survival, but parathyroidectomy was not. ( J Am Acad Dermatol 2007;56:569-79.)

Calciphylaxis is a rare, usually fatal, vasculo-pathic disorder characterized by cutaneousischemia and necrosis due to calcification,

intimal fibroplasia, and thrombosis of panniculararterioles. It most commonly affects patients whohave end-stage kidney failure and traditionally hasbeen classified as metastatic calcification, in whichtissue calcification is caused by high serum levels ofcalcium and phosphate. However, a considerablenumber of patients with calciphylaxis have minimalor no renal impairment and normal calcium-phosphate indices. Previously implicated risk fac-tors for the development of calciphylaxis include

hyperparathyroidism, an elevated calcium-phos-phate product, diabetes mellitus, female sex, obesity,warfarin use, and protein C or S deficiency. However,no large controlled studies of risk factors, prognosticvariables, and treatment responses have been per-formed. To better understand the natural history, riskfactors, and variables that may influence survivalin patients with calciphylaxis, we analyzed a largecohort of patients from a single institution.

METHODSThe study was approved by the Institutional

Review Board of Mayo Foundation and consistedof a retrospective review of the medical records of64 patients in whom calciphylaxis was diagnosed atMayo Clinic, Rochester, Minnesota, over an 11-yearperiod (1992 to 2002). This included 16 patientsin the previous study of Kang et al.1 Of the 64 pa-tients, 49 (77%) were receiving dialysis for end-stagerenal failure (dialysis patients). The remaining15 patients were designated nondialysis patients.Two control dialysis patients (dialysis controls)were age- and sex-matched to each of the 49 dialysispatients for the determination of risk factors. Dialysiscontrol patients were selected from a general poolof dialysis patients who received dialysis between

From the Department of Dermatologya and the Division of

Nephrology,b Mayo Clinic.

*Visiting Medical Student, Mayo Clinic College of Medicine.

Funding sources: None.

Conflicts of interest: None identified.

Accepted for publication August 31, 2006.

Reprint requests: Roger H. Weenig, MD, Department of Derma-

tology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

E-mail: weenig.roger@mayo.edu.

Published online December 12, 2006.

0190-9622/$32.00

2007 by the American Academy of Dermatology, Inc.doi:10.1016/j.jaad.2006.08.065

569REPO

Calciphylaxis: Natural hisand ou

Roger H. Weenig, MD,a Lindsay D. SJames T. McCarthy, MD,b a

Rochester,

Background: Calciphylaxis is characterized by isineffective treatment.

Methods: We conducted a retrospective study of 6patients age- and sex-matched to 98 dialysis controls

Results: The estimated 1-year survival rate of calcincluded obesity, liver disease, systemic corticostermg2/dL2, and serum aluminum greater than 25 ng/received parathyroidectomy and 47 who did not. Anfor 17 patients receiving surgical debridement compa

Limitations: The study was limited by its retrospec15 nondialysis cases.

Conclusions: Calciphylaxis is multifactorial and uscorrection of risk factors identified in this study. SRTS

tory, risk factor analysis,tcome

ewell, MD,a,* Mark D. P. Davis, MD,a

nd Mark R. Pittelkow, MDa

Minnesota

chemic cutaneous ulceration, high mortality, and

4 patients with calciphylaxis (including 49 dialysis).

iphylaxis was 45.8%. Risk factors for calciphylaxisoid use, calcium-phosphate product more than 70mL. Survival rates were similar for 16 patients whoestimated 1-year survival rate of 61.6% was observedred with 27.4% for the 46 who did not (P = .008).

tive design and there was no control group for the

ually fatal. Prevention of calciphylaxis may includeurgical debridement was associated with improved

1992 and 2002 and resided in Olmsted County,Minnesota. The data abstracted from the medicalrecords included the clinical appearance and distri-bution of cutaneous lesions, cause of renal failure,duration of dialysis before the onset of calciphylaxisfor cases or before data abstraction date for controls,dialysis type (hemodialysis or peritoneal dialysis),

inflammatory diseases, and malignancy), bodymass index, medications used before the onset ofcalciphylaxis, laboratory investigations, therapies forcalciphylaxis, length of survival, and cause of death.

