Intravenous Sodium Thiosulfate for the Treatment of Calciphylaxis (Calcific Uraemic Arteriolopathy)

Calciphylaxis or calcific uraemic arteriolopathy (CUA) is a complication that may be associated with end stage renal disease (ESRD). Previously thought to be a rare complication, it is now gaining an increase in recognition due to a greater awareness of the associated clinical signs and risk factors. CUA occurs mainly in patients with ESRD and in renal transplant recipients; however, there have been reports of non-uraemic cases.

CUA is associated with extremely high morbidity and mortality rates. The mortality rate associated with CUA has been reported to be in the realm of 60% to 80% in patients with chronic kidney disease (CKD). It is difficult to determine the incidence and prevalence of this condition; a German registry has reported approximately 35 cases per year and a total of 160 prospectively collected cases to date.

There are several risk factors which have been identified for the development of this condition, with the most predominant being CKD, and particularly in those with ESRD. Other risk factors have been identified, many of which relate to disturbances in calcium-phosphate homeostasis. These include hyperparathyroidism, hyperphosphataemia, hypercalcaemia, hypoalbuminaemia, dialysis, vitamin D, vitamin K antagonists, diabetes mellitus, obesity, female gender and Caucasian ethnicity.

The pathophysiology of CUA is complex and not very well understood. It is thought to involve disturbances of calcium-phosphate homeostasis, inhibitors of vascular calcification such as fetuin-A and matrix gamma-carboxyglutamic acid (Gla) protein, and endothelial dysfunction due to oxidative stress and reactive oxygen species. The resulting calcification of arteries and soft tissue causes skin and fat necrosis. Clinical manifestations can include painful skin lesions, altered sensation, and also subcutaneous nodules; all of which may lead to extremely painful, ischaemic, and necrotic ulcers.

CUA is a rare condition and as such, there have been no randomised, large-scale controlled trials that have looked into treatment modalities. Treatment for CUA as reported in the literature is multi-modal and there does not appear to be a ‘one size fits all’ regimen. Interventions that have been reported have come from case series and reports, and treatment has ranged from surgical debridement, hyperbaric oxygen, parathyroidectomy, calcimimetics, low calcium dialysis, bisphosphonate therapy, and now sodium thiosulfate.

In Australia, sodium thiosulfate (Na2S2O3) is approved for use as an antidote to cyanide poisoning. Its role however, has expanded and it has been used off-label in the treatment of CUA. The use of sodium thiosulfate in the treatment of CUA has been described in a number of case reports. Details of some of these case reports in patients treated with sodium thiosulfate are listed below.

There have been a number of proposed mechanisms for sodium thiosulfate’s role in the treatment of CUA. It is thought that the molecule complexes with calcium resulting in a soluble compound and reducing calcium phosphate precipitations. Other mechanisms proposed for sodium thiosulfate include potential antioxidant effects as well as an improvement in vascular endothelial function and vasodilatory effects.

Pharmacists can play a role in the management of patients with calciphylaxis. Counselling patients to ensure that prescribed phosphate binders are taken correctly will help to control serum phosphate levels. Recommendations may also be made to switch patients from calcium-containing phosphate binders to non-calcium containing products such as sevelamer.

Pharmacists can also advise on the administration of sodium thiosulfate. Sodium thiosulfate is cleared renally, and given its small size and solubility in water, is likely to be removed by dialysis. As such, infusions should be given over an hour after dialysis. In patients who undergo haemodialysis, it is recommended that administration is given after the dialysis session.

Calciphylaxis is a rare and complex condition that is not very well understood. Treatment has been largely based around case reports and is often multi-modal. Sodium thiosulfate appears to be very well tolerated and has shown to improve pain and result in complete healing of lesions in patients with calciphylaxis. Although evidence has only been acquired through case reports, it appears to be a promising treatment which requires further investigation through large-scale, randomised controlled trials.

