Calciphylaxis Review

JEADV ISSN 1468-3083

JEADV

2006,

20

, 493–502 © 2006 European Academy of Dermatology and Venereology

493

Blackwell Publishing Ltd

REVIEW ARTICLE

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

end-stage renal disease (ESRD), calcific uraemic

arteriolopathy (CUA), calciphylaxis, secondary

hyperparathyroidism, skin ulceration

*

Corresponding author, Department of

Dermatology, Ninewells Hospital and Medical

School, Dundee DD1 9SY, Scotland, UK,

tel.

+

1382 632294;

fax.

+

1382 633916;

E-mail: [email protected]

Received: 28 October 2004, accepted 27 January

2005

DOI: 10.1111/j.1468-3083.2006.01506.x

Abstract

‘Calciphylaxis’, a calcification syndrome associated with ischaemic cutaneousnecrosis, is acquired naturally in humans in disease states. It is a life and limb-threatening complication, usually observed in patients with renal disease andsecondary hyperparathyroidism, but known to occur in the absence of renalor parathyroid disease. The reported mortality rate, which ranges from 60–80%,relates to wound infection, sepsis and organ failure. It is a small-vesselvasculopathy, which is estimated to occur in about 4% of haemodialysispatients. Clinically, violaceous, reticulate areas of cutaneous necrosis andeschar may be evident, particularly in the extremities. In addition to the clinicalpicture, a raised calcium phosphorous product, an elevated parathyroidhormone level, radiographic evidence of vessel and soft-tissue calcification andthe finding of mural calcification affecting small arteries and arterioles onhistopathology help to confirm the diagnosis of this entity which generally hasa poor prognosis. A high index of suspicion and an active multidisciplinarymanagement approach, with rigorous attention to wound care and preventionof sepsis, are vital in the management of these patients. In this overview, wediscuss the pathophysiology, clinical features and associations, risk factors,diagnosis and management issues relating to calciphylaxis.

Pathophysiology

Atherosclerosis, arteriosclerosis and Mönckeberg’ssclerosis are vascular diseases associated with calcificationand it is recognized that Mönckeberg’s sclerosis, whichaffects smaller elastic arteries, is a cardiovascular risk factorin patients with diabetes mellitus.

1,2

Arterial calcificationis considered to be a strong independent risk factor forcardiovascular morbidity and mortality, and hyper-phosphataemia, as well as an increased calcium phosphorousproduct, are recognized as predictors of cardiovascularrisk in patients with chronic renal disease.

3–5

Calciphylaxisis a relatively poorly understood syndrome which pre-dominantly affects small- and medium-sized blood vessels,and is a life-threatening entity usually seen in patientswith renal disease, and may manifest as ischaemiccutaneous necrosis (Box 1). Calcification of cutaneousvasculature is known to be associated with chronic renaldisease.

6

The association between cutaneous gangrene andvascular calcification was described by Bryandt and Whitein 1898.

7

Calciphylaxis was described by Hans Selye in 1962

following experimental observations in animal models.Selye utilized ‘sensitizing’ agents (parathyroid hormone,dihydrotachysterol) followed by ‘challenging’ agents suchas metal salts, egg white or yolk and albumin to inducecalcification. As the process was considered to be one of‘induced hypersensitivity’, resulting in local calcificationfollowing the two-step process of sensitizing and challenging

Box 1 Calciphylaxis

• A small and medium vessel vasculopathy

• First described by Hans Selye in 1962

• Referred to as calcific uraemic arteriolopathy (CUA), when vascular

calcification occurs

• Usually associated with chronic renal disease and secondary

hyperparathyroidism

• Estimated to occur in about 4% of haemodialysis patients10

• Incidence of new cases, 1 case per 100 haemodialysis patients per

year

• Known to occur in the absence of renal or parathyroid disease

• Mortality, ranging from 60–80%, relates to sepsis and organ failure

• May manifest as cutaneous necrosis


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(i.e. analogous to anaphylaxis), it was termed calciphylaxis.

