INTRODUCTION — Congenital cystic renal 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, presence of contralateral disease or compensatory hypertrophy in unilateral cases, other organ involvement, and the extent of kidney damage determined by characteristics of the particular 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 renal cysts and/or increased cortical echogenicity. In cases with extrarenal anomalies, the risk of a chromosomal anomaly is increased. However, genetic pathology is rare for solitary cysts with normal renal parenchyma and in isolated unilateral multicystic dysplastic kidney or cystic dysplasia [1,2].
Ultrasound is the most common imaging method for diagnosis of fetal renal cystic diseases. Congenital cystic renal diseases that can be diagnosed by antenatal ultrasound examination will be reviewed here. The diagnosis, clinical manifestations, and prognosis of renal cysts and cystic disorders in children are discussed separately, including:
●(See "Overview of congenital anomalies of the kidney and urinary tract (CAKUT)".)
●(See "Renal cystic diseases in children".)
●(See "Autosomal dominant polycystic kidney disease (ADPKD) in children".)
●(See "Autosomal recessive polycystic kidney disease in children".)
ULTRASOUND EVALUATION OF THE KIDNEYS AND AMNIOTIC FLUID VOLUME FOR CYSTIC RENAL DISEASE — Ultrasound examination of fetuses with cystic renal changes or hyperechoic kidneys includes assessment of [3]:
●Amniotic fluid volume – In the second half of pregnancy, amniotic fluid volume is produced by fetal kidneys and lungs. Therefore, a normal amniotic fluid volume is the best predictor of normal fetal kidney function.
●Kidney size – Maximal midsagittal length, width, and depth at the level of the hilum should be measured, and renal volume should be calculated using 2D or 3D imaging [4,5].
●Corticomedullary differentiation (CMD) – Normal CMD is defined as a relatively hyperechoic cortex compared with the medulla. CMD is visualized starting at 15 to 16 weeks and becomes more prominent at 20 weeks. Normal CMD should be present in all fetuses once visualized. The absence of CMD and increased or reversed CMD are concerning for a fetal renal pathology [6].
●Level of renal echogenicity and location and size of renal cysts – The cortical echogenicity is compared with the liver and spleen, and the medullar echogenicity is compared with the 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 early second trimester to a hypoechogenic pattern as compared with liver or spleen in the third trimester, with no fetus displaying cortical hyperechogenicity after 32 weeks. At 21 to 25 weeks, the most frequent pattern (92 percent) was hyperechogenicity of the renal cortex while hypoechogenicity was the most common pattern at 34 to 37 weeks (70 percent).
Fetal renal cystic disease is characterized by small or large cysts and renal hyperechogenicity. Renal cystic structures can be localized to the cortex, medulla, or both, and represent dilated tubules, glomerular cystic dilation, or real cysts. Renal hyperechogenicity is secondary to the numerous interfaces created by microscopic cysts and dilated tubules and to interstitial fibrosis and inflammation [7]. Of note, echogenic kidneys <+4 standard deviation enlargement without cysts and with normal amniotic fluid volume may represent a variant of normal [8].
CLASSIFICATION — Several classification systems for congenital cystic renal disease have been proposed, taking into account the pathologic, clinical, and genetic features of these disorders [9]. For clinical purposes, it is useful to classify cystic renal diseases that present in the fetus in the following way:
●Hereditary disorders
•Autosomal recessive polycystic kidney disease
•Autosomal dominant polycystic kidney disease
•Renal cysts seen with syndromes/sequences (glomerulocystic and medullary cystic dysplasia/ nephronophthisis)
●Nonhereditary disorders
•Renal dysplasia
-Multicystic kidney disease
-Obstructive cystic renal dysplasia
•Nondysplastic nonhereditary renal cysts
-Renal cystic tumors
-Simple renal cysts
DIAGNOSTIC WORK-UP AND DIFFERENTIAL DIAGNOSIS — The diagnostic work-up of fetal hyperechogenic kidneys with or without renal cysts should include a thorough fetal anatomic survey; review of the family's genetic history; and ultrasound examination of the kidneys of the parents, grandparents, and siblings of the fetus. Risk for an abnormal fetal karyotype, copy number variants, and monogenic disease should be discussed. Other appropriate genetic testing, including molecular genetic investigation, should be discussed with the parents depending on the nature of the renal abnormality, presence of extrarenal abnormalities, and family history.
