Calciphylaxis (calcific uraemic arteriolopathy) — SAQ

Stem

A 67-year-old woman on haemodialysis for 8 years taking warfarin for atrial fibrillation presents with a 6-week history of an exquisitely painful, indurated violaceous plaque on her medial right thigh. Examination reveals a central geographic ulcer with a black, leathery eschar and surrounding livedo racemosa (irregular, branching, dusky patches). NEWS2 = 4 (HR 102, RR 22, lactate 1.8 mmol/L). Biochemistry on a pre-dialysis morning draw shows phosphate 2.4 mmol/L (7.4 mg/dL), corrected calcium 2.55 mmol/L (10.2 mg/dL), Ca × P product 75 mg²/dL², intact PTH 740 pg/mL, warfarin INR 2.4. [1]

Questions

a) What is the most likely diagnosis and what clinical features support it? (2 marks) [1]

b) What is the most appropriate confirmatory investigation, and why is a punch biopsy inadequate? (2 marks) [1]

c) Outline your medical management plan for the next 7 days, with agent, dose, route, and rationale for each. (4 marks) [1]

d) What is the approximate 1-year mortality, and which factor in this case confers the highest prognostic risk? (2 marks) [1]

Model answer (marking guide)

a) Diagnosis and clinical features (2 marks) Diagnosis: calciphylaxis (calcific uraemic arteriolopathy, CUA). Supporting features — (1) long-term haemodialysis patient; (2) on warfarin for AF; (3) exquisite pain out of proportion to visible lesion (the bedside cardinal clue); (4) indurated violaceous plaque with central geographic ulcer, black eschar, and surrounding livedo racemosa (broken, branching patches, not livedo reticularis); (5) medial thigh = proximal phenotype; (6) metabolic risk markers — elevated Ca × P (75) and elevated PTH (740). [1]

b) Confirmatory investigation and biopsy technique (2 marks) Deep incisional biopsy (fusiform ellipse or 6-8 mm punch extending into subcutaneous fat) taken from the edge of an active (non-ulcerated) lesion, with sections stained for H&E plus von Kossa or Alizarin red for calcium phosphate. A standard 3-4 mm punch biopsy is inadequate because the diagnostic vessels (subcutaneous arterioles 100-600 µm) lie 1-2 cm deep to the epidermis; punch misses the target in 30-40% of cases. Pathognomonic finding: medial calcification of subcutaneous arterioles with intimal hyperplasia and microthrombi (Bahrani et al. PMID 32604207). Plain X-ray of medial thighs and technetium-99m MDP bone scintigraphy are non-invasive adjuncts that may show vascular calcification. [1]

c) Medical management (4 marks)

• STOP warfarin immediately. Switch to apixaban 5 mg PO twice daily (no dose reduction in haemodialysis; preferred DOAC for AF in HD); rationale — uncarboxylated matrix Gla protein cannot inhibit medial calcification, and warfarin perpetuates the disease (Yu 2017 PMID 28099971).
• Sodium thiosulfate 25 g IV during the last 30-60 min of haemodialysis, 3x/week (Wen 2023 PMID 37099293); rationale — calcium chelation + antioxidant. Monitor bicarbonate (anion-gap acidosis), QTc, BP.
• Hold active vitamin D analogues (calcitriol/paricalcitol if prescribed); switch calcium-based phosphate binders to sevelamer 800-1600 mg PO with meals; reduce calcium dialysate to 1.0 mmol/L; intensify dialysis to 4-5 sessions/week × 4 hours; target Ca × P < 55 mg²/dL², phosphate < 1.5 mmol/L.
• Start cinacalcet 30 mg PO daily for PTH 740 pg/mL; titrate 2-4 weekly to PTH 150-300 pg/mL.
• Vitamin K₁ 100 mg IV/PO 3x/week for 4 weeks to re-carboxylate MGP and osteocalcin.
• Wound care and analgesia — moisture-retentive dressing; multimodal analgesia (oral oxycodone step 3 WHO + gabapentin 100-300 mg TDS titrating to pain); avoid debridement unless infected; consider HBOT 2.0-2.5 ATA, 5-7x/week for 4-6 weeks.
• Recognise sepsis — if NEWS2 ≥ 5 or fever, blood cultures before broad-spectrum antibiotics covering MRSA and Pseudomonas; escalate to ICU/HDU. [1]

d) Prognosis (2 marks) 1-year mortality 60-80% for proximal disease (medial thighs/abdomen); the highest prognostic risk factor in this case is proximal distribution + sepsis at presentation (NEWS2 4) + PTH > 500 + Ca × P > 70. Mean time to death is 2-3 months in the highest-risk subgroup. Independent predictors (Glennon PMID 40409721): proximal site (HR ≈ 2.5), sepsis (HR ≈ 3.0), PTH > 500 (HR ≈ 2.0), Ca × P > 70 (HR ≈ 2.0), warfarin continuation (HR ≈ 2.0). Early palliative-care involvement is appropriate given the high mortality. [1]

References

1. [1]Nigwekar SU, Thadhani R, Brandenburg VM Calciphylaxis N Engl J Med, 2018.PMID 29719190
2. [2]García-Lozano JA, Ocampo-Candiani J, Martínez-Cabriales SA, Garza-Rodríguez V An Update on Calciphylaxis Am J Clin Dermatol, 2018.PMID 29808451
3. [3]Gallo Marin B, Aghagoli G, Hu SL, Massoud CM, Robinson-Bostom L Calciphylaxis and Kidney Disease: A Review Am J Kidney Dis, 2023.PMID 35970430
4. [4]Kodumudi V, Jeha GM, Mydlo N, Kaye AD Management of Cutaneous Calciphylaxis Adv Ther, 2020.PMID 32997277
5. [5]Yu WY, Bhutani T, Kornik R, Pincus LB, Mauro T, Rosenblum MD, Fox LP Warfarin-Associated Nonuremic Calciphylaxis JAMA Dermatol, 2017.PMID 28099971
6. [6]Wen W, Portales-Castillo I, Seethapathy R, Nigwekar SU Intravenous Sodium Thiosulphate for Calciphylaxis of Chronic Kidney Disease: A Systematic Review and Meta-analysis JAMA Netw Open, 2023.PMID 37099293
7. [7]Bahrani E, Perkins JA, Shaver CM, Williams LR, Cook CB, Lober WR, Feldman KW Diagnosing Calciphylaxis: A Review With Emphasis on Histopathology Am J Dermatopathol, 2020.PMID 32604207
8. [8]Glennon CM, Behnam KT, Cheung K, Cordova A, Cummings B, Dobry A, El-Azhary R, et al. Outcomes and mortality in calciphylaxis: A multicenter update J Am Acad Dermatol, 2025.PMID 40409721