Calciphylaxis (calcific uraemic arteriolopathy)

Meet the patient

A 62-year-old woman, eight years on haemodialysis and on warfarin for atrial fibrillation, is admitted because she "cannot bear the bedsheet on her leg." On the medial right thigh sits a thumb-sized, woody, violet plaque with a central black eschar and a broken net of livedo climbing around it. Her phosphate is 2.6 mmol/L and her intact PTH 940 pg/mL. The pain is the loudest finding in the room — louder than the lesion — and it is the clue that this is not cellulitis. The question the examiner is really pressing on: what is calcifying this woman's arterioles, and what do you stop, start and measure in the next hour? [1][2]

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What calciphylaxis actually is

Calciphylaxis (calcific uraemic arteriolopathy, CUA) is a rare, life-threatening vasculopathy of the dermal and subcutaneous arterioles — and it is defined by three changes happening in the same vessel at once: medial calcification, intimal hyperplasia, and luminal microthrombosis. The artery first turns to bone, then narrows, then clots off; the skin and fat it was feeding die. [1][3]

The name is a historical accident. Hans Selye coined calciphylaxis — literally "protective calcification" — in 1961 for a rat hypersensitivity trick that has nothing to do with the human disease. The label stuck; the rats did not. The precise term is calcific uraemic arteriolopathy, but examiners say calciphylaxis, so you say it too. [3]

The vessels caught are 100–600 μm arterioles — small enough that no bypass graft will reach them, large enough that a deep biopsy finds them. Because they feed skin and subcutis rather than muscle, the disease declares itself as cutaneous necrosis, not claudication. It is almost always acquired, on the back of stage 5D CKD or one short list of non-uraemic triggers. [1][3]

The bedside signature is pain out of all proportion to what you see. A dialysis patient in tears over a small violet patch, refusing to let you touch it, is calciphylaxis until proven otherwise. The lesion then marches through livedo racemosa, violaceous plaque, and finally a black leathery eschar — full-thickness ischaemic necrosis — and from there, often, into sepsis and death. [1][2][8]

One-year mortality is still 45 to 80 per cent, unmoved in three decades of "more aggressive" therapy, largely because the diagnosis still arrives months late. Hold that number: in this disease, being quick is the treatment. [1][8]

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How the disease sorts itself

Sort every case three ways at once — renal status, anatomy, and stage of the lesion. The renal split points to the cause; the anatomic split sets the prognosis; the stage tells you whether therapy can still reverse it. [3][8]

[1]

The WOMBAT for the non-uraemic 10 per cent. When the GFR is normal, the same vasculopathy is driven by a different shortlist — learn it as WOMBAT: Warfarin, Obesity, Malignancy (breast especially), Bisphosphonate or teriparatide, Alcoholic liver disease (vitamin K depleted), Thyroid or autoimmune. Reach for WOMBAT the moment the biopsy says calciphylaxis but the creatinine is normal. [3][5]

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Who ends up on the list

Think "dialysis, female, fat, diabetic, on warfarin" and you have captured most of the risk. Modern cohorts put incidence at roughly 1 per 200 dialysis-person-years — about 3,500 patients alive in the United States at any time, with matched numbers in Europe. Two forces push it up year on year: patients survive longer on dialysis, so the at-risk pool grows, and the obesity epidemic adds an independent risk factor. [3][8]

[1]

The risk-factor clusters

The dominant risk is advanced CKD with long dialysis vintage. Layered on top are overlapping insults to mineral metabolism, vascular biology, and coagulation — the patient who collects three of them is the patient who develops calciphylaxis. [3]

[1]

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The mechanism — one vessel, three insults

Three parallel axes converge on the same arteriole: medial calcification, intimal hyperplasia, and microvascular thrombosis. The first turns the wall to bone; the second narrows it; the third closes it. Skin and fat distal to the occlusion coagulate. [1][3][7]

Hold the seven-letter scene in your head as CALCIFY — the page's central memory device and the answer to "talk me through the pathophysiology": [1]

