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REVIEWS

Calciphylaxis

R V Mathur, J R Shortland, A M El Nahas

Abstract phosphate diet act as sensitising agents result- The phenomenon of is rare, ing in a high -phosphate product (Ca × but potentially fatal. It has been recog- P; normal range 4.2–5.6 mmol2/l2) with result- nised for a long time in patients with ant precipitation of Ca-P crystals.14 This results chronic renal failure with secondary hy- in diVuse calcification of the media and perparathyroidism. Disturbed calcium internal elastic lamina of small to medium and phosphate metabolism can result in sized arteries and arterioles with intimal prolif- painful necrosis of , subcutaneous tis- eration and rarely arterial occlusion causing sue and acral gangrene. Appearance of the tissue necrosis. This entity was given the term lesions is distinctive but the pathogenesis cutis to signify vascular calcification remains uncertain. The beneficial eVects with ischaemic epidermolysis as seen in of are controversial. patients with chronic renal failure on However, correction of hyperphosphatae- haemodialysis.15–17 Other triggering events in- mia or occasionally is clude intravenous iron dextran and albumin imperative. Fulminant as a conse- infusion, low serum albumin, corticosteroids, quence of secondary infection of necrotic , trauma, subcutaneous in- and gangrenous tissue is a frequent cause jections in obese patients, and protein C and S of patient morbidity and mortality. deficiencies causing hypercoagulability and 8 12 16 18–25 (Postgrad Med J 2001;77:557–561) subsequent . has recently been established as a risk factor Keywords: calciphylaxis; calcium-phosphate product; primarily due to large deposits of secondary ; chronic renal failure that may be associated with reduction of local blood flow.918232526 Diabetics with chronic renal failure are especially prone to develop The syndrome of calciphylaxis is ischaemic acral necrosis partly due to extensive vascular ulceration of skin due to metastatic calcification calcifications.10 Deposition of Ca-P crystals in of subcutaneous tissue and small arteries occur- the interstitium and connective tissue of ring as a consequence of hyperparathyroidism in various organs is designated as systemic uraemic patients (box 1). Bryant and White first calcinosis or metastatic calcifica- http://pmj.bmj.com/ recorded the occurrence of calciphylaxis in tion.4510151618192728 In spite of the high uraemia in 1898 in Guy’s Hospital Reports. Selye incidence of vascular calcification reported in in 1962 coined the term calciphylaxis for acute haemodialysis patients and renal transplant local calcification of various organs and equated recipients, the incidence of tissue necrosis with this to a reaction. This is 72930 vascular calcification is rare. Levin et al inappropriate, as there is no relation to IgE type have estimated the incidence as approximately 1 mediated allergy. He induced extensive soft

one case per hundred haemodialysis patients on September 28, 2021 by guest. Protected copyright. tissue calcification in rats that were previously per year and have suggested a mathematical sensitised by high doses of analogues formula (2× [Ca × P−5]×alkaline phosphatase or , by local injection of (IU) × parathyroid hormone ratio) to assess the 1–10 irritants designated as challengers. These risk of developing calciphylaxis.31 Gipstein et al experimental conditions were not comparable Northern General are credited for the first compiled series of 11 Hospital, SheYeld, with the clinical situations in the context of the patients with calciphylaxis in 1976.1 An exten- UK: SheYeld absence of uraemic milieu and ischaemic necro- sive review by Hafner et al found that a total of Institute sis from medial calcification and intimal hyper- 155 cases have been reported from 1936 to R V Mathur plasia of small arteries. Hence the suitability of 1996, including nine of their own.510 Other A M El Nahas 4 5 10–12 the term was doubtful. However, the term sporadic case reports have appeared in the Department of calcinosis fails to distinguish secondary calcifica- literature since then probably owing to a Pathology tion in a necrotic tissue from ischaemic tissue greater awareness of the condition.32–39 Docu- J R Shortland necrosis due to arterial calcification.12 Hafner et mented listing of cases of calciphylaxis in al in 1995 termed this phenomenon as uraemic humans obtained from web site http:// Correspondence to: Dr Rashmi V Mathur, Renal small artery disease to characterise skin necrosis www.ncbi.nlm.nih.gov/PubMed on 4 July Academic OYce, Seminar and acral gangrene consequent to medial calcifi- 2000 has increased to 377 compared with 285 Room 4, Vickers Corridor, cation and intimal hyperplasia in arteries of sub- on 1 July 1999. This database also includes 61 Northern General Hospital, 510 Herries Road, SheYeld cutaneous tissue and those of hands and feet. cases of ocular calciphylaxis in haemodialysis S5 7AU, UK patients and 30 cases of tracheopathia [email protected] Pathogenic factors chondro-osteoplastica—a condition indistin- 13 Submitted 24 July 2000 Pathogenesis remains speculative. Chronic guishable from calciphylaxis because of accu- Accepted 2 October 2000 renal failure, hyperparathyroidism, and a high mulation of calcium salts in the tracheal

