Development of a Kidney Calcification Inhibitor Employing Image-Based Profiling: A Proof-of-Concept Study.

Abstract

Kidney calcification increases the risk of chronic kidney disease. However, to date, renal calcium phosphate crystallization, a main initiating and driving factor of kidney calcification, has not been explored as a drug target. Pre-clinical drug development is hampered by limited knowledge on the broad range of kidney calcification disorders, characterized by a multifactorial process of disease progression. In this work, we first established an in vitro calcification profiling platform to accelerate pre-clinical drug discovery. The image-based profiling assay allowed the rapid testing of several ionic stimuli and/or inhibitory molecules. We then leveraged a previously established library of inositol hexakisphosphate analogues to identify a renal calcium phosphate inhibitor. A lead compound showed in vitro and in vivo efficacy to prevent calcium phosphate-induced kidney damage. In conclusion, this work reports a renal calcium phosphate inhibitor that could efficiently reduce kidney damage and emphasizes the utility and translational value of the in vitro calcification platform.