Calciphylaxis is a poorly understood disorder. Narrowed and calcified microvessels lead to low-grade, chronic ischemia. Further occlusion of vessels, provoked by microthrombi and endothelial injury, causes infarction.15,28 Irrespective of systemic hypercoagulability,29 thrombosis could be due to a local prothrombotic state.28 Microvascular calcification in calciphylaxis is an active cell-mediated process that depends on the balance between inhibitors and promoters of calcification28,30,31; there is impaired inhibition of calcium phosphate precipitation,32 probably due to the deficiency of calcification inhibitors.
Matrix G1a protein (MGP) is an extracellular matrix protein, synthesized by endothelial cells and vascular smooth muscle, which inhibit calcification. Another potent calcification inhibitor is carboxylated MGP.33 A relative reduction of these proteins is noted in the circulation34 and cutaneous tissue.28 In addition, carboxylated MGP inhibits procalcifying factors, including bone morphogenetic protein (BMP) 2 and BMP-4.35 Deficiency of carboxylated MGP upregulates the expression of BMP-2,28 BMP-4,36 and osteogenic transcription, with the latter characterized by increased runt-related transcription factor 2.28,37 Reduced circulating levels of carboxylated MGP also predict ulcer formation and more extensive lesions.34
Fetuin-A, involved in the transport of mineral nanocrystals via the formation of calciprotein particles, is another calcification inhibitor.25 Fetuin-A is downregulated in CKD.32,38 Severe, functional deficiency of fetuin-A in calciphylaxis is evidenced by a pronounced burden of calciprotein particles.38,39 Polymorphisms in gene 5′-nucleotidase (NT5E) (rs4431401 and rs9444348) are overrepresented in calciphylaxis.21 The gene NT5E is involved in regulating pyrophosphate metabolism (a critical inhibitor of calcification).40,41 Predominant inclusion of areas with abundant adipose tissue also suggests the involvement of adipocytes. Via the release of adipokines, mature adipocytes exposed to high levels of phosphate calcify and induce vascular smooth muscle cells calcification unidirectionally.42 A potential adipokine, vascular endothelial growth factor A (VEGF-A), produces a procalcific response through BMP-4. Polyneuropathy, Organomegaly, Endocrinopathy, M component, and Skin changes (POEMS) syndrome is characterized by marked elevations in VEGF-A and also has a high prevalence of calciphylaxis (4%)43 (Figure 8).
Differential diagnoses of calciphylaxis include conditions like warfarin-induced skin necrosis, venous stasis ulcer, ischemia from atherosclerotic arterial occlusive disease, nephrogenic systemic fibrosis, cellulitis, necrotizing vasculitis, livedoid vasculopathy, pyoderma gangrenosum, purpura fulminans, Martorell’s ulcer, cholesterol embolism syndrome, dystrophic calcinosis cutis, oxalosis, and lipodermatosclerosis.3,9
Due to the complexity of the condition, an interdisciplinary approach is recommended to expedite diagnosis and management (dermatology, nephrology, plastic surgery, nutrition, wound care, pain, and palliative medicine).9 Skin biopsy (ie, punch) is recommended in atypical or early lesions in a nonuremic patient. Specialized stains are necessary to avoid missing subtle calcifications (eg, von Kossa stain uncovers phosphate within hydroxyapatite).9 Plain radiographs showing subcutaneous calcification in a netlike pattern and nuclear bone scans demonstrating increased heterogenous radiotracer uptake in soft tissues have good specificity for calciphylaxis.44,45 Currently, there are no approved therapies for calciphylaxis.
