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2. JEADV ISSN 1468-3083
REVIEW ARTICLE
Blackwell Publishing Ltd
Calciphylaxis – a topical overview
G Arseculeratne,*† AT Evans‡, SM Morley†
†Department of Dermatology and ‡Department of Pathology, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK
Keywords Abstract
end-stage renal disease (ESRD), calcific uraemic
arteriolopathy (CUA), calciphylaxis, secondary ‘Calciphylaxis’, a calcification syndrome associated with ischaemic cutaneous
hyperparathyroidism, skin ulceration necrosis, is acquired naturally in humans in disease states. It is a life and limb-
threatening complication, usually observed in patients with renal disease and
secondary hyperparathyroidism, but known to occur in the absence of renal
*Corresponding author, Department of or parathyroid disease. The reported mortality rate, which ranges from 60– 80%,
Dermatology, Ninewells Hospital and Medical relates to wound infection, sepsis and organ failure. It is a small-vessel
School, Dundee DD1 9SY, Scotland, UK,
vasculopathy, which is estimated to occur in about 4% of haemodialysis
tel. +1382 632294;
patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and
fax. +1382 633916;
E-mail: gehan.arseculeratne@tuht.scot.nhs.uk eschar may be evident, particularly in the extremities. In addition to the clinical
picture, a raised calcium phosphorous product, an elevated parathyroid
Received: 28 October 2004, accepted 27 January hormone level, radiographic evidence of vessel and soft-tissue calcification and
2005 the finding of mural calcification affecting small arteries and arterioles on
histopathology help to confirm the diagnosis of this entity which generally has
DOI: 10.1111/j.1468-3083.2006.01506.x
a poor prognosis. A high index of suspicion and an active multidisciplinary
management approach, with rigorous attention to wound care and prevention
of sepsis, are vital in the management of these patients. In this overview, we
discuss the pathophysiology, clinical features and associations, risk factors,
diagnosis and management issues relating to calciphylaxis.
following experimental observations in animal models.
Pathophysiology Selye utilized ‘sensitizing’ agents (parathyroid hormone,
Atherosclerosis, arteriosclerosis and Mönckeberg’s dihydrotachysterol) followed by ‘challenging’ agents such
sclerosis are vascular diseases associated with calcification as metal salts, egg white or yolk and albumin to induce
and it is recognized that Mönckeberg’s sclerosis, which calcification. As the process was considered to be one of
affects smaller elastic arteries, is a cardiovascular risk factor ‘induced hypersensitivity’, resulting in local calcification
in patients with diabetes mellitus.1,2 Arterial calcification following the two-step process of sensitizing and challenging
is considered to be a strong independent risk factor for
cardiovascular morbidity and mortality, and hyper- Box 1 Calciphylaxis
phosphataemia, as well as an increased calcium phosphorous
product, are recognized as predictors of cardiovascular • A small and medium vessel vasculopathy
• First described by Hans Selye in 1962
risk in patients with chronic renal disease.3–5 Calciphylaxis
• Referred to as calcific uraemic arteriolopathy (CUA), when vascular
is a relatively poorly understood syndrome which pre-
calcification occurs
dominantly affects small- and medium-sized blood vessels, • Usually associated with chronic renal disease and secondary
and is a life-threatening entity usually seen in patients hyperparathyroidism
with renal disease, and may manifest as ischaemic • Estimated to occur in about 4% of haemodialysis patients10
cutaneous necrosis (Box 1). Calcification of cutaneous • Incidence of new cases, 1 case per 100 haemodialysis patients per
vasculature is known to be associated with chronic renal year
• Known to occur in the absence of renal or parathyroid disease
disease.6 The association between cutaneous gangrene and
• Mortality, ranging from 60 –80%, relates to sepsis and organ failure
vascular calcification was described by Bryandt and White
• May manifest as cutaneous necrosis
in 1898.7 Calciphylaxis was described by Hans Selye in 1962
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3. Calciphylaxis – a topical overview Arseculeratne et al.
