Polycystic kidneys

In this disorder there are bilaterally enlarged kidneys with increased echogenicity, usually identified after 24 weeks of gestation. The kidneys appear brighter than the fetal liver due to the presence of numerous small cysts (<4mm). The kidney function is usually abnormal, with gradual onset oligohydramnios and non-visualization of the fetal bladder. ARPKD is further classified into prenatal, neonatal, infantile and juvenile forms, depending on the age at presentation.

The estimated incidence of the condition is 1/20.000 - 1/40.000 live births.

Autosomal Recessive Polycystic Kidney Disease occurs due to mutations in one single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), located on chromosome 6. This gene encodes a cell membrane protein called fibrocystin or polyductin, which is believed to be involved in the formation and maintenance of tubular epithelial structures in renal and biliary ducts. Mutations in this gene lead to malformations in renal collecting tubules and formation of cysts, but the exact pathophysiologic mechanism has not been elucidated yet. Histopathology reveals diffuse cystic dilatation of the collecting tubules in the renal medulla, oriented with the long axis perpendicular to the renal capsule. The outer cortex remains normal. There is also biliary dysgenesis and hepatic fibrosis.

There is hepatic fibrosis and biliary duct dysgenesis, but this cannot be usually assessed on prenatal ultrasound. ARPKD is not associated with chromosomal abnormalities or any other genetic syndrome.

Since this is a recessive disease, recurrence rates are about 25%.

In most of the cases the diagnosis is made late in the second trimester or even later in the third trimester. Both kidneys appear to be enlarged (4-15 SDs above the average size) and are hyperechogenic (brighter than the liver) due to the presence of numerous microcysts in the renal parenchyma. The fetal bladder and the renal pelvises cannot be visualized and there is usually severe oligohydramnios. The decrease in amniotic fluid usually starts at about 16 weeks of gestation. During the third trimester, there might be loss of differentiation between the cortex and the medulla. Sometimes, the diagnosis can be supported by the history of affected siblings. It is important to note that in APKRD, apart from the severe anhydramnios and possibly liver fibrosis, there are no other congenital anomalies. Concurrent anatomical malformations in other structures (e.g. brain) imply that the diagnosis might not be ARPKD.

The main condition to be differentiated from is Autosomal Dominant Polycystic Kidney Disease. This is associated with normal amniotic fluid volume and a normal bladder. Contrary to ARPKD, the corticomedullary differentiation is more pronounced. In addition, there will probably be a positive family history, as the disease follows the dominant pattern of inheritance.

A thorough examination is very important in order to assess all fetal organs and exclude other causes associated with renal dysplasia. This includes syndromes such as Meckel Gruber (also polydactyly and encephalocele), Beckwith-Wiedemann (also macroglossia and omphalocele), Bardet-Biedl (also polydactyly and genital anomalies) and Perlman syndrome (also macrosomia, cleft palate, diaphragmatic hernia and cardiac anomalies).

Other conditions that have been associated with renal dysplasia include aneuploidies (trisomies 21, 18, 13), VACTERL association, prenatal renal vein thrombosis and congenital infections.

Short term prognosis mainly depends on amniotic fluid volume. Fetuses affected with the prenatal type (about 40 percent of ARPKD cases) associated with severe oligohydramnios have extremely poor prognosis due to pulmonary hypoplasia and renal failure. Cases with normal amniotic fluid volume will later progress to end-stage renal disease requiring renal transplantation, usually before adulthood. They might also manifest complications related to the liver fibrosis such as portal hypertension and require combined liver kidney transplantation.

When the diagnosis is suspected, genetic testing for mutations in PKHD1 gene can be performed via invasive procedures (CVS if amniocentesis is not feasible). If the diagnosis is confirmed, additional counseling by neonatologists and pediatric nephrologists is necessary to discuss prognosis, postnatal management plan or possibly palliative care. In cases of severe oligohydramnios (prenatal type ARPKD), based on the extremely poor prognosis after birth, termination of pregnancy can be offered to the parents.

If the parents opt to carry on with the pregnancy, follow up every 4 weeks to assess growth and liquor volume is essential. It should be noted that amniotic fluid volume in this instance does not reflect fetal well-being. Delivery should be done in a tertiary hospital with appropriate neonatal intensive care unit, around 38 weeks, aiming for a normal vaginal delivery (e.g. to avoid a caesarean section for a baby with extremely poor prognosis). A caesarean section might be an option in cases of increased fetal abdominal circumference caused by the enlarged kidneys.

There is no prevention available for the condition at the moment. The carrier frequency for a PKHD1 pathogenic variant in the general population has been estimated at 1:70. There are commercially available carrier screening panels which include this specific gene, but universal screening is not currently recommended.

