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

The first skin changes in calciphylaxis lesions are mottling of the skin and induration in a livedo reticularis pattern. As tissue thrombosis and infarction occurs, a black, leathery eschar in an ulcer with adherent black slough develops. Surrounding the ulcers is usually a plate-like area of indurated skin.^[4] These lesions are always extremely painful and most often occur on the lower extremities, abdomen, buttocks, and penis. Lesions are also commonly multiple and bilateral.^[1] Because the tissue has infarcted, wound healing seldom occurs, and ulcers are more likely to become secondarily infected. Many cases of calciphylaxis lead to systemic bacterial infection and death.^[5]

Calciphylaxis is characterized by the following histologic findings:

1. systemic medial calcification of the arteries, i.e. calcification of tunica media. Unlike other forms of vascular calcifications (e.g., intimal, medial, valvular), calciphylaxis is characterized also by
2. small vessel mural calcification with or without endovascular fibrosis, extravascular calcification and vascular thrombosis, leading to tissue ischemia (including skin ischemia and, hence, skin necrosis).

Heart of stone

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.^[6]

Cause

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.^[7] 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.^[8] 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.^[8]

Reported risk factors include female sex,

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.[11] 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.^[1] Bone scintigraphy can be performed in cases where skin biopsy is contraindicated. Results of the study show increased tracer accumulation in the soft tissues.^[12] In certain patients, an anti-nuclear antibody test may play a role in diagnosis of calciphylaxis.^[13] Plain radiography and mammography may also show calcifications but these tests are less sensitive.^[8] Laboratory studies, such as phosphate levels, calcium levels, and parathyroid levels, are nonspecific and unhelpful for diagnosis of calciphylaxis.^[1]

Treatment

The treatment of calciphylaxis requires a multidisciplinary approach, using the knowledge of nephrologists, plastic surgeons, dermatologists, and wound care specialists working together to manage the disease and its outcomes.^[8] The key to treating calciphylaxis is prevention via rigorous control of phosphate and calcium balance and management of risk factors in patients who have increased chances of developing calciphylaxis. There is no specific treatment. Most treatment recommendations lack significant data, and none are internationally recognized as the standard of care. It is generally accepted to apply a multi-pronged approach to each patient.^{[citation needed]}

Analgesia and wound management

Pain management and choice of analgesia is a challenging task in managing calciphylaxis. Pain is one of the most severe and pervasive symptoms of the disease and can be unresponsive to high-dose opioids. Fentanyl and methadone are preferred analgesics over morphine, since morphine breakdown produces active metabolites that accumulate in the body of patients with kidney failure.^[8] Adjunct medications such as gabapentin and ketamine may also be used for analgesia. In refractory cases, spinal anesthetics (nerve blocks) can be used for more comprehensive pain relief.^[1] Wound care for calciphylaxis lesions involves using appropriate dressings, wound debridement (removal of dead tissue), and prevention of infection. Wound infections lead to sepsis, which is one of the leading causes of death in patients with calciphylaxis. Surgical wound debridement carries increased risk for infection, so it should only be considered as therapy if the survival benefit outweighs the chances of continued wound non-healing and pain.^[1]

Sodium thiosulfate is commonly prescribed for treatment in patients with calciphylaxis. The actual mechanism of the drug is unknown, but several explanations have been proposed, including chelation of calcium, vasodilation, antioxidant properties, and restoration of endothelial function. Adverse effects of sodium thiosulfate include high anion gap metabolic acidosis and high sodium levels (hypernatremia).^[16]

Other acceptable treatments may include one or more of the following:

• Clot-dissolving agents (
  tissue plasminogen activator
  )
• Maggot larval debridement
• Correction of the underlying plasma calcium and phosphorus abnormalities (lowering the Ca x P product below 55 mg2/dL2)
• Avoiding further local tissue trauma (including avoiding all subcutaneous injections, and all not-absolutely-necessary infusions and transfusions)
• Patients who have received kidney transplants also receive immunosuppression. Considering lowering the dose of or discontinuing the use of immunosuppressive drugs in people who have received kidney transplants and continue to have persistent or progressive calciphylactic skin lesions can contribute to an acceptable treatment of calciphylaxis.
• A group in 2013 reported
  plasma exchange effective and proposed a serum marker and perhaps a mechanistic mediator (calciprotein)^[18]

Overall, the clinical prognosis for calciphylaxis is poor. The 1-year mortality rate in patients who have end-stage kidney disease is 45-80%.[1] Median survival in patients who do not have end-stage kidney disease is 4.2 months.^[19] 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.^[1]

Epidemiology

Calciphylaxis most commonly occurs in patients with end-stage renal disease who are on hemodialysis or who have recently received a kidney transplant. When reported in patients without end-stage renal disease (such as in earlier stages of chronic kidney disease or in normal kidney function), it is called non-uremic calciphylaxis by Nigwekar et al.