- Email: [email protected]
Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis
G Model BONSOI-4200; No. of Pages 4
ARTICLE IN PRESS Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Case report
Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis b,c ˜ Stéphanie Malbos a , Pablo Urena-Torres , Thomas Bardin a,d , Hang-Korng Ea a,∗,d,e a
Service de rhumatologie, pôle appareil locomoteur, centre Viggo-Petersen, hôpital Lariboisière, AP–HP, 2, rue Ambroise-Paré, 75010 Paris, France Clinique du Landy, 93400 Saint-Ouen, France Service des explorations fonctionnelles rénales, hôpital Necker, 75015 Paris, France d UFR de médecine, université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France e Inserm, UMR-1132, hôpital Lariboisière, 75010 Paris, France b c
a r t i c l e
i n f o
Article history: Accepted 9 March 2015 Available online xxx Keywords: Calciphylaxis Calcific uremic arteriolopathy Vascular calcifications Sodium thiosulfate Apatite Dialysis
a b s t r a c t Background: Calcific uremic arteriolopathy (CUA) or calciphylaxis is a severe complication of advanced chronic kidney disease (CKD) and dialysis. Few effective treatments are available and the mortality rate is high. We report 4 cases in which sodium thiosulfate therapy was rapidly effective. Cases: Sodium thiosulfate therapy was given to 4 Caucasian patients (3 females and 1 male aged 49 to 91 years) with CUA. The causes of end-stage CKD were nephroangiosclerosis (n = 2) and diabetic nephropathy (n = 2). The lesions developed 1 to 6.5 years after the initiation of hemodialysis and involved the lower limbs in 2 patients, the fingers in 1 patient, and a breast in the remaining patient. They were responsible for pain and skin necrosis in all 4 patients. Local superinfection occurred in 3 patients. Intravenous sodium thiosulfate was given in a dosage of 12.5 to 25 g after each hemodialysis session, for 12 to 24 weeks. The pain and trophic disorders resolved fully in all 4 patients. The side effects consisted of nausea and vomiting (n = 2) and a moderate blood pressure decrease (n = 1). No recurrences were noted during the follow-up of 5 to 17 months after treatment discontinuation. Conclusion: The findings from this small case-series suggest that sodium thiosulfate may hold promise for the treatment of CUA. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Calciphylaxis or calcific uremic arteriolopathy (CUA), first described in 1962, is characterized by calcifications of the cutaneous and subcutaneous arterioles. Ninety percent of cases of CUA develop in patients with end-stage chronic kidney disease (CKD) [1]. CUA is associated with high mortality rates ranging from 40 to 86%. The skin lesions predominate at the lower limbs and are more common in proximal areas. They consist of erythematous mottling and indurated nodules or plaques that are often extremely painful and usually progress to form ulcers. Histological studies show vasculopathy without vasculitis. Calcifications are visible in the media of the small arteries and arterioles of the dermis and hypodermis, which also exhibit intimal hypertrophy and endovascular fibrosis. Calcium deposition within the blood vessels is an early and crucial event in the development of CUA plaques [2]. The calcifications are believed to result chiefly from mineral and
bone homeostasis disorders with hyperphosphatemia and elevation of the calcium-phosphate product, abnormally high or low parathyroid hormone levels, adynamic bone disease, excess vitamin D, and/or aluminum toxicity. Other local and systemic factors are involved, such as inflammation, malnutrition with hypoalbuminemia, vitamin K antagonist therapy, endothelial dysfunction, and/or an imbalance between promineralizing factors and calcification inhibitors. The treatment of CUA is difficult and standard measures often lack efficacy. Sodium thiosulfate (STS) has been used for over a century to treat cyanide poisoning. There are reports of successful STS therapy in patients with ectopic calcifications such as recurrent urinary lithiasis and uremic tumoral calcinosis [3]. In case-series of patients with CUA, STS therapy produced inconsistent results. Here, we report 4 cases of CUA in patients on chronic hemodialysis who responded to STS therapy. 2. Case-reports 2.1. Case #1
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (H.-K. Ea).
