Cholesterol crystal embolization syndrome: Systemic and end-organ injury.

Cholesterol embolization syndrome refers to embolization of the contents of an atherosclerotic plaque (primarily cholesterol crystals) from a proximal large-caliber artery to distal small to medium arteries causing end-organ damage by mechanical plugging and an inflammatory response. Synonyms used in the medical literature include atheromatous embolization, cholesterol crystal embolization, and atheroembolism. Cholesterol embolization syndrome should be distinguished from the related and much more common syndrome of arterio-arterial thromboembolism in which fragments of a thrombus that forms atop an atheromatous plaque in the aorta or a large artery travel distally and occlude medium to large arteries.1 Cholesterol embolization syndrome is generally characterized by a multitude of small emboli (showers of microemboli) occurring over time. This is in contrast to arterio-arterial thromboembolism, which is usually characterized by an abrupt release of 1 or a few large emboli, leading to severe ischemia of target organs. Cholesterol embolization syndrome has a variety of clinical presentations. Cholesterol emboli originating in the descending thoracic and abdominal aorta may lead to renal failure, gut ischemia, and emboli to the skeletal muscles and the skin. Dermatologic manifestations (most commonly livedo reticularis and blue toe syndrome) are usually confined to the lower extremities but may extend to the abdomen and the chest. Cholesterol emboli originating in the ascending aorta may in addition cause neurological damage that is typically diffuse and due to small infarcts. Cholesterol embolization syndrome is also characterized by a nonspecific acute inflammatory response leading to constitutional symptoms (such as fever and malaise) and abnormalities in laboratory tests (such as hypereosinophilia and elevated erythrocyte sedimentation rate). These manifestations will be discussed in detail later in the text. Danish physician Fenger and his colleagues appear to have provided the first description of atheroembolism in the Danish medical brochure Ugeskrift for Laeger (Doctors’ Weekly).2 In 1844, they …

of toes), strongly suggests this disease. Biopsy of the skin or the kidney demonstrates cholesterol crystals, biconvex, needle-shaped clefts whitin the occluded vessel. These intraluminal lesions are often accompanied by a perivascular inflammatory reaction that may contain eosinophils [2] . The reported incidence of renal atheroembolic disease during the last 10 years seems to have increased by several reasons, such as the increased longevity of patients with atherosclerotic vascular disease that may explain the increase in the number of invasive vascular procedures and the generalized use of anticoagulants and thrombolytics [3] . In fact, cholesterol crystal embolism has been described not only in native kidneys, but also in renal allografts and in dialysis patients [1] . Piccoli et al. [4] present in this issue cholesterol crystal embolism in 6 dialysis patients, the largest experience published [4] . All patients had severe atherosclerosis, 5 had ischemic heart disease, and 4 patients had received a renal transplant, 1 of them three grafts. Interestingly, in 3 cases a precipitating factor was present, and in the other 3 patients cholesterol crystal embolization developed spontaneously. Skin manifestations were the key for the diagnosis, particularly livedo reticularis and necrotic lesions in legs, toes, and feet. Notably, steroid treatment (with prostaglandin analogs in 4 cases) was successful in the short term, although 1 patient died of sepsis, and another needed amputation performed over the knee 6 months later. From this interesting article, several points of interest should be considered. First, cholesterol crystal embolization is also a potential complication in dialysis patients, Cholesterol crystal embolization, also called atheroembolism or atheroembolic renal disease, is still an underdiagnosed entity. Atheroembolic renal disease is caused by cholesterol crystals from an atherosclerotic aorta and is a particularly severe ulcerated plaque atherosclerosis that occludes small renal arteries. The kidney is frequently involved because of the proximity of the renal arteries to the abdominal aorta. Cholesterol crystal embolization can also occur in many anatomic sites, including skin, liver, heart, pancreas, gastrointestinal tract, spleen, prostate, penis, testes, bladder, spinal cord, intracerebral vessels, retina, subcutaneous tissue, and skeletal muscle. Therefore, cholesterol crystal embolization has been considered a multisystemic disease [1–3] . Although cholesterol crystal embolization can occur spontaneously (in around 20% of the cases), it characteristically appears after an invasive vascular procedure, such as manipulation of the aorta or other large arteries during arteriography, angioplasty, or surgery. It can also occur after anticoagulant and thrombolytic treatment. The same risk factors as for atherosclerosis, such as male sex, age

