Atheroembolic Kidney Disease

Etiology

Atheroembolic renal disease occurs in patients with atherosclerotic vascular disease, and typically, these patients have significant atherosclerotic plaques in the aorta and large-to-medium-sized vessels. These plaques have a lipid-rich core and a thin fibrous cap. Mechanical and hemodynamic stresses can rupture the fibrous cap and release the underlying extracellular cholesterol-rich matrix, which enters circulation and eventually lodges at a distal site, causing vascular occlusion.[10]

Frequently an iatrogenic disease, AERD may follow surgical procedures like coronary artery bypass grafting, coronary stenting, abdominal aortic aneurysm repair, angiography, angioplasty, or endovascular grafting. In a small number of patients, atheroembolic renal disease may occur spontaneously without any inciting or triggering factors.[11][12][13] The release of cholesterol emboli into the circulation may occur spontaneously, post-intravascular trauma caused by angiographic catheters, or due to the use of anticoagulants and thrombolytics. Like the native kidneys, atheroembolic renal disease can also affect a transplanted kidney and must be considered when diagnosing a patient with worsening renal allograft function.[14][15][16]

The most common cause of AERD is coronary angiography with an estimated incidence of 0.06% to 1.8%. This condition can also result from hemodynamic stress, reported in up to 30% of cases.[4] A transbrachial artery approach may cause fewer renal emboli than a transfemoral, but this has not been definitively proven.[17] Cholesterol emboli can cause damage to other organs in the vascular territory of the embolic source. Extra-renal manifestations can include pancreatitis, gastric ulcers, and intestinal ischemia.[18]

There are 3 forms of atheroembolic renal disease:

1. An acute form that develops a few days after the inciting event and is due to a massive embolization.
2. The second type of AERD develops subacutely or in a stepwise fashion, probably due to recurrent embolization or endothelial inflammation that follows an initial ischemic insult and which results in further vessel occlusion. This is the most frequently observed form of AERD.
3. A third variety presents as chronic and slowly progressive impairment of renal function and is often mistaken for nephrosclerosis or ischemic nephropathy.[19][20][21]

In the first type involving massive embolization, a rise in creatinine will be immediate. On the other hand, with subacute or chronic embolization, the rise in creatinine may occur days or weeks after the initial insult.[22]

Epidemiology

Atheroembolic renal disease occurs in patients with systemic generalized atherosclerosis. Risk factors include older age, male sex, diabetes, hypertension, hyperlipidemia, and smoking. These patients frequently have coronary artery disease, cerebrovascular disease, renal artery stenosis, renal insufficiency, aortic aneurysm, or other similar atherosclerotic diseases.[8][22]

The reported incidence ranges between 1% and 5% based on different study protocols and criteria used for diagnosis.[9][11][13][18] In older adults with atherosclerosis, atheroembolic renal disease is being increasingly seen. Results from a study found that 60% of patients with atheroembolic renal disease were older than 70.[19] The exact prevalence of atheroembolic renal disease is unknown; AERD is likely an underdiagnosed condition.[8] Clinical data is based on isolated case reports, case series, and clinicopathologic case discussions.

Pathophysiology

During surgical procedures, mechanical trauma (incision, clamping, or manipulation of the vessel) may disrupt the atherosclerotic plaques. During angiography or angioplasty, catheter manipulations disrupt the plaques, exposing the soft, cholesterol-laden core of the plaque to the arterial circulation. Anticoagulants and thrombolytic therapy prevent the formation of a protective thrombus overlying an ulcerated plaque and can also initiate disruption of a plaque by causing hemorrhage into it, therefore exposing plaques to the hemodynamic stress of circulating blood.[13] Once in circulation, cholesterol crystal emboli lodge in small arteries, 150 mm to 200 mm in diameter. These emboli cause partial occlusion of the vessel and distal ischemia, and this is followed by an inflammatory reaction, intimal proliferation, and intravascular fibrosis. The entire process results in further obliteration of the lumen and more ischemic changes.[6]

The exact mechanism underlying atheroembolic renal disease is not fully known. The local tissue necrosis and inflammatory response invoked by cholesterol crystals play a significant role. Furthermore, the renin-angiotensin-aldosterone system and complement activation also contribute to the development of atheroembolic renal disease.

Necroinflammation

Cholesterol crystals cause tissue damage directly by a mechanical obstruction, leading to vessel obstruction, tissue ischemia, and cell necrosis, which is referred to as “necroinflammation.”[23] The local inflammatory cascade initiated by cholesterol crystals plays a crucial part in luminal occlusion and consequent renal insufficiency. The cholesterol crystals set off a foreign-body inflammatory response around the arterioles, causing infiltration of the macrophages and a giant cell reaction.