8,9

It is known, however, that the clinical appearance and thehistolopathogical findings on which a diagnosis ofcalciphylaxis is made, differ between animal models andhumans. Experimental calcinosis is known to produceextravascular rather than arteriolar/arterial calcification,hence the term calcific uraemic arteriolopathy (CUA),proposed by Coates

et al

. when vascular calcificationoccurs.

11,12

Calciphylaxis as a syndrome was proposed byGipstein

et al

. in 1976 and Winklemann and Keatingdescribed vascular calcification and cutaneous necrosis,developing on a background of hyperparathyroidism result-ing from adenoma/carcinoma.

13,14

In patients with end-stage renal disease (ESRD), increased dietary calcium,calcium-based phosphate binders, calcium absorptionfrom dialysate, abnormalities of bone buffering andturnover contribute to positive calcium balance.

15

Thewidespread use of oral phosphate binders to combaturaemic osteodystrophy has been implicated as a causativefactor in accelerating uraemic vasculopathy in the dialysispopulation.

16

Attention to mineral metabolism is vital in themanagement of patients with renal disease. The United StatesNational Kidney Foundation Clinical Practice Guidelinesrecommends that in stage 5 chronic kidney disease, theserum calcium, phosphate and the calcium phosphorousproduct should be maintained between 8.4 and 9.5 mg/dL, 3.5–5.5 mg/dL and less than 55 mg

2

/dL

2

, respectively.

17

Several proteins are known to play key roles in thepathogenesis of calcification. Studies on vascular diseaseincluding calciphylaxis in humans have revealed glycopro-teins such as matrix Gla protein (MGP) and osteopontin(OPN), in pathological arteries, and these findings supportthe view that they play a role in the development ofvascular fibrosis and calcification.

18

In animal models,OPN has been shown to play a nephro-protective role

invivo

as an inhibitor of calcium oxalate crystal formation inthe renal tubules.

19

Alpha 2-Heremans-Schmid glycoprotein/fetuin A (ahsg/fetuin) is a serum protein, produced by theliver in adults, which has been shown to play a preventativerole in the pathogenesis of calcification.

20

This protein isknown to act systemically to inhibit ectopic calcification,and fetuin-A knock-out mice are known to develop extra-skeletal calcification in the presence of hypercalcaemia,demonstrating that this protein plays a key role in theinhibition of calcification. Normalization of impairedinhibition of hydroxyapatite precipitation followingaddition of fetuin-A to the serum of dialysis patients hav-ing calciphylaxis has been demonstrated.

21

Core-bindingfactor alpha 1 (Cbfa 1), a transcription factor, is consideredto play a key role in activating stem cells into osteoblastsand Cbfa knock-out mice have been shown to be unableto produce mineralized bone.

22,23

It has also been demon-strated that, together with arterial mineralization, Cbfa

expression occurs in arteries from MGP knock-out miceand phosphorous has been shown to induce the expressionof Cbfa1 in vascular smooth muscle cells – Cbfa 1 is eviden-tially considered to play a key role in blood vessel calcifi-cation in the dialysis population.

24–26

Bone proteins areknown to be expressed in calcified arteries in patients withcalciphylaxis and there is evidence to suggest that mineral-forming micro-organisms (nanobacteria) can inducecalcium deposition in mammalian cell cultures and mayplay a role in human diseases characterized by extra-osseouscalcification.

27–29

Bone morphogenic protein-4 (BMP-4),which is physiologically involved in bone metabolism, isconsidered to play a role as a promoter of vascular medialcalcification.

30

Clinical features

Metastatic calcification is a well-recognized complicationobserved in patients with chronic renal disease and occursas a result of elevated calcium or phosphate levels resultingin calcium deposition in normal tissue. Relatively acutecutaneous necrosis is a recognised feature of calciphylaxis(Box 2). Early lesions may have a purpuric componentwhile violaceous reticulate skin lesions, painful induratedareas (‘peau de orange’), tender subcutaneous nodules,irregularly ulcerated areas and eschar formation beingevident subsequently (fig. 1). Violaceous, mottled, painfulcutaneous lesions should alert clinicians to the possibilityof calciphylaxis.

