A 54-year-old man presents to a hospice inpatient unit for pain management and wound care. The patient’s medical history includes end-stage renal disease (ESRD), calciphylaxis, and type 2 diabetes. Review of his medical history reveals that the patient initially presented 6 months prior with superficial reddening of the skin.

The patient was subsequently diagnosed with calciphylaxis and treated with cinacalcet and narcotic pain medication for severe pain. The reddening rapidly progressed into nonhealing ulcers and the patient underwent above the knee amputation. Postsurgery, the amputated leg became necrotic and was covered in eschar. Antibiotic therapy proved ineffective as the surgical site was not healing with wet to dry wound dressing. The patient was then referred to hospice care. The time frame between dialysis initiation to calciphylaxis diagnosis was 4 years and between calciphylaxis diagnosis to death was 6 months.


Calciphylaxis is a relatively rare condition characterized by ischemic skin lesions resulting from calcium deposits occluding microvessels creating painful areas of ecchymoses that lead to dark-colored lesions and eventually necrosis. The occlusions occur in the dermis and subcutaneous fat tissue.1,2

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Calciphylaxis is classified as uremic (patients diagnosed with ESRD and undergoing hemodialysis) and nonuremic (patients with earlier stages of chronic kidney disease and not on dialysis).1 The majority of patients with calciphylaxis have uremic calciphylaxis, which affects an estimated 35 out of 10,000 patients undergoing dialysis annually in the United States.3,4 Risk factors for calciphylaxis include type 2 diabetes, obesity, female sex, and dialysis dependence for 2 or more years.1,4 Patients treated with warfarin, with or without renal disease, have a higher incidence of calciphylaxis.1,4 Warfarin treatment is also associated with higher mortality rates in calciphylaxis.4 The most common site of calciphylaxis injury is the lower extremities followed by the breasts and abdomen.5

Morbidity and mortality associated with septicemia are high as the integrity of the skin and underlying subcutaneous fat is compromised resulting in an environment conducive to bacterial colonization.1,4 One-year mortality rates are greater than 50%.1


The pathogenesis of calciphylaxis is unclear.4 One possible mechanism is dysregulation of bone morphogenic proteins 2 and 4 (BMP-2 and BMP-4).4 These proteins are osteoinductive components derived from bone. Dysregulation of BMPs leads to excess calcium deposits in the vasculature and subcutaneous fat.6 Microvascular calcifications may lead to ischemia, malodorous nonhealing ulcers, and pain.4 Calciphylaxis is prevalent in body areas with increased adipose tissue such as the abdomen and thighs. The role of adipose tissue in manifestations of calciphylaxis is poorly understood.

Making the Diagnosis

Taking a detailed patient history and conducting a physical examination can assist in the differential diagnosis. Other conditions with similar manifestations as calciphylaxis include trauma, cellulitis, and venous stasis ulcer (Table).2,4 Questions to ask the patient include:

  • Have you had any falls?
  • Have you bumped against furniture or another hard surface?
  • Have you traveled outside of the area?

Warfarin necrosis, unlike calciphylaxis, immediately begins to resolve upon discontinuation of warfarin, allowing the clinician to rule out this condition quickly.2

Table. Differential Diagnosis of Calciphylaxis2,4

• Warfarin necrosis
• Venous stasis ulcer
• Cellulitis
• Necrotizing vasculitis
• Atherosclerotic cardiovascular disease
• Nephrogenic systemic fibrosis
• Dystrophic calcinosis cutis
• Breast cancer (breast lesions)
• Martorell ulcer

Calciphylaxis should be considered in patients presenting with painful nonhealing skin ulcers who have chronic kidney disease, obesity, have been on hemodialysis, and/or are of White race and female sex.1,4 Skin changes associated with calciphylaxis have sudden onset and progress rapidly to open ulcerations and then necrosis.4

A thorough physical examination of the patient, preferably with the torso and lower extremities exposed, can assist the clinician in visualizing the patient’s lesions and assessing skin integrity. A painful necrotic ulcer covered with black eschar that started as painful ecchymoses is usually the presenting symptom; patients often mistake initial reddening for a bruise and delay seeking medical care.4 The presence of malodorous, dusky, and/or necrotic lesions should increase suspicion of calciphylaxis.4 Clinical findings include purple or red net-like areas of ecchymoses that are painful or nonhealing ulcers that are painful. The physical examination may show lesions from shoulder to elbow, elbow to fingertip, and length of the leg from hip to toe.

