Calciphylaxis, also known as calcific uremic arteriolopathy, is a potentially fatal condition characterized clinically by progressive cutaneous necrosis as a result of calcification and thrombosis of the dermal arterioles[i]. Calciphylaxis is seen in 1% of patients with chronic renal failure and in 4.1% of patient receiving hemodialysis. In addition, it usually occurs in patients with Type 2 diabetes and end-stage renal disease who have been on hemodialysis for more than 10 years.[ii] In these patients, it is classified as uremic calciphylaxis. Other risk factors for calciphylaxis include female sex, obesity, diabetes, recurrent hypotension, elevated time-averaged serum phosphorous levels, reduced time-averaged serum albumin levels, any hypercoaguable condition (e.g. antithrombin deficiency, lupus anticoagulants, Protein C and S deficiency), and warfarin therapy which correlates with a Vitamin K deficiency.[iii] In the absence of end-stage renal disease, the disorder is classified as non-uremic calciphylaxis.[iv]

The pathogenesis of calciphylaxis involves progressive narrowing of the cutaneous blood vessels as a result of calcification within the media layer of the vessel walls and proliferation of endothelial cells with fibrosis under the intima of the vessel. Subsequently, thromboses develop in the vessel lumen, leading to tissue ischemia and necrosis. (See Photo) The vascular calcification is actually like ectopic bone formation in the vessel walls, which is related to hyperphosphatemia, hypercalcemia, and hyperglycemia.[v] VEGF-A and leptin appear to be the mediators that transform the vascular cells from smooth muscle cells to calcified cells; both of these are released from adipocytes. These same conditions that cause vessel calcification are the conditions that exist in the above mentioned risk factors.⁵

           The initial cutaneous manifestations of calciphylaxis are sudden-appearing red or violaceous mottled plaques in a livedo reticularis pattern accompanied with severe pain that is either ischemic or neuropathic. The early ischemic lesions often progress to gangrenous, poorly defined, black plaques and/or nodules. With time, the plaques ulcerate and are exquisitely tender. Usually ulcers are on the lower extremities, bilateral, symmetric, and extend into the adipose tissue. The injured sites can sometimes occur at the sites of repeated trauma, e.g. the thighs or abdomen where insulin injections are administered.[vi]

Medical Management Multiple approaches to medical management of calciphylaxis are recommended to prevent infection, manage pain, and optimize outcomes by chelating the arterial calcium. Treatment strategies include the following:

■  Systemic antibiotics

■  Opioid pain medication (morphine can cause hypotension and slow blood flow in the arterioles, as well as diminish appetite and lead to malnutrition)

■  Phosphate binders such as sevelamer

■  Sodium thiosulfate as a chelating agent for calcium deposits in the tissue

■  Bisphosphonate therapy to help remove arterial calcification

■  Low calcium hemodialysis for patients with ESRD

■  Cinacalcet to lower parathyroid levels and improve calcium-phosphorus homeostasis

■  Hyperbaric oxygen therapy to increase local tissue oxygen perfusion

■  Low calcium diet that will also optimize nutrition and provide adequate calorie and protein intake for wound healing[vii]^,[viii]

In the past, parathyroidectomy was performed in an effort to increase calcium uptake; however, this procedure has not been shown to be significantly effective and is reserved for patients with known hyperparathyroidism[ix]. Also, systemic corticosteroids are not recommended as they may exacerbate arteriolar calcification.

Wound Management Debridement of necrotic tissue and calcified vessels is needed for reversal of the inflammatory response to calciphylaxis; however, this is difficult to perform bedside if the necrosis is extensive because of the intense pain levels associated with the disease. Surgical debridement followed by negative pressure wound therapy is the most expeditious approach if the patient is medically stable for surgery. This is complemented by skin grafting with either autologous or tissue-engineered skin, or use of a dermal replacement matrix. Intralesional sodium thiosulfate (250 mg/mL) injected or instilled into areas of clinically active disease has been shown to reduce pain and resolve the purpura of calciphylaxis lesions, and pentoxifylline can facilitate vasodilation.^7,8 Electrical stimulation and hyperbaric oxygen therapy may be beneficial adjunct therapies. In addition to the meticulous wound care (using aseptic technique to prevent infection), nutritional supplements and monitoring is advised because patients may have difficulty eating sufficient calories for wound healing given the amount of pain medicine required to manage the anoxic pain.

              In summary, calciphylaxis is a disorder that causes calcification and thrombosis of the cutaneous blood vessels, resulting in painful ischemic skin and subcutaneous wounds that require a multidisciplinary approach for medical and wound management.  In addition, rehabilitation services are required to enable the patient to return to the previous level of function, given the involvement of the trunk and lower extremities.

[i] Bhambri A. Dell Rosso JQ. Calciphylaxis: A review. J Clin Aesthet Dermatol. 2008;1(2):38-41.

[ii] Weening RH, Sewell D, Davis MD, et al. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol. 2007;56:569-579.

[iii] Zhang Y, Corapi K, Luongo M, Thadhani R, Nigwekar S. Calciphylaxis in peritoneal dialysis patients: a single center cohort study. International Journal of Nephrology and Renovascular Disease. 2016;19(9):235-241.

[iv] Nigwekar SE, Wolf M, Sems RH, Hix JK. Calciphylaxis from nonuremic causes: A systematic review. Clin J Soc Nephrol. 2008;3(4):1139-1143.

[v] Chang JJ. Calciphylaxis: Diagnosis, pathogenesis, and treatment. Advances in Skin & Wound Care. 2019;32(5):205-215.

[vi] Nigweker SU, Zhao S, Wenger J, et al. A nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016;27:3421-3429.

[vii] Nigwekar S, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol. 2013;8(7):1162-1170.

[viii] Strazzula L, Nigwekar SU, Steele D, et al. Intralesional sodium thiosulfate for the treatment of calciphylaxis. JAMA Dermatol. 2013;149(8):946-949.

[ix] Solanky D, Hwang SM, Stone G, Gillenwater J, Carey JN. Successful surgical treatment of severe calciphylaxis using a bilayer dermal replacement matrix. Wounds. 2015;27(11):302-307.