Cholesterol crystal (CC) embolism is a complication of advanced atherosclerotic plaques located in the major arteries. This pathological condition is primarily induced by interventional and surgical procedures or occurs spontaneously. CC can induce a wide range of tissue injuries including CC embolism syndrome, a spontaneous or intervention-induced complication of advanced atherosclerosis, while treatment of CC embolism has remained empiric. Vascular occlusions caused by CC embolism may exceed the ischemia tolerance of many tissues, particularly when small arteries are affected. The main approach to CC embolism is primary prophylaxis in patients at risk by stabilizing atherosclerotic plaques and avoiding unnecessary catheter interventions. During CC embolism, the use of platelet inhibitors to avoid abnormal activation and aggregation and anticoagulants may reduce the risk of vascular occlusions and tissue ischemia. This probably explains the relatively low prevalence of clinical manifestations of CC embolism, which are frequently found in autopsy studies. In this review, we summarized the current knowledge on the pathophysiology of CC embolism syndrome deriving from clinical observations and experimental mouse models. Furthermore, we described the risk factors of CC embolism in humans as well as the experimental studies based on empiric treatments. We also discuss potential therapeutic interventions based on recent experimental data and emerging drug options evolving from other research domains. Given the substantial unmet medical need to improve the outcomes of CC embolism, the identification of effective treatment strategies is urgently needed.

A 65‐year‐old man with longstanding seropositive rheumatoid arthritis and lower extremity ulceration

Cholesterol crystal embolism, known as atheroembolic disease, is caused by showers of cholesterol crystals from an atherosclerotic plaque that occludes small arteries. Embolization can occur spontaneously or as an iatrogenic complication from an invasive vascular procedure (angiography or vascular surgery) and after anticoagulant therapy. The atheroembolism can give rise to different degrees of renal impairment. Some patients show a moderate loss of renal function, others severe renal failure requiring dialysis. Renal outcome can be variable: some patients deteriorate or remain on dialysis, some improve and some remain with chronic renal impairment. Clinically, three types of atheroembolic renal disease have been described: acute, subacute or chronic. More frequently a progressive loss of renal function occurs over weeks. Atheroembolization can involve the skin, gastrointestinal system and central nervous system. The diagnosis is difficult and controversial for the protean extrarenal manifestations. In the past, the diagnosis was often made post-mortem. In the last 10 yrs, awareness of atheroembolic renal disease has improved. The correct diagnosis requires the clinician to be alert. The typical patient is a white male aged >60 yrs with a history of hypertension, smoking and arterial disease. The presence of a classic triad (precipitating event, renal failure and peripheral cholesterol crystal embolization) suggests the diagnosis. This can be confirmed by a biopsy of the target organs. A specific treatment is lacking; however, it is an important diagnosis to make because an aggressive therapeutic approach can be associated with a more favorable clinical outcome.

To describe cholesterol embolization syndrome (CES) and its risk factors, pathophysiology, clinical presentation, diagnosis and treatment. To date, no specific diagnostic test (other than biopsy) for CES has been developed. Effective treatments for CES are yet to be developed. CES (also referred to as cholesterol crystal embolization, atheromatous embolization or atheroembolism) occurs when cholesterol crystals and other contents of an atherosclerotic plaque embolize from a large proximal artery to smaller distal arteries, causing ischemic end-organ damage. Clinical manifestations of CES include constitutional symptoms (fever, anorexia, weight loss, fatigue and myalgias), signs of systemic inflammation (anemia, thrombocytopenia leukocytosis, high erythrocyte sedimentation rate, elevated levels of C-reactive protein, hypocomplementemia), hypereosinophilia, eosinophiluria, acute onset of diffuse neurologic deficit, amaurosis fugax, acute renal failure, gut ischemia, livedo reticularis and blue-toe syndrome. CES may occur spontaneously or after an arterial procedure. There is no specific laboratory test for CES. Retinal exam demonstrating Hollenhorst plaques supports the diagnosis of CES. Biopsy of target organs (usually skin, skeletal muscles or kidneys) is the only means of confirming the diagnosis of CES. Treatment consists of supportive care and general management of atherosclerosis and arterial ischemia.

AB0398 CASE SERIES OF PATIENTS WITH CHOLESTEROL CRYSTAL EMBOLISM SYNDROME THAT MIMICS SYSTEMIC VASCULITIS

Cholesterol-embolization syndrome (CES) is a multisystemic disease with various clinical manifestations. CES is caused by embolization of cholesterol crystals (CCs) from atherosclerotic plaques located in the major arteries, and is induced mostly iatrogenically by interventional and surgical procedures; however, it may also occur spontaneously. Embolized CCs lead to both ischemic and inflammatory damage to the target organ. Therefore, anti-inflammatory agents, such as corticosteroids and cyclophosphamide, have been investigated as treatment for CES in several studies, with conflicting results. Recent research has revealed that CES is actually a kind of autoinflammatory disease in which inflammasome pathways, such as NLRP3 and IL1, are induced by CCs. These recent findings may have clinical implications such that colchicine and IL1 inhibitors, namely canakinumab, may be beneficial in the early stages of CES.

