Brief CommunicationsTolvaptan plus Pasireotide Shows Enhanced Efficacy in a PKD1 ModelHopp, Katharina*; Hommerding, Cynthia J.*; Wang, Xiaofang*; Ye, Hong*; Harris, Peter C.*,†; Torres, Vicente E.* Author Information *Division of Nephrology and Hypertension and †Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota Correspondence: Dr. Vicente E. Torres, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Email: [email protected] Received December 17, 2013 Accepted May 14, 2014 Journal of the American Society of Nephrology 26(1):p 39-47, January 2015. | DOI: 10.1681/ASN.2013121312 Buy Metrics Abstract Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 3′, 5′-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1R3277C/R3277C (Pkd1RC/RC), in a 5-month preclinical trial. Initially, the Pkd1RC/RC model was inbred into the C57BL/6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1RC/RC mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD. Copyright © 2015 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.