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Box 1: Calciphylaxis Box 2: Presentation x Painful necrosis of skin, subcutaneous tis- x Lesions begin as painful, symmetrical, sue and acral gangrene. violaceous discolouration. x Hyperphosphataemia and raised x Lesions evolve into well demarcated, calcium-phosphate product consequent non-healing ulcers that become necrotic to secondary hyperparathyroidism is an and gangrenous. important predisposing factor. x Lesions may have proximal or distal localisation. x Proximal lesions have poorer prognosis. mucosa with no abnormality of calcium and phosphate metabolism. A large number of ani- mal studies and non-syndrome patients have localisation died compared with eight of 25 also been cited.9 Angelis et al have reported a with distal localisation.8 These findings were prevalence of 4.1% in their haemodialysis consistent with Hafner et al’s review. Thirty patients.40 eight of 60 (63%) patients with proximal lesions died as compared with 15/65 (23%) Clinical features with distal localisation or acral gangrene.510 The lesions begin as painful, symmetrical, vio- Duh et al reported that less than 1% of laceous discolouration and evolve into well patients with digital gangrene have calciphy- demarcated non-healing ulcers that become laxis.7 However, it should be suspected in necrotic and gangrenous (fig 1A and B). The patients of uraemia with painful digital gan- lesions on the shoulders (fig 1C), trunk, grene. Calf pain and tenderness are a rare buttocks, and thighs are considered as proxi- presentation. mally localised and have a poorer prognosis On review of the literature no correlation essentially due to the larger bulk of necrotic could be established between age at onset and and infected tissue (fig 1D). Lesions with distal outcome of the disease. Age at onset ranges localisation may involve the calves, forearms, from 6 months to 83 years with a mean age of acral sites (hands, fingers, feet, and toes) and 48 ± 16 years.510 A female preponderance genitalia (box 2).41 42 Facial involvement as seen (61%) is noted due to the tendency to deposit in our patient has not been described so far. fat in subcutaneous sites.5910253343 White Chan et al, in their review of 47 cases, patients were found to be more predisposed to reported that 19 of 22 patients with proximal develop the condition,25 although a few case http://pmj.bmj.com/ on September 28, 2021 by guest. Protected copyright.

Figure 1 (A) and (B) Lesions begin as violaceous discolouration and evolve into well demarcated non-healing ulcers. (C) Metastatic calcification presenting as a hard painful subcutaneous lump 4 × 3 cm on the left shoulder. (D) Proximally localised lesions on the right thigh that have become necrotic and gangrenous.