The first patient was a 91-year-old man who had been receiving standard hemodialysis at our center for 1 year (Table 1). He
http://dx.doi.org/10.1016/j.jbspin.2015.03.007 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
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S. Malbos et al. / Joint Bone Spine xxx (2015) xxx–xxx
2
Table 1 Clinical features in 4 patients with calcific uremic arteriolopathy and effects of sodium thiosulfate therapy. Patient #1
Patient #2
Patient #3
Patient #4
Age/sex Ethnicity CV risk factors
91/H Caucasian HT, dyslipidemia, MI
Location Time from HD to onset (years) Previous treatments
Nephroangiosclerosis Hemodialysis Pain, infection, sinus tract, necrosis Fingers 1 Phosphate chelation
49/F Caucasian HT, diabetes, dyslipidemia, MI Diabetic nephropathy Hemodialysis Pain, infection, necrosis
91/F Caucasian HT, MI
Type of CKD Dialysis Clinical features
55/F African HT, diabetes, dyslipidemia, LLOAD, angina Diabetic nephropathy Hemodialysis Pain, infection, necrosis Right breast 6.5 Calcium-channel inhibitors
Lower limbs 1.5 Phosphate chelation
STS dosage Duration of STS use (weeks) Outcome Follow-up (months)
25 g/48 h 16 Full recovery 0 (died)
12.5 g/48 h 24 Full recovery 5
12.5 g/48 h 16 Full recovery 8
Lower limbs 5.5 Phosphate chelation, calcium-channel inhibitors 25 g/48 h 12 Full recovery 17
Nephroangiosclerosis Hemodialysis Pain, necrosis
F: female; M: male; CKD: chronic kidney disease; CV: cardiovascular; HD: hemodialysis; HT: hypertension; MI: myocardial infarction; LLOAD: lower limb occlusive arterial disease; STS: sodium thiosulfate.
was overweight and had dyslipidemia. His cardiovascular history included hypertension, percutaneous coronary angioplasty to treat myocardial infarction, diffuse arteriosclerosis, and heart failure due to a combination of hypertension, coronary artery disease, and valvular disease. He had early-stage secondary hyperparathyroidism. His chronic medications consisted of the antiplatelet agent clopidogrel, a lipid-lowering agent, and two antihypertensive drugs (a beta-blocker and a nitrate). In February 2006, he was started on chronic hemodialysis, three 4-hour sessions per week, for endstage renal failure due to nephroangiosclerosis. Extremely painful ulcers and necrotic lesions developed over the fingers of his right hand 21 months later (Fig. 1). Radiographs of the hands visualized subcutaneous calcifications measuring 1 to 4 mm in diameter
and located under the skin lesions. These clinical and radiographic features strongly suggested CUA, making a biopsy unnecessary. The skin lesions ran a complicated course, with the formation of sinus tracts, bacterial infection, and ischemic necrosis. Laboratory findings at the diagnosis of CUA were as follows: serum calcium: 2.66 mmol/L; serum phosphate: 1.85 mmol/L; calcium-phosphate product: 4.92 mmol2 /L2 ; 25(OH) D: 41.40 ng/mL; 1,25(OH)2 D: 11 ng/L; parathyroid hormone: 80 ng/L; bone alkaline phosphatase: 12.9 g/L; and CTX: 1320 ng/mL. Markers for systemic inflammation were moderately elevated (C-reactive protein: 7.10 mg/L; and erythrocyte sedimentation rate: 38 mm/h). He initially received analgesics and treatments to eradicate the local infection. Phosphate chelation therapy and a vitamin D analog were given to
Fig. 1. Patient #1. Course of the ulcerated and necrotic skin lesions during treatment with sodium thiosulfate (STS). The necrotic lesions on the fingers developed after 21 months of chronic hemodialysis. They resolved rapidly with STS therapy.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
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improve the calcium-phosphate balance. These measures failed to induce marked clinical or radiographic improvements. STS therapy was therefore considered. The patient accepted this option, and a temporary authorization for STS therapy was obtained according to French legislation. STS in a dose of 25 g was administered as a slow intravenous infusion over 30 minutes at the end of each hemodialysis session, i.e., three times a week. This treatment was well tolerated. Dramatic clinical and radiographic improvements were noted. The patient became pain-free within a few weeks and his trophic disorders had resolved partially by the end of the first month. After 2 months, the lesions were almost fully healed. STS therapy was not associated with the development of any laboratory abnormalities. After 16 weeks of STS therapy, the patient died of a myocardial infarction. A causal role for STS therapy in this event is unlikely given the patient’s history of cardiovascular disease and time to occurrence. 