Transcript Calciphylaxis in ESRD

Calciphylaxis:
it’s not anaphylaxis from calcium
Dr. Christopher Caputo
Queens Nassau Nephrology Services, LLPC
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Objectives
S Briefly review renal bone disease as well as the different forms of
calcification that occur in ESRD patients
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Understand the epidemiology and risk factors for calciphylaxis
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Review the clinical, laboratory, histologic and radiographic
manifestations of calciphylaxis
S Review the current best treatment as well as newer, experimental
approaches to calciphylaxis
Case Study
S A 62 year old obese white woman is evaluated for an
extremely tender right thigh lesion. She has a long-standing
history of ESRD from uncontrolled diabetes mellitus
requiring long term hemodialysis. A skin biopsy
demonstrated arteriolar calcification and mural thrombosis
associated with septal panniculitis consistent with a
diagnosis of calciphylaxis
Case Study
S Her laboratory data are as follows: serum PTH 160 pg/mL,
serum calcium 8.1 mg/dL, serum phosphorous 3.9 mg/dL,
serum albumin 3.2 g/dL.
S Which risk factors and treatment strategies should be
considered for further evaluation and management?
Calciphylaxis: Overview
S Rare disease with high morbidity and mortality
S Predominantly affects patients with ESRD treated with
dialysis
S Morbidity is related to severe pain, non healing wounds,
recurrent hospitalizations, adverse effects of treatments
S 1-year mortality is reported at 45-80%
Calciphylaxis: Overview
S Ulcerated lesions associated with higher mortality compared with
non ulcerated lesions
S Sepsis is the leading cause of death
S Mortality rates in long-term hemodialysis patients with
calciphylaxis were almost 3 times higher than for those without in
the US Renal Data System
S Some studies report that the incidence of calciphylaxis is
increasing in the dialysis population
Historical Perspective
4 Types of CV calcification
S Classic calcified atherosclerotic plaque SLOW
S Arterial media calcification (Monckberg’s disease) SLOW
S Cardiac valvular calcifications SLOW
S Calciphylaxis or calcific uremic arteriolopathy FAST
Vascular Calcification
Cardiovascular calcification
S CKD is an independent cardiovascular (CV) risk factor and the
risk of death increases exponentially with the progressive decline
of renal function
S Traditional and non-traditional CV risk factors, including
disorders of mineral and bone metabolism, are suggested to
account for the extreme CV morbidity and mortality rates in CKD
patients
S Intense crosstalk exists between bone and the vasculature that
results in accelerated vascular aging
CKD-MBD represents a synopsis of three closely related disease conditions: laboratory
abnormalities indicative of disturbed bone and mineral metabolism; renal osteodystrophy
summarizing the variety of bone lesion subtypes occurring in CKD; cardiovascular disease
representing accelerated arteriosclerosis, left ventricular hypertrophy and a variety of
additional pathologies in the vasculature and the heart in patients with CKD.
Mario Cozzolino et al. Nephrol. Dial. Transplant.
2014;ndt.gft514
© The Author 2014. Published by Oxford University Press onbehalf of ERA-EDTA. All rights
reserved.
(A) Aortic valve with massive macroscopically detectable calcification, explanted due to
calcific aortic stenosis, from a dialysis patient.
Jordi Bover et al. Nephrol. Dial. Transplant. 2015;30:345351
© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved.
Pathogenesis of CUA:
Super accelerated vascular calcification
S Poorly understood but likely the result of the same process
that leads to vascular and soft-tissue calcification in ESRD
S Reduction in arteriolar blood flow is a consequence of
intimal fibrosis associated with massive mural calcifications
of the dermo-hypodermic arterioles, and thrombus
formation within the venules
S Frank tissue infarction is end result
Pathogenesis of CUA:
PTH to blame?
S Historically, HPT, active vitamin D administration,
hyperphosphatemia and elevated Ca x PO4 product were
implicated in the genesis of CUA
S A role for PTH is supported by the reported clinical
improvement following parathyroidectomy, but…
S Most patients with severe HPT do not have skin necrosis
and many patients with CUA do not have HPT
Pathogenesis of CUA:
Vitamin D to blame?
