Introduction

Cystinuria is a disorder characterized chronic kidney stone formation and caused by genetic mutations in the heterodimeric cystine transporter (SLC3A1 and SLC7A9) that is responsible for cystine reabsorption. Individuals afflicted with cystinuria are often treated by hyper-hydration, urine alkalization, and/or pharmacological interventions aimed at increasing cystine solubility in urine. However, these treatments are limited in their effectiveness and often have serious adverse side effects. The objective of this study is to use a mouse model of cystinuria to identify novel approaches towards the treatment of cystinuria.

Methods

Methods: Using longitudinal micro-computed tomography, Slc3a1-/- mouse cystine bladder stone formation was calculated at growth rate of approximately 1 mm3/day. This measure was used to evaluate interventions aimed at attenuating stone growth. A linear mixed model with random intercept was used to assess stone growth rates between treated versus control mice.

Results

Lipoic acid was found to be a potent inhibitor of cystine stone formation in a Slc3a1-/- mouse model of cystinuria. Treatment with lipoic acid attenuated existing cystine stone growth, and prevented stone formation in young Slc3a1-/- mice. The inhibitory effect was found to be dose-dependent, and independent of lipoic acid effects on the antioxidant response pathway. Ex vivo cystine precipitation analysis revealed that lipoic acid treatment increased cystine solubility in urine.

Conclusions

Treatment with the nutritional supplement lipoic acid protects against stone formation in a mouse model of cystinuria. This result identifies a novel application of lipoic acid that increases urinary cystine solubility independently of pH, and may highlight a new avenue for understanding treatment strategies for cystinuric patients.

Funding

NIH P20 DK100863