2.2. Patients #2, #3, and #4 Three other patients with CUA received STS therapy at our center. They were females, with an age range of 49–91 years and a history of hypertension and coronary artery disease whose symptoms ranged from angina pectoris to acute coronary syndrome requiring aortocoronary bypass surgery; 2 patients also had type 2 diabetes mellitus and dyslipidemia. All 3 patients had end-stage renal failure, due to diabetic nephropathy (n = 2) or nephroangiosclerosis (n = 1), and required chronic hemodialysis, three 4-hour sessions per week. The calcium concentration in the dialysis solution was 1.50 to 1.60 mmol/L. The time from hemodialysis initiation to development of the CUA lesions was 6.5, 1.5, and 5.7 years, respectively. The calcifications were located in the subcutaneous tissue of the right breast in 1 patient and in the lower limbs in the other 2 patients. The diagnosis of CUA relied on the clinical features, with no histological documentation. The lesions became infected in patients #2 and #3. The initial treatment consisted of a calcium-channel inhibitor (n = 1), a phosphate chelator containing no calcium or aluminum (n = 2), and/or 1␣ vitamin D (n = 1). None of these treatments was effective. Temporary authorization for STS therapy was obtained as required by French law. STS was given intravenously in a dosage of 12.5 to 25 g over 30 minutes at the end of each hemodialysis session. Treatment duration was 24, 16, and 12 weeks, respectively. STS therapy was effective in all 3 patients, with healing of the lesions and complete pain relief. The adverse effects were mild and did not require treatment discontinuation; they consisted of nausea and vomiting (n = 2) and self-limited hypotension (n = 1). Serum calcium and phosphate levels and the calcium-phosphate product were normal in all 3 patients and did not change significantly during STS therapy. STS was discontinued when the lesions were fully healed and the patients were free of pain. Follow-up duration after STS discontinuation was 5, 8, and 17 months, respectively. There were no recurrences. Table 1 reports the main data in the 4 patients. The case of patient #2 deserves comment. She was initially managed at another center, where she received STS on two occasions. She developed CUA of the right breast during hemodialysis and received an intravenous infusion of 10 g of STS after each hemodialysis session, for 7 months. The outcome was favorable and STS therapy was discontinued in February 2008. In 2009, after kidney transplantation, new CUA lesions developed over the abdomen, both thighs, and the right breast. STS therapy was resumed, as a 25-g intravenous infusion three times a week then once a week; total treatment duration was 7 months. Although the existing lesions decreased in size, new lesions developed over the right breast. Subsequently, hypercalcemia and acute renal failure required resumption of the chronic hemodialysis, which she received at our center.
3
3. Discussion Our case-reports demonstrate that intravenous STS therapy is rapidly effective against CUA complicating chronic hemodialysis in patients with end-stage CKD. CUA is a well-documented and extremely severe complication of end-stage renal failure requiring chronic hemodialysis. Women are predominantly affected (male/female ratio, 1/3). Among patients with CUA, 80% have hyperparathyroidism, 68% hyperphosphatemia, 20% hypercalcemia, and 33% a high calcium-phosphate ratio [4]. In our small case-series, a single patient had hyperparathyroidism and none had abnormal calcium and phosphate levels. Obtaining histological documentation is not mandatory when the clinical setting and lesions are typical, particularly as the biopsy procedure can worsen the lesions. None of our patients underwent histological examination, which was performed in 53% of patients in the largest published case-series of CUA complicating hemodialysis and treated with STS [5]. The treatment of CUA is challenging. The standard approach consists in restoring the calcium-phosphate balance by eliminating calcium and vitamin D intakes, decreasing the dietary intake of phosphate, administrating phosphate chelators that contain no calcium or aluminum, controlling parathyroid