Protein interactions that control calcium oxalate kidney stone formation.

Kidney stones are an organic-inorganic composite that forms spontaneously in the urine of about 10% of Americans, causing significant discomfort and disruption of lives sporadically in those affected. Stone prevention is currently limited to efforts to reduce the urine supersaturation with respect to the inorganic crystals; calcium oxalate in about ¾'s of patients, but these treatments are incompletely effective. We have focused on the protein (organic) components that bind the crystals together to better understand the process and identify new treatment pathways. We have used mass spectrometry-proteomics methods to characterize the distribution of proteins found in patient stones, Using insight gained from in vitro studies of protein-calcium oxalate crystal interactions, we have identified key features of the protein mixtures that likely control stone formation. Key features include interaction of strongly anionic proteins with the crystal surface, and protein aggregation induced by strongly cationic proteins, along with inclusion of weakly charged proteins in the aggregates, apparently controlled at least in part by large total numbers of charged residues in proteins with near zero net charge. This complex mixture of components combines to form hard, dense crystal aggregates.