(i.e. analogous to anaphylaxis), it was termed calciphylaxis.8,9 expression occurs in arteries from MGP knock-out mice
It is known, however, that the clinical appearance and the and phosphorous has been shown to induce the expression
histolopathogical findings on which a diagnosis of of Cbfa1 in vascular smooth muscle cells – Cbfa 1 is eviden-
calciphylaxis is made, differ between animal models and tially considered to play a key role in blood vessel calcifi-
humans. Experimental calcinosis is known to produce cation in the dialysis population.24–26 Bone proteins are
extravascular rather than arteriolar/arterial calcification, known to be expressed in calcified arteries in patients with
hence the term calcific uraemic arteriolopathy (CUA), calciphylaxis and there is evidence to suggest that mineral-
proposed by Coates et al. when vascular calcification forming micro-organisms (nanobacteria) can induce
occurs.11,12 Calciphylaxis as a syndrome was proposed by calcium deposition in mammalian cell cultures and may
Gipstein et al. in 1976 and Winklemann and Keating play a role in human diseases characterized by extra-osseous
described vascular calcification and cutaneous necrosis, calcification.27–29 Bone morphogenic protein-4 (BMP-4),
developing on a background of hyperparathyroidism result- which is physiologically involved in bone metabolism, is
ing from adenoma/carcinoma.13,14 In patients with end- considered to play a role as a promoter of vascular medial
stage renal disease (ESRD), increased dietary calcium, calcification.30
calcium-based phosphate binders, calcium absorption
from dialysate, abnormalities of bone buffering and
turnover contribute to positive calcium balance.15 The Clinical features
widespread use of oral phosphate binders to combat Metastatic calcification is a well-recognized complication
uraemic osteodystrophy has been implicated as a causative observed in patients with chronic renal disease and occurs
factor in accelerating uraemic vasculopathy in the dialysis as a result of elevated calcium or phosphate levels resulting
population.16 Attention to mineral metabolism is vital in the in calcium deposition in normal tissue. Relatively acute
management of patients with renal disease. The United States cutaneous necrosis is a recognised feature of calciphylaxis
National Kidney Foundation Clinical Practice Guidelines (Box 2). Early lesions may have a purpuric component
recommends that in stage 5 chronic kidney disease, the while violaceous reticulate skin lesions, painful indurated
serum calcium, phosphate and the calcium phosphorous areas (‘peau de orange’), tender subcutaneous nodules,
product should be maintained between 8.4 and 9.5 mg/ irregularly ulcerated areas and eschar formation being
dL, 3.5–5.5 mg/dL and less than 55 mg2/dL2, respectively.17 evident subsequently (fig. 1). Violaceous, mottled, painful
Several proteins are known to play key roles in the cutaneous lesions should alert clinicians to the possibility
pathogenesis of calcification. Studies on vascular disease of calciphylaxis.31 The initial presentation may appear
including calciphylaxis in humans have revealed glycopro- similar to that of thrombophlebitis and calf pain is a
teins such as matrix Gla protein (MGP) and osteopontin recognized presenting symptom.32,33 Patients may present
(OPN), in pathological arteries, and these findings support with indurated plaques without ulceration, painful ulcerated
the view that they play a role in the development of plaques and livedoid bleeding in the lower limbs, leading
vascular fibrosis and calcification.18 In animal models, to sepsis and death in about 60% of such patients.34,35
OPN has been shown to play a nephro-protective role in Extra-cutaneous calciphylaxis has been described involving
vivo as an inhibitor of calcium oxalate crystal formation in muscle and rhabdomyolysis, resulting in leg pain and
the renal tubules.19 Alpha 2-Heremans-Schmid glycoprotein/ weakness, has been reported in calciphylaxis in the