31

The initial presentation may appearsimilar to that of thrombophlebitis and calf pain is arecognized presenting symptom.

32,33

Patients may presentwith indurated plaques without ulceration, painful ulceratedplaques and livedoid bleeding in the lower limbs, leadingto sepsis and death in about 60% of such patients.

34,35

Extra-cutaneous calciphylaxis has been described involvingmuscle and rhabdomyolysis, resulting in leg pain andweakness, has been reported in calciphylaxis in theabsence of chronic renal failure.

36,37

Acute calcification ofmajor organs such as the heart and lungs may give rise tothe syndrome of ‘bony’ heart and lungs, the latter beinga cause of acute respiratory failure in these patients.

38,39

Intractable cardiac failure may follow renal transplantation

Box 2 Clinical features of calciphylaxis

• Purpuric/violaceous reticulate or mottled areas of cutaneous

discoloration

• Proximal or distal involvement

• Non-healing ulcers

• Painful cutaneous or subcutaneous necrosis/gangrene

• Eschar formation

• Clinical similarity to thrombophlebitis

• Calf pain and tenderness

• May be associated with calcification of internal organs

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as a result of cardiac calciphylaxis. Cardiac calciphylaxismay be localized and has been described in association withnanobacteria affecting the mitral valve.

40

Penile gangreneas well as Fournier’s gangrene are known complicationsof calciphylaxis and rarely, areas such as the tongue maybe affected by calciphylaxis.

41–43

Calcific cerebral embolismis a recognized cause of neurological symptomatology inpatients with renal disease.

44

The occurrence of the rashin meningococcal sepsis is considered to be associatedwith extravasation of calcium from the intravascularspace into the interstitium and therefore bears somesimilarity to the pathophysiology of calciphylaxis.

45

Differential diagnoses

Vasculitic syndromes, cholesterol embolization syndrome,cryoglobulinaemia, cryofibrinogenaemia, warfarin-inducedskin necrosis (WISN) and disseminated intravascularcoagulation (DIC) may present with cutaneous featuressimilar to that of calciphylaxis (Box 3).

46,47

Cowper

et al.

described scleromyxoedema-like cutaneous disease inhaemodialysis patients and nephrogenic fibrosingdermopathy (NFD) in renal transplant patients.

48

Boththese entities are associated with thickening of skin inpatients with renal disease and need to be considered inthe differential diagnosis. An increase in the number offibroblasts, as well as thickening of collagen fibres are seenin this rare fibrosing disorder of NFD, and its occurrencewith calciphylaxis, has been reported.

49

Scleromyxoedema,a rare entity which is characterized by papular mucinousdeposits, dermal fibroblast proliferation and monoclonalparaproteinaemia, also needs to be considered in thedifferential diagnosis of calciphylaxis.

50

Type 1 primaryoxaluria, a cause of cutaneous necrosis, needs to be con-sidered in the differential diagnosis.

51

Skin manifestationsof connective tissue diseases, such as livedoid erythema,may mimic some of the manifestations of calciphylaxis.

52

Antiphospholipid antibody syndrome, deep fungalinfections, panniculitides, pyoderma gangrenosum,

atherosclerotic peripheral vascular disease, cellulitisand necrotizing fasciitis may all have clinical featuresresembling those of calciphylaxis and need exclusion.

53

Calciphylaxis has a wide differential diagnosis and therefore,in addition to the routine haematological and biochemicalparameters, investigations such as a vasculitis screen,estimation of cryoglobulins and cryofibrinogens, fibrindegradation products (FDPs), antiphospholipid antibodies,and Doppler assessment of limb vessels need to be considered.Involvement of subcutaneous arterioles in calciphylaxiscan be assessed by xeroradiography, a technique which isknown to demonstrate that the appearance of arteriolarcalcification differs from that of atherosclerosis.

