01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Calciphylaxis is a thrombotic calcific arteriolopathy rather than simple deposition of calcium in skin. Medial calcification and intimal change narrow small dermal and subcutaneous arteries; superimposed thrombosis abruptly deprives fat and skin of oxygen. The clinical warning is pain that exceeds visible findings, often within a firm plaque on thighs, abdomen, buttocks, breasts or distal limbs. Mottling becomes a fixed angular purple or black network, then ulceration exposes necrotic adipose tissue. Proximal adipose-rich disease is common and can be difficult to examine respectfully, so consent, privacy and complete skin assessment matter.
Advanced kidney disease creates the dominant risk environment, but the diagnosis is not ruled in by a high calcium–phosphate product or ruled out by normal contemporary blood values. Dialysis vintage, hyperparathyroidism, inflammation, hypoalbuminaemia, diabetes, adiposity, warfarin and tissue trauma contribute differently in each patient. Non-uraemic disease occurs with severe liver disease, malignancy, connective-tissue disease, corticosteroid exposure and other settings, so the morphology and histological mechanism remain important outside dialysis.
Treatment evidence is largely observational and no single intervention reliably reverses disease. A coordinated bundle starts the same day: adequate renal-adjusted analgesia, sepsis surveillance, pressure and wound protection, nutrition, dialysis adequacy, removal of avoidable calcium loading, control of phosphate and PTH and review of warfarin and injected medicines. Sodium thiosulfate and hyperbaric oxygen may be offered in selected centres. Wounds and pain take months to improve, and repeated goals-of-care conversations should accompany rather than replace active attempts at healing.
Key points
- Calciphylaxis is calcific uraemic arteriolopathy: an uncommon, intensely painful occlusive small-artery disease seen mainly in advanced CKD and dialysis, although non-uraemic cases occur.
- Deep burning pain and firm woody subcutaneous induration can precede visible change; lesions evolve through mottled livedoid or retiform purple-grey plaques to ulcer and black eschar.
- On brown or black skin, early colour may be deep violet, grey-brown or subtle; exquisite focal pain, hardness, temperature and an angular vascular outline should trigger examination under good light and touch.
- Risk rises with dialysis duration, diabetes, obesity, female sex, hypoalbuminaemia, severe CKD-mineral disorder, warfarin, calcium loading, injection trauma and systemic inflammation, but normal calcium or phosphate does not exclude disease.
- Diagnosis is clinical and multidisciplinary; there is no perfectly sensitive gold-standard test. Deep edge biopsy can show calcified thrombosed arterioles but may cause a non-healing ulcer, infection or false-negative result.
- First-line action is not one drug: control pain, search for infection, optimise dialysis and calcium–phosphate–PTH management, review promoting medicines and deliver expert wound care concurrently.
- Sodium thiosulfate is widely used off-label, commonly after haemodialysis, but controlled efficacy evidence remains uncertain and metabolic acidosis, hypotension, nausea, sodium load and QT effects require monitoring.
- Review warfarin urgently with the anticoagulation indication owner; do not stop it unsafely or assume substitution is straightforward in mechanical valves or high-risk APS.
- Debridement is individualised: infected wet necrosis may need surgical source control, whereas dry stable eschar with poor perfusion can be harmed by reflex excision.
- Early palliative and psychological support complements active treatment because pain, mortality and prolonged wound burden are severe; it does not signal abandonment.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Advanced kidney disease milieu
Uraemia, dialysis, mineral imbalance, inflammation and oxidative stress promote vascular smooth-muscle transformation and loss of normal inhibitors of calcification.
Metabolic and tissue vulnerability
Diabetes, adiposity, hypoalbuminaemia, female sex, malnutrition and prolonged dialysis together reduce microvascular reserve and the capacity of damaged wounds to heal.
Medicine and trauma exposure
Warfarin reduces vitamin-K-dependent calcification inhibitors, while calcium loading, active vitamin D, corticosteroids and repeated injections may add risk in susceptible tissue.
Non-uraemic disease
Severe liver disease, malignancy, connective-tissue disease, primary hyperparathyroidism and other systemic states can produce the same calcific thrombotic arteriolopathy without dialysis.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Arteriolar media calcifies
Small dermal and subcutaneous arteries deposit calcium within their muscular wall, stiffening vessels and narrowing the effective lumen.
