Autosomal Recessive Polycystic Kidney Disease – PKHD1

Clinical characteristics: Autosomal recessive polycystic kidney disease – PKHD1 (ARPKD-PKHD1) is characterized by primary involvement of the kidneys and liver with mostly secondary effects seen in other organ systems. Of the three ages of initial presentation of kidney disease, the two most common are perinatal (i.e., prenatal/neonatal) and infantile (four weeks to age one year) with the classic finding of enlarged kidneys. The major difference between the perinatal and infantile presentations, which typically have similar kidney and liver findings, is the frequent occurrence of pulmonary involvement in the perinatal presentation, which is a major cause of morbidity and mortality in neonates. The less common initial presentation in childhood (after age one year) to young adulthood can be associated with predominant hepatobiliary manifestations characterized by the clinical consequences of developmental anomalies of biliary ductal plate remodeling (also known as Caroli disease). Although the short-term and long-term mortality rates of ARPKD remain significant, the survival of individuals with ARPKD has improved with modern neonatal respiratory support, kidney replacement therapy (KRT) including dialysis and kidney transplantation (KTx), and liver transplantation (LTx) or combined liver and kidney transplantation (CLKTx).

Diagnosis/testing: The molecular diagnosis of ARPKD-PKHD1 is established in a proband with suggestive findings and biallelic pathogenic variants in PKHD1 identified by molecular genetic testing.

Management: Treatment of manifestations: Multidisciplinary care including (1) kidney disease and nutrition specialists to ensure optimal metabolic control and growth and timely institution of KRT; (2) hepatobiliary disease specialists to assure timely management of complications (that can include ascending cholangitis, cholestasis, and portal hypertension) and LTx/CLKTx; and (3) psychologists and social workers for ongoing family support.

Surveillance: Regularly scheduled follow up as specified by the treating multidisciplinary specialists.

Agents/circumstances to avoid: High-salt diet, smoking, obesity, and sympathomimetic agents (especially individuals who have hypertension). Minimizing use of known nephrotoxic agents including nonsteroidal anti-inflammatory drugs (NSAIDs) and aminoglycosides (unless otherwise advised) and of potentially hepatotoxic agents (e.g., acetaminophen doses >30 mg/kg/day, herbal supplements, and alcohol) is advised.

Evaluation of relatives at risk: Early screening and genetic testing of apparently asymptomatic at-risk sibs can be considered with the goal of identifying those who may benefit from additional examinations and potentially preventive measures. Ultrasonography of the parents of children with ARPKD-PKHD1 is warranted (1) to confirm the clinical diagnosis and (2) because individuals heterozygous for a PKHD1 pathogenic variant may, in rare instances, have very mild cystic kidney manifestations or, more frequently, liver cysts.

Genetic counseling: ARPKD-PKHD1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PKHD1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of being unaffected and not a carrier. Heterozygotes for a PKHD1 pathogenic variant are not at risk of developing ARPKD-PKHD1; however, hyperechogenicity in the kidneys with mild kidney cysts as well as hepatic cysts have been described in individuals with monoallelic PKHD1 pathogenic variants. Once the PKHD1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal testing and preimplantation genetic testing are possible.