Calciphylaxis (calcific uraemic arteriolopathy) — Viva · MBBS viva

Viva scenario

A 67-year-old woman on haemodialysis for 8 years presents with a 6-week history of exquisite pain and an indurated violaceous plaque with central black eschar on the medial right thigh.

Q1 — Definition and classification (2 minutes)

Q. What is calciphylaxis, and how is it classified?

A. Calciphylaxis (calcific uraemic arteriolopathy, CUA) is a rare, life-threatening vasculopathy of the dermal and subcutaneous arterioles (100-600 µm) characterised by medial calcification + intimal hyperplasia + microthrombosis producing ischaemic skin necrosis. Classification:

By renal status — uraemic (~90%, CKD-5D) vs non-uraemic (~10%, e.g. warfarin, obesity, primary hyperparathyroidism, malignancy)
By anatomic distribution — proximal (thighs/abdomen/buttocks; 60-80% mortality) vs distal (calves/forearms; 20-40%) vs penile (>80%)
By clinical course — early indurated plaque → violaceous plaque → ulcer with eschar → sepsis. [1]

Q2 — Clinical presentation and bedside clue (2 minutes)

Q. What is the cardinal bedside clue, and which body sites are most often involved?

A. Pain out of proportion to the visible lesion — the cardinal bedside clue. Patients describe the lesion as the worst pain of my life and refuse to let the area be touched. Sites (in order): medial thighs > calves > abdomen > buttocks > breasts > penile shaft. Examine for livedo racemosa (irregular, branching, broken net — not the fine net of livedo reticularis). Induration feels wooden on palpation. Differential count of skin colouration matters: in dark skin, the violaceous phase appears ashen or grey-violet — the induration and pain must drive suspicion. [1]

Q3 — Differential diagnosis (3 minutes)

Q. Distinguish from MARTORELL ulcer, livedoid vasculopathy, pyoderma gangrenosum, cholesterol emboli, warfarin necrosis, and necrotising fasciitis.

MARTORELL hypertensive ischaemic leg ulcer — long-standing hypertension, subcutaneous hyaline arteriolosclerosis WITHOUT calcification (von Kossa negative), lateral or pretibial leg, ABI normal.
Livedoid vasculopathy — antiphospholipid antibodies, recurrent crops of ulcers along ankles, fibrin thrombi in superficial dermal venules, NO calcification, atrophie blanche scars.
Pyoderma gangrenosum — violaceous undermined border, pathergy (debridement worsens), IBD/RA association, sterile neutrophilic infiltrate, NO calcification, NEVER debride.
Cholesterol crystal emboli — acral livedo, blue toe, eosinophilia, recent vascular procedure, cholesterol clefts on biopsy.
Warfarin-induced skin necrosis — onset day 3-10 of starting warfarin, breast/thigh, protein C depletion, NO calcification.
Necrotising fasciitis — toxic, gas on imaging, sweet smell, surgical emergency; rapid extension. [1]

The discriminator is biopsy with von Kossa stain: medial calcification of subcutaneous arterioles is pathognomonic for calciphylaxis. [1]

Q4 — Investigations (2 minutes)

Q. What is the confirmatory investigation, and what is the laboratory panel?

A. Confirmatory: deep incisional biopsy of the edge of an active lesion (fusiform ellipse or 6-8 mm punch to fat) with H&E + von Kossa/Alizarin red stain. Show medial calcification of subcutaneous arterioles + intimal hyperplasia + microthrombi ± panniculitis. Plain X-ray of medial thighs may show tram-track vascular calcification; bone scintigraphy with technetium-99m MDP shows extraosseous uptake. Laboratory panel: corrected calcium, phosphate, Ca × P product, intact PTH (target 150-300 pg/mL), 25-OH vitamin D, alkaline phosphatase, INR, protein C/S, ferritin/transferrin saturation, blood cultures if febrile, wound swab. [1]

Q5 — Pathophysiology (3 minutes)

Q. Explain the warfarin–matrix Gla protein–calcium axis, the calcium-phosphate product, and the role of osteogenic transdifferentiation of vascular smooth muscle cells.

Warfarin–MGP–calcium axis — warfarin inhibits vitamin K epoxide reductase (VKORC1). Without reduced vitamin K, gamma-glutamyl carboxylase cannot carboxylate five glutamate residues on matrix Gla protein (MGP), the vascular smooth muscle cell–derived brake on medial calcium-phosphate deposition. The uncarboxylated MGP cannot bind hydroxyapatite crystals → unopposed medial calcification.
Calcium-phosphate product — calculated Ca (mg/dL) × P (mg/dL); above 55 mg²/dL² the risk of metastatic calcification rises steeply; above 70 the rate is high. Therapeutic target < 55 in active calciphylaxis.
VSMC osteogenic transdifferentiation — uraemic VSMCs down-regulate smooth-muscle markers (SM22α, α-actin) and up-regulate RUNX2, osterix, BMP-2, alkaline phosphatase → osteoblast-like phenotype → hydroxyapatite deposition in tunica media (visible as dark-black precipitate on von Kossa stain).
Inhibitor loss — fetuin-A falls to 30-50% of normal in dialysis; the fetuin-A-mineral complex that buffers calcium-phosphate overshoot disappears. [1]

