Calciphylaxis

Calciphylaxis, also known as calcific uremic arteriolopathy (CUA) or “Grey Scale”, is a rare syndrome characterized by painful skin lesions. The pathogenesis of calciphylaxis is unclear but believed to involve calcification of the small blood vessels located within the fatty tissue and deeper layers of the skin, blood clots, and eventual death of skin cells due to lack of blood flow. Calciphylaxis is a rare but serious disease, believed to affect 1 4% of all dialysis patients. It results in chronic non healing wounds and indicates poor prognosis, with typical life expectancy of less than one year.

Severe forms of calciphylaxis may cause diastolic heart failure from cardiac calcification, called heart of stone. Widespread intravascular calcification typical of calciphylaxis lesions occur in the myocardium and prevent normal diastolic filling of the ventricles.

The cause of calciphylaxis is unknown. Calciphylaxis is not a hypersensitivity reaction (i. e., allergic reaction) leading to sudden local calcification. The disease is also known as calcific uremic arteriolopathy; however, the disease is not limited to patients with kidney failure. The current belief is that in end stage kidney disease, abnormal calcium and phosphate homeostasis result in the deposition of calcium in the vessels, also known as metastatic calcification. Once the calcium has been deposited, a thrombotic event occurs within the lumen of these vessels, resulting in occlusion of the vessel and subsequent tissue infarction. Specific triggers for either thrombotic or ischemic events are unknown. Adipocytes have been shown to calcify vascular smooth muscle cells when exposed to high phosphate levels in vitro, mediated by vascular endothelial growth factor A (VEGF A) and leptin released by adipocytes. Given that calciphylaxis tends to affect adipose tissue, this may be a contributing explanation. Another hypothesis has been proposed, that vitamin K deficiency contributes to the development of calciphylaxis. Vitamin K acts as an inhibitor of calcification in vessel walls by activating matrix Gla protein (MGP), which in turn inhibits calcification. End stage kidney disease patients are more likely to have vitamin K deficiency due to dietary restrictions meant to limit potassium and sodium. Many end stage kidney disease patients are also on a medication called warfarin, a vitamin K antagonist, that limits vitamin K recycling in the body. Patients who require or have undergone any type of vascular procedures are also at increased risk for poor outcomes.

There is no diagnostic test for calciphylaxis. The diagnosis is a clinical one. The characteristic lesions are the ischemic skin lesions (usually with areas of skin necrosis). The necrotic skin lesions (i. e. the dying or already dead skin areas) typically appear as violaceous (dark bluish purple) lesions and/or completely black leathery lesions. They can be extensive and found in multiples. The suspected diagnosis can be supported by a skin biopsy, usually a punch biopsy, which shows arterial calcification and occlusion in the absence of vasculitis. Excisional biopsy should not be done due to increased risk of further ulceration and necrosis. In certain patients, an anti nuclear antibody test may play a role in diagnosis of calciphylaxis. Plain radiography and mammography may also show calcifications but these tests are less sensitive. Surgical parathyroidectomy is also recommended for those who have difficulty managing phosphate and calcium level balance. However, risks include development of post operative hungry bone syndrome (HBS), a disease state that causes low calcium and requires use of calcium supplementation and calcitriol, which should be avoided in patients with end stage kidney disease and calciphylaxis. Bisphosphonates are a popular choice for the treatment of osteoporosis, but they have also been used to treat calciphylaxis even though the exact mechanism in calciphylaxis is unknown. They are most beneficial in patients who have a genetic ENPP1 deficiency and have been shown to slow development of calciphylaxis lesions in a small prospective study. The ability of vitamin K supplementation to slow calcification of blood vessels in calciphylaxis is not well studied. Warfarin, a vitamin K antagonist discussed above, should be discontinued if possible.

Overall, the clinical prognosis for calciphylaxis is poor. The 1 year mortality rate in patients who have end stage kidney disease is 45 80%. Response to treatment is not guaranteed. The most common cause of death in calciphylaxis patients is sepsis, severe infection originating from a non healing ulcer. Non uremic calciphylaxis has been observed in patients with primary hyperparathyroidism, breast cancer (treated with chemotherapy), liver cirrhosis (due to hazardous alcohol use), cholangiocarcinoma, Crohn's disease, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). Calciphylaxis, regardless of etiology, has been reported at an incidence of 35 in 10,000 dialysis patients per year in the United States, and less than 1 in 10,000 patients in Japan. It is unknown whether the higher incidence in the United States is due to genuinely higher incidence or due to underreporting in other countries. Annual incidence in kidney transplant patients and in non uremic calciphylaxis patients is also unknown. The median age of patients at diagnosis of calciphylaxis is 60 years and the majority of these patients are women (60 70%). The location of lesions, central (located on the trunk) or peripheral (located on the extremities), is dependent on several risk factors. Central lesions are associated with younger patients, patients with a higher body mass index, and a higher risk of death than those who have peripheral only lesions.