54

Clinical associations

Calciphylaxis has been described in association withmetastatic malignancies, primary hyperparathyroidism(with normal renal function), end-stage liver disease/alcoholic liver disease, rheumatoid arthritis and long-termsteroid and methotrexate use and protein S deficiency inthe absence of renal disease.

55–60

Among other associationsare cholangiocarcinoma, malignant melanoma of softparts (clear-cell sarcoma) with calciphylactic changes inthe absence of renal or parathyroid disease, necrotizingmastopathy (caused by calciphylaxis) and long-standingCrohn’s disease.

61–64

Ultraviolet light treatment wasconsidered to have triggered calciphylaxis in a patientwho had renal disease secondary to systemic lupuserythematosus.

65

Calciphylaxis can be associated withwidespread visceral injury and a case with massive gastro-intestinal haemorrhage has been described.

66

Coexistenceof benign nodular calcification and calciphylaxis havebeen described in a haemodialysed patient.

67

Widespread

fig. 1 Calciphylaxis affecting right leg with ulceration and eschar formation.

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

• Pyoderma gangrenosum

• Antiphospholipid antibody syndrome

• Cellulitis

• Panniculitis

• Deep fungal infections

• Necrotizing fasciitis


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calciphylaxis has been described in patients with theacquired immunodeficiency syndrome in associationwith renal disease and has also been reported to occur inassociation with osteosclerotic myeloma.

68,69

Coexistentantiphospholipid antibody syndrome and calciphylaxis hasbeen documented and calciphylaxis has also been reportedin association with POEMS (Crowe–Fukase) syndrome, aplasma-cell lymphoproliferative disease.

70,71

A recent casereport documents calciphylaxis in a patient with chronicmyelomonocytic leukaemia.

72

Calciphylaxis needs to beconsidered in the differential diagnosis of renal failure inpatients with transplanted kidneys.

73

Risk/trigger factors

Risk/trigger factors for calciphylaxis include renal impair-ment, being a female, Caucasian race, obesity, warfarinuse, hypercoaguable states, diabetes mellitus, dialysisdependency, protein malnutrition and those receivingcalcium salts and vitamin D therapy (Box 4).

74–78

Albumininfusions as well as subcutaneous insulin injections havebeen considered as being precipitants of calciphylaxis.

79,80

In most series, patients with co-morbid conditionsgenerally have had a worse prognosis. It has beenestimated that the incidence of new cases of calciphylaxisis 1 case per 100 haemodialysis patients per year and amathematical formula {2

×

[CaP0(4) – 5]

×

alkalinephosphatase level (IU)

×

PTH ratio} has been suggested asbeing useful in identifying patients at risk of developingcalciphylaxis, this arithmetic model being based on aliterature review of calciphylaxis, clinical observationsand physiological principles.

81

Diagnosis and prognosis

The diagnosis of calciphylaxis is based on clinical,biochemical and histopathological features.

82

A highindex of suspicion needs to be maintained, particularly inpatients with renal impairment. An elevated PTH level,high calcium, an elevated phosphate level, an elevatedcalcium phosphorous product, elevated alkaline phos-phatase, a high urea and creatinine value and anaemiamay be noted. It is recognized, however, that calciphylaxiscan occur despite normal calcium and phosphate levels.Elevation of the enzyme alkaline phosphatase may reflectchronicity of the underlying renal disease and hyper-parathyroidism while anaemia may reflect underlyingrenal disease or poor nutrition as a result of chronicillness. A ‘pipe-stem’ pattern of vascular calcification maybe noted on conventional radiography and calcificationof subcutaneous arterioles may be noted on xeroradio-graphy. A recent case report documents increased traceraccumulation in subcutaneous tissue in a patient withESRD and calciphylaxis, who underwent a bone scanfor pain in the extremities.

