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Controversies

in

Pathogenesis,

Diagnosis and

Treatment

“Calciphylaxis”Arturo R Dominguez, MD

Assistant Professor

University of Texas Southwestern Medical Center

Departments of Dermatology

& Internal Medicine

I do not have any relevant relationships with industry

I will be discussing off -label use of medications

DISCLOSURE OF RELEVANT

RELATIONSHIPS WITH INDUSTRY

PATHOPHYSIOLOGY

2/2 secondary & tertiary

hyperparathyroidism 2/2

hyperphosphatemia &

hypocalcaemia due to CKD

Clinically:

▪ Bone Resorption

▪ Metastatic calcifications in

soft tissue (skin & cartilage)

▪ Dystrophic vascular deposits in

media in medium-sized

vessels, aorta and heart valves

RENAL OSTEODYSTROPHY

W.-T. Lin, and C.-M. Chao QJM 2014;107:387

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Small-vessel

disease:

▪Arterioles

▪Subcutaneous

capillaries (<0.6 mm

diameter)

“Calciphylaxis”: Calcific Uremic

Arteriolopathy

Progressive medial calcification

Sub-intimal fibrosis & intimal hyperplasia

Thrombotic vaso-occlusion

Cutaneous necrosis

Systemic disease?

▪ Pulmonary and GI?

▪ Myositis, neuropathy

▪ Increased cardiovascular events

“Calciphylaxis”: Calcific Uremic

Arteriolopathy

Factors other than Ca-Phos promote

calcification in renal disease

▪Phosphate binders and cinacalcet (calcimimetic)

do not prevent vascular calcification, CV events &

mortality

▪ Increased recognition of cases in patients without

ESRD

CALCIFICATION IN RENAL DISEASE

EVOLVE Trial Investigators et al. Effect of

cinacalcet on cardiovascular disease in

patients undergoing dialysis. N Engl J Med.

2012 Dec 27;367(26):2482-94.

Skin lesions

morphologically identical

to CUA

Mortality rate 52%

▪ Improving

Risk factors:

▪ Warfarin, Female gender,

obesity, primary

hyperparathyroidism,

alcoholic liver disease,

malignancy and connective

tissue disease

NON-UREMIC CALCIPHYLAXIS

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1. Calcification of vascular smooth

muscle cell(s) (VSMC)

▪NFKB-mediated: Increased Bone morphogenic

protein (BMP) activity

▪Endothelial-mesenchynal transition (EMT)

TWO-HIT HYPOTHESIS IN CALCIPHYLAXIS

2. Thrombotic occlusion of arteriole

and capillary endothelial cells

▪Impaired blood flow in adipose rich-areas

▪Systemic hypercoagulability

▪Two recent studies (Mayo and Partners) with

hypercoagulable states

TWO-HIT HYPOTHESIS IN CALCIPHYLAXIS

Warfarin association

▪ Increased risk in German and Japanese Registries and other

studies

MGP: activated through Vitamin K decarboxylation

▪ Inhibits vascular calcification by inhibiting BMP-2

▪ Inhibition might promote both calcification and thrombosis

WARFARIN AS RISK FACTOR FOR

CALCIPHYLAXIS

Nigwekar SU, Bhan I, Turchin A, Skentzos SC,

Hajhosseiny R, Steele D, Nazarian RM, Wenger J, Parikh S, Karumanchi A, Thadhani R. Statin

use and calcific uremic arteriolopathy: a

matched case-control study. Am J Nephrol. 2013;37(4):325-32. doi: 10.1159/000348806

HD patients: 4.5-fold higher of inactive uncarboxylated

MGP

Correlates with vascular calcification in HD patients

Low uncarb-MGP = increased all-cause & CV mortality

Cirrhosis: Vitamin K deficiency 2/2 decreased bile salt

synthesis and impaired absorption

CKD/VITAMIN K/MGP

Delanaye P, Krzesinski JM, Warling X, Moonen M,

Smelten N, Médart L, Pottel H, Cavalier E. Dephosphorylated-uncarboxylated Matrix Gla protein

concentration is predictive of vitamin K status and is

correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014 Sep 4;15:145.

doi: 10.1186/1471-2369-15-145

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HISTORY & PHYSICAL

EXAM

Risk Factor Mechanism

ESRD and HD ↑ RANkL, Hemodialysis ↓fetuin-A, high levels of inactive MGP

Hyperphosphotemia and Hypercalcemia Less likely metastatic calcification and precipitation, ↑ NFkB

Alcoholic Liver Disease IL-1 and TNF-α ↑ RANkL, ↓ active MGP, ↓ Protein C&S, ↓ Fetuin-A

Hyperparathyroidism ↑ RANkL, ↓OGP

Glucocorticoids ↑ RANkL, ↓ OGP

Warfarin\Dietary Vitamin K deficiency

(Gastric bypass)

↓ of Vitamin K-dependent MGP

Aluminum ↑ calpain, an inhibitor of NFkB inhibitory protein

Autoimmune disease and Inflammation IL-1 and TNF-α ↑ RANkL upregulation, ↓ fetuin-A

Obesity Chronic tension on septae and arterioles promotes dystrophic

calcification, TNF-α

Female Gender, Age>50 (Menopause) Estrogen: ↑OPG expression

Vitamin D analogues ↑ RANkL

CALCIPHYLAXIS RISK FACTORS

Symptoms:

▪Active cutaneous disease:

▪Severe pain, induration, erythema

Morphologies depend on stage of disease:

▪Livedoid changes, panniculitis, bullae, stellate

ulcers & eschar

CALCIPHYLAXIS: HISTORY AND PHYSICAL EXAM

Location: Adipose-rich areas

▪Medial and lateral thighs

▪Calves

▪Buttocks

▪Abdominal pannus

▪Lower back

▪Breasts

▪Atypical areas in advanced disease: upper

extremities, scalp, face

CALCIPHYLAXIS: HISTORY AND PHYSICAL EXAM

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Livedo

Racemosa

CALCIPHYLAXIS

Pann iculi t is

CALCIPHYLAXIS

Livedo

Racemosa wi th

cen t ral pal lor

and skin

necrosis

CALCIPHYLAXIS

RETIFORM-

SHAPE

ESCHAR

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Less common presentation

Acral necrosis and gangrene

▪Hands and fingers

▪Feet and toes

▪Penile

▪Vulvar (case reports)

Can coexist with more typical disease

DISTAL/ACRAL CALCIPHYLAXIS

ACRAL

CALIPHYLAXIS

- Note re t i form

purpura on

super ior aspect

of foreskin

PENILE

CALCIPHYLAXIS

DIFFERENTIAL

DIAGNOSIS

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Clinically indistinguishable

▪ Adipose-rich areas

Presents within 10 days of

initiation

vs warfarin-induced Calciphylaxis

▪ After months or years of treatment

Biopsy:

▪ + subcutaneous thrombosis without

calcification

WARFARIN SKIN NECROSIS

Antiphospholipid

Antibody Syndrome

HITT

Cold-precipitating protein

disease (Cryos)

Peripheral vascular

disease

OTHER THROMBOTIC DISEASE

DIAGNOSIS

In a patient with ESRD presenting with a painful erythematous livedoid skin changes on adipose -rich areas

▪ Diagnosis is Calciphylaxis unless proven otherwise

Skin Biopsy?

▪ Unknown/Low sensitivity and specificity

▪ Limited depth of the specimen,

▪ Biopsy site

▪ Clinical stage at the time of biopsy

▪ Risk of poor wound healing and new lesion formation

PRIMARILY A CLINICAL DIAGNOSIS

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Small-sized arteries

and arterioles:

▪Medial calcification

and intimal fibrosis

HISTOPATHOLOGY OF CALCIPHYLAXIS

Subcutaneous

tissue:

▪Lobular capillary

and arteriolar

▪ Calcification

▪ Thrombosis

HISTOPATHOLOGY OF CALCIPHYLAXIS

Retrospective review of the histopathologic findings in 56

biopsies from confirmed calciphylaxis:

▪ Classic features: only 18% of samples

BIOPSY FOR CALCIPHYLAXIS

Mochel MC et al. Cutaneous

calciphylaxis: a retrospective

histopathologic evaluatioN.

2013

Mochel MC et a l . Cutaneous calc iphylax is: a retrospective

h istopathologic evaluatioN. 2013

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Non-inflammatory thrombosis may be only finding in early calciphylaxis

▪ Present in 66-86% of cases.

▪ Not specific to calciphylaxis

Presence of both subcutaneous capil lary thrombosis & calcificationmore specific

Thrombosis (but not calcification) also seen in Warfarin-induced skin necrosis

HISTOPATHOLOGY PITFALLS

Is biopsy needed?

▪ Lab evaluation may be adequate

▪ More useful in non-uremic

Adequate biopsy

▪ 6-8 mm punch at edge with telescoping 4 mm down to fat

▪ Wedge biopsy of surrounding skin, wound edge and base down to fat

Experienced Dermatopathologist or Pathologist

Von Kossa and Alizarin-red stains for peri-eccrine calcification may increase sensitivity

If biopsy is performed….

Two major goals:

▪Assess for the presence of risk factors

▪Rule out other vasculopathic or vasculitic

disorders

LABORATORY EVALUATION OF SUSPECTED

CALCIPHYLAXIS

Labs:

▪PTT, PT/INR, D-dimer,

Fibrinogen, LDH

▪ANA, ENA, ANCA’s (IF

and ELISA)

▪Antiphospholipid

antibodies

▪ Lupus Anticoagulant

▪ Anti-cardiolipin

▪ Anti-b2-glycoprotein

▪ Anti-phosphatidylserine

Hypercoagulability/Vasculitis workup

Labs:

▪SPEP/UPEP

▪Cryoglobulins&

Cryofibrinogens, RF

▪Protein C&S, anti-

thrombin III, Vitamin K

▪Possibly Factor V

Leiden mutation

▪Possibly Prothrombin

mutation

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BUN/Creatinine

PTH, Vitamin D

Serum Calcium and Phosphorus

▪ Calcium-phosphorus product > 70 mg2 /dL classic

▪ Important to look back at all labs

RENAL FUNCTION/MINERAL

BONE PARAMETERS EVALUATION

TTE or TEE:

▪ Rule out embolic disease

Vascular Studies:▪ ABI

▪ Arterial duplex U/S or CT-A

▪ Rule out “steal syndrome”

Buerger’s disease:

▪ Tobacco use

Paraneoplastic vascular syndromes

STUDIES: ACRAL CALCIPHYLAXIS

Bone Scan

▪ Not currently

recommended

due to unclear

sensitivity

XR

Mammogram

technique

▪ Lack of controls?

ADDITIONAL IMAGING

Halasz CL, Munger DP, Frimmer H,

Dicorato M, Wainwright S. Calciphylaxis: Comparison of radiologic imaging and

histopathology. J Am Acad Dermatol.

2017 Aug;77(2):241-246.e3. doi: 10.1016/j.jaad.2017.01.040. Epub 2017

Mar 9.

