Tuesday Clinical Case Conference

9/11/07Zae 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?

Epidemiologyretrospective autopsy studyantemortem biopsy study

Incidence:retrospective autopsy studies

Reference Incidence (%) Population Under Study

Autopsy studies

Kealy 1 Unselected series (n = 2,126)

Cross 2.4 Unselected series (n = 372)

Moolenar and Lamers 0.31 Unselected series (n = 89,075)

12.3 Severe aortic atherosclerosis (n = 57)

1 Moderate aortic atherosclerosis (n = 147)

Flory

0 No aortic atherosclerosis (n = 63)

77 Aortic surgery (n = 22)

31 Nonoperated aneurysm (n = 42)

15.8 Severe atherosclerosis (n = 38)

Thurlbeck and Castleman

0 Minimal atherosclerosis (n = 44)

Gore and Collins 17.6 Subjects >60 y (n = 34)

Ramirez et al 27 Cardiac catheterization (n = 71)

Incidence: antemortem biopsy studies

Reference Incidence (%) Population Under Study

Kidney biopsy studies

Jones and Iannacone 1 Consecutive biopsies (n = 755)

Lie 1 Consecutive biopsies (n = 4,580)

Preston et al 3.4 Subjects 65 y (n = 334)

0.8 Consecutive biopsies (n = 1,219) Stone and Fogo

5.5 Elderly subjects (n = 91)

Incidence:

Reference Incidence (%) Population Under Study

Angiographic studies

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)

Risk factors

Risk factors

PARAMETER BELENFANT THADHANI VIDT FINE

Publication year 1998 1995 1989 1987

Demographics

Number of patients 67 52 24 221

Mean age (range, yr) 69 ± 8 69 ± 7 62 (45–75) 66 (26–90)

Male (%) 96 75 80 77

White rate (%) 100[b] 100 ? 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

Fine et al Lye et al Thadhani

et al Belenfant

et al Scolari et

al

No. of patients 221 129 52 67 52

Outcome

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

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/77638334-4/620123283/1201/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/heartattack3.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

Kasinath, 1987 Scloari, 1996 Thadhin, 1995 N 80 13 37 Eosinophilia 57 (71%) 10 (77%) 5 (14%)

Wilson, 1991 Thadhin, 1995 N 9 37 Eosinophiluria 8 (88%) 5 (14%)

Eosinophiluria

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 P

MN

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