What is calciphylaxis?

Calciphylaxis: A Rare and Life-Threatening Vascular Calcification Disorder

Calciphylaxis is a rare but life-threatening condition characterized by vascular calcification leading to ischemic skin ulceration, primarily affecting patients with end-stage renal disease. 1, 2

Definition and Pathophysiology

• Calciphylaxis, also known as calcific uremic arteriolopathy, involves calcification, fibrosis, and thrombosis of small to medium-sized dermal vessels, resulting in painful skin lesions and tissue necrosis 3, 4
• It is characterized by the failure of bone to properly modulate calcium and phosphate levels, leading to metastatic calcification in soft tissues 5
• The condition represents a severe manifestation of chronic kidney disease-mineral and bone disorder (CKD-MBD) 1

Clinical Presentation

• Painful, non-healing skin ulcers are the predominant presenting feature, most commonly affecting the lower legs (88% of cases) 6
• Lesions may also appear in fatty regions such as abdomen, thighs, and gluteal areas 7
• Early recognition is critical as mortality rates are extremely high, primarily due to sepsis from infected cutaneous ulcers 7

Risk Factors

• Primary risk factors include:

  • End-stage renal disease, particularly patients on dialysis 4
  • Use of vitamin K antagonists (e.g., warfarin), which increases risk up to 11-fold 2, 1
  • Obesity and diabetes mellitus 7
  • Female gender 7
  • Adynamic bone disease with low PTH levels 5
  • Inflammation (detected by elevated C-reactive protein) 1
  • Hypotension episodes during dialysis 7

• Secondary hyperparathyroidism can also be associated with calciphylaxis, though more recent cases have shown low PTH levels and adynamic bone histology 5

Diagnosis

• Diagnosis is primarily clinical but can be supported by:

  • C-reactive protein measurement (most helpful laboratory test reflecting inflammation) 1, 2
  • Skin biopsy, though this has significant limitations:
    • Variable sensitivity (20-80%)
    • Risk of traumatizing vulnerable tissue
    • No established validated histologic diagnostic criteria 1, 2

• Serum calcium and phosphate levels are not predictive of outcomes and cannot reliably guide therapy, as calciphylaxis can occur even with normal levels 2, 1

Treatment Approaches

• First-line therapeutic interventions:

  • Sodium thiosulfate (12.5-25g/session, 2-3 times/week for 3-6 months) 2, 4
  • Discontinuation of vitamin K antagonists 2, 7
  • Limitation of excess calcium and phosphate exposure 2
  • Intensification of dialysis regimen 4
  • Diligent wound care to prevent secondary infections 4

• Advanced therapeutic options:

  • Parathyroidectomy for patients with elevated PTH levels (>500 pg/mL) 2, 5
  • SNF472 (hexaphosphate phytate) shows promise in clinical trials for improving wound healing and reducing hospitalizations 2, 1
  • Magnesium supplementation may help prevent phosphate-induced vascular calcification 2

Prognosis and Monitoring

• Prognosis is generally poor with high mortality rates, primarily due to sepsis from infected ulcers 7, 8
• Regular monitoring should include:
  • Wound healing assessment
  • Inflammatory markers (C-reactive protein)
  • Vascular surveillance for calcification progression 2

Important Considerations and Pitfalls

• Avoid aggressive phosphate-lowering therapy in patients without overt hyperphosphatemia 2
• Be aware that both uremic (CKD-related) and non-uremic calciphylaxis exist, with different risk profiles and treatment approaches 6
• Early recognition and prompt multidisciplinary intervention are essential to improve outcomes 8
• Preventive strategies through risk factor modification are crucial given the limited effectiveness of current treatments 4