TREATMENT

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No randomized controlled trials addressing proposed

interventions

▪ Retrospective cohort studies, case report and series

▪ Expert opinion based on clinical experience and observational

data

Some recommendations may run counter to standard

medical practice and all meds are off -label

▪ Anticoagulants in patient with CKD and ESRD

▪ Bisphosphonates in patients with ESRD

CALCIPHYLAXIS TREATMENT

SUPPORTIVE AND

WOUND CARE

Multidisciplinary care is key:

▪ Derm

▪ Renal

▪ Cardiology/Pulmonary/Hematology

▪ Hepatology

▪ Wound Care

▪ Pain Management/Palliative care

▪ PCP

PROGNOSIS AND PALLIATIVE CARE

Prognosis is grim:

▪ One-year survival rates: 45.8%

▪ Two-year survival rate: 20%

▪ Mortality increased at 1,2,5 years even when when controlling

for HD

Factors related to increased mortality

▪ Proximal (above the knee) disease probably worse

▪ Combination of both distal and proximal disease worst

▪ Penile involvement: mortality rate of 69% within 6 months

PROGNOSIS AND PALLIATIVE CARE

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Early discussion with patients and families:

▪Prognosis

▪Approach to future therapy

▪ Months not weeks

Not uncommon to have patient stop HD 2/2

pain

Referral to Palliative care

PROGNOSIS AND PALLIATIVE CARE

Refer to Pain or Palliative care

Challenging due to decreased renal clearance (Morphine)

Narcotics

▪ Baseline: Fentanyl patch

▪ Breakthrough and Dressing changes: Hydrocodone,

Hydromorphone (not renally cleared)

Other adjunctive:

▪ Gabapentin, Pregabalin

▪ Lidocaine gel

PAIN CONTROL

Recommendations:

▪Avoid trauma and debridement during active ischemic phase

▪ SQ injections

▪Exception: Signs of active infection

▪Follow patient weekly

▪Refer to Wound Care clinic

WOUND CARE AND DEBRIDEMENT

Inactive wound (no signs of ischemia):

▪Gentle debridement of eschar:▪ Hydrocolloid dressings

(Duoderm™)

▪ Medihoney

▪ Q3-5 days

▪Atraumatic debridement methods:▪ Maggot debridement therapy

▪ Water jet irrigation;

▪ Ultrasonic assisted wound treatment (UAW)

WOUND CARE AND DEBRIDEMENT

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Lucilia sericata

Debridement of necrotic tissue,

stimulation of granulation

tissue, antimicrobial effect

Cost effective: $100 for 250

maggots from Monarch labs

Performed at bedside over 48

hours

▪ 2-4 cycles generally needed

MAGGOT DEBRIDEMENT THERAPY

Hyperbaric oxygen

▪ Limited by patient claustrophobia, access to treatment, and

cost

▪ Consider as second-line therapy

WOUND CARE

Nutrition consult

Malnutrition frequently present

▪ Inhibits wound healing

▪ Hypoalbuminemia associated with calciphylaxis

▪ Vitamin K deficiency

Gastric tube or parenteral nutrition.

NUTRITION - CALCIPHYLAXIS

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MEDICAL MANAGEMENT

Currently preferred treatment based on

numerous case reports and case series

▪ Multiple case series with “improvement”

▪ Questionable mortality benefit

▪ 1-year mortality in three studies (pts): 35% (172),

52%(27), 71% (14)

Mechanism: Unknown

▪ Increases solubility of calcium and forms a

dialyzable salt

▪ Vasodilatory and antioxidant properties

▪ ?Decrease in fetuin-CPP particles following

treatment

SODIUM THIOSULFATE (STS)

Cai MM et al Fetuin-A-containing

calciprotein particle levels can be

reduced by dialysis, Nathio and plasma

exchange. Potential therapeutic

implications for calciphylaxis?

Nephrology (Carlton). 2013

Nov;18(11):724-7.

Preferred dosing:

▪12.5-25 g intravenously in 100 mL of

NS during last 30 min of HD BIW - TIW

▪Continued until lesions are healed

Intralesional for isolated disease

▪Possibly effective for limited disease

▪Risk of worsening with

Koebnerization and Trauma?

SODIUM THIOSULFATE

Side effects:

▪ Nausea, headache, hypotension

▪ Premedication

▪ Start lower dose: 12.5 grams

▪ Improvement with subsequent infusions

Rare side effects:

▪ Severe metabolic gap acidosis

Accessibility of treatment:

▪ Obtaining medication and coordination with HD center

▪ Cost: $10,000 per month

SODIUM THIOSULFATES: PITFALLS

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Nephrology optimizes to National Kidney Foundation –

Kidney Disease Outcomes Quality Initiative (NKF -

KDOQ) goals of dialysis adequacy

Intensive HD (i.e. increasing to 5X per week)

▪ Unclear benefit

Peritoneal dialysis:

▪ Higher calciphylaxis risk vs HD?

▪ Not standard practice to transition PD to HD

▪ Avoid intraperitoneal STS (peritonitis and death)

HD MANAGEMENT

Non-calcium phosphorus binders: Sevelamer

Serum PTH: 150-300 ng/mL

▪Cinacalcet: preferred treatment

▪Surgical parathyroidectomy: 2nd line

Avoidance:

▪ Calcium supplements

▪ High dialysate calcium bath

▪ Vitamin D preparations

CKD–Mineral Bone Disease Axis

Abnormalities

Two questions:

1. Is there an indication for full anticoagulation

in all patients with calciphylaxis?

2. Patients presenting with calciphylaxis

already on warfarin for other indications?

