Kidney stones are one of the most common types of urinary tract diseases with the number of afflicted people on the rise. In the United States, ca. 12% of men and 6% of women develop kidney stones in their lifetime, and approximately 50% of previous stone-formers are inclined to experience reoccurring formation of stones. Unfortunately, there has not been any substantial improvement in therapeutic treatments over the last 30 years. Calcium oxalate monohydrate (COM) is the most common component in human kidney stones. There are four critical steps in stone formation: Crystal nucleation, growth, aggregation, and retention. Inhibiting any of these steps is sufficient to suppress stone pathogenesis. There are, in fact, many urinary components that play a crucial role in preventing stone formation, such as osteopontin, Tamm-Horsfall protein, and nephrocalcin. These components are rich in anionic groups, which promote inhibitor-crystal interactions. Moreover, the crystallographically distinct faces of COM crystals exhibit different spatial distribution and densities of calcium ions, which invoke site-specific binding of growth inhibitors. Here, we will present our studies employing a series of small organic molecules, termed organic growth modifiers (OGMs), which we benchmark against citrate (a current therapeutic agent and moderate growth inhibitor). Bulk crystallization studies were used to observe the effect of OGMs on crystal size and morphology, while the efficacy of OGMs was quantified by kinetic studies. In situ atomic force microscopy (AFM) was used to monitor COM crystal surface growth. Time-resolved AFM images provide microscopic validation of OGM efficacy and molecular recognition for different COM crystal surfaces. Collectively, these studies establish a platform for the rational design of crystal modifiers and new drugs for stone disease.

Tailoring organic growth modifiers of calcium oxalate monohydrate crystallization

247th National Meeting (2014)

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