SODIUM THIOSSULFATE TREATMENT FOR CALCIPHYLAXIS: IS THERE AN OPTIMAL DURATION OF THERAPY?

Calciphylaxis is a rare and serious condition characterized by vascular calcification, occlusion of microvessels in the dermis, subcutaneous adipose tissue, visceral organs and in the musculature1. The pathophysiology is uncertain; however it is believed that occlusion of cutaneous blood vessels occurs due to calcification within the media layer of the vessel walls with proliferation of endothelial cells and fibrosis under the intima that evolve with ischemic lesions. Vascular smooth muscle cells transform into osteoblast-like cells capable of producing and depositing hydroxyapatite crystals in response to hyperphosphatemia, hypercalcemia and hyperglycemia2.

The estimate annual incidence of calciphylaxis is 3 cases per 10.000 patients on hemodialysis in the United States and 4 cases per 10.000 patients in Europe.3

Studies have suggested the major risk factors for the development of calciphylaxis are chronic kidney disease (CKD) and secondary hyperparathyroidism (sHPT). Other factors are use of vitamin K inhibitors, liver disease, gastric bypass, female gender, obesity and diseases that alter the clotting status.4 

The diagnosis of calciphylaxis is clinical. Calciphylaxis should be suspected in CKD patients presenting with nodular, purpuric/erythematous lesions or painful subcutaneous plaques, livedo reticularis, non-healing ulcers and/or skin necrosis, especially on the thighs and other areas of increased adiposity. 

The treatment requires a multidisciplinary approach involving nephrology, dermatology, pain management and plastic surgery, although there are no clinical protocols based on randomized clinical trials, so management and treatment are based on specialists’ opinion5. Sodium thiosulphate (STS) is often used due to its vasodilator and antioxidant properties and action as a calcium chelator, but there is no definition regarding the duration of use6. Most reports show a wide variation in duration, with an average of 3 to 6 months, however there are reports in literature using for 1 to 2 years, often established by the severity of the case.

The present report describes a CKD patient on hemodialysis with calciphylaxis, who underwent treatment for 2 years with STS associated with debridement and reconstructive plastic surgery with good response and control of the disease.

Female patient, 41 years old, white, engineer, with chronic kidney disease (CKD) secondary to glomerulonephritis, on hemodialysis since 2013. In January 2020, she went to the hospital due to the onset of severe pain, burning, hyperemia, bruise, stiffened abdominal wall with progressive worsening in one month. She had some comorbidities like systemic arterial hypertension (SAH), obesity, dyslipidemia, , and hyperparathyroidism secondary (sHPT) to CKD. In clinical investigation, laboratory tests, viral serologies, biopsy and culture of the lesion were performed, with results within the reference values, except for PTH 2.000pg/mL, Phosphorus 8mg/dL Calcium 9.4mg/dL and slightly increased c-reactive protein. The anatomopathological  showed calciphylaxis, predominantly septal panniculitis, without vasculitis, presence of calcification of the wall of arterioles in the subcutaneous and deep dermis, as well as small caliber vessels in the subcutaneous tissue. Due to local infection, antibiotic therapy was started. During this period, the patient   had   a upper gastrointestinal bleeding requiring exploratory laparoscopy, duodenectomy and ulcerorraphy. After improvement of the digestive condition, sodium thiosulphate 25g per hemodialysis session was started, three times a week. The patient remained hospitalized during  3 months  and required 14 surgical debridements and reconstructive plastic. Due to the worsening of the COVID-19 pandemic in December 2020 in Brazil, which led to difficulty in hospitalizations for other causes and the suspension of elective surgeries, just nine months after the first hospitalization, a subtotal parathyroidectomy was performed. He developed persistent PTH in the seventh month after surgery, and total parathyroidectomy was performed with autotransplantation of parathyroid tissue in the right parasternal muscles associated with right partial thyroidectomy, evolving with hypoparathyroidism.

So far, there are no clinical studies that prove the evidence of treatment for calciphylaxis. Because it is a rare condition, current management is based on expert experience.

The STS is often used despite uncertain effects. It is believed that its benefits result from antioxidant, vasodilator and calcium chelating mechanisms, leading to the reduction of cutaneous nodules, calcification and healing6,7.

In literature, there are several records with different times of treatment with STS, without a well-defined protocol regarding this duration. Tangkijngamvong N et al. 8 described a series of 8 cases with calciphylaxis, whose patients underwent hemodialysis and presented ulcer and necrosis classified as moderate to severe and were divided into two groups: non-responders who underwent a 20-week treatment with a 25-week survival % after one year, and responders who underwent an average of 30 weeks of treatment with 100% survival after one year. Salmhofer H et al9, described a series of 5 cases, in which the treatment was performed in combination with STS, cinacalcet, and sevelamer. The time of treatment with STS was one year and one month, without major side effects and with a survival rate of 80-100% after 1 year of treatment.

A systematic review carried out in 201710 analyzed 45 articles and 96% of patients were on dialysis with a median duration of 44.5 months and 75% were female. The impact of STS on effective treatment, non-responsive treatment and mortality was evaluated. Effective treatment was defined as patients who had stable lesions without remission, which occurred in 70.1% of patients. Treatment non-responsive was defined as stable skin lesions without remission or exacerbation of disease in patients who remained alive. All-cause mortality after STS treatment was defined as death due to exacerbation of calciphylaxis or other complications of advanced CKD, with a rate of 37.6%. There was no significant difference in efficacy between the different methods of STS administration (p = 0.19); however, the mean treatment time is not described.

In the present case, the patient had well-established risk factors for the development of calciphylaxis, such as female gender, prolonged time on hemodialysis, obesity mineral and bone disorders sHPTS. In addition, she developed very serious life-threatening manifestations, which led to the choice of prolonged use of the STS. In this case, administration of sodium thiosulphate was not associated with side effects such as nausea, vomiting, or metabolic acidosis. The patient is being followed up at the outpatient clinic, has been on treatment with STS for 2 years and the skin lesions have not recurred so far, despite the radiographic examinations showing no evidence of vascular improvement. From this case, we demonstrate the long-term benefit and safety of using STS, in a patient with severe manifestations of calciphylaxis.

From this case, we demonstrate the long-term benefit and safety of using STS, in a patient with severe manifestations of calciphylaxis.