Imaging studies such as radiograph and bone scan may support the diagnosis by allowing for determination of areas of microcalcifications in calciphylaxis (Figure).2,4 A positive bone scan has a high sensitivity rate of 97% in cases of calciphylaxis.2 Laboratory tests such as renal function tests, serum calcium, alkaline phosphatase, phosphorous, and vitamin D can evaluate potential risk factors.4 Laboratory tests for prothrombin time (PT), international normalized ratio (INR), partial thromboplastin time (PTT), protein C, protein S, and PTT can assess the patient’s coagulation status and inflammation status.4

The gold standard for diagnosing calciphylaxis is skin biopsy.4 Clinicians with adequate training should perform the skin biopsy to prevent further trauma to skin that is already fragile and difficult to heal. Clinicians must weigh the benefits and risks of biopsy; patients with ESRD and classic presentation of calciphylaxis do not require biopsy.4 The double-punch technique, where a punch biopsy is followed by a second punch inserted through the center of the first punch, can offer an improved yield on the composition of the skin and underlying structures.4 A punch biopsy may also be used and is preferred over a large, excisional biopsy but has limited depth.4 Once diagnosis of calciphylaxis is made, referral to a dermatologist is helpful for management of the damaged skin.

Treatment and Referral

Treatment of calciphylaxis requires pain management, wound care, sepsis prevention, and timely referral to specialty care. No evidence-based clinical guidelines on prevention and treatment of the disease are available, and no medications are FDA-approved for calciphylaxis.7 Medications such as sodium thiosulfate and cinacalcet are used as off-label treatments.7 The most successful treatment plans are those that include treatment of the underlying issue such as hypercalcemia, hyperparathyroidism, and kidney disease.8

Treatment of pain with opioids may not provide adequate analgesia relief and patients with ESRD need dose adjustment to account for renal fragility.4 Adjuvant pain therapies such as gabapentin, ketamine, and spinal anesthesia may provide relief in refractory cases.4 Experimental treatments such as intravenous sodium thiosulfate, phosphate binders, and calcimimetics are being tested; these treatments have not demonstrated a mortality benefit in pooled cohort studies and further investigation in randomized controlled trials is needed.7

Wound care to decrease sepsis should be taught to patients and caregivers.4,7 Home health referral may be needed for adequate wound management in the home environment. If not already involved, a nephrologist referral is needed for patients with nephrogenic-related calciphylaxis. Dermatology referral is essential for assisting in maintaining skin integrity and optimal wound care management.


The role of the parathyroid is to increase serum calcium. Parathyroid hormone (PTH) stimulates the release of calcium and phosphate from the bone matrix and increases calcium reabsorption by the kidneys. Small retrospective studies suggest that surgical parathyroidectomy improves calciphylaxis-related outcomes, but might not be suitable for some patients such as those at risk for postoperative complications.7 In some cases, patients may develop calciphylaxis even after parathyroidectomy.7 Researchers suggest that this treatment should be reserved for patients with poorly controlled hyperparathyroidism that is unresponsive to calcimimetics.6,7 Parathyroid hormone suppression is a risk factor for calciphylaxis.9

Sodium Thiosulfate

Sodium thiosulfate is an antioxidant used to treat metal poisoning. In a case series, more than 70% of patients receiving intravenous sodium thiosulfate showed improvement or resolution of their skin lesions and the mortality rate was lower than that in historically published data.1 Use of oral and intralesional delivery of sodium thiosulfate is being investigated in calciphylaxis. It is thought the anti-inflammatory and anticalcification properties in sodium thiosulfate may decrease symptoms.4,7 Sodium thiosulfate also may stop adipose tissue from inducing calcification in vascular smooth cells.10 With limited efficacy and safety data, more studies are needed to determine if sodium thiosulfate can become a preferred treatment for calciphylaxis. Sodium thiosulfate is considered successful when pain intensity is decreased, wound progression slows, and wound appearance is improved.