- 2Intima thickens
Fibroplasia and endothelial dysfunction further constrict already calcified arterioles and reduce their ability to adapt flow to tissue demand.
- 3Thrombosis closes the vessel
A superimposed clot converts chronic narrowing into acute ischaemia, producing sudden severe pain and a branching infarct pattern.
- 4Adipose tissue becomes hypoxic
Subcutaneous fat supplied by affected arterioles undergoes inflammation and necrosis, creating woody induration before epidermal breakdown becomes visible.
- 5Ulcer invites systemic infection
Infarcted skin opens into a poorly perfused necrotic wound where bacteria evade host clearance and can cause cellulitis, bacteraemia and fatal sepsis.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
Deep burning or stabbing focal pain and exquisite touch sensitivity appears within seemingly normal or only subtly mottled skin before ulceration.
Firm subcutaneous thickening develops in adipose-rich thighs, abdomen, buttocks or breasts or around a distal livedoid lesion.
Fixed angulated violet, grey, brown or black branches map ischaemic territories and progress from livedoid mottling towards infarction.
A painful irregular ulcer exposes yellow-black fat and develops adherent black eschar, with a high risk of bacterial invasion and sepsis.
Digits, lower legs or penis can be affected and demand urgent perfusion, infection, urological and alternative-occlusion assessment because tissue loss can be rapid.
New warmth, spreading erythema, purulence, crepitus, fever, delirium or hypotension over a necrotic lesion indicates invasive infection until proved otherwise.
The same painful retiform induration and necrosis can occur without end-stage kidney disease, requiring liver, malignant, autoimmune, medicine and metabolic assessment.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
Clinical risk and full-skin assessmentFirst step - Why
- Recognise the syndrome early and document distribution before ulceration obscures the active edge.
- Interpretation and limitations
- Map pain, induration, livedoid outline, necrosis and infection with consented photographs and examine pressure and injection sites; absence of dialysis does not exclude non-uraemic disease.
- 02
Calcium, phosphate, PTH and alkaline phosphatase - Why
- Characterise modifiable CKD-mineral disorder and establish a treatment baseline.
- Interpretation and limitations
- Interpret serial corrected or ionised calcium, phosphate and PTH together with dialysis and medicines; normal values at presentation cannot undo prior vascular calcification or exclude calciphylaxis.
- 03
FBC, CRP, renal, liver and albumin - Why
- Assess infection, inflammation, dialysis context, hepatic risk, nutrition and treatment tolerance.
- Interpretation and limitations
- Leucocytosis and CRP are nonspecific in tissue necrosis; cultures and clinical physiology determine infection, while albumin reflects inflammation as well as nutrition.
- 04
Coagulation and medicine review - Why
- Identify warfarin exposure, bleeding risk and other potentially modifiable promoters.
- Interpretation and limitations
- Record indication and INR and review calcium binders, active vitamin D, iron or other injections and corticosteroids; changes require the prescribing specialty because abrupt anticoagulant withdrawal may thrombose.
- 05
Infection cultures and imaging - Why
- Detect bacteraemia, abscess, gas, deep extension and osteomyelitis within necrotic wounds.
- Interpretation and limitations
- Take blood cultures when systemically ill and cleaned deep tissue when source control occurs; surface colonisation alone does not diagnose invasion, and imaging must not delay surgery for necrotising infection.
- 06
Vascular assessment - Why
- Exclude macrovascular arterial disease and define healing potential before debridement or compression.
- Interpretation and limitations
- Examine pulses and use Doppler, toe pressure and duplex or angiography from anatomy and urgency; calciphylaxis affects small vessels but can coexist with PAD.
- 07
Deep active-edge biopsy - Why
- Demonstrate calcified narrowed thrombosed dermal or subcutaneous arterioles when diagnostic uncertainty would change high-risk treatment.
- Interpretation and limitations
- Coordinate an adequately deep sample from viable margin with dermatology and pathology and discuss non-healing, infection and false negatives; avoid superficial punch and dead eschar centre.
- 08
Supportive imaging for calcification - Why
- Add non-invasive evidence when biopsy risk is disproportionate or anatomical extent is uncertain.
