Calciphylaxis is a topic covered in the 5-Minute Clinical Consult.

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Basics

Description

  • Rare, highly morbid, obliterative vasculopathy, characterized by ischemic or necrotic skin lesions
  • Affects patients with end-stage renal disease (ESRD)—calcific uremic arteriolopathy (CUA)
  • Rarely in those without ESRD: nonuremic calciphylaxis
  • Skin lesions
    • Early: extremely painful, dense, subcutaneous plaques or nodules; fixed livedo reticularis (racemosa)
    • Late: nonhealing ulcers, necrosis, eschars, potentially causing sepsis and death
    • Location: distal areas: most commonly isolated calf involvement; proximal areas overlying thick adipose tissue (thighs, buttocks, abdomen, breasts, penis)
  • Systemic deposition into other internal organ systems including GI tract, lungs, brain, muscle is rare but reported.
  • Pathogenesis involves medial calcification and intimal proliferation in subcutaneous vessels along with hypercoagulable state leading to ischemia.
  • As high as 85% mortality from secondary infections leading to sepsis
  • Synonym(s): calcific uremic arteriolopathy; uremic gangrene syndrome; calcifying panniculitis

Epidemiology

Incidence
3.5 new cases/1,000 patient-years among patient with ESRD on chronic dialysis


Prevalence
  • ~1–4% of the dialysis population
  • May be increasing due to increasing awareness

Etiology and Pathophysiology

  • Pathogenesis is a two-step process involving initial obliterative medial wall calcification, followed by ischemic tissue necrosis.
  • Vascular lesions
    • Characterized by arteriolar medial calcification, intimal proliferation, endovascular fibrosis
    • May involve capillaries, venules, and small arteries of both dermis and SC fat
  • Tissue lesions
    • Ischemic infarction distal to damaged (obliterated, thrombosed) vessels
    • Local trauma, hypotension, thrombosis, procoagulant states may trigger process.
  • ESRD patients commonly develop vascular calcification in absence of calciphylaxis; mechanisms involve
    • Deficiency in inhibitory factors of vascular calcification
      • Matrix G1a protein (inhibits vascular smooth muscle calcification; vitamin K–dependent, thus may be reduced by warfarin)
      • Fetuin-A (clears serum of excess calcium [Ca] and phosphorus [P]; downregulated in inflammatory states)
    • Phenotypic transformation of vascular smooth muscle cells into osteoblast-like cells
      • Elevated P stimulates this transformation.
      • Bone morphogenetic protein 2 (BMP-2)—potential stimuli for transformation
  • Disturbances in Ca/P/parathyroid hormone (PTH) homeostasis have been implicated but are inconclusive.
    • Elevated Ca, P, and Ca × P product promote Ca/phosphate crystal growth.
    • Animals sensitized with active vitamin D, Ca, P, and PTH develop lesions of calciphylaxis when challenged with inflammatory stimuli.
    • Reports of clinical improvement following parathyroidectomy
      • Improvement does not prove causality.
      • Abrupt decline in PTH induces leeching of Ca and P back into bone (hungry bone syndrome).
    • Disturbances in Ca, P, and PTH homeostasis are common in ESRD patients, most of whom do not develop calciphylaxis.
  • Obesity is an important etiologic factor.
    • Skin lesions commonly occur in areas of greatest subcutaneous adipose thickness.
    • Abdominal adipose tissue has diminished blood flow in obese versus nonobese patients; gravity-mediated tension promotes partial occlusion of adipose vessels.
    • Vascular calcification may exacerbate already reduced blood flow to critically low levels.

Risk Factors

  • ESRD (<15 mL/min GFR)
    • Managed by hemodialysis or peritoneal dialysis
    • Renal transplant recipients
  • Female gender (female > male ratio = 5:1)
  • Obesity (BMI >30)
  • Derangements in Ca, P, PTH metabolism
    • Hyperphosphatemia
    • Hypercalcemia
    • Elevated Ca × P product
    • Hyperparathyroidism
  • Caucasian race
  • Diabetes mellitus
  • Treatment with warfarin, vitamin D analogs, calcitriol, iron, Ca-based phosphate binders, systemic corticosteroids
  • Longer dialysis vintage of >6 to 7 years
  • Hypercoagulability states (protein C or S deficiency, antiphospholipid syndrome, antithrombin III deficiency, cryofibrinogenemia)
  • Protein malnutrition, hypoalbuminemia
  • Liver disease
  • Elevated serum aluminum
  • In patients without renal impairment: primary hyperparathyroidism, alcoholic liver disease, malignancy, chronic inflammatory disease, autoimmune disorders
  • Statins may have protective effect.

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Citation

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TY - ELEC T1 - Calciphylaxis ID - 816114 ED - Baldor,Robert A, ED - Domino,Frank J, ED - Golding,Jeremy, ED - Stephens,Mark B, BT - 5-Minute Clinical Consult, Updating UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/816114/all/Calciphylaxis PB - Wolters Kluwer ET - 27 DB - Medicine Central DP - Unbound Medicine ER -