Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD)

Abstract

This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.

Hereditary polycystic kidney disease: genetic diagnosis and counseling

“…In some families, the disease has a different progression among affected siblings and molecular test can determine if a brother with mild signs is affected or not (C). 8,15 Since a high percentage of individuals affected with ARPKD survive until (and throughout) adolescence, molecular tests allow to identify them prior to onset of symptoms. In these individuals, the verification of the effects of hypertension and portal hypertension enables treatment, prolonging life (C).…”

Transcriptional Complexity in Autosomal Recessive Polycystic Kidney Disease

“…Patients were chosen for analysis if they showed typical clinical and/or histologic features of ARPKD as previously described in detail (2,5,8). We performed PKHD1 mutation analysis in a large cohort of .500 patients with polycystic kidney disease phenotypes using conventional Sanger sequencing or a targeted next-generation sequencing approach.…”

“…About one half of patients with ARPKD die shortly after birth from respiratory insufficiency due to pulmonary hypoplasia and thoracic compression by the excessively enlarged kidneys. Although ARPKD clearly represents a pediatric disorder, adult patients have also been described with a relatively mild clinical course (4,5). Patients with ARPKD invariably exhibit histologic liver involvement characterized by defective remodeling of the ductal plate with congenital hepatic fibrosis and biliary duct ectasia (so-called ductal plate malformation).…”

“…To date, .700 different PKHD1 mutations are known (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). The longest open reading frame of PKHD1 comprises 66 exons and encodes a single-transmembrane protein, called polyductin/fibrocystin, which is mainly expressed in the kidney and liver/cholangiocytes (6,7,19).…”

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference

“…[1][2][3][4][5] Fibrocystin/polyductin, the protein encoded by PKHD1, is expressed on the primary cilia of renal and bile duct epithelial cells and is believed to function to maintain the 3-dimensional tubular architecture. 6 Kidney cysts in ARPKD are nonobstructive dilations of the collecting ducts.…”