S Vitamin D administration (at high doses) can also induce
CUA in experimental models, perhaps via actions to
increase serum PO4, or directly, through their effect on
vasculature
S Whether excessive doses of active vitamin D analogs are
associated with an increased incidence of CUA in ESRD is
unclear
Pathogenesis of CUA:
imbalance between promoters and inhibitors of calcification
Figure 3 Factors that affect vascular calcification
Reprinted from Osteoporosis, 4th edition, Ott, S. M. & Elder, G. Osteoporosis associated with
chronic kidney disease. 1387–1424 © (2013) with permission from Elsevier
Ott, S. M. (2013) Therapy for patients with CKD and low bone mineral density
Nat. Rev. Nephrol. doi:10.1038/nrneph.2013.182
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Risk Factors for Calciphylaxis
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Obesity
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Liver disease
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Previous calcium/vitamin D
therapy including calcitriol
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Female sex
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High alkaline phosphatase
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Not using statins
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High serum calcium levels
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Longer dialysis vintage?
Systemic corticosteroid use
Low albumin levels
Warfarin use
High serum phosphorous
Risk factors: demographics
S Most commonly reported in 5th decade of life
S More commonly seen in women compared with men, with
a 2:1 female predominance
S More common in whites compared with nonwhites
Risk factors: comorbid
conditions
S Diabetes: no date re: control/duration affects risk
S Obesity: risk factor for proximal calciphylaxis
S Autoimmune conditions (SLE, APL, TA, RA):
corticosteroids, methotrexate, UV light have been implicated
as potential triggers for calciphylaxis
S Hypercoaguable conditions
Risk factors: comorbid
conditions
S Hepatitis (of any kind): mediated by inflammation or
protein C/S deficiency
S Longer dialysis vintage of more than 6-7 years
S Peritoneal dialysis may confer higher calciphylaxis risk
when compared to hemodialysis
S Hypoalbuminemia
Risk factors: hypoalbuminemia
S Inflammation down regulates a powerful calcification
inhibitor, i.e. fetuin-A
S Malnutrition in general may indicate additional non
measured deficiencies in other nutrients, i.e. vitamin K, or
other non-identified protective factors
Risk factors: medications
S Calcium supplements
S Calcium based phosphate binders
S Active Vitamin D
S Warfarin
S Corticosteroids
S Iron therapy
S Trauma from SC insulin or heparin injections
Risk factors: CKD-MBD
S Calciphylaxis has traditionally been considered as a
manifestation of severely dysregulated Ca x PO4
metabolism in dialysis patients
S However, although MBD abnormalities are highly
prevalent, calciphylaxis is a rare disease
Risk factors:
hyperparathyroidism
S Insignificantly higher PTH levels in CUA patients versus
controls (310 vs. 246 pg/mL)
S 67% dialysis patients with CUA had PTH < 300 pg/mL.
Half of these were < 150 pg/mL
S Therefore, additional lowering of PTH in CUA patients may
not be the primary treatment target of choice
Risk factors:
Vitamin D
S Historical experience suggests that large doses of calcitriol
or other active vitamin D compounds can accelerate
vascular calcification
S However, there are no large RCTS that have investigated the
effects of active vitamin D derivatives on calcification
progress
Vitamin K Antagonists:
the straw that breaks the camel’s back?
S VKA interferes with the posttranslational activation of matrix-
G1a protein (MGP)
S MGP is a potent inhibitor of vascular calcification
S An absence of MGP causes premature death in rodents owing to
fracture-like lesions in the aorta
S CUA may be a severe adverse event resulting from VKA treatment
S Unique therapeutic options then include stopping VKA and
vitamin K replenishment
Calciphylaxis:
Signs & Symptoms
S Excruciatingly painful ischemic necrosis in areas of greatest
adiposity, including abdomen, buttock and thigh
S Livedo reticularis -> violaceous, plaque-like subcutaneous
nodules -> ischemic/necrotic ulcers -> eschars
(superinfection)
S Ischemic myopathy (painful proximal muscle weakness)
S Peripheral pulses often are intact!
Calciphylaxis:
Signs & Symptoms
S Patients have been reported to have vascular calcifications in
skeletal muscle, brain, lungs, intestines, eyes and mesentery
S CUA can be considered as a continuum of a systemic
process leading to arterial calcifications in many vascular
beds
Calciphylaxis: dermatologic
findings
Calciphylaxis: dermatologic
findings
Calciphylaxis: dermatologic
findings
Diagnostic tests: skin biopsy
S Definitive diagnosis requires a skin biopsy and should be
considered whenever the calciphylaxis diagnosis is entertained
S Discussion of risks and benefits is essential
S Punch biopsy of 4-5 mm depth from the lesion margin or deep
incisional wedge skin biopsy is likely to have the best yield
S In the hands of an experienced dermatologist or surgeon, the
potential yield can be maximized
Skin Biopsy
Risks
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Ulceration
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Superimposed infection
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Propagation of new lesions
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Bleeding
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Induction of necrosis
Benefits
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Exclusion of other conditions
that can mimic calciphylaxis
Histopathology of calciphylaxis
Diagnosis: laboratory
evaluation
S There are NO specific lab findings!