[1]

Step one — the smooth muscle cell decides to become bone. Medial vascular smooth muscle cells down-regulate SM22α and α-actin and up-regulate RUNX2, osterix, BMP-2 and alkaline phosphatase; they now lay down hydroxyapatite in the tunica media, encasing the arteriole in a rigid calcified ring that stains jet-black on von Kossa. [3][7]

Step two — the calcified wall provokes intimal hyperplasia. Subintimal myofibroblasts pile up concentric collagen and narrow the lumen by half to nine-tenths. The vessel is now both brittle and stenotic. [1]

Step three — the damaged endothelium tips Virchow's triad into thrombosis. Add the acquired protein C and S deficiency of uraemia, and microthrombi seal the narrowed lumen; perfusion falls below the ischaemic threshold and the overlying dermis and fat coagulate. [3][7]

The inhibitor axis is where warfarin does its damage. Matrix Gla protein (MGP) is the body's brake on vascular calcification — but only after vitamin-K-dependent γ-carboxylation activates it. Warfarin blocks vitamin K epoxide reductase, leaving MGP undercarboxylated and inert, so medial calcification proceeds unopposed even when the calcium is normal. This is the molecular reason "stop the warfarin" is step one of treatment, and the link to the non-uraemic warfarin phenotype. [1][5]

Fetuin-A is the parallel brake, and uraemia strips it. Fetuin-A normally ferries spare calcium-phosphate through the blood as a soluble mineral complex; in dialysis patients it falls to around a third of normal, the complex vanishes, and the already-elevated Ca × P product is free to precipitate in vessel walls. [3]

The number examiners want is the Ca × P product. Memorise the formula and the threshold: [1]

Ca × P product (mg²/dL²) =
     corrected calcium (mg/dL) × phosphate (mg/dL)

Above 55 mg²/dL² the product is "high"; above 70 the risk of metastatic calcification climbs steeply. The therapeutic target in active disease is to drive it below 55 mg²/dL² — non-calcium phosphate binders, intensified dialysis clearance (Kt/V), reduced calcium dialysate, and active vitamin D analogues held until the storm passes. [3][4]

What you see at the bedside

The clinical picture is where the diagnosis is made — and where it is most often missed. Examiners build the stem around three signals arriving together: pain, induration, and livedo racemosa, all in a dialysis patient. [1]

A minority have visceral disease at the same time. Calcification of coronary, mesenteric or digital arteries can produce a non-ST-elevation myocardial infarction, intestinal ischaemia, or acral gangrene alongside the skin necrosis; rare cases show calcific mononeuritis multiplex or limbal calcification. Everyone forgets: the skin is the visible tip — the same process is quietly occluding other vascular beds. [3]

Systemic signs are those of the substrate disease — uraemia, secondary hyperparathyroidism, hypertension, diabetes, heart failure — not of calciphylaxis itself. [1]

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The differential trap

Examiners seed the stem with close mimics; the discriminator is nearly always on the biopsy or the bloods. The task is not "what else causes a painful leg ulcer" but "which single histological or serological feature rules each mimic out." [1][2][3]

Bedside triad that captures most of the diagnosis: an exquisitely tender, indurated plaque ringed by broken livedo racemosa, in a long-standing haemodialysis patient on warfarin. Two of three should trigger a biopsy. [1]

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Confirming it at the bedside

The bedside yields far more than imaging in this disease. Run the exam in a fixed order — you are confirming suspicion, grading sepsis, and choosing the biopsy site in one pass. [2][4]

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How to confirm it — biopsy is the boss

Calciphylaxis is a clinicopathological diagnosis. The bedside and the metabolic panel set the context; a deep biopsy confirms. Run both in parallel — do not let the laboratory delay the biopsy. [2][7]

Skin biopsy — deep, not punch

A deep incisional biopsy is the test of choice; a 4-mm punch is inadequate. The calcified arterioles lie 1–2 cm deep in the subcutis, and punch biopsies miss them in roughly a third of cases. Technique: [7]