hormone levels, reducing the intake of aluminum, and optimizing the dialysis parameters (increasing session duration and or frequency, improving performance by using biocompatible highly permeable membranes, and using low-calcium dialysis solutions). Many drugs intended to dissolve calcific deposits are inconsistently effective when used to treat ectopic calcifications. These drugs include bisphosphonates, calcium-channel inhibitors, low-dose vitamin K antagonists, probenecid, vinpocetine, calcimimetics, and TNF␣ antagonists. STS, in contrast, has been used successfully in CUA, as reported for the first time by Cicone et al. in 2004 [6]. Subsequently, several small case-series were published, followed by a large study in 172 patients [5], in which STS therapy was effective in three-quarters of patients (full resolution: 26.4%; marked improvement: 18.9%; and improvement: 28.3%) [5]. Our patients received STS intravenously in a dosage of 12.5 to 25 g per injection depending on patient tolerance, at the end of each hemodialysis session. This treatment regimen ensured healing of the lesions within a few weeks with no recurrences 5 to 17 months after treatment discontinuation. However, longer follow-ups are needed. In our case-series and previously published studies, STS appeared safe. The exact mechanism of action of STS still awaits elucidation. The initially hypothesized calcium-chelating effect has been ruled out by recent studies [7,8]. In vitro, STS failed to diminish ionized calcium levels in culture media [8] and, in contrast to ethylenediamine-tetra-acetic disodium acid (EDTA), did not bind to calcium crystals in hydroxyapatite [7]. However, STS inhibited calcification of previously injured aorta, suggesting a direct effect on the extracellular matrix and cellular effects [8]. A 2014 in vitro study established that STS inhibited the calcification of mature adipocytes stimulated by high concentrations of phosphate [9]. STS also prevented adipocyte-induced calcification of vascular smooth muscle cells, by decreasing the production of vascular endothelial growth factor (VEGF) and leptin [9]. Other reported effects of STS include generation of the antioxidant glutathione and nitric oxide production responsible for vasodilation and improved endothelial cell function [10,11]. Our case-reports support STS as a promising treatment for CUA. Studies are needed to unravel the mechanisms of action of STS. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
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Authors’ contributions: S.M.: data collection and analysis, drafting and critical revision of the manuscript; P.U.T.: data collection and analysis, drafting and critical revision of the manuscript; T.B.: data analysis, drafting and critical revision of the manuscript; H.K.E.: data analysis, drafting and critical revision of the manuscript. All authors read and approved the final version of the manuscript. Acknowledgments This work was supported by four non-profit organizations: Association pour la recherche en pathologie synoviale (ARPS), ART Viggo, Prévention et Traitement des Décalcifications – Cristaux et Cartilage, and Rhumatisme et Travail. References [1] Rogers NM, Teubner DJ, Coates PT. Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial 2007;20:150–7.
[2] Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol 1995;26:1055–64. [3] Malbos S, Urena-Torres P, Cohen-Solal M, et al. Sodium thiosulphate treatment of uraemic tumoral calcinosis. Rheumatology (Oxford) 2013;53: 547–51. [4] Budisavljevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol 1996;7:978–82. [5] Nigwekar SU, Brunelli SM, Meade D, et al. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol 2013;8:1162–70. [6] Cicone JS, Petronis JB, Embert CD, et al. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis 2004;43: 1104–8. [7] Lei Y, Grover A, Sinha A, et al. Efficacy of reversal of aortic calcification by chelating agents. Calcif Tissue Int 2013;93:426–35. [8] O’Neill WC, Hardcastle KI. The chemistry of thiosulfate and vascular calcification. Nephrol Dial Transplant 2012;27:521–6. [9] Chen NX, O’Neill K, Akl NK, et al. Adipocyte induced arterial calcification is prevented with sodium thiosulfate. Biochem Biophys Res Commun 2014;449:151–6. [10] Pasch A, Schaffner T, Huynh-Do U, et al. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int 2008;74:1444–53. [11] Ross EA. What is the role of using sodium thiosulfate or bisphosphonates in the treatment for calciphylaxis? Semin Dial 2011;24:434–6.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