Statistical analysisAll abstracted variables were assessed for risk

Fig 1. Kaplan-Meier survival rates for (A) 63 patients with calciphylaxis; B, 48 dialysis casesand 98 dialysis controls (P \ .001); C, patients with calciphylaxis according to location oflesions: proximal vs distal location vs both proximal and distal locations (P = .91);D, 48 dialysispatients with calciphylaxis compared with 15 nondialysis patients with calciphylaxis (P = .16);E, patients with calciphylaxis who had parathyroidectomy compared with those who did not(P = .92); F, patients with calciphylaxis who had surgical debridement compared with thosewho did not (P = .008).570 Weenig et alcomorbid states (hypertension, diabetes mellitus,J AM ACAD DERMATOLAPRIL 2007factor determination (49 dialysis patients vs 98

J AM ACAD DERMATOLVOLUME 56, NUMBER 4

Weenig et al 571Table I. Demographic and clinical characteristics of cases and controls

Total

cases

(n = 64)

Nondialysis

cases

(n = 15)

Dialysis

cases

(n = 49)

Dialysis

controls

(n = 98)

Odds

ratio*

(P value) 95% CI

Mean age (range), y 59 (36-93) 60 (40-93) 59 (36-78) 58 (36-78) N/A N/AGender, No. (%)

Male 11 (17) 1 (7) 10 (20) 20 (20) N/A N/AFemale 53 (83) 14 (93) 39 (80) 78 (80) N/A N/A

Comorbid diagnoses, No. (%)Diabetes mellitus 27 (42) 5 (33) 22 (45) 40 (41) 1.18 (.637)y .59-2.36Hepatobiliary diseasez 14 (22) 5 (33) 9 (18) 2 (2) 8.00 (.007)y 1.60-40.13

14.9 (.002)

Autoimmune/inflammatoryk 25 (39) 9 (60) 16 (33) 23 (23) 1.58 (.236)y .74-3.37Median body mass index 30.0 28.0 30.2 26.6 1.10 (\.001)y 1.05-1.16

Body massindex[30, No. (%)

33 (52) 7 (47) 26 (53) 22 (22) 3.91 (\.001)y 1.87-8.144.77 (\.001) \.001

Medications used beforediagnosis, No. (%)

Systemic corticosteroids 29 (45) 12 (80) 17 (35) 25 (26) 3.19 (.005)y 1.41-7.212.98 (.026) .026

Vitamin D or vitamin Danalogue

9 (14) 2 (13) 7 (14) 18 (18) 0.74 (.536)y .29-1.92

Warfarin 29 (45) 9 (60) 20 (41) 27 (28) 1.67 (.168)y .81-3.44Erythropoietin 32 (50) 1 (7) 31 (63) 50 (51) 1.65 (.161)y .82-3.34Phosphate-binding agents 37 (58) 0 31 (63) 62 (63) 1.00 (1.00)y .49-2.04Iron

Oral 13 (20) 0 13 (27) 20 (20) 1.41 (.403)y .63-3.14Iron dextran 4 (6) 0 4 (8) 2 (2) 4.27 (.096)y .75-24.16

Calcium 22 (34) 5 (33) 17 (35) 26 (27) 1.47 (.306)y .70-3.08Estrogenfemales 5 (8) 1 (7) 4 (8) 15 (15) 0.48 (.222)y .15-1.56Aspirin 15 (23) 1 (7) 14 (29) 25 (26) 1.17 (.692)y .54-2.52

Cause of renalfailure, No. (%)

Diabetes mellitus N/A N/A 14 (29) 34 (35) 1.18 (.637)y .37-1.64Inflammatory N/A N/A 13 (27) 25 (26) N/A N/AHypertension N/A N/A 9 (18) 11 (11) 2.26 (.090)y 88-5.80Other{ N/A N/A 9 (18) 23 (23) N/AUnknown N/A N/A 4 (8) 5 (5) N/A

Type of dialysisHemodialysis

New# N/A N/A 12 (24) 12 (12) 2.32 (.063)Chronic N/A N/A 29 (59) 77 (79) 0.47 (.044) .23-.98

Peritoneal N/A N/A 9 (18) 9 (9) 2.23 (.116)Median duration

of dialysis beforediagnosis (case) or dataabstraction (control), mo

N/A N/A 9.2 19 (.024)

Specific locationof lesions, No. (%)

