Abstract
Calcium oxalate (CaOx) crystal‐induced nephropathies comprise a range of kidney disorders, for which there are no efficient pharmacological treatments. Although CaOx crystallization inhibitors have been suggested as a therapeutic modality already decades ago, limited progress has been made in the discovery of potent molecules with efficacy in animal disease models. Herein, an image‐based machine learning approach to systematically screen chemically modified myo‐inositol hexakisphosphate (IP6) analogues is utilized, which enables the identification of a highly active divalent inositol phosphate molecule. To date, this is the first molecule shown to completely inhibit the crystallization process in the nanomolar range, reduce crystal–cell interactions, thereby preventing CaOx‐induced transcriptomic changes, and decrease renal CaOx deposition and kidney injury in a mouse model of hyperoxaluria. In conclusion, IP6 analogues based on such a scaffold may represent a new treatment option for CaOx nephropathies.
Highlights
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While IP6 is a known inhibitor of calcium phosphate crystallization,[27,28] little is known about the inhibitory properties of IP6 on Calcium oxalate (CaOx) crystallization.[31]
To assess CaOx crystallization in a physiologically relevant setting, human urine was spiked with 1 mm sodium oxalate (NaOx), representing the upper concentrations reached within the renal tubules.[32]
Summary
While IP6 is a known inhibitor of calcium phosphate crystallization,[27,28] little is known about the inhibitory properties of IP6 on CaOx crystallization.[31]. To assess CaOx crystallization in a physiologically relevant setting, human urine was spiked with 1 mm sodium oxalate (NaOx), representing the upper concentrations reached within the renal tubules.[32] Changes in the crystallization pattern with respect to the size and proportion of different CaOx hydrate crystal forms were monitored by light microscopy combined with a semi-supervised image analysis approach. A training dataset was created by manually adjusting single features to distinguish the different crystal types on single images, which served as input to train a support vector machine (SVM) classifier. Kinetic analysis of oxalate-spiked human urine showed first the appearance of CaOx dihydrate (COD) crystals, followed by CaOx monohydrate (COM) crystals over the time course of 24 h (Figure S2, Supporting Information). COM crystals were more abundant but smaller in size compared to COD, with an approximate length of 10 and 20 μm, respectively
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