Renal anomalies are detected in 10%–20% of prenatal ultrasounds (1). These anomalies are most commonly described as bilateral enlarged and/or hyperechogenic kidneys and can be clustered into three major groups. The first comprises the inherited hepatorenal fibrocystic diseases (HRFD), a set of monogenic disorders characterized by fibrocystic abnormalities of the kidney and dysgenesis of the porto-biliary tract. These disorders involve mutations in genes encoding proteins that function in the primary cilium or centrosome, and thus HRFDs are considered a renal subset of the larger group of ciliopathy disorders (2). In childhood, the polycystic kidney diseases, e.g., autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD), are the most common renal ciliopathies or HRFDs, followed by nephronophthisis (NPHP), Joubert syndrome (JBTS), Meckel-Gruber syndrome (MKS), and Bardet-Biedl syndrome (BBS) (2). The second group encompasses the congenital anomalies of the kidney and urinary tract (CAKUT) spectrum of disorders, which can present as renal hypoplasia, ureteropelvic junction obstruction (UPJO), primary megaureter, vesicoureteral reflux (VUR), ureterovesical junction obstruction (UVJO), or posterior urethral valves (PUV), with or without associated renal cystic disease (3, 4). The final group involves patients with chromosomal or syndromic disorders. Clinical presentation in all groups can vary from mild to severe with anhydramnios and pulmonary hypoplasia causing significant perinatal mortality (5). From a sonographic imaging perspective, these diverse set of disorders often mimic or phenocopy one another.

Taken as a whole, renal cystic diseases are a common cause of pediatric end-stage kidney disease (ESKD), with an overall incidence of approximately 4 cases per 10,000 births (6). Among the HRFDs, ADPKD can present in the perinatal period, over the course of childhood, or in young adulthood, and is caused primarily by mutations in two genes, PKD1 (78% of cases) and PKD2 (15% of cases), with the remaining 5%–10% of cases due to rare mutations in other loci (7). In comparison, ARPKD is less frequent, with an incidence of 1 in 26,500 live births (8). It is caused primarily by mutations in the PKHD1 gene (9). In its most severe antenatal presentation, ARPKD is characterized by bilaterally enlarged echogenic kidneys and oligohydramnios, with 21% perinatal mortality due to pulmonary hypoplasia (8, 10). Surviving patients typically reach adulthood, due to medical advances in childhood kidney replacement therapy (KRT) and kidney transplantation (11). The rarer forms of HRFDs, such as NPHP, JBTS, MKS, and BBS, are characterized not only by renal cystic disease, but can involve diverse extra-renal features including polydactyly, occipital encephalocele, hepatic fibrosis, obesity, and retinal degeneration.

CAKUT represents a diverse group of structural malformations originating from a failure at any point during the embryonic development of the kidney and urinary tract. It is the main cause of ESKD in childhood (∼40%) with an incidence of 3–6 affected children per 1,000 births (12). Clinical presentation can vary from isolated renal anomalies to syndromic phenotypes. Familial clustering has been observed. More than 50 genes have been implicated in CAKUT. The most common mutations involve 12 genes, e.g., BMP7, CDC5l, CHD1l, EYA1, GATA3, HNF1B, PAX2, RET, ROBO2, SALL1, SIX2, and SIX5 (13). However, single-gene mutations only explain 10% to 20% of the CAKUT cases (14). In addition, copy number variants (CNVs), i.e., duplications or deletions of genomic segments, underlie 5%–10% of CAKUT cases. A recent high-density SNP array analysis involving almost 3,000 patients with CAKUT and more than 21,000 control individuals identified numerous disease-associated CNVs (45 at 37 loci), consistent with the known genetic heterogeneity of CAKUT. Notably, in the majority of patients (65%) CNVs were detected in 6 loci (1q21, 4p16.1–p16.3, 16p11.2, 16p11.3, 17q12, 22q11.2), suggesting that these are critical regions in the development of kidney and urinary tract (15).

In this retrospective study, we reviewed 11-years of data from our Prenatal Pediatrics Institute program and identified all cases of prenatally detected echogenic and/or enlarged kidney with or without cysts. We compiled the clinical and imaging data with available genetic testing results and post-natal management plans. This single center study demonstrates that for infants with bilateral renal cystic disease there is often a gap in transition planning from prenatal diagnosis to postnatal specialty management.

