Primary Causes of Calciphylaxis
Calciphylaxis is primarily caused by chronic kidney disease-mineral and bone disorder (CKD-MBD), where the bone fails to properly regulate calcium and phosphate metabolism, leading to metastatic calcification in small to medium-sized dermal vessels. 1
Core Pathophysiologic Mechanism
The fundamental cause is end-stage renal disease (ESRD) with associated mineral metabolism derangements, though the exact pathogenesis remains incompletely understood. 2, 3 The condition results from calcification, fibrosis, and thrombosis of dermal arterioles, causing ischemic skin necrosis. 4
Major Contributing Risk Factors
Medication-Related Causes
- Vitamin K antagonists (warfarin) increase calciphylaxis risk up to 11-fold, particularly in ESRD patients 1, 5
- High doses of active vitamin D derivatives contribute to risk 6
- Calcium-containing phosphate binders may promote calcium loading 7
Metabolic Derangements
- Hyperparathyroidism with elevated PTH levels (particularly >500 pg/mL) is commonly associated, though not universally present 7, 8
- Adynamic bone disease with low PTH levels paradoxically also increases risk 1
- Elevated calcium-phosphate product (though calciphylaxis can occur with normal levels) 2, 3
Important caveat: Serum calcium and phosphate levels are NOT predictive of calciphylaxis development and cannot reliably guide therapy—patients can develop calciphylaxis even with normal mineral levels. 6, 5
Inflammatory Component
- Elevated C-reactive protein reflecting systemic inflammation is a significant risk factor 1, 6
- This inflammatory state appears central to pathogenesis beyond simple mineral deposition 6
Secondary Contributing Factors
- Diabetes mellitus in ESRD patients increases likelihood of acral gangrene presentation (61% vs 34% in non-diabetics) 8
- Prolonged dialysis duration correlates with risk 3
- Excess calcium loading from dialysate and oral supplements may contribute to vascular calcification 7, 5
Clinical Context
The condition occurs almost exclusively in ESRD patients on dialysis or recent transplant recipients with chronic allograft nephropathy. 3 Rare cases occur in pediatric ESRD patients and occasionally in patients with normal renal function. 2, 9 The cumulative incidence in dialysis populations is approximately 1.17%. 3
Critical pitfall: The specific triggers that cause calciphylaxis to develop in some ESRD patients but not others remain unclear, despite similar metabolic profiles. 3 This suggests additional unidentified factors beyond traditional mineral metabolism parameters play crucial roles in disease development.