Uniformly echogenic fetal kidneys without visible macrocysts are not an uncommon incidental finding on obstetric ultrasound examination. It is essential to differentiate significant renal disease from normal variants, which are characterized by normal kidney size, moderately bright cortex, visible corticomedullary differentiation (after 20 weeks gestational age), normal bladder size, and normal amniotic fluid volume [6,10]. Since nephrogenesis is completed in the third trimester, an early diagnosis can represent a false-positive result [11]. Serial scans may be helpful to assess the amniotic fluid volume and the appearance of the kidneys in such cases. However, prenatal ultrasound alone cannot predict etiology or long-term outcome in the absence of family history, postmortem, or postnatal data. In general, normal or slightly increased kidney size and normal amniotic fluid volume predict a good outcome [8].
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 present] 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, renal 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).
●Syndromes that present with hyperechoic kidneys and/or renal 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 (31/93), ADPKD (28/93), Bardet-Biedl syndrome (11/93), Meckel-Gruber syndrome (9/93), Ivemark II syndrome (6/93), trisomy 18 (5/93), Jarcho-Levin syndrome (spondylothoracic dysplasia; 1/93), Beemer syndrome (narrow ribs, micromelia, with or without polydactyly; 1/93), and Meckel-like syndrome (1/93) [6].
Fetal magnetic resonance imaging (MRI) can be helpful for identifying extrarenal anomalies in cases with oligohydramnios and to rule out coccygeal teratoma in cases of a pelvic ectopic multicystic dysplastic kidney. Fetal MRI can also help in differentiating ARPKD from congenital renal 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 [12].
HEREDITARY DISORDERS — Most of the hereditary cystic renal 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 [13].
Primary ciliopathies are secondary to single gene variants that lead to defective proteins and abnormal ciliary formation or function. 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. 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 [14].
Differential diagnosis is dependent on the location of renal involvement typical of the disease, family history, and characteristic associated anomalies.
Autosomal dominant polycystic kidney disease
Overview — ADPKD is the most common inherited renal cystic disease. Although the typical age of clinical onset is in the third to fifth decade of life, rarely (<1 percent of cases) ADPKD can present in utero or in the neonatal period with ultrasound changes.
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 renal 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. This is different from ARPKD in which cysts are derived from collecting tubules and remain connected to the nephron of origin [15]. 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 renal disease, requiring transplant or dialysis by late middle age. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth" and "Autosomal dominant polycystic kidney disease (ADPKD): Treatment".)
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 [16]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)
The estimated incidence at birth is 1:400 to 1000 deliveries; however, this disorder is rarely identified prenatally [17]. ADPKD is inherited as an autosomal dominant trait with complete penetrance. The disease is caused by variants in either of the two genes encoding plasma membrane-spanning polycystin 1 and polycystin 2, PKD1 (on chromosome 16p13.3) and PKD2 (on chromosome 4q21), respectively. 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 (accounting for 85 percent of cases), are likely to be associated with more renal cysts, and lead to earlier development of renal insufficiency (on average 20 years earlier) [17]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Genetics of the disease and mechanisms of cyst growth".)
The renal manifestations, ex utero diagnosis, and course of this disorder in children are discussed elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children".)
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. The medulla can be hypoechogenic or hyperechogenic. A hypoechogenic medulla resulting in increased corticomedullary differentiation was reported in 25 of 27 (77 percent) prenatally diagnosed cases; absent or decreased corticomedullary differentiation with hyperechoic medulla was less frequent [18]. 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 [19]. ARPKD kidneys in utero are 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 [20]. However, ADPKD can mimic the prenatal presentation of ARPKD with increased cortical echogenicity, decreased corticomedullary differentiation, multiple medullary cysts, and decreased amniotic fluid [21]. High-resolution ultrasound may detect the dilated tubular branching collecting ducts in ARPKD, which are readily distinguishable from the round cysts of ADPKD [20].