This was a retrospective observational study for an 11-year period from January of 2012 to December of 2022. Pregnant mothers were referred to the Prenatal Pediatrics Institute by their primary providers for evaluation of oligo- or anhydramnios, and/or urogenital, cardiac, or CNS malformations on screening sonography. Evaluation included detailed obstetric ultrasound as well as fetal echocardiography and fetal MRI with fetal brain MRI, when indicated.

We reviewed the Prenatal Pediatrics Institute databases to identify fetuses diagnosed with genito-urinary (GU) tract abnormalities at the initial evaluation and then used the search terms of polycystic kidney disease, renal cyst, enlarged kidney, and echogenic kidney to identify a subset of fetuses with various forms of kidney cysts (n = 105). Spot review of individual patient charts revealed that a number of patients had both renal cystic disease and GU tract anomalies. Therefore, we conducted a further detailed review using the inclusion criteria of enlarged and/or echogenic kidneys with or without cysts to capture the subset of patients with bilateral renal cystic disease as their predominant anomaly (n = 72).

For each of these 72 fetuses and their mothers, clinical, imaging, and genetic information was extracted from the Prenatal Pediatrics Institute databases, as well as the maternal medical records, and captured in a structured REDCap-based Database. The data elements included: demographics (sex and race), maternal information (age, history of diabetes and/or obesity), imaging findings (enlarged/echogenic kidneys with or without cystic changes, cysts size, major extrarenal anomalies including cardiac, skeletal, gastrointestinal, and CNS), perinatal outcomes of affected fetuses [survival rate, admission to the neonatal intensive care unit (NICU), need for ventilatory support], genetic evaluation platforms (karyotype, FISH, microarray, personalized sequencing panel, exome sequencing) and nephrology follow up. The data were analyzed using descriptive statistics. The Institutional Board Review (IRB) of Children's National Hospital approved the study (ID: Pro00016398).

Over the 11-years covered in this retrospective observational study, our Prenatal Pediatric Institute received >7,500 pregnancy referrals. As would be expected for a referral center, a fetal anomaly was detected in the overwhelming majority of cases (88%). On average, GU tract abnormalities were identified in 17% of these fetuses, with the majority (91%) having non-renal GU anomalies and only 105 (9%) having some form of kidney cysts. Among this later subset, 72/105 (69%) had bilateral renal cystic disease.

Detailed chart review revealed that only 17/72 (24%) fetuses had a suspected renal ciliopathy, with genetic resolution in 13 (76%). Among these 13 patients, the most frequent diagnosis was ARPKD (30%), followed by ADPKD and HNF1B-related disease, both well-known ARPKD phenocopy disorders (18). Other diagnoses included Meckel-Gruber (MKS) and Bardet-Biedl (BBS) syndrome, both multi-system ciliopathies.

ARPKD is the prototype of the hepato-renal fibrocystic diseases (19) with mutations in the PKHD1 gene accounting for >98% of cases (20). A recent electronic health record-based analysis estimated that 21% of affected infants died in the immediate perinatal period due to the consequences of their associated pulmonary hypoplasia (8). In the current study, all 4 infants with ARPKD had the classic sonographic features of enlarged, hyperechoic kidneys. Of note, all the three that suffered perinatal demise had anhydramnios and cardiac abnormalities, e.g., pericardial effusion (n = 2); thickened myocardium (n = 1), raising the question of whether cardiac dysfunction contributed to their demise. While the association of ARPKD and cardiac impairment is not well described, a recent single center study demonstrated that children with ARPKD have significant prevalence of subclinical left ventricular hypertrophy, abnormal cardiac remodeling, and systolic mechano-dysfunction (21). However, this study was conducted in post-natal survivors across a broad age range (0–18 years). It remains to be determined whether subclinical cardiac dysfunction is prevalent in fetuses with ARPKD and whether it is an under-appreciated contributor to perinatal demise.