Cholesterol crystals appear as an endogenous instigator of inflammation. Results from one study reported that cholesterol crystals induce activation of interleukin (IL)-1β in mononuclear phagocytes via the nucleotide-binding and oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome.[24] This inflammasome is an intracellular platform for the translation of several danger signals into the activation of caspase-1 and the release of interleukin-1β. The NLRP3 inflammasome activates the macrophages to secrete mature IL-1β and α, causing cell necrosis.[25] Additionally, the cholesterol emboli induce the production of IL-α/β via the activation of PI3K and Syk in macrophages and dendritic cells.[26] Moreover, the atheroemboli directly adhere to the human macrophage-inducible C-type lectin, releasing pro-inflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2) and tumor necrosis factor (TNF).[27][6][27]

Activation of the Renin-Angiotensin-Aldosterone System 

Blood pressure in patients with AERD can be difficult to control, as it activates the renin-angiotensin-aldosterone system. Obstruction of the renal vasculature by cholesterol crystals reduces focal blood perfusion and increases oxidative stress. This, in turn, leads to apoptosis, inflammation, and fibrosis.[25]

Complement Activation

Complement activation is associated with the inflammatory response secondary to atherosclerosis. Cholesterol crystals trigger both the classical and alternative complement pathways.[28][29] Emboli can activate the classical complement cascade and cause TNF release, which leads to endothelial activation in vitro.[30] 

Histopathology

In the kidney, emboli typically lodge in the arcuate and interlobar arteries and are seen on light microscopy as elongated biconvex transparent needle-shaped clefts. These clefts represent the cholesterol crystals that are dissolved during tissue processing and are sometimes called "ghost cells".[22] Endothelial inflammatory response ensues and eventually leads to complete obliteration of blood flow within weeks or months.[31] Distal to the occlusion, inflammatory and necrotic changes may be present.[22] Glomeruli may appear normal in the initial stages, but eventually, there may be glomerular collapse or shrinkage. Other changes in histology may include acute tubular necrosis, interstitial fibrosis, and tubular atrophy.[31] Please see Images. Cholesterol Emboli in Glomerulus.

History and Physical

Atheroembolic renal disease is usually part of generalized atheroembolic disease, and the most commonly affected sites are the skin, lower extremity skeletal muscles, gastrointestinal tract, kidneys, and brain. Constitutional symptoms may include fever, weight loss, fatigue, or anorexia. Clinical manifestations include livedo reticularis, blue toe/purple toe syndrome, abdominal pain, and neurological deficits. Neurologic deficits may include amaurosis fugax, tia, stroke, headache, mental status changes, neuropathy, or spinal cord infarction.[6] AERD presents with acute/subacute/chronic renal failure, mild-to-moderate proteinuria, hematuria, accelerated hypertension, or new onset hypertension.[4][8][32] 

If the embolic source is the ascending aorta (although a descending aortic source would be more common), Hollenhorst plaques may be visualized on the retina. See StatPearls' companion review, "Hollenhorst Plaque," for further review and imagery. Skin findings suggestive of cholesterol emboli include livedo reticularis, blue toe syndrome (painful bluish/purple discoloration), and purpura, although these findings can also be seen with vasculitis.[22][33] Changes associated with these emboli may include edema.[34]

The most common extra-renal manifestation is in the skin, with abnormalities noted in 75% to 96% of known cholesterol emboli cases. Extra-renal manifestations are possible, especially in the gastrointestinal territory, given the proximity of its vascular territory. If this is the case, manifestations such as abdominal pain, nausea, or vomiting may occur. Pancreatic infarcts can cause pancreatitis and its associated symptoms.[6][18]  

Evaluation

The combination of risk factors, inciting or triggering events, acute/subacute renal failure, and signs of peripheral emboli suggest an AERD diagnosis. If these are present, the diagnosis of AERD can be made without a kidney biopsy. Renal biopsy, however, may be required in some cases to exclude processes like vasculitis, acute tubular necrosis, and allergic interstitial nephritis and may provide a definite diagnosis.

If there are skin lesions (digital infarcts, livedo reticularis), a skin biopsy may be a simple and minimally invasive way to diagnose the condition. If muscle damage is present and a specific muscle can be identified, a muscle biopsy may be another minimally invasive way to establish the diagnosis.[18] One laboratory finding suggestive of AERD is eosinophilia (present in about 80% of cases), but this may be a transitory sign.[22] Eosinophiluria, elevated C-reactive peptide, and hypocomplementemia may also occur, but these are not sensitive nor specific to AERD.[6][8][32]

Treatment / Management

There is no specific therapy for atheroembolic renal disease and treatment is mostly symptomatic and supportive. Anticoagulation should be discontinued, and the performance of more invasive diagnostic/therapeutic vascular procedures or surgery should be avoided or delayed, if possible. Treatment with aspirin and statins, smoking cessation, blood pressure control, and glycemic control are part of atherosclerosis management. Distal protection vascular devices are being used in interventional procedures to prevent embolic material from lodging in distal sites.[8] 

The aim of treatment is to slow or halt the progression of ischemia of the tissues and further showering of cholesterol crystals. Avoiding nephrotoxins and limiting contrast exposure can also help decrease the incidence of AERD. Animal studies have also shown that hyperglycemia and hyperuricemia worsen cholesterol emboli-associated renal disease through different mechanisms. Renal replacement therapy may be required for supportive management if renal function does not improve.[5][35]

Corticosteroids

The purpose of corticosteroid use is to decrease the inflammatory response to atheroembolization. However, the effects of steroids remain controversial. Some studies demonstrate that the administration of oral prednisolone at a dose of 1 mg/kg/day results in overall clinical improvement and better renal outcomes.[36] However, other studies reveal that steroids do not have a significant long-term effect on renