JEADV ISSN 1468-3083

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), calcic uraemic arteriolopathy (CUA), calciphylaxis, secondary hyperparathyroidism, skin ulceration

Abstract
Calciphylaxis, a calcication syndrome associated with ischaemic cutaneous necrosis, is acquired naturally in humans in disease states. It is a life and limbthreatening complication, usually observed in patients with renal disease and secondary hyperparathyroidism, but known to occur in the absence of renal or parathyroid disease. The reported mortality rate, which ranges from 60 80%, relates to wound infection, sepsis and organ failure. It is a small-vessel vasculopathy, which is estimated to occur in about 4% of haemodialysis patients. Clinically, violaceous, reticulate areas of cutaneous necrosis and eschar may be evident, particularly in the extremities. In addition to the clinical picture, a raised calcium phosphorous product, an elevated parathyroid hormone level, radiographic evidence of vessel and soft-tissue calcication and the nding of mural calcication affecting small arteries and arterioles on histopathology help to conrm the diagnosis of this entity which generally has 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.

*Corresponding author, Department of Dermatology, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland, UK, tel. +1382 632294; fax. +1382 633916; E-mail: gehan.arseculeratne@tuht.scot.nhs.uk Received: 28 October 2004, accepted 27 January 2005 DOI: 10.1111/j.1468-3083.2006.01506.x

Pathophysiology
Atherosclerosis, arteriosclerosis and Mnckebergs sclerosis are vascular diseases associated with calcication and it is recognized that Mnckebergs sclerosis, which affects smaller elastic arteries, is a cardiovascular risk factor in patients with diabetes mellitus.1,2 Arterial calcication is considered to be a strong independent risk factor for cardiovascular morbidity and mortality, and hyperphosphataemia, as well as an increased calcium phosphorous product, are recognized as predictors of cardiovascular risk in patients with chronic renal disease.35 Calciphylaxis is a relatively poorly understood syndrome which predominantly affects small- and medium-sized blood vessels, and is a life-threatening entity usually seen in patients with renal disease, and may manifest as ischaemic cutaneous necrosis (Box 1). Calcication of cutaneous vasculature is known to be associated with chronic renal disease.6 The association between cutaneous gangrene and vascular calcication was described by Bryandt and White in 1898.7 Calciphylaxis was described by Hans Selye in 1962
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following experimental observations in animal models. Selye utilized sensitizing agents (parathyroid hormone, dihydrotachysterol) followed by challenging agents such as metal salts, egg white or yolk and albumin to induce calcication. As the process was considered to be one of induced hypersensitivity, resulting in local calcication following 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 calcic uraemic arteriolopathy (CUA), when vascular calcication 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 the histolopathogical ndings on which a diagnosis of calciphylaxis is made, differ between animal models and humans. Experimental calcinosis is known to produce extravascular rather than arteriolar/arterial calcication, hence the term calcic uraemic arteriolopathy (CUA), proposed by Coates et al. when vascular calcication occurs.11,12 Calciphylaxis as a syndrome was proposed by Gipstein et al. in 1976 and Winklemann and Keating described vascular calcication and cutaneous necrosis, developing on a background of hyperparathyroidism resulting from adenoma/carcinoma.13,14 In patients with endstage renal disease (ESRD), increased dietary calcium, calcium-based phosphate binders, calcium absorption from dialysate, abnormalities of bone buffering and turnover contribute to positive calcium balance.15 The widespread use of oral phosphate binders to combat uraemic osteodystrophy has been implicated as a causative factor in accelerating uraemic vasculopathy in the dialysis population.16 Attention to mineral metabolism is vital in the management of patients with renal disease. The United States National Kidney Foundation Clinical Practice Guidelines recommends that in stage 5 chronic kidney disease, the serum calcium, phosphate and the calcium phosphorous product should be maintained between 8.4 and 9.5 mg/ dL, 3.55.5 mg/dL and less than 55 mg2/dL2, respectively.17 Several proteins are known to play key roles in the pathogenesis of calcication. Studies on vascular disease including calciphylaxis in humans have revealed glycoproteins such as matrix Gla protein (MGP) and osteopontin (OPN), in pathological arteries, and these ndings support the view that they play a role in the development of vascular brosis and calcication.18 In animal models, OPN has been shown to play a nephro-protective role in vivo as an inhibitor of calcium oxalate crystal formation in the renal tubules.19 Alpha 2-Heremans-Schmid glycoprotein/ fetuin A (ahsg/fetuin) is a serum protein, produced by the liver in adults, which has been shown to play a preventative role in the pathogenesis of calcication.20 This protein is known to act systemically to inhibit ectopic calcication, and fetuin-A knock-out mice are known to develop extraskeletal calcication in the presence of hypercalcaemia, demonstrating that this protein plays a key role in the inhibition of calcication. Normalization of impaired inhibition of hydroxyapatite precipitation following addition of fetuin-A to the serum of dialysis patients having calciphylaxis has been demonstrated.21 Core-binding factor alpha 1 (Cbfa 1), a transcription factor, is considered to play a key role in activating stem cells into osteoblasts and Cbfa knock-out mice have been shown to be unable to produce mineralized bone.22,23 It has also been demonstrated that, together with arterial mineralization, Cbfa
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expression occurs in arteries from MGP knock-out mice and phosphorous has been shown to induce the expression of Cbfa1 in vascular smooth muscle cells Cbfa 1 is evidentially considered to play a key role in blood vessel calcication in the dialysis population.2426 Bone proteins are known to be expressed in calcied arteries in patients with calciphylaxis and there is evidence to suggest that mineralforming micro-organisms (nanobacteria) can induce calcium deposition in mammalian cell cultures and may play a role in human diseases characterized by extra-osseous calcication.2729 Bone morphogenic protein-4 (BMP-4), which is physiologically involved in bone metabolism, is considered to play a role as a promoter of vascular medial calcication.30

