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      Sodium thiosulfate for the treatment of warfarin-induced calciphylaxis in a nondialysis patient

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          Abstract

          Calciphylaxis or uremic arteriolopathy is a complex process typically seen in patients with end-stage renal disease, but has also been reported in patients with normal renal function. However, therapies for calciphylaxis are based on reports of traditional patients (i.e., end-stage renal disease). A mainstay of therapy, sodium thiosulfate (STS), has been shown to be effective for the treatment of calciphylaxis. Without a standardized therapy reported for nondialysis patients there is a need for evidence-based therapy. Here, we report a case of a 63-year-old woman with an acute injury on chronic kidney disease (CrCl Baseline = 48 mL/min, CrCl AKI = 36 mL/min), not requiring dialysis, with warfarin-induced calciphylaxis. After 4 weeks of therapy with STS, sevelamer, alendronate, and enzymatic debridement the patient subjectively reported slight improvement of the necrotic ulcers but developed cellulitis on her nonaffected limb. Additionally, after 12 weeks of therapy she was readmitted for renal failure and subsequently required dialysis.

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          Sodium thiosulfate, bisphosphonates, and cinacalcet for treatment of calciphylaxis.

          The use of sodium thiosulfate, bisphosphonates, and cinacalcet for the treatment of calciphylaxis in adults with chronic kidney disease (CKD) is discussed. Calciphylaxis, generally characterized by extraosseous calcification of soft tissues, typically occurs in patients with stage 4 or 5 CKD. Very little data are available regarding the treatment of calciphylaxis. The role of elevated calcium and phosphate concentrations and hyperparathyroidism as risk factors for calciphylaxis has led clinicians to explore therapies that modify these factors, including sodium thiosulfate, bisphosphonates, and cinacalcet. Sodium thiosulfate has been shown to produce clinical improvement of calciphylaxis lesions. Bisphosphonates have been shown to be effective in animal models of calciphylaxis, and the mechanism of action is believed to be due to inhibition of macrophages and local proinflammatory cytokines and binding to calcified vascular smooth muscle cells to inhibit further arterial calcification. Cinacalcet, a calcimimetic agent that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland to calcium, is believed to decrease serum parathyroid hormone levels and stabilize calcium and phosphate concentrations. Cinacalcet has been associated with improved pain control and ulcer healing. Cases describing the use of combination therapy with cinacalcet and sodium thiosulfate for the treatment of calciphylaxis have been published, but the positive effect on wound healing is difficult to attribute to a single drug. Evidence for the treatment of calciphylaxis with pharmacotherapeutic interventions is limited to case reports. Further research is necessary to fully describe the optimal use of sodium thiosulfate, bisphosphonates, and cinacalcet for the treatment of calciphylaxis, including their pharmacokinetics in adults with CKD, optimal dosing strategies, and duration of therapy.
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            Multi-Modal Treatment Of Calciphylaxis With Sodium-Thiosulfate, Cinacalcet And Sevelamer Including Long-Term Data

            Background: Calciphylaxis is a rare, yet life-threatening disease mainly occurring in dialysis patients. Traditional options of treatment remain unsatisfactory. Methods: Here we present a novel, combined approach, treating calciphylaxis with IV sodium thiosulfate, cinacalcet and sevelamer. In a case series five hemodialysis patients, have been successfully treated with this regimen. Treatment and survival data were analyzed using descriptive statistics. Results: In all patients, a rapid decrease in pain, improvement of general condition and wound healing within six months occurred. Side effects were low. Drug dosages: IV sodium thiosulfate initial dose 119.4 +/- 84.9 g/m 2 /week, maintenance dose 40.6 +/- 9 g/m 2 /week; cinacalcet: maintenance dose 36 +/- 32.9 mg/d and sevelamer maintenance dose 3320 +/-1671 mg/d. One and two year survivals were 100 % and 80 %, respectively. We also report on long-term application of IV sodium thiosulfate of up to 52 months. Patient survival after diagnosis was 52, 84, 21, 36 and 30 months, respectively. Survival since initiation of hemodialysis was 76, 136, 89, 36 and 35 months, respectively. Conclusion: This novel combined approach, a multi-modal treatment of calciphylaxis with persistent hyperparathyroidism, using IV sodium thiosulfate, cinacalcet and sevelamer seems to improve the outcome of this devastating disease.
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              Evolution of Treatment Strategies for Calciphylaxis

              Treatment strategies for calciphylaxis are limited by inadequate understanding of its pathophysiology. Mortality reaches 80%, due to progressive skin ischemia, necrosis and infections. In addition to calcium and parathyroid disorders, hypercoagulability can have a role: primary thrombotic disorders as well as secondary, such as proposed warfarin procoagulant effects. Traditional care addresses the calcium-phosphate-PTH axis: minimizing calcium intake, calcimimetics, cautious vitamin D analogs, strict phosphate control, and surgical parathyroidectomy if necessary. Newer approaches focus on extraosseous mineralization: dissolution of calcium deposits, altering osteoprotegerin and NF-ĸB pathways, and treating macrophage or cytokine-mediated inflammation. Sodium thiosulfate has reported success, and is thought to be due to enhanced calcium solubility and dialysis clearance. Bisphosphonates may have efficacy by lowering bone turnover or a variety of vascular tissue mechanisms. The literature for both agents is very limited, and optimal dosing regimens remain unclear. Patients responsive to a medication will have decreasing pain in days and lesions beginning to heal within approximately 2 weeks. Due to high mortality, early use of combination therapy is advocated, although specific protocols have not been well established. The often dramatic improvements in case-based literature are very encouraging and will hopefully lead to more rigorous studies.
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                Author and article information

                Journal
                J Pharmacol Pharmacother
                J Pharmacol Pharmacother
                JPP
                Journal of Pharmacology & Pharmacotherapeutics
                Medknow Publications & Media Pvt Ltd (India )
                0976-500X
                0976-5018
                Oct-Dec 2015
                : 6
                : 4
                : 222-224
                Affiliations
                [1] Department of Pharmacy Practice, The University of Mississippi School of Pharmacy, Jackson, Mississippi, USA
                Author notes
                Address for correspondence: Emily J. Carrell, 213 CR 162, Oxford, Mississippi, USA. E-mail: ejcarrel@ 123456go.olemiss.edu
                Article
                JPP-6-222
                10.4103/0976-500X.171882
                4714392
                c74c7353-4e9b-4520-b92d-7f123add788e
                Copyright: © Journal of Pharmacology and Pharmacotherapeutics

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

                History
                : 24 November 2014
                : 24 November 2014
                : 09 April 2015
                Categories
                Case Report

                Pharmacology & Pharmaceutical medicine
                calciphylaxis,chronic kidney disease,nondialysis,sodium thiosulfate,warfarin-induced

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