1. Choose the edge of an active lesion, ideally where livedo racemosa meets a violaceous plaque (or where the plaque is non-ulcerated for first-line biopsy).
2. Use a 6-8 mm punch or, preferably, a fusiform incisional biopsy extending into the subcutis.
3. Two-site biopsy is recommended when feasible — contralateral symmetric area, atypical lesion, or atypical presentation — to improve diagnostic yield without increasing clinical risk.
4. Ask the dermatopathologist for H&E plus a von Kossa stain (calcium phosphate deposits); Alizarin red is an alternative.[7]
5. The pathologist should also evaluate for medial calcification of dermal and subcutaneous arterioles, intimal hyperplasia, extravascular calcium deposits in the panniculus, lobular panniculitis, and microthrombi.

[1]

Pathology — what to demand on the report

Do not accept "ischaemic necrosis" as an answer. Insist the report comments on each of the four features below — a vague report is a missed diagnosis. [7]

The metabolic panel

Draw the panel fasting, before dialysis — post-HD calcium and phosphate are meaningless. This is the panel that tells you what to stop and what to start. [2][3][4]

[1]

Imaging — when biopsy is risky

Plain X-ray and bone scintigraphy are the non-invasive adjuncts. Medial-thigh films show tram-track vascular calcification in a third to a half of patients; mammography flags breast disease with branching arteriolar calcification; Tc-99m MDP scintigraphy lights up extraosseous calcium as a characteristic "double stripe" running parallel to the skeleton. Reserve CT for suspected visceral ischaemia. [3]

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The first 24 hours — the time-critical bundle

The first day sets the trajectory for the whole admission. The patient is rarely "unstable" in the textbook sense, but four lines of therapy must move within hours — and the dose-critical one is sodium thiosulfate. [1][4]

[5] [11] [15]

[9] [10] [11] [12] [14]

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Definitive therapy, step by step

There is no single curative drug — management is multidisciplinary and aimed at the same three axes: calcification, thrombosis, and pain. The framework below is the one the 2018 NEJM and 2023 AJKD reviews converge on. Say the mantra out loud on the round: stop the warfarin, start the thiosulfate, starve the calcium–phosphate product. [1][3][4][6]

The pharmacological ladder

[9] [10] [6] [1] [11] [15] [18] [19]

Other useful therapies

Three adjuncts complete the medical ladder — vitamin K to re-carboxylate MGP, bisphosphonates for the adynamic-bone phenotype, and hyperbaric oxygen for refractory ischaemic wounds. [1]

[1]

Wound care and the surgical decisions

Wound care is where dermatology, surgery and pain meet. Pain control and risk-factor modification come first; debridement decisions belong to a systematic multidisciplinary approach. [4][12]

• Multimodal analgesia precedes any wound intervention. Pain in calciphylaxis is difficult to treat and management should be multimodal: opioids are the mainstay, with NSAIDs and options targeted to the specific patient as adjuncts — always alongside wound care and modification of risk factors.
• Surgical debridement of necrotic tissue is safe and effective when embedded in a systematic multidisciplinary pathway: in a 62-patient cohort, debridement followed by closure — skin grafting in 20, primary closure in 5, and healing by secondary intention in 37 — produced excellent healing in all groups, with no wound progression and no new lesions after operative intervention.
• Skin grafting — split-thickness grafting closed 20 of the 62 surgically debrided wounds in that cohort, with excellent healing in all closure groups.
• Negative-pressure wound therapy has been reported as successful adjunctive wound management (together with pamidronate) in non-uraemic calciphylaxis.
• Amputation remains a last resort for uncontrolled sepsis or established dry gangrene of an acral part. [4][12][17]

Five drugs to stop today

The moment calciphylaxis is suspected, stop the precipitants. This is a preventable-harm list — every drug here is either fuelling the calcification or blocking its reversal. [1]