Renal ultrasound evaluation of the parents 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 can result from de novo variants. 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 [18], 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) [18].
●Associated abnormalities – Associated structural abnormalities, such as cysts in the liver and spleen, have not been identified prenatally.
Genetic studies — There is no family history in 10 to 15 percent of patients. This can be secondary to de novo mutations in 5 percent, mild PKD2 cases, nontruncating PKD1 mutations due to mild course, or unavailability of parental records [22]. 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 renal 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 through amniocentesis or chorionic villus sampling. Most cases (approximately 90 to 95 percent) are inherited. Direct DNA sequencing of the PKD1 and PKD2 genes detects pathogenic variants in up to 91 percent of cases. [23]. The potential of next-generation sequencing (NGS) technologies for high-throughput mutation screening of both PKD1 and PKD2 has been demonstrated [24]. (See "Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis", section on 'Establishing the diagnosis of ADPKD'.)
Prognosis — Although renal function is preserved and the amniotic fluid volume remains normal in most cases, prenatal presentation may be associated with more rapid progression of the disease after birth [25,26]. In one study of patients diagnosed prenatally, 43 percent died within the first year of life, 3 percent developed renal failure by age 3 years, and 67 percent developed hypertension [26]. Another study of 26 children with a mean follow-up of 76 months reported a more favorable prognosis [25]. In this study, 19 children were asymptomatic, 5 had hypertension, 2 had proteinuria, and 2 had chronic renal insufficiency. A high proportion of siblings developed early renal cysts. (See "Autosomal dominant polycystic kidney disease (ADPKD) in children", section on 'Outcome'.)
Autosomal recessive polycystic kidney disease
Overview — 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 pulmonary insufficiency [15].
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 renal 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 [27]. ARPKD can also be caused by other mutations, including the DAZ interacting zinc finger protein 1-like gene (DZIP1L), and can be mimicked by mutations 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. DZIP1L mutations present prenatally or in early childhood and appear to be associated with a moderate course [28]. (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 renal hyperechogenicity. In a study of 62 pregnancies with bilateral hyperechoic kidneys, HNF1B variants were found in 29 percent of cases [29]. 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 renal 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 renal dysplasia, renal agenesis, pelvicalyceal dilation, and multicystic dysplastic kidney [29,30].
HNF1B is inherited in an autosomal dominant fashion with 50 percent recurrence risk for 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 [28].
The phenotype of ARPKD can also be mimicked by either dominant or recessive mutations 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 [28].
Renal pathology in ARPKD is characterized by nonobstructive dilatation or ectasia of the collecting tubules located in the renal medulla, resulting in microcysts up to 2 mm in diameter. The cysts may expand into the cortex in severe cases. The outer renal cortex remains normal since there are no tubules in this area. The severity of the renal disease is proportional to the percentage of nephrons affected by cysts and is correlated with the severity of the PKHD1 variants [31]. All affected individuals have some degree of liver involvement with biliary dysgenesis and hepatic fibrosis.
ARPKD has been subclassified into perinatal, neonatal, infantile, and juvenile types. Renal involvement is more common in cases with perinatal presentation, whereas liver involvement is more typical of later diagnosis of ARPKD.
The pathogenesis, pathology, and clinical manifestations of ARPKD are discussed 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 diagnosis of ARPKD is likely when there are bilateral, significantly enlarged echogenic kidneys, a small or absent bladder, and oligohydramnios; however, a precise prenatal diagnosis cannot be made with certainty by ultrasound alone.
The sonographic features of ARPKD can initially appear anytime during gestation. Elongated hyperechogenic kidneys with normal transverse and anteroposterior diameters may be the only ultrasound finding before the third trimester [32]. 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 [33]. Due to the large kidney size, the abdominal circumference is larger than expected for menstrual dates.