fetuin A (ahsg/fetuin) is a serum protein, produced by the absence of chronic renal failure.36,37 Acute calcification of
liver in adults, which has been shown to play a preventative major organs such as the heart and lungs may give rise to
role in the pathogenesis of calcification.20 This protein is the syndrome of ‘bony’ heart and lungs, the latter being
known to act systemically to inhibit ectopic calcification, a cause of acute respiratory failure in these patients.38,39
and fetuin-A knock-out mice are known to develop extra- Intractable cardiac failure may follow renal transplantation
skeletal calcification in the presence of hypercalcaemia,
demonstrating that this protein plays a key role in the Box 2 Clinical features of calciphylaxis
inhibition of calcification. Normalization of impaired
• Purpuric/violaceous reticulate or mottled areas of cutaneous
inhibition of hydroxyapatite precipitation following discoloration
addition of fetuin-A to the serum of dialysis patients hav- • Proximal or distal involvement
ing calciphylaxis has been demonstrated.21 Core-binding • Non-healing ulcers
factor alpha 1 (Cbfa 1), a transcription factor, is considered • Painful cutaneous or subcutaneous necrosis/gangrene
to play a key role in activating stem cells into osteoblasts • Eschar formation
• Clinical similarity to thrombophlebitis
and Cbfa knock-out mice have been shown to be unable
• Calf pain and tenderness
to produce mineralized bone.22,23 It has also been demon-
• May be associated with calcification of internal organs
strated that, together with arterial mineralization, Cbfa
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4. Arseculeratne et al. Calciphylaxis – a topical overview
Box 3 Differential diagnosis of calciphylaxis
• Vasculitic syndromes
• Cryoglobulinaemia (type 1)
• Cryofibrinogenaemia
• Cholesterol embolism syndrome
• Warfarin-induced skin necrosis (WISN)
• Disseminated intravascular coagulation (DIC)
• Nephrogenic fibrosing dermopathy (NFD)
• Scleromyxedema
• Primary hyperoxaluria
• Connective tissue diseases
• Atherosclerotic peripheral vascular disease
fig. 1 Calciphylaxis affecting right leg with ulceration and eschar formation. • Pyoderma gangrenosum
• Antiphospholipid antibody syndrome
• Cellulitis
as a result of cardiac calciphylaxis. Cardiac calciphylaxis • Panniculitis
may be localized and has been described in association with • Deep fungal infections
• Necrotizing fasciitis
nanobacteria affecting the mitral valve.40 Penile gangrene
as well as Fournier’s gangrene are known complications
of calciphylaxis and rarely, areas such as the tongue may
be affected by calciphylaxis.41–43 Calcific cerebral embolism atherosclerotic peripheral vascular disease, cellulitis
is a recognized cause of neurological symptomatology in and necrotizing fasciitis may all have clinical features
patients with renal disease.44 The occurrence of the rash resembling those of calciphylaxis and need exclusion.53
in meningococcal sepsis is considered to be associated Calciphylaxis has a wide differential diagnosis and therefore,
with extravasation of calcium from the intravascular in addition to the routine haematological and biochemical
space into the interstitium and therefore bears some parameters, investigations such as a vasculitis screen,
similarity to the pathophysiology of calciphylaxis.45 estimation of cryoglobulins and cryofibrinogens, fibrin
degradation products (FDPs), antiphospholipid antibodies,
and Doppler assessment of limb vessels need to be considered.
Differential diagnoses Involvement of subcutaneous arterioles in calciphylaxis
Vasculitic syndromes, cholesterol embolization syndrome, can be assessed by xeroradiography, a technique which is
cryoglobulinaemia, cryofibrinogenaemia, warfarin-induced known to demonstrate that the appearance of arteriolar
skin necrosis (WISN) and disseminated intravascular calcification differs from that of atherosclerosis.54
coagulation (DIC) may present with cutaneous features
similar to that of calciphylaxis (Box 3).46,47 Cowper et al.