Q6 — Management (3 minutes)

Q. Outline the first-line specific therapy, the five drugs to stop, the metabolic ladder, and the wound-care approach.

First-line specific therapy — sodium thiosulfate 25 g IV during the last 30-60 min of haemodialysis 3x/week (Wen JAMA Netw Open 2023 PMID 37099293); forms soluble calcium thiosulfate; antioxidant. Monitor bicarbonate (anion-gap acidosis), QTc.
STOP — (i) warfarin (switch to apixaban/LMWH); (ii) calcium-based binders (sevelamer, lanthanum); (iii) active vitamin D analogues; (iv) IV iron; (v) corticosteroids.
Metabolic ladder — phosphate < 1.5 mmol/L; Ca < 2.5 mmol/L; Ca × P < 55; iPTH 150-300 pg/mL; low-calcium (1.0 mmol/L) dialysate; intensify dialysis 4-5x/week × 4 hours.
Cinacalcet 30 mg → titrate 30-180 mg/day for PTH > 300-500 pg/mL.
Vitamin K₁ 100 mg IV/PO 3x/week for 4 weeks — re-carboxylates MGP and osteocalcin.
Wound care — moisture-retentive dressing, serial sharp debridement only if infected, maggot debridement, NPWT, HBOT 2.0-2.5 ATA × 5-7x/week for 4-6 weeks.
Pain — multimodal: opioid rotation (oxycodone/fentanyl) + gabapentin/pregabalin + ketamine 0.1-0.3 mg/kg/h ± regional block.
Parathyroidectomy for tertiary hyperparathyroidism (PTH > 800 pg/mL refractory to cinacalcet); bisphosphonates for adynamic bone disease. [1]

Q7 — Complications and prognosis (2 minutes)

Q. What is the leading cause of death, and what are the strongest prognostic predictors?

A. Sepsis from infected necrotic ulcers is the leading cause of death. Strongest prognostic predictors (Glennon 2025 PMID 40409721):

Proximal distribution (HR ≈ 2.5 vs distal)
Bacteraemia / sepsis at presentation (HR ≈ 3.0)
Intact PTH > 500 pg/mL (HR ≈ 2.0)
Ca × P > 70 mg²/dL² (HR ≈ 2.0)
Warfarin continuation (HR ≈ 2.0)
Persistent ulceration at 3-6 months of STS (HR ≈ 2.5) [1]

1-year mortality — overall 45-80%; proximal 60-80%; distal 20-40%; penile > 80%. Early palliative-care referral is appropriate. [1]

Q8 — Pharmacology deep dive (2 minutes)

Q. Give the specific dose, route, frequency, mechanism, and monitoring plan for sodium thiosulfate.

A. Sodium thiosulfate 25 g IV administered during the last 30-60 min of haemodialysis 3x/week, continued until ulcers healed and metabolic control sustained (usually 3-6 months). Mechanism — thiosulfate anion (S₂O₃²⁻) chelates Ca²⁺ to form water-soluble calcium thiosulfate; antioxidant through hydrogen sulfide; vasodilatory via NO. Monitoring — pre-dialysis bicarbonate (anion-gap acidosis is dose-limiting; supplement if HCO3 < 22 mmol/L); QTc; blood pressure; volume status. Adverse effects — nausea, headache, hypotension, infusion-site irritation, anion-gap acidosis, oxalate stones (long-term). Caution — extravasation causes severe tissue injury; use a dedicated IV line. [1]

Q9 — Renal pharmacology (3 minutes)

Q. How does warfarin cause calciphylaxis, what is the alternative anticoagulant, and what is the role of calcium-based binders, active vitamin D analogues, IV iron, and cinacalcet?

Warfarin — inhibits VKORC1 → uncarboxylated, inactive matrix Gla protein → unopposed medial calcification of arterioles (Yu 2017). Switch to apixaban (preferred) for AF, or LMWH for mechanical valves.
Calcium-based binders — worsen Ca × P; replace with sevelamer 800-1600 mg PO with meals or lanthanum.
Active vitamin D analogues — calcitriol/paricalcitol raise Ca × P; hold during active disease.
IV iron — generates hydroxyl radicals; defer.
Cinacalcet — allosteric calcimimetic of CaSR; for PTH > 500-800 pg/mL; titrate 30-180 mg/day; monitor corrected Ca (hypocalcaemia), phosphate. [1]

References

[1]Nigwekar SU, Thadhani R, Brandenburg VM Calciphylaxis N Engl J Med, 2018.PMID 29719190
[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]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]Kodumudi V, Jeha GM, Mydlo N, Kaye AD Management of Cutaneous Calciphylaxis Adv Ther, 2020.PMID 32997277
[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]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]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]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