II. Definitions

  1. Calciphylaxis (Calcific Uremic Arteriolopathy)
    1. Rare, often lethal complication of Hemodialysis in End Stage Renal Disease
    2. Characterized by cutaneous arteriolar calcification, thrombosis and skin necrosis

III. Epidemiology

  1. Incidence in Hemodialysis patients: 0.04 to 4%
  2. Rare outside of Kidney disease

IV. Pathophysiology

  1. Nearly exclusive to Hemodialysis patients (may require cessation of Hemodialysis)
  2. Pathogenesis
    1. Vascular endothelial injury
    2. Vascular calcification of the tunica media (middle) layer of arterioles and small arteries
    3. Microthrombi complicate an already narrowed arteriole lumen resulting in tissue ischemia and infarction
    4. Skin lesions are pathognomonic, but arteriole calcification is systemic and diffuse end organ effects may occur
  3. In part secondary to abnormal metabolism of Calcium and Phosphorus
    1. However, additional poorly understood, modifying factors are required to trigger Calciphylaxis

V. Risk Factors

  1. Renal Osteodystrophy (Calcium and Phophorus Metabolism in Chronic Kidney Disease)
  2. Longterm Hemodialysis
  3. Hyperparathyroidism
  4. Female gender
  5. Caucasian
  6. Obesity
  7. Diabetes Mellitus
  8. Autoimmune disorders (e.g. SLE)
  9. Hypoalbuminemia
  10. Malignancy
  11. Liver disease
  12. Medications
    1. Calcium-based Phosphate Binders (e.g. Calcium Carbonate, Calcium acetate)
    2. Corticosteroids
    3. Activated Vitamin D
    4. Warfarin
    5. Iron Therapy
    6. Frequent Subcutaneous Injections (e.g. Insulin)

VI. Symptoms

  1. Severe generalized pain (especially at skin lesions)

VII. Signs

  1. Tender skin lesions
  2. Skin lesion distribution (in order of high to low frequency)
    1. Lower leg
    2. Upper Leg, thighs and buttocks
    3. Abdomen
    4. Distal arms
    5. Proximal arms
  3. Skin lesion course
    1. Red to purple skin lesions, Subcutaneous Nodules and Plaques
    2. Skin Ulceration
    3. Skin necrosis and eschar (may be complicated by Cellulitis)
  4. Associated Findings
    1. Livedo Reticularis may be present

VIII. Labs

  1. See Renal Osteodystrophy
  2. Skin Biopsy
    1. Precautions
      1. Calciphylaxis is often a clinical diagnosis that does not require skin biopsy
      2. Skin biopsy sites may heal poorly and risk infection
    2. Findings
      1. Tunica intima layer fibrosis
      2. Small artery and arteriole calcifications (esp. capillary calcification within adipose tissue)
      3. Intra-arteriole thrombus may be present
      4. Dermal and epidermal ulcerations and necrosis

IX. Differential Diagnosis

  1. Cellulitis
  2. Vasculitis
  3. Warfarin Skin Necrosis
  4. Endarteritis Obliterans
  5. Antiphospholipid Syndrome
  6. Cholesterol embolization

X. Management

  1. Precautions
    1. Under-recognized condition outside of Hemodialysis centers (missed diagnosis is not uncommon)
    2. Very high morbidity and mortality
  2. Pain management
    1. Pain is severe and debilitating and results in frequent clinical encounters
    2. Consider Amitriptyline, Pregabalin in addition to Analgesics
  3. Renal Osteodystrophy (Calcium and Phophorus Metabolism in Chronic Kidney Disease)
    1. See Renal Osteodystrophy
    2. Maintain Serum Phosphate <5.5 mg/dl
    3. Avoid Hypercalcemia
      1. Avoid Calcium-based Phosphate Binders
      2. Avoid Calcium supplements
      3. Avoid high Calcium dialysate baths (>2.5 meq/L)
    4. Secondary Hyperparathyroidism
      1. Maintain Parathyroid Hormone 150 to 300 ng/ml
      2. Avoid activated Vitamin D
      3. Calcimimetic agent (e.g. cinacalcet) as needed to lower PTH levels
      4. Parathyroidectomy may be considered
  4. Eliminate medications associated with Calciphylaxis
    1. Replace Warfarin with Direct Acting Anticoagulants (DOACs)
  5. Skin Lesion Management
    1. Sodium Thiosulfate IV (infused during Dialysis)
      1. Sodium Thiosulfate has an unclear mechanism, but has vasodilation and antioxidant properties
      2. Benefit in >70% of patients
      3. Nigwekar (2013) Clin J Am Soc Nephrol 8(7):1162-70 +PMID:23520041 [PubMed]
    2. Wound care
      1. Debride necrotic, non-viable tissue
      2. Consider hyperbaric oxygen therapy
      3. Prevent infection
        1. Prophylactic antibiotics are NOT recommended
        2. Start antibiotics at first signs of infection

XI. Complications

  1. Non-Healing Wounds
  2. Skin infarction and necrosis
  3. Cellulitis often associated with Sepsis (primary cause of death)

XII. Course

  1. Skin ischemia may progress to skin necrosis
  2. One year survival is <50%
    1. Mortality typically due to Sepsis

XIII. Resources

  1. Westphal (2022) Calciphylaxis, StatPearls, Treasure Island (FL)
    1. https://www.ncbi.nlm.nih.gov/books/NBK519020/

XIV. References

  1. Mason and Swaminathan in Swadron (2022) EM:Rap 22(10): 1-3
  2. Nigwekar (2015) Am J Kidney Dis 66(1):133-46 +PMID: 25960299 [PubMed]

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Ontology: Calciphylaxis (C0006666)

Definition (NCI) A rare syndrome characterized by vascular calcification and skin necrosis. It seen in patients with end stage renal disease.
Definition (MSH) Condition of induced systemic hypersensitivity in which tissues respond to appropriate challenging agents with a sudden local calcification.
Concepts Disease or Syndrome (T047)
MSH D002115
SnomedCT 237900002
English Calciphylaxes, Calciphylaxis, calciphylaxis (diagnosis), calciphylaxis, Calciphylaxis [Disease/Finding], Idiopathic Calciphylaxis, Calciphylaxis, Idiopathic, calciphylaxes, Calciphylaxis (disorder)
Italian Calciofilassi, Calcifilassi
Swedish Kalcifylax
Japanese カルシフィラキシス, カルシフィラキシー, カルシフィラキシス
Czech kalcifylaxe, Kalcifylaxe, Calcific Uremic Arteriolopathy, kalcifikující uremická arteriolopatie, CUA, syndrom uremické gangrény
Finnish Kalsifylaksi
Russian KAL'TSIFILAKSIIA, КАЛЬЦИФИЛАКСИЯ
French Calciphylaxie idiopathique, Calciphylaxie
Polish Kalcyfilaksja
Hungarian Calciphylaxis
Norwegian Idiopatisk kalsifylaksi, Kalsifylaksi
Spanish calcifilaxis (trastorno), calcifilaxis, Calcifilaxis, Calcifilaxia
Portuguese Calcifilaxia, Calciofilaxia
Dutch calciphylaxis, Calcifylaxie
German Kalziphylaxie