Fetuin-A (α2-Heremans-Schmid glycoprotein) is a member of the superfamily of cysteine protease inhibitors. Unlike local inhibitors of calcification, fetuin-A is a ubiquitous serum protein that inhibits calcification at a systemic level by sequestrating circulating calcium and phosphate into colloidal spheres [60]. Mice lacking fetuin-A, although phenotypically normal, developed diffuse STC when fed a vitamin D-rich diet (12897203). In CKD patients, chronic inflammation may promote the development of calciphylaxis via reduction of fetuin-A levels [12]. Clearance of serum fetuin–mineral complex resulting in low serum fetuin-A levels may underlie vitamin D-induced vascular calcification [61]. In an cross-sectional study of 312 stable hemodialysis patients, low levels of fetuin-A were associated with increased cardiovascular mortality [62]. Low fetuin-A levels may also mediate STC in the absence of renal impairment [63].

Another strong inhibitor of vascular calcification is the vitamin K-dependent matrix Gla protein (MGP). This protein is synthesized by chondrocytes, VSMCs, endothelial cells, and fibroblasts [64]. Gamma-carboxylation is necessary for its activation [65]. The mechanisms whereby MGP inhibits vascular mineralization are multifarious including inhibition of calcium–phosphate precipitation and neutralization of bone morphogenic protein (BMP)-2-mediated calcification [66]. BMP-2 is implicated in transition of VSMCs to osteoclast-like cells, a crucial step in the development of vascular calcification. Recently, it has been shown that hyperphosphatemia-induced vascular calcification may be abolished by the calcimimetic calindol via upregulation of MGP synthesis [67].

An under-recognized aspect of the observed entity of calciphylaxis is thrombosis of the calcified vessels—Mayo Clinic researchers feel this is fundamental to the observed mortality and morbidity. After all, calcification of blood vessel walls alone occurs in many disease processes such as diabetes, but often does not lead to morbidity. In calciphylaxis, it is thrombosis of the blood vessels that is the “tipping point”—leading to skin ulceration, which becomes infected, patients become septic and die. Weenig et al. reported in the Mayo Clinic series that 80 % of skin biopsies in calciphylaxis demonstrate thrombosis. He theorized that the only reason the figure was not 100 % was sampling on skin biopsy.

Why thrombosis? The answer is unknown, but several factors can be considered. First, the calcification of the blood vessels can act as a nidus for thrombosis (analogous to atherosclerosis in the coronary arteries). Second, patients with renal failure and other underlying conditions may be in a pro-thrombotic state-indeed preliminary studies, though few, have demonstrated low protein C and S, or antiphospholipid syndrome.

Calciphylaxis presents with a spectrum of skin lesions ranging from livedo reticularis- or racemosa-like pattern to deep ulcerations. Very early changes may be clinically imperceptible or manifest as patchy areas with a net-like vascular pattern (livedo reticularis exquisitely tender, indurated) or a broken and branching morphology (livedo racemosa). At this stage, the histopathological correlate is the presence of cutaneous arteriolar stenosis due to intimal fibrosis and media calcification, leading to narrowing of the vessel lumen and reduced blood. When true vascular thrombosis with complete luminal obliteration ensues, purpuric-like lesions and deep and excruciatingly painful ulcerations and subcutaneous nodules appear. They usually retain their retiform configuration, a clue towards the correct diagnosis for the trained eye. Moreover, the same net-like blood vessel calcification configuration can be appreciated in soft-tissue radiographs and may serve as an additional diagnostic tool with a specificity approaching 90 % [68]. Not infrequently, however, they may adopt bizarre shapes with overlying necrotic eschars and dry gangrene.

In terms of distribution, lesions favor areas of high adiposity such as the abdomen, thighs, and buttocks [8, 69, 70] (Fig. 10.1). The head and neck are usually spared. Proximal necrotic lesions (trunk, buttocks, and thighs) are associated with higher mortality as compared to distal (below the knee) and acral disease [71].

