The present pilot study shows that short-term (60 doses over 5 months) intravenous STS (12.5–18.75 g/treatment 3 times/week) is feasible and fairly well tolerated (with the exception of nausea and vomiting which was controlled by decreasing or avoiding the higher doses). STS treatment showed no overall statistically significant progression of vascular calcification of the coronary and carotid arteries, or of the thoracic aorta. Changes in thoracic aorta calcification, but not carotid arteries, correlated with those of the coronary arteries. There were no adverse effects of treatment on vascular or cardiac structure and function. Furthermore, L1-L2 vertebral bone density remained unchanged with STS treatment in the entire group. However, subgroup analysis revealed progression in 14 of 22 patients. No baseline or treatment variables were associated with progression.
The use of STS for reduction of vascular calcification is supported by studies reporting efficacy in calcific uremic arteriopathy (CUA), urolithiasis and tumoral calcinosis [13
]. Disruption of normal calcium-phosphate homeostasis is considered a primary cause for calcium-phosphate deposition in CUA, but this entity can be seen in the presence of normal calcium, phosphate and serum PTH levels [4
]. Therefore, other factors can lead to ectopic osteogenesis in the absence of direct calcium/phosphate deposition. STS was first described as an antidote for cyanide poisoning over 110 years ago. It is also used as a dechlorinator, a modifier of platinum-based treatment toxicity, and a topical treatment for acne and pityriasis versicolor [4
]. In uremic patients, STS may reduce vascular calcification by forming a soluble complex with calcium that lowers free calcium ions, and/or by antioxidant effects (with improved endothelial function and vasodilatation) [14
]. STS has unpaired electrons that may scavenge free radicals to stimulate glutathione production (an antioxidant). Moreover, STS may generate hydrogen sulfide which is a vasodilator and has anti-inflammatory properties and analgesic effects.
Although no large, prospective, randomized trials examining the role of STS in reducing vascular calcification have been published, one small nonrandomized study has studied this in HD patients [15
]. In this study, 49 patients with a CAC Agatston score ≥300 were enrolled; of these, 16 were selected to receive STS and another 15 comprised a concurrent nonrandomized control group. Patients in the treatment group received 12 g of STS twice a week after dialysis for 4 months. The authors found that STS treatment was associated with no overall progression of CAC. Only 4 of 16 in the STS group were ‘progressors’ versus 10 of 15 in the control group. The sole predictor of CAC progression was STS treatment. Similarities between the present and the previous study include the lack of a significant increase in the CAC with STS treatment. In addition, the present study also showed no increase in calcium scores of the thoracic aorta and carotid arteries. Furthermore, vascular and cardiac structure and function were evaluated in the present study and found to not change with treatment. Thus, taken together, the results of these 2 pilot studies provide preliminary data supporting the hypothesis that STS treatment may be effective in decreasing progression of vascular calcification in HD patients.
The effects of STS on bone density are different in the 2 studies. The present study showed no change in calcium score in the L1-L2 vertebrae, but the hip was not evaluated. In contrast, hip bone mineral density was decreased, but the vertebral spine was not evaluated in the in the previous study. A recent animal study showed that those treated with STS exhibited decreased bone strength compared to placebo [5
]. Thus, the effects of STS on bone density are a potentially serious complication that requires further evaluation.
Several other differences between these 2 studies are worth discussing. First, the patient populations are different: a predominantly African-American population in the present study versus a Thai population in the previous. Second, STS treatment in the present study occurred 3 times/week for 5 months versus 2 times/week for 4 months in the previous study. The doses were similar, with STS 12.5 g/treatment being the predominant dose used in both studies. However, the optimal STS dose and treatment duration remains to be determined.
Studies evaluating progression of established CAC in ESRD patients report annualized increases of 6–104% [16
]. Variability in progression with these studies may be due to heterogeneity in design, differences in CT scanner type and scoring systems, dialysis vintage, comorbidities (e.g. diabetes and age), and variation in baseline levels of calcium, phosphorus and PTH. Renal transplantation seems to slow the progression of CAC in the ESRD population, but uremia alone does not explain ongoing vascular calcification [20
]. Prior studies have demonstrated the effectiveness of statin therapy on reducing CAC progression in those without renal failure: 25–39% annual progression in the untreated versus 8–15% in the treated group [24
]. Moreover diabetic status (33% greater annual progression over nondiabetic subjects) and abdominal obesity are predictive of progression [25
This work may have important implications for vascular calcification in dialysis patients. First, vascular calcification is associated with high cardiovascular morbidity and mortality. Second, vascular calcification tends to be rapidly progressive. Finally, other than noncalcium-containing phosphate binders, treatment options are currently limited for reducing the rate of vascular calcification.
Neither this study nor the previous one enrolled a prospective, randomized, placebo-controlled, double-blind control group; therefore, a conclusive statement about the risks and benefits of STS treatment cannot be made. Furthermore, the sample size for both studies was small. The randomization of several hundred HD patients to receive prolonged treatment with STS or placebo likely would be necessary to attain adequate power in determining STS benefits and risks. Unfortunately, this was beyond our capacity.