Treatment of polycystic kidney disease with a novel tyrosine kinase inhibitor

Background. We have previously demonstrated an essential role for increased epidermal growth factor receptor (EGFR) activity in mediating renal cyst f ormation and biliary epithelial hyperplasia in murine models of autosomal r ecessive polycystic kidney disease (ARPKD). This study was designed to dete rmine whether or not treatment with a newly developed inhibitor of EGFR tyr osine kinase activity (EKI-785) would reduce renal and biliary abnormalitie s in murine ARPKD. Methods. Balb/c-bpk/bpk (BPK) litters were treated with EKI-785, an EGFR-sp ecific tyrosine kinase inhibitor. Animals were treated by intraperitoneal i njection beginning at postnatal day 7 and were treated until postnatal day 24 or 48. EKI-785's effectiveness was measured by a reduction in the renal cystic index, an increased life span, and maintenance of normal renal funct ion. Results. Treatment of BPK mice with EKI-785 resulted in a marked reduction of collecting tubule (CT) cystic lesions, improved renal function, decrease d biliary epithelial abnormalities, and an increased life span. Untreated c ystic animals died of renal failure at postnatal day 24 (P-24) with a CT cy stic index of 4.8, a maximal urine osmolarity of 361 mOsm, and moderate to severe biliary abnormalities. Cystic animals treated with EKI-785 to postna tal day 48 (P-48) were alive and well with normal renal function, a reduced CT cystic index of 2.0 (P < 0.02), a threefold increased in maximum urinar y concentrating ability (P < 0.01), and a significant decrease in biliary e pithelial proliferation/fibrosis (P < 0.01). Conclusion. This study demonstrates that EKI-785 has therapeutic effectiven ess in improving histopathologic abnormalities and decreasing mortality in murine ARPKD.