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

Kidney Int. 2005 Mar;67(3):829-48. doi: 10.1111/j.1523-1755.2005.00148.x.


Background: ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived.

Methods: We examined the clinical course of 164 neonatal survivors (126 unrelated families) over a mean observation period of 6 years (range 0 to 35 years). PKHD1 mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) for the 66 exons encoding the 4074 aa fibrocystin/polyductin protein.

Results and conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Female
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mutation*
  • Phenotype
  • Polycystic Kidney, Autosomal Recessive / genetics*
  • Polymorphism, Genetic
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics*


  • PKHD1 protein, human
  • Receptors, Cell Surface