REPORTS

Calciphylaxis: Natural history, risk factor analysis,

and outcome
Roger H. Weenig, MD,a Lindsay D. Sewell, MD,a,* Mark D. P. Davis, MD,a
James T. McCarthy, MD,b and Mark R. Pittelkow, MDa
Rochester, Minnesota
Background: Calciphylaxis is characterized by ischemic cutaneous ulceration, high mortality, and
ineffective treatment.
Methods: We conducted a retrospective study of 64 patients with calciphylaxis (including 49 dialysis
patients age- and sex-matched to 98 dialysis controls).
Results: The estimated 1-year survival rate of calciphylaxis was 45.8%. Risk factors for calciphylaxis
included obesity, liver disease, systemic corticosteroid use, calcium-phosphate product more than 70
mg2/dL2, and serum aluminum greater than 25 ng/mL. Survival rates were similar for 16 patients who
received parathyroidectomy and 47 who did not. An estimated 1-year survival rate of 61.6% was observed
for 17 patients receiving surgical debridement compared with 27.4% for the 46 who did not (P = .008).
Limitations: The study was limited by its retrospective design and there was no control group for the
15 nondialysis cases.
Conclusions: Calciphylaxis is multifactorial and usually fatal. Prevention of calciphylaxis may include
correction of risk factors identified in this study. Surgical debridement was associated with improved
survival, but parathyroidectomy was not. ( J Am Acad Dermatol 2007;56:569-79.)

alciphylaxis is a rare, usually fatal, vasculopathic disorder characterized by cutaneous

ischemia and necrosis due to calcification,
intimal fibroplasia, and thrombosis of pannicular
arterioles. It most commonly affects patients who
have end-stage kidney failure and traditionally has
been classified as metastatic calcification, in which
tissue calcification is caused by high serum levels of
calcium and phosphate. However, a considerable
number of patients with calciphylaxis have minimal
or no renal impairment and normal calciumphosphate indices. Previously implicated risk factors for the development of calciphylaxis include

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 Dermatology, 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

hyperparathyroidism, an elevated calcium-phosphate product, diabetes mellitus, female sex, obesity,

warfarin use, and protein C or S deficiency. However,
no large controlled studies of risk factors, prognostic
variables, and treatment responses have been performed. To better understand the natural history, risk
factors, and variables that may influence survival
in patients with calciphylaxis, we analyzed a large
cohort of patients from a single institution.

METHODS
The study was approved by the Institutional
Review Board of Mayo Foundation and consisted
of a retrospective review of the medical records of
64 patients in whom calciphylaxis was diagnosed at
Mayo Clinic, Rochester, Minnesota, over an 11-year
period (1992 to 2002). This included 16 patients
in the previous study of Kang et al.1 Of the 64 patients, 49 (77%) were receiving dialysis for end-stage
renal failure (dialysis patients). The remaining
15 patients were designated nondialysis patients.
Two control dialysis patients (dialysis controls)
were age- and sex-matched to each of the 49 dialysis
patients for the determination of risk factors. Dialysis
control patients were selected from a general pool
of dialysis patients who received dialysis between
569

570 Weenig et al

J AM ACAD DERMATOL
APRIL 2007

Fig 1. Kaplan-Meier survival rates for (A) 63 patients with calciphylaxis; B, 48 dialysis cases
and 98 dialysis controls (P \ .001); C, patients with calciphylaxis according to location of
lesions: proximal vs distal location vs both proximal and distal locations (P = .91); D, 48 dialysis
patients 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 those
who did not (P = .008).

