A patient aged 21 years presents with painful erythematous patches on her bilateral thighs and calves. She had undergone a kidney transplant in childhood that was complicated by transplant failure. She has been on peritoneal dialysis for the past two years.
The patient is admitted to the hospital. On exam, the erythematous areas are extremely tender to palpation.Within two weeks these areas have progressed to eschars. The lesions’ progression is pictured.
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Calciphylaxis is a potentially fatal syndrome of progressive vascular media calcification, thrombotic ischemia, and necrotic ulceration. Also known as calcific uremic arteriolopathy, it usually occurs among patients with chronic renal failure, often comorbid with type 2 diabetes and/or obesity. Calciphylaxis can also be associated with autoimmune or malignant conditions.
Prevalence is about 1% to 4% in hemodialysis patients, and about 4% in peritoneal dialysis patients. Due to hormonal predisposition to thrombosis, calciphylaxis is predominat in females (with a male-female ratio of about 3:1 to 4:1).
In cutaneous calciphylaxis, subcutaneous nodules and infiltrated plaques may or may not precede the appearance of fixed livedo reticularis, which subsequently progresses to violaceous, purpuric, bullous and necrotic lesions. Irregularly-shaped, painful necrotic ulcers may develop in severe cases and indicate poor prognosis.
Most commonly, skin pathology is observed in poorly oxygenated tissue, with the lower legs affected in 90% of patients. About two-thirds of patients present with proximal lesions on the medial thighs, buttocks, abdomen, genitals and/or female breasts. These areas may be subject to low blood flow or reduced circulation due to tethering and kinking of vessels under gravity.
Onset of livedo and necrotic ulcers may be gradual or sudden in response to decreased perfusion, and precedes vascular thrombosis. Prothrombotic states, such as female gender, warfarin administration, trauma, underlying malignancy, or edema may predispose patients to the progression of calciphylaxis once necrosis is evident.
As progressive atherosclerosis narrows blood vessels by plaque formation, so does intimal calcification gradually lead to vessel stenosis, with both pathologies potentially resulting in thrombosis and downstream anoxia and necrosis.
Although treatment efforts in both pathologies should focus on prevention, universal guidelines exist to slow atherosclerotic progression. It is unclear how to prevent intimal calcification in patients with renal disease.
In terms of diagnostic tests, the multiplicative product of serum calcium and serum potassium concentrations will exceed 70 in only about 20% of calciphylaxis patients. The diagnosis may also be supported by plain radiographs demonstrating a net-like pattern of calcification.
Definitive diagnosis of cutaneous calciphylaxis is achieved by biopsy adjacent to areas of necrosis, ideally in a region of erythema or early purpura, and deep enough to demonstrate necrosis, extravascular calcification, and thrombosis in dermal and subcutaneous arterioles.
Excisional biopsy may be required beyond a standard punch biopsy to demonstrate these diagnostic features. Septal calcifying panniculitis as visualized by von Kossa stain on histology is diagnostic, but calcification alone cannot confirm the diagnosis of calciphylaxis, as vascular calcification is prevalent among all patients with chronic renal failure.
Ulcers in the setting of cutaneous calciphylaxis cause exquisite pain for patients, and narcotic analgesia may be necessary.
Once pain control is achieved, treatment must target abnormal calcium metabolism through mono- or combination therapy with low-calcium dialysis, oral phosphate binders, cinacalcet, bisphosphonates, or intravenous sodium thiosulfate. Parathyroidectomy may be necessary in refractory cases with elevated PTH.
Ischemic myopathy and muscle pain may herald the subsequent development of skin findings. In the context of poor perfusion, necrotic skin lesions heal poorly, promoting easy infection and potential septicemia and death.
Aggressive surgical debridement of ulcers has been shown to significantly improve the one-year survival rate for patients. Treatment efforts should aim to remove eschars and bacterial biofilms, as well as inflamed adipose tissue, given the depth of skin involvement in calciphylaxis, as evidenced histologically.
Hyperbaric oxygen therapy for ulcers may also facilitate wound healing. Surgical revascularization, multiple aggressive debridement procedures and skin transplantation may prevent amputation in many cases.
Despite aggressive intervention, calciphylaxis is often deadly, with 40% survival at one year and only 10% survival for patients with both proximal and distal involvement. Although no general consensus exists on the optimal treatment of calciphylaxis, the approach should undoubtedly be multidisciplinary.
Megan Schlichte, BS, is a medical student at Baylor College of Medicine.
Adam Rees, MD, is a graduate of the University of California Los Angeles School of Medicine and a resident in the Department of Dermatology at Baylor College of Medicine also in Houston.
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