Thiosulfate Reduces Calcium Phosphate Nephrolithiasis

An uncontrolled trial reported that sodium thiosulfate reduces formation of calcium kidney stones in humans, but this has not been established in a controlled human study or animal model. Using the genetic hypercalciuric rat, an animal model of calcium phosphate stone formation, we studied the effect of sodium thiosulfate on urine chemistries and stone formation. We fed genetic hypercalciuric rats normal food with or without sodium thiosulfate for 18 wk and measured urine chemistries, supersaturation, and the upper limit of metastability of urine. Eleven of 12 untreated rats formed stones compared with only three of 12 thiosulfate-treated rats (P < 0.002). Urine calcium and phosphorus were higher and urine citrate and volume were lower in the thiosulfate-treated rats, changes that would increase calcium phosphate supersaturation. Thiosulfate treatment lowered urine pH, which would lower calcium phosphate supersaturation. Overall, there were no statistically significant differences in calcium phosphate supersaturation or upper limit of metastability between thiosulfate-treated and control rats. In vitro, thiosulfate only minimally affected ionized calcium, suggesting a mechanism of action other than calcium chelation. In summary, sodium thiosulfate reduces calcium phosphate stone formation in the genetic hypercalciuric rat. Controlled trials testing the efficacy and safety of sodium thiosulfate for recurrent kidney stones in humans are needed.Nephrolithiasis is one of the most common disorders of the urinary tract, affecting approximately 12% of men and 6% of women during their lifetimes in industrialized countries.¹ Approximately 80% of kidney stones are composed primarily of calcium salts. Despite the high prevalence of kidney stone disease, there has been little progress in developing new therapies to prevent stone formation, especially in patients who have formed a kidney stone and who are at significantly increased risk for forming additional stones. The lack of progress in identifying new therapies for nephrolithiasis has been disappointing to the many patients who experience recurrent stone formation.Sodium thiosulfate (STS), Na₂S₂O₃, is a compound with a long history of medicinal use.^2,3 Currently, it is used for treatment of cyanide toxicity and as a neutralizing agent to reduce the toxicity of cisplatin chemotherapy.^4–6 The effectiveness of STS in these diseases lies in its antioxidant activity and the availability of a sulfur group for donation. In 1985, Yatzidis⁷ reported on using STS as treatment for recurrent calcium nephrolithiasis. In a 4-yr study of 34 patients, he reported an 80% reduction in stone rates, compared with the patients’ own pretreatment stone formation rate. Unfortunately, no follow-up, prospective, controlled trials have been performed to determine the effectiveness of STS in preventing recurrent stone formation; however, anecdotal reports of successful treatment of calciphylaxis with STS in patients with end-stage kidney disease have stimulated interest in this compound as a potential therapy for disorders of calcium deposition, including stone disease.^8–16 The mechanism by which STS affects calcium deposition is not known.Before pursuing new studies in humans, we chose first to study this drug in the genetic hypercalciuric stone-forming (GHS) rats because 40 to 50% of humans with kidney stones will have hypercalciuria, making it the most common metabolic abnormality. The GHS rat colony has been bred for hypercalciuria and now excretes approximately 8 to 10 times more urine calcium than similarly fed control rats.¹⁷ The pathophysiology of the hypercalciuria seems similar to that in humans in that it involves intestinal hyperabsorption,^18,19 reduced renal tubular reabsorption,²⁰ and increased bone mineral lability.^21,22 Virtually all of the GHS rats form kidney stones, whereas control rats have no evidence of stone formation.²³ On a standard rat diet, the kidney stones formed contain only calcium and phosphate.²⁴ Here we report the results of a controlled trial to determine whether STS reduces stone formation in an animal model of spontaneous calcium phosphate stone formation.