Simulation-Based Sodium Thiosulfate Dosing Strategies for the Treatment of Calciphylaxis

Singh, Rajendra; Derendorf, Hartmut; Ross, Edward A.

doi:10.2215/cjn.09671010

Cited by 33 publications

(27 citation statements)

References 25 publications

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“…S-adenosylmethionine and pyridoxal-5′-phosphate stimulate CSE activity to increase H 2 S production (69,70). Alternatively to increasing CSE expression as a therapeutic option, rescue may be provoked by STS because our data show a protective effect of this compound as well, and it is tolerated by humans in high concentrations (71,72).…”

Section: Discussionmentioning

confidence: 90%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.

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Section: Discussionmentioning

confidence: 90%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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“…Only a prospective randomized trial can definitively address such bias, but the rarity and complexity of CUA make a randomized trial very challenging. The dose and frequency of STS administration were chosen by the treating providers; standardized pharmacokinetic simulations that consider the frequency and length of HD sessions were not applied (38). This may have introduced suboptimal STS dosing for some patients.…”

Section: Discussionmentioning

confidence: 99%

Sodium Thiosulfate Therapy for Calcific Uremic Arteriolopathy

Nigwekar

Brunelli

Meade

et al. 2013

Clinical Journal of the American Society of Nephrology

183

136

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SummaryBackground and objective Calcific uremic arteriolopathy (CUA) is an often fatal condition with no effective treatment. Multiple case reports and case series have described intravenous sodium thiosulfate (STS) administration in CUA, but no studies have systematically evaluated this treatment.Design, setting, participants, & measurements This study included 172 patients undergoing maintenance hemodialysis who had CUA and were treated with STS between August 2006 and June 2009 at Fresenius Medical Care North America. Of these, 85% completed STS therapy. Clinical, laboratory, and mortality data were abstracted from clinical information systems. Responses to survey questionnaires sent to treating physicians regarding patient-level outcomes were available for 53 patients. Effect on CUA lesions and mortality were summarized as CUA outcomes. Relevant laboratory measures, weight (using pairwise comparisons of values before, during, and after STS), and adverse events were summarized as safety parameters.Results Mean age of the cohort was 55 years, and 74% of patients were women. Median STS dose was 25 g, and median number of doses was 38. Among surveyed patients, CUA completely resolved in 26.4%, markedly improved in 18.9%, improved in 28.3%, and did not improve in 5.7%; in the remaining patients (20.8%), the response was unknown. One-year mortality in patients treated with STS was 35%. Adverse events, laboratory abnormalities, and weight-related changes were mild. Significant reductions in serum phosphorous (P=0.02) and parathyroid hormone (P=0.01) were noted during STS treatment in patients who completed the therapy.Conclusions Although conclusive evidence regarding its efficacy is lacking, a majority of patients who received STS demonstrated clinical improvement in this study.

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“…Typically, 25 g is given intravenously over 1 h after each of the thrice weekly high-flux hemodialysis treatments [14,15,16]. We feel it is important that the dose be adjusted for dialysis clearance when utilizing more intense or frequent intermittent treatments or for continuous modalities [17] (table 2). Until such time that blood levels are readily available, dosing for various dialysis strategies can be predicted by computerized modeling simulations.…”

Section: Treatmentmentioning

confidence: 99%

Evolution of Treatment Strategies for Calciphylaxis

Ross

2011

Am J Nephrol

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Treatment strategies for calciphylaxis are limited by inadequate understanding of its pathophysiology. Mortality reaches 80%, due to progressive skin ischemia, necrosis and infections. In addition to calcium and parathyroid disorders, hypercoagulability can have a role: primary thrombotic disorders as well as secondary, such as proposed warfarin procoagulant effects. Traditional care addresses the calcium-phosphate-PTH axis: minimizing calcium intake, calcimimetics, cautious vitamin D analogs, strict phosphate control, and surgical parathyroidectomy if necessary. Newer approaches focus on extraosseous mineralization: dissolution of calcium deposits, altering osteoprotegerin and NF-ĸB pathways, and treating macrophage or cytokine-mediated inflammation. Sodium thiosulfate has reported success, and is thought to be due to enhanced calcium solubility and dialysis clearance. Bisphosphonates may have efficacy by lowering bone turnover or a variety of vascular tissue mechanisms. The literature for both agents is very limited, and optimal dosing regimens remain unclear. Patients responsive to a medication will have decreasing pain in days and lesions beginning to heal within approximately 2 weeks. Due to high mortality, early use of combination therapy is advocated, although specific protocols have not been well established. The often dramatic improvements in case-based literature are very encouraging and will hopefully lead to more rigorous studies.

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Simulation-Based Sodium Thiosulfate Dosing Strategies for the Treatment of Calciphylaxis

Cited by 33 publications

References 25 publications

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Sodium Thiosulfate Therapy for Calcific Uremic Arteriolopathy

Evolution of Treatment Strategies for Calciphylaxis

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