George F. Cohen, MD; Nikki S. Vyas, BS
Dr. Cohen is from Department of Dermatology and Cutaneous Surgery, University of South Florida Morsani College of Medicine, Tampa, Florida; Nikki S. Vyas is from University of South Florida Morsani College of Medicine, Tampa, Florida
Disclosure: The authors report no relevant conflicts of interest.
The authors review the presentation, diagnosis, and treatment of calciphylaxis and also describe applications of a novel therapeutic option, sodium thiosulfate. Two cases of advanced uremic calciphylaxis from both clinic and hospital settings are presented. One patient, a 57-year-old woman with end-stage renal disease, was treated with surgical debridement and sodium thiosulfate 25g three times a week. After introducing sodium thiosulfate treatment, the affected sites continue to heal with encouraging improvement of ulcer depth. Sodium thiosulfate was well-tolerated and facilitated wound healing. The patient did not develop sepsis. Sodium thiosulfate appears to be a viable first-line treatment for calciphylaxis and should be seriously considered early in the course of treatment.
(J Clin Aesthet Dermatol. 2013;6(5):41–44.)
Calciphylaxis is an obliterative vasculopathy that causes ischemia and necrosis of the skin, subcutaneous fat, visceral organs, and skeletal muscle. Early lesions resemble livedo reticularis and can appear as indurated, erythematous papules, nodules, plaques, or bullae. As the lesions grow, they become more stellate and develop necrotic foci, eventually becoming painful ulcerations. Proximal involvement at high-trauma sites (thighs, abdomen, buttocks, and breasts) is most common and associated with a higher mortality rate.
While the pathogenesis of calciphylaxis is poorly understood, it is theorized to be a two-stage process. The first stage involves vascular injury in the form of mural calcification, intimal hyperplasia, and endovascular fibrosis. This vessel damage sensitizes the supplied tissue areas to ischemia. In the second stage, additional vascular damage is triggered by clinical events, such as local trauma, hypotension, or thrombosis and leads to the development of an ischemic infarct, dystrophic calcification, or ulceration.1 Histological findings include a mixed inflammatory infiltrate, a giant cell reaction, and panniculitis with subcutaneous calcium deposits, and fat necrosis.
Calciphylaxis affects 1 to 4 percent of patients with end-stage renal disease (ESRD),[1,2] but can also impact patients with normal calcium levels and renal function. In addition to renal impairment and dialysis dependency, predisposing factors that increase a patient’s risk for developing calciphylaxis include female gender, Caucasian race, obesity, warfarin use, systemic steroid use, hypercoagulable states, diabetes mellitus, liver disease, protein malnutrition, calcium salts and vitamin D treatment, raised serum calcium phosphate product (>70mg/m2), raised serum phosphate, and raised serum aluminium. Prognosis for calciphylaxis generally remains poor due to the high risk of complications, namely sepsis. The estimated one-year survival rate is 45.8 percent.
Sodium thiosulfate (STS) is a powerful antioxidant and chelating agent, which has been traditionally used for cyanide poisoning and cisplatin toxicity. There are increasing reports of STS being used off-label to successfully treat both uremic[4–11] and nonuremic[12–15] calciphylaxis.
A 57-year-old woman presented to the dermatology clinic with a five-month history of extremely painful bilateral ulcerations of the medial thighs, which were suggestive of calciphylaxis. One area on the left thigh had formed a deep ulcer with a necrotic eschar (Figure 1). Her medical history included ESRD requiring peritoneal dialysis for the past year, chronic hypertension, type 2 diabetes mellitus, gastric bypass surgery, and obesity. Ciprofloxacin 500mg twice a day for one week was prescribed prophylactically and an excisional biopsy was taken.
Histological findings showed diffuse inflammatory infiltrate extending throughout the subcutaneous fat with extensive fat necrosis and calcium deposition in addition to calcified vessel walls, haphazardly arranged elastic fibers, panniculitis, and vascular thrombi (Figure 2 and Figure 3). Laboratory investigations showed elevated levels of blood urea nitrogen (BUN) 29mg/dL, serum creatinine 7.7mg/dL, phosphorus 4.9mg/dL, serum kappa 68mg/L, and lambda 84.5mg/L free chains. There were decreased levels of albumin 1.4g/dL, total serum protein (4.2g/dL), and vitamin D 25 OH 4ng/mL. Values for serum calcium, parathyroid hormone (PTH), prothrombin time (PT), and partial thromboplastin time (PTT) were all within normal limits. An acute hepatitis panel also showed no abnormalities.
Two weeks later, the patient’s condition had worsened. The lower extremity ulcers were now producing white, clear drainage. She was subsequently admitted to the hospital, where wound cultures revealed heavy Staphylococcus aureus growth as well as Enterococcus (streptococcus) faecalis colonization. The S. aureus growth was resistant to erythromycin and penicillin, and the patient’s nares tested positive for presence of methicillin-resistant S. aureus (MRSA) deoxyribonucleic acid.
In the hospital, a nephrology consult was placed and the patient was transitioned from peritoneal dialysis to hemodialysis three times a week, along with intravenous STS 25g to be administered with each hemodialysis session. Cephalexin 500mg once a day for 10 days was also prescribed. After discharge from the hospital, hemodialysis and STS were continued on an outpatient basis with a local dialysis center.
After 10 weeks of STS treatment, while the patient’s condition improved, the progress had been limited. Therefore, at this time it was decided to surgically debride the necrotic eschar in addition to maintaining the aforementioned STS regimen. One month later (14 weeks after initiating treatment with STS), the surgically debrided areas were healing well with good granulation tissue. Currently, the patient continues to achieve gradual improvement of existing ulcers with no reported side effects.
