The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. ducts and liver cysts originating from intrahepatic bile ducts, is characteristic of ADPKD.2-3 ADI'KD accounts for approximately 10% of endstage renal disease requiring hernodialysis or renal transplantation.* Present in more than 50% ofADPKD patients, hepatic cysts are the most common extrarenal manifestation and are a significant source of morbidity in ADPKD whose importance is likely to increase as treatments for renal manifestations progress. l . 5 ADPKD cysts begin as focal dilations that expand and detach from the original nephron or duct to form an autonomous, enclosed cyst. Expanding cysts displace the surrounding parenchyma. The principal clinical manifestation ofADPKD liver disease, cyst enlargement results in prominent abdominal distention, compression of surrounding organs, and impingement on vascular flow (Fig. 1). Elevated plasma levels of specific growth factors in ADPKD subjects suggests these factors drive errant cyst growth and expansion.6 Further, ADPKD renal cyst fluid contains a number of cytokines and growth factors,7?* and

The principal extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD) involves formation of liver cysts derived from intrahepatic bile ducts. Autocrine and paracrine factors secreted into the cyst would be positioned to modulate the rate of hepatic cyst growth. The aim of this study was to identify potential growth factors present in human ADPKD liver cyst fluid. Cytokine array and enzyme-linked immunosorbent assay analysis of human ADPKD liver cyst fluid detected epithelial neutrophil attractant 78, interleukin (IL)-6 (503 +/- 121 pg/mL); and IL-8 (4,488 +/- 355 pg/mL); and elevated levels of vascular endothelial growth factor compared with non-ADPKD bile (849 +/- 144 pg/mL vs. 270 pg/mL maximum concentration). ADPKD liver cyst cell cultures also released IL-8 and vascular endothelial growth factor, suggesting that cystic epithelial cells themselves are capable of secreting these factors. Western blotting of cultured cyst cells and immunostaining of intact cysts demonstrate that cysteine-X-cysteine receptor 2, an epithelial neutrophil attractant 78 and IL-8 receptor, is expressed at the apical domain of cyst lining epithelial cells. Suggesting the cystic epithelial cells may exist in hypoxic conditions, electron microscopy of the ADPKD liver cyst epithelium revealed morphological features similar to those observed in ischemic bile ducts. These features include elongation, altered structure, and diminished abundance of apical microvilli. In conclusion, IL-8, epithelial neutrophil attractant 78, IL-6, and vascular endothelial growth factor may serve as autocrine and paracrine factors to direct errant growth of ADPKD liver cyst epithelia. Interruption of these signaling pathways may provide therapeutic targets for inhibiting liver cyst expansion.