described scleromyxoedema-like cutaneous disease in Clinical associations
haemodialysis patients and nephrogenic fibrosing Calciphylaxis has been described in association with
dermopathy (NFD) in renal transplant patients.48 Both metastatic malignancies, primary hyperparathyroidism
these entities are associated with thickening of skin in (with normal renal function), end-stage liver disease/
patients with renal disease and need to be considered in alcoholic liver disease, rheumatoid arthritis and long-term
the differential diagnosis. An increase in the number of steroid and methotrexate use and protein S deficiency in
fibroblasts, as well as thickening of collagen fibres are seen the absence of renal disease.55–60 Among other associations
in this rare fibrosing disorder of NFD, and its occurrence are cholangiocarcinoma, malignant melanoma of soft
with calciphylaxis, has been reported.49 Scleromyxoedema, parts (clear-cell sarcoma) with calciphylactic changes in
a rare entity which is characterized by papular mucinous the absence of renal or parathyroid disease, necrotizing
deposits, dermal fibroblast proliferation and monoclonal mastopathy (caused by calciphylaxis) and long-standing
paraproteinaemia, also needs to be considered in the Crohn’s disease.61–64 Ultraviolet light treatment was
differential diagnosis of calciphylaxis.50 Type 1 primary considered to have triggered calciphylaxis in a patient
oxaluria, a cause of cutaneous necrosis, needs to be con- who had renal disease secondary to systemic lupus
sidered in the differential diagnosis.51 Skin manifestations erythematosus.65 Calciphylaxis can be associated with
of connective tissue diseases, such as livedoid erythema, widespread visceral injury and a case with massive gastro-
may mimic some of the manifestations of calciphylaxis.52 intestinal haemorrhage has been described.66 Coexistence
Antiphospholipid antibody syndrome, deep fungal of benign nodular calcification and calciphylaxis have
infections, panniculitides, pyoderma gangrenosum, been described in a haemodialysed patient.67 Widespread
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5. Calciphylaxis – a topical overview Arseculeratne et al.
Box 4 Calciphylaxis-recognized risk/trigger factors and precipitants
Diagnosis and prognosis
• High calcium-phosphate product
The diagnosis of calciphylaxis is based on clinical,
• Hypercalcaemia
biochemical and histopathological features.82 A high
• Hyperphosphataemia
• Hyperparathyroidism index of suspicion needs to be maintained, particularly in
• Females patients with renal impairment. An elevated PTH level,
• Caucasians high calcium, an elevated phosphate level, an elevated
• Long-term obesity calcium phosphorous product, elevated alkaline phos-
• Corticosteroids phatase, a high urea and creatinine value and anaemia
• Hypercoaguable states
may be noted. It is recognized, however, that calciphylaxis
• Low serum albumin
can occur despite normal calcium and phosphate levels.
• Albumin infusions
• Iron-dextran injections Elevation of the enzyme alkaline phosphatase may reflect
• Warfarin chronicity of the underlying renal disease and hyper-
• Vitamin D treatment parathyroidism while anaemia may reflect underlying
• Immunosuppression renal disease or poor nutrition as a result of chronic
• Trauma illness. A ‘pipe-stem’ pattern of vascular calcification may
• Diabetes mellitus
be noted on conventional radiography and calcification
• Subcutaneous insulin injections
of subcutaneous arterioles may be noted on xeroradio-
• Dialysis dependency
graphy. A recent case report documents increased tracer
accumulation in subcutaneous tissue in a patient with
ESRD and calciphylaxis, who underwent a bone scan
calciphylaxis has been described in patients with the for pain in the extremities.83 Radiography may reveal
acquired immunodeficiency syndrome in association subperiosteal bone resorption and enlargement of the
with renal disease and has also been reported to occur in parathyroid glands may be evident on echography. Vascular
association with osteosclerotic myeloma.68,69 Coexistent mural calcification has been noted to be an early and
antiphospholipid antibody syndrome and calciphylaxis has essential process in the development of calciphylaxis
been documented and calciphylaxis has also been reported plaques.84 Mural calcification occurs in small and medium
in association with POEMS (Crowe–Fukase) syndrome, a sized blood vessel walls (arteries and arterioles) and
plasma-cell lymphoproliferative disease.70,71 A recent case intimal proliferation may be noted (fig. 2a). Special stains
report documents calciphylaxis in a patient with chronic may demonstrate calcium deposits and degeneration of
myelomonocytic leukaemia.72 Calciphylaxis needs to be elastic fibres. Inflammation may be absent or minimal.