Late in pregnancy, isolated macroscopic cysts less than 10 mm in size are visible in the renal medulla in one-third of cases. In ARPKD, there are no collecting ducts/tubules in the cortex so the cortex is diffusely hyperechogenic, thus a normal relatively hypoechoic peripheral rim can help in differential diagnosis [33]. Pyramidal hyperechogenicity resembling medullary nephrocalcinosis (calcium deposits) with reversal of corticomedullary differentiation has also been reported [34]. This finding is important since there are very few other causes of reversed corticomedullary differentiation. By comparison, in children and adults, the kidney size 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 [10].
●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. In cases where amniotic fluid volume is preserved, the prognosis is better [33].
●Associated anomalies – Associated liver disease develops in late childhood and is not evident on prenatal ultrasound. This may be important in the differential diagnosis with other syndromes and HNF1B mutation-related cystic kidney disease that can present with elevated liver enzymes.
Genetic studies — Prenatal diagnosis is possible using haplotype analysis or direct mutation analysis on the PKHD1 gene. PKHD1 is a large gene extending over a 500-kilobase genomic segment on chromosome 6p12. Direct mutation analysis has been reported to detect 85 percent of cases [35]. However, a wide range of variants and high frequency of compound heterozygotes make the prediction of phenotype challenging.
At this time, targeted NGS panels including ARPKD-associated genotypes are recommended for a complete differential diagnosis of the ARPKD-related phenotype [36]. Molecular genetic testing is discussed in detail separately. (See "Autosomal recessive polycystic kidney disease in children", section on 'Molecular genetic testing'.)
Obstetric management — Follow-up in pregnancy involves assessment of the kidneys and amniotic fluid volume every two weeks.
Asymptomatic siblings of affected children should be evaluated for hepatic fibrosis and renal lesions. (See "Autosomal recessive polycystic kidney disease in children", section on 'Genetic counseling'.)
Cesarean delivery due to abdominal dystocia for massively enlarged kidneys and delivery at a facility with level IV neonatal intensive care capacity should also be discussed with parents. Given the high perinatal mortality and need for hemodialysis in survivors and renal transplant in the long-term, detailed discussion with parents regarding their preferences for aggressive perinatal treatment should take place.
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, there is a higher likelihood of survival.
Age at diagnosis impacts the age at end-stage kidney disease. In one cohort, 25 percent of patients who were symptomatic at birth or up to day 30 of life required renal replacement therapy by 11 years [37]. 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 renal 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 [38]. Long-term pulmonary function appears to be good in those who did not require mechanical ventilation in the newborn period [39,40]. (See "Autosomal recessive polycystic kidney disease in children", section on 'Outcome'.)
Renal cysts seen with syndromes/sequences — Many syndromes present with hyperechoic cystic kidneys. The distinction between the glomerulocystic, medullary cystic dysplasia, nephronophthisis/medullary cystic dysplasia complex requires examination of renal 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.
Combining the information obtained from a thorough family genetic history and comprehensive sonographic fetal anatomic survey helps to narrow the differential diagnosis:
●ADPKD glomerulocystic type – The cysts in ADPKD are initially isolated and located in the cortex [19]. 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 X-linked recessive, OFD1 is usually lethal for males during gestation and thus predominantly affects females. (See "Etiology, prenatal diagnosis, obstetric management, and recurrence of cleft lip and/or palate", section on 'Syndromic cases'.)
●Short rib-polydactyly syndromes – These 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, shortening of all bones, proportionately small head, 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 – Renal cortical cysts can be seen in 17 percent of the fetuses with trisomy 18. Other renal abnormalities include duplication of the collecting system, horseshoe kidney, and hydronephrosis [41]. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 18 syndrome'.)
