and other anomalies than unilateral MCDK [68].

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 [12,70]. Parenchymal tissue between the cysts is often hyperechogenic. MCDK can also occur in horseshoe kidney or in an ectopic kidney [71].

●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 [72]. 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 [68]. The risk of aneuploidy is reported as high as 14 percent. Aneuploidy and extrarenal anomalies are much less common in isolated unilateral MCDK [73-75].

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) [17,73,76]. 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 [77,78]. Gene panel testing or exome sequencing should be considered in cases with associated abnormalities or family history suggesting a specific syndrome.

MCDK has been linked to the HNF1B disease spectrum and associated with other ciliopathies, such as Meckel-Gruber syndrome, although HNF1B genetic variants in unilateral isolated MCDK are rare.

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 [79]. 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 worse outcome, with 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 [12].

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 [12]. (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".)

NONDYSPLASTIC NONHEREDITARY KIDNEY CYSTS

Cystic 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 [12,80]. 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 [81].

Simple 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 [82]. 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

●Overview

•Fetal cystic kidney disease is one of the major causes of end-stage kidney disease in children and adults. (See 'Introduction' above.)

•Fetal cystic kidney disease is characterized by small or large cysts and/or kidney hyperechogenicity on ultrasound examination. (See 'Prenatal diagnosis of cystic kidney disease' above.)

-A family and genetic history should be taken and the size, cortical and medullary echogenicity and corticomedullary differentiation, fluid volume, as well as a detailed anatomical examination, should be performed for associated anomalies. (See 'Diagnostic evaluation' above.)

-Fetal magnetic resonance imaging (MRI) can be helpful for identifying extrarenal anomalies in cases with oligohydramnios. (See 'Diagnostic evaluation' above and 'Differential diagnosis' 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. (See 'Introduction' above.)

•Genetic pathology is less common for solitary cysts with normal kidney parenchyma and in isolated unilateral multicystic dysplastic kidney (MCDK) or cystic dysplasia. (See 'Introduction' above.)

•Bilateral hyperechogenic or polycystic kidneys in a fetus should prompt investigation of the kidneys in the rest of the family. (See 'Diagnostic evaluation' above.)

•Once nonhereditary dysplastic lesions and kidney cystic tumors/cysts are ruled out, hereditary etiologies should be investigated. Ciliopathies comprise the most common hereditary etiology for hyperechogenic or polycystic kidneys. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are the most common ciliopathies and mainly present with hepatorenal involvement; however, less common multisystem ciliopathies should be included in the differential diagnosis. (See 'Nondysplastic nonhereditary kidney cysts' above and 'Hereditary disorders' above.)

•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.)

•Hepatocyte nuclear factor-1-beta (HNF1B) variants are a common cause for bilateral fetal kidney hyperechogenicity or cysts and usually present with normal size or slightly enlarged kidneys with normal amniotic fluid volume or polyhydramnios. Targeted next generation sequencing of the relevant genes is recommended for bilateral hyperechogenic/cystic kidney disease including PKHD1, PKD1, PKD2, HNF1B, DZIP1L, and other genes as appropriate. (See 'HNF1B-related nephropathy' above.)

●The ultrasonographic differential diagnosis of prenatal renal cystic disease includes:

•Hereditary etiology

-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) – Findings include moderately enlarged kidneys, usually normal amniotic fluid volume, increased corticomedullary differentiation, cysts (if visible) usually in cortical location (but rarely presents in the prenatal period). (See 'Autosomal dominant polycystic kidney disease' above.)

-HNF1B nephropathy – Findings include normal or slightly enlarged echogenic kidneys, normal amniotic fluid volume. Less likely findings include oligo/anhydramnios and massively enlarged polycystic kidneys, polyhydramnios. HNF1B-related disease due to mutations in the gene located at 17q12 is the most common monogenic cause for congenital renal disease. It should be included in the differential diagnosis of hyperechogenic and/or polycystic kidneys, and MCDK. (See 'HNF1B-related nephropathy' above.)

-Other – Syndromes that present with hyperechogenic kidneys and/or kidney cysts are differentiated by the associated anomalies and include, but are not limited to: Bardet-Biedl syndrome, Meckel-Gruber syndrome, Joubert syndrome, trisomy 18, trisomy 13, Ivemark II syndrome, Beckwith-Wiedemann syndrome, Jeune syndrome, short rib polydactyly syndromes, Zellweger syndrome, oral-facial-digital syndrome type 1 (OFD1), McKusick-Kaufman syndrome, Beemer syndrome, Jarcho-Levin syndrome, overgrowth syndromes, and Mainzer-Saldino syndrome. Obstructive dysplasia (hyperechogenic kidneys, cortical cysts with or without dilated upper or lower urinary tract). (See 'Kidney cysts seen with other syndromes' above.)

•Nonhereditary etiology

-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 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 cysts' above.)