Among neonates presenting with enlarged, echogenic kidneys, mutations in the ADPKD genes, PKD1 and less frequent PKD2, are detected almost as frequently as PKHD1 mutations. These mutations may be vertically transmitted, arise de novo, or less commonly, affect both alleles in a recessive mode (22). This genetic epidemiology is consistent with our ADPKD cohort where single allele PKD1 mutations were identified in both cases. These infants had enlarged, echogenic kidneys without gross cysts and normal amniotic fluid indices.

Mutations in HNF1B cause a pleotropic set of GU anomalies, including CAKUT and various forms of renal cystic disease (e.g., hyperechogenic kidneys (phenocopying ARPKD), multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, and hyperuricemic tubulointerstitial nephropathy (23–25). In our cohort, both fetuses had enlarged echogenic kidneys and one had polyhydramnios, an association that has been reported previously (26).

MKS is an autosomal recessive multisystem ciliopathy, that is usually lethal in the neonatal period. Most patients have pathogenic variants in the MKS1, TMEM216, and TMEM67 genes (27), though more than 14 loci have been identified. This syndrome is characterized by a classic combination of occipital encephalocele, large polycystic kidneys, hepatic fibrosis, and postaxial polydactyly (27). Both fetuses in our cohort had enlarged echogenic kidneys, but an otherwise incomplete phenotype with polydactyly in one and an occipital encephalocele in the other. One pregnancy was carried to term and resulted in perinatal demise, in part due to hypoplastic left heart syndrome, a known MKS extra-renal anomaly (28).

BBS is also an autosomal recessive multisystem ciliopathy caused by mutations in more than 22 genes, the most disease-associated genes being BBS1, BBS10, and BBS2 (29). Renal manifestations range from enlarged, echogenic kidneys with reduced cortico-medullary differentiation to a variety of CAKUT phenotypes, including duplex, ectopic or horseshoe kidney, or renal agenesis. In addition to polydactyly, extra-renal manifestations include retinal degeneration, obesity, intellectual impairment, and hypogonadism (27), which are typically not expressed in infancy, causing delay in the median age of clinical diagnosis to 9 years (30).

It is interesting to consider our single center data in the context of a recent report from Germany that analyzed 98 fetuses with bilateral polycystic kidney disease identified from the 20-year experience of referral centers in Bonn and Cologne (31). In this study, 90/98 (92%) fetuses had a genetically confirmed renal ciliopathy, whereas our study identified 72 fetuses with bilateral renal cystic disease from an 11-year experience, of which only 17/72 (24%) had a suspected renal ciliopathy, with genetic conformation in 13 (76%). The differences between these two contemporaneous studies are striking. Both were retrospective observational studies. In both cohorts, detailed fetal imaging and genetic evaluation were performed and the distribution of confirmed renal ciliopathies were comparable. It is possible that the total number of referred pregnancies in the German study were significantly higher than our study, given that the experience was twice as long and two large centers were involved. In addition, while the German study specifically focused on fetuses with isolated bilateral polycystic kidney disease, our study was more permissive, excluding CAKUT, chromosomal abnormalities, and syndromic disorders only in the final analysis of the suspected renal ciliopathy cohort.

Our study had as a second goal the systematic analysis of longitudinal post-natal follow-up for patients with bilateral renal cystic disease, including those with confirmed renal ciliopathies. Our analysis reveals that while 11/13 (85%) neonatal survivors with renal ciliopathies were referred for post-natal management to either our center's Inherited Renal Diseases Program or the General Nephrology clinic, nephrology care was much more limited for patients with bilateral renal cystic disease in the context of CAKUT (50%), chromosomal disorders (33%), or syndromes (17%). Only 2/6 patients with genetically-unresolved enlarged, echogenic kidneys at birth had documented post-natal nephrology follow-up.

Therefore, this single center study makes clear the need for a structure management plan as fetuses with renal cystic disease transition to post-natal life. Such a detailed framework for prenatal evaluation, delivery, and post-natal management of cystic renal disease was recently proposed by the European Network for Early Onset Cystic Kidney Disease (NEOCYST) consortium (32). Widespread implementation of these guidelines, similar to the model widely embraced for congenital heart disease (33, 34) would streamline and optimize the management of these neonatal survivors.