Sodium Thiosulfate: New Hope for the Treatment of Calciphylaxis Melvin R. Hayden and David J. A. Goldsmith Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, and King’s Health Partners, Guy’s Hospital Campus, London, United Kingdom ABSTRACT Calciphylaxis / calcific uremic arteriolopathy is rare but an important cause of morbidity and mortality in patients with chronic and end-stage kidney disease with increasing preva- lence. Intravenous sodium thiosulfate (STS) has rapidly emerged from a seldom used therapy for the treatment of calciphylaxis / calcific uremic arteriolopathy to a treatment that is being increasingly utilized globally due to multiple positive outcomes shared in the form of case reports and reviews during the past 6 years. Its role as a rather potent antioxidant has uniquely been associated with a prompt decrease in pain and its slower chelating properties are associated with regression of subcutaneous calcifications. Excessive reactive oxygen species (ROS) activate nuclear transcription factor, NF j B and down- stream cytokines resulting in inflammation, which may result in dysregulated hepatic protein synthesis. Indeed, inflamma- tion activates acute-phase reactant synthesis, while concur- rently inhibiting synthesis of fetuin-A (an inhibitor of extraosseous calcification) and the antioxidant albumin. Addi- tionally, ROS may decrease locally synthesized matrix GLA proteins and this combination may contribute to increased vascular and subcutaneous calcification. STS used alone or in combination with other novel emerging therapies may result in the improved clinical outcomes in this challenging clinical condition. One of the first reported cases of cyanide poisoning treated successfully with intravenous sodium thiosulfate (STS) was published as a case report approximately six decades ago. Now interest has again focused on this agent, this time for its therapeutic use in another rare sit- uation—the treatment of calciphylaxis / calcific uremic arteriolopathy (CUA) (1). Calciphylaxis / CUA has been increasingly reported in the literature in the past decade and remains an important cause of morbidity and mortality in patients with CKD requiring renal replacement (2). It has been recently stated that the use of STS has resulted in the most significant progress in the treatment of calciphylaxis / CUA since its recognition, a statement we staunchly agree with (3). In 2008, there were at least 11 cited papers discussing positive outcomes using STS in the treatment of calciphylaxis (2), and a recent review of PubMed now reports additional 10 papers as of the end of 2009 (4–13). Published literature, especially in rare conditions such as calciphylaxis / CUA, can lag some way behind progress, so it is also salutary to note that 30 patients with calciphylaxis / CUA were reported at the 29th Annual Dialysis Conference to have been successfully treated in the United States and Canada during the past year (MRH, personal communications, Houston, Texas, March 2009). These clinical outcomes are unlikely to be expeditiously or completely reported in the literature due to the increasingly limited space allocated by journals to case reports as well as the effort required to prepare them. From Selye to Thiosulfates Using a rodent model in the early 1960s, Hans Selye (14) set the stage for the eventual understanding of this phenomenon in humans (coining the term calciphylaxis in the process). Rees and Coles adeptly translated Selye’s findings to their patient with renal failure in 1969. Their patient had been treated with iron-dextran and devel- oped widespread tissue calcification; they were the first to use the term calciphylaxis in human (15). Later, in 1985, Yatzidis successfully used STS in the treatment for recurrent calcium urolithiasis (16) and, in 1987, treated soft-tissue calcifications in patients with end-stage renal disease (17). But such is the rarity of the condition, and its sporadic and fragmentary literature, that little happened thereaf- ter. However, reports of STS therapy for calciphylaxis / CUA began to increase at various nephrology and dermatology meetings in 2005 following the publication by Cicone et al. (18) of their successful use of intravenous STS in a patient. Will this emerging therapy stand the test of time? The answer at this time is probably yes, at least, until newer Address correspondence to: Melvin R. Hayden, MD, Research Professor, Department of Internal Medicine, Endocrinology Diabetes and Metabolism, University of Missouri School of Medicine, P.O. Box 1140 Columbia, MO, Tel.: 573-346-3019, or e-mail: mrh29@usmo.com. Seminars in Dialysis—Vol 23, No 3 (May–June) 2010 pp. 258– 262 DOI: 10.1111/j.1525-139X.2010.00738.x ª 2010 Wiley Periodicals, Inc. 258