ARPKD arises from biallelic pathogenic variants inherited in an autosomal recessive pattern, meaning two pathogenic copies of the disease-associated gene — one from each parent — are required for disease expression. Carriers of a single pathogenic variant generally do not develop the condition, though isolated renal findings have been rarely observed in carriers. The underlying pathogenic process involves abnormal renal collecting duct development and defective biliary ductal plate remodeling. Genotype-phenotype correlations have been documented: individuals with two truncating variants tend toward the most severe phenotypes, including the highest rates of early kidney failure and perinatal demise, while individuals carrying at least one missense variant generally follow a milder clinical course, though significant clinical variability exists within all genotypic categories.

Diagnosis of ARPKD relies on age-specific clinical, ultrasonographic, and molecular criteria. Prenatal ultrasonography may reveal enlarged, hyperechogenic kidneys with reduced corticomedullary differentiation and a characteristic salt-and-pepper appearance; oligohydramnios or anhydramnios signals severe kidney involvement. In neonates and infants, bilateral nephromegaly with the described sonographic pattern, combined with hepatic findings such as hepatomegaly, dilated bile ducts, or periportal fibrosis, is characteristic. Magnetic resonance cholangiopancreatography (MRCP) provides detailed characterization of biliary ductal anatomy and has largely replaced liver biopsy for assessing biliary involvement. Molecular genetic testing confirms the diagnosis. Kidney biopsy is not indicated for establishing the ARPKD diagnosis.

Differential diagnosis encompasses autosomal dominant polycystic kidney disease — which can present in the perinatal period and closely resemble ARPKD — as well as other congenital hepatorenal fibrocystic syndromes and phenocopies caused by variants in other genes. Consensus expert recommendations for the clinical diagnosis of ARPKD were published in 2014.

No curative therapy for ARPKD exists. Supportive care directed at stabilizing organ function and reducing complications forms the basis of management, ideally delivered through interdisciplinary teams encompassing pediatric nephrology, hepatology, pulmonology, and nutritional support specialists.

In the perinatal and infantile periods, initial management focuses on stabilization of pulmonary and kidney function. Respiratory support — ranging from non-invasive modalities to invasive ventilation and, in selected cases, extracorporal membrane oxygenation — addresses pulmonary hypoplasia. Peritoneal dialysis is the most commonly employed modality for neonatal kidney failure; kidney transplantation is available for individuals progressing to kidney failure. Aggressive nutritional support in the first two years of life has been documented to improve growth rates even in the context of significant organ dysfunction.

Hepatic complications including portal hypertension are managed using established approaches for congenital hepatic fibrosis. Surgical interventions, including nephrectomy in carefully selected cases of critically ill neonates, have been employed, though the supporting evidence base is limited.

A Phase 3 clinical trial of tolvaptan in infants and children with ARPKD (NCT04782258), sponsored by Otsuka Pharmaceutical Development and Commercialization, is actively recruiting with an anticipated completion date of August 2028.

Prognosis in ARPKD varies substantially by age at presentation and underlying genotype. Perinatal presentation associated with biallelic truncating variants carries the highest risk of early mortality from pulmonary complications or kidney failure. Among individuals surviving the neonatal period, published 15-year survival rates free of kidney replacement therapy range from approximately 34% for those with biallelic truncating variants to 64–82% for those with at least one missense variant. Fifteen-year rates free of clinical signs of portal hypertension range from approximately 36–51% depending on genotype. Kidney function can improve in the first months of life even among severely affected neonates. Among individuals with childhood or young adulthood presentations, the disease course may be dominated by hepatobiliary manifestations rather than kidney failure. Long-term pulmonary function is generally favorable in individuals who did not require mechanical ventilation in the newborn period.

Active investigational efforts span observational registries, natural history studies, imaging research, and therapeutic trials. The ARPKD Database Study (NCT01401998), coordinated through the Children's Hospital of Philadelphia, is an ongoing long-term registry with enrollment anticipated through 2030. The National Registry of Rare Kidney Diseases (NCT06065852), coordinated by the UK Kidney Association, enrolls individuals with rare kidney disorders including ARPKD with enrollment extending through 2039. An imaging study coordinated by The Cleveland Clinic (NCT07201025) is evaluating methods to assess kidney disease progression, with anticipated enrollment through 2029.

A Phase 3 safety and tolerability trial of tolvaptan (NCT04782258) sponsored by Otsuka Pharmaceutical is actively recruiting infants and children through 2028. Preclinical studies of a multikinase inhibitor, tesevatinib, have demonstrated promise in animal models of ARPKD, with Phase 1/2 multicenter clinical trial results pending publication. Published research output encompasses 111 classified publications including gene therapy, biomarker, and clinical trial-related work, with case reports (35) and reviews (12) forming substantial portions of the literature.