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Calcific Uremic Arteriolopathy
‘Calciphylaxis’
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David Shure
Calciphylaxis Syndrome
• ‘Coined by Hans Selye ‘62
• Nephrectomized rat model
1) Systemic Sensitization induced by agents i.e.
PTH, vitamin D, or high Ca, P diet
2) After ‘critical period’, exposure to appropriate
challengers via SC injections of iron salt, egg
albumin, polymyxin, glucocorticoids, causing
local trauma, led to macroscopic visible
deposits of calcium salts systemically and at
site of injection
Calciphylaxis
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Calciphylaxis
• Metastatic systemic
calcifications after
invasive
manipulation of
animal model
• No vascular
calcifications found
CUA
CUA
• Occurs in presence of
uremia
• Abnormalities in
divalent ion ie PTH, Ca,
PO4 (not required)
• Vascular calcifications
at site of lesions
CUA First Described
• Early 1970’s
• Cutaneous eruptions usu in pt’s on HD or after Renal
Tx
• Painful skin lesions with superficial violaceous
nodules on tips of digits, ankles, thighs or buttocks
• Progressed to hemorrhagic eruptions with ischemic
necrosis
• Bilaterally symmetrical, superficial, maintained
persistent distal pulses
• Progressed to necrosis, ischemic severe pain,
gangrene
Pathogenesis Unclear
• Pathogenic Factors
– Uremic milieu + high Ca x P
– Ca content of skin noted to be high in HD pts and
higher when dialysate Ca concentrations of 4.0
meq/L. Lowering dialysate Ca improved CUA in
some pts. Also avoiding ca based po4 binders
– Presence of high PTH levels: PTX effective in
some pts
CUA associated with:
• Most primary renal diseases including
DM
• Occurs rarely in non-renal failure
diseases, ie primary
hyperparathyroidism and alcohol-related
cirrhosis
Necrotic Skin Lesions
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Lesion Evolution
• Primary: calcium salts accumulate in media of
small arteries
– intima is thickened by loose CT
– lumen narrows
• Secondary Lesion
• Infarcts of the subcut tissue and skin comprise the
secondary lesions, responsible for initial clinical
manifestations of the syndrome.
• Before skin ulcerations, tissue ischemia leads to hard
lumpy and/or plaque-like charac to the SC tissue.
Secondary Lesion
• Primary lesion alone not sufficient to
initiate infarction ie, thrombosis or
reduced perfusion contribute
– Thrombi often found in primary lesios
– Preexisting disturbances of coagulation are
relevant to the pathogenesis: protein c/s
and cryofibrinogen
– Also iron dextran suggested to aggravate
or initiate the secondary lesions
Skin Biopsy of the Presented
Pt
HE Stain
• Intimal Constriction
• Vascular
Calcification of small
SC arteries and or
arterioles and
infarctions of
adjacent subcutis
and skin
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Prevalence
• 1-4% of ESRD population
• Increasing prevalence suspected due to incr
use of vit d analogues and calcium based p04
binders, in addition to increased reporting
• Whites > Blacks
• Females > Males 3:1
• Obesity confers risk
• Mortality: 60-80%
– Sepsis from infected/necrotic skin lesions
– Higher mortality in proximal dz than acral dz
Prototype
• Obese Middle Aged Woman on HD
• Tender, lumpy, induration of subcutis over
lower abd wall, upper thighs and leg
• Pedal pulses remain intact
• Serum Ca x P and PTH elevated
• Mottled skin ulcerates, exposing necrotic SC
adipose tissue
• Necrosis progresses and despite intensive
wound care, pt dies of sepsis
Obesity
• Consistent localization of secondary
lesions in body areas of greatest
adiposity
– Women deposit more of their fat in SC than
internal adipose stored
– Bleyer, et al AJKD 1998 identified obesity
and low serum alb as highly predictive of
CUA
– RR of calciphylaxis incr with incr wt
Differential Diagnosis
•
•
•
•
•
•
•
Systemic Vasculitis
Warfarin Necrosis
Lupus Panniculitis
Polyarteritis of SLE
HSP
Pancreatic panniculitis
Weber-Christian Syndrome: panniculitis
sometimes with necrotic ulcers
• Acquired protein C deficiency
Management
• Normalization of Ca x P product with ctrl of
secondary HPT
• Aggressive wound care with debridement of
necrotic tissue and systemic Abx therapy
• PTX performed in select cases, shown not
successful in most pts: Chan et al, Br Jrnl
Derm 47 cases survival rate of pts who
underwent PTX showed same outcomes.
• CUA also described in pts after PTX.
Management Cont:
• HD with low dialysate Ca concentration
no greater than 2.5 meq/L
• Avoid Ca containing po4 binders
• Local injections in adipose areas where
lesions usu develop should be avoided
• Other potential triggers: blood products,
corticosteroids, immunosuppressant
should be avoided
Cutaneous Necrosis from Calcific
Uremic Arteriolopathy
Coates et al; AJKD, 1998
•
•
•
•
16 Cases Reviewed
14 mortalities
13 female, 3 male
All developed painful livedo reticularis lesions
followed by cutaneous necrosis
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Pt Details
• 7 cases experienced significant loss of
body wt > 10% in 6 mths preceding
development of CUA
• Cause of wt loss was in assoc w/failing
renal tx x 2, progressive severe CRF x
2, severe dieting x 1, combo dieting and
diuretics x 1.