Legs 59 (92) 15 (100) 44 (90) N/A N/A N/AArms 6 (9) 1 (7) 5 (10) N/A N/A N/ATrunk 19 (30) 3 (20) 16 (33) N/A N/A N/AButtocks/hips 14 (22) 5 (33) 9 (18) N/A N/A N/AGenitalia N/A N/A

Continued

RESULTSFollow-up information was available for 63 of the

64 patients with calciphylaxis, of whom 51 (81%) haddied by the completion of the study. The mediansurvival from the date of diagnosis for these 63patients was 2.64 months (range, 0-7 years). Overalland group-specific survival curves are presentedin Fig 1. At the time of death, calciphylaxis-relatedcutaneous ulceration was present in 34 patients(67%), and the estimated cause-specific survivalrate at 1 year was 45.8%. Sepsis was a concomitantcontributory cause of death in 14 (41%) of the 34patients who died with calciphylaxis. For the other20 patients, the cause of death was reported asprogression of calciphylaxis (n = 10), renal failure(n = 2), myocardial infarction (n = 1), or multiple-organ failure (n = 7).

Demographic and clinical characteristics of casesand controls are presented in Table I. The mean age

quired opiate-type pain relievers, and 33 (52%)were wheelchair-bound or bedridden because ofcalciphylaxis.

Of the 44 dialysis patients who had skin biopsy,42 (95%) had histologic features compatible with theclinical diagnosis of calciphylaxis. Histologic featuresincluded medial calcification and intimal fibroplasiaof pannicular arterioles associated with cutaneousnecrosis at various levels (epidermal, dermal, andpannicular). Extravascular calcium deposition wasoccasionally observed. Thrombosis of pannicular ordermal arterioles was observed in 38 of 44 (86%)patients who had biopsy (Fig 3).

Follow-up information was available for 48 of the49 dialysis patients and for all 98 dialysis controls.The median duration of dialysis for the 49 dialysispatients was 9.2 months compared with 19 monthsfor the 98 dialysis controls (P = .024). The age andduration of dialysis-adjusted survival rates weredialysis controls) using univariate (exact methods)and multivariate (multiple logistic regression) analy-ses. Covariate survival rates were estimated by usingthe Kaplan-Meier method for the entire cohort of 64patients with calciphylaxis, and variables associatedwith survival were assessed using log-rank testsand Cox proportional hazards regression models.A P value less than .05 was considered statisticallysignificant. Laboratory values were obtained usingspecific result codes from the Mayo laboratory infor-mation system, and the data were abstracted for thedate closest to but before the onset of calciphylaxis.For the dialysis patients and dialysis controls, resultsobtained before the initiation of dialysis wereexcluded.

Table I. Contd

Total

cases

(n = 64)

Nondialysis

cases

(n = 15)

General distributionof lesions, No. (%)

Proximal 39 (61) 7 (47)Distal 17 (27) 7 (47)Both proximal and distal 8 (12) 1 (7)

CI, Confidence interval; N/A, not applicable or not analyzed for specifi

*Odds of association with dialysis cases relative to dialysis controls.yUnivariate analysis performed by exact methods.zHepatobiliary disease: autoimmune hepatitis, ethanol-related liver disMultivariate analysis performed by multiple logistic regression and ad

corticosteroid use, and body mass index[30.kAutoimmune/inflammatory: lupus erythematosus, rheumatoid arthriti{Drug-induced renal failure, bulimia nervosa, IgA nephropathy, polycy#New hemodialysis: hemodialysis initiated within 1 month after diagno

572 Weenig et alat diagnosis of the 64 patients with calciphylaxis was59 years (range, 36-93 years). Fifty-three (83%) ofthem were female (female/male ratio = 5:1). Patientspresented with necrotic cutaneous ulcers (Fig 2, A),livedo racemosa (Fig 2, B), hemorrhagic patches(Fig 2, C ), indurated plaques (Fig 2, D), or hemor-rhagic bullae (or some combination) on the lowerextremities (92%), trunk (30%), buttocks (22%),upper extremities (9%), or genitalia (3%) (or inmore than one of these areas). The distributionof cutaneous areas affected by calciphylaxis wasproximal (above the knee or elbow) in 39 patients(61%), distal (below the knee or elbow) in 17 (27%),or both in 8 (12%). Forty-eight patients (75%)were hospitalized for severe cutaneous ulcera-tion, 63 (98%) complained of severe pain inthe areas affected by calciphylaxis, 54 (84%) re-

Dialysis

cases

(n = 49)

Dialysis

controls

(n = 98)

Odds

ratio*

(P value) 95% CI

32 (65) N/A N/A N/A10 (20) N/A N/A N/A7 (14) N/A N/A N/A

c group.

ease, chronic active hepatitis C.

justed for the following covariates: hepatobiliary disease, systemic

s, sarcoidosis, polymyositis, Sjogrens syndrome.

stic kidney disease.

sis (cases) or data abstraction (controls).