ARTICLE IN PRESS Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Case report
Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis b,c ˜ Stéphanie Malbos a , Pablo Urena-Torres , Thomas Bardin a,d , Hang-Korng Ea a,∗,d,e a
Service de rhumatologie, pôle appareil locomoteur, centre Viggo-Petersen, hôpital Lariboisière, AP–HP, 2, rue Ambroise-Paré, 75010 Paris, France Clinique du Landy, 93400 Saint-Ouen, France Service des explorations fonctionnelles rénales, hôpital Necker, 75015 Paris, France d UFR de médecine, université Paris Diderot, Sorbonne Paris Cité, 75205 Paris, France e Inserm, UMR-1132, hôpital Lariboisière, 75010 Paris, France b c
a r t i c l e
i n f o
Article history: Accepted 9 March 2015 Available online xxx Keywords: Calciphylaxis Calcific uremic arteriolopathy Vascular calcifications Sodium thiosulfate Apatite Dialysis
a b s t r a c t Background: Calcific uremic arteriolopathy (CUA) or calciphylaxis is a severe complication of advanced chronic kidney disease (CKD) and dialysis. Few effective treatments are available and the mortality rate is high. We report 4 cases in which sodium thiosulfate therapy was rapidly effective. Cases: Sodium thiosulfate therapy was given to 4 Caucasian patients (3 females and 1 male aged 49 to 91 years) with CUA. The causes of end-stage CKD were nephroangiosclerosis (n = 2) and diabetic nephropathy (n = 2). The lesions developed 1 to 6.5 years after the initiation of hemodialysis and involved the lower limbs in 2 patients, the fingers in 1 patient, and a breast in the remaining patient. They were responsible for pain and skin necrosis in all 4 patients. Local superinfection occurred in 3 patients. Intravenous sodium thiosulfate was given in a dosage of 12.5 to 25 g after each hemodialysis session, for 12 to 24 weeks. The pain and trophic disorders resolved fully in all 4 patients. The side effects consisted of nausea and vomiting (n = 2) and a moderate blood pressure decrease (n = 1). No recurrences were noted during the follow-up of 5 to 17 months after treatment discontinuation. Conclusion: The findings from this small case-series suggest that sodium thiosulfate may hold promise for the treatment of CUA. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Calciphylaxis or calcific uremic arteriolopathy (CUA), first described in 1962, is characterized by calcifications of the cutaneous and subcutaneous arterioles. Ninety percent of cases of CUA develop in patients with end-stage chronic kidney disease (CKD) [1]. CUA is associated with high mortality rates ranging from 40 to 86%. The skin lesions predominate at the lower limbs and are more common in proximal areas. They consist of erythematous mottling and indurated nodules or plaques that are often extremely painful and usually progress to form ulcers. Histological studies show vasculopathy without vasculitis. Calcifications are visible in the media of the small arteries and arterioles of the dermis and hypodermis, which also exhibit intimal hypertrophy and endovascular fibrosis. Calcium deposition within the blood vessels is an early and crucial event in the development of CUA plaques [2]. The calcifications are believed to result chiefly from mineral and
bone homeostasis disorders with hyperphosphatemia and elevation of the calcium-phosphate product, abnormally high or low parathyroid hormone levels, adynamic bone disease, excess vitamin D, and/or aluminum toxicity. Other local and systemic factors are involved, such as inflammation, malnutrition with hypoalbuminemia, vitamin K antagonist therapy, endothelial dysfunction, and/or an imbalance between promineralizing factors and calcification inhibitors. The treatment of CUA is difficult and standard measures often lack efficacy. Sodium thiosulfate (STS) has been used for over a century to treat cyanide poisoning. There are reports of successful STS therapy in patients with ectopic calcifications such as recurrent urinary lithiasis and uremic tumoral calcinosis [3]. In case-series of patients with CUA, STS therapy produced inconsistent results. Here, we report 4 cases of CUA in patients on chronic hemodialysis who responded to STS therapy. 2. Case-reports 2.1. Case #1
∗ Corresponding author. E-mail addresses: [email protected], [email protected] (H.-K. Ea).
