Calciphylaxis

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: stellate, nonhealing ulcers, necrosis, eschars, potentially causing sepsis and death
• Extracutaneous vascular calcifications can lead to skeletal myopathy, intestinal bleeding, and visual impairment.
• 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

• 35 cases per 10,000 ESRD patients undergoing HD in United States
• Increasing incidence reported due to increasing awareness

Prevalence
~1–4% of the dialysis population

Etiology and Pathophysiology

• Pathogenesis is a two-step process involving initial obliterative medial wall calcification, followed by ischemic, occlusion, and tissue necrosis.
• Vascular lesions
  • Characterized by arteriolar medial calcification, intimal proliferation, endovascular fibrosis
  • May involve capillaries, venules, and small arteries of both dermis and subcutaneous 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
• Dependence on dialysis >2 years
• Thrombophilia (protein C or S deficiency, antiphospholipid syndrome, antithrombin III deficiency, cryofibrinogenemia)
• Protein malnutrition, hypoalbuminemia
• Hepatobiliary disease
• Elevated serum aluminum
• POEMS syndrome
• In patients without renal impairment: primary hyperparathyroidism, alcoholic liver disease, malignancy, chronic inflammatory disease, autoimmune disorders
• Statins may have protective effect.