autosomal dominant polycystic kidney disease
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Digital cases
Case 4 (HPC:4) : 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#