1992 and 2002 and resided in Olmsted County,

Minnesota. The data abstracted from the medical
records included the clinical appearance and distribution of cutaneous lesions, cause of renal failure,
duration of dialysis before the onset of calciphylaxis
for cases or before data abstraction date for controls,
dialysis type (hemodialysis or peritoneal dialysis),
comorbid states (hypertension, diabetes mellitus,

inflammatory diseases, and malignancy), body

mass index, medications used before the onset of
calciphylaxis, laboratory investigations, therapies for
calciphylaxis, length of survival, and cause of death.
Statistical analysis
All abstracted variables were assessed for risk
factor determination (49 dialysis patients vs 98

Weenig et al 571

J AM ACAD DERMATOL
VOLUME 56, NUMBER 4

Table 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

Gender, No. (%)
Male
Female
Comorbid diagnoses, No. (%)
Diabetes mellitus
Hepatobiliary diseasez

59 (36-93)

60 (40-93)

59 (36-78)

58 (36-78)

N/A

N/A

11 (17)
53 (83)

1 (7)
14 (93)

10 (20)
39 (80)

20 (20)
78 (80)

N/A
N/A

N/A
N/A

27 (42)
14 (22)

5 (33)
5 (33)

22 (45)
9 (18)

40 (41)
2 (2)

Autoimmune/inflammatoryk
Median body mass index
Body mass
index [30, No. (%)
Medications used before
diagnosis, No. (%)
Systemic corticosteroids

25 (39)
30.0
33 (52)

9 (60)
28.0
7 (47)

16 (33)
30.2
26 (53)

23 (23)
26.6
22 (22)

29 (45)

12 (80)

17 (35)

25 (26)

9 (14)

2 (13)

7 (14)

29 (45)
32 (50)
37 (58)

9 (60)
1 (7)
0

13
4
22
5
15

(20)
(6)
(34)
(8)
(23)

Vitamin D or vitamin D
analogue
Warfarin
Erythropoietin
Phosphate-binding agents
Iron
Oral
Iron dextran
Calcium
Estrogenfemales
Aspirin
Cause of renal
failure, No. (%)
Diabetes mellitus
Inflammatory
Hypertension
Other{
Unknown
Type of dialysis
Hemodialysis
New#
Chronic
Peritoneal
Median duration
of dialysis before
diagnosis (case) or data
abstraction (control), mo
Specific location
of lesions, No. (%)
Legs
Arms
Trunk
Buttocks/hips
Genitalia

59
6
19
14

1.18
8.00
14.9
1.58
1.10
3.91
4.77

(.637)y
(.007)y
(.002)
(.236)y
(\.001)y
(\.001)y
(\.001)

.59-2.36
1.60-40.13
.74-3.37
1.05-1.16
1.87-8.14
\.001

18 (18)

3.19 (.005)y
2.98 (.026)
0.74 (.536)y

1.41-7.21
.026
.29-1.92

20 (41)
31 (63)
31 (63)

27 (28)
50 (51)
62 (63)

1.67 (.168)y
1.65 (.161)y
1.00 (1.00)y

.81-3.44
.82-3.34
.49-2.04

0
0
5 (33)
1 (7)
1 (7)

13
4
17
4
14

(27)
(8)
(35)
(8)
(29)

20
2
26
15
25

(20)
(2)
(27)
(15)
(26)

1.41
4.27
1.47
0.48
1.17

N/A
N/A
N/A
N/A
N/A

N/A
N/A
N/A
N/A
N/A

14
13
9
9
4

(29)
(27)
(18)
(18)
(8)

34
25
11
23
5

(35)
(26)
(11)
(23)
(5)

1.18 (.637)y
N/A
2.26 (.090)y
N/A
N/A

N/A
N/A
N/A
N/A

N/A
N/A
N/A
N/A

12 (24)
29 (59)
9 (18)
9.2

(100)
(7)
(20)
(33)

44
5
16
9

(92)
(9)
(30)
(22)

15
1
3
5

(90)
(10)
(33)
(18)

12 (12)
77 (79)
9 (9)
19

N/A
N/A
N/A
N/A

(.403)y
(.096)y
(.306)y
(.222)y
(.692)y

2.32 (.063)
0.47 (.044)
2.23 (.116)
(.024)

N/A
N/A
N/A
N/A
N/A

.63-3.14
.75-24.16
.70-3.08
.15-1.56
.54-2.52

.37-1.64
N/A
88-5.80

.23-.98

N/A
N/A
N/A
N/A
N/A
Continued

572 Weenig et al

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Table I. Contd
Total
cases
(n = 64)

General distribution
of lesions, No. (%)
Proximal
Distal
Both proximal and distal