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Box 3: Biochemical abnormalities Box 4: Treatment x Hyperphosphataemia >1.7mmol/l (>5 x Essentially supportive involving mg/dl), raised in 68% of cases. multidisciplinary approach. x Ca×P >5.6–12 mmol2/l2 (>70 mg2/dl2), x Early supplementation of vitamin D raised in 33% of cases. analogues—less hypercalcaemic and less x Serum calcium: normal or mildly raised hyperphosphataemic. >2.6 mmol/l (>10.5 mg/dl) in 20% of x Early total parathyroidectomy with cases. autotransplantation (non-compliant x Serum parathyroid hormone: mild to patient) or subtotal parathyroidectomy. moderately raised, >2–3 × upper limit of x Low phosphate diet. normal, raised in 80% of patients. x Open therapy of wounds with judicious x Raised urea/creatinine. use of antibiotics. x Anaemia of chronic renal insuYciency. x Hyperbaric oxygen therapy as in the x Neutrophil leucocytosis due to wound treatment of problem wounds. sepsis. x Low molecular weight heparin—under x Mildly raised serum alkaline phosphatase evaluation. due to hyperparathyroid bone disease.

reports of African-Americans have been pub- increase in serum calcium may frequently but lished.18 26 The role of , kidney trans- not consistently be seen with this phenomenon plantation, and immunosuppression in the (box 3). Roentgenography does not identify development of uraemic small artery disease patients at risk for developing calciphylaxis, as remains speculative. There was, however, a vascular and soft tissue calcification without positive correlation with the duration of skin necrosis is a frequent observation in azotaemia, which may alter the internal milieu patients with chronic renal failure on renal to an extent to intensify vascular calcification. replacement therapy. Xeroradiography is the The presence of a proximal ulcer in the absence best technique to study soft tissue calcifica- of neuropathy and peripheral vascular disease tions. is evocative of calciphylaxis as arterial calcifica- tion is usually localised to the tunica media. Histopathology Vascular insuYciency causing tissue necrosis Skin biopsy reveals extensive medial calcifica- may coexist due to fibrous obliteration of tion of small to medium sized arteries/ lumen in response to medial calcifica- arterioles with intimal proliferation. The depo- 37162944 tion. sition of calcium is either segmental or circumferential and leads to atrophy of the Diagnosis smooth muscle fibres of the media. The arterial The diagnosis of calciphylaxis requires a high lumen is usually preserved (fig 2). These index of suspicion in a uraemic patient who lesions have occasionally been designated as http://pmj.bmj.com/ presents with characteristic lesions on a primary. Subcutaneous calcification with is- background of abnormal biochemistry. Hyper- chaemic epidermolysis manifesting as the phosphataemia, raised Ca × P (>5.6–12 2 2 initial clinical presentation constitutes second- mmol /l ), mild to moderately raised serum ary lesions.9 These lesions are specific but not parathyroid hormone, and a normal or mild pathognomonic of calciphylaxis.

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Di erential diagnosis on September 28, 2021 by guest. Protected copyright. These lesions have to be distinguished from dystrophic calcifications that occur in well defined sites with normal concentration of divalent ions, in an abnormal microenviron- ment of necrosis. Significant cutaneous calcifi- cation is occasionally seen in adult cases of dematomyositis but is not associated with necrosis.45 Negative serologies and the pres- ence of vessel calcification can rule out a vasculitic skin rash. In pancreatic panniculitis necrosis is widespread and frequently pretibial with rapidly normalising serum amylase. Cuta- neous infarcts of type 1 (monoclonal) cryo- globulinaemia can be ruled out by the absence of cryogobulin and those associated with disseminated intravascular coagulation are acute in onset with invariable multiorgan failure. Ischaemic changes due to cholesterol emboli manifest more often as livedo reticula- ris, but can also present as smaller areas of Figure 2 Blood vessels within subcutaneous fat display medial calcification, which is circumferential in an arteriole. There is no significant intimal proliferation and both vessels non-healing vascular ulcerations and gangrene are patent. of the feet or legs.718334345