Clinical features
Metastatic calcication is a well-recognized complication observed in patients with chronic renal disease and occurs as a result of elevated calcium or phosphate levels resulting in calcium deposition in normal tissue. Relatively acute cutaneous necrosis is a recognised feature of calciphylaxis (Box 2). Early lesions may have a purpuric component while violaceous reticulate skin lesions, painful indurated areas (peau de orange), tender subcutaneous nodules, irregularly ulcerated areas and eschar formation being evident subsequently (g. 1). Violaceous, mottled, painful cutaneous lesions should alert clinicians to the possibility of calciphylaxis.31 The initial presentation may appear similar to that of thrombophlebitis and calf pain is a recognized presenting symptom.32,33 Patients may present with indurated plaques without ulceration, painful ulcerated plaques and livedoid bleeding in the lower limbs, leading to sepsis and death in about 60% of such patients.34,35 Extra-cutaneous calciphylaxis has been described involving muscle and rhabdomyolysis, resulting in leg pain and weakness, has been reported in calciphylaxis in the absence of chronic renal failure.36,37 Acute calcication of major organs such as the heart and lungs may give rise to the syndrome of bony heart and lungs, the latter being a 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 calcication of internal organs

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Box 3 Differential diagnosis of calciphylaxis Vasculitic syndromes Cryoglobulinaemia (type 1) Cryobrinogenaemia Cholesterol embolism syndrome Warfarin-induced skin necrosis (WISN) Disseminated intravascular coagulation (DIC) Nephrogenic brosing dermopathy (NFD) Scleromyxedema Primary hyperoxaluria Connective tissue diseases Atherosclerotic peripheral vascular disease Pyoderma gangrenosum Antiphospholipid antibody syndrome Cellulitis Panniculitis Deep fungal infections Necrotizing fasciitis

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

as a result of cardiac calciphylaxis. Cardiac calciphylaxis may be localized and has been described in association with nanobacteria affecting the mitral valve.40 Penile gangrene as well as Fourniers gangrene are known complications of calciphylaxis and rarely, areas such as the tongue may be affected by calciphylaxis.4143 Calcic cerebral embolism is a recognized cause of neurological symptomatology in patients with renal disease.44 The occurrence of the rash in meningococcal sepsis is considered to be associated with extravasation of calcium from the intravascular space into the interstitium and therefore bears some similarity to the pathophysiology of calciphylaxis.45

Differential diagnoses
Vasculitic syndromes, cholesterol embolization syndrome, cryoglobulinaemia, cryobrinogenaemia, warfarin-induced skin necrosis (WISN) and disseminated intravascular 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 haemodialysis patients and nephrogenic brosing dermopathy (NFD) in renal transplant patients.48 Both these entities are associated with thickening of skin in patients with renal disease and need to be considered in the differential diagnosis. An increase in the number of broblasts, as well as thickening of collagen bres are seen in this rare brosing disorder of NFD, and its occurrence with calciphylaxis, has been reported.49 Scleromyxoedema, a rare entity which is characterized by papular mucinous deposits, dermal broblast proliferation and monoclonal paraproteinaemia, also needs to be considered in the differential diagnosis of calciphylaxis.50 Type 1 primary oxaluria, a cause of cutaneous necrosis, needs to be considered in the differential diagnosis.51 Skin manifestations of connective tissue diseases, such as livedoid erythema, may mimic some of the manifestations of calciphylaxis.52 Antiphospholipid antibody syndrome, deep fungal infections, panniculitides, pyoderma gangrenosum,

atherosclerotic peripheral vascular disease, cellulitis and necrotizing fasciitis may all have clinical features resembling those of calciphylaxis and need exclusion.53 Calciphylaxis has a wide differential diagnosis and therefore, in addition to the routine haematological and biochemical parameters, investigations such as a vasculitis screen, estimation of cryoglobulins and cryobrinogens, brin degradation products (FDPs), antiphospholipid antibodies, and Doppler assessment of limb vessels need to be considered. Involvement of subcutaneous arterioles in calciphylaxis can be assessed by xeroradiography, a technique which is known to demonstrate that the appearance of arteriolar calcication differs from that of atherosclerosis.54

