Fig. 32.1
Advanced calciphylaxis

Although the majority of case reports describe deep ulcerations as the hallmark finding on initial physical exam, this may in fact represent a delayed recognition of the disorder as early lesions can be easily mistaken for cellulitis or other dermatologic disorders. One Canadian series noted that the presenting symptom in 80 % of their patients was subcutaneous indurated plaques on their lower extremities. After identifying their first five patients with calciphylaxis, they prospectively studied and diagnosed a total of 36 patients over 7 years. Such heightened awareness of the disease likely led to recognition of lesions earlier in their evolution [16]. Although skin findings are the most common clinical presentation, other symptoms such as painful myopathy or rhabodmyolysis have been reported as the initial symptom, preceding the appearance of skin lesions [17].

The distribution of cutaneous lesions is described as being located either distal (extremities) or proximal (trunk/buttocks/face), with distal lesions appearing to have a better survival rate. Typically such lesions appear to occur in areas of high adipose content. Although skin lesions are the more classic presentation, visceral calciphylaxis has been described with rare case reports describing findings such as in cardiac, pancreatic, and ocular locations [1820]. In one case report, a patient with ESRD and rhinoorbitocerebral mucormycosis developed temporal artery calciphylaxis by biopsy and 2 weeks later presented with cutaneous extremity lesions [21]. Penile calciphylaxis is another rare but well described presentation, with over 30 cases reported in the literature over the previous decade, the majority of whom had ESRD and additional lesions in other sites besides the genitalia [22].

The differential diagnosis for calciphylaxis includes atherosclerotic vascular disease, cholesterol embolization, nephrogenic systemic fibrosis, oxalate vasculopathy, purpura fulminans, vasculitis, diabetic gangrene, and warfarin necrosis [3]. It may be difficult to determine the type of lesion as many other disease processes can mimic the appearance of ulcerating lesions, particularly ischemic necrosis and diabetic gangrene in the population of patients with ESRD from vascular or diabetic etiologies. A thorough history and physical exam, including evaluation for risk factors should be performed on patients presenting with clinical findings concerning for calciphylaxis.

Calciphylaxis is associated with high morbidity rates that are a consequence of severe pain, wound infections, recurrent hospitalizations, and multiple surgical interventions. Mortality rates are extremely high. The 1-year mortality has been reported between 45 and 80 %, with severe systemic infection and subsequent sepsis being the leading cause of death [3, 16, 23]. Patients with skin lesions that progress from subcutaneous to ulcerating lesions also appear to have higher mortality rates, up to 89 % described in one series [16].


Laboratory Evaluation

There are no specific laboratory values that make the diagnosis of calciphylaxis. Patients can present with either uremia or normal renal function. Therefore selection of laboratory values to obtain should be based on the differential diagnosis and risk factors. Thorough investigation includes pursuing studies in the following systems: (1) renal function evaluation: serum urea nitrogen, creatinine, glomerular filtration rate; (2) mineral bone parameters: serum calcium, phosphorus, alkaline phosphorus, intact PTH, 25-hydroxyvitamin D; (3) liver evaluation: liver function panel including albumin; (4) infectious workup: complete blood count, blood cultures if indicated; (5) coagulation panel; (6) hypercoagulation panel: protein C, protein S, antithrombin III, antiphospholipid antibody; (7) evaluation for autoimmune or other inflammatory conditions or malignancies [3].

Radiographic Evaluation

Imaging with X-rays and nuclear bone scans has been reported in some case series as a tool to diagnose calciphylaxis [16]. Findings may show vascular and soft tissue calcification. However, there has not been systematic evidence describing the utility of imaging in the diagnosis or treatment of calciphylaxis. At this time there is no routine imaging that is recommended.

Histopathologic Evaluation

A definitive diagnosis of calciphylaxis can be made based on pathologic evaluation of the affected lesions combined with clinical examination and history. However, while the diagnostic advantages of performing a skin biopsy are clear, there are certain risks that must be considered. Importantly, biopsy of affected lesions can potentially propagate new lesions or lead to superinfection, bleeding, and worsening of already present ulcerations. If biopsy is necessary to rule out other potential diagnoses, it is critical that an experienced dermatologist or surgeon perform the procedure in order to maximize tissue yield and reduce the risk of requiring a repeat procedure. Generally a punch biopsy is preferred over incisional biopsy, with greatest diagnostic yield at the periphery of the ulcer rather than the base [3].