considered in the differential diagnosis of renal failure in Histological features of pseudoxanthoma elasticum have
patients with transplanted kidneys.73 been observed in association with calciphylaxis.85 Perineural
calcification may occur in association with vascular
calcification in patients with calciphylaxis, and may be
Risk/trigger factors contributory to pain associated with the syndrome86
Risk/trigger factors for calciphylaxis include renal impair- (fig. 2b). Experimental neurotropic calcification has been
ment, being a female, Caucasian race, obesity, warfarin demonstrated in animal models.87 Oxalate crystals may
use, hypercoaguable states, diabetes mellitus, dialysis be noted in tissue biopsies in cases of primary oxaluria,
dependency, protein malnutrition and those receiving and in deep skin biopsies, calcifying septal panniculitis
calcium salts and vitamin D therapy (Box 4).74–78 Albumin may be noted. An endovascular giant cell reaction may be
infusions as well as subcutaneous insulin injections have observed microscopically and early endovascular fibro-
been considered as being precipitants of calciphylaxis.79,80 blastic activation has been found to be statistically
In most series, patients with co-morbid conditions strongly associated with the presence of giant cells.88 A
generally have had a worse prognosis. It has been deep incisional biopsy is likely to provide a better
estimated that the incidence of new cases of calciphylaxis histological yield but in cases where a biopsy is inadvisable
is 1 case per 100 haemodialysis patients per year and a owing to sepsis or the potential to aggravate ulceration,
mathematical formula {2 × [CaP0(4) – 5] × alkaline the biochemical and endocrine profile may be sufficient
phosphatase level (IU) × PTH ratio} has been suggested as to make the diagnosis and institute early management
being useful in identifying patients at risk of developing strategies. High-resolution high-frequency ultrasound
calciphylaxis, this arithmetic model being based on a may aid in the diagnosis of lesions, prior to the occurrence
literature review of calciphylaxis, clinical observations of the typical skin lesions.89 In a case series of five patients,
and physiological principles.81 extensive tissue involvement, previous renal transplant
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6. Arseculeratne et al. Calciphylaxis – a topical overview
poor prognosis (Box 5). Prevention of systemic infection
is vital. Diligent wound care, avoidance of trauma, and
appropriate antibiotic usage together with nutritional
support and adequate pain control are important aspects
of general care of these patients. Neurolytic lumbar
sympathetic blockade (LSB) has been proven to be a useful
method of alleviating pain associated with calciphylaxis.93
In the initial stages when skin is eroded, gentle handling
is important and careful dressing of wounds with material
such as petrolatum-impregnated gauze help to minimize
tissue damage. Debridement and skin grafting may be
warranted – however, the role of debridement is con-
troversial and it has been suggested that debridement is
contraindicated for wounds covered with dry, non-infected
eschars.94 Sterile maggot therapy and pentoxyfillin has
been used to treat ulcerated areas in calciphylaxis.95
Transcutaneous oxygen tension (TCPO2) measurement
has been used as a rapid non-invasive screening for skin
ischaemia before the development of skin lesions.96
Attention to calcium and phosphate levels are vital in the
management of patients with this syndrome and referral to
a dietician is an important facet of treatment. Increased
frequency of haemodialysis too has been employed as
a management strategy. Calcium- and aluminium-free
phosphate binders such as sevelamer hydrochloride
(RenaGel) have been found to be useful in the manage-
ment of renal osteodystrophy particularly in patients with
extraskeletal calcification and hypercalcaemia.97 In a
study by Chertow et al. haemodialysis patients treated
with sevelamer were found to be protected from increased
calcification of the aorta and coronary arteries.98 Caution
should be exercised with the use of calcium-containing
fig. 2 (A) Histological appearance of circumferential mural calcification of heparins as calcifying panniculitits has been reported
an arteriole affected by calciphylaxis (H&E preparation, magnification
following subcutaneous injections of nadroparin-
×300). (B) histological appearance of perineural calcification in calciphy-
calcium in a patient with osteomalacia.99 Hyperbaric
laxis (H&E preparation, magnification ×200).
