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CASE REPORT OPEN ACCESS

Is sodium thiosulfate a therapeutic option for non­uremic calciphylaxis?

Alexander Vonbank, Christoph Mayr, Edgar Meusburger, Karl Lhotta

ABSTRACT is recommended in order to enhance its efficacy and avoid unwanted side effects. Introduction: Non­uremic calciphylaxis, a rare disorder with high mortality, is associated with Keywords: Calciphylaxis, Sodium thiosulfate, severe calcifications of the media of arterioles Pharmacokinetics which cause vascular occlusion and tissue necrosis. Case Report: A non­uremic calciphylaxis ********* of the lower limb, possibly caused by coumarin therapy for atrial fibrillation. Treatment Vonbank A, Mayr C, Meusburger E, Lhotta K. Is sodium consisting of coumarin avoidance, vitamin K thiosulfate a therapeutic option for non­uremic supplementation and thrice weekly infusion of calciphylaxis? International Journal of Case Reports 20 g of sodium thiosulfate for three weeks led to and Images 2012;3(8):27–30. complete healing of the leg ulcers. Conclusion: Sodium thiosulfate produces a considerable ********* sodium load and may induce a decrease in serum calcium, potassium and phosphate levels doi:10.5348/ijcri­2012­08­161­CR­8 as well as an increase in the anion gap. We suggest that sodium thiosulfate is effective in the treatment of non­uremic calciphylaxis, but its use requires monitoring of electrolytes, acid­ base and volume status. Based on previous INTRODUCTION studies of sodium thiosulfate pharmacokinetics in individuals with normal renal function, which Calcific uremic arteriolopathy (CUA), also called showed rapid excretion by the kidneys, calciphylaxis, is a rare small vessel disease almost application as a slow infusion over several hours exclusively found in patients with end­stage renal disease [1]. Severe calcification of the media of arterioles cause 1 2 2 Ashish Bhargava , Vasavi Paidpally , Pragati Bhargava , vascular occlusion and tissue necrosis. The pathogenesis Alexander Vonbank1 ,2,3, Christoph Mayr1 , Edgar of the condition is incompletely understood. It appears Meusburger1 , Karl Lhotta1 ,2 Affiliations: 1 Department of Nephrology and Dialysis, to be associated with deranged calcium and phosphate Academic Teaching Hospital Feldkirch, Austria, metabolism and a lack of inhibitors of calcification 2Vorarlberg Institute for Vascular Investigation and secondary to chronic kidney disease [2]. Compared to Treatment (VIVIT), Feldkirch, Austria, 3Private University CUA, coumarin necrosis is associated with protein­c of the Principality of Liechtenstein, Triesen, Liechtenstein. deficiency and local microthromboembolic events. Non­ Corresponding Author: Alexander Vonbank, Department of uremic calciphylaxis (NUC) seems to be extremely rare. Nephrology and Dialysis, Academic Teaching Hospital A recent review of literature described 36 cases of NUC Feldkirch, Carinagasse 47, A-6800 Feldkirch, Austria; Ph: [3]. According to this report, NUC is associated with a +43 5522 303 2670; Fax: +43 5522 303 7506; Email: high mortality of 52% and an effective treatment for this [email protected] condition does not exist [3]. A patient with NUC who had a complete remission Received: 02 February 201 2 under sodium thiosulfate (STS) therapy and explain the Accepted: 07 April 201 2 alterations in serum and urinary electrolytes caused by Published: 01 August 201 2 STS is discussed here.

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CASE REPORT

The patient, an 88­year­old Caucasian woman, had a medical history of coronary artery disease, hypertension, ischemic stroke and permanent atrial fibrillation (CHADS² score 5 points) requiring oral anticoagulation with coumarins (initial INR value of 3.9). The patient was on coumarin therapy for 1.5 years. She presented with a two­week history of extremely painful circular necrotic ulcerations on the right lower leg (Figure 1). Peripheral artery disease was excluded with arterial duplex sonography with a Philipps iU22 ultrasound system. A soft tissue radiogram of the lower right leg using mammography film (low voltage and high resolution) showed small vessel calcification. A skin biopsy revealed extensive tissue necrosis and was Figure 1: Extensive necrotic ulcers are visible on the patient’s otherwise inconclusive. right leg. A diagnosis of NUC, possibly caused by coumarin therapy, was made on the basis of these clinical and radiological findings. Table 1: Laboratory results before and immediately after STS The patient’s condition deteriorated rapidly, with an infusion. increase in ulcerations and severe pain necessitating intravenous morphine. At hospital admission, the patient had normal serum calcium levels (2.27 mmol/L), borderline hypophosphatemia (0.77 mmol/L) and an eGFR of 59 mL/min. Parathyroid hormone (PTH) levels were elevated (116 pg/mL), and the patient had low 25­OH vitamin D3 levels (19.4 nmol/L). Coumarin therapy was discontinued and anticoagulation changed to low molecular heparin (enoxaparin). Intensive wound care was performed with chlorhexidine paraffin dressing (Bactigras®) and sulfadiazine unguent. The patient received 20 mg of oral vitamin K per day. Furthermore, intravenous STS 20 g per day, infused over 30 min, three times per week, was started. This infusion therapy was continued over the next three weeks. Therapy was well tolerated. For safety reasons and to determine STS pharmacokinetics, we measured serum and urine electrolytes before and immediately after STS infusion (Table 1). The ulcers on both legs improved rapidly after a three­week treatment. Analgesic therapy was finally reduced to low­dose oral therapy. Two months later, the leg ulcers had completely healed (Figure 2).