Histopathologic features of calciphylaxis can be considered based on location: (1) vasculature—vascular calcification of small and medium sized vessels, intimal hyperplasia, and intra-luminal thrombus; (2) extravascular—extravascular soft tissue calcification, septal and lobular panniculitis, dermal-epidermal separation, epidermal ulceration. By pathogenesis it is likely that arteriolar calcification is the primary event, with intimal proliferation and intravascular thrombosis being secondary and leading to ischemic necrosis and ulceration. Unfortunately histology alone cannot always provide a clear diagnosis as the differential diagnosis for medial calcification and panniculitis include atherosclerotic peripheral vascular disease, Mönckeberg sclerosis, warfarin skin necrosis, and other thrombotic disorders. Additionally, calcification of medium-sized vessels is a well-recognized histologic feature of patients with long-term renal failure on hemodialysis. Therefore it is important to use clinical history and exam in addition to histopathologic findings to aid in the diagnosis of calciphylaxis.

Specific diagnostic markers for calciphylaxis based on histology are forthcoming. Various histochemical stains can be employed for the detection of calciphylaxis. One study compared the usefulness of von Kossa versus Alizarin red staining and found that both types of stains appeared to be comparable although Alizarin red appeared larger and birefringent [12]. Perieccrine and pericapillary calcium deposits may also be features more specific to calciphylaxis [12, 24]. One study investigated the use of osteopontin expression as a potential diagnostic marker for calciphylaxis. Smooth muscle cells within the vessel wall may produce ectopic osteopontin as one of the early processes in the calcification that occurs during calciphylaxis, making such study of osteopontin interesting as a diagnostic marker. In a series of 25 biopsies from patients diagnosed with calciphylaxis, immunohistochemical staining for osteopontin was performed in addition to von Kossa staining. Osteopontin was predominantly located in subcutaneous fat and calcified vessels, although it was also found in vessels without calcification. Although there was no clear diagnostic utility, it is possible that higher levels of osteopontin in histologic staining can be suggestive of calciphylaxis and can help direct therapeutic interventions to reduce expression [4].


The treatment for calciphylaxis requires a multidisciplinary approach. Contributions from the disciplines of nephrology, dermatology, pathology, infectious disease, pain management, nutrition, and surgery are key to optimizing management and determining the best interventions for each patient. Multiple treatment strategies have been described for calciphylaxis but unfortunately the quality of evidence remains poor and is limited to institutional experience, retrospective and cohort studies, case series, and case reports [25]. However, as the pathophysiology of calciphylaxis becomes better elucidated, physiology-directed treatment strategies and early diagnosis offer patients a better chance for improved outcomes [26]. Early therapy was once guided by wound management and supportive care for underlying sepsis. While these modalities are pillars in the treatment of calciphylaxis, further investigations in the medical management and reduction of risk factors are becoming prevalent. Today general treatment strategies focus on decreasing calcium and phosphate levels, controlling risk factors, pain control, aggressive wound management, and parathyroidectomy.

Wound Care Management

Routine surgical management is controversial for calciphylaxis and an attempt to minimize surgical debridement is encouraged. Some investigators argue that there may be an increased risk of furthering massive ulcerations in patients already predisposed to poor wound healing. Calciphylaxis lesions should therefore be approached according to the general principles of local wound care management. In order to facilitate healing, a wound bed must be free of devitalized tissue, biofilm, and exudate. As with all wounds, the need for surgical debridement must be made on a case by case analysis by an experienced surgeon. Noninfected, superficial, dry wounds with eschar may not require surgical debridement, while clearly necrotic wounds with exudate and infected, nonviable tissue in patients with sepsis should undergo debridement for control of the infection and prevention of further tissue necrosis. Early defect closure in select patients may facilitate wound healing. One case series of seven calciphylaxis patients described managing ulcers with deep shaving of subcutaneous tissue down to fascia and immediate autologous split-skin grafting. The authors found a 30–90 % take rate of the grafts with complete healing of the ulcers in six of the seven patients [27].