Cholesterol crystal embolism (CCE) is an underrecognized multisystemic disease caused by the displacement of cholesterol crystals from atheromatous aortic plaques to distal vascular beds, leading to ischemic injury of target organs, particularly the kidneys, i.e., atheroembolic renal disease (ARD). According to recent research, cellular necrosis, induced by crystal-induced cytotoxicity, enhances the autoinflammatory cascade of the NLPR3 inflammasome, leading in turn to the so-called "necroinflammation". The purported involvement of the latter in CCE offers a rationale for the therapeutic approach with anti-inflammatory drugs such as glucocorticoids, the use of which has long been a matter of debate in CCE. Diagnostic delay and no consistent evidence regarding efficacious treatment, leading to inconsistency in clinical practice, may worsen the already poor prognosis of ARD. The possible role of glucocorticoids in the treatment of ARD is thereby herein explored in a narrative fashion, analyzing the limited data from case reports and clinical trials.

Cholesterol crystal (CC) embolism causes acute kidney injury (AKI) and ischaemic cortical necrosis associated with high mortality. We speculated that sustaining the fibrinolytic system with Glu-plasminogen (Glu-Plg) could be a safe way to attenuate AKI and prevent ischaemic infarction upon CC embolism. We induced CC embolism by injecting CC into the left kidney artery of C57BL/6J mice. The primary endpoint was glomerular filtration rate (GFR). Starting as early as 2h after CC embolism, thrombotic angiopathy progressed gradually in the interlobular, arcuate and interlobar arteries. This was associated with a decrease of GFR reaching a peak at 18h, i.e. AKI, and progressive ischaemic kidney necrosis developing between 12-48h after CC injection. Human plasma Glu-Plg extracts injected intravenously 4h after CC embolism attenuated thrombotic angiopathy, GFR loss as well as ischaemic necrosis in a dose-dependent manner. No bleeding complications occurred after Glu-Plg injection. Injection of an intermediate dose (0.6mg/kg) had only a transient protective effect on microvascular occlusions lasting for a few hours without a sustained protective effect on AKI at 18-48h or cortical necrosis, while 1.5mg/kg were fully protective. Importantly, no bleeding complications occurred. These results provide the first experimental evidence that Glu-Plg could be an innovative therapeutic strategy to attenuate thrombotic angiopathy, AKI, kidney necrosis and potentially other clinical manifestations of CC embolism syndrome.

Atheroembolic renal disease

To the Editor, We present here a scenario of acute renal failure in the setting of blue toe syndrome. A 62-year-old male with a past medical history of hyperlipidaemia, hypertension and stroke presented with a 2-week history of severe diarrhoea, generalized weakness and myalgias. His home medications included Lipitor, Coumadin, Lopressor, Aspirin and lisinopril. During his prior hospitalization, one and a half months ago, he had undergone coronary artery bypass graft which was complicated by an ascending and descending aortic dissection post-operatively. The ascending dissection was surgically repaired. The origin of the celiac axis, superior mesenteric artery and renal arteries was from the true lumen, and thus, the blood flow was not compromised from the descending aortic dissection (Figure 1a). On examination, the patient’s blood pressure was 157/91 mmHg and pulse 85 beats/minute of equal strength in both upper and lower extremities. His systemic examination was significant for painful bluish discoloration of the toes bilaterally (Figure 1b). Initial laboratory results revealed blood urea nitrogen 111 mg/dL, serum creatinine 10.8 mg/dL, potassium 5.8 mEq/L, bicarbonate 15 mEq/L and creatinine phosphokinase 12 893 IU/L. Complement C3 level was decreased. Urine analysis did not reveal muddy brown casts. The remainder of the laboratory panel was also unremarkable. Lipitor was discontinued. Despite adequate hydration, the patient remained oliguric with no improvement in his renal function (Figure 1c). In the setting of surgical history and blue toe syndrome, an atheroembolic phenomenon as the cause of renal failure was considered. Direct ophthalmoscopy and slit lamp examination of the eye revealed cholesterol crystal emboli in the retinal arterioles (Hollenhorst plaques, Figure 1) and thus confirmed the diagnosis of atheroembolic disease. The patient was started on haemodialysis. Fig. 1 (a)The aortic dissection/aneurysm at the level of the left renal artery measured 3.5 cm, and the renal arteries originated from the true lumen. In addition, there was no evidence of aortic leak, and at the level of the origin of the celiac artery and ... Atheroembolic disease may present with general symptoms of fever, myalgias, headache, weight loss and diarrhea [1]. Though sometimes subtle, the pathological process of dislodging multitude of cholesterol crystals from atherosclerotic plaques in the arteries (often post-operatively) can manifest symptomatically diversely. The emboli may travel to the capillary beds of the renal, mesenteric, retinal, tibial and peroneal arteries capable of producing digital or skin ischaemia, and even overt organ failure. Therefore, a high degree of clinical suspicion is warranted since, in the setting of gastrointestinal symptoms, abnormal renal parameters may be confused for acute renal failure secondary to severe dehydration. While the cholesterol showers to the lower extremities are often labeled as ‘blue toe syndrome’, the actual cutaneous manifestations of the bluish discoloration are uncommonly seen in only 5% of patients with atheroembolic disease [1]. In our patient, the blue toes were the sole dermatological manifestation. Other more classical manifestations include cord-like purplish cutaneous discoloration in the lower extremities (livedo reticularis). Acute renal failure is present in 25–50% of atheroembolic cases [2]. Although the disease commonly occurs after invasive vascular procedures (i.e. coronary angiography via femoral artery), instances of spontaneous embolization have also been reported. In the latter cases, the diagnosis may be difficult to establish without a renal biopsy confirmation. However, other embolic signs may be used to reach a presumptive diagnosis. In our patient, the presence of Hollenhorst plaques in the retina with the recent history of aortic surgery was thus diagnostic of atheroembolic renal disease. Blue toe syndrome may be the sole dermatological manifestation of atheroembolic renal disease. Hollenhorst plaques in the retina may aid in the diagnosis. Conflict of interest statement. None declared.

