What Is It, Signs, Symptoms, Diagnosis, and More

Author:Lily Guo

Editors:Alyssa Haag,Ian Mannarino, MD, MBA,Kelsey LaFayette, DNP, ARNP, FNP-C

Illustrator:Jessica Reynolds, MS

Copyeditor:Stacy Johnson, LMSW

What is calciphylaxis?

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare condition that refers to the formation of calcifications in the arterioles and capillaries in the skin’s dermis and subcutaneous adipose tissue. Calcification can lead to tissue necrosis and ulceration, most frequently occurring in the lower extremities but may occur in any part of the body. Calciphylaxis is most commonly diagnosed in individuals with end-stage kidney disease (ESKD), also called end-stage renal disease (ESRD), but can occur in other kidney-related disorders. Unfortunately, it is a lethal disease with high morbidity and mortality, with an estimated six-month survival of approximately 50 percent. 

Necrotic lesion in skin due to calcification of surrounding arterioles.

What causes calciphylaxis?

The exact mechanism and cause of calciphylaxis are not well understood; however, it is thought to be related to changes in calcium and phosphate metabolism. These metabolic changes can be seen in those with ESRD. The skin lesions in calciphylaxis result from reductions in the arteriolar blood flow caused by vascular calcification, fibrosis, and thrombus formation. 

Calciphylaxis is also commonly associated with primary hyperparathyroidism, a condition associated with increased levels of parathyroid hormone (PTH), a regulator of calcium levels in the blood. Malignancy, protein C and S deficiency, and antiphospholipid syndrome are also associated with calciphylaxis since they typically cause a hypercoagulable state. Individuals with hypoalbuminemia are predisposed to calciphylaxis since albumin binds to excess calcium and regulates calcium and phosphate balance. Calcium and phosphate may accumulate in blood vessels with lower albumin levels. Individuals with vasculopathy, including atherosclerosis, may also be more susceptible to vascular calcification. Other risk factors for calciphylaxis include chronic inflammatory conditions such as diabetes mellitus; obesity (i.e., body mass index [BMI] >30); and autoimmune disorders (e.g., systemic lupus erythematosus [SLE], polymyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, and Crohn disease). 

Lastly, certain medications such as warfarin, vitamin D, oral glucocorticoids, and iron supplementation may increase the risk for calciphylaxis.

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What are the signs and symptoms of calciphylaxis?

The signs and symptoms of calciphylaxis include extremely painful, ischemic, and necrotic skin lesions that are slow to heal. In some cases of calciphylaxis, the pain may precede the development of skin lesions. Early in the disease course, calciphylaxis lesions may appear plaque-like, violaceous, and indurated (i.e., thickened and hardened). As the disease progresses, these areas can become ischemic, necrotic ulcers with eschar (i.e., dead tissue). While lesions frequently develop in regions with adipose tissue (e.g., lower extremities and trunk), the upper extremities, buttocks, and genitalia can be affected in some cases of calciphylaxis. Areas of eschar can also become superimposed with bacterial infections. 

Other atypical manifestations include papules, erythema resembling cellulitis, and erosions with hemorrhagic crust. Systemic manifestations of calciphylaxis may include fatigue, weakness, and easy bruising and bleeding. 

How is calciphylaxis diagnosed?

Calciphylaxis is frequently diagnosed by conducting a thorough interview and physical examination. Healthcare professionals, specifically dermatologists, evaluate and rule out conditions that mimic calciphylaxis (e.g., cellulitis, deep vein thrombosis, or other forms of vasculitis). Often, the diagnosis can be made based on the examination finding of painful ulcerated lesions covered by a black eschar, particularly in an individual with ESRD. 