ANTICOAGULATION

Thrombosis is a key feature in histopathlogy

of calciphylaxis

Non-uremic calciphylaxis

Systemic hypercoagulable states

▪Likely increases risk for calciphylaxis

ARGUMENTS FOR ANTICOAGULATION IN

ALL PATIENTS?

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Full long-term anticoagulation not currently recommended

in patients without other underlying indication

▪ Lack of safe options other than Warfarin

Alternatives:

▪ Pentoxifylline 400-800 mg po qday

▪ Reduces blood viscosity

▪ Decreases platelet aggregation and inhibits thrombus formation

▪ Anti-inflammatory (anti-TNF) effect

ANTICOAGULATION IN ALL PATIENTS

WITH CALCIPHYLAXIS?

Risk-Benefits:

Discussion with prescribing physician should

focus on the following:

Calciphylaxis has high mortality (yearly) vs CVA

prevention (over 5 years)

Growing awareness among nephrologists

WARFARIN ALTERNATIVES IN PATIENTS

REQUIRING LONG-TERM ANTICOAGULATION

No data whether discontinuation of warfarin

improves outcomes

Evaluate whether full anticoagulation still indicated

▪ Provoked DVT’s (1 year)

▪ Atrial Fibrillation in ESRD (possible lack of benefit)

Tough cases:

▪ Cardiac assist devices

▪ Mechanical heart valves

▪ Antiphospholipid antibody syndrome

WARFARIN ALTERNATIVES IN PATIENTS

REQUIRING LONG-TERM ANTICOAGULATION

Aspirin

New target-specific oral anticoagulants:

▪ Off-label in patients with CKD

▪ Apixiban 5 mg po bid,

▪ 2.5 mg bid: age 80 years or body weight 60 kg

▪ Not approved for mechanical heart valves, cardiac assist

devices, ?APLS

WARFARIN ALTERNATIVES IN PATIENTS

REQUIRING LONG-TERM ANTICOAGULATION

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Inpatient admission for continuous IV heparin

infusion

LMWH with Factor Xa monitoring

Full-intensity unfractionated subcutaneous

heparin

WARFARIN ALTERNATIVES IN PATIENTS

REQUIRING LONG-TERM ANTICOAGULATION

Bisphosphonates:

Pamidronate (30 mg qday x 3, repeated monthly) and Etidronate

Alendronate 10 mg po qday, 70 mg po qweek

2nd line in ESRD - Typically contraindicated in severe renal impairment

Adjunctive 1st line in non-uremic calciphylaxis

Denosumab:

▪ Theoretical benefit through RANKL inhibition

▪ No case reports

OTHER ADJUNCTS

K1: 30 mg per week

▪ Cheaper OTC

K2 (menaquinone-7 [MK-7]): 360-1080 µg TIW

▪ K2 supplementation in patients on chronic HD decreases levels of

uncarboxylated MGP

Safety: ? Thrombosis

▪ No toxic dose exists

▪ High doses have not been shown to increase clotting risk in mouse

studies

OTHER ADJUNCTS: VITAMIN K

Pucaj K, Rasmussen H, Møller M,

Preston T. Safety and toxicological evaluation of a synthetic vitamin K2,

menaquinone-7. Toxicol Mech Methods.

2011 Sep;21(7):520-32.

Reports of both resolution of calciphylaxis and new

onset of calciphylaxis after transplantation

▪ Cytokine release related to surgery

▪ Corticosteroids

Infection & poor wound healing 2/2 corticosteroids

RENAL TRANSPLANTATION

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Patients often discharged with active thrombotic

disease

▪ Goals:

▪ Initiation of STS and other treatments in hospital

▪ Pain control

Patients commonly discharged to LTAC or SNF

▪ Difficulty in obtaining and paying for STS

▪ Choice of LTAC and SNF with experience

COORDINATION OF CARE

SUMMARY

Clinical diagnosis: In a patient with ESRD presenting with

painful erythematous livedoid skin changes on adipose -rich

areas

▪ Diagnosis is Calciphylaxis unless proven otherwise

Acral calciphylaxis dif ficult due to concomitant PVD

If diagnosis is in question, biopsy can be performed after

discussing risks and benefits

▪ Specimen must contain fat

▪ Should be read by experienced Dermatopathologist

Non-uremic Calciphylaxis exists

SUMMARY

Currently favored treatment: Sodium thiosulfate 12 -25 grams biw-tiw

Consider:

▪ Vitamin K supplementation (at least 35 mg per week), or K2 720 micrograms

▪ Bisphosphonate for progressive disease or non -uremic calciphylaxis

▪ Pentoxyfylline 400 mg po tid in non-uremic calciphylaxis

Reevaluate need for Warfarin and other associated medications

▪ Apxiban

▪ Aspirin

Avoid debridement during acute “thrombotic” phase unless visibly infected

SUMMARY

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Do not discharge patient until coordination of outpatient care occurs

▪ End-of-life discussion

▪ Sodium Thiosulfate procurement

▪ Wound care plan

▪ Nutrition

▪ Pain control

Improvement generally takes many months

Disease can recur

▪ Consider life-long Vitamin K supplementation

Multispecialty coordination is critical

SUMMARY

C o a t e s T , K i r k l a n d G S , D y m o c k R B , e t a l . C u t a n e o u s n e c r o s i s f r o m c a l c i f i c u r e m i c a r t e r i o l o p a t h y . A m J K i d n e y D i s . 1 9 9 8 ; 3 2 : 3 8 4 - 9 1 .

