Tuesday Clinical Case Conference
9/11/07
Zae Kim
Atheroembolic disease
(Cholesterol Crystal Embolism)
• Epidemiology
• Clinical and pathologic
findings
• Diagnosis
• Pathogenesis
• Treatment
Atheroembolic Renal Disease (AERD)
• An underdiagnosed and increasing cause of
renal failure
• Caused by showers of cholesterol crystals from
an atherosclerotic aorta that occlude small
renal arteries
• Often multisystemic
• Iatrogenic complication
• Treatment?
Epidemiology
retrospective autopsy study
antemortem biopsy study
Incidence:
retrospective autopsy studies
Reference
Incidence (%)
Population Under Study
Kealy
1
Unselected series (n = 2,126)
Cross
2.4
Unselected series (n = 372)
Moolenar and Lamers
0.31
Unselected series (n = 89,075)
Flory
12.3
Severe aortic atherosclerosis (n = 57)
1
Moderate aortic atherosclerosis (n = 147)
0
No aortic atherosclerosis (n = 63)
77
Aortic surgery (n = 22)
31
Nonoperated aneurysm (n = 42)
15.8
Severe atherosclerosis (n = 38)
0
Minimal atherosclerosis (n = 44)
Gore and Collins
17.6
Subjects >60 y (n = 34)
Ramirez et al
27
Cardiac catheterization (n = 71)
Autopsy studies
Thurlbeck and Castleman
Incidence:
antemortem biopsy studies
Incidence:
Reference
Incidence (%)
Population Under Study
Drost et al
0.15
Cardiac catheterization (n = 4,578)
Colt et al
0.18
Cardiac catheterization (n = 3,733)
Johnson et al
0.06
Coronary angioplasty (n = 1,579)
Frock et al
0.1
Angiography (n = 14,998)
Angiographic studies
Risk factors
Risk factors
PARAMETER
Publication year
BELENFANT THADHANI
1998
1995
VIDT
1989
FINE
1987
Demographics
Number of patients
67
52
24
221
Mean age (range, yr)
69 ± 8
69 ± 7
62 (45–75)
66 (26–90)
Male (%)
White rate (%)
96
100[b]
75
100
80
?
77
94
Risk factors
PARAMETER
BELENFANT THADHANI
VIDT
FINE
Clinical Characteristics
Cigarette smoking history (%)
79
90
92
?
Hypertension (%)
91
81
100
61
Baseline mean serum creatinine
(mg/dL)
2.0 ± 0.9
1.67 ± 0.59 2.0 (1.0–6.5)
?
Baseline medical problems (%)
Hypercholesterolemia
?
49
29
?
Diabetes mellitus
?
33
8.3
?
Coronary artery disease
54
73
67
44
Peripheral vascular disease
57
69
75
?
Cerebrovascular disease
32
46
62
?
Abdominal aortic aneurysm
67
48
29
25
Risk factors
PARAMETER
BELENFANT THADHANI
VIDT
FINE
Precipitating factors (%)
Angiography
85
96
?
18
Vascular surgery
36
8
?
9
Anticoagulation or thrombolytics
76
37
?
14
Risk factors
•
•
•
•
•
•
•
Age >60
Male gender
White
HTN
Tobacco use
DM
Atherosclerosis
– CAD
– AAA
– PVD
Clinical and laboratory presentation
Clinical Features
• Atheroembolic renal
disease is part of a
multisystem
• Renal
– ~50% patients affected
• Multiple presentation
– Acute
– Subacute
– Chronic
Clinical Presentation
Fine et al
Lye et al
Thadhani
et al
Belenfant
et al
Scolari et
al
No. of patients
221
129
52
67
52
Skin lesions (%)
35
43
50
90
96
GI involvement (%)
10
10
29
33
8
CNS involvement (%)
--
12
23
4
8
Retinal emboli (%)
6
10
25
22
8
Eosinophilia (%)
73
71
22
59
62
Clinical and Laboratory Presentation
Fine et al
Lye et al
Thadhani
et al
Belenfant
et al
Scolari et
al
No. of patients
221
129
52
67
52
Skin lesions (%)
35
43
50
90
96
GI involvement (%)
10
10
29
33
8
CNS involvement (%)
--
12
23
4
8
Retinal emboli (%)
6
10
25
22
8
Eosinophilia (%)
73
71
22
59
62
GI
Gastric mucosal and
submucosal biopsy
-cholesterol crystals
in the submucosal
arterioles
Clinical and Laboratory Presentation
Fine et al
Lye et al
Thadhani
et al
Belenfant
et al
Scolari et
al
No. of patients
221
129
52
67
52
Skin lesions (%)
35
43
50
90
96
GI involvement (%)
10
10
29
33
8
CNS involvement (%)
--
12
23
4
8
Retinal emboli (%)
6
10
25
22
8
Eosinophilia (%)
73
71
22
59
62
Cholesterol crystals lodged in the retinal vessels (Hollenhorst plaques) on
funduscopic examination.