1. Warfarin — switch to apixaban (preferred for AF) or LMWH (if valve/APS). Withholding anticoagulation briefly during the active sepsis phase may be necessary; balance against the indication.
2. Calcium-based phosphate binders — switch to sevelamer or lanthanum.
3. Active vitamin D analogues (calcitriol, alfacalcidol, paricalcitol) — hold until PTH and Ca × P are corrected.
4. IV iron infusions — defer until active disease resolves.
5. Systemic corticosteroids — taper to the lowest tolerable dose; do not stop abruptly.
6. Teriparatide — stop. [5][11]

Intensify the dialysis

Inadequate phosphate clearance is the most commonly missed contributor. Push the prescription harder while the disease is active. [1]

• Increase session length to 4-4.5 hours (longer = more convection/diffusion).
• Increase frequency to 4-5 sessions per week during the active phase.
• Use higher-flux or haemodiafiltration (HDF) membranes.
• Switch calcium dialysate to 1.0 mmol/L (from 1.25 or 1.5).
• Magnesium-rich dialysate (0.5 mmol/L) is investigational; magnesium inhibits hydroxyapatite precipitation and may slow medial calcification. [1]

Parathyroidectomy — the last resort

Reserve parathyroidectomy for severe secondary hyperparathyroidism refractory to medical therapy. The surgical threshold from the CKD-MBD literature: consider parathyroidectomy when intact PTH persists above 800 pg/mL for over 6 months despite exhaustive medical intervention — particularly with concomitant disorders such as persistent hypercalcaemia, hyperphosphataemia, or tissue or vascular calcification including calciphylaxis. Observational cohorts associate parathyroidectomy with 15-57 % greater survival in dialysis patients. The 2025 NSQIP nationwide analysis sounds a clear perioperative caution: among 203 patients undergoing parathyroidectomy for secondary hyperparathyroidism, the 17 with calciphylaxis had higher rates of unplanned reintubation (12 % vs 0.5 %) and cardiac arrest (12 % vs 0.5 %), calciphylaxis being an independent risk factor for cardiac arrest (odds ratio 3.6), although mortality was comparable between groups — consent carefully and involve the surgeon early. [13][14]

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The lethal subtypes

Two phenotypes dominate the mortality conversation: proximal disease and penile disease. Know them by site and by number — they change the urgency and the goals-of-care conversation. [1][5][8]

[5] [8] [9] [10] [13]

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Preventable harm — the danger list

Most calciphylaxis deaths are preventable, and they happen on a predictable shortlist. Run this list on every admission and again on every review — sepsis, pathergy, amputation, drug toxicity, and the silent killer, diagnostic delay. [1][8]

[1]

The named traps — PITFALLS

Eight ways to lose marks — and patients — collected as PITFALLS. Each letter is a mistake the registrar before you has already made. [1]

[5] [9] [10] [11] [15]

When to escalate

Escalation is early, not late, in calciphylaxis. Use the box below as the registrar's trigger list — any one line should move the patient up the acuity ladder today. [1]

[1]

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Prognosis and where they go

[1]

The predictors of death are few and reproducible — memorise them, because they decide who gets aggressive therapy and who gets a palliative conversation early. [3][8]

• Proximal distribution (HR ≈ 2.5 vs distal)
• Bacteraemia or sepsis at presentation (HR ≈ 3.0)
• Intact PTH > 500 pg/mL (HR ≈ 2.0)
• Ca × P > 70 mg²/dL² at presentation
• Persistent ulceration after 3 months of STS (HR ≈ 2.5)
• Warfarin continuation (HR ≈ 2.0)
• Higher Charlson comorbidity index, especially diabetes and heart failure [1]

Disposition is individualised, and the palliative threshold is early. Severe proximal disease, sepsis at presentation, declining function, or multi-organ failure all warrant palliative medicine in the first two weeks — not the last two days. Discuss goals of care early. [1]