Clinical associations
Calciphylaxis has been described in association with metastatic malignancies, primary hyperparathyroidism (with normal renal function), end-stage liver disease/ alcoholic liver disease, rheumatoid arthritis and long-term steroid and methotrexate use and protein S deciency in the absence of renal disease.5560 Among other associations are cholangiocarcinoma, malignant melanoma of soft parts (clear-cell sarcoma) with calciphylactic changes in the absence of renal or parathyroid disease, necrotizing mastopathy (caused by calciphylaxis) and long-standing Crohns disease.6164 Ultraviolet light treatment was considered to have triggered calciphylaxis in a patient who had renal disease secondary to systemic lupus erythematosus.65 Calciphylaxis can be associated with widespread visceral injury and a case with massive gastrointestinal haemorrhage has been described.66 Coexistence of benign nodular calcication and calciphylaxis have been described in a haemodialysed patient.67 Widespread
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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

Diagnosis and prognosis

The diagnosis of calciphylaxis is based on clinical, biochemical and histopathological features.82 A high index of suspicion needs to be maintained, particularly in patients with renal impairment. An elevated PTH level, high calcium, an elevated phosphate level, an elevated calcium phosphorous product, elevated alkaline phosphatase, a high urea and creatinine value and anaemia may be noted. It is recognized, however, that calciphylaxis can occur despite normal calcium and phosphate levels. Elevation of the enzyme alkaline phosphatase may reect chronicity of the underlying renal disease and hyperparathyroidism while anaemia may reect underlying renal disease or poor nutrition as a result of chronic illness. A pipe-stem pattern of vascular calcication may be noted on conventional radiography and calcication of subcutaneous arterioles may be noted on xeroradiography. A recent case report documents increased tracer accumulation in subcutaneous tissue in a patient with ESRD and calciphylaxis, who underwent a bone scan for pain in the extremities.83 Radiography may reveal subperiosteal bone resorption and enlargement of the parathyroid glands may be evident on echography. Vascular mural calcication has been noted to be an early and essential process in the development of calciphylaxis plaques.84 Mural calcication occurs in small and medium sized blood vessel walls (arteries and arterioles) and intimal proliferation may be noted (g. 2a). Special stains may demonstrate calcium deposits and degeneration of elastic bres. Inammation may be absent or minimal. Histological features of pseudoxanthoma elasticum have been observed in association with calciphylaxis.85 Perineural calcication may occur in association with vascular calcication in patients with calciphylaxis, and may be contributory to pain associated with the syndrome86 (g. 2b). Experimental neurotropic calcication has been demonstrated in animal models.87 Oxalate crystals may be noted in tissue biopsies in cases of primary oxaluria, and in deep skin biopsies, calcifying septal panniculitis may be noted. An endovascular giant cell reaction may be observed microscopically and early endovascular broblastic activation has been found to be statistically strongly associated with the presence of giant cells.88 A deep incisional biopsy is likely to provide a better histological yield but in cases where a biopsy is inadvisable owing to sepsis or the potential to aggravate ulceration, the biochemical and endocrine prole may be sufcient to make the diagnosis and institute early management strategies. High-resolution high-frequency ultrasound may aid in the diagnosis of lesions, prior to the occurrence of the typical skin lesions.89 In a case series of ve patients, extensive tissue involvement, previous renal transplant

calciphylaxis has been described in patients with the acquired immunodeciency syndrome in association with renal disease and has also been reported to occur in association with osteosclerotic myeloma.68,69 Coexistent antiphospholipid antibody syndrome and calciphylaxis has been documented and calciphylaxis has also been reported in association with POEMS (CroweFukase) syndrome, a plasma-cell lymphoproliferative disease.70,71 A recent case report documents calciphylaxis in a patient with chronic myelomonocytic leukaemia.72 Calciphylaxis needs to be considered in the differential diagnosis of renal failure in patients with transplanted kidneys.73

