DermatologyTier 1Disease (DEADMAN)

Calciphylaxis

Description

Calcific uraemic arteriolopathy - medial calcification + intimal fibrosis of dermal/subcutaneous arterioles -> thrombosis -> ischaemic panniculitis and skin necrosis
A vascular occlusive disease, not a calcium-deposition disease - serum calcium and phosphate are frequently normal
Two patterns:
- Central/proximal (abdomen, buttock, thigh) - adipose-rich, worse prognosis
- Distal/acral (calf, ankle, digits) - better prognosis
Non-uraemic calciphylaxis exists (~5-10%) - normal renal function; think primary hyperparathyroidism, malignancy, warfarin, autoimmune disease, POEMS

Vascular smooth muscle cells undergo osteochondrogenic transdifferentiation (RUNX2)
- Loss of calcification inhibitors: matrix Gla protein (vitamin K-dependent), fetuin-A, pyrophosphate
- -> medial calcification of arterioles
Plus intimal hyperplasia + microthrombosis -> occlusion -> ischaemic necrosis
Warfarin: inhibits vitamin K-dependent carboxylation of matrix Gla protein -> uninhibited calcification (the single most modifiable drug risk)

Risk factors

Renal - ESKD (esp. peritoneal dialysis), rapid eGFR decline
Mineral - hyperphosphataemia, hypercalcaemia, hyperparathyroidism or over-suppressed PTH (adynamic bone)
Patient - female, obesity, diabetes, white ancestry
Drugs - warfarin, calcium-based binders, active vitamin D, IV iron, recombinant PTH (teriparatide), systemic steroids
Prothrombotic - protein C/S or antithrombin deficiency, lupus anticoagulant
Local trauma - subcutaneous injection sites (insulin, heparin, ESA) are a classic starting point
Other - hypoalbuminaemia, liver disease, autoimmune disease, POEMS, vitamin K deficiency

Clinical - the diagnosis is clinical

Pain out of proportion to visible lesion, preceding the lesion - the earliest and most reliable clue
Evolution:
- Tender indurated subcutaneous nodules/plaques, retiform (branching) purpura, livedo racemosa
- -> bullae -> stellate black eschar with surrounding leathery induration
- -> malodorous non-healing ulcer
Bilateral, symmetrical; adipose-rich sites

Investigations

Ca, PO4, PTH, ALP, 25-OH vitamin D, albumin
Thrombophilia screen if non-uraemic or atypical
Imaging: plain X-ray/mammography may show net-like subcutaneous vascular calcification (supportive, insensitive)

Biopsy

Deep incisional or punch of the lesion edge - not the eschar
Shows medial calcification + intimal fibroplasia + thrombosis of dermal/subcutaneous arterioles, septal panniculitis
*Biopsy may itself precipitate a new ulcer (pathergy-like) - reserve for diagnostic uncertainty*

Differential

	Discriminator
Warfarin skin necrosis	Days 3-5 of warfarin, protein C deficiency, breast/thigh
Cholesterol embolisation	Post-arterial instrumentation, eosinophilia, low C3
Peripheral arterial disease	Absent pulses, acral, unilateral
Venous ulcer / Martorell's HYTILU	Gaiter area; Martorell = HTN, lateral leg, exquisitely painful
Pyoderma gangrenosum	Undermined violaceous border, pathergy, IBD/RA
Necrotising vasculitis, purpura fulminans, nephrogenic systemic fibrosis, oxalosis, calcinosis cutis

No RCT-proven therapy. Multidisciplinary: nephrology, dermatology, pain, wound care, palliative care.

1. Wound and pain - the highest-yield intervention

Aggressive multimodal analgesia - opioids often needed at high dose; ketamine, gabapentinoids
- Morphine accumulates in ESKD - use hydromorphone/fentanyl/methadone
Moist wound care, specialist wound service
Surgical debridement only for infected or clearly necrotic wounds +/- negative pressure therapy
- Debriding viable ischaemic tissue extends the wound
Low threshold for antibiotics - sepsis from wound infection is the leading cause of death

2. Remove the drivers

Stop warfarin - switch to alternative anticoagulation (apixaban or LMWH) if anticoagulation still indicated
Stop calcium-based phosphate binders, active vitamin D analogues, teriparatide; minimise IV iron and steroids
Stop subcutaneous injections into affected areas

3. Correct mineral metabolism

Target normal Ca and PO4: non-calcium binder (sevelamer, lanthanum), low-calcium dialysate
Cinacalcet for hyperparathyroidism (preferred over parathyroidectomy in most)
Intensify dialysis (increase frequency/duration); consider switch from peritoneal to haemodialysis
Vitamin K supplementation - mechanistically rational, evidence weak

4. Sodium thiosulfate

IV STS 25 g in 100 mL over 30-60 min, 3x/week, with the last hour of each HD session; start 12.5 g test dose
Antioxidant, vasodilator, calcium chelator; inhibits adipocyte-driven VSMC calcification
*Observational meta-analyses show no survival or wound benefit* - widely used, poorly evidenced; trial for >=4 weeks, reassess
Adverse effects: volume and sodium load, metabolic acidosis (high anion gap), hypocalcaemia, QT prolongation, hypotension, nausea

5. Other

Hyperbaric oxygen - selected refractory distal disease
Hexasodium fytate (SNF472) - phase 3 CALCIPHYX did not meet its co-primary endpoint; not available
Early palliative care involvement in all - mortality is high and symptom burden is extreme

ESKD - more frequent with peritoneal than haemodialysis
Diabetes mellitus, obesity
Primary and secondary hyperparathyroidism; adynamic bone disease
Warfarin therapy
Thrombophilia - protein C/S deficiency, antithrombin deficiency, lupus anticoagulant
Autoimmune disease, POEMS syndrome, multiple myeloma
Alcoholic liver disease (non-uraemic)
Post-kidney-transplant (may occur on normal graft function)

6-month mortality ~50%; 1-yr mortality 45-80%
Sepsis from ulcerated wounds is the commonest cause of death, not the vascular lesion itself
Worse prognosis:
- Proximal/central (truncal) lesions
- Ulceration at presentation (vs non-ulcerated plaque)
- Obesity, female, diabetes, peritoneal dialysis
Median survival after ulceration ~6 months
Complications: intractable pain, wound sepsis, amputation, malnutrition, opioid dependence, depression
Discuss prognosis and goals of care early - many patients die of an intercurrent event during protracted treatment

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