Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the gradual enlargement of multiple fluid filled cysts in both kidneys, which compress and destroy normal adjacent nephrons, typically resulting in ESRD by the fifth decade of life. Management has traditionally been limited to the treatment of the complications of hypertension and renal failure; however, several promising new therapies are on the horizon, such as nonpeptide vasopressin 2 receptor antagonists, inhibitors of the receptors for EGF and vascular endothelial growth factor (VEGF), and inhibitors of cmyc expression. All of which have been shown to inhibit disease progression in experimental models of PKD.
The mTOR inhibitor Sirolimus (Rapamycin) is another promising potential therapy, having also been shown to slow cyst development in rat models. Interestingly, it also slows the increase in size of native polycystic kidneys in human renal transplant recipients. It is currently the subject of three clinical trails underway in the US and Europe. Mechanistically, the cytoplasmic tail of wild-type Polycystin 1 normally interacts with, and inhibits, mTOR; loss of function of Polycystin 1, as seen in ADPKD, results in marked activation of mTOR within the epithelial cells of renal cysts. Sirolimus is believed to exert its effect via this mechanism. As mutations in PKD1, which encodes PC1, account for 85% of cases of ADPKD, Sirolimus has the potential to ameriorate the condition of the vast majority of APCKD patients.