Sodium thiosulfate prevents vascular calcifications in uremic rats

Abstract

Accelerated vascular calcification is a severe complication of chronic kidney disease contributing to high morbidity and mortality in patients undergoing renal replacement therapy. Sodium thiosulfate is increasingly used for the treatment of soft tissue calcifications in calciphylaxis. Therefore, we determined whether it also prevents development of vascular calcifications in chronic kidney disease. We found that uremic rats treated by thiosulfate had no histological evidence of calcification in the aortic wall whereas almost three-fourths of untreated uremic rats showed aortic calcification. Urinary calcium excretion was elevated and the calcium content of aortic, heart, and renal tissue was significantly reduced in the thiosulfate-treated compared to non-treated animals. Sodium thiosulfate treatment transiently lowered plasma ionized calcium and induced metabolic acidosis. It also lowered bone strength in the treated animals compared to their normal controls. Hence, sodium thiosulfate prevented vascular calcifications in uremic rats, likely by enhancing acid- and/or chelation-induced urinary calcium loss. The negative impact on rat bone integrity necessitates a careful risk-benefit analysis before sodium thiosulfate can be used in individual human patients.

Sodium Thiosulfate Pharmacokinetics in Hemodialysis Patients and Healthy Volunteers

“…The therapeutic endpoint of STS with respect to calciphylaxis or vascular calcification is the disappearance of calcium deposited in soft tissues and the vasculature. TS serum concentrations between 5 and 10 mmol/L have been shown to transiently lower ionized serum calcium in vitro and in vivo (13). Such high concentrations are achieved only for Ͻ30 minutes when the usual dose of 25 g of STS is given to patients off-dialysis ( Figure 3A).…”

“…Recently, STS has been prescribed for the treatment of soft-tissue calcifications in patients with calciphylaxis (7)(8)(9)(10)(11)(12). Furthermore, systematic studies in rats (13) and humans (14) have investigated the effect of STS on aortic and coronary artery calcifications. These studies support the notion of vascular calcification, slowing or even preventing properties of STS.…”

“…The underlying mechanism for the efficacy of STS is not clear. Apparently, the beneficial effects of STS are mediated by a combination of calciumsolubilizing, antioxidative, acidosis-inducing, and possibly other not-yet-identified mechanisms (13,(15)(16)(17). Given the favorable tolerability even in long-term use along with its low cost, STS has the potential to become a more widely applied therapeutic agent for patients predisposed to vascular calcifications.…”

Sodium Thiosulfate

“…Although there are no data proving efficacy of STS in CUA in humans, STS does reduce medial arterial calcification in a model of uremic vascular calcification in rats (12) and in an ex vivo model of calcification in cultured rat aortas (13). However, neither is a model of CUA.…”

“…However, thiosulfate is not an acid and it does not alter pH when added to blood ex vivo (12) and the inhibition of calcification in cultured vessels occurred without a change in the pH of the culture medium (13). The expansion acidosis that STS does produce in vivo is too mild to have much of an effect on calcification (12). Lastly, an antioxidant action that targets inflammation and intimal hyperplasia has been proposed based on the fact that thiosulfate can be oxidized to sulfate.…”