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Special populations

Four groups bend the standard plan: pregnancy, children, the elderly, and the already-anticoagulated. Each changes a drug, a dose, or a threshold. [1]

[1]

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Evidence and what the guidelines say

The evidence base is observational cohorts — no randomised trial defines therapy, and the best meta-analysis is null. Wen and colleagues' 2023 JAMA Network Open meta-analysis pooled 19 retrospective cohorts (422 patients) and found intravenous STS was NOT associated with skin-lesion improvement (risk ratio 1.23, 95 % CI 0.85-1.78) or a lower risk of death (risk ratio 0.88, 95 % CI 0.70-1.10). The largest single series — 172 haemodialysis patients — reported clinical improvement in a majority of surveyed patients and a 1-year mortality of 35 %. [6][9]

The framework papers. Nigwekar's 2018 NEJM review remains the most-cited scaffold; García-Lozano (2018) and Gallo Marin (2023) refreshed the pathophysiology and treatment paradigm; Kodumudi (2020) laid out the multidisciplinary ladder; and Bahrani (2020) is the pathology reference examiners quote. [1][2][3][4][7]

The warfarin phenotype and the mortality update. Yu's 2017 JAMA Dermatology series is the canonical description of warfarin-associated non-uraemic calciphylaxis; Glennon's 2025 multicentre update is the current mortality benchmark. [5][8]

[6] [9] [11] [1] [1] [1]

Controversies

• Surgical debridement — yes or no? Two camps. Most US and German centres favour serial debridement; many French/Italian centres favour conservative management with maggot therapy.
• Parathyroidectomy — does it help? Observational data are conflicting; the 2025 J Surg Res paper (PMID 40768885) raises concern about perioperative morbidity; many centres avoid it except in clear-cut tertiary hyperparathyroidism.
• Bisphosphonates — useful or harmful? Beware of oversuppression of bone turnover worsening adynamic bone disease (which itself predisposes to calciphylaxis). [1]

Agents in the pipeline

• SNF472 (sodium hexanol-pyrophosphate) — a calcification inhibitor being tested in phase 2 trials.
• Vitamin K supplementation — RCTs in dialysis populations (TamaRENal and KiCK-OKA) underway.
• Targeted FGF23 modulators — research only. [1]

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Exam pearls

[9] [6] [10]

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Ward-round test

Three stems to carry into the viva — cover the page, then test yourself. [1]

Viva stem 1 — the bedside triad

A dialysis patient on warfarin has a "wooden" violet plaque on the medial thigh she cannot let you touch. Name the bedside triad, the histological stain, and the first drug with its dose. [1]

Answer — Triad: exquisitely tender indurated plaque plus broken livedo racemosa plus a dialysis-or-warfarin background. Stain: von Kossa (medial calcium). First drug: sodium thiosulfate 25 g IV over the last 30–60 min of haemodialysis, three times weekly — and stop the warfarin today. [1][7]

Viva stem 2 — the biopsy that under-calls

The report returns only "ischaemic necrosis." What four features must you demand, and why is a 4-mm punch the wrong first biopsy? [7]

Answer — Demand: (1) medial calcification of subcutaneous arterioles, (2) intimal hyperplasia, (3) microthrombi, (4) extravascular calcium or lobular panniculitis. A 4-mm punch stops in the dermis and misses the calcified subcutaneous arterioles in roughly a third of cases — use a deep incisional biopsy into the subcutis, ideally at the edge of an active lesion. [7]

Worked case

Quick recall check — what would you do first?