Causes of Death
• 14 mortalities
– Sepsis x 6 cases
– Withdrawal form HD x 3 cases
– Cardiac arrest x 3
– GI hemorrhage x 2
Survivors
• Cases 10 and 14
– Both w/ predominantly distal dz, had slow healing
of lesions
– Case 10: developed necrotic ulcers over lower ant
aspect LE after trauma to LE while on warfarin for
DVT
– Rx: bed rest, saline soak dressings, abx,
coumadin converted to LMWH
– Lesions healed over 3 mths and pt followed x 18
months without recurrence
Survivor Case 14
• Bilat lower limb necrosis in Aug 1992 in
assoc secondary hyperparathyroidism
and hypercalcemia
– Rx: total PTX and split skin grafting
– Pt healed and was ulcer free x 4 years
Case 15
• Developed CUA while on warfarin rx for
AF
• Rx: substitution of LMWH for warfarin
assoc with arrest of progression of CUA
• During healing phase of skin lesions, pt
had cardiac arrest
Pathology
• Small Vessel calcification and
endovascular fibrosis
• Panniculitis with vascular calcification
• Fat necrosis and acute inflammation
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Weight Loss as a
Predisposing Factor
• 7/16 cases had mean wt loss 13 kg over
preceding 6 mths
– Rapid wt loss may be assoc w/relative
intravascular volume depletion and a reduction in
tissue perfusion
– Previously heavily calcified vessels may be unable
to relatively vasodilate to increase skin BF and
ischemic areas may develop exacerbated by bed
rest in turn predisposing to pressure ulcers
High Prevalence of Warfarin
Therapy
• 8/14 cases
– Only 2 pts had evidence of PVD , therefore
unlikely that warfarin usage is only a marker of
those pts with PVD
– Fluctuating levels of protein c and s implicated in
pathogenesis of ischemic tissue necrosis lesions
and in addition to warfarin might predispose to
formation of lesions
– May be a risk factor but clear causation not proven
Calciphylaxis Precipitated by UV Light in a Pt
with ESRD Secondary to SLE
James, et al AJKD 1998
• 39 F, ESRD due to SLE, on CAPD, p/w 3wk
hx bilat thigh pain
• Dx in ‘84 w/SLE and APLA after recurrent
DVT and PE, on chronic prednisone,
azathioprine, coumadin
• Developed generalized pruritis refractory to
topical agents, including steroid based
creams. Dermatologist rx: phototherapy
• Developed erythematous, macular rash on
left thigh 2d after 2nd UV rx
Skin Lesion Progression
• Similar rash developed on rt thigh 2d
later, w/assoc burning and
hyperesthesia of both thighs
• Serum calcium 8.4, albumin 3.6
• Po4 5.5, iPTH 119, INR 2.0
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UV light induced CUA
• CUA developed 2d after exposure to UV
photoradiation
• Pt had been taking warfarin for 7 years prior
to skin lesions, therefore not suspected to be
coumadin necrosis
• Cannot r/o role of steroids and cytotoxic
drugs as inciting agents for CUA
• APLA induced ischemic cutaneous necrosis
from recurrent arterial/venous thromboses
show thrombi in small arteries/veins without
medial calcification or intimal thickening did
not support APLA syndrome as the cause
Sodium Thiosulfate Treatment for CUA in
Children and Young Adults
Araya, et al JASN 2006
• IV Sodium Thiosulfate (STS)
– Antioxidant and chelator of cations (e.g. Ca),
initially used as antidote for Cn and cisplatin
toxicity
– AOX properties restore endothelial cell function
and promotes VD
– Enhanced aqueous solubility of Ca thiosulfate
allows for successful mobilization and clearance of
vascular and ST calcium deposits
Methods
• CUA dx histologically and confirmed
w/nuclear medicine bone scan
• STS 25% solution after each HD
session tiwk
• HD performed with high flux dialyzer
Pt’s
• 1: 21 white M, esrd at age of 5 mths due to
bilat multicystic dysplastic kidney dz, now s/p
one living-related and 2 deceased donor
kidney tx. Refractory hyperPTH led to PTX
• 2: 12 y/o white boy, in-utero posterior urethral
valves, progressed to esrd, received tx at age
3, CVC left femoral DVT on coumadin,
developed 2 hyperparathyroidism with levels
129 to 974
• 3: 21 white F with CF bilat lung tx at age 18,
developed calcineurin nephrotoxicity and
CRF. HD at age 20, developed SVC thrombus
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STS
• Leads to enhanced solubility of calcium
deposits in aqueous solution
• Admin of STS in CUA could facilitate the
mobilization of calcium from affected vessels
• Animal data, demonstrate that STS
distributes rapidly throughout the EC space
• In RF VOD doubles and the metabolic
clearance rate decreases drastically
• Believed to be eliminated via biliary secretion
in ESRD pt’s
STS
• First described benefits by Yatzidis in 1985
w/respect to rx 34 pt’s with recurrent
urolithiasis and decreased rate of new stone
development
• In CUA, assoc with reduced pain/
inflammation, improved healing
• Most dramatic reported benefit is in pain
relief, usu noted within first days after
initiation of Rx. It is hypothesized due to AOX
properties of STS, by restoring endothelial
function can enhance NO production,
promoting VD and reducing pain.
Long-Term IV STS in Treatment of a Pt
with Calciphylaxis
Brucculeri, et al 2005 Seminar In Dialysis
• ESRD pt w/severe CUA
• Treated for 34 months
• Found measurable qty of drug more
than 50 hrs after Rx, in addition to a
markedly elevated t1/2 of 478 minutes
MOA
• Suggested: the physical properties of its more
aqueous soluble calcium salt allow it to
dissolve away other relatively insoluble
calcium salts from supersaturated tissues
• When compared to other calcium salts
(sulfate, citrate, phosphate, oxalate),
Ca thiosulfate is 250-100,000 times more
soluble in aqueous solution. Yatzidis, 1984
• Plausible that STS admin may in essence
chelate calcium from the precipitated mineral
that comprises the ST deposits.
• Additionally, STS appears to have AOX
Pharmakokinetics STS