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autosomal dominant polycystic kidney disease

Tuesday 13 April 2004

Digital cases (Digital slides)

- HPC4 : autosomal dominant polycystic kidney disease (ADPKD)
- UI:763 : autosomal dominant polycystic kidney disease (ADPKD)

Definition: Autosomal dominant polycystic kidney disease. ADPKD is the most frequent lethal dominant disease in humans, with a prevalence of 1 in 1,000.

Synopsis

- ADPKD in adults
- fetal ADPKD and neonatal ADPKD

  • normal to enlarged kidneys
  • round renal cysts
    • from microscopic to 3cm
    • unilateral or bilateral cysts
    • renal cortical cysts or renal medullary cysts
  • from any part of the nephron

Etiology

- mutations in PKD1 encoding the transmembrane protein polycystin-1 (PC1)
- mutations in PKD2 encoding the transmembrane proteins polycystin-2 (PC2)

Pathogenesis

- Mutations in the polycystic kidney disease genes PKD1 and PKD2 cause autosomal dominant polycystic kidney disease (ADPKD). The PKD1 and PKD2 proteins, polycystin-1 and polyctin-2, interact physically and function as mechanosensors of extracellular fluid flow in the primary cilia of the renal epithelium that regulates intracellular Ca2+ flux.

- Two genes, PKD1 and PKD2, which have been implicated in ADPKD, encode polycystin-1 (PKD1) and polycystin-2 (PKD2): two proteins that have a role in the maintenance of renal tubular cell differentiation.

- A ’two-hit’ model has been proposed for the pathogenesis of ADPKD21. It states that a germline mutation in PKD1 or PKD2 segregates within a kindred in an autosomal dominant fashion. A renal cyst arises only if the other PKD allele undergoes a somatic spontaneous mutation (second hit), as has been described for tumour suppressor genes such as the retinoblastoma gene.

- If the germline mutation involves PKD1, the second hit might occur in PKD1 or in PKD2, or vice versa, so creating a transheterozygote.

- Consistent with the two-hit hypothesis, not all nephrons of patients with ADPKD develop into cysts. In addition, a severe renal cystic phenotype in mouse models of polycystic kidney disease (PKD) is associated with null alleles. Whether the two-hit mechanism is the only means to generate cysts in ADPKD remains an open question.

Videos

- Adult polycystic disease by Washington deceit

References

- Lina F, Satlinb LM. Polycystic kidney disease: the cilium as a common pathway in cystogenesis. Curr Opin Pediatr. 2004 Apr;16(2):171-6. PMID: #15021197#

- Cantiello HF. A tale of two tails: ciliary mechanotransduction in ADPKD. Trends Mol Med. 2003 Jun;9(6):234-6. PMID: #12829010#

- Pei Y. A "two-hit" model of cystogenesis in autosomal dominant polycystic kidney disease? Trends Mol Med. 2001 Apr;7(4):151-6. PMID: #11286938#

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