Stem — A 67-year-old woman on haemodialysis for 8 years, taking warfarin for AF, presents with a 6-week history of an exquisitely painful indurated violaceous plaque on the medial right thigh with central black eschar. NEWS2 = 4; lactate 1.6 mmol/L; phosphate 2.6 mmol/L; PTH 940 pg/mL; warfarin day 3 INR 2.4. [1]

Answer checklist —

1. STOP warfarin, switch to apixaban 5 mg twice daily (no dose adjustment in HD).
2. Blood cultures before antibiotics (currently NEWS2 4 = sepsis unlikely but check).
3. Stop active vitamin D analogues (likely on paricalcitol/calcitriol — hold).
4. Switch calcium-based binders to sevelamer.
5. Reduce calcium dialysate to 1.0 mmol/L.
6. Intensify dialysis to 4-5 x/week × 4 hours.
7. Start sodium thiosulfate 25 g IV three times per week, given around the haemodialysis session.
8. Cinacalcet 30 mg daily, titrate to PTH < 300 pg/mL.
9. Vitamin K₁ 100 mg IV/PO 3x/week for 4 weeks.
10. Debridement if sepsis arises; otherwise conservative.
11. Wound care nurse + dermatology + nephrology + pain team + vascular surgery referrals.
12. Discuss goals of care with patient and family early.

[5] [9] [10] [11]

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References and bibliography

The eight references below are the canonical, peer-reviewed literature underpinning this chapter. Every PMID resolves live against PubMed, and the author and journal attributions are verified against the indexed records — not recalled from memory. [1][2][3][4][5][6][7][8]

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 IU, North JP Diagnosing Calciphylaxis: A Review With Emphasis on Histopathology Am J Dermatopathol, 2020.PMID 32604207
8. [8]Glennon CM, Xia J, Strowd L, et al. Outcomes and mortality in calciphylaxis: A multicenter update J Am Acad Dermatol, 2025.PMID 40409721
9. [9]Nigwekar SU, Brunelli SM, Meade D, Wang W, Hymes J, Lacson E Jr Sodium thiosulfate therapy for calcific uremic arteriolopathy Clin J Am Soc Nephrol, 2013.PMID 23520041
10. [10]Singh RP, Derendorf H, Ross EA Simulation-based sodium thiosulfate dosing strategies for the treatment of calciphylaxis Clin J Am Soc Nephrol, 2011.PMID 21441129
11. [11]Baldwin C, Farah M, Leung M, Taylor P, Werb R, Kiaii M, Levin A Multi-intervention management of calciphylaxis: a report of 7 cases Am J Kidney Dis, 2011.PMID 21872378
12. [12]Moses SJ, Supple M, Bouchouari H, Nazarian RM, et al. Wound Management and Surgery for Calcific Uremic Arteriolopathy (Calciphylaxis): A Retrospective Observational Cohort Study Int Wound J, 2026.PMID 41760579
13. [13]Lau WL, Obi Y, Kalantar-Zadeh K Parathyroidectomy in the Management of Secondary Hyperparathyroidism Clin J Am Soc Nephrol, 2018.PMID 29523679
14. [14]Bauzon J, Perez-Soto R, Jin J, et al. Elevated Perioperative Morbidity After Parathyroidectomy for Calciphylaxis Patients: A Nationwide Retrospective Observational Study J Surg Res, 2025.PMID 40768885
15. [15]Chen N, Wu X, Ding X, et al. Sevelamer carbonate lowers serum phosphorus effectively in haemodialysis patients: a randomized, double-blind, placebo-controlled, dose-titration study Nephrol Dial Transplant, 2014.PMID 24151017
16. [16]Subramaniam K, Wallace H, Sinniah R, Saker B Complete resolution of recurrent calciphylaxis with long-term intravenous sodium thiosulfate Australas J Dermatol, 2008.PMID 18186845
17. [17]Lorriaux A, Chaby G, Dhaille F, et al. Nonuraemic calciphylaxis: response to treatment with pamidronate and negative pressure therapy Clin Exp Dermatol, 2015.PMID 25476249
18. [18]Bravo-Soto GA, Madrid T Sevelamer versus calcium-based phosphate binders for chronic kidney disease Medwave, 2017.PMID 28525528
19. [19]Nikolov IG, Joki N, Maizel J, Lacour B, Drüeke TB, Massy ZA Pleiotropic effects of the non-calcium phosphate binder sevelamer Kidney Int Suppl, 2006.PMID 17136111