39 (61)
17 (27)
8 (12)

Nondialysis
cases
(n = 15)

7 (47)
7 (47)
1 (7)

Dialysis
cases
(n = 49)

32 (65)
10 (20)
7 (14)

Dialysis
controls
(n = 98)

Odds
ratio*
(P value)

95% CI

N/A
N/A
N/A

N/A
N/A
N/A

N/A
N/A
N/A

CI, Confidence interval; N/A, not applicable or not analyzed for specific group.
*Odds of association with dialysis cases relative to dialysis controls.
y
Univariate analysis performed by exact methods.
z
Hepatobiliary disease: autoimmune hepatitis, ethanol-related liver disease, chronic active hepatitis C.

Multivariate analysis performed by multiple logistic regression and adjusted for the following covariates: hepatobiliary disease, systemic
corticosteroid use, and body mass index [30.
k
Autoimmune/inflammatory: lupus erythematosus, rheumatoid arthritis, sarcoidosis, polymyositis, Sjogrens syndrome.
{
Drug-induced renal failure, bulimia nervosa, IgA nephropathy, polycystic kidney disease.
#
New hemodialysis: hemodialysis initiated within 1 month after diagnosis (cases) or data abstraction (controls).

dialysis controls) using univariate (exact methods)

and multivariate (multiple logistic regression) analyses. Covariate survival rates were estimated by using
the Kaplan-Meier method for the entire cohort of 64
patients with calciphylaxis, and variables associated
with survival were assessed using log-rank tests
and Cox proportional hazards regression models.
A P value less than .05 was considered statistically
significant. Laboratory values were obtained using
specific result codes from the Mayo laboratory information system, and the data were abstracted for the
date closest to but before the onset of calciphylaxis.
For the dialysis patients and dialysis controls, results
obtained before the initiation of dialysis were
excluded.

RESULTS
Follow-up information was available for 63 of the
64 patients with calciphylaxis, of whom 51 (81%) had
died by the completion of the study. The median
survival from the date of diagnosis for these 63
patients was 2.64 months (range, 0-7 years). Overall
and group-specific survival curves are presented
in Fig 1. At the time of death, calciphylaxis-related
cutaneous ulceration was present in 34 patients
(67%), and the estimated cause-specific survival
rate at 1 year was 45.8%. Sepsis was a concomitant
contributory cause of death in 14 (41%) of the 34
patients who died with calciphylaxis. For the other
20 patients, the cause of death was reported as
progression of calciphylaxis (n = 10), renal failure
(n = 2), myocardial infarction (n = 1), or multipleorgan failure (n = 7).
Demographic and clinical characteristics of cases
and controls are presented in Table I. The mean age
at diagnosis of the 64 patients with calciphylaxis was

59 years (range, 36-93 years). Fifty-three (83%) of

them were female (female/male ratio = 5:1). Patients
presented with necrotic cutaneous ulcers (Fig 2, A),
livedo racemosa (Fig 2, B), hemorrhagic patches
(Fig 2, C ), indurated plaques (Fig 2, D), or hemorrhagic bullae (or some combination) on the lower
extremities (92%), trunk (30%), buttocks (22%),
upper extremities (9%), or genitalia (3%) (or in
more than one of these areas). The distribution
of cutaneous areas affected by calciphylaxis was
proximal (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 ulceration, 63 (98%) complained of severe pain in
the areas affected by calciphylaxis, 54 (84%) required opiate-type pain relievers, and 33 (52%)
were wheelchair-bound or bedridden because of
calciphylaxis.
Of the 44 dialysis patients who had skin biopsy,
42 (95%) had histologic features compatible with the
clinical diagnosis of calciphylaxis. Histologic features
included medial calcification and intimal fibroplasia
of pannicular arterioles associated with cutaneous
necrosis at various levels (epidermal, dermal, and
pannicular). Extravascular calcium deposition was
occasionally observed. Thrombosis of pannicular or
dermal arterioles was observed in 38 of 44 (86%)
patients who had biopsy (Fig 3).
Follow-up information was available for 48 of the
49 dialysis patients and for all 98 dialysis controls.
The median duration of dialysis for the 49 dialysis
patients was 9.2 months compared with 19 months
for the 98 dialysis controls (P = .024). The age and
duration of dialysis-adjusted survival rates were
significantly reduced for the 48 dialysis patients