Cinacalcet counteracts the calcium dysfunction associated with calciphylaxis. The mechanism of action is an increase in the sensitivity of calcium receptors, allowing more calcium to bind to receptors and decreasing the amount of serum calcium. Cinacalcet also decreases PTH secretion.4 In patients undergoing dialysis with PTH level >300 pg/mL, cinacalcet 30 mg to 180 mg daily is prescribed to maintain PTH level between 150 and 300 pg/mL.11


Calciphylaxis is a poorly understood disease that is associated with high morbidity and mortality, but early diagnosis offers pain relief and decreased psychological stress. Although this condition most commonly occurs in patients with ESRD, calciphylaxis can be found in patients with less severe forms of kidney dysfunction. Several medication trials were recently initiated and may provide further guidance on strategies to decrease morbidity and mortality in calciphylaxis. Current management strategies are patient-centered with a focus on managing the underlying condition and providing analgesic relief, wound management, and appropriate referral for an interdisciplinary approach to care. Sepsis secondary to infected wounds is the main cause of death in calciphylaxis and clinicians must carefully rule out other causes of skin involvement to ensure early diagnosis and treatment.

Timika Bracken, BSN, RN, MBA, CHPN, FNP-S, is a full-time DNP student with a family nurse practitioner focus at the University of North Florida. Timika has a background in hospice, home health, and substance abuse. She currently works as a COVID-19 vaccine and testing nurse.


1. Westphal SG, Plumb T. Calciphylaxis. In: StatPearls. StatPearls Publishing; 2022 Jan-. August 11, 2021. https://www.ncbi.nlm.nih.gov/books/NBK519020/

2. Baby D, Upadhyay M, Joseph MD, et al. Calciphylaxis and its diagnosis: a review. J Family Med Prim Care. 2019;8(9):2763-2767. doi:10.4103/jfmpc.jfmpc_588_19

3. Nigwekar SU, Zhao S, Wenger J, Hymes JL, Maddux FW, Thadhani RI, Chan KE. A Nationally representative study of calcific uremic arteriolopathy risk factors. J Am Soc Nephrol. 2016;27(11):3421-3429. doi:10.1681/ASN.2015091065.

4. Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378(18):1704-1714. doi:10.1056/NEJMra1505292

5. Bonchak JG, Park KK, Vethanayagamony T, Sheikh MM, Winterfield LS. Calciphylaxis: a case series and the role of radiology in diagnosis. Int J Dermatol. 2016;55(5):e275-279. doi:10.1111/ijd.13043

6. Nigwekar SU, Jiramongkolchai P, Wunderer F, et al. Increased bone morphogenetic protein signaling in the cutaneous vasculature of patients with calciphylaxis. Am J Nephrol. 2017;46(5):429-438. doi:10.1159/000484418

7. Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, Susantitaphong P. Treatment of calciphylaxis in CKD: a systematic review and meta-analysis. Kidney Int Rep. 2018;4(2):231-244. doi:10.1016/j.ekir.2018.10.002

8. Magro CM, Simman R, Jackson S. Calciphylaxis: a review. J Am Col Certif Wound Spec. 2011;2(4):66-72. doi:10.1016/j.jcws.2011.03.001

9. Nigwekar SU, Kroshinsky D, Nazarian RM, Goverman J, Malhotra R, Jackson VA, Kamdar MM, Steele DJ, Thadhani RI. Calciphylaxis: risk factors, diagnosis, and treatment. Am J Kidney Dis. 2015;66(1):133-46. doi:10.1053/j.ajkd.2015.01.034

10. Chen NX, O’Neill K, Akl NK, Moe SM. Adipocyte induced arterial calcification is prevented with sodium thiosulfate. Biochem Biophys Res Commun. 2014;449(1):151-156. doi:10.1016/j.bbrc.2014.05.005

11. Sensipar. Package insert. Amgen; 2019.