Autosomal Recessive Polycystic Kidney Disease (ARPKD) is the rare pediatric form of polycystic kidney disease. It has a tremendous and early impact on child health e.g. frequently requiring breathing assistance within the first year of life. Kidneys are often grossly enlarged at birth and there is mandatory hepatic involvement. ARPKD occurs with an estimated incidence of 1:20.000. Still, ARPKD is responsible for a significant number of patients with cystic kidneys in pediatric centers. There is major unexplained phenotypic variability. ARPKD is caused by mutations in a single gene, PKHD1. PKHD1 encodes a huge transmembrane protein called Fibrocystin (FC).

The pathophysiology, clinical heterogeneity and long-term evolution of the disorder remain poorly understood, explaining why treatment currently continues to be mostly symptomatic and opinion-based. Even in most-advanced medical centers mortality remains high, mainly related to pulmonary problems. Kidney dysfunction is progressive frequently leading to early and severe chronic kidney disease, and a need for dialysis and kidney transplantation within the first two decades of life. In addition, severe liver fibrosis and portal hypertension develop in a major fraction of patients. Combined liver and kidney transplantation may be required. However, even the assessment of the clinical severity and prognosis of renal function and hepatic fibrosis is challenging. Clear-cut reliable predictors are missing. Severe and very early arterial hypertension is common and treatment often remains challenging. There is currently no consensus on clinical, histological or biochemical characteristics that would predict a severe, rapidly progressive course of disease and therapeutic experience remains sparse even in large pediatric centers. One example is that ARPKD is a main underlying condition of combined kidney-and-liver transplantation in children, but outcome data are currently very scarce. There is also no in-depth understanding of the genetic mechanisms underlying the observed phenotypic variability of ARPKD. Therapeutic initiatives for ARPKD are facing the challenge of small and clinically variable cohorts for which specific primary end points for ARPKD need to be established. Hence there is an urgent need for novel, reliable clinical and biochemical markers predicting clinical courses.

On a cellular level FC localizes to primary cilia of renal tubular cells, classifying ARPKD as a ciliopathy. Ciliary localization depends on a specific ciliary targeting motif in the cytoplasmic tail of FC. However, little is known about the cellular function of the protein. Recent evidence suggests a common role with the protein affected in the more frequent autosomal dominant polycystic kidney disease (ADPKD) in the regulation of intracellular signaling cascades.