Cystinuria is a rare (1:15,000) autosomal recessive disease characterized by markedly elevated levels of urinary cystine, and recurrent episodes of painful, tissue damaging kidney stone formation. There is no successful medical management of this disorder and even though patients may receive temporary relief through surgical intervention, the period of remission is typically brief and they have a higher risk of end-stage renal disease over time. We propose a novel treatment for cystinuria, to be tested in a Phase 2 randomized double-blind, placebo- controlled clinical trial to assess the impact of alpha-lipoic acid (lipoic acid) on cystine stone growth and recurrence, and need for surgical intervention. Using a mouse model of cystinuria, we have found that this widely used, well tolerated and naturally occurring dietary supplement, both prevents the onset of cystine stone formation and slows the growth of existing stones. These results dramatically overshadow the minimal action of existing pharmaceuticals tested in the same murine model and used in humans to treat cystinuria. In this mouse cystinuria model lipoic acid-supplemented diets did not impact mice weight, water consumption or activity levels. These promising murine data inspired this human trial. We propose a randomized double-blind placebo-controlled trial enrolling 50 cystinuric patients from our established clinical stone center (>30 years) that will facilitate rapid enrollment. The design will assess how daily 1200 mg of lipoic acid supplementation for three years will impact clinical outcomes. Outcome measures will include: 1) clinical progression of disease, marked by stone recurrence based on routine imaging, quality of life measurement, stone passage, and/or the need for surgical intervention; 2) quantitative urinary cystine levels and cystine solubility on traditional 24-hour urine collection; and 3) metabolomic and metallomic analyses of stone and urine samples. As per normal, routine clinical care, study participants will be seen every 4 months for comprehensive clinical evaluation including serum labs, imaging, and 24-hour urine studies. In addition to clinical data, stone, urine, and blood samples will be collected over the study to determine metabolomic and metallomic profiles and urinary cystine solubility, to identify biomarkers to help predict treatment effect and to form the basis of personalized medicine for patients with this rare disease. These latter measures represent an effort to identify readily available predictive makers of stone initiation and formation (none of which exist at the present time), and provide insight into the possible mechanism of action of lipoic acid. If successful, the use of lipoic acid will radically change the health and life- styles of patients with cystinuria, a rare, orphan and debilitating disease. Furthermore, the study of appropriate metabolomics and metallomic biomarkers for cystinuria may also yield important insights into other types of urinary stones.

Public Health Relevance

Lipoic acid dramatically reduced or eliminated cystine stones in our knockout murine model for the orphan disease, cystinuria. A randomized double-blind placebo-controlled trial is proposed to assess the impact of lipoic acid in cystinuric urinary stone patients in hopes of minimizing recurrent stones and need for surgical intervention. Using metabolomics and metallomic analyses, predictive biomarkers for stone formation will also be investigated in these patients.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1)
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Russell, Karen
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Wiener, Scott V; Ho, Sunita P; Stoller, Marshall L (2018) Beginnings of nephrolithiasis: insights into the past, present and future of Randall's plaque formation research. Curr Opin Nephrol Hypertens 27:236-242
Chi, Thomas; Kim, Man Su; Lang, Sven et al. (2015) A Drosophila model identifies a critical role for zinc in mineralization for kidney stone disease. PLoS One 10:e0124150