Other adjunct therapies that have been described with variable success are vacuum-assisted closure of wounds, hyperbaric oxygen therapy, and sterile maggots [28]. One case report described using vacuum-assisted closure in two patients with calciphylaxis lesions affecting 10 and 48 % of the total body surface area. The latter patient died from fungal superinfection while the former patient survived [29]. Hyperbaric oxygen therapy has been used with some success in the treatment of nonhealing vascular wounds and necrotizing soft tissue infections. The therapy requires remaining in a sealed chamber and breathing 100 % O2 in order to restore tissue PO2 to higher levels and promote fibroblast proliferation and angiogenesis. This therapy, however, is limited by lack of access at many facilities and claustrophobia for patients. The use of sterile maggots in patients who were unable to tolerate routine local wound care has been described in sporadic case reports with success [30].


Parathyroidectomy has been used as a treatment for calciphylaxis in patients with ESRD and secondary hyperparathyroidism in an attempt to reduce PTH, calcium, and phosphate levels. Numerous small case series and reports have described improved wound healing and prolonged survival in patients who have received parathyroidectomy [31, 32]. Girotto and colleagues retrospectively reviewed outcomes of 13 calciphylaxis patients who had undergone either medical therapy (n = 7) or parathyroidectomy (n = 6). All six patients who received parathyroidectomy had significant reductions in PTH, calcium, and phosphate levels opposed to those who were treated medically. The median survival of those who underwent parathyroidectomy was also longer than those who did not (36 vs. 3 months, P = 0.021) [33]. However, recent retrospective studies have not shown significant differences in outcomes between those who received parathyroidectomy and those who received only medical therapy [23, 34]. The lack of patients studied in both retrospective studies and case reports make it a major limitation in determining the efficacy of parathyroidectomy.

Sodium Thiosulfate

Sodium thiosulfate has been used for over 100 years as an antidote for cyanide poisoning and more recently for prevention of ototoxicity related to carboplatin treatment. In recent decades it has played a role in treating recurrent calcium urolithiasis and tumoral soft tissue calcifications in patients with ESRD [35]. It was first described as a successful treatment for calciphylaxis in a 2004 case report by Cicone and colleagues, with over 40 cases being subsequently reported in the literature [3638]. Treatment with sodium thiosulfate typically results in rapid relief of pain and regression of skin lesions over the weeks following initiation of therapy. Although the exact mechanism of therapeutic action is unknown, it is hypothesized that the antioxidant effects and chelating property of sodium thiosulfate (thiosulfate binds with calcium, resulting in a highly soluble calcium thiosulfate salt) are the reasons for the improvement in symptoms. With no current randomized controlled trials available to validate the efficacy of therapy or the optimal dosing, route and duration of treatment, administration of treatment varies across reports. Sodium thiosulfate dosages range from 5 to 25 g intravenously, three times a week for up to several months [25, 38].


Bisphosphonates are known inhibitors of osteoclasts and are used in various disorders (osteoporosis, Paget’s disease, and hypercalcemia of malignancy) to help prevent loss of bone mass. In recent years several case reports have described successful treatment of calciphylaxis using bisphosphonates, with rapid pain relief and wound healing within months [3941]. The mechanism of action is believed to be due to inhibition of macrophages and suppression of inflammatory cytokine release [42]. Adverse reactions to bisphophonates include hypocalcemia, hypophosphatemia, fever, osteonecrosis of the jaw, and should be used cautiously in patients with chronic renal failure with glomerular filtration rate of less than 30 ml/min. However, the use of bisphophonates in patients on hemodialysis may be mitigated by their ability to be dialyzed. There are currently no randomized trials investigating the use of bisphosphonates for calciphylaxis, and such therapy should be used on a case by case basis.

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Aug 28, 2017 | Posted by in OTOLARYNGOLOGY | Comments Off on Calciphylaxis

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