Cystine crystal nucleation and decay in the context of cystinuria pathogenesis and treatment†

Abstract

Cystinuria is a rare disease which results in the precipitation of cystine in the renal filtrate, which may cause acute kidney injury due to mechanical trauma. In this work, we attempt to explore the origin of supersaturated cystine in this context to understand disease pathogenesis. This has enabled us to reproduce the clinical habit of cystine following a comprehensive study of cystine nucleation and growth in saline, artificial and human urine. Then, we describe the physical behaviour of these crystals in the presence of: cysteamine, sodium bicarbonate, captopril, tiopronin, penicillamine, glutathione and α-lipoic acid. Surprisingly, we observe that, in vitro, only cysteamine and saturated sodium bicarbonate dissolve crystals at a faster rate than saline, and that when solution pH is adjusted to physiological conditions, crystal dissolution for all agents is reduced to the rate of saline alone. We highlight that the conventional hypothesis of mixed disulphide formation in cysteamine is not the fastest mechanism of cystine dissolution, but rather that cystine dissolution (in the order of hours) is dominated by pH effects. This, combined with cysteamine's ability to take part in disulfide exchange reactions may explain cysteamine's effectiveness in this condition. Overall, our findings not only contribute to an understanding of cystinuria pathogenesis but also offer insights into how we should evaluate emerging treatments.