J AM ACAD DERMATOLAPRIL 2007significantly reduced for the 48 dialysis patients

(median, 0.2 years; range, 0 to 7 years) comparedwith that of the 98 dialysis controls (median, 3.3years; range, 0 to 17 years). The estimated (Kaplan-Meier) overall survival rates at 1, 2, and 5 years were29.0%, 14.5%, and 9.1%, respectively, for the dialysispatients and 88.1%, 74.4%, and 46.9%, for the dialysiscontrols (P\ .001) (Fig 1, B).

The risk of association for calciphylaxis withcomorbid diseases, medications used, cause of renalfailure, and the type and duration of dialysis ispresented in Table I. As a continuously scaled vari-able, each one-unit increase in the body mass indexwas associatedwith a 10% risk for calciphylaxis (oddsratio [OR] = 1.10, P\.001). Obesity (bodymass index[30) conferred a 4-fold increased risk for calciphy-laxis (univariateOR=3.91,P= .001;multivariateOR=4.77, P\.001). The median serum intact parathyroidhormone levelwas not significantly differentbetweenthe dialysis patients and the dialysis controls in whomthis test was performed (OR = 1.01, P = .234). Inaddition, a comparison of parathyroid hormone levelby tertiles revealed no significant difference betweendialysis cases and controls. Liver disease was presentin 9 of the dialysis patients (18%) and in 2 of thedialysis controls (2%), conferring an 8-fold risk ofassociation with calciphylaxis (univariate OR = 8.0,P = .007; multivariate OR = 14.9, P = .002). Systemiccorticosteroid use was 3 times more common indialysis patients than in dialysis controls (univariateOR = 3.19, P = .005; multivariate OR = 2.89, P = .026).The following variables were found to be indepen-dent risk factors for the development of calciphylaxisby multivariate analysis: obesity, liver disease, andcorticosteroid use. The following variables were notsignificantly different between dialysis patients anddialysis controls: diabetes mellitus, hypertension,cause of renal failure, low-density or high-densitylipoprotein, total cholesterol, or the use of warfarin(new or long-term), vitamin D or vitamin D ana-logues, phosphate-binding agents, iron or irondextran, hormone replacement therapy (female pa-tients), erythropoietin, cyclosporine, or aspirin.

Serum laboratory investigations for 49 dialysiscases and 98 dialysis controls are presented inTable II. The median serum calcium-phosphate pro-duct was 50 mg2/dL2 for cases compared with 46mg2/dL2 for controls; this difference was not statisti-cally significant (OR = 1.02, P = .050). A calcium-phosphateproduct greater than 70mg2/dL2was closeto 5 times more common in cases than controls(OR = 4.6, P = .012), which yielded a specificity of95%. However, the sensitivity of calcium-phosphatewas poor (21%), as illustrated by 51% of the casesthat had a calcium-phosphate product less than

2 2

J AM ACAD DERMATOLVOLUME 56, NUMBER 450 mg /dL . As a continuously scaled variable, eachone-unit increase in the erythrocyte sedimentationrate was associated with a 3% increased risk forcalciphylaxis (OR=1.03,P= .003). Themedian serumaluminum level was 17 ng/mL for cases and 8 ng/mLfor controls. This difference did not reach statisticalsignificance as a continuously scaled variable (OR =1.04, P = .064). However, of the dialysis cases tested,35% had a serum aluminum level greater than

Fig 2. Clinical presentation of calciphylaxis. A, Necroticulceration. B, Livedo racemosaelike purpura. C, Hemor-rhagic patches. D, Indurated plaque.