The first patient was a 91-year-old man who had been receiving standard hemodialysis at our center for 1 year (Table 1). He
http://dx.doi.org/10.1016/j.jbspin.2015.03.007 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
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Table 1 Clinical features in 4 patients with calcific uremic arteriolopathy and effects of sodium thiosulfate therapy. Patient #1
Patient #2
Patient #3
Patient #4
Age/sex Ethnicity CV risk factors
91/H Caucasian HT, dyslipidemia, MI
Location Time from HD to onset (years) Previous treatments
Nephroangiosclerosis Hemodialysis Pain, infection, sinus tract, necrosis Fingers 1 Phosphate chelation
49/F Caucasian HT, diabetes, dyslipidemia, MI Diabetic nephropathy Hemodialysis Pain, infection, necrosis
91/F Caucasian HT, MI
Type of CKD Dialysis Clinical features
55/F African HT, diabetes, dyslipidemia, LLOAD, angina Diabetic nephropathy Hemodialysis Pain, infection, necrosis Right breast 6.5 Calcium-channel inhibitors
Lower limbs 1.5 Phosphate chelation
STS dosage Duration of STS use (weeks) Outcome Follow-up (months)
25 g/48 h 16 Full recovery 0 (died)
12.5 g/48 h 24 Full recovery 5
12.5 g/48 h 16 Full recovery 8
Lower limbs 5.5 Phosphate chelation, calcium-channel inhibitors 25 g/48 h 12 Full recovery 17
Nephroangiosclerosis Hemodialysis Pain, necrosis
F: female; M: male; CKD: chronic kidney disease; CV: cardiovascular; HD: hemodialysis; HT: hypertension; MI: myocardial infarction; LLOAD: lower limb occlusive arterial disease; STS: sodium thiosulfate.
was overweight and had dyslipidemia. His cardiovascular history included hypertension, percutaneous coronary angioplasty to treat myocardial infarction, diffuse arteriosclerosis, and heart failure due to a combination of hypertension, coronary artery disease, and valvular disease. He had early-stage secondary hyperparathyroidism. His chronic medications consisted of the antiplatelet agent clopidogrel, a lipid-lowering agent, and two antihypertensive drugs (a beta-blocker and a nitrate). In February 2006, he was started on chronic hemodialysis, three 4-hour sessions per week, for endstage renal failure due to nephroangiosclerosis. Extremely painful ulcers and necrotic lesions developed over the fingers of his right hand 21 months later (Fig. 1). Radiographs of the hands visualized subcutaneous calcifications measuring 1 to 4 mm in diameter
and located under the skin lesions. These clinical and radiographic features strongly suggested CUA, making a biopsy unnecessary. The skin lesions ran a complicated course, with the formation of sinus tracts, bacterial infection, and ischemic necrosis. Laboratory findings at the diagnosis of CUA were as follows: serum calcium: 2.66 mmol/L; serum phosphate: 1.85 mmol/L; calcium-phosphate product: 4.92 mmol2 /L2 ; 25(OH) D: 41.40 ng/mL; 1,25(OH)2 D: 11 ng/L; parathyroid hormone: 80 ng/L; bone alkaline phosphatase: 12.9 g/L; and CTX: 1320 ng/mL. Markers for systemic inflammation were moderately elevated (C-reactive protein: 7.10 mg/L; and erythrocyte sedimentation rate: 38 mm/h). He initially received analgesics and treatments to eradicate the local infection. Phosphate chelation therapy and a vitamin D analog were given to
Fig. 1. Patient #1. Course of the ulcerated and necrotic skin lesions during treatment with sodium thiosulfate (STS). The necrotic lesions on the fingers developed after 21 months of chronic hemodialysis. They resolved rapidly with STS therapy.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
G Model BONSOI-4200; No. of Pages 4
ARTICLE IN PRESS S. Malbos et al. / Joint Bone Spine xxx (2015) xxx–xxx
improve the calcium-phosphate balance. These measures failed to induce marked clinical or radiographic improvements. STS therapy was therefore considered. The patient accepted this option, and a temporary authorization for STS therapy was obtained according to French legislation. STS in a dose of 25 g was administered as a slow intravenous infusion over 30 minutes at the end of each hemodialysis session, i.e., three times a week. This treatment was well tolerated. Dramatic clinical and radiographic improvements were noted. The patient became pain-free within a few weeks and his trophic disorders had resolved partially by the end of the first month. After 2 months, the lesions were almost fully healed. STS therapy was not associated with the development of any laboratory abnormalities. After 16 weeks of STS therapy, the patient died of a myocardial infarction. A causal role for STS therapy in this event is unlikely given the patient’s history of cardiovascular disease and time to occurrence. 