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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 .
REFERENCES
H a y a s h i M , T a k a m a t s u I , K a n n o Y , e t a l . A c a s e - c o n t r o l s t u d y o f c a l c i p h y l a x i s i n J a p a n e s e e n d - s t a g e r e n a l d i s e a s e p a t i e n t s . N e p h r o l D i a l T r a n s p l a n t .
2 0 1 2 ; 2 7 ( 4 ) : 1 5 8 0 - 1 5 8 4 .
P r i c e P A , F a u s S A , W i l l i a m s o n M K . W a r f a r i n c a u s e s r a p i d c a l c i f i c a t i o n o f t h e e l a s t i c l a m e l l a e i n r a t a r t e r i e s a n d h e a r t v a l v e s . A r t e r i o s c l e r T h r o m b V a s c
B i o l . 1 9 9 8 ; 1 8 ( 9 ) : 1 4 0 0 - 1 4 0 7
F u s a r o M , N o a l e M , V i l a V , e t a l . V i t a m i n K , v e r t e b r a l f r a c t u r e s , v a s c u l a r c a l c i f i c a t i o n s , a n d m o r t a l i t y : V i t a m i n K I t a l i a n ( V I K I ) d i a l y s i s s t u d y . J B o n e M i n e r
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L e e J L , N a g u w a S M , C h e e m a G , G e r s h w i n M E . R e c o g n i z i n g 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 a u t o i m m u n e d i s e a s e : a n e m e r g i n g m i m i c k e r o f v a s c u l i t i s .
A u t o i m m u n R e v . 2 0 0 8 ; 7 ( 8 ) : 6 3 8 - 6 4 3 .
N a z a r i a n R M , V a n C o t t E M , Z e m b o w i c z A , D u n c a n L M . 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 . J A m A c a d D e r m a t o l . 2 0 0 9 ; 6 1 ( 2 ) : 3 2 5 - 3 3 2 .
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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T i t t e l b a c h J , G r a e f e T , W o l l i n a U . P a i n f u l u l c e r s i n c a l c i p h y l a x i s – c o m b i n e d t r e a t m e n t w i t h m a g g o t t h e r a p y a n d o r a l
p e n t o x y f i l l i n . J D e r m a t o l o g T r e a t . 2 0 0 1 ; 1 2 ( 4 ) : 2 1 1 - 2 1 4 .
A k a i A , O k a m o t o H , S h i g e m a t s u K , M i y a t a T , W a t a n a b e T . R e v a s c u l a r i z a t i o n s u r g e r y f o r p e n i l e c a l c i p h y l a x i s . J V a s c S u r g .
2 0 1 3 ; 5 8 ( 6 ) : 1 6 6 5 - 1 6 6 7 .
F r i e d m a n S G . L e g r e v a s c u l a r i z a t i o n 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 . A m S u r g . 2 0 0 2 ; 6 8 ( 7 ) : 5 9 1 - 5 9 2 .
L a i G , N o w e l l A G , L i a o J , S u g g S L , W e i g e l R J , H o w e J R . D e t e r m i n a n t s o f s u r v i v a l 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 : a m u l t i v a r i a t e
a n a l y s i s . S u r g e r y . 2 0 0 9 ; 1 4 6 ( 6 ) : 1 0 2 8 - 1 0 3 4 .
S c h m i d P , F i s c h e r A G , W u i l l e m i n W A . L o w - m o l e c u l a r - w e i g h t h e p a r i n i n p a t i e n t s w i t h r e n a l i n s u f f i c i e n c y . S w i s s M e d W k l y .
2 0 0 9 ; 1 3 9 ( 3 1 - 3 2 ) : 4 3 8 - 4 5 2 .
A s a k u r a H , M y o u S , O n t a c h i Y , M i z u t a n i T , K a t o M , S a i t o M , M o r i s h i t a E , Y a m a z a k i M , N a k a o S . V i t a m i n K a d m i n i s t r a t i o n t o
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 .
O s t e o p o r o s I n t . 2 0 0 1 D e c ; 1 2 ( 1 2 ) : 9 9 6 - 1 0 0 0 . P u b M e d P M I D : 1 1 8 4 6 3 3 4 .
U s h i r o y a m a T , I k e d a A , U e k i M . E f f e c t o f c o n t i n u o u s c o m b i n e d t h e r a p y w i t h v i t a m i n K ( 2 ) a n d v i t a m i n D ( 3 ) o n b o n e m i n e r a l
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 .
M o e S M , C h e n N X . M e c h a n i s m s o f v a s c u l a r 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 . J A m S o c N e p h r o l . 2 0 0 8 ; 2 3 : 2 1 3 - 2 1 6 .
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 .
O x i d M e d C e l l L o n g e v . 2 0 1 0 ; 3 ( 2 ) : 1 0 9 - 1 2 1 .
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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
K a t s a m a k i s G , L u k o v i t s T G , G o r e l i c k P B . C a l c i f i c c e r e b r a l e m b o l i s m i n s y s t e m i c c a l c i p h y l a x i s . N e u r o l o g y . 1 9 9 8 ; 5 1 ( 1 ) : 2 9 5 - 2 9 7 .
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 .
2 0 1 4 ; 1 4 ( 3 ) : 3 8 0 - 3 8 5 .
Z a c h a r i a s J M , F o n t a i n e B , F i n e . C a l c i u m u s e i n c r e a s e s r i s k o f c a l c i p h y l a x i s : a c a s e - c o n t r o l s t u d y . P e r i t D i a l I n t . 1 9 9 9 ; 1 9 ( 3 ) :
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 .
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