- Interpretation and limitations
- Plain radiography, mammography-pattern imaging or bone scintigraphy may show small-vessel or soft-tissue calcification, but none independently confirms or excludes the clinical syndrome.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Necrotising infection
Shock, crepitus, gas, rapid fascial spread and deep toxicity require immediate surgical and antibiotic care even if calciphylaxis is also possible.
Cholesterol embolisation
Blue toes, livedo, eosinophilia and renal decline after arterial instrumentation with preserved pulses suggests cholesterol crystal showering.
Vasculitis or APS
Palpable purpura, systemic inflammatory organs or thrombotic and pregnancy history with vessel inflammation or bland clots supports an immune vascular mechanism.
Warfarin skin necrosis
Painful necrosis beginning soon after warfarin initiation, often in fatty areas, reflects acute protein-C imbalance rather than chronic calcific arteriolopathy.
Pyoderma gangrenosum
A rapidly expanding undermined violaceous pathergic ulcer with neutrophilic disease associations can mimic necrosis and may worsen with unplanned debridement.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01First-line recognition sequenceAct on pain and induration before escharFirst stepFirst lineA dialysis or high-risk patient develops new focal severe skin pain, hardness or livedoid change.+
- 1Examine the complete painful region and all skin with consent, document depth, temperature, retiform outline and infection and assess ABCDE and limb perfusion.
- 2Contact nephrology and dermatology the same day and involve tissue viability and pain specialists before waiting for ulceration or a biopsy appointment.
- 3Obtain mineral, inflammatory, renal, liver, nutrition, coagulation and infection baselines and decide collectively whether clinical certainty is sufficient or deep edge tissue will alter management.
02Immediate treatment bundleTreat five mechanisms in parallelCalciphylaxis is clinically likely or confirmed and the patient is not in immediate operative sepsis care.+
- 1Provide renal-adjusted multimodal analgesia with early pain or palliative expertise, protect from pressure and trauma and use non-adherent exudate-managing wound care.
- 2Optimise dialysis dose and frequency where appropriate and correct phosphate, calcium loading and severe PTH disturbance through the CKD-MBD pathway without chasing one laboratory product.
- 3Review warfarin, calcium-containing binders, active vitamin D, systemic corticosteroid and injection sites with responsible prescribers and treat confirmed infection promptly.
03Sodium-thiosulfate routeUse an off-label trial with explicit uncertaintyA renal multidisciplinary team judges potential benefit greater than treatment burden.+
- 1Document baseline bicarbonate, anion gap, sodium, calcium, blood pressure, ECG risk and nausea and explain that observational benefit does not establish certain efficacy.
- 2Give the centre's weight- and tolerance-adjusted intravenous regimen after haemodialysis, commonly 25 g three times weekly, with slower or lower initial dosing when toxicity risk is high.
- 3Track pain, new-lesion formation, wound area and biochemical toxicity and reduce or stop for severe acidosis, hypotension, intolerable vomiting, sodium overload or absent agreed benefit.
04Wound and infection routeChoose debridement by tissue and physiologyEschar, exudate, odour or clinical infection complicates an ulcer.+
- 1Assess perfusion, depth, wet versus stable dry necrosis, pain, bleeding risk and goals with tissue viability, surgery and dermatology before removing tissue.
- 2Debride infected wet necrosis or drain collections when source control benefit exceeds operative risk, while protecting stable dry poorly perfused eschar from reflex excision.
- 3Use systemic antibiotic for cellulitis, sepsis, deep infection or osteomyelitis, obtain appropriate cultures and reassess repeatedly because immune signs can be blunted in dialysis.
05Refractory-disease reviewRecheck diagnosis, burden and goalsPain, necrosis or new lesions progress despite the initial bundle.+
- 1AlternativeAudit pressure, dialysis, calcium and phosphate inputs, PTH control, warfarin plan, infection source, sodium-thiosulfate delivery and alternative vasculopathy diagnoses.
- 2Discuss selected hyperbaric oxygen, parathyroid surgery for otherwise refractory severe hyperparathyroidism, or reconstructive options only through experienced multidisciplinary review.
- 3Integrate psychological, family, rehabilitation and palliative support and revisit the balance between hospital burden, wound interventions and the patient's goals throughout treatment.