Case Studies – Calciphylaxis Treatment:

1. Ciccone et al 2004
   • 69 year old Caucasian female, obese, receiving continuous ambulatory peritoneal dialysis. Medications included calcitriol, calcium acetate. Labs showed hyperphosphataemia.
   • Painful subcutaneous lesions on the leg, confirmed by x-ray technetium scans. Typical clinical presentation.
   • Initially treated with conventional therapy. Sevelemar started and prednisolone 40mg every other day initiated. Sodium thiosulfate 25g IV over 30 to 60 minutes, 3 times a week for a total of 8 months. Adverse effects seen included mild rhinorrhoea, sinus congestion. Serum HCO3- fell and anion gap rose during treatment.
   • Pain improved at 2 weeks, by week 8 pain had ceased and lesions reduced in size.
2. Guerra et al 2005
   • 46 years old, Caucasian female, history of liver transplantation. GFR 19mL/min. Medications included cyclosporine, corticosteroids.
   • Painful bilateral lower leg lesions. Multiple tender, erythematous nodular and necrotic lesions.
   • Sevelemar and haemodialysis started. As skin lesions progressed and her pain increased, CVVH (continuous veno-venous haemofiltration) initiated with sodium thiosulfate 25g IV over 60 minutes every other day. No complications seen with the use of sodium thiosulfate.
   • Improvement seen 2 weeks after commencement on CVVH and sodium thiosulfate. Her pain remained at a minimal level and she was discharged a month later with the lesions almost healed. She remained on sodium thiosulfate 3 times a week as an outpatient for 6 months.
3. Brucceleri et al 2005
   • 48 year old Caucasian female, ESRD receiving haemodialysis. Past history of 2 x parathyroidectomies and remained hyperphosphataemic. Medications included calcitriol, calcium carbonate.
   • Painful skin ulceration in the fatty tissue of the abdomen, breasts, hips and proximal thighs.
   • Dialysis frequency increased from 3 to 4 times per week (5 hours), doses of calcium free phosphate binders, calcium-free dialysate used. Parathyroid hormone (PTH) levels reduced however, wounds progressively worsened. Wound debridement was performed.
   • Hyperbaric oxygen treatment initiated but then ceased.
   • Sodium thiosulfate therapy initiated at 5g IV over 10 minutes 4 times a week at haemodialysis. Mild nausea and a change in acid-base (decrease in HCO3- and increase in anion gap) status seen.
   • After 6 months, wound healing was excellent.
4. Meissner et al 2006
   • 35 year old Caucasian female, ESRD receiving haemodialysis. Past medical history includes secondary hyperparathyroidism. Laboratory results demonstrate hyperphosphataemia, hypercalcaemia, hyperparathyroidism.
   • Large, painful necrotic ulcers and necrosis of the skin on thighs, buttocks and abdomen.
   • Intensified haemodialysis (5 hours, 3 times per week), professional wound care and antibiotics were initially prescribed; however lesions progressed and pain worsened resulting in escalated doses of opioids. Calcium acetate, calcidiol and warfarin were ceased. Sodium thiosulfate 25g IV over 60 minutes was eventually started.
   • After 2 weeks, no new lesions were observed and pain dramatically resolved.
   • Patient was discharged after 5 weeks in hospital after the first sodium thiosulfate infusion, and 7 weeks later, the ulcers had closed. Sodium thiosulfate was administered for a total of 6 weeks.
5. Subramaniam et al 2008
   • 50 year old female, chronic renal impairment, obese, on haemodialysis, secondary hyperparathyroidism
   • Elevated phosphate, parathyroid hormone, CRP before undergoing a sub-total parathyroidectomy.
   • Tender, indurated subcutaneous nodules over abdomen, buttock and hip. Biopsy revealed extensive cutaneous ulceration and necrosis.
   • Intensified haemodialysis with low calcium dialysate, sevelamer commenced, analgesia and aggressive wound care instituted. Within one month, new lesions developed, pain increased with increasing analgesia required. Commenced on sodium thiosulfate 25g IV 3 times per week after haemodialysis. No adverse effects seen.
   • Pain resolved after 2 weeks, lesions healed in 12 weeks and sodium thiosulfate infusion ceased.
   • Lesions began to appear 1 month after treatment ceased. Sodium thiosulfate recommenced, pain disappeared after 2 weeks, skin healed within 12 weeks, treatment continued for 8 months.
   • No recurrence of lesions seen at 18 months.