A 35-year-old African-American woman with a history of ESRD secondary to human immunodeficiency virus (HIV) and cocaine use presented to the hospital with exquisitely tender nodules and necrotic ulcers of the lower extremities (Figures 4a and 4b). Excisional biopsy of affected skin confirmed the diagnosis of calciphylaxis. The patient subsequently underwent surgical debridement of her wounds, and referrals to nephrology and internal medicine were placed. Unfortunately, the patient experienced rapidly progressive renal deterioration, leading to multiple organ failure and death.
STS prevents precipitation and formation of calcium deposits by binding calcium to form calcium thiosulfate, a highly soluble calcium salt. Additionally, antioxidant properties of STS may reverse the endothelial dysfunction seen in calciphylaxis. Although STS is relatively safe, potential side effects include nausea,[7,10,11] rhinorrhea, sinus congestion, increased appetite, prolonged QT interval, headache, weakness, vomiting,[7,11] mild phlebitis, and an increased anion gap metabolic acidosis.
In this report, STS and surgical debridement were safely utilized in a 57-year-old woman with advanced uremic calciphylaxis and normal calcium and phosphate levels. Her triggers for developing calciphylaxis were renal insufficiency, female gender, Caucasian race, obesity, dialysis dependency, diabetes mellitus, and protein malnutrition. The main goal was to heal the ulcerations before sepsis could develop. STS was selected to treat this patient after numerous successful reports of symptomatic relief and clinical improvement occurring as early as two weeks. Recent literature even suggests STS as a first-line agent, especially in absence of hyperparathyroidism. While wound debridement remains controversial, one retrospective study found surgical debridement seemed to improve success rate.
Most cases in the literature use STS 25g intravenously 3 to 4 times per week.[6,10] In one study, calciphylaxis patients receiving STS had better prognosis with higher doses and earlier intervention. In the same study, STS therapy had little impact on overall mortality for obese patients and patients on long-term renal replacement therapy.
STS promoted reduced healing time in a patient with advanced calciphylaxis. There are no double-blind trials or uniformly effective therapy. STS appears to be a viable alternative and early use should be considered. Optimal dosage and duration of therapy still needs to be determined.
1. Wilmer WA, Magro CM. Calciphylaxis: emerging concepts in prevention, diagnosis, and treatment. Semin Dial. 2002;15(3):172–186.
2. Angelis M, Wong LL, Myers SA, et al. Calciphylaxis in patients on hemodialysis: a prevalence study. Surgery. 1997;122(6): 1083–1089; discussion 1089–1090.
3. Weenig RH, Sewell LD, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56(4):569–579.
4. Cicone JS, Petronis JB, Embert CD, et al. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis. 2004;43(6):1104–1108.
5. Meissner M, Bauer R, Beier C, et al. Sodium thiosulphate as a promising therapeutic option to treat calciphylaxis. Dermatology. 2006;212(4):373–376.
6. Ackermann F, Levy A, Daugas E, et al. Sodium thiosulfate as first-line treatment for calciphylaxis. Arch Dermatol. 2007;143(10):1336–1337; author reply 1338.
7. Baker BL, Fitzgibbons CA, Buescher LS. Calciphylaxis responding to sodium thiosulfate therapy. Arch Dermatol. 2007;143(2):269–270.
8. Subramaniam K, Wallace H, SinniahR, et al. Complete resolution of recurrent calciphylaxis with long-term intravenous sodium thiosulfate. Australas J Dermatol. 2008;49(1):30–34.
9. Kalisiak M, et al. Calcific uremic arteriolopathy (calciphylaxis): successful treatment with sodium thiosulfate in spite of elevated serum phosphate. J Cutan Med Surg. 2009;13(Suppl 1):S29–S34.
10. Auriemma M, Carbone A, Di Liberato L, et al. Treatment of cutaneous calciphylaxis with sodium thiosulfate: two case reports and a review of the literature. Am J Clin Dermatol. 2011;12(5):339–346.
11. Scola N, et al. Complete clearance of calciphylaxis following combined treatment with cinacalcet and sodium thiosulfate. J Dtsch Dermatol Ges. 2011;9(12):1030–1031.
12. Hackett BC, McAleer MA, Sheehan G, et al. Calciphylaxis in a patient with normal renal function: response to treatment with sodium thiosulfate. Clin Exp Dermatol. 2009;34(1): 39–42.
13. Ong S, Coulson IH. Normo-renal calciphylaxis: response to sodium thiosulfate. J Am Acad Dermatol. 2011;64(5): e82–e84.
14. Stanciu M, Gagne-Henley A, Therien G. Unusual case of proximal calciphylaxis without renal failure. J Cutan Med Surg. 2011;15(5):290–292.
15. Kalajian AH, Malhotra PS, Callen JP, et al. Calciphylaxis with normal renal and parathyroid function: not as rare as previously believed. Arch Dermatol. 2009;145(4):451–458.
16. Hayden MR, Tyagi SC, Kolb L, et al. Vascular ossification-calcification in metabolic syndrome, type 2 diabetes mellitus, chronic kidney disease, and calciphylaxis-calcific uremic arteriolopathy: the emerging role of sodium thiosulfate. Cardiovasc Diabetol. 2005;4(1):4.
17. Noureddine L, Landis M, Patel N, et al. Efficacy of sodium thiosulfate for the treatment for calciphylaxis. Clin Nephrol. 2011;75(6):485–490.