●Trisomy 13 – Renal cortical cysts are noted in one-third of fetuses with trisomy 13, and hydronephrosis is seen in 21 percent [41]. (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 magnetic resonance imaging (MRI) may be helpful to identify renal and cortical manifestations [42]. Prevalence is 1:5800, and inheritance is autosomal dominant, but two-thirds of cases result from a de novo variant.
Renal cysts are observed in 14 to 33 percent of TSC patients. The renal cysts are usually single or multiple small lesions and rarely symptomatic. Less commonly, TSC coexists with polycystic kidney disease. In these cases, the renal cysts are multiple, large, and frequently symptomatic in the postnatal period. The TSC2 locus is adjacent to the PKD1 gene leading to presentation of both phenotypes (TSC2/PKD1 contiguous gene syndrome) [43]. (See "Tuberous sclerosis complex: Genetics, clinical features, and diagnosis".)
●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, and renal and hepatic anomalies. Although some patients can live into adolescence or adulthood, it is frequently lethal in infancy. Prevalence is 1:100,000 to 130,000, and inheritance is autosomal recessive. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias".)
●Zellweger syndrome (cerebrohepatorenal syndrome) – Zellweger syndrome is a lethal ciliopathy syndrome and the most severe form of a spectrum of conditions called Zellweger spectrum. It is a part 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 renal cortical cysts, epiphyseal stippling, and neuronal migration defects. It is a rare disorder, with prevalence less than 1:50,000. (See "Peroxisomal disorders", section on 'Zellweger syndrome'.)
●Ivemark II syndrome – Ivemark II syndrome, also referred to as the renal-pancreatic dysplasia sequence, includes polycystic kidneys or renal cortical cysts, enlarged pancreas, pancreatic cysts, liver anomalies, absent or undeveloped spleen, heart anomalies, dilated bile ducts, and dilated pancreatic ducts [44]. This is a rare autosomal recessive syndrome, usually diagnosed by fetopathologic examination.
Medullary cystic dysplasia/nephronophthisis — Medullary cystic dysplasia is characterized by tubular cysts. Nephronophthisis is an autosomal recessive disorder characterized by tubular distention and cysts at the corticomedullary junction, tubulointerstitial nephritis, and glomerulosclerosis. Ten to 20 percent of nephronophthisis cases are syndromic. 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, there are medullary cysts with mottled appearance of medulla and relatively hyperechoic cortex without cysts. In late pregnancy, there is diffuse involvement of the kidney with both medullary and cortical cysts [45]. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Meckel syndrome'.)
●Bardet-Biedl syndrome (BBS) – BBS is an autosomal recessive ciliopathy that displays retinal dystrophy, truncal obesity, polydactyly, cognitive impairment, urogenital anomalies, and renal 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 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 [46]. Prevalence is 1:125,000 to 160,000. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Bardet-Biedl syndrome'.)
●Beckwith-Wiedemann syndrome – Beckwith-Wiedemann syndrome is an overgrowth disorder characterized by macrosomia, macroglossia, visceromegaly, embryonal tumors (eg, Wilms' tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma), omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, and renal abnormalities (eg, medullary dysplasia, nephrocalcinosis, medullary sponge kidney, and nephromegaly). Prenatal findings include macroglossia, macrosomia, omphalocele, hemihyperplasia, enlarged kidneys, renal cysts, polyhydramnios, and enlargement of the placenta and liver. Prevalence is approximately 1:14,000 births. It is an imprinting disorder, which follows a predominantly sporadic inheritance pattern in 85 percent of cases. (See "Beckwith-Wiedemann syndrome".)
●Joubert syndrome – Joubert syndrome is an autosomal recessive ciliopathy characterized by cerebellar vermis hypoplasia (demonstrated by MRI as the molar tooth sign), polydactyly, hypotonia, congenital hepatic fibrosis, developmental delay, retinal dystrophy, ocular coloboma, abnormal eye movements, and renal involvement. Renal findings include cystic renal dysplasia or nephronophthisis (tubulointerstitial nephritis and cysts at the corticomedullary junction) with normal- sized hyperechoic kidneys without corticomedullary differentiation, but with cysts at the corticomedullary junction on ultrasound. (See "Clinical manifestations, diagnosis, and treatment of nephronophthisis", section on 'Joubert syndrome'.)
