Natural History of Autosomal Recessive Polycystic Kidney Disease/Congenital Hepatic Fibrosis (ARPKD/CHF). M. Gunay-Aygun¹, E. Font-Montgomery¹, P. Choyke², L. Guay-Woodford³, T. Heller⁴, R. Kleta¹, P. Mohan⁵, Z. Quezado⁶, W. Gahl¹. 1) NIH, NHGRI, MGB, Bethesda, MD; 2) NCI; 3) University of Alabama, Birmingham AL; 4) NIDDK; 5) CNMC, Washington, DC; 6) NIH Clinical Center.
   ARPKD/CHF is a developmental disorder of the kidneys and liver caused by mutations in the PKHD1 gene. The kidney cysts in ARPKD are non-obstructive dilatations of the collecting ducts. CHF, an invariable part of ARPKD, results from malformation of the developing ductal plate. Approximately 30-50 percent of ARPKD patients present perinatally with enlarged kidneys. Although severely affected neonates die in infancy, survival has dramatically increased because of wide availability of prenatal ultrasound and improved neonatal care. In most patients both kidney and liver disease are progressive, with variable rates of deterioration. More than half of the patients require renal transplantation before 20 years of age. Portal hypertension, the major clinical problem associated with CHF, causes hypersplenism and esophageal varices. A subset of patients also exhibit cystic dilatation of the medium sized and larger intrahepatic bile ducts (Carolis syndrome). Hypertension, renal insufficiency, bleeding from esophageal varices, and recurrent cholangitis are the major sources of morbidity; only symptomatic therapy is available. The natural history of ARPKD has not been elucidated in a detailed, longitudinal fashion. To date, we have evaluated 55 patients through an ongoing natural history study of ARPKD/CHF (www.clinicaltrials.gov, trial NCT00068224). Here we present data on 35 typical ARPKD/CHF patients, based on clinical and/or molecular data. Significant findings include normal urinary protein, glucose and calcium excretion, largely intact proximal tubule function, mildly impaired distal tubule function, normal plasma norepinephrine, mildly elevated serum ammonia, and small cystic dilatations of the peripheral intrahepatic bile ducts in the face of normally sized central ducts. We continue to produce comprehensive longitudinal data on ARPKD/CHF to provide the groundwork for more focused studies and future therapeutic interventions.