Polycystic kidney disease (PKD)

ADPKD

Renal manifestations include progressive cyst formation throughout the nephron and collecting ducts and bilateral kidney enlargement. Patients frequently exhibit extrarenal manifestations. Liver cysts are present in more than 90% of patients older than 35 years. Symptomatic polycystic liver disease affects approximately 20% of patients and may cause pain, early satiety, gastro-oesophageal reflux and, in rare most severe cases, portal hypertension with ascites and pleural effusion.

The prevalence of intracranial aneurysms is four times higher than in the general population, ranging from 9% to 12%. In patients with a positive family history of intracranial aneurysms, prevalence is approximately 22%, compared with 6% in those without such history. Other extrarenal manifestations include pancreatic cysts (8% of cases), hernias and valvular heart disease.

ARPKD

The classic phenotype is characterised by early onset with bilateral renal enlargement and impairment of renal function, congenital liver fibrosis with development of portal hypertension and dilatation of the bile ducts with risk of ascending cholangitis. Gastrointestinal varices are detected in 15–37% of patients.

ARPKD is typically detected in utero or at birth. In the most severe cases, it includes Potter sequence, low amniotic fluid levels, pulmonary hypoplasia and bilaterally enlarged echogenic kidneys. Kidney involvement usually occurs early in childhood, whereas liver involvement tends to appear later.

ARPKD is generally associated with shortened life expectancy. A mortality rate of 30–40% has been described in cases of neonatal respiratory difficulties, and about 50% of patients who survive the neonatal period develop terminal renal failure within the first decade of life. Despite the classic neonatal presentation, there is significant variability in age at onset and clinical symptoms, including within families.

ADPKD has a prevalence of approximately 1:2,000–2,500 in Europe. ARPKD occurs in approximately 1:20,000 live births.

ADPKD

The primary molecular causes are pathogenic variants in PKD1 (78% of cases) and PKD2 (15% of cases). PKD1 comprises 46 exons, with exons 1–32 proximally located on chromosome 16 in six duplicated pseudogene copies, while PKD2 comprises 15 exons. All classes of pathogenic variants have been identified, with genomic deletions being relatively rare (approximately 4% for PKD1 and less than 1% for PKD2), except in the TSC2/PKD1 contiguous gene syndrome, where large deletions involve both genes and are associated with early renal cyst manifestation and clinical features of tuberous sclerosis. Rare causes include pathogenic variants in GANAB (approximately 0.3%) and DNAJB11 (approximately 1.2%), as well as variants in HNF1B, which can lead to an ADPKD-like phenotype. Currently, 7–10% of affected families remain genetically unresolved, and up to 25% of patients have no positive family history, with approximately 15–20% explained by de novo variants.

Carriers of pathogenic variants in PKD1 typically show earlier disease manifestation and develop renal failure on average 20 years earlier than carriers of PKD2 variants (approximately 58 versus 79 years). Non–protein-truncating PKD1 variants are associated with a milder clinical course compared with protein-truncating variants. In fewer than 1% of families with very early disease onset, biallelic inheritance has been reported. Rare cases of digenic inheritance involving PKD1 and PKD2 or PKD1 and HNF1B have also been described and are associated with more severe disease.

The gene products polycystin-1 and polycystin-2 are transmembrane glycoproteins located in the primary cilia of renal epithelial cells and interact via their cytoplasmic C-termini. Cyst development follows a two-hit model with loss of heterozygosity and functional inactivation of both proteins. GANAB encodes the alpha subunit of glucosidase II, while PRKCSH encodes the beta subunit; both are involved in N-linked glycosylation in the endoplasmic reticulum. The product of DNAJB11 is a co-factor of BiP (HSPA5/GRP78). These genes are thought to impair folding, maturation and transport of membrane or secretory proteins in the endoplasmic reticulum, resulting in cyst formation.

ARPKD

The most frequent molecular cause is pathogenic variants in PKHD1. The heterozygote frequency in the Caucasian population is approximately 1:70. In 13–20% of cases, no causative PKHD1 variants are identified by sequencing. Genomic deletions or duplications are rare. Rarely, pathogenic variants in DZIP1L are identified. Variants in other genes, often belonging to ciliopathies, can result in ARPKD-like genotypes. Very early-onset forms of ADPKD or HNF1B-associated nephropathies are considered phenocopies.

ADPKD follows an autosomal dominant inheritance pattern. Up to 25% of patients have no positive family history, and approximately 15–20% of cases arise from de novo variants. Rare biallelic or digenic inheritance has been described.

ARPKD follows an autosomal recessive inheritance pattern. A single heterozygous PKHD1 variant is a relatively common incidental finding and does not necessarily imply a second undetected pathogenic variant.

Diagnosis of ADPKD is based on clinical presentation and imaging findings of bilateral polycystic kidneys and extrarenal manifestations. Molecular genetic testing can identify pathogenic variants in PKD1, PKD2 and other associated genes. Screening for intracranial aneurysms by magnetic resonance angiography is recommended for patients with a conspicuous family history or high-risk occupations.

Diagnosis of ARPKD is based on clinical presentation, imaging findings of enlarged echogenic kidneys and hepatic involvement, and molecular genetic testing. Sequencing of PKHD1 is the primary diagnostic approach, with consideration of other genes such as DZIP1L.

In ADPKD, differential diagnoses include very early-onset forms of ARPKD and HNF1B-associated nephropathies.

In ARPKD, differential diagnoses include very early-onset ADPKD, HNF1B-associated nephropathies, and other ciliopathies presenting with similar renal and hepatic features.

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