oxygen therapy has been used particularly in the absence
of severe secondary hyperparathyroidism where relatively
and higher preoperative leucocyte counts (over 20 000 few therapeutic options are available.100,101 Attention to
cells/mL) were found to be factors related to early death and regulation of divalent metabolism is required prior to
in patients with calciphylaxis.90 In another case series of considering revascularization procedures in patients with
six patients with CUA, a relationship between distal calciphylaxis.102 Parathyroidectomy is known to be
location of the lesions, normal serum albumin and early associated with resolution of pain, wound healing and a
diagnosis were related to survival, rather than the type longer median survival in patients with calciphylaxis.103–110
of treatment patients received.91 In a study of seven Total parathyroidectomy and auto-transplantation of
patients with calciphylaxis, lesion severity at time of tissue to the forearm has proven to be satisfactory in some
parathyroidectomy correlated with clinical outcome.92 cases, subtotal parathyroidectomy being an alternative
surgical approach.111 Healing of lower extremity ulcers in
22 patients with calciphylaxis has been reported following
Management ‘near total’ parathyroidectomy (where a vascularized
Maintenance of a high index of suspicion, early recognition parathyroid remnant is left in situ); this procedure also
and timely, appropriate intervention as well as an active being noted to improve bone density in patients with
multidisciplinary approach are mandatory in com- hyperparathyroidism.112 Recurrent hyperparathyroidism
bating the syndrome of calciphylaxis, which has a has been reported and re-operation may be warranted in
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7. Calciphylaxis – a topical overview Arseculeratne et al.
Box 5 Management of calciphylaxis
Principles
• Maintenance of a high index of suspicion
• Early intervention
• An active, multidisciplinary approach
Prevention/Treatment Options
• Use of calcium-free/aluminium-free phosphate binders (e.g. sevelamer hydrochloride)
• Institution of a low-phosphate diet
• Increased frequency of haemodialysis
• Correction of anaemia
• Use of less calcaemic vitamin D analogues
• Wound care debridement/skin grafting
• Use of appropriate antibiotics
• Adequate pain control
• Parathyroidectomy (total, subtotal, near-total)
• Hyberbaric oxygen therapy
• Intravenous bisphosphonates
• Intravenous sodium thiosulphate
• Continuous veno-venous haemofiltration and intravenous sodium thiosulphate
• Intravenous maxacalcitol and percutaneous ethanol injection therapy (PEIT) (a preventative role)
such cases.113 Revascularization and amputation may other disease entities in the absence of renal or parathyroid
have to be resorted to in cases where all other supportive disease. A high index of suspicion, early intervention, and an
and conservative measures have failed. Steroid use has active multidisciplinary medical and surgical approach are
been associated with calciphylaxis, but treatment of a vital aspects of the management strategy. Discovery of serum
patient with renal failure with oral prednisolone followed proteins, which play key regulatory roles in calcium
by cimetidine has been reported to have reversed changes homeostasis, is likely to lead to novel therapeutic concepts
of calcifying panniculitis.114 Sodium thiosulphate, an which will broaden the therapeutic armamentarium avail-
antidote for cyanide poisoning, is recognized to be a able to clinicians who manage patients with calciphylaxis.
potent antioxidant as well as a chelator of calcium.115
Intravenous sodium thiosulphate may have an adjunctive
role in therapy – it has been documented to reverse the Acknowledgements
signs and symptoms of calciphylaxis.116,117 Rapid resolution We are grateful to the Computing and Media Services
of calciphylaxis has been reported following intravenous Department, Ninewells Hospital and Medical School,
sodium thiosulphate and continuous veno-venous Dundee, Scotland, for providing the illustrations.
haemofiltration.118 In experimental animal models, the
amino bisphosphonate ibandronate has been found to
inhibit arterial calcification at doses that inhibit bone References
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