M o c h e l M C , A r a k a r i R Y , W a n g G , K r o s h i n s k y D , H o a n g M P . C u t a n e o u s c a l c i p h y l a x i s : a r e t r o s p e c t i v e h i s t o p a t h o l o g i c e v a l u a t i o n . A m J D e r m a t o p a t h o l . 2 0 1 3

J u l ; 3 5 ( 5 ) : 5 8 2 - 5 8 6

Z e m b o w i c z A , N a v a r r o P , W a l t e r s S , L y l e S R , M o s c h e l l a S L , M i l l e r D . S u b c u t a n e o u s t h r o m b o t i c v a s c u l o p a t h y s y n d r o m e : a n o m i n o u s c o n d i t i o n r e m i n i s c e n t

o f c a l c i p h y l a x i s : c a l c i p h y l a x i s s i n e c a l c i f i c a t i o n s ? A m J D e r m a t o p a t h o l . 2 0 1 1 D e c ; 3 3 ( 8 ) : 7 9 6 - 8 0 2 .

H a f n e r J , K e u s c h G , W a h l C , e t a l . U r e m i c s m a l l - a r t e r y d i s e a s e w i t h m e d i a l c a l c i f i c a t i o n a n d i n t i m a l h y p e r p l a s i a ( s o - c a l l e d c a l c i p h y l a x i s ) : a c o m p l i c a t i o n

o f c h r o n i c r e n a l f a i l u r e a n d b e n e f i t f r o m p a r a t h y r o i d e c t o m y . J A m A c a d D e r m a t o l . 1 9 9 5 ; 3 3 : 9 5 4 - 9 6 2 .

R o g e r s N M , T e u b n e r D J O , C o a t e s P T H . C a l c i f i c u r e m i c a r t e r i o l o p a t h y : a d v a n c e s i n p a t h o g e n e s i s a n d t r e a t m e n t . S e m i n D i a l . 2 0 0 7 M a r - A p r ; 2 0 ( 2 ) : 1 5 0 - 7 .

H a n d a S , S t r z e l c z a k D . U r e m i c s m a l l a r t e r y d i s e a s e : c a l c i p h y l a x i s w i t h p e n i s i n v o l v e m e n t . C l i n N e p h r o l . 1 9 9 8 ; 5 0 : 2 5 8 - 2 6 1 .

B a r b e r a V , D i L u l l o L , G o r i n i A , e t a l . P e n i l e c a l c i p h y l a x i s i n e n d s t a g e r e n a l d i s e a s e . C a s e R e p U r o l . 2 0 1 3 ; 2 0 1 3 : 9 6 8 9 1 6 .

K a z a n j i N , F a l a t k o J , N e u p a n e S , e t a l . C a l c i p h y l a x i s p r e s e n t i n g a s d i g i t a l i s c h e m i a . I n t e r n E m e r g M e d . 2 0 1 4 D e c 1 6 . [ E p u b a h e a d o f p r i n t ]

M a c l e a n C , B r a h n E . S y s t e m i c l u p u s e r y t h e m a t o s u s : c a l c i p h y l a x i s i n d u c e d c a r d i o m y o p a t h y . J R h e u m a t o l . 1 9 9 5 ; 2 2 : 1 7 7 - 1 7 9 .

M a t s u o T , T s u k a m o t o Y , T a m u r a M , e t a l . A c u t e r e s p i r a t o r y f a i l u r e d u e t o “ p u l m o n a r y c a l c i p h y l a x i s ” i n a m a i n t e n a n c e h a e m o d i a l y s i s p a t i e n t . N e p h r o n .

2 0 0 1 ; 8 7 : 7 5 - 7 9 .

K l a s s e n - B r o e k e m a N , v a n B i j s t e r v e l d O . A l o c a l c h a l l e n g e r o f o c u l a r c a l c i p h y l a x i s i n p a t i e n t s w i t h c h r o n i c r e n a l f a i l u r e : a h y p o t h e s i s . G r a e f e s A r c h C l i n

E x p O p h t h a l m o l . 1 9 9 5 ; 2 3 3 : 7 1 7 - 7 2 0 .

R o g e r s N M , C o a t e s P T H . C a l c i f i c u r a e m i c a r t e r i o l o p a t h y : a n u p d a t e . C u r r O p i n N e p h r o l H y p e r t e n s . 2 0 0 8 N o v ; 1 7 ( 6 ) : 6 2 9 - 3 4 .

A n g e l i s M , W o n g L L , M y e r s S A , e t a l . C a l c i p h y l a x i s i n p a t i e n t s o n h e m o d i a l y s i s : a p r e v a l e n c e s t u d y . S u r g e r y . 1 9 9 7 D e c ; 1 2 2 ( 6 ) : 1 0 8 3 - 1 0 8 9 , d i s c u s s i o n

1 0 8 9 - 1 0 9 0 .

F i n e A , F o n t a i n e B . C a l c i p h y l a x i s : t h e b e g i n n i n g o f t h e e n d ? P e r i t D i a l I n t . 2 0 0 8 M a y - J u n ; 2 8 ( 3 ) : 2 6 8 - 2 7 0 .

P o l l o c k B , C u n l i f f e W , M e r c h a n t W . C a l c i p h y l a x i s i n t h e a b s e n c e o f r e n a l f a i l u r e . C l i n E x p D e r m a t o l . 2 0 0 0 ; 2 5 : 3 8 9 .

G o y a l S , H u h n K , P r o v o s t T . C a l c i p h y l a x i s i n a p a t i e n t w i t h o u t r e n a l f a i l u r e o r e l e v a t e d p a r a t h y r o i d h o r m o n e : t h e p o s s i b l e a e t i o l o g i c a l r o l e o f

c h e m o t h e r a p y . B r J D e r m a t o l . 2 0 0 0 ; 1 4 3 : 1 0 8 7 .