2.2. Patients #2, #3, and #4 Three other patients with CUA received STS therapy at our center. They were females, with an age range of 49–91 years and a history of hypertension and coronary artery disease whose symptoms ranged from angina pectoris to acute coronary syndrome requiring aortocoronary bypass surgery; 2 patients also had type 2 diabetes mellitus and dyslipidemia. All 3 patients had end-stage renal failure, due to diabetic nephropathy (n = 2) or nephroangiosclerosis (n = 1), and required chronic hemodialysis, three 4-hour sessions per week. The calcium concentration in the dialysis solution was 1.50 to 1.60 mmol/L. The time from hemodialysis initiation to development of the CUA lesions was 6.5, 1.5, and 5.7 years, respectively. The calcifications were located in the subcutaneous tissue of the right breast in 1 patient and in the lower limbs in the other 2 patients. The diagnosis of CUA relied on the clinical features, with no histological documentation. The lesions became infected in patients #2 and #3. The initial treatment consisted of a calcium-channel inhibitor (n = 1), a phosphate chelator containing no calcium or aluminum (n = 2), and/or 1␣ vitamin D (n = 1). None of these treatments was effective. Temporary authorization for STS therapy was obtained as required by French law. STS was given intravenously in a dosage of 12.5 to 25 g over 30 minutes at the end of each hemodialysis session. Treatment duration was 24, 16, and 12 weeks, respectively. STS therapy was effective in all 3 patients, with healing of the lesions and complete pain relief. The adverse effects were mild and did not require treatment discontinuation; they consisted of nausea and vomiting (n = 2) and self-limited hypotension (n = 1). Serum calcium and phosphate levels and the calcium-phosphate product were normal in all 3 patients and did not change significantly during STS therapy. STS was discontinued when the lesions were fully healed and the patients were free of pain. Follow-up duration after STS discontinuation was 5, 8, and 17 months, respectively. There were no recurrences. Table 1 reports the main data in the 4 patients. The case of patient #2 deserves comment. She was initially managed at another center, where she received STS on two occasions. She developed CUA of the right breast during hemodialysis and received an intravenous infusion of 10 g of STS after each hemodialysis session, for 7 months. The outcome was favorable and STS therapy was discontinued in February 2008. In 2009, after kidney transplantation, new CUA lesions developed over the abdomen, both thighs, and the right breast. STS therapy was resumed, as a 25-g intravenous infusion three times a week then once a week; total treatment duration was 7 months. Although the existing lesions decreased in size, new lesions developed over the right breast. Subsequently, hypercalcemia and acute renal failure required resumption of the chronic hemodialysis, which she received at our center.
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3. Discussion Our case-reports demonstrate that intravenous STS therapy is rapidly effective against CUA complicating chronic hemodialysis in patients with end-stage CKD. CUA is a well-documented and extremely severe complication of end-stage renal failure requiring chronic hemodialysis. Women are predominantly affected (male/female ratio, 1/3). Among patients with CUA, 80% have hyperparathyroidism, 68% hyperphosphatemia, 20% hypercalcemia, and 33% a high calcium-phosphate ratio [4]. In our small case-series, a single patient had hyperparathyroidism and none had abnormal calcium and phosphate levels. Obtaining histological documentation is not mandatory when the clinical setting and lesions are typical, particularly as the biopsy procedure can worsen the lesions. None of our patients underwent histological examination, which was performed in 53% of patients in the largest published case-series of CUA complicating hemodialysis and treated with STS [5]. The treatment of CUA is challenging. The standard approach consists in restoring the calcium-phosphate balance by eliminating calcium and vitamin D intakes, decreasing the dietary intake of phosphate, administrating phosphate chelators that contain no calcium or aluminum, controlling parathyroid hormone levels, reducing the intake of aluminum, and optimizing the dialysis parameters (increasing session duration and or frequency, improving performance by using biocompatible highly permeable membranes, and using low-calcium dialysis solutions). Many drugs intended to dissolve calcific deposits are inconsistently effective when used to treat ectopic calcifications. These drugs include