In-depth Review
Cholesterol crystal embolism: A recognizable cause of renal disease*

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Abstract

Cholesterol crystal embolism, sometimes separately designated atheroembolism, is an increasing and still underdiagnosed cause of renal dysfunction antemortem in elderly patients. Renal cholesterol crystal embolization, also known as atheroembolic renal disease, is caused by showers of cholesterol crystals from an atherosclerotic aorta that occlude small renal arteries. Although cholesterol crystal embolization can occur spontaneously, it is increasingly recognized as an iatrogenic complication from an invasive vascular procedure, such as manipulation of the aorta during angiography or vascular surgery, and after anticoagulant and fibrinolytic therapy. Cholesterol crystal embolism may give rise to different degrees of renal impairment. Some patients show only a moderate loss of renal function; in others, severe renal failure requiring dialysis ensues. An acute scenario with abrupt and sudden onset of renal failure may be observed. More frequently, a progressive loss of renal function occurs over weeks. A third clinical form of renal atheroemboli has been described, presenting as chronic, stable, and asymptomatic renal insufficiency. The renal outcome may be variable; some patients deteriorate or remain on dialysis, some improve, and some remain with chronic renal impairment. In addition to the kidneys, atheroembolization may involve the skin, gastrointestinal system, and central nervous system. Renal atheroembolic disease is a difficult and controversial diagnosis for the protean extrarenal manifestations of the disease. In the past, the diagnosis was often made postmortem. However, in the last decade, awareness of atheroembolic renal disease has improved, enabling us to make a correct premortem diagnosis in a number of patients. Correct diagnosis requires the clinician to be alert to the possibility. The typical patient is a white man aged older than 60 years with a baseline history of hypertension, smoking, and arterial disease. The presence of a classic triad characterized by a precipitating event, acute or subacute renal failure, and peripheral cholesterol crystal embolization strongly suggests the diagnosis. The confirmatory diagnosis can be made by means of biopsy of the target organs, including kidneys, skin, and the gastrointestinal system. Thus, Cinderella and her shoe now can be well matched during life. Patients with renal atheroemboli have a dismal outlook. A specific treatment is lacking. However, it is an important diagnosis to make because it may save the patient from inappropriate treatment. Finally, recent data suggest that an aggressive therapeutic approach with patient-tailored supportive measures may be associated with a favorable clinical outcome.

Section snippets

The aorta in atheroembolic renal disease

The hypothesis that cholesterol crystal embolism may originate from a diseased atherosclerotic aorta was first made by Flory8 in 1945. Among 267 consecutive autopsies, he observed nine instances of cholesterol crystal embolism: none in 63 cases in which aortic plaque ulceration was absent, two instances in 147 cases (1%) with moderate aortic plaque erosion, and seven instances in 57 cases (12%) with severe aortic plaque ulceration. Since then, other investigators have confirmed the strict

Fate of atheroemboli

Once in the circulation, cholesterol crystal emboli lodge in small arteries 150 to 200 μm in diameter. The lodgment of cholesterol clefts is followed by an inflammatory reaction, often of a granulomatous type, involving macrophage and giant-cell infiltration. The foreign-body inflammatory reaction leads to an endothelial reaction, causing intimal proliferation and intravascular fibrosis of the affected vessels. The entire process of cholesterol crystal embolism and vascular reaction results in

Epidemiological characteristics

The syndrome of renal cholesterol crystal embolism usually affects elderly men with a history of diffuse atherosclerosis.1, 2, 3 In the largest reports, mean age varied from 66 to 70 years (range, 45 to 84 years).2, 3, 11, 12, 13, 14 The disease is more frequently diagnosed in men than women,1, 2, 3, 11, 12, 13, 14 which may be explained by a difference in the prevalence of atherosclerosis between these groups.2 A review of the literature regarding the racial incidence of atheroembolism

Pathological characteristics

The histological features of renal cholesterol crystal embolization are highly characteristic.1, 2, 3, 25 The hallmark of the condition is an occlusion of the lumen of small arteries by atherosclerotic material. Because the lipids are dissolved by the techniques used to prepare the tissue for histological examination, the cholesterol crystals may be identified by the presence of needle-shaped spaces, which appear empty in routine histological sections. Thus, clefts are found that remain after

Clinical features

The clinical consequences of cholesterol crystal embolization vary considerably. Patients may be completely asymptomatic when the diagnosis is made coincidentally at renal biopsy, or they may present with a distinct clinical syndrome, ranging from a cyanotic toe to a multiorgan systemic disease that can mimic other systemic diseases1, 2, 3, 4, 5, 6, 11, 12, 13, 14 (Table 3).

. Clinical and Laboratory Features of Atheroembolic Renal Disease in the Five Largest Case Series

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Laboratory features

Laboratory features are nonspecific in patients with cholesterol crystal emboli. However, various laboratory tests help establish the diagnosis of cholesterol crystal embolism. Renal atheroembolic disease is first characterized by elevations in serum creatinine and blood urea nitrogen levels. The variable clinical forms of renal involvement (acute, subacute, and chronic) have been mentioned earlier. Urinary investigation is generally nondiagnostic because it shows such nonspecific alterations

Diagnosis

From a diagnostic point of view, cholesterol crystal embolism has challenged physicians for more than a century. This is likely because atheroembolism is ubiquitous, with random and variable distributions in the body. Thus, cholesterol crystal embolism may mimic a variety of disorders, including systemic vasculitis.1, 2, 3

Antemortem diagnosis of renal cholesterol crystal embolization is difficult and requires a high index of suspicion. Knowledge of the associated risk factors, recognition of

Differential diagnosis

The symptoms and signs of renal cholesterol crystal embolization are nonspecific, diverse, and variable, explaining the notoriety of the disease as the great masquerader.24 Thus, a number of clinical entities can simulate cholesterol crystal embolization. The differential diagnosis should include contrast nephropathy, small-vessel vasculitis, and acute interstitial nephritis.

In the immediate phase after an invasive procedure in which dye has been used, differentiation from dye-induced

Cholesterol crystal embolic disease in renal allografts

Although the clinical features of cholesterol crystal embolism in the native kidney have been well delineated, cholesterol crystal embolization to renal allografts is much less well described. The finding of atheroemboli in the renal allograft was first described in 1985 by Cosio et al,59 who found atheroemboli in transplant nephrectomy specimens of a patient who experienced oliguria after cadaveric renal transplantation. Atheroemboli causing injury to the renal allograft may arise from either

Management and outcome

The aim of treatment should be to halt the progression of tissue ischemia and prevent repeated showers of renal cholesterol crystal embolism. At present, no effective treatment is available for this condition. No controlled studies show that medical treatment helps after atheroembolism has occurred. Anticoagulants should be avoided because they may potentiate the problem.1, 2, 3, 4, 5, 6, 11, 12, 13 A number of antiplatelet drugs have been tried without success.1, 2, 37 Anecdotal case reports

Acknowledgements

Acknowledgment: The authors thank Fabio Facchetti (Chair of Pathology, University of Brescia) for supplying the photographs for this manuscript.

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    *

    Address reprint requests to Francesco Scolari, MD, Division of Nephrology, Spedali Civili, P le Spedali Civili, 1, 25125 Brescia, Italy. E-mail: [email protected]

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