Cardiovascular disease is the major cause of death in the hemodialysis population and
calcification of the major arteries (coronary, aorta, and carotid) are a play a central role
in this process. The major causes of the calcification are many, including high levels of
phosphorus, low levels of inhibitors of calcification, positive calcium balance, and
oxidative stress. Once vascular calcification is present, it is usually progressive. There
is no known treatment to reverse established vascular calcification.
Sodium thiosulfate has been used extensively and safely to treat calcific uremic
arteriopathy (a disease, in part due to calcification of small arteries) in dialysis
patients. It increases the solubility of calcium by up to 100,000 fold and is also a potent
anti-oxidant. It therefore has to potential to also decrease the amount of calcium in large
arteries in dialysis patients and, hence improve survival.
We will study hemodialysis (HD) patients at high risk for cardiovascular disease and death
by obtaining a multigated CT (MDCT) Scan of the coronary arteries, carotid arteries and
aorta and an assessment of coronary artery stenoses by a simultaneous intravenous infusion
of contrast. At the same setting, we will perform tests of pulse wave velocity (PWV) and
carotid ultrasound (CIMT)studies. In those patients at high risk for cardiovascular death,
defined as a coronary artery calcification score (CACS)of greater than 50, sodium
thiosulfate at a dose of 12.5-25 gm/1.73 M2 will be infused over 15-30 minutes after each
dialysis treatment for 5 months. The above studies will then be repeated.
Hypothesis 1: The treatment of HD patients with high CAC scores with sodium thiosulfate for
5 months will decrease the amount of calcium in their coronary arteries.
Patients who are at high risk for having coronary calcification (history of MI, ischemic
heart disease, peripheral or carotid artery disease) will be selected to undergo testing.
We will recruit 60 HD patients receiving treatment in our units to undergo MDCT scanning
along with non-invasive testing of PWV and CIMT. Assuming that 60% will have a CAC score of
≥50, 36 patients will be treated with sodium thiosulfate. We will administer 25% sodium
thiosulfate solution (American Reagent Laboratories, Shirley, NY) at a dose of
12.5-25g/1.73m2 per over 15-30 minutes after each hemodialysis session for a total of 60
treatments (5 months). Assuming a 35% attrition rate, 23 patients will complete the entire
protocol and undergo a repeat study of the initial battery of tests.
Rationale for treatment with sodium thiosulfate: Sodium thiosulfate, used as an antidote for
cyanide poisoning for more than a century, is also an anti-oxidant, and binds with calcium
to form a highly soluble calcium thiosulfate salt. The solubility of calcium thiosulfate
salt is 250-100,000 fold higher than calcium oxalate or calcium phosphate salt. It has been
used to treat recurrent calcium kidney stones and tumoral calcinosis (ectopic calcification
usually around joints). It has also been used successfully in treating calcific uremic
arteriopathy, a disease of small artery and soft tissue calcification, in several studies of
dialysis patients and in our own experience of 5 patients. By 2 months there is
radiological evidence of reduction in soft tissue calcification. Unpublished data also have
demonstrated regression of established aortic calcification in uremic rats.
Sodium thiosulfate is a FDA approved medication for the treatment of cyanide poisoning. It
is classified by the FDA as "generally recognized as safe". There are no known
contraindications. The only side effects reported during intravenous (IV) administration in
ESRD patients are nausea, vomiting and hyperosmia during the administration, which can be
alleviated by pre-administration of anti-emetic medications. Sodium thiosulfate is slowly
given through the dialysis venous line toward the end of HD treatments. The selected dose
for this pilot study is the same as that used for the treatment of calcific uremic
Hypothesis 2: Decreasing the CAC score will be associated with a decrease in the calcium
content in other large arteries such as the thoracic aorta and carotid arteries.
Hypothesis 3: Decreasing the CAC score will be associated with a functional improvement of
the vascular system (as assessed by pulse wave velocity).
Hypothesis 4: Decreasing the CAC score will be associated with a decrease in the severity of
coronary artery stenoses.
Hypothesis 5: Decreasing the CAC will be associated with an increase in inhibitors of
vascular calcification (such as fetuin-A) and/or decrease in promoters of vascular
calcification (such as CRP).
Hypothesis 6: Sodium thiosulfate treatment will decrease the metabolic activity of plaques
in the coronary and aortic arteries.
We will freeze 10 ml of serum obtained prior to and then monthly during treatment for
subsequent analyses. Included in the analysis will be Fetuin-A levels but other relevant
markers will be considered. Blood will also be frozen for future genomic studies.
- Hemodialysis patient with thrice weekly treatments
- Coronary artery calcium score greater than 50
- Age greater than 18
- Compliant with hemodialysis treatments
- Informed consent
- Allergy to sodium thiosulfate
- Enrollment in another study
- Life expectancy less than 5 months
- Expectation of recovery of renal function
- Urine output of greater than 200 ml/day or contrast allergy will not receive