Cholesterol crystal embolism: A recognizable cause of renal disease

Renal disease caused by cholesterol crystal embolism (CCE) occurs when cholesterol crystals become lodged in small renal arteries after small pieces of atheromatous plaques break off from the aorta or renal arteries and shower the downstream vascular bed. CCE is a multisystemic disease but kidneys are particularly vulnerable to atheroembolic disease, which can cause an acute, subacute, or chronic decline in renal function. This life-threatening disease may be underdiagnosed and overlooked as a cause of chronic kidney disease (CKD) among patients with advanced atherosclerosis. CCE can result from vascular surgery, angiography, or administration of anticoagulants. Atheroembolic renal disease has various clinical features that resemble those found in other kidney disorders and systemic diseases. It is commonly misdiagnosed in clinic, but confirmed by characteristic renal biopsy findings. Therapeutic options are limited, and prognosis is considered to be poor. Expanding knowledge of atheroembolic renal disease due to CCE opens perspectives for recognition, diagnosis, and treatment of this cause of progressive renal insufficiency.

A 69-year-old man with history of CAD admitted for melena without abdominal pain. He had triple vessel CABG 2 months ago. Physical examination revealed pale palpebral conjunctiva and non-tender abdomen. Initial laboratories were depicted in table 1. The patient was started on pantoprazole drip and PRBCs were transfused. After stabilization of his hemodynamics, EGD was done revealing a large, subepithelial mass with ulcerated center, arising from the 2nd portion of the duodenum. CT abdomen and EUS revealed an exophytic solid mass arising from the muscularis propia of the duodenum. FNA biopsy revealed a spindle cell neoplasm. Immunohistochemical stains were compatible with a leiomyoma. Surgery was deferred because of increasing renal functions. Renal biopsy revealed multiple intra-luminal clefts and spaces within the glomerulus consistent with renal cholesterol embolic disease. His creatinine eventually stabilized and thus, surgery was done. Gross pathology revealed a tan-pink irregular ovoid shaped mass measuring 9 cm with a smooth surface, prominent vasculature and a 2.5 x 1.5 cm central ulcer. Microscopic examination confirmed leiomyoma with large submucosal blood vessels containing multiple intra-luminal clefts and spaces consistent with cholesterol emboli. Patient did well however, his renal functions did not return to his baseline. Cholesterol crystal emboli (CCE) are migrations of cholesterol crystals from ulcerated arterial atherosclerosis plaques resulting in tissue ischemia and necrosis. Microscopically, the crystals dissolve during the histotechnical procedure, leaving pathognomonic needle shaped lacunae in the lumina of arterioles. The risk of cholesterol crystal formation is directly related to the severity of atherosclerosis. Risk factors for embolization include the presence of an abdominal aortic aneurysm, endovascular instrumentation and anticoagulation or thrombolytic therapy. CCE can occur in any organ. In the gastrointestinal system, the colon and small bowel are most commonly affected. However, embolization to a duodenal leiomyoma is uncommon. Gastrointestinal involvement presents as abdominal pain, bleeding, colitis, ileus or intestinal obstruction. Treatment includes management of risk factors and end-organ ischemia. Anticoagulation therapy is controversial. The prognosis in medically treated patients is poor. Mortality rates may be as high as 80 percent when post-mortem diagnoses are included.Table: Table. Laboratory workup