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Q1: What is the diagnosis?
The diagnosis is calciphylaxis, also known as the uraemic gangrene syndrome, vascular calcification cutaneous necrosis syndrome, azotaemic calcific arteriolopathy, or calcifying panniculitis.
Q2: What are the risk factors for this condition?
Significant risk factors include white race, female gender, morbid obesity, recent severe weight loss, prolonged dialysis, insulin dependent diabetes mellitus, warfarin therapy, the use of calcium carbonate or corticosteroids, hypoalbuminaemia, iron overload, polycythaemia, peripheral vascular disease, Crohn's disease, AIDS, and hypotension. In a subset of patients, a hypercoagulable state may underlie the development of the disorder. A mathematical formula (2 × [CaPO4 in mmol/l—5] × alkaline phosphatase in IU/l × PTH value ÷ upper limit of normal PTH reference range) was empirically developed to aid in the identification of high risk patients (those with results greater than 1000).1
Q3: Can this condition occur in patients without renal disease?
Although calciphylaxis occurs predominantly in patients with end stage renal disease, or those who have recently received a renal transplant, this entity can infrequently be seen with any cause of hypercalcaemia including primary hyperparathyroidism, vitamin D intoxication, the milk alkali syndrome, idiopathic neonatal hypercalcaemia, metastatic bone disease, various haematological malignancies, as well as end stage liver disease and after excess parenteral phosphate infusions during the treatment of sepsis.
Calciphylaxis, first described by Hans Selye in 1962, is a rare, potentially life and limb threatening condition of progressive tissue necrosis related to microvascular calcification.2 In severe cases, there may be associated metastatic calcification of the subcutaneous fat, lungs, kidneys, stomach, pancreas, and heart. The pathogenesis of calciphylaxis is poorly understood.3 It evolves rapidly from a multitude of predisposing and/or sensitising events that are commonly present in the uraemic milieu. Some factor(s) other than renal failure, raised PTH, calcium and/or phosphate appears to be involved in its pathogenesis, since these parameters do not always accurately predict its development or severity.4Recent observations suggest that infection by certain novel micro-organisms (nanobacteria) may provide a nidus for pathological calcification.5 For reasons that are still unclear, factors in addition to calcific arteriolopathy must trigger calciphylaxis, because calcification of arteries (Monckeberg's sclerosis) commonly occurring in uraemic patients alone rarely results in tissue ischaemia. Possible mechanisms to account for reduced blood flow include complete obliteration of vessels by calcium salts, intimal fibrosis and proliferation, thrombosis, acquired protein C or S deficiency, a direct vasoconstrictive effect of calcium, and autonomic dysfunction. Precipitating events may include local skin trauma, injections, decreased systemic and local blood flow, ultraviolet light, albumin infusions, corticosteroids, oral phosphates, radio-opaque contrast media, and blood transfusion products. Calciphylaxis after renal transplantation may be due to immunosuppression.
Calciphylaxis manifests with livedo reticularis and/or painful violaceous skin plaques that typically progress to deep non-healing ulcers with underlying tissue necrosis and eschars of the trunk or limbs. Gangrene of digits may require amputation. Blood flow is usually demonstrable distal or deep to the necrosis. Involvement of the penis may also occur. Digital (peripheral) ischaemia has a better prognosis than proximal (central) necrosis. Infrequent complications include ischaemic myopathy, pancreatitis, and gastrointestinal haemorrhage. Superinfection is the primary cause of the high mortality (up to 60%–80%) associated with this condition. Clinically, calciphylaxis may simulate atherosclerotic peripheral vascular disease, atheroembolisation, septic embolism, warfarin sodium necrosis, connective tissue diseases and other vasculitides, necrotising fasciitis, deep fungal infections, deep venous thrombosis, disseminated intravascular coagulation, cellulitis, dermatomyositis, pyoderma gangrenosum, necrobiosis lipoidica, autoimmune bullous dermatoses, necrotising araneism, the antiphospholipid syndrome, protein C and S deficiencies, cryofibrinogenaemia, oxalosis, and the glucagonoma syndrome. There is no diagnostic laboratory test for calciphylaxis. Calciphylaxis is not associated with immunoglobulin deposition or autoimmune antibodies. While high plasma levels of PTH, phosphate, and calcium are consistent with the diagnosis, all of these abnormalities are not always present. Skin biopsies incorporating subcutaneous tissue offer an important means of establishing the diagnosis. Large biopsies are desirable because histological findings are segmental and may be missed. The diagnosis can sometimes be suggested radiologically by vessel and/or soft tissue calcification.
Given the high mortality and morbidity associated with calciphylaxis early recognition and treatment of this entity are essential. Treatment is primarily supportive with emphasis on eliminating the sensitiser and challenger. This includes rigorous control of phosphate and calcium balance, avoiding challenging agents, including the possible withdrawal of immunosuppression in the renal transplant patient. Wound care, debridement of necrotic tissue, and the administration of antibiotics for infected tissue is also imperative. Treatment with low calcium dialysate and phosphate binding antacids is indicated. Parathyroidectomy in patients with evidence of hyperparathyroidism has proved successful. The efficacy of calcium channel blockers and other vasodilators, anticoagulants, and hyperbaric oxygen therapy has not been refined. Despite therapy, the prognosis remains poor.
In this case, the patient recovered after withdrawal of warfarin sodium, meticulous wound care, administration of broad spectrum antibiotics, repeated surgical debridement of necrotic tissue, and haemodialysis three times per week.
Calciphylaxis occurring in the setting of chronic renal failure.
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