S In some patients, elevated levels of PTH, PO4, calcium and
calcium-PO4 product may be observed
Diagnosis: laboratory
evaluation
S Liver evaluation: transaminases, alkaline phosphatase, albumin
S Infection evaluation: CBC, blood cultures
S Coagulation evaluation: PT/INR, PTT, protein C, protein S,
antithrombin III, antiphospholipid antibody
S Inflammation evaluation: C-reactive protein & albumin
S Evaluate for auto immune disease and malignancy as guided by
clinical suspicion
Radiologic diagnosis:
Bone Scan
Radiologic diagnosis:
Plain film
Radiologic diagnosis:
CT scan
Radiologic diagnosis:
Mammography
Treatment of Calciphylaxis
S Multidisciplinary and multiinterventional approach
involving input from the following disciplines is important:
nephrology, dermatology, dermatopathology, wound or
burn center, nutrition, and pain management
S Input should be obtained as soon as the diagnosis of
calciphylaxis is suspected to formulate a comprehensive and
consistent management plan
Summary of Treatment
Approach
S Wound management
S Pain management
S Sodium thiosulfate
S Management of mineral bone disease
S Dialysis prescription
S Nutrition management
S Management of other risk factors
Wound Management
S Selection of dressings, chemical debriding agents, frequency of
dressing changes, and negative pressure wound therapy
S Surgical wound debridement should be considered on a case-by-
case basis. One retrospective analysis shows improved survival
with debridement at one year (62 versus 27%)
S Hyperbaric oxygen therapy can be considered as a second-line
treatment if wounds not improving
S Antibiotic administration should be guided by clinical
appearances of lesions and accompanying systemic features
Hyperbaric Oxygen
S Series # 1: resolution of lesions in 8 of 9 CUA patients
treated with HBO for 90 minutes at 2.5 atm with a mean of
41 sessions
S Series # 2: complete healing of extensive necrotic ulcers in
2 of 5 patients treated with 25-35 90-minute sessions at 2.5
atm
S It is costly with potential side effects, not readily available,
requires transportation and presents logistical issues
Pain Management
S Often narcotic analgesics are required to control severe pain
associated with calciphylaxis
S Morphine, codeine and hydrocodone should be avoided in
dialysis patients due to accumulation of neurotoxic
metabolites
S Oxycodone, hydromorphone and fentanyl can be used in
ESRD patients but require close monitoring
Management of MBD
S Serum calcium and phosphorous levels should be maintained in
the normal range and serum PTH should be maintained 150-300
pg/mL
S Calcium supplements, high dialysis calcium bath, vitamin D
preparations should be avoided and instead cinacalcet to be
considered to treat HPT. Excessive suppression of PTH should be
avoided.
S Surgical parathyroidectomy is indicated in patients with refractory
hyperparathyroidism
Calcium & Phosphate Balance
S Dialysate calcium concentrations of 2.5 meq/L are usually
associated with near neutral balance. There is no evidence
that going lower will improve outcomes, but 2.0 meq/L has
been suggested by some experts
S There is consistent evidence that calcium containing
phosphate binders should be avoided in patients with
reasonable life expectancy
Sevelamer Versus CaCO3 in Incident Hemodialysis Patients:
Results of an Open-Label 24-Month Randomized Clinical Trial
Other management options
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Dialysis prescription should be
optimized to achieve NKFKDOQI goals
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Malnutrition is frequently present
in calciphylaxis patients.