NONHEREDITARY DISORDERS
Renal dysplasia — 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)".)
Renal dysplasia is a continuum that has many subtypes, ranging from hypoplasia to renal agenesis to massive cystic kidneys, and is the leading etiology of end stage renal disease in children. It is characterized by structural disorganization of the renal tissue, poorly branched/differentiated nephrons and collecting ducts, increased stroma, and, occasionally, cysts and metaplastic tissues, such as cartilage. Renal dysplasia originates from abnormal interaction between the ureteral bud and metanephric blastema.
Dysplastic kidneys may occur randomly or secondary to genetic defects, lower urinary tract obstruction (obstructive dysplasia [ORD]), or teratogen exposure [47]. Approximately 10 percent of affected fetuses have a family history of significant renal/urinary tract malformation. Monogenic causes include variants in individual genes, such as TCF2/hepatocyte nuclear factor-1beta (HNF1B), PAX2, and uroplakins. Compound heterozygote variants in several renal/urinary tract developmental genes have also been reported [47-49].
The TCF2 gene encodes the protein HNF1B, which is involved in early renal 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. Humans who carry HNF1B mutations develop heterogeneous renal abnormalities, including multicystic dysplastic kidneys (MCDK), glomerulocystic kidney disease, renal agenesis, renal hypoplasia, and renal interstitial fibrosis, pyelectasis, and renal cysts. 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 [50], as well as maturity-onset diabetes of the young type 5, genital tract abnormalities, and liver and intestinal abnormalities [51].
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 renal malformations. Uroplakins are cell membrane proteins distributed in the apical surface of the urothelium.
NEK8 variants are associated with severe renal cystic dysplasia [52]. NEK8 is a major gene for renal 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 renal 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 frequently undergoes involution when the cysts shrink from absence of urine production. This leads to a picture similar to renal agenesis. (See "Renal agenesis: Prenatal diagnosis".)
Most cases of MCDK are unilateral [53]. 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 [54], but it is more likely to be associated with syndromes, field defects, neural tube defects, and other anomalies than unilateral MCDK [53].
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 renal 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, nonreniform outline and no visible renal pelvis in early pregnancy, but often there is a decrease in size as pregnancy progresses; the kidneys can become severely shrunken (terminal phase). In severe bilateral cases, the condition can 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 renal 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 [10,55]. Parenchymal tissue between the cysts is often hyperechogenic. MCDK can also occur in horseshoe kidney or in an ectopic kidney [56].
●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 – Renal anomalies (ipsilateral or contralateral) are the most common associated anomalies, most often vesicoureteral reflux and obstruction of the ureteropelvic junction. The most common extrarenal abnormalities are heart defects, esophageal or intestinal atresia, spinal abnormalities, and VATER association. The risk of aneuploidy is reported as high as 14 percent; the majority of these fetuses also have associated extrarenal anomalies and bilateral MCDK [57-59].
Genetic studies — Referral to genetic counseling should be offered, and counseling should include discussion of inherited conditions and amniocentesis for microarray on amniocytes in cases of bilateral and nonisolated MCDK cases [13,57,60]. In one study, the risk of an abnormal karyotype was as low as 4.7 percent; however, the microarray analysis in cases with a normal karyotype revealed pathogenic deletions or duplications in 16.7 percent of the cases, with the majority not having extrarenal structural abnormalities [61]. Aneuploidy is much less common in isolated unilateral MCDK [59].
MCDK has been linked to the HNF1B disease spectrum and associated with other ciliopathies, such as Meckel-Gruber syndrome, although the 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 renal function, infrequent urinary tract infections, and compensatory contralateral renal 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 [62]. 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 "Renal 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 renal insufficiency or failure. The prognosis is poor in bilateral disease with anhydramnios. The option of pregnancy termination should be discussed in these cases.