F i n e A , Z a c h a r i a s J . C a l c i p h y l a x i s i s u s u a l l y n o n u l c e r a t i n g : r i s k f a c t o r s , o u t c o m e a n d t h e r a p y . K i d n e y I n t . 2 0 0 2 ; 6 1 : 2 2 1 0 - 2 2 1 7 .

M a z h a r A R , J o h n s o n R J , G i l l e n D , e t a l . R i s k f a c t o r s a n d m o r t a l i t y a s s o c i a t e d w i t h c a l c i p h y l a x i s i n e n d - s t a g e r e n a l d i s e a s e . K i d n e y I n t . 2 0 0 1 ; 6 0 : 3 2 4 - 3 3 2 .

W e e n i g R , S e w e l l L , D a v i s M , e t a l . C a l c i p h y l a x i s : n a t u r a l h i s t o r y , r i s k f a c t o r a n a l y s i s , a n d o u t c o m e . J A m A c a d D e r m a t o l . 2 0 0 7 ; 5 6 : 5 6 9 - 5 7 9 .

B l e y e r A J , C h o i M , I g w e m e z i e B , e t a l . A c a s e c o n t r o l s t u d y o f p r o x i m a l c a l c i p h y l a x i s . A m J K i d n e y D i s . 1 9 9 8 ; 3 2 : 3 7 6 - 8 3 .

A h m e d S , O ’ N e i l l K D , H o o d A F , e t a l . C a l c i p h y l a x i s i s a s s o c i a t e d w i t h h y p e r p h o s p h a t e m i a a n d i n c r e a s e d o s t e o p o n t i n e x p r e s s i o n b y v a s c u l a r s m o o t h m u s c l e

c e l l s . A m J K i d n e y D i s . 2 0 0 1 ; 3 7 : 2 6 7 - 7 6 .

B r a n d e n b u r g V M , C o z z o l i n o M , K e t t e l e r M . C a l c i p h y l a x i s : a s t i l l u n m e t c h a l l e n g e . J N e p h r o l . 2 0 1 1 M a r - A p r ; 2 4 ( 2 ) : 1 4 2 - 8 .

S e l y e H , G e n t i l e G , P r i o r e s c h i P . C u t a n e o u s m o l t i n d u c e d b y c a l c i p h y l a x i s i n t h e r a t . S c i e n c e . 1 9 6 1 ; 1 3 4 : 1 8 7 6 - 1 8 7 7 .

B l o c k G . C o n t r o l o f s e r u m p h o s p h o r u s : i m p l i c a t i o n s f o r c o r o n a r y a r t e r y c a l c i f i c a t i o n a n d c a l c i f i c u r e m i c a r t e r i o l o p a t h y ( c a l c i p h y l a x i s ) . C u r r O p i n N e p h r o l

H y p e r t e n s . 2 0 0 1 ; 1 0 : 7 4 1 - 7 4 7 .

R e y n o l d s J , J o a n n i d e s A , S k e p p e r J , e t a l . H u m a n v a s c u l a r s m o o t h m u s c l e c e l l s u n d e r g o v e s i c l e - m e d i a t e d c a l c i f i c a t i o n i n r e s p o n s e t o c h a n g e s i n

e x t r a c e l l u l a r c a l c i u m a n d p h o s p h a t e c o n c e n t r a t i o n s : a p o t e n t i a l m e c h a n i s m f o r a c c e l e r a t e d v a s c u l a r c a l c i f i c a t i o n i n E S R D . J A m S o c N e p h r o l . 2 0 0 4 ; 1 5 :

2 8 5 7 - 2 8 6 7 .

S h a n a h a n C M , C r o u t h a m e l M H , K a p u s t i n A , G i a c h e l l i C M . A r t e r i a l c a l c i f i c a t i o n i n c h r o n i c k i d n e y d i s e a s e : k e y r o l e s f o r c a l c i u m a n d p h o s p h a t e . C i r c R e s .

2 0 1 1 ; 1 0 9 ( 6 ) : 6 9 7 - 7 1 1 .

F o n d e r M A , L a z a r u s G S , C o w a n D A , A r o n s o n - C o o k B , K o h l i A R , M a m e l a k A J . T r e a t i n g t h e c h r o n i c w o u n d : a p r a c t i c a l a p p r o a c h t o t h e c a r e o f n o n h e a l i n g

w o u n d s a n d w o u n d c a r e d r e s s i n g s . J A m A c a d D e r m a t o l . 2 0 0 8 ; 5 8 ( 2 ) : 1 8 5 - 2 0 6 .

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A u t o i m m u n R e v . 2 0 0 8 ; 7 ( 8 ) : 6 3 8 - 6 4 3 .

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E s s e x D W , W y n n S S , J i n D K . L a t e - o n s e t w a r f a r i n - i n d u c e d s k i n n e c r o s i s : c a s e r e p o r t a n d r e v i e w o f t h e l i t e r a t u r e . A m J H e m a t o l . 1 9 9 8 ; 5 7 ( 3 ) : 2 3 3 - 2 3 7 .