J AM ACAD DERMATOL

Weenig et al 573

VOLUME 56, NUMBER 4

(median, 0.2 years; range, 0 to 7 years) compared

with that of the 98 dialysis controls (median, 3.3
years; range, 0 to 17 years). The estimated (KaplanMeier) overall survival rates at 1, 2, and 5 years were
29.0%, 14.5%, and 9.1%, respectively, for the dialysis
patients and 88.1%, 74.4%, and 46.9%, for the dialysis
controls (P \.001) (Fig 1, B).
The risk of association for calciphylaxis with
comorbid diseases, medications used, cause of renal
failure, and the type and duration of dialysis is
presented in Table I. As a continuously scaled variable, each one-unit increase in the body mass index
was associated with a 10% risk for calciphylaxis (odds
ratio [OR] = 1.10, P\.001). Obesity (body mass index
[30) conferred a 4-fold increased risk for calciphylaxis (univariate OR = 3.91, P = .001; multivariate OR =
4.77, P \.001). The median serum intact parathyroid
hormone level was not significantly different between
the dialysis patients and the dialysis controls in whom
this test was performed (OR = 1.01, P = .234). In
addition, a comparison of parathyroid hormone level
by tertiles revealed no significant difference between
dialysis cases and controls. Liver disease was present
in 9 of the dialysis patients (18%) and in 2 of the
dialysis controls (2%), conferring an 8-fold risk of
association with calciphylaxis (univariate OR = 8.0,
P = .007; multivariate OR = 14.9, P = .002). Systemic
corticosteroid use was 3 times more common in
dialysis patients than in dialysis controls (univariate
OR = 3.19, P = .005; multivariate OR = 2.89, P = .026).
The following variables were found to be independent risk factors for the development of calciphylaxis
by multivariate analysis: obesity, liver disease, and
corticosteroid use. The following variables were not
significantly different between dialysis patients and
dialysis controls: diabetes mellitus, hypertension,
cause of renal failure, low-density or high-density
lipoprotein, total cholesterol, or the use of warfarin
(new or long-term), vitamin D or vitamin D analogues, phosphate-binding agents, iron or iron
dextran, hormone replacement therapy (female patients), erythropoietin, cyclosporine, or aspirin.
Serum laboratory investigations for 49 dialysis
cases and 98 dialysis controls are presented in
Table II. The median serum calcium-phosphate product was 50 mg2/dL2 for cases compared with 46
mg2/dL2 for controls; this difference was not statistically significant (OR = 1.02, P = .050). A calciumphosphate product greater than 70 mg2/dL2 was close
to 5 times more common in cases than controls
(OR = 4.6, P = .012), which yielded a specificity of
95%. However, the sensitivity of calcium-phosphate
was poor (21%), as illustrated by 51% of the cases
that had a calcium-phosphate product less than
50 mg2/dL2. As a continuously scaled variable, each

Fig 2. Clinical presentation of calciphylaxis. A, Necrotic

ulceration. B, Livedo racemosaelike purpura. C, Hemorrhagic patches. D, Indurated plaque.

one-unit increase in the erythrocyte sedimentation

rate was associated with a 3% increased risk for
calciphylaxis (OR = 1.03, P = .003). The median serum
aluminum level was 17 ng/mL for cases and 8 ng/mL
for controls. This difference did not reach statistical
significance as a continuously scaled variable (OR =
1.04, P = .064). However, of the dialysis cases tested,
35% had a serum aluminum level greater than
25 ng/mL, compared with 11% of controls. Thus,

574 Weenig et al

J AM ACAD DERMATOL
APRIL 2007

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.)

a serum aluminum level greater than 25 ng/mL

conferred a 4-fold increased risk for calciphylaxis
(OR = 4.36, P = .045). No significant difference was
observed between cases and controls for the following laboratory investigations: serum albumin, serum
calcium, serum phosphate, coagulation profile
(protein C, protein S, antithrombin III, or serum
homocysteine levels), low-density lipoprotein,
high-density lipoprotein, or total cholesterol.