Key medicines and prescribing safety1 treatment · regimens, roles and cautions+
Intravenous sodium thiosulfate
A common off-label haemodialysis regimen is 25 g intravenously during the final hour of or immediately after each dialysis session three times weekly, using a lower starting dose when body size or tolerance requires it.Monitor bicarbonate and anion gap, sodium and calcium, blood pressure, volume, nausea, QT risk and venous access. Severe metabolic acidosis, hypotension, vomiting or sodium overload requires dose reduction or cessation; non-dialysis dosing needs specialist pharmacokinetic planning.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Intractable pain
Ischaemic, inflammatory, wound and neuropathic components produce severe pain that limits dialysis, sleep, mobility, nutrition, dressing care and psychological resilience.
Wound sepsis
Necrotic poorly perfused ulcers permit cellulitis, abscess, osteomyelitis and bacteraemia, with sepsis a leading immediate cause of death.
Progressive tissue loss
Retiform infarction enlarges into deep ulcers, genital or digital necrosis, exposed structures, scar, contracture and occasional amputation.
Metabolic treatment toxicity
Sodium thiosulfate, dialysis changes and aggressive mineral therapy can cause acidosis, hypotension, nausea, electrolyte disturbance, arrhythmia and treatment burden.
High mortality and distress
Combined kidney disease, infection, malnutrition and extensive wounds confer poor survival and major anxiety, depression, family burden and complex goals-of-care decisions.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- Assess pain at rest, touch and dressing change daily during instability and record function and opioid adverse effects alongside a renal-adjusted analgesic plan.
- Use serial photographs and measurements to count new plaques, retiform extension, ulcer area, eschar, exudate and granulation without repeatedly traumatising the border.
- Monitor observations, surrounding erythema, purulence, crepitus, mental state and blood cultures because wound sepsis can evolve rapidly and carries high mortality.
- Review dialysis delivery, corrected or ionised calcium, phosphate, PTH, alkaline phosphatase, bicarbonate, nutrition and all calcium, vitamin D and injection exposures.
- If sodium thiosulfate is used, trend acid-base status, sodium, calcium, pressure, ECG risk, nausea, pain and lesion activity against the predefined continuation threshold.
- Reassess warfarin indication and replacement feasibility with anticoagulation experts rather than allowing an unresolved recommendation to persist across admissions.
- Include mood, sleep, mobility, family burden, treatment fatigue and goals of care at regular reviews and introduce palliative expertise early while active therapy continues.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
Pain can lead colour
Arteriolar ischaemia begins in subcutaneous tissue, so new focal severe pain and hardness in a high-risk patient can be diagnostic before visible retiform change.
Normal minerals do not reassure
Current serum calcium and phosphate are snapshots and can be normal after years of vascular calcification, inflammation and earlier mineral imbalance.
Biopsy is a treatment decision
Tissue can resolve an important mimic but creates a new wound in poorly perfused skin, so the expected diagnostic gain must exceed the site-specific harm.
Warfarin cannot simply vanish
The medicine is a recognised risk factor, yet mechanical valves and high-risk thrombosis may make abrupt withdrawal more dangerous than a planned specialist alternative.
Debridement has two truths
Source control of infected wet necrosis can save life, while unnecessary removal of stable dry ischaemic eschar can enlarge a wound that cannot heal.
Palliative care supports treatment
Specialist symptom and goals support improves analgesia and decision quality during active dialysis and wound therapy and is not restricted to final days.
11Common pitfallsFrequent interpretation and management errors.
- 01
Waiting for black eschar before considering calciphylaxis in a dialysis patient with focal severe pain and induration.
- 02
Excluding disease because calcium, phosphate or their calculated product is normal on one blood draw.
- 03
Performing a shallow biopsy through dead centre without discussing false-negative yield and non-healing risk.
- 04
Stopping warfarin without confirming why it was prescribed and arranging a safe anticoagulation plan.
- 05
Presenting sodium thiosulfate as proven curative therapy or giving it without acid-base and haemodynamic monitoring.
- 06
Giving prophylactic antibiotic for colonisation while overlooking perfusion, wet necrosis, abscess or sepsis.
- 07
Debriding every black heel or retiform plaque before assessing vascular supply, infection and wound goals.
- 08
Delaying pain and palliative input until disease-directed options have been exhausted.