Advances in the pathogenesis and treatment of polycystic kidney disease.

PURPOSE OF REVIEW: Polycystic kidney disease (PKD) is the most common genetic cause of chronic renal failure. Mouse models of PKD, especially those with mutations in genes that are orthologous to human disease genes, have provided insights into the pathogenesis of cyst formation and advanced the preclinical testing of new drugs.

RECENT FINDINGS: PKD is a ciliopathy that arises from abnormalities in the primary cilium, a sensory organelle present on the surface of most cells. The primary cilium is required for the maintenance of planar cell polarity, which regulates tubular diameter. Acute kidney injury stimulates cell proliferation and promotes cyst formation in a mouse model of PKD. Studies of signaling pathways that are perturbed in PKD have identified new potential therapeutic targets. Drugs that have shown beneficial effects in orthologous animal models of PKD include tolvaptan, octreotide, src inhibitors, CFTR inhibitors, pioglitazone, etanercept, and triptolide.

SUMMARY: Abnormalities in the primary cilium perturb signaling pathways that regulate renal epithelial cell growth and differentiation and lead to the formation of kidney cysts. Acute kidney injury promotes cyst formation and may underlie the variability in disease progression that is observed in affected individuals. Several promising new therapeutic agents that have been validated in orthologous animal models have entered clinical trials in humans.