83

Radiography may revealsubperiosteal bone resorption and enlargement of theparathyroid glands may be evident on echography. Vascularmural calcification has been noted to be an early andessential process in the development of calciphylaxisplaques.

84

Mural calcification occurs in small and mediumsized blood vessel walls (arteries and arterioles) andintimal proliferation may be noted (fig. 2a). Special stainsmay demonstrate calcium deposits and degeneration ofelastic fibres. Inflammation may be absent or minimal.Histological features of pseudoxanthoma elasticum havebeen observed in association with calciphylaxis.

85

Perineuralcalcification may occur in association with vascularcalcification in patients with calciphylaxis, and may becontributory to pain associated with the syndrome

86

(fig. 2b). Experimental neurotropic calcification has beendemonstrated in animal models.

87

Oxalate crystals maybe noted in tissue biopsies in cases of primary oxaluria,and in deep skin biopsies, calcifying septal panniculitismay be noted. An endovascular giant cell reaction may beobserved microscopically and early endovascular fibro-blastic activation has been found to be statisticallystrongly associated with the presence of giant cells.

88

Adeep incisional biopsy is likely to provide a betterhistological yield but in cases where a biopsy is inadvisableowing to sepsis or the potential to aggravate ulceration,the biochemical and endocrine profile may be sufficientto make the diagnosis and institute early managementstrategies. High-resolution high-frequency ultrasoundmay aid in the diagnosis of lesions, prior to the occurrenceof the typical skin lesions.

89

In a case series of five patients,extensive tissue involvement, previous renal transplant

Box 4 Calciphylaxis-recognized risk/trigger factors and precipitants

• High calcium-phosphate product

• Hypercalcaemia

• Hyperphosphataemia

• Hyperparathyroidism

• Females

• Caucasians

• Long-term obesity

• Corticosteroids

• Hypercoaguable states

• Low serum albumin

• Albumin infusions

• Iron-dextran injections

• Warfarin

• Vitamin D treatment

• Immunosuppression

• Trauma

• Diabetes mellitus

• Subcutaneous insulin injections

• Dialysis dependency

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and higher preoperative leucocyte counts (over 20 000cells/mL) were found to be factors related to early deathin patients with calciphylaxis.

90

In another case series ofsix patients with CUA, a relationship between distallocation of the lesions, normal serum albumin and earlydiagnosis were related to survival, rather than the typeof treatment patients received.

91

In a study of sevenpatients with calciphylaxis, lesion severity at time ofparathyroidectomy correlated with clinical outcome.

92

Management

Maintenance of a high index of suspicion, early recognitionand timely, appropriate intervention as well as an activemultidisciplinary approach are mandatory in com-bating the syndrome of calciphylaxis, which has a

poor prognosis (Box 5). Prevention of systemic infectionis vital. Diligent wound care, avoidance of trauma, andappropriate antibiotic usage together with nutritionalsupport and adequate pain control are important aspectsof general care of these patients. Neurolytic lumbarsympathetic blockade (LSB) has been proven to be a usefulmethod of alleviating pain associated with calciphylaxis.

93

In the initial stages when skin is eroded, gentle handlingis important and careful dressing of wounds with materialsuch as petrolatum-impregnated gauze help to minimizetissue damage. Debridement and skin grafting may bewarranted – however, the role of debridement is con-troversial and it has been suggested that debridement iscontraindicated for wounds covered with dry, non-infectedeschars.

94

Sterile maggot therapy and pentoxyfillin hasbeen used to treat ulcerated areas in calciphylaxis.

95

Transcutaneous oxygen tension (TCPO2) measurementhas been used as a rapid non-invasive screening for skinischaemia before the development of skin lesions.