The prognosis of calciphylaxis is ominous with mortality rates approaching 46 % at 1 year and 80 % at 2 years from diagnosis [47]. The presence of ulceration portends a bad prognosis with a twofold increase in mortality [72]. Another study documented that 1-year survival rate is about 45 versus 35 % at 5 years [73]. For patients undergoing surgical debridement the 1-year survival rate is nearly 62 % [47].

Few studies have been published. Intriguingly however, a study of three patients with calciphylaxis who had postmortem evaluation at Mayo Clinic demonstrated that calciphylaxis only involved the skin: there was no evidence of a similar process internally. The reason for these findings is unclear [74].

Multiple entities can mimic calciphylaxis. Therefore, for definitive diagnosis a deep skin biopsy, including sampling of the subcutaneous tissue, is needed. Histopathologic findings vary depending on the age of the lesion. Early lesions may show only subtle changes. Late lesions are characterized by dermal necrosis and intramural calcium deposition of dermal and pannicular vessels [75] as well as vascular thrombosis and endovascular fibroblastic proliferation [47, 75] (Fig. 10.2). The most common finding overall is the presence of calcifying septal panniculitis [75]. More recently, it has been suggested that when typical features of vascular and extravascular calcification are not evident, the presence of perieccrine calcification may point towards the correct diagnosis [76]. Fragmented and calcified elastic fibers as seen in pseudoxanthoma elasticum may also be a histopathologic finding [77]. A von Kossa stain highlights calcium deposits in the vascular walls and in collagenous septa of subcutaneous tissue [78].

Fully developed lesions of calciphylaxis have a distinct clinical appearance referred to as retiform purpura. A number of cutaneous disorders share a similar morphology and should be considered in the differential diagnosis (Table 10.2). A thorough history, careful examination of the skin lesions, risk factor analysis, and histopathologic evaluation will render the correct diagnosis. In the right clinical setting, visual recognition alone will be highly suggestive but incisional biopsy (to include subcutaneous fat) is necessary for confirmatory purposes.

ESRD is the most important and widely recognized condition associated with calciphylaxis [47, 79]. Within this patient population several risk factors have been linked to an increased risk for development of calciphylaxis including: white race [49], liver disease, systemic steroid use, CPP greater than 70 mg²/dL², serum aluminum more than 25 ng/mL, obesity [47], female gender, peritoneal dialysis, diabetes mellitus, concurrent therapy with calcium salts and vitamin D [50, 80], increased serum phosphate levels, elevated alkaline phosphatase [73], warfarin therapy, poor nutritional status [48], and increased sedimentation rate [81].

Non-uremic calciphylaxis cases have also been reported in patients with normal renal and parathyroid function and in association with connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis, giant cell arteritis), hematologic malignancies (multiple myeloma, chronic myelocytic leukemia), diabetes (without concomitant renal failure), primary hyperparathyroidism, vitamin D deficiency, protein C and S deficiency, warfarin therapy, factor V Leiden deficiency, Crohn disease, primary autoimmune myelofibrosis, and liver disease [14, 46, 49, 53, 82–88]. It is expected that this list will continue to expand with increased recognition of this condition.

Table 10.3 lists a recommended initial workup for patients in whom calciphylaxis is suspected. In the authors’ opinion a deep skin, preferentially excisional, biopsy to include subcutaneous tissue is of utmost importance in establishing the diagnosis.

Management of calciphylaxis is challenging; multiple authors now suggest that multidisciplinary collaboration is essential. The main goals of treatment are identification and correction of underlying metabolic derangements, addressing vessel thrombosis that is leading to the ulcerations, arresting disease progression, wound care, pain control, and prevention of gangrene formation and fatal sepsis. To this end, aggressive wound care are of utmost importance.

In practice, efforts must be focused additionally on pain control, symptomatic management, and palliative care.