No significant difference in survival was observed

in relation to the area involved by calciphylaxis. The
estimated overall survival rates at 1 year were 44.7%,
32.2%, and 12.5%, respectively, for 38 patients with
proximal, 17 with distal, and 8 with both proximal
and distal calciphylaxis (P = .910, Fig 1, C ).
Although statistical significance was not reached,
a trend toward a reduced median survival was
observed for the 48 dialysis patients (2.4 months)

Weenig et al 575

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Table II. Serum laboratory values for dialysis cases (before diagnosis) and controls
Dialysis
cases
(n = 49)

Dialysis
controls
(n = 98)

Odds
ratio*
(P value)

39
9.3 (7.8-12.1)

97
9.3 (7.3-11.3)

2.00 (.082)

0.92-4.39

40
5.4 (2.7-10.0)

94
4.8 (1.6-11.3)

1.20 (.073)

0.98-1.47

39
50
30
19
10
8

94
46
64
35
19
5

1.02
1.56
1.60
1.36
4.59

1.00-1.05
0.66-3.70
0.75-3.41
0.57-3.27
1.40-15.10

Reference
range

Calcium, mg/dL
No. tested
Median (range)
Phosphate, mg/dL
No. tested
Median (range)
Calcium (Ca) 3 phosphate (PO4),
mg2/dL2
No. tested
Median (range)
Ca 3 PO4 [40 mg2/dL2, No. (%)
Ca 3 PO4 [50 mg2/dL2, No. (%)
Ca 3 PO4 [60 mg2/dL2, No. (%)
Ca 3 PO4 [70 mg2/dL2, No. (%)
Whole parathyroid, pmol/L
No. tested
Median (range)
ESR, mm/h
No. tested
Median (range)
ESR [30, No. (%)
ESR [40, No. (%)
ESR [50, No. (%)
ESR [60, No. (%)
Aluminum, ng/mL
No. tested
Median (range)
Aluminum [25 ng/mL, No. (%)
Albumin, g/dL
No. tested
Median (range)
Total cholesterol, mg/dL
No. tested
Median (range)
LDL cholesterol, mg/dL
No. tested
Median (range)
HDL cholesterol, mg/dL
No. tested
Median (range)
Protein C activity
No. tested
Median (range)
Protein S antigen
No. tested
Median (range)
Antithrombin III activity
No. tested
Median (range)
Homocysteine, mol/L
No. tested
Median (range)

95% CI

8.9-10.1

2.5-4.5

22.2-45.5

(23-92)
(77)
(49)
(26)
(21)

(17-106)
(68)
(37)
(20)
(5)

(.050)
(.310)
(.221)
(.491)
(.012)

1.0-5.2
35
8.9 (0.3-140.0)

67
8.4 (0.2-130.0)

1.01 (.234)

0.99-1.03

24
51
20
16
12
11

52
35
31
20
16
7

1.03
3.39
3.20
2.25
5.44

(.003)
(.048)
(.025)
(.110)
(.003)

1.01-1.04
1.01-11.34
1.16-8.84
0.83-6.08
1.76-16.85

0-29
(20-140)
(83)
(67)
(50)
(46)

(1-140)
(60)
(39)
(31)
(14)

0-6
17
17 (4-140)
6 (35.3)

36
8 (5-69)
4 (11.1)

1.04 (.064)
4.36 (.045)

1.00-1.08
1.04-18.39

35
3.3 (1.9-4.5)

84
3.3 (1.3-4.7)

0.64 (.153)

0.34-1.18

25
165 (50-384)

76
169 (64-296)

1.00 (.914)

0.99-1.01

23
90 (22-172)

71
82 (21-199)

1.00 (.797)

0.99-1.01

24
37 (16-73)

76
44 (17-88)

0.97 (.123)

0.94-1.01

7
89 (14-116)

9
84 (42-111)

0.99 (.636)

0.96-1.03

7
114 (55-147)

9
108 (71-164)

0.99 (.684)

0.96-1.03

7
77 (16-106)

9
70 (56-102)

0.99 (.747)

0.95-1.04

8
10 (5-20)

12
13 (6-27)

0.94 (.447)

0.81-1.10

3.5-5.0

\200

#100

$ 40

70-130

50-120

80-123

#13

ESR, Erythrocyte sedimentation rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
*Odds of association with dialysis cases relative to dialysis controls; univariate analysis performed by exact methods.