Imaging studies are not routinely ordered to diagnose calciphylaxis; however, radiography and computed tomography (CT) have been shown to detect tissue calcifications in patients with calciphylaxis. Laboratory tests may be ordered to measure calcium, phosphorus, and parathyroid hormone levels. They may also check for other markers of kidney failure, such as creatinine and blood urea nitrogen (BUN). Additionally, a three-phase technetium 99m methylene diphosphonate bone scan can identify cutaneous calcifications and support the diagnosis of calciphylaxis. 

If the diagnosis remains uncertain or the presentation is atypical, a dermatologist or a surgeon may perform a skin biopsy, either with a punch or telescoping biopsy technique, which provides a definitive diagnosis. 

How is calciphylaxis treated?

The treatment of calciphylaxis primarily involves pain control and wound care. An interprofessional team approach is frequently used, collaborating with dermatologists, nephrologists, wound care specialists, and pain and palliative care specialists. Pain control can be achieved with the help of opioid analgesics and consultation with a pain management service to improve quality of life. Wound care is a critical aspect in the management of calciphylaxis and includes proper dressing application and debridement of necrotic tissue. Hyperbaric oxygen therapy may be administered to promote wound healing. Repetitive local trauma to the skin (e.g., subcutaneous injections) is usually avoided due to the risk of worsening symptoms. While there is no approved treatment for calciphylaxis, medications such as sodium thiosulfate (STS), bisphosphonates, and calcimimetics are frequently used; however, their efficacy remains unproven. 

Preventing disease by mitigating risk factors and controlling underlying medical conditions is essential for calciphylaxis. If necessary, individuals may control serum calcium, phosphorus, and parathyroid hormone levels through diet, medications, and dialysis. A healthy diet is similarly helpful in treating diabetes and obesity. Lastly, surgery may be necessary to remove necrotic tissue and repair damaged blood vessels.

What are the most important facts to know about calciphylaxis?

Calciphylaxis is a rare condition characterized by calcification of the arterioles and capillaries of the dermis and subcutaneous tissue, which results in painful ulceration and skin necrosis. It is most commonly seen in those with chronic renal disease, primary hyperparathyroidism, malignancy, and various autoimmune diseases. The skin lesions are primarily on the lower extremities but can also localize to the abdomen and buttocks. Diagnosis is based mainly on clinical examination though laboratory tests, imaging studies, and biopsies can also be used. Treatment for calciphylaxis includes pain management, wound care, and disease prevention. The prognosis for calciphylaxis is typically poor as it is associated with a high risk of morbidity and mortality.

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Related links

Parathyroid disorders and calcium imbalance: Pathology review
Phosphate, calcium, and magnesium homeostasis
Renal failure: Pathology review

Resources for research and reference

Ahmed, S, O'Neill, KD, Hood, AF, et al. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis. 2001;37(6):1267-1276. doi:10.1053/ajkd.2001.24533

Arch-Ferrer, JE, Beenken, SW, Rue, LW, et al. Therapy for calciphylaxis: an outcome analysis. Surgery. 2003;134(6):941-945. doi:10.1016/j.surg.2003.07.001

Bajaj R, Courbebaisse M, Kroshinsky D, Thadhani RI, Nigwekar SU. Calciphylaxis in patients with normal renal function: a case series and systematic review. Mayo Clin Proc. 2018;93(9):1202-1212. doi:10.1016/j.mayocp.2018.06.001

Brandenburg VM, Kramann R, Rothe H, et al. Calcific uraemic arteriolopathy (calciphylaxis): data from a large nationwide registry. Nephrol Dial Transplant. 2017;32(1):126-132. doi:10.1093/ndt/gfv438

Jeong HS, Dominguez AR. Calciphylaxis: Controversies in pathogenesis, diagnosis and treatment. Am J Med Sci. 2016;351(2):217-227. doi:10.1016/j.amjms.2015.11.015

Nigwekar SU, Zhao S, Wenger J, et al. A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016;27(11):3421-3429. doi:10.1681/ASN.2015091065

Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56(4):569-579. doi:10.1016/j.jaad.2006.08.065