bisphosphonates, calcium-channel inhibitors, low-dose vitamin K antagonists, probenecid, vinpocetine, calcimimetics, and TNF␣ antagonists. STS, in contrast, has been used successfully in CUA, as reported for the first time by Cicone et al. in 2004 [6]. Subsequently, several small case-series were published, followed by a large study in 172 patients [5], in which STS therapy was effective in three-quarters of patients (full resolution: 26.4%; marked improvement: 18.9%; and improvement: 28.3%) [5]. Our patients received STS intravenously in a dosage of 12.5 to 25 g per injection depending on patient tolerance, at the end of each hemodialysis session. This treatment regimen ensured healing of the lesions within a few weeks with no recurrences 5 to 17 months after treatment discontinuation. However, longer follow-ups are needed. In our case-series and previously published studies, STS appeared safe. The exact mechanism of action of STS still awaits elucidation. The initially hypothesized calcium-chelating effect has been ruled out by recent studies [7,8]. In vitro, STS failed to diminish ionized calcium levels in culture media [8] and, in contrast to ethylenediamine-tetra-acetic disodium acid (EDTA), did not bind to calcium crystals in hydroxyapatite [7]. However, STS inhibited calcification of previously injured aorta, suggesting a direct effect on the extracellular matrix and cellular effects [8]. A 2014 in vitro study established that STS inhibited the calcification of mature adipocytes stimulated by high concentrations of phosphate [9]. STS also prevented adipocyte-induced calcification of vascular smooth muscle cells, by decreasing the production of vascular endothelial growth factor (VEGF) and leptin [9]. Other reported effects of STS include generation of the antioxidant glutathione and nitric oxide production responsible for vasodilation and improved endothelial cell function [10,11]. Our case-reports support STS as a promising treatment for CUA. Studies are needed to unravel the mechanisms of action of STS. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007
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ARTICLE IN PRESS S. Malbos et al. / Joint Bone Spine xxx (2015) xxx–xxx
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Authors’ contributions: S.M.: data collection and analysis, drafting and critical revision of the manuscript; P.U.T.: data collection and analysis, drafting and critical revision of the manuscript; T.B.: data analysis, drafting and critical revision of the manuscript; H.K.E.: data analysis, drafting and critical revision of the manuscript. All authors read and approved the final version of the manuscript. Acknowledgments This work was supported by four non-profit organizations: Association pour la recherche en pathologie synoviale (ARPS), ART Viggo, Prévention et Traitement des Décalcifications – Cristaux et Cartilage, and Rhumatisme et Travail. References [1] Rogers NM, Teubner DJ, Coates PT. Calcific uremic arteriolopathy: advances in pathogenesis and treatment. Semin Dial 2007;20:150–7.
[2] Fischer AH, Morris DJ. Pathogenesis of calciphylaxis: study of three cases with literature review. Hum Pathol 1995;26:1055–64. [3] Malbos S, Urena-Torres P, Cohen-Solal M, et al. Sodium thiosulphate treatment of uraemic tumoral calcinosis. Rheumatology (Oxford) 2013;53: 547–51. [4] Budisavljevic MN, Cheek D, Ploth DW. Calciphylaxis in chronic renal failure. J Am Soc Nephrol 1996;7:978–82. [5] Nigwekar SU, Brunelli SM, Meade D, et al. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol 2013;8:1162–70. [6] Cicone JS, Petronis JB, Embert CD, et al. Successful treatment of calciphylaxis with intravenous sodium thiosulfate. Am J Kidney Dis 2004;43: 1104–8. [7] Lei Y, Grover A, Sinha A, et al. Efficacy of reversal of aortic calcification by chelating agents. Calcif Tissue Int 2013;93:426–35. [8] O’Neill WC, Hardcastle KI. The chemistry of thiosulfate and vascular calcification. Nephrol Dial Transplant 2012;27:521–6. [9] Chen NX, O’Neill K, Akl NK, et al. Adipocyte induced arterial calcification is prevented with sodium thiosulfate. Biochem Biophys Res Commun 2014;449:151–6. [10] Pasch A, Schaffner T, Huynh-Do U, et al. Sodium thiosulfate prevents vascular calcifications in uremic rats. Kidney Int 2008;74:1444–53. [11] Ross EA. What is the role of using sodium thiosulfate or bisphosphonates in the treatment for calciphylaxis? Semin Dial 2011;24:434–6.
Please cite this article in press as: Malbos S, et al. Sodium thiosulfate is effective in calcific uremic arteriolopathy complicating chronic hemodialysis. Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.03.007