outcome
outcome
Thadhani Belenfant Scolari et
et al
et al
al
Fine et al
Lye et al
221
129
52
67
52
CRF requiring dialysis
(%)
28
40
44
61
35
Recovery from dialysis
dependence (%)
--
21
26
32
27
1-Year mortality rate (%)
81
64
87
23
31
No. of patients
Outcome
Survival rate (Kaplan Meier) of 67 patients with
disseminated CCE
Laboratory Features
• Variable and NONE ARE PATHOGNOMIC
• Serum chemistry
– Elevated BUN, creatinine
– amylase, CPK, LFTs
• Hematology
– leukocytosis, thrombocytopenia, and eosinophilia
– Elevated ESR, CRP
• Serologic
– Elevated ESR
– Decreased serum complement
• Urine (abnormal but nonspecific)
– proteinuria, hematuria, eosinophilia
Pathogenesis
• Flory (1945)
– 267 consecutive autopsies
• 9 cases of cholesterol crystal
embolism
– 2/147 (1%) with moderate aortic plaque
erosion
– 7/57 (12%) with severe aortic plaque
erosion
• 0 in 63 cases with absence of aortic
plaque ulceration
http://www.mdconsult.com/das/book/body/776383344/620123283/1201/I4-u1.0-B0-7216-0164-2..50036-7-f10.fig?tocnode=50835407
Atheroma
• How vulnerable
plaque is formed…
•
•
•
•
•
Fat droplet absorption
Cytokine release
Inflammation
Monocyte->macrophage
Further fat collection
• The fat-filled cells
form a plaque with a
thin covering.
http://heart.health.ivillage.com/cholesterol/hearta
ttack3.cfm
Pathology
• CCE lodge in multiple small arteries (150-200
μm in diameter)
– Interlobular, afferent arterioles, terminal arterioles,
and glomerular capillaries
Thin section, toluidine blue
stain shows the characteristic
cholesterol clefts (due to
washout of the cholesterol
crystals during histologic
processing) of an
atheroembolus in the small
renal artery
Histologic features
• In acute lesion
• Occlusion of lumen of small
vessel
• Inflammatory response: PMN
leukocytes and eosinophils
• Later stage
• Foreign-body giant cells
• Endothelial proliferation
• Fibrous tissue surrounding the
crystals
Diagnosis
• “great masquerader”
– CCE is ubiquitous with random and variable
distributions in the body
– Mimic many other clinical syndromes
• Ddx
• Vasculitis
• Subacute endocarditis
• Polymyositis
• Myoglobinuric renal failure
• Drug-induced interstitial nephritis
• Renal artery thrombosis or thromboembolism
Definitive diagnosis - biopsy
• Biopsy
– Characteristic needle-shaped empty clefts within
arterioles
• “ghost cells” because crystals are dissolved during tissue
fixation
– Muscle, kidney, or skin
• Cutaneous biopsy with 92% yield
Treatment
• No effective treatment available
• Secondary Prevention
– Avoid precipitating factors
– aggressive risk factor modification, and
– optimal medical mgmt of CVD
• smoking cessation, anti-platelet tx, and bp control,
cholesterol and glucose
– Statin – uncertain?
– Steroid?
• Surgical – with clear embolic source
What is the implication of
eosinophilia/-uria and
hypocomplementemia?
Eosinophilia
N
Eosinophilia
Kasinath, 1987
80
57 (71%)
Scloari, 1996
13
10 (77%)
Eosinophiluria
N
Eosinophiluria
Wilson, 1991
9
8 (88%)
Thadhin, 1995
37
5 (14%)
Thadhin, 1995
37
5 (14%)
Hypocomplementemia
• Complement and inflammatory response may
play a role in pathogenesis of AERD.
– Hammerschmidt (J lab Clin med 1981)…
Generation of PMN-aggregating
activity in plasma incubated with
lipids extracted from
atheromatous aortas
Aggregating activity of PMN
Role of steroid?
• Use of corticosteroid was associated with 100%
mortality (Fine, Agiology, 1987)
• Belenfant’s experience (1999)
–
–
–
–
N=18
Patients with laboratory evidence of inflammation
Corticosteroid treatment using prednisolone 0.3mg/kg
Outcome:
• Therapy credited with the relief of lower limb and/or
gastrointestinal pain and definite improvement in food intake and
clinical status
conclusion
• Under-recognized cause of kidney failure
– Think about it before precipitating risk
– Think about it in your differential
– Look for it
Belenfant: Supportive treatment improves survival in
multivisceral cholesterol crystal embolism. Am J Kidney
Dis 1999, 33:840-850.
• Highlighted the potential benefits of avoiding
further precipitating insults in conjunction with
optmal medical management
Belenfant
• Larges series to date, n=67, w catastrophic
atheroembolism
• Prospective with f/u to 4 yrs
• N=2102 admit to renal intensive care unit over
11-yr period
• Dx
– Based on clinical and histologic findings
– Excluded patients with other causes of acute or
acute on chronic renal impairment (also excluded
CIN or perioperative associated renal failure)
The end