User:Kak3456/Calciphylaxis

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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. It is seen mostly in people with end-stage kidney disease but can occur in earlier stages of chronic kidney disease and rarely in people with normally functioning kidneys. It results in chronic non-healing wounds and indicates poor prognosis with typical life expectancy of less than one year. Calciphylaxis is a rare but serious disease, reportedly affecting 1-4% of all dialysis patients.

Calciphylaxis is one type of extraskeletal calcification. Similar extraskeletal calcifications are observed in some people with high levels of calcium in the blood, including people with milk-alkali syndrome, sarcoidosis, primary hyperparathyroidism, and hypervitaminosis D. In rare cases, certain medications such as warfarin can also result in calciphylaxis.

Signs and symptoms
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 are found. Surrounding the ulcers is usually a plate-like area of indurated skin. These lesions are always extremely painful and most often occur on the lower extremities, abdomen, buttocks, and penis, and usually have multiple bilateral lesions. Because the tissue has infarcted, wound healing seldom occurs, and ulcers are more likely to become infected. Many cases of calciphylaxis lead to systemic bacterial infection and death.

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 occurs in the myocardium and prevents normal diastolic filling of the ventricles.

Cause
The cause of calciphylaxis is unknown. Calciphylaxis is not a hypersensitivity reaction (i.e., allergic reaction) leading to sudden local calcification. It 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 cutaneous blood 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 the 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 reason. Another theory 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 renal disease patients are more likely to have vitamin K deficiency due to dietary restrictions meant to limit potassium and sodium. Many ESRD patients are also on a medication called warfarin, a vitamin K antagonist.

Reported risk factors include female sex, obesity, elevated calcium-phosphate product, medications such as warfarin, vitamin D derivatives (e.g. calcitriol, calcium-based binders, or systemic steroids), protein C or S deficiency, low blood albumin levels, and diabetes mellitus. Patients who require any type of vascular procedures are also at increased risk for poor outcomes.

Diagnosis
The diagnosis of calciphylaxis is clinical. There is no diagnostic test for calciphylaxis. The characteristic lesions are ischemic skin lesions, usually with areas of skin necrosis. Early lesions are painful indurated subcutaneous masses with superficial reticulated pattern. These lesions will progress to non-healing, stellate shaped violaceous (dark bluish purple) lesions and/or completely black leathery lesions. They can be extensive and are usually found in multiples. The suspected diagnosis can be supported by a skin biopsy, typically 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. Sometimes, bone scintigraphy can be done in cases where skin biopsy cannot be done. Results should show increased tracer accumulation in the soft tissues. In certain patients, an anti-nuclear antibody test may play a role. Plain radiography and mammography may also show calcifications but these tests are less sensitive.

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. 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. As 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.

Analgesia and Wound Management
Pain management and choice of analgesia is a challenging task in managing calciphylaxis. Pain is one of the most pervasive symptoms of the disease and can be unresponsive to high-dose opioids. Fentanyl and methadone are preferred over morphine, since morphine breakdown produces active metabolites that accumulate in the body in patients with kidney failure. Adjunct medications such as gabapentin and ketamine may also be used. In refractory cases, spinal anesthetics (nerve blocks) can be applied for more comprehensive pain relief.

Wound care for calciphylaxis lesions involves using appropriate dressings, wound debridement (removal of dead tissue), and prevention of infection. Wound infections can lead to sepsis, which is one of the leading causes of death in patients with calciphylaxis. Surgical wound debridement carries increased risk for infection as well, so the therapy should only be considered if survival benefit outweighs the chances of non-healing and pain.

Hyperbaric oxygen may also be considered. There are some smaller retrospective studies that show the use of hyperbaric oxygen in improving delivery of oxygen to wounds, which improves blood flow and helps with wound healing.

Risk factor mitigation
Most patients with calciphylaxis are already on hemodialysis or simply dialysis, but the length or frequency of sessions may be increased. The majority of dialysis patients are on a 4-hour three times per week schedule. Indications for increasing dialysis session length or frequency include electrolyte and mineral abnormalities, such as hyperphosphatemia, hypercalcemia, and hyperparathyroidism, all of which are also risk factors for development of calciphylaxis. Peritoneal dialysis patients should also transition to hemodialysis, as only hemodialysis carries the added benefit of better phosphate and calcium control. 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, a disease state that causes low calcium and requires use of calcium and calcitriol, which should be avoided in patients with end-stage kidney disease and calciphylaxis.

Pharmacotherapy
Sodium thiosulfate is commonly prescribed for treatment in patients with calciphylaxis. The actual mechanism of the drug is unknown, but several theories 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). Bisphosphonates are a popular choice for the treatment of osteoporosis, but they have also been used to treat calciphylaxis even though their mechanism 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. Cinacalcet (medical parathyroidectomy) is an oral medication that can be used to suppress the parathyroid glands for patients who may not be able to undergo surgery. Vitamin K supplementation has also been shown to slow development of calcification in coronary arteries and the aortic valve in older patients. The ability for vitamin K to slow calcification of blood vessels in calciphylaxis lesions is not well studied. Warfarin, a vitamin K antagonist discussed above, should be discontinued if possible.

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 calcium-phosphorus product below 55 mg^2/dL^2)
 * Avoiding further local tissue trauma (including avoiding all subcutaneous injections, and all not-absolutely-necessary infusions and transfusions)
 * Patients who receive 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 has reported plasma exchange effective and propose a serum marker and perhaps mediator (calciprotein particles)

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

Epidemiology
Calciphylaxis most commonly occurs in patients with end-stage kidney 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. Non-uremic calciphylaxis has been observed in patients with primary hyperparathyroidism, breast cancer treated with chemotherapy, liver cirrhosis, 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, 4 in 10,000 patients in Germany , 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 patients are women (60-70%). The location of lesions, central (located on the trunk) or peripheral (located on the extremities), depends on different risk factors. Central lesions are associated with younger patients, patients with a higher Body mass index, and higher risk of death than those who have peripheral-only lesions.