Risk/trigger factors
Risk/trigger factors for calciphylaxis include renal impairment, being a female, Caucasian race, obesity, warfarin use, hypercoaguable states, diabetes mellitus, dialysis dependency, protein malnutrition and those receiving calcium salts and vitamin D therapy (Box 4).7478 Albumin infusions as well as subcutaneous insulin injections have been considered as being precipitants of calciphylaxis.79,80 In most series, patients with co-morbid conditions generally have had a worse prognosis. It has been estimated that the incidence of new cases of calciphylaxis is 1 case per 100 haemodialysis patients per year and a mathematical formula {2 [CaP0(4) 5] alkaline phosphatase level (IU) PTH ratio} has been suggested as being useful in identifying patients at risk of developing calciphylaxis, this arithmetic model being based on a literature review of calciphylaxis, clinical observations and physiological principles.81
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g. 2 (A) Histological appearance of circumferential mural calcication of an arteriole affected by calciphylaxis (H&E preparation, magnication 300). (B) histological appearance of perineural calcication in calciphylaxis (H&E preparation, magnication 200).

and higher preoperative leucocyte counts (over 20 000 cells/mL) were found to be factors related to early death in patients with calciphylaxis.90 In another case series of six patients with CUA, a relationship between distal location of the lesions, normal serum albumin and early diagnosis were related to survival, rather than the type of treatment patients received.91 In a study of seven patients with calciphylaxis, lesion severity at time of parathyroidectomy correlated with clinical outcome.92

Management
Maintenance of a high index of suspicion, early recognition and timely, appropriate intervention as well as an active multidisciplinary approach are mandatory in combating the syndrome of calciphylaxis, which has a

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 controversial and it has been suggested that debridement is contraindicated for wounds covered with dry, non-infected eschars.94 Sterile maggot therapy and pentoxyllin 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 management of renal osteodystrophy particularly in patients with extraskeletal calcication and hypercalcaemia.97 In a study by Chertow et al. haemodialysis patients treated with sevelamer were found to be protected from increased calcication of the aorta and coronary arteries.98 Caution should be exercised with the use of calcium-containing heparins as calcifying panniculitits has been reported following subcutaneous injections of nadroparincalcium in a patient with osteomalacia.99 Hyperbaric oxygen therapy has been used particularly in the absence of severe secondary hyperparathyroidism where relatively few therapeutic options are available.100,101 Attention to and regulation of divalent metabolism is required prior to considering revascularization procedures in patients with calciphylaxis.102 Parathyroidectomy is known to be associated with resolution of pain, wound healing and a longer median survival in patients with calciphylaxis.103110 Total parathyroidectomy and auto-transplantation of tissue to the forearm has proven to be satisfactory in some cases, subtotal parathyroidectomy being an alternative surgical approach.111 Healing of lower extremity ulcers in 22 patients with calciphylaxis has been reported following near total parathyroidectomy (where a vascularized parathyroid remnant is left in situ); this procedure also being noted to improve bone density in patients with hyperparathyroidism.112 Recurrent hyperparathyroidism has been reported and re-operation may be warranted in
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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 haemoltration and intravenous sodium thiosulphate Intravenous maxacalcitol and percutaneous ethanol injection therapy (PEIT) (a preventative role)

such cases.113 Revascularization and amputation may have to be resorted to in cases where all other supportive and conservative measures have failed. Steroid use has been associated with calciphylaxis, but treatment of a patient with renal failure with oral prednisolone followed by cimetidine has been reported to have reversed changes of calcifying panniculitis.114 Sodium thiosulphate, an antidote for cyanide poisoning, is recognized to be a 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 signs and symptoms of calciphylaxis.116,117 Rapid resolution of calciphylaxis has been reported following intravenous sodium thiosulphate and continuous veno-venous haemoltration.118 In experimental animal models, the amino bisphosphonate ibandronate has been found to inhibit arterial calcication at doses that inhibit bone resorption, and improvement of calciphylaxis has been reported after the intravenous use of pamidronate in a patient with chronic renal failure.119,120 Intravenous maxacalcitol, a vitamin D (3) formulation, used in conjunction with percutaneous ethanol injection therapy (PEIT) has been documented to lead to a reduction in PTH secretion, regression of parathyroid hyperplasia and control of the calcium-phosphorous product in dialysis patients this combination is also considered to have a preventative role in vascular calcication in the dialysis population.121

other disease entities in the absence of renal or parathyroid disease. A high index of suspicion, early intervention, and an active multidisciplinary medical and surgical approach are vital aspects of the management strategy. Discovery of serum proteins, which play key regulatory roles in calcium homeostasis, is likely to lead to novel therapeutic concepts which will broaden the therapeutic armamentarium available to clinicians who manage patients with calciphylaxis.

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

References
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Conclusions
Calciphylaxis is potentially lethal syndrome seen usually in patients with end-stage renal disease and secondary hyperparathyroidism. It may, however, be associated with
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