Obstructive dysplasia or cystic renal 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 renal cysts and/or reduction in size of an initially enlarged kidney with compensatory hypertrophy of the contralateral kidney [10].
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 [10]. (See "Renal cystic diseases in children", section on 'Nonhereditary: Cystic renal 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 RENAL CYSTS
Renal cystic tumors — Renal 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 [10,63]. 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 renal tumor of infancy can also present as multilocular cystic masses; however, most cases have minor nodular solid components associated with the cystic components [64].
Simple renal cysts — Simple renal 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 [65]. 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 renal disease in children and adults. Bilateral polycystic kidneys in a fetus should prompt investigation of the kidneys in the rest of the family. (See 'Autosomal recessive polycystic kidney disease' above and 'Autosomal dominant polycystic kidney disease' above.)
•Fetal cystic kidney disease presents with hyperechogenic kidneys with or without cysts on prenatal ultrasound and warrant a thorough anatomical examination, family history, and genetic counseling and testing, as appropriate. Once nonhereditary dysplastic lesions and renal cystic tumors/cysts are ruled out, autosomal recessive polycystic kidney disease (ARPKD), autosomal dominant polycystic kidney disease (ADPKD), and syndromic origins should be investigated. However, 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 'Ultrasound evaluation of the kidneys and amniotic fluid volume for cystic renal disease' above and 'Diagnostic work-up and differential diagnosis' above.)
•Targeted next-generation sequencing of the relevant genes is preferred for bilateral cystic renal disease including PKHD1, PKD1, PKD2, hepatocyte nuclear factor-1beta (HNF1B), DZIP1L, and others. HNF1B variants are the most common cause for bilateral fetal renal hyperechogenicity and usually present with normal size or slightly enlarged kidneys with normal amniotic fluid volume or polyhydramnios. Cortical or diffuse renal cysts may accompany prenatal presentation. (See 'Diagnostic work-up and differential diagnosis' above.)
●Prenatal diagnosis of ARPKD – The predominant prenatal ultrasound feature of ARPKD is uniform, massive enlargement of the kidneys bilaterally with preservation of the reniform shape and loss of corticomedullary differentiation. The sonographic features can initially appear at any time during gestation, including the third trimester. A hyperechogenic appearance of the kidneys with normal amniotic fluid volume in the first trimester may be an early indication of this disorder. In the second trimester, there is usually massive uniform echogenic enlargement of the kidneys bilaterally associated with oligohydramnios and a small or absent bladder (image 1A-B). Serial ultrasound examinations that confirm progressive enlargement and reduction in amniotic fluid volume help establish the diagnosis. However, hyperechogenicity and elongation of the kidney may be the only ultrasound finding until the third trimester in rare cases. (See 'Fetal findings' above.)
●Prenatal diagnosis of ADPKD – The typical clinical presentation of ADPKD is in the third to fifth decade of life. The kidneys appear normal prenatally in most cases. Rarely, the fetal kidneys appear enlarged and echogenic with a reniform shape and usually increased corticomedullary differentiation. If either parent has ADPKD, the finding of enlarged echogenic kidneys in the fetus strongly suggests the diagnosis. A negative (normal) ultrasound in a fetus at risk provides only limited reassurance of the absence of ADPKD because of the variability in ultrasound findings and late presentation of this disorder. (See 'Fetal findings' above.)
●Prenatal diagnosis of MCDK – Multicystic dysplastic kidney (MCDK) can be unilateral or bilateral and presents with randomly located renal cysts that do not connect. The contralateral kidney has an abnormality in one third of unilateral cases. Extrarenal malformations are noted in 15 to 25 percent of MCDK cases. (See 'Multicystic dysplastic kidney' above.)
●Prenatal diagnosis of obstructive dysplasia – Obstructive dysplasia is secondary to urinary tract obstruction or reflux and presents with hyperechogenic kidneys with or without cysts and a dilated urinary tract. (See 'Obstructive dysplasia or cystic renal dysplasia' above.)