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Box 5: Key references Questions (answer true or false; x Hafner J, Keusch G, Wahl C, et al. answers on next page) Uremic small-artery disease with medial (1) Lesions of calciphylaxis usually present as: calcification and intimal hyperplasia (so- x Painful, symmetrical, well demarcated, called calciphylaxis): a complication of non-healing ulcers. chronic renal failure and benefit from x Painless, asymmetrical, ill defined, parathyroidectomy. J Am Acad Dermatol granulating ulcers. 1995;33:954–62. x . x Janigan DT, Hirch DJ, Klassen GA, et al. x Hyperkeratotic papules. Calcified subcutaneous arterioles with x Foot ulcers with callosities at the pres- infarcts of the subcutis and skin (“cal- sure points. ciphylaxis”) in chronic renal failure. Am (2) Calciphylaxis is more likely in the pres- J Kidney Dis 2000;35:588–97. ence of: x Duh QY, Lim RC, Clark OH. Calciphy- x Peripheral neuropathy. laxis in secondary hyperparathyroidism. x Acute vascular obstructive disease. Diagnosis and parathyroidectomy. Arch x Chronic degenerative vascular disease. Surg 1991;126:1213–19. x Microvascular calcification. x Llach F. Hyperphosphataemia in end- x Coagulopathies. stage renal disease patients: pathophysi- (3) Soft tissue calcification can be best studied ological consequences. Kidney Int by: 1999;56(suppl 73):S31–7. x Roentgenography. x Vassa N, Twardowski ZJ, Campbell J. x Skin biopsy. Hyperbaric oxygen therapy in x Xeroradiography. calciphylaxis-induced skin necrosis in a x Fine needle aspiration cytology. peritoneal dialysis patient. Am J Kidney x x Ray diVraction analysis Dis 1994;23:878–81. (4) The phenomenon of calciphylaxis may be related to: x IgE mediated hypersensitivity reac- Treatment tion. Therapeutic options are limited, unsatisfac- x Immune complex mediated response. tory, and essentially supportive involving x Delayed hypersensitivity reaction. multidisciplinary teamwork (see box 4). x Previous sensitisation with challengers Prophylaxis with rigorous control of uraemia like parathyroid hormone and vitamin and prevention of development of secondary D analogues. hyperparathyroidism is important. To normal- x Decreased transcutaneous oxygen ten- ise Ca × P in dialysis patients, besides a low sion at the site of the lesions. phosphate diet, the early supplementation of (5) Poor prognosis in calciphylaxis is associ- preferably less hypercalcaemic and less hyper- ated with: phosphataemic vitamin D products (24,25 x Uraemia. http://pmj.bmj.com/ dihydroxy cholecalciferol, 22 oxacalcitriol, x Wound sepsis. etc), or use of calcium free (and aluminium x Hyperparathyroidism. free) phosphate binders such as sevelamer x Proximal lesions. hydrochloride (Renagel), should be aimed x Distal lesions. for.911303346 Local treatment of the ulcers is similar to open therapy for burns with judicious use of underwent hyperbaric oxygen therapy five

antibiotics. The role of wound debridement is times a week, breathing 100% of oxygen while on September 28, 2021 by guest. Protected copyright. controversial.47111830 exposed to external pressure of 2.4 A. This Until now the eVect from parathyroid resulted in an oxygen pressure of 1000–1700 surgery has been equivocal, although recent mm Hg at the wound site. To avoid oxygen series have shown that parathyroidectomised toxicity three 30 minute, 100% oxygen inhala- patients have a better outcome with rapid tions were separated by 10 minute periods of wound healing and drastic reduction of Ca × P. breathing room air. Debridement of the ulcers Subtotal parathyroidectomy or total parathy- and skin grafting continued during this period. roidectomy with autotransplantation are the The eVect of subcutaneous fractionated preferred options.579102933 Survival benefit heparin in combination with hyperbaric oxygen was statistically non-significant in parathyroid- therapy is currently under study.20 24 48 ectomised individuals in one review.8 However, Hafner et al stated that 49/70 (70%) of patients Prognosis who underwent parathyroidectomy survived, The outcome of this disease is poor with a compared with 20/47 (43%) of those who did mortality of 60%–70%, mainly from uncon- not have parathyroidectomy.510 trolled sepsis from wound infection.49 Diagno- Vassa et al recommended treatment of skin sis is often delayed as the presentation may ulcers by hyperbaric oxygen therapy.47 They simulate more common conditions and be due found that transcutaneous oxygen tension in to a lack of pathognomonic investigations. tissues surrounding ulcer craters in calciphy- Patients with distal localisation have a better laxis was low and speculated that hypoxic con- outcome. Parathyroidectomy, though debat- dition existed within the ulcers. Skin lesions able, when performed before the onset of sep- healed after 38 treatments in patients who sis may be a reasonable step towards preventing