576 Weenig et al

J AM ACAD DERMATOL
APRIL 2007

Table III. Clinical features of 15 nondialysis

patients with calciphylaxis

alcoholic hepatitis, hepatocellular carcinoma, or

cholangiocarcinoma (33%) (Table III).

Patient Estimated Warfarin Prednisone

No.
GFR*
use
use

DISCUSSION

[60

Yes

Yes

2
3
4
5
6
7
8
9

41-60
41-60
41-60
20-40
20-40
20-40
20-40
20-40

Yes
No
No
Yes
Yes
No
Yes
Yes

Yes
Yes
No
Yes
Yes
Yes
No
Yes

10

20-40

Yes

Yes

11
12

20-40
20-40

Yes
No

No
Yes

13
14
15

\20
\20
\20

No
Yes
No

Yes
Yes
Yes

Comorbidities

Polymyositis,
Sjogrens syndrome
Autoimmune hepatitis
Rheumatoid arthritis
Chronic ethanol abuse
Sarcoidosis
Sarcoidosis
Cholangiocarcinoma
Systemic lupus
erythematosus
Systemic lupus
erythematosus
Diabetes mellitus
Ethanol-related
steatohepatitis
Pemphigus foliaceus
Osteoporosis
Osteoporosis, diabetes
mellitus

GFR, Glomerular filtration rate.

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

compared with the 15 nondialysis patients (8.4

months) (P = .16, Fig 1, D).
Parathyroidectomy did not offer a survival advantage for the 16 patients with calciphylaxis who had
this procedure compared with 47 who did not. The
estimated overall survival rates at 1 year were 33.3%
for the parathyroidectomy group and 38.3% for
the nonparathyroidectomy group (P = .92, Fig 1, E ).
However, surgical debridement was significantly
associated with survival. The estimated overall survival rate at 1 year for the 17 patients who had surgical 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 function
for the 15 nondialysis patients was severely impaired
(glomerular filtration rate [GFR], \20 mL/min) in 3
patients, moderately impaired (GFR, 21-40 mL/min)
in 8, mildly impaired (GFR, 41-60 mL/min) in 3, and
normal (GFR [60 mL/min) in 1. Common features
of the nondialysis patients included prednisone
use (80%); an autoimmune or inflammatory condition, including systemic lupus erythematosus,
polymyositis, sarcoidosis, hepatitis, ulcerative colitis,
rheumatoid arthritis, Sjogrens syndrome, or pemphigus (60%); warfarin use (60%); and hepatobiliary
disease, including chronic active viral hepatitis,