96

Attention to calcium and phosphate levels are vital in themanagement of patients with this syndrome and referral toa dietician is an important facet of treatment. Increasedfrequency of haemodialysis too has been employed asa management strategy. Calcium- and aluminium-freephosphate binders such as sevelamer hydrochloride(RenaGel) have been found to be useful in the manage-ment of renal osteodystrophy particularly in patients withextraskeletal calcification and hypercalcaemia.

97

In astudy by Chertow

et al

. haemodialysis patients treatedwith sevelamer were found to be protected from increasedcalcification of the aorta and coronary arteries.

98

Cautionshould be exercised with the use of calcium-containingheparins as calcifying panniculitits has been reportedfollowing subcutaneous injections of nadroparin-calcium in a patient with osteomalacia.

99

Hyperbaricoxygen therapy has been used particularly in the absenceof severe secondary hyperparathyroidism where relativelyfew therapeutic options are available.

100,101

Attention toand regulation of divalent metabolism is required prior toconsidering revascularization procedures in patients withcalciphylaxis.

102

Parathyroidectomy is known to beassociated with resolution of pain, wound healing and alonger median survival in patients with calciphylaxis.

103–110

Total parathyroidectomy and auto-transplantation oftissue to the forearm has proven to be satisfactory in somecases, subtotal parathyroidectomy being an alternativesurgical approach.

111

Healing of lower extremity ulcers in22 patients with calciphylaxis has been reported following‘near total’ parathyroidectomy (where a vascularizedparathyroid remnant is left

in situ

); this procedure alsobeing noted to improve bone density in patients withhyperparathyroidism.

112

Recurrent hyperparathyroidismhas been reported and re-operation may be warranted in

fig. 2 (A) Histological appearance of circumferential mural calcification of

an arteriole affected by calciphylaxis (H&E preparation, magnification

×300). (B) histological appearance of perineural calcification in calciphy-

laxis (H&E preparation, magnification ×200).


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such cases.

113

Revascularization and amputation mayhave to be resorted to in cases where all other supportiveand conservative measures have failed. Steroid use hasbeen associated with calciphylaxis, but treatment of apatient with renal failure with oral prednisolone followedby cimetidine has been reported to have reversed changesof calcifying panniculitis.

114

Sodium thiosulphate, anantidote for cyanide poisoning, is recognized to be apotent antioxidant as well as a chelator of calcium.

115

Intravenous sodium thiosulphate may have an adjunctiverole in therapy – it has been documented to reverse thesigns and symptoms of calciphylaxis.

116,117

Rapid resolutionof calciphylaxis has been reported following intravenoussodium thiosulphate and continuous veno-venoushaemofiltration.

118

In experimental animal models, theamino bisphosphonate ibandronate has been found toinhibit arterial calcification at doses that inhibit boneresorption, and improvement of calciphylaxis has beenreported after the intravenous use of pamidronate in apatient with chronic renal failure.

119,120

Intravenous maxa-calcitol, a vitamin D (3) formulation, used in conjunctionwith percutaneous ethanol injection therapy (PEIT) hasbeen documented to lead to a reduction in PTH secretion,regression of parathyroid hyperplasia and control of thecalcium-phosphorous product in dialysis patients – thiscombination is also considered to have a preventative rolein vascular calcification in the dialysis population.

121

Conclusions

Calciphylaxis is potentially lethal syndrome seen usuallyin patients with end-stage renal disease and secondaryhyperparathyroidism. It may, however, be associated with

other disease entities in the absence of renal or parathyroiddisease. A high index of suspicion, early intervention, and anactive multidisciplinary medical and surgical approach arevital aspects of the management strategy. Discovery of serumproteins, which play key regulatory roles in calciumhomeostasis, is likely to lead to novel therapeutic conceptswhich will broaden the therapeutic armamentarium avail-able to clinicians who manage patients with calciphylaxis.

Acknowledgements

We are grateful to the Computing and Media ServicesDepartment, Ninewells Hospital and Medical School,Dundee, Scotland, for providing the illustrations.

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Prevention/Treatment Options

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E-pub 2005 Sept 13.

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