Weenig et al 57325 ng/mL, compared with 11% of controls. Thus,

a serum aluminum level greater than 25 ng/mLconferred a 4-fold increased risk for calciphylaxis(OR = 4.36, P = .045). No significant difference wasobserved between cases and controls for the follow-ing laboratory investigations: serum albumin, serumcalcium, serum phosphate, coagulation profile(protein C, protein S, antithrombin III, or serumhomocysteine levels), low-density lipoprotein,

No significant difference in survival was observedin relation to the area involved by calciphylaxis. Theestimated overall survival rates at 1 year were 44.7%,32.2%, and 12.5%, respectively, for 38 patients withproximal, 17 with distal, and 8 with both proximaland distal calciphylaxis (P = .910, Fig 1, C ).

Although statistical significance was not reached,a trend toward a reduced median survival was

Fig 3. Histopathologic features of calciphylaxis. A, Medial calcification of pannicular arterioles(arrowheads). B, Enlarged view of calcified arteriole. C, Intimal fibroplasia (arrowhead ).D, Pannicular calcification (arrows) and necrosis (arrowheads). E, Luminal thrombosis(arrowheads). (A-E, Hematoxylin-eosin; original magnifications: A, 325; B and D, 3200;C and E, 3400.)574 Weenig et alhigh-density lipoprotein, or total cholesterol.J AM ACAD DERMATOLAPRIL 2007observed for the 48 dialysis patients (2.4 months)

Table II. Serum laboratory values for dialysis cases (before diagnosis) and controls

Reference

range

Dialysis

cases

(n = 49)

Dialysis

controls

(n = 98)

Odds

ratio*

(P value) 95% CI

Calcium, mg/dL 8.9-10.1No. tested 39 97Median (range) 9.3 (7.8-12.1) 9.3 (7.3-11.3) 2.00 (.082) 0.92-4.39

Phosphate, mg/dL 2.5-4.5No. tested 40 94Median (range) 5.4 (2.7-10.0) 4.8 (1.6-11.3) 1.20 (.073) 0.98-1.47

Calcium (Ca) 3 phosphate (PO4),mg2/dL2

22.2-45.5

No. tested 39 94Median (range) 50 (23-92) 46 (17-106) 1.02 (.050) 1.00-1.05Ca 3 PO4[40 mg

2/dL2, No. (%) 30 (77) 64 (68) 1.56 (.310) 0.66-3.70Ca 3 PO4[50 mg

2/dL2, No. (%) 19 (49) 35 (37) 1.60 (.221) 0.75-3.41Ca 3 PO4[60 mg2/dL2, No. (%) 10 (26) 19 (20) 1.36 (.491) 0.57-3.27Ca 3 PO4[70 mg

2/dL2, No. (%) 8 (21) 5 (5) 4.59 (.012) 1.40-15.10Whole parathyroid, pmol/L 1.0-5.2

No. tested 35 67Median (range) 8.9 (0.3-140.0) 8.4 (0.2-130.0) 1.01 (.234) 0.99-1.03

ESR, mm/h 0-29No. tested 24 52Median (range) 51 (20-140) 35 (1-140) 1.03 (.003) 1.01-1.04ESR[30, No. (%) 20 (83) 31 (60) 3.39 (.048) 1.01-11.34ESR[40, No. (%) 16 (67) 20 (39) 3.20 (.025) 1.16-8.84ESR[50, No. (%) 12 (50) 16 (31) 2.25 (.110) 0.83-6.08ESR[60, No. (%) 11 (46) 7 (14) 5.44 (.003) 1.76-16.85

Aluminum, ng/mL 0-6No. tested 17 36Median (range) 17 (4-140) 8 (5-69) 1.04 (.064) 1.00-1.08Aluminum[25 ng/mL, No. (%) 6 (35.3) 4 (11.1) 4.36 (.045) 1.04-18.39

Albumin, g/dL 3.5-5.0No. tested 35 84Median (range) 3.3 (1.9-4.5) 3.3 (1.3-4.7) 0.64 (.153) 0.34-1.18

Total cholesterol, mg/dL \200No. tested 25 76Median (range) 165 (50-384) 169 (64-296) 1.00 (.914) 0.99-1.01

LDL cholesterol, mg/dL #100No. tested 23 71Median (range) 90 (22-172) 82 (21-199) 1.00 (.797) 0.99-1.01

HDL cholesterol, mg/dL $ 40No. tested 24 76Median (range) 37 (16-73) 44 (17-88) 0.97 (.123) 0.94-1.01

Protein C activity 70-130No. tested 7 9Median (range) 89 (14-116) 84 (42-111) 0.99 (.636) 0.96-1.03

Protein S antigen 50-120No. tested 7 9Median (range) 114 (55-147) 108 (71-164) 0.99 (.684) 0.96-1.03

Antithrombin III activity 80-123No. tested 7 9Median (range) 77 (16-106) 70 (56-102) 0.99 (.747) 0.95-1.04

Homocysteine, mol/L #13No. tested 8 12Median (range) 10 (5-20) 13 (6-27) 0.94 (.447) 0.81-1.10

ESR, Erythrocyte sedimentation rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein.