In 1961, Selye, Gentile, and Prioreschi2 defined

calciphylaxis as a systemic hypersensitivity reaction analogous to an allergic reaction (anaphylaxis).
In experiments on rodents, Selye and coworkers
induced calcification of various organs (including
the skin) after animals had been sensitized with
one of several agents they referred to as calcifiers
(eg, dihydrotachysterol, vitamin D2, vitamin D3, and
parathyroid hormone), followed by exposure to a
challenger (eg, metallic salts such as iron and
aluminum, egg albumin, or trauma). A few years
after Selye coined the term, calciphylaxis was reported in humans. Investigators have recognized
that vascular calcification, as opposed to tissue
calcification, predominated in the human cases of
calciphylaxis. As a result, other terms, including
calcific small-vessel ischemic disease,3 calcifying
panniculitis of renal failure,4 vascular calcificatione
cutaneous necrosis syndrome,5 calcified subcutaneous arterioles with infarcts of the subcutis and skin
in chronic renal failure,6 calcific uremic arteriolopathy,7 endovascular lithiasis,8 and uraemic
gangrene syndrome,9 have been proposed, but
calciphylaxis is still widely used to designate the
human syndrome.
Recent work in cardiovascular and bone diseases
has identified a link between bone and vascular
calcification. The molecular and cytochemical factors (receptor activator of nuclear factor-kB [RANK],
RANK ligand, and osteoprotegerin) crucial to mineral deposition and resorption of bone also appear to
regulate extraskeletal mineralization. Derangement
of this system has been tied to certain bone diseases
and may underlie the pathogenesis of calciphylaxis.
Parathyroid hormone, corticosteroids, aluminum,
liver disease, and various forms of inflammation
are capable of increasing the expression of RANK
ligand, decreasing the expression of osteoprotegerin, activating nuclear factor-kB, or degrading the
inhibitory protein of nuclear factor-kB (or a combination of these).10-16 In addition, warfarin may be
an important cofactor augmenting vascular calcification through the inhibition of vitamin Kedependent
g-carboxylation of matrix-Gla protein.17 All our
patients with calciphylaxis had at least one of the
foregoing factors that may promote vascular calcification through an effect on the nuclear factor-kB
pathway.
Our study did not confirm that warfarin use
or protein C or S deficiency is a risk factor for
the development of calciphylaxis, as has been

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Table IV. Therapeutic interventions for patients with calciphylaxis

No. of
patients

Estimated 1-y
survival (P value)

Parathyroidectomy

16

33.3% (.92)

No parathyroidectomy
Surgical debridement

47
17

38.3%
61.6% (.008)

No surgical debridement
Other
Medical management of CaPO4*
Vitamin K replacement
Low-dose tPA
Renal transplant

46

27.4%

Amputation
Fingers
Bilateral, below knee
Left, above knee

Treatment-associated outcome

Resolution in 1 patient, 9 patients (56%)

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

5
1
1
2

N/A
N/A
N/A
N/A

No apparent benefit as solitary therapy

Progression and death
Resolution
Resolution (1 patient had debridement,
BKA in othery)

1
2

N/A
N/A

N/A

No apparent benefit
Resolution in 1 patient who also received renal
transplanty; no benefit in other patient
No apparent benefit

BKA, Below-knee amputation; N/A, not accessed for this subgroup; tPA, tissue plasminogen activator.
*Aggressive dialysis; phosphate-binding agents; discontinue calcium, vitamin D, or vitamin D analogue.
y
Same patient.

suggested.18-21 However, in both dialysis patients

and dialysis controls, warfarin use was common and
the serum levels of protein C or S were not tested
frequently. Therefore further prospective studies are
needed to exclude warfarin use, protein C or S
deficiency, or other coagulation abnormalities as
risk factors for calciphylaxis. The pathologic changes
of calciphylaxis (progressive luminal narrowing
by mural calcification and intimal fibrosis) coupled
with the low-pressure system of the cutaneous vasculature as well as potential tethering and kinking
of pannicular arterioles in fatty regions (breasts, hips,
thighs) would promote thrombus formation on a
mechanical basis alone. Therefore a superimposed
hypercoagulable state would likely initiate or exacerbate calciphylaxis in a predisposed patient.
There was no statistical difference in parathyroid
hormone level between dialysis cases and controls.
High or low levels of parathyroid hormone induce
high-turnover bone disease (renal osteodystrophy)
or adynamic bone disease, respectively, and both
are associated with vascular calcification in renal
failure. In fact, dialysis patients with the lowest
parathyroid hormone levels have the most severe
arterial calcification.22,23 Although additional mechanisms may be involved, hypoparathyroidism results
in hyperphosphatemia, which contributes to vascular
mineral deposition. Of note, 67% of the dialysis
patients in our study (cases and controls) had either
high or low parathyroid hormone levels. Thus,
although parathyroid hormone abnormalities may

