Calciphylaxis, also known as Calcific Uremic Arteriolopathy (CUA), is a chronic disease characterized by calcification of the medial layer of medium and small arteries and arterioles that progresses to thrombotic ischemia and necrotic cutaneous ulceration.  Although a rare condition, it occurs most commonly in patients with End-Stage-Renal Disease, affecting an estimated 4% of patients on dialysis.  However, it may also present in patients with normal renal function.  Other risk factors for calciphylaxis include warfarin use, diabetes mellitus, obesity, female sex, hypercalcemia, hypoalbuminemia, hyperphosphatemia, Antiphospholipid Syndrome, Protein C Deficiency, and Protein S Deficiency.

Clinical Presentation:

Patients present with blistering skin ulcerations and a superficial, burning pain.  Initially the skin lesions appear to be subcutaneous violaceous plaque-like nodules that progress to a necrotic black eschar.  Additional ischemic manifestations such as levedo reticularis and reticulate purpura may also be present.  Areas most commonly affected include the legs, abdomen, and buttocks.  Superinfections of the lesions and septicemia are possible worrisome sequelae.  Calciphylaxis is associated with a high morbidity and mortality, with an estimated 45.8% one year survival, which is primarily attributed to infection.

Pathophysiology:

Initiation of calciphylaxis occurs when inflammation leads to paracrine signals that trigger the smooth muscle cells of the arterial vessel wall to differentiate into osteoid-like cells.  This results in a new cell type that promotes calcification without increased proliferation of cells.  Proposed mechanisms of unrestricted calcium deposits include loss of calcification inhibition, induction of extra-osseous calcification, and deposition of circulating calcium complexes.

Diagnosis and differential diagnosis:

Definitive diagnosis is made by skin biopsy.  Characteristic histological findings include calcification, microthrombosis, and subintimal fibrosis.  Special stains such as von Kossa or Alizeran red stain may be required to identify calcification.  Radiographic studies including plain film X-rays and 3-phase bone scans can also suggest calciphylaxsis in cases where biopsy is not practical. Labs are performed to identify potential precipitating factors and should include the evaluation of kidney function, bone health, and liver function.  Additional labs that should be performed to look for precipitating factors include coagulation studies, inflammatory markers, and evaluation of hypercoaguable states and autoimmune diseases.  Differential diagnoses include: warfarin necrosis, cellulitis, cholesterol embolization, atherosclerotic vascular disease, endarteritis obliterans, and radiation arteritis.

Treatment:

Treatment of calciphylaxis is multi-dimensional and complex.  Debridement of the wound can be controversial, although suggested in cases if signs or symptoms of infection coexist.  Pain control is also an important aspect of patient care, as these ulcers can be exquisitely painful. Hyperbaric oxygen therapy is a possible treatment modality but is not a Medicare covered indication for treatment. Hyperbaric oxygen delivered at 2.5 ATA x 90 minutes/day is a recommended protocol.  Other recommendations include IV sodium thiosulfate, parathyroidectomy, normalization of calcium and phosphorous blood levels, and increased hemodialysis.  Therapy should also target any other underlying precipitating factors.

Calciphylaxis is a serious disease associated with a high morbidity and mortality.  Clinicians must have a high index of suspicion due to the overall rarity of the disease.  It is important to recognize the signs and symptoms of calcification early in order to treat the underlying cause and prevent the progression of the disease.

A calciphylaxsis registy has been established by the University of Kansas Medical Center and can be accessed at the following URL http://www2.kumc.edu/CalciphylaxisRegistry/

Thank you to contributing author Heather Wagner MS3, Campbell University School of Osteopathic Medicine

References:

Nigwekar, S., Kroshinsky, D., Nazarian, R., Goverman, J., Malhotra, R., Jackson, V., Thadhani, R. (2015). Calciphylaxis: Risk Factors, Diagnosis, and Treatment. American Journal of Kidney Diseases, 66(1), 133-146. doi:10.1053

Santos, P., Hartle II, J., & Quarles, L. (2015, June 17). Calciphylaxis (calcific uremic arteriolopathy). Retrieved August 29, 2015, from http://www.uptodate.com

Wollina, U. (2013). Update on cutaneous calciphylaxis. Indian Journal of Dermatology Indian J Dermatol, 58(2), 87-87. doi:10.4103/0019-5154.108026

Mochel, M., Arakaki, R., Wang, G., & Kroshinsky, D. (2013). Cutaneous Calciphylaxis: A Retrospective Histopathologic Evaluation. American Journal of Dermatopathology, 35(5), 582-6. doi:10.1097/DAD.0b013e31827c7f5d