J AM ACAD DERMATOLVOLUME 56, NUMBER 4

Weenig et al 575*Odds of association with dialysis cases relative to dialysis controls; univariate analysis performed by exact methods.

compared with the 15 nondialysis patients (8.4months) (P = .16, Fig 1, D).

Parathyroidectomy did not offer a survival advan-tage for the 16 patients with calciphylaxis who hadthis procedure compared with 47 who did not. Theestimated overall survival rates at 1 year were 33.3%for the parathyroidectomy group and 38.3% forthe nonparathyroidectomy group (P = .92, Fig 1, E ).However, surgical debridement was significantlyassociated with survival. The estimated overall sur-vival rate at 1 year for the 17 patients who had surg-ical debridement was 61.6% compared with 27.4%for those who did not have the ulcers debrided(P = .008, Fig 1, F ).

The estimated (Cockcroft-Gault) renal functionfor the 15 nondialysis patients was severely impaired(glomerular filtration rate [GFR],\20 mL/min) in 3patients, moderately impaired (GFR, 21-40 mL/min)in 8, mildly impaired (GFR, 41-60 mL/min) in 3, andnormal (GFR[60 mL/min) in 1. Common featuresof the nondialysis patients included prednisoneuse (80%); an autoimmune or inflammatory con-dition, including systemic lupus erythematosus,polymyositis, sarcoidosis, hepatitis, ulcerative colitis,rheumatoid arthritis, Sjogrens syndrome, or pem-phigus (60%); warfarin use (60%); and hepatobiliary

Table III. Clinical features of 15 nondialysispatients with calciphylaxis

Patient

No.

Estimated

GFR*

Warfarin

use

Prednisone

use Comorbidities

1 [60 Yes Yes Polymyositis,Sjogrens syndrome

2 41-60 Yes Yes Autoimmune hepatitis3 41-60 No Yes Rheumatoid arthritis4 41-60 No No Chronic ethanol abuse5 20-40 Yes Yes6 20-40 Yes Yes Sarcoidosis7 20-40 No Yes Sarcoidosis8 20-40 Yes No Cholangiocarcinoma9 20-40 Yes Yes Systemic lupus

erythematosus10 20-40 Yes Yes Systemic lupus

erythematosus11 20-40 Yes No Diabetes mellitus12 20-40 No Yes Ethanol-related

steatohepatitis13 \20 No Yes Pemphigus foliaceus14 \20 Yes Yes Osteoporosis15 \20 No Yes Osteoporosis, diabetes

mellitus

GFR, Glomerular filtration rate.

*Estimated (Cockcroft-Gault) GFR, mL/min.

576 Weenig et aldisease, including chronic active viral hepatitis,alcoholic hepatitis, hepatocellular carcinoma, orcholangiocarcinoma (33%) (Table III).

DISCUSSIONIn 1961, Selye, Gentile, and Prioreschi2 defined

calciphylaxis as a systemic hypersensitivity reac-tion analogous to an allergic reaction (anaphylaxis).In experiments on rodents, Selye and coworkersinduced calcification of various organs (includingthe skin) after animals had been sensitized withone of several agents they referred to as calcifiers(eg, dihydrotachysterol, vitamin D2, vitamin D3, andparathyroid hormone), followed by exposure to achallenger (eg, metallic salts such as iron andaluminum, egg albumin, or trauma). A few yearsafter Selye coined the term, calciphylaxis was re-ported in humans. Investigators have recognizedthat vascular calcification, as opposed to tissuecalcification, predominated in the human cases ofcalciphylaxis. As a result, other terms, includingcalcific small-vessel ischemic disease,3 calcifyingpanniculitis of renal failure,4 vascular calcificationecutaneous necrosis syndrome,5 calcified subcuta-neous arterioles with infarcts of the subcutis and skinin chronic renal failure,6 calcific uremic arteriol-opathy,7 endovascular lithiasis,8 and uraemicgangrene syndrome,9 have been proposed, butcalciphylaxis is still widely used to designate thehuman syndrome.

