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New Treatment Prevents Formation of Cystine Stones, a Type of Kidney Stone, in Mice

In a recent study, the antioxidant α-lipoic acid was shown to prevent the formation of cystine stones in mice. Kidney stone disease, also referred to as urinary stone disease, is a painful and increasingly common problem, with some people experiencing recurrent episodes. Despite the high prevalence and health and economic burden of the disease, little is known about how stones form or which are easily passed through the urinary tract. Advances in treatments in the past 30 years have evolved from open surgery to remove large stones, to new technologies. Unfortunately, these new advances have not benefited people who form cystine stones, and thus research efforts continue, toward preventing or slowing the formation of this type of stone.

Researchers recently used a mouse model of cystine stone disease to identify compounds that slowed the growth of this stone type. This genetically engineered model readily forms cystine stones in the bladder of the male mouse. Two compounds believed to have anti-cystine stone formation properties, tiopronin and L-CDME, were initially evaluated in this model system but were ineffective. In contrast to these two drugs, α-lipoic acid significantly slowed the growth rate of cystine stone formation compared with untreated animals in the model system. Prior to the time when these mice would begin to form stones, they were treated with or without α-lipoic acid to assess its ability to alter cystine stone formation. This experimental design demonstrated that α-lipoic acid significantly prevented stone formation, delayed the time needed for stone formation, and/or reduced the overall size of stones that did form. Notably, when α-lipoic acid treatment was discontinued, the mice subsequently resumed producing cystine stones, indicating that α-lipoic acid treatment is reversible.

Additional results of the study indicated similar amounts of cystine were present in the urine from both untreated and α-lipoic acid-treated animals in the model system. Given this finding, the investigators hypothesized that the urine obtained from α-lipoic acid-treated animals provided an environment in which cystine is less likely to crystalize and begin to form stones compared to untreated animals. The investigators confirmed this is a likely mechanism by demonstrating that the urine from α-lipoic acid-treated animals formed significantly less cystine precipitate (solid deposits that form from the compound in solution) during a 3-day period in the laboratory. Thus, it appears that the urine obtained from α-lipoic acid-treated animals can maintain larger amounts of cystine “in solution”—thereby shutting down the pathway that ultimately leads to stone formation.

Research efforts continue that ultimately seek to prevent cystine stone formation in people. One effort is assessing the efficacy of cystine mimetics (compounds with similar structure) to block the cystine crystallization process in human urine and stone formation in the model system used above. A second effort will evaluate how daily α-lipoic acid supplementation over 3 years affects cystine stone recurrence in 50 people.

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