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If patients are not able to
improve dietary intake, consider
gastric tube or parenteral
nutrition
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Discontinuing warfarin should be
strongly considered
Intensifying dialysis by
increasing duration or frequency
has been described, but not
validated
Transitioning from PD to HD
can be considered
Sodium
Thiosulfate
Reducing agent that forms
water-soluble complexes with
many metals
Its use in calciphylaxis was first
reported in 2004 in a case
report
There are NO prospective trial
data for this agent
Sodium Thiosulfate
S Dose: Intravenous sodium thiosulfate at doses ranging from
12.5-25 grams in the last 30 minutes of each hemodialysis
session. Lower dose should be used in patients weighing
less than 60 kg or getting more frequent hemodialysis than
thrice weekly
S Adverse Effects: Nausea, metabolic acidosis, hypotension,
and volume overload are potential adverse effects
Sodium Thiosulfate
S Calciphylaxis improves in > 70% of patients
S Improvement in pain within 1-2 weeks after initiation of sodium
thiosulfate is an important predictor of long-term response
S Dose should be adjusted for patients who weigh < 60 kg
S Intraperitoneal administration should be avoided due to risks of
chemical peritonitis
S Intralesional sodium thiosulfate has been described to aid in the
resolution of calciphylaxis lesions
EVOLVE Trial: Cinacalcet
S 3,883 patients with sHPT receiving HD were randomly assigned 1:1
to receive cinacalcet or placebo in addition to conventional therapy
for CKD-MBD
S Eligible participants had PTH > 300 pg/mL, calcium > 8.4 and Ca x
PO4 > 45
S The primary composite endpoints were all-cause mortality and major
cardiovascular events (MI, unstable angina, CHF or peripheral
vascular event)
S All adverse events, including CUA, were collected while patients were
receiving study drug
EVOLVE Trial: Cinacalcet
S Among the 3,861 trial participants who received at least one
dose of study drug, 24 patients developed CUA: 18 patients
randomly assigned to placebo and six patients assigned to
cinacalcet (unadjusted relative hazard, 0.31 and adjusted
relative hazard, 0.25)
S Thus, EVOLVE is the first randomized controlled trial to
show a reduced risk of CUA, by 69-75%
Cumulative incidence plot of time to calcific uremic arteriolopathy adverse event (safety
analysis set).
Jürgen Floege et al. CJASN 2015;10:800-807
©2015 by American Society of Nephrology
VitaVasK Trial
S Hemodialysis patients will be given 5 mg of Vitamin K1
thrice weekly while calcification progress is monitored over
18 months
S Hypothesis: Vitamin K supplementation will maximize the
activation of important endogenous inhibitors of vascular
calcification such as matrix G1a protein (MGP) which will
in turn slow down the rate of vascular calcification and
decrease the incidence of calciphylaxis
Successful treatment of a patient with severe CUA by
etidronate disodium
Am J Kidney Dis 2006 July;48(1):151-4
S 59 year old woman with a 10-year history of hemodialysis was
admitted with painful skin ulcers on her right thigh, right calf and
left upper arm. Skin biopsy showed CUA
S Despite antibiotics, aggressive wound care for 2 months, the skin
ulcers enlarged and her general condition worsened
S Oral administration of etidronate 200 mg/day strikingly improved
the focal infection and decreased the size of the skin ulcers within
several days. In 2 months time, epithelialization of the ulcers was
almost complete
Successful treatment of CUA with bisphosphonates
Nefrologia 2012 May 14;32(3): 329-34
S The series consisted of 8 patients (including 4 men, 5 HD patients,
3 with functioning allografts) who were treated with IV
ibandronate for at least 6 months
S In ALL patients progression of skin lesions stopped between 2-4
weeks after starting therapy, with no changes in blood levels of Ca
or PO4
S No recurrences have been observed after follow-up periods
between 1 and 9 years. Treatment was well tolerated and no
adverse effects were observed
Case Study - Outcome
S The patient described at the beginning of this lecture
underwent systematic assessment for calciphylaxis risk
factors. These included female sex, diabetes mellitus, long
dialysis vintage, and low serum albumin. She underwent
aggressive wound care, pain management, treatment with
IV sodium thiosulfate, and optimization of nutrition status.
She had initial improvement in lesions over the first 3
months, but subsequently developed new ulcerated
calciphylaxis lesions and died of septic shock.
Summary
S Calciphylaxis is a rare, devestating arteriolopathy most
commonly observed in ESRD patients, that results in frank
tissue infarction and non-healing wounds with a very high
morbidity and mortality. Incidence is likely increasing.
S Pathogenesis is poorly understood, but most likely due to
abnormalities of MBD as well as an imbalance between
calcification promoters & inhibitors. Warfarin is an
important trigger.
Summary
S Clinical signs include livedo reticularis and/or violaceous,
painful, plaque-like SC nodules, which progress to necrotic
ulcers that often become superinfected
S Diagnosis is suggested by characteristic lesions and their
distribution. Skin biopsy is generally recommended to rule
out other causes such as vasculitis. Bones scans and plain
radiography/mammography may aid in diagnosis
Summary
S Optimal therapy is multi factorial and includes wound care,
pain control, control of MBD without calcium containing
binders, cinacalcet (rather than vitamin D analogs), possibly
parathyroidectomy, IV sodium thiosulfate, low calcium bath
and discontinuation of warfarin if feasible. Hyperbaric
oxygen can also be instituted if no response to above.
S Newer treatments need more investigation and include
bisphosphonates and vitamin K repletion