Adequate pain relief is essential for severe pain (high-dose opioids, ketamine, spinal anesthetics, and gabapentin have been used).46 The ischemic tissue bed can be extremely painful, often healing poorly; operative debridement and negative pressure wound therapy are recommended, with split-thickness skin grafting for wound closure, once the wound has stabilized with the formation of granulation tissue.9 As transcutaneous oxygen tension is reduced in lesions,47 hyperbaric oxygen may be associated with healing when intensive therapy sessions are administered over 2 months, especially in peripheral lesions.48 Vitamin D and calcium intake (including calcium-based phosphate binders) should be discontinued.9 Cinacalcet (a calcimimetic agent) is preferred over parathyroidectomy (used in refractory cases, ie, PTH > 600 pg/mL), as the latter will cause irreversible reduction of PTH levels and hungry bone syndrome requiring calcium and calcitriol.49 Warfarin use also must be discontinued, and, if ongoing anticoagulation is favored, an agent should be selected based on indication for anticoagulation and kidney function.50 Bisphosphonates are pyrophosphate analogues that modify bone (ie, receptor activator of nuclear factor-κB ligand inhibitor and antisclerostin antibody) and have been successfully used to treat calciphylaxis patients with a genetic ectonucleotide pyrophosphatase and phosphodiesterase 1 deficiency.51
Since its first use in 2004, STS is frequently used to treat calciphylaxis. It has been demonstrated to heal lesions and improve the associated severe pain.52 Sodium thiosulfate has vasodilatory and antioxidant properties. It also inhibits calcification of adipocyte and blocks their ability to induce vascular smooth muscle cell calcification.39,42 Sodium thiosulfate is not an acid, as it does not donate protons40; however, thiosulfate is oxidized to sulfate by either intestinal bacteria or hepatic oxidation.53 Unfortunately, there are no established evidence-based guidelines to follow with respect to treatment dose initiation in patients who are not on dialysis; thus, the dosages for nonuremic patients is not standardized. The optimal dose is unknown and requires titrations, depending on the estimated glomerular filtration rate (eGFR) and development of side effects. In patients with eGFR greater than 60 mL per minute per 1.73 msq, 25 g at 3 to 5 times weekly may be given.54,55 For patients with an eGFR over 60 mL per minute per 1.73 msq, the initiating dose should be reduced, because STS is renally cleared. Further dose adjustments depend upon the development of side effects, including hypotension or metabolic acidosis. In patients with an eGFR less than 60 mL per minute per 1.73 msq, depending upon progress or response, so long as side effects (hypotension, metabolic acidosis) have not developed, the dose may be gradually increased to a maximum of 25 g 3 times weekly typically for a 3-month IV course.56 A dramatic reduction in pain has been noted within 2 weeks of starting therapy57 and almost complete resolution of lesions within 6 months.57,58 The clinical response within the first couple of weeks of treatment may be a predictor of favorable response. Intralesional STS is an alternative for patients who do not tolerate the IV form. The use of 1 mL to 3 mL of 250 mg/mL STS injected weekly in the clinically active calciphylaxis areas may lead to improvement.59 Important side effects include nausea, vomiting, severe metabolic acidosis, hypotension, hypocalcemia, QT prolongation, and volume overload.60,61 Typically, STS is excreted quickly and hence only partially metabolized. Thus, the excretion of the nonmetabolized drug is decreased in patients on hemodialysis, causing an increase in its metabolism to sulfate. In these patients, high-bicarbonate dialysate use may help reduce STS-induced metabolic acidosis.58 With long-term treatment involving IV formulation, an increased propensity for skeletal fractures has been reported.62 The role of supplementation of vitamin K is currently unsupported, with no available studies endorsing the superiority of specific forms of vitamin K (ie, K1 or K2).9
The present patient had no obvious triggers for calciphylaxis (ie, ESRD on dialysis, warfarin use, trauma due to subcutaneous injections, or the existence of an autoimmune process). The patient’s risk factors included female sex, obesity, DM, elevated alkaline phosphatase, and CKD. In addition, she had peripheral lesions (sparing breasts, thighs, buttocks), or more specifically, lesions that carry better a prognosis; 1 lesion on her abdomen resolved with treatment.
The present case used half of the dose of STS reported for patients without hemodialysis and with risk factors for calciphylaxis in the literature,52,63,64 thus successfully showing a lower dose of STS can be used effectively for treatment of calciphylaxis in patients with stage 3 CKD. The authors recommend that serious consideration should be given to STS as a practical measure of treatment, as documented in a case series of 8 patients.65
This case illustrates that early diagnosis, intervention, and an interdisciplinary approach are of utmost importance in the management of calciphylaxis. It highlights the fact that STS, when used in the correct clinical setting, can actually improve a patient's prognosis.