In families with a previously affected child (usually diagnosed postnatally with genetic testing) where both parents are confirmed carriers, invasive testing can be offered in the 1st trimester of a subsequent pregnancy (CVS).

This is a renal anomaly associated prenatally with moderately enlarged hyperechogenic kidneys. The increase in size is not as marked as in ARPKD. While initial nephron development is normal, there are cysts arising from all areas of the nephron, in contrast with ARPKD, where the cortex is spared. There is no oligohydramnios, hence renal pelvises and bladder are visible. ADPKD is generally a late-onset disease and cysts can develop later in childhood or adult life, and prenatal scans can also be normal.

The frequency of the disease is about 1/1000 in the general population.

ADPKD is associated with mutations in the PKD-1 and PKD-2 genes, which encode the production of polycystin-1 and polycystin-2 respectively. These proteins are located in the cilia of renal tubules and are responsible of maintaining normal renal tubular structure and function. The vast majority of cases (85%) are associated with mutations in PKD-1 and about 10% are associated with PKD-2, with the penetrance being nearly 100% throughout a person’s lifespan. There is also a third form of the disease that has been recently identified, caused by mutations in the GANAB gene.

Currently, the prevailing theory for the pathogenesis of the disease is the second-hit theory. PKD-1 and 2 are genes susceptible to new mutations. Patients with 1 copy of the mutated gene during their lifetime develop additionally somatic mutations in the normal allele and cysts arise from renal cells affected by the ‘’second hit’’, hence only a small proportion of the total number of cells in each nephron becomes cystic. Genetic and environmental factors are significant modulators of the clinical expression, therefore severity of the disease varies considerably from patient to patient.

Macrocysts might be visible in the fetal liver or pancreas. Other than that, ADPKD is not associated with extrarenal malformations, genetic syndromes or chromosomal anomalies.

Since this is a dominant condition, recurrence rate is about 50%.

Prenatal diagnosis of ADPKD based on ultrasonography alone is not common, as the disease usually manifests during childhood or even later. When findings are present on the antenatal scan, usually in the third trimester, kidneys appear to have mildly increased size (not as marked as in cases with ARPKD) with accentuated corticomedullary differentiation (significantly brighter renal cortex). The renal pelvises and the fetal bladder are normal, with normal amniotic fluid volume. In many cases there is a positive family history of ADPKD, or there will be renal cysts detectable by ultrasound in one of the parents.

In the majority of cases, where there is a mutation in PKD-1, genetic diagnosis through whole exome sequencing might not provide reliable results due to allelic heterogeneity and homology of the gene with six pseudogenes. This does not affect cases where there is a mutation in PKD-2 and GANAB genes.

It should also be noted that presence of normal kidneys in a fetus of an affected parent does not exclude the possibility of becoming symptomatic later in life.

The main condition to be differentiated from is Autosomal Recessive Kidney Disease. This is associated with severely reduced amniotic fluid volume and non-visible bladder. Contrary to ADPKD, the corticomedullary differentiation is reduced and there might be a hypoechogenic outer cortex rim.

A thorough examination is very important in order to assess all fetal organs and exclude other causes associated with cystic kidney dysplasia. This includes syndromes such as Meckel Gruber (also polydactyly and encephalocele), Beckwith-Wiedemann (also macroglossia and omphalocele), Bardet-Biedl (also polydactyly and genital anomalies) and Perlman (also macrosomia, cleft palate, diaphragmatic hernia and cardiac anomalies) syndrome.

Other conditions that have been associated with renal dysplasia include aneuploidies (trisomies 21, 18, 13), VACTERL association, prenatal renal vein thrombosis and congenital infections.

Compared to ARPKD prognosis is favourable. Complications of ADPKD in childhood include hypertension and proteinuria, and patients will probably require renal replacement therapy at some point during adult life.

Taking into account that the disease manifests later in life, it should be noted that current prognosis is based on patients born many decades ago. Early diagnosis and treatment with novel therapies might delay the onset of renal failure and hypertension related complications, and patients born today might have a better prognosis.

When the diseased is suspected or confirmed during pregnancy, ultrasound scans for assessment of renal anatomy and amniotic fluid volume should be performed every 4 weeks until delivery. It is essential to offer a kidney ultrasound scan to both parents and siblings. If the expectant mother is found to have ADPKD (as she might still be undiagnosed by that time), nephrological workup and close monitoring is indicated for early identification of potential obstetric complications (e.g. hypertension, preeclampsia).

There is no prevention available for the condition at the moment. As mentioned already early diagnosis and treatment with novel therapies might delay the onset of renal failure and hypertension related complications, and patients born today might have a better prognosis.