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258–61. http://pmj.bmj.com/ etiology of progressive vascular calcification and gangrene? 43 Ross CN, Cassidy MJD, Thompson M, et al. Proximal cuta- Ann Surg 1973;177:206–10. neous necrosis associated with small vessel calcification in 17 Meema HE, Oreopoulos DG. Morphology, progression, renal failure. 1991; :443–50. and regression of arterial and periarterial calcifications in QJMed 289 44 Ibels LS, Alfrey AC, HuVer WE, Arterial calcification patients with end-stage renal disease. Radiology 1986;158: et al. 671–7. and pathology in uremic patients undergoing dialysis. Am J 18 Ruggian JC, Maesaka JK, Fishbane S. Proximal calciphy- Med 1979;66:790–6. laxis in four insulin-requiring diabetic hemodialysis patients. 45 Flanigan KM, Bromberg MB, Gregory M, et al. Calciphy- Am J Kidney Dis 1996;28:409–14. laxis mimicking . Ischemic myopathy com- 19 Mehta RL, Scott G, Sloand JA, et al. Skin necrosis plicating renal failure. Neurology 1998;51:1634–40. associated with acquired protein C deficiency in patients 46 Fournier A, Morinie’re PH, Oprisiu R, et al. 1-Alpha- hydroxyvitamin D3 derivatives in the treatment of renal bone

with renal failure and calciphylaxis. Am J Med 1990;88:252– on September 28, 2021 by guest. Protected copyright. 7. diseases: justification and optimal modalities of administra- 20 Goldsmith DJA. Calciphylaxis, thrombotic diathesis and tion. Nephron 1995;71:254–83. defects in coagulation regulation. Nephrol Dial Transplant 47 Vassa N, Twardowski ZJ, Campbell J, et al. Hyperbaric oxy- 1997;12:1082–3 (letter). gen therapy in calciphylaxis-induced skin necrosis in a peri- 21 Kant KS, Glueck HI, Coots MC, et al. Protein S deficiency toneal dialysis patient. Am J Kidney Dis 1994;23:878–81. and skin necrosis associated with continuous ambulatory 48 Coates T, Kirkland GS, Dymock RB, et al. Cutaneous peritoneal dialysis. Am J Kidney Dis 1992;19:264–71. necrosis from calcific uremic arteriolopathy. Am J Kidney 22 Sankarasubbaiyan S, Scott Glynis, Holley JL. Dis 1998;32:384–91. Cryofibrinogenemia: an addition to the diVerential diagno- 49 Adrogue’ HJ, Frazier MR, ZeluV B, et al. Systemic calciphy- sis of calciphylaxis in end-stage renal disease. Am J Kidney laxis revisited. Am J Nephrol 1981;1:177–83. Dis 1998;32:494–8. 23 Braden G , Goerdt P, Pekow P, et al. Calciphylaxis in hemo- dialysis patients: patients’ profiles and temporal association with IV iron dextran. J Am Soc Nephrol 1997;8:549(abstr). Answers (true (T)/false (F) 24 Perez-Mijares R, Guzman-Zamudio JL, Payan-Lopez J, et al. Calciphylaxis in a haemodialysis patient: functional pro- (1) T, F, T, F, F; (2) F, F, T, T, F; (3) F, F, T, F, T; (4) tein S deficiency? Nephrol Dial Transplant 1996;11:1856–9. F, F, F, T, T; (5) F, T, F, T, F.

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