Recent work in cardiovascular and bone diseaseshas identified a link between bone and vascularcalcification. The molecular and cytochemical fac-tors (receptor activator of nuclear factor-kB [RANK],RANK ligand, and osteoprotegerin) crucial to min-eral deposition and resorption of bone also appear toregulate extraskeletal mineralization. Derangementof this system has been tied to certain bone diseasesand may underlie the pathogenesis of calciphylaxis.

Parathyroid hormone, corticosteroids, aluminum,liver disease, and various forms of inflammationare capable of increasing the expression of RANKligand, decreasing the expression of osteoprote-gerin, activating nuclear factor-kB, or degrading theinhibitory protein of nuclear factor-kB (or a combi-nation of these).10-16 In addition, warfarin may bean important cofactor augmenting vascular calcifica-tion through the inhibition of vitamin Kedependentg-carboxylation of matrix-Gla protein.17 All ourpatients with calciphylaxis had at least one of theforegoing factors that may promote vascular calcifi-cation through an effect on the nuclear factor-kBpathway.

Our study did not confirm that warfarin useor protein C or S deficiency is a risk factor for

J AM ACAD DERMATOLAPRIL 2007the development of calciphylaxis, as has been

risk factors for calciphylaxis. The pathologic changesof calciphylaxis (progressive luminal narrowingby mural calcification and intimal fibrosis) coupledwith the low-pressure system of the cutaneous vas-culature as well as potential tethering and kinkingof pannicular arterioles in fatty regions (breasts, hips,thighs) would promote thrombus formation on amechanical basis alone. Therefore a superimposedhypercoagulable state would likely initiate or exac-erbate calciphylaxis in a predisposed patient.

There was no statistical difference in parathyroidhormone level between dialysis cases and controls.High or low levels of parathyroid hormone inducehigh-turnover bone disease (renal osteodystrophy)or adynamic bone disease, respectively, and bothare associated with vascular calcification in renalfailure. In fact, dialysis patients with the lowestparathyroid hormone levels have the most severearterial calcification.22,23 Although additional mech-anisms may be involved, hypoparathyroidism resultsin hyperphosphatemia,which contributes to vascularmineral deposition. Of note, 67% of the dialysispatients in our study (cases and controls) had either

ment. Our study identified a serum level of alumi-num greater than 25 ng/mL to be 4 times morecommon in calciphylaxis patients than in controls.Of significance to this finding, the severity of alumi-num deposition in bone was recently found to berelated directly to the severity of arterial calcificationin end-stage renal disease.22 Previously, aluminumaccumulation and associated toxicity (most notably,aluminum-associated osteomalacia) occurred indialysis patients because of the high aluminum con-tent in dialysis replacement fluids. However, noneof our patients who had increased aluminum levelshad received dialysis in the era of aluminum-tainteddialysis fluids. Current sources of relatively highaluminum content include certain medications (alu-minum-containing antacids, analgesics, intravenousmedications) and foods (cornbread, processedcheese, and fish sticks).

The fact that 23% of the calciphylaxis patientsin this study were nondialysis patients indicatesthat there is not a specific dialysis-related factorthat causes calciphylaxis. However, given that 77% ofcalciphylaxis patients were receiving dialysis andsuggested.18-21 However, in both dialysis patientsand dialysis controls, warfarin use was common andthe serum levels of protein C or S were not testedfrequently. Therefore further prospective studies areneeded to exclude warfarin use, protein C or Sdeficiency, or other coagulation abnormalities as

Table IV. Therapeutic interventions for patients with ca

No. of

patients

Estimate

survival (P

Parathyroidectomy 16 33.3% (

No parathyroidectomy 47 38.3%Surgical debridement 17 61.6% (

No surgical debridement 46 27.4%Other

Medical management of CaPO4* 5 N/AVitamin K replacement 1 N/ALow-dose tPA 1 N/ARenal transplant 2 N/A

AmputationFingers 1 N/ABilateral, below knee 2 N/A

Left, above knee 1 N/A

BKA, Below-knee amputation; N/A, not accessed for this subgroup; tPA

*Aggressive dialysis; phosphate-binding agents; discontinue calcium, vySame patient.