S h m i d t E , M u r t h y N S , K n u d s e n J M , e t a l . N e t - l i k e p a t t e r n o f c a l c i f i c a t i o n o n p l a i n s o f t - t i s s u e r a d i o g r a p h s i n p a t i e n t s w i t h c a l c i p h y l a x i s . J A m A c a d

D e r m a t o l . 2 0 1 2 ; 6 7 ( 6 ) : 1 2 9 6 - 1 3 0 1

H a n M M , P a n g J , S h i n k a i K , F r a n c B , H a w k i n s R , A p a r i c i C M . C a l c i p h y l a x i s a n d b o n e s c i n t i g r a p h y : c a s e r e p o r t w i t h h i s t o l o g i c a l c o n f i r m a t i o n a n d r e v i e w o f

t h e l i t e r a t u r e . A n n N u c l M e d . 2 0 0 7 ; 2 1 ( 4 ) : 2 3 5 - 2 3 8

S t r a z z u l a L , N i g w e k a r S U , S t e e l e D , e t a l . I n t r a l e s i o n a l s o d i u m t h i o s u l f a t e f o r t h e t r e a t m e n t o f c a l c i p h y l a x i s . J A M A D e r m a t o l . 2 0 1 3 ; 1 4 9 ( 8 ) : 9 4 6 - 9 .

G a r c i a C p , R o s o n E , P e o n G , e t a l . C a l c i p h y l a x i s t r e a t e d w i t h s o d i u m t h i o s u l f a t e : r e p o r t o f t w o c a s e s . D e r m a t o l O n l i n e J . 2 0 1 3 ; 1 9 ( 9 ) : 1 9 6 1 6

S e l k N , R o d b y R A . U n e x p e c t e d l y s e v e r e m e t a b o l i c a c i d o s i s a s s o c i a t e d w i t h s o d i u m t h i o s u l f a t e t h e r a p y i n a p a t i e n t w i t h c a l c i f i c u r e m i c a r t e r i o l o p a t h y .

S e m i n D i a l . 2 0 1 1 ; 2 4 ( 1 ) : 8 5 - 8 8 .

S c h l i e p e r G , B r a n d e n b u r g V , K e t t e l e r M , F l o e g e J . S o d i u m t h i o s u l f a t e i n t h e t r e a t m e n t o f c a l c i f i c u r e m i c a r t e r i o l o p a t h y . N a t R e v N e p h r o l . 2 0 0 9 ; 5 ( 9 ) : 5 3 9 -

5 4 3 .

A l B u g a m i M M , W i l s o n J A , C l a r k e J R , S o r o k a S D . O r a l s o d i u m t h i o s u l f a t e a s m a i n t e n a n c e t h e r a p y f o r c a l c i f i c u r e m i c a r t e r i o l o p a t h y : a c a s e s e r i e s . A m J

N e p h r o l . 2 0 1 3 ; 3 7 ( 2 ) : 1 0 4 - 1 0 9 .

D e r e e J , M a r t i n s J O , m e l b o s t a d H , L o o m i s W H , C o i m b r a R . I n s i g h t s i n t o t h e r e g u l a t i o n o f T N F - a l p h a p r o d u c t i o n i n h u m a n m o n o n u c l e a r c e l l s : t h e e f f e c t s o f

n o n - s p e c i f i c p h o s p h o d i e s t e r a s e i n h i b i t i o n . C l i n i c s ( S a o P a o l o ) . 2 0 0 8 ; 6 3 ( 3 ) : 3 2 1 - 3 2 8

M a r q u e s L J , Z h e n g L , P o u l a k i s N , G u z m a n J , C o s t a b e l U . P e n t o x i f y l l i n e i n h i b i t s T N F - a l p h a p r o d u c t i o n f r o m h u m a n a l v e o l a r m a c r o p h a g e s . A m J R e s p i r C r i t

C a r e M e d . 1 9 9 9 ; 1 5 9 ( 2 ) : 5 0 8 - 5 1 1

W a r d A , C l i s s o l d S P . P e n t o x i f y l l i n e . A r e v i e w o f i t s p h a r m a c o d y n a m i c a n d p h a r m a c o k i n e t i c p r o p e r t i e s , a n d i t s t h e r a p e u t i c e f f i c i e n c y . D r u g s . 1 9 8 7 ; 3 4 ( 1 ) :

5 0 - 9 7 .

F u l l R , D e l m o r e T , C a r t e r C , e t a l . A d j u s t e d s u b c u t a n e o u s h e p a r i n v e r s u s w a r f a r i n s o d i u m i n t h e l o n g - t e r m t r e a t m e n t o f v e n o u s t h r o m b o s i s . N E n g l J M e d .

1 9 9 2 ; 3 0 6 ( 4 ) : 1 8 9 - 1 9 4 .

P a u t a s E , G o u i n I , B e l l o t O , A n d r e u x J P , S i g u r e t V . S a f e t y p r o f i l e o f t i n z a p a r i n a d m i n i s t e r e d o n c e d a i l y a t a s t a n d a r d c u r a t i v e d o s e i n t w o h u n d r e d v e r y

e l d e r l y p a t i e n t s . D r u g S a f . 2 0 0 2 ; 2 5 ( 1 0 ) : 7 2 5 - 7 3 3 .

R o s e n b a u m D P , M a n d e v i l l e W H , P i t r u z z e l l o M , G o l d b e r g D I . E f f e c t s o f R e n a G e l , a n o n - a b s o r b a b l e , c r o s s - l i n k e d , p o l y m e r i c p h o s p h a t e b i n d e r , o n u r i n a r y

p h o s p h o r u s e x c r e t i o n i n r a t s . N e p h r o l D i a l T r a n s p l a n t . 1 9 9 7 ; 1 2 ( 5 ) : 9 6 1 1 - 9 6 4 .

G a r g J P , C h a s a n - T a b e r S , B l a i r A , e t a l . E f f e c t s o f s e v e l a m e r a n d c a l c i u m - b a s e d p h o s p h a t e b i n d e r s o n u r i c a c i d c o n c e n t r a t i o n s i n p a t i e n t s u n d e r g o i n g

h e m o d i a l y s i s : a r a n d o m i z e d c l i n i c a l t r i a l . A r t h r i t i s R h e u m . 2 0 0 5 ; 5 2 ( 1 ) : 2 9 0 - 2 9 5 .