be a cofactor in the pathogenesis of vascular calcification renal failure, the parathyroid hormone level
should not be used to establish or refute a diagnosis of
calciphylaxis.
Aluminum is cleared by the kidney, and toxic
levels of aluminum are rare without renal impairment. Our study identified a serum level of aluminum greater than 25 ng/mL to be 4 times more
common in calciphylaxis patients than in controls.
Of significance to this finding, the severity of aluminum deposition in bone was recently found to be
related directly to the severity of arterial calcification
in end-stage renal disease.22 Previously, aluminum
accumulation and associated toxicity (most notably,
aluminum-associated osteomalacia) occurred in
dialysis patients because of the high aluminum content in dialysis replacement fluids. However, none
of our patients who had increased aluminum levels
had received dialysis in the era of aluminum-tainted
dialysis fluids. Current sources of relatively high
aluminum content include certain medications (aluminum-containing antacids, analgesics, intravenous
medications) and foods (cornbread, processed
cheese, and fish sticks).
The fact that 23% of the calciphylaxis patients
in this study were nondialysis patients indicates
that there is not a specific dialysis-related factor
that causes calciphylaxis. However, given that 77% of
calciphylaxis patients were receiving dialysis and
11 of 15 (69%) nondialysis patients had moderate to
severe renal impairment, kidney failure is the most

578 Weenig et al

J AM ACAD DERMATOL
APRIL 2007

important risk factor associated with the development of calciphylaxis.

Because vascular calcification may be silent and
progress insidiously in dialysis patients, this study
may have neglected or underestimated some risk
factors or cofactors requisite to calciphylaxis. Another weakness of our study is the lack of a nondialysis control group for the 15 nondialysis patients
with calciphylaxis. This was not attempted because
of the heterogeneity of this subgroup.
No standard or universally effective therapy for
calciphylaxis exists. Systemic corticosteroids are of
no benefit to patients with calciphylaxis and may
contribute to arteriolar calcification as well as exacerbate calcium and phosphate abnormalities by the
induction of adynamic bone disease. Parathyroidectomy should be avoided in patients without proven
hyperparathyroidism and used judiciously when
there is evidence for severe hyperparathyroidism.
Surgical debridement of devitalized tissue is often a
necessary component of the therapy of calciphylaxis
and was associated with prolonged survival in our
study. Anecdotally, complete resolution was associated with low-dose tissue plasminogen activator
therapy in one patient and kidney transplantation (in
combination with surgical debridement or amputation of the affected limb) in two patients (Table IV).
Identifying and correcting metabolic disturbances
(hyperparathyroidism, hypercalcemia, hyperphosphatemia) in patients with calciphylaxis makes
good clinical sense. However, once cutaneous
hypoperfusion is critically low and ischemic necrosis
ensues, aggressive measures to halt disease progression and restore perfusion would likely be required.
Thrombolytic therapy (such as low-dose tissue plasminogen activator that was effective in reversing
calciphylaxis in one of our recent patients) may
prove effective in restoring perfusion in salvageable
vessels.
Further characterization and confirmation of specific mediators of vascular calcification may lead to
new therapies for the prevention and treatment of
calciphylaxis, such as recombinant osteoprotegerin,
which prevents vitamin D and warfarin-induced
vascular calcification in rats24 and holds promise
for the treatment of osteoporosis.
In conclusion, our findings indicate that calciphylaxis is a multifactorial disease associated with a
high mortality rate. The estimated disease-specific
survival rate for calciphylaxis 1 year after the diagnosis is 45.8%. This study supports previous reports
that obesity and systemic corticosteroid use are risk
factors associated with calciphylaxis. Although a
calcium-phosphate product of 70 or more had a
highly specific (95%) association with calciphylaxis,

it lacked sensitivity (21%), and more than 50% of

patients had a calcium-phosphate product less than
50. Therefore the calcium-phosphate product does
not reliably confirm or exclude a diagnosis of
calciphylaxis. Other risk factors identified in our
study included liver disease, an increased serum
level of aluminum, and an increased erythrocyte
sedimentation rate. Surgical debridement, but not
parathyroidectomy, was associated with improved
survival.
Primary and secondary prevention of calciphylaxis may include modification or avoidance of risk
factors identified in this study.
We thank Christine M. Lohse for her assistance with
data organization and statistical analyses.
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