J AM ACAD DERMATOLVOLUME 56, NUMBER 4high or low parathyroid hormone levels. Thus,although parathyroid hormone abnormalities maybe a cofactor in the pathogenesis of vascular calcifi-cation renal failure, the parathyroid hormone levelshould not beused to establishor refute adiagnosis ofcalciphylaxis.

Aluminum is cleared by the kidney, and toxiclevels of aluminum are rare without renal impair-

lciphylaxis

d 1-y

value) Treatment-associated outcome

.92) Resolution in 1 patient, 9 patients (56%)died with active calciphylaxis

.008) Resolution in 3 patients, 6 patients (35%)died with active calciphylaxis

No apparent benefit as solitary therapyProgression and deathResolutionResolution (1 patient had debridement,

BKA in othery)

No apparent benefitResolution in 1 patient who also received renal

transplanty; no benefit in other patientNo apparent benefit

, tissue plasminogen activator.

itamin D, or vitamin D analogue.

Weenig et al 57711 of 15 (69%) nondialysis patients had moderate tosevere renal impairment, kidney failure is the most

important risk factor associated with the develop-ment of calciphylaxis.

Because vascular calcification may be silent andprogress insidiously in dialysis patients, this studymay have neglected or underestimated some riskfactors or cofactors requisite to calciphylaxis. An-other weakness of our study is the lack of a non-dialysis control group for the 15 nondialysis patientswith calciphylaxis. This was not attempted becauseof the heterogeneity of this subgroup.

No standard or universally effective therapy forcalciphylaxis exists. Systemic corticosteroids are ofno benefit to patients with calciphylaxis and maycontribute to arteriolar calcification as well as exac-erbate calcium and phosphate abnormalities by theinduction of adynamic bone disease. Parathyroidec-tomy should be avoided in patients without provenhyperparathyroidism and used judiciously whenthere is evidence for severe hyperparathyroidism.Surgical debridement of devitalized tissue is often anecessary component of the therapy of calciphylaxisand was associated with prolonged survival in ourstudy. Anecdotally, complete resolution was asso-ciated with low-dose tissue plasminogen activatortherapy in one patient and kidney transplantation (incombination with surgical debridement or amputa-tion of the affected limb) in two patients (Table IV).

Identifying and correcting metabolic disturbances(hyperparathyroidism, hypercalcemia, hyperphos-phatemia) in patients with calciphylaxis makesgood clinical sense. However, once cutaneoushypoperfusion is critically low and ischemic necrosisensues, aggressive measures to halt disease progres-sion and restore perfusion would likely be required.Thrombolytic therapy (such as low-dose tissue plas-minogen activator that was effective in reversingcalciphylaxis in one of our recent patients) mayprove effective in restoring perfusion in salvageablevessels.

Further characterization and confirmation of spe-cific mediators of vascular calcification may lead tonew therapies for the prevention and treatment ofcalciphylaxis, such as recombinant osteoprotegerin,which prevents vitamin D and warfarin-inducedvascular calcification in rats24 and holds promisefor the treatment of osteoporosis.

In conclusion, our findings indicate that calci-phylaxis is a multifactorial disease associated with ahigh mortality rate. The estimated disease-specificsurvival rate for calciphylaxis 1 year after the diag-nosis is 45.8%. This study supports previous reportsthat obesity and systemic corticosteroid use are riskfactors associated with calciphylaxis. Although acalcium-phosphate product of 70 or more had a

578 Weenig et alhighly specific (95%) association with calciphylaxis,it lacked sensitivity (21%), and more than 50% ofpatients had a calcium-phosphate product less than50. Therefore the calcium-phosphate product doesnot reliably confirm or exclude a diagnosis ofcalciphylaxis. Other risk factors identified in ourstudy included liver disease, an increased serumlevel of aluminum, and an increased erythrocytesedimentation rate. Surgical debridement, but notparathyroidectomy, was associated with improvedsurvival.

Primary and secondary prevention of calciphy-laxis may include modification or avoidance of riskfactors identified in this study.

We thank Christine M. Lohse for her assistance withdata organization and statistical analyses.

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J AM ACAD DERMATOLVOLUME 56, NUMBER 4

Weenig et al 579

Calciphylaxis: Natural history, risk factor analysis, and outcomeMethodsStatistical analysis

ResultsDiscussionREFERENCES