JEADV ISSN 1468-3083

Blackwell Publishing Ltd

Calciphylaxis – a topical overview
G Arseculeratne,*† ...
Calciphylaxis – a topical overview                                                                                        ...
Arseculeratne et al.                                                                                                   Cal...
Calciphylaxis – a topical overview                                                                                        ...
Arseculeratne et al.                                                                                            Calciphyla...
Calciphylaxis – a topical overview                                                                                        ...
Arseculeratne et al.                                                                                             Calciphyl...
Calciphylaxis – a topical overview                                                                                        ...
Arseculeratne et al.                                                                                                Calcip...
Calciphylaxis – a topical overview                                                                                        ...
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Calcifilaxia iv


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al tratamiento local en una paciente
con calcifilaxis proximal

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Calcifilaxia iv

  1. 1. 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: 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 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology 493
  2. 2. 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 494 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology
  3. 3. 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 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology 495
  4. 4. 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 496 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology
  5. 5. 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 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology 497
  6. 6. 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 resorption, and improvement of calciphylaxis has been 1 Lehto S, Niskanen L, Suhonen M et al. Medial artery reported after the intravenous use of pamidronate in a calcification. A neglected harbinger of cardiovascular patient with chronic renal failure.119,120 Intravenous maxa- complications in non-insulin-dependant diabetes mellitus. calcitol, a vitamin D (3) formulation, used in conjunction Arterioscler Thromb Vasc Biol 1996; 16: 978–983. with percutaneous ethanol injection therapy (PEIT) has 2 Niskanen L, Siitonen O, Suhonen M et al. Medial artery been documented to lead to a reduction in PTH secretion, calcification predicts cardiovascular mortality in patients regression of parathyroid hyperplasia and control of the with NIDDM. Diabetes Care 1994; 17: 1252–1256. calcium-phosphorous product in dialysis patients – this 3 Block GA. Control of serum phosphorous: implications combination is also considered to have a preventative role for coronary artery calcification and calcific uremic in vascular calcification in the dialysis population.121 arteriolopathy (calciphylaxis). Curr Opin Nephrol Hypertens 2001; 10: 741–747. 4 Block GA. Prevalence and clinical consequences of Conclusions elevated Ca X P product in hemodialysis patients. Clin Calciphylaxis is potentially lethal syndrome seen usually Nephrol 2000; 54: 318–324. in patients with end-stage renal disease and secondary 5 Cannata-Andia JB, Rodriguez-Garcia B. hyperparathyroidism. It may, however, be associated with Hyperphosphataemia as a cardiovascular risk factor-how 498 JEADV 2006, 20, 493–502 © 2006 European Academy of Dermatology and Venereology
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