DISCUSSION precipitate vessel calcification [6]. In the above case To our knowledge, there is only one report of report of a patient with NUC and hypoparathyreoidism, successful treatment of NUC with STS [4]. NUC itself STS had to be administered over a prolonged period of seems to be extremely rare. In their review of 36 cases 46 weeks [4]. We observed complete remission of leg Nigwekar et al. [3] describe several risk factors for the ulcers after only three weeks of treatment. This disease, among them female gender, non­uremic difference may be explained by the far more advanced chronic kidney disease and coumarin use, all of which disease affecting the abdominal wall in the patient were present in our patient. described by Hackett et al. [4]. Another report describes It has been suggested that coumarins can alter the successful treatment of iatrogenic calcinosis cutis, which balance of calcification promoters and inhibitors by was caused by extravasation of calcium gluconate during inhibiting vitamin K­dependent carboxylation of matrix treatment for tumor lysis syndrome in a child with GLA protein, a potent inhibitor of calcification [5], and lymphoblastic leukemia [7]. in animal models coumarins have been shown to

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excretion. Urinary phosphate fell, probably as a consequence of the drop in serum phosphate. We also found a marked increase in the urine anion gap from 60 to 260 mval. We suspect that this unidentified anion is TS at a concentration of 100 mmol/L. From these data, we conclude that a large proportion of the infused STS were rapidly excreted by the kidneys. Under normal conditions only small amounts of TS are produced in the body by metabolism of sulfur containing amino acids. Normal serum levels are around 0.1 mmol/L [11]. The main physiologic function of TS is detoxification of cyanide to thiocyanate by the mitochondrial enzyme rhodanese (thiosulfate cyanide transsulfurase). Thiosulfate is freely filtered in the glomeruli and almost completely reabsorbed by the tubuli [11]. This is mediated by the sodium–coupled transporters NaS1 and NaS2, members of the SLC13 Figure 2: A photograph taken two months later shows family expressed by proximal tubular cells [12]. complete remission and healing of the ulcers. However, tubular reabsorption capacity seems to be very limited and infused STS is rapidly excreted by the kidney. Indeed, STS infusion has been used to measure Cicone et al. [8] reported the first case of successful glomerular filtration rate in the past [13]. Studies of a treatment of calciphylaxis with STS in a patient with bolus injection of 150 mg/kg STS in healthy volunteers chronic renal failure in 2004. showed a hundred­fold increase in serum TS levels The beneficial effect was ascribed to the fact that immediately after injection with a rapid fall towards calcium thiosulfate salts have an extremely high normal levels within three hours [11]. This fall was solubility and that STS therefore dissolves already caused by distribution of TS in the extracellular fluid precipitated calcium salts in the vessels. Furthermore, and renal excretion of 42% of the injected TS in the STS has a potent antioxidant effect, which helps urine within the three­hour period. In another study, in neutralize reactive oxygen species, and generates the which 12 g/m2 STS was infused over six hours in antioxidant glutathione [9]. In addition, STS is patients also receiving cisplatin chemotherapy, only metabolized to hydrogen sulfide, a potent vasodilator. 28% of TS was recovered in the urine up to four hours This last effect may explain the rapid improvement in after infusion [14]. In that study peak TS concentrations pain associated with STS use. Further case reports and in plasma were on average 1.5 mmol/L, which is small case series have been documented successful considerably lower than the level estimated in our treatment of calciphylaxis with sodium thiosulfate [10]. patient, and again fell to normal values within three A 10% STS solution (100 mL) contains 40 mmol hours. The results of these studies are in agreement with thiosulfate (TS) and 80 mval Na+. Thus, each treatment the serum and urine TS levels we derived from with 20 g STS contained 80 mmol TS and 160 mval Na+. measuring the serum and urine anion gaps. These data In order to study any other effects of STS on also suggest that when administered at slower infusion electrolyte metabolism, we measured serum electrolytes rates more TS is retained in the body than for a bolus immediately before and after infusion of STS. In serum, infusion, thus inferring that at a slow infusion rate more we detected a small decrease in ionised calcium, TS is oxidised to sulfate and metabolised to hydrogen possibly caused by its complexation with TS or by an sulfide and thereby exerts an antioxidative and increase in renal calcium loss. This drop in ionised vasodilatory effect. We would therefore suggest that in calcium was accompanied by an increase in the PTH patients with preserved renal function STS should be level. We also found a decrease in serum potassium infused over a period of several hours to increase its despite stable renal potassium excretion. Despite the efficacy. Short­time bolus infusion will cause rapid renal sodium load, serum sodium remained constant. Another excretion of a large proportion of infused TS. Long­term unexpected finding was a marked drop in serum infusion will also avoid high peak concentrations, which phosphate levels. A possible explanation would be cause nausea and vomiting [11]. In dialysis patients, intracellular shifting of anionic phosphate caused by the who do not have significant urinary excretion of infusion of TS anion. Previous reports describe a high thiosulfate, STS is expected to remain in the body for a anion gap acidosis in uremic patients treated with STS longer period of time and be able to induce its beneficial [8]. We observed a small decrease in pH, a drop in effects. Whether the amount of TS retained in the body bicarbonate and an increase in the anion gap. Assuming in our patient was high enough to exert any positive that this increase of 7 mval represents TS, which is a effect on NUC is presently unknown. In addition to STS divalent anion, a serum TS concentration of 3.5 mmol/L our patient was treated by discontinuing coumarins, can be calculated. prescribing oral vitamin K and local wound care, all of In the urine, we observed massive natriuresis which may have contributed to rapid improvement and accompanied by a more than twofold increase in calcium remission of the disease.

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CONCLUSION REFERENCES

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