R a m k u m a r N , B e d d h u S , E g g e r s P , P a p p a s L M , C h e u n g A K . P a t i e n t p r e f e r e n c e s f o r i n - c e n t e r i n t e n s e h e m o d i a l y s i s . H e m o d i a l I n t . 2 0 0 5 ; 9 ( 3 ) : 2 8 1 - 2 9 5 .

C a l u w e R , V a n d e c a s t e e l e S , V a n V l e m B , V e r m e e r C , D e V r i e s e A S . V i t a m i n K 2 s u p p l e m e n t a t i o n i n h a e m o d i a l y s i s p a t i e n t s : a r a n d o m i z e d d o s e - f i n d i n g s t u d y .

N e p h r o l D i a l T r a n s p l a n t . 2 0 1 4 ; 2 9 ( 7 ) : 1 3 8 5 - 1 3 9 0 .

K a n e W J , P e t t y P M , S t e r i o f f S , e t a l . T h e u r e m i c g a n g r e n e s y n d r o m e : i m p r o v e d h e a l i n g i n s p o n t a n e o u s l y f o r m i n g w o u n d s f o l l o w i n g s u b t o t a l

p a r a t h y r o i d e c t o m y . P l a s t R e c o n s t r S u r g . 1 9 9 6 S e p ; 9 8 ( 4 ) : 6 7 1 - 8 .

B h a t S , H e d g e S , B e l l o v i c h K , E l - G h o r o u r y M . C o m p l e t e r e s o l u t i o n o f c a l c i p h y l a x i s a f t e r k i d n e y t r a n s p l a n t a t i o n . A m J K i d n e y D i s . 2 0 1 3 ; 6 2 ( 1 ) : 1 3 2 - 4 .

V a n b e l l e g h e m H , T e r r y n W , V a n l e u v e n L , V a n C a e s b r o e c k D , D e m e t t e r P , L a m e i r e N . A d r a m a t i c c a s e o f c a l c i p h y l a x i s 2 0 y e a r s a f t e r k i d n e y t r a n s p l a n t a t i o n .

N e p h r o l D i a l T r a n s p l a n t . 2 0 0 4 ; 1 9 ( 1 2 ) : 3 1 8 3 - 3 1 8 5 .

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e l d e r l y p a t i e n t s w i t h o s t e o p o r o s i s i n d u c e s n o h e m o s t a t i c a c t i v a t i o n , e v e n i n t h o s e w i t h s u s p e c t e d v i t a m i n K d e f i c i e n c y .

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d e n s i t y a n d c o a g u l o f i b r i n o l y s i s f u n c t i o n i n p o s t m e n o p a u s a l w o m e n . M a t u r i t a s . 2 0 0 2 M a r 2 5 ; 4 1 ( 3 ) : 2 1 1 - 2 1 . P u b M e d P M I D :

1 1 8 8 6 7 6 7 .

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S o w e r s K M , H a y d e n M R . C a l c i f i c u r e m i c a r t e r i o l o p a t h y : p a t h o p h y s i o l o g y , r e a c t i v e o x y g e n s p e c i e s , a n d t h e r a p e u t i c a p p r o a c h e s .

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F e n g J Q , X i n g L , Z h a n g J H , X h a o M , H o r n D , C h a n J , e t a l . N F K a p p a B s p e c i f i c a l l y a c t i v a t e s B M P - 2 g e n e e x p r e s s i o n i n g r o w t h

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2 0 0 8 ; 3 ( 1 1 ) : 3 9 - 4 3 .

E d e l s t e i n C L , W i c k h a m M K , K i r b y P A . S y s t e m i c c a l c i p h y l a x i s p r e s e n t i n g a s a p a i n f u l , p r o x i m a l m y o p a t h y . P o s t g r a d M e d J .

1 9 9 2 ; 6 8 ( 7 9 7 ) : 2 0 9 - 2 1 1

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Y e r r a m P , C h a u d h a r y K . C a l c i f i c u r e m i c a r t e r i o l o p a t h y i n e n d s t a g e r e n a l d i s e a s e : p a t h o p h y s i o l o g y a n d m a n a g e m e n t . O c h s n e r J .

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2 4 8 - 2 5 2

R u g g i a n J C , M a e s a k a J K , F i a s h b a n e S . P r o x i m a l c a l c i p h y l a x i s i n f o u r i n s u l i n - r e q u i r i n g d i a b e t i c h e m o d i a l y s i s - p a t i e n t s . A m J

K i d n e y D i s . 1 9 9 6 ; 2 8 ( 3 ) : 4 0 9 - 4 1 4 .

G a l l o w a y P A , E l - D a m a n a w i R , B a r d s l e y V . V i t a m i n K a n t a g o n i s t s p r e d i s p o s e t o c a l c i p h y l a x i s i n p a t i e n t s w i t h e n d - s t a g e r e n a l

d i s e a s e . N e p h r o n . 2 0 1 5 F e b 2 6 [ E p u b a h e a d o f p r i n t ] .

A n J , D e v a n e y B , O o i K Y , F o r d S , F r a w l e y G , M e n a h e m S . H y p e r b a i c o x y g e n i n t h e t r e a t m e n t o f c a l c i p h y l a x i s : a c a s e s e r i e s a n d

l i t e r a t u r e r e v i e w . N e p h r o l o g y ( C a r l t o n ) . 2 0 1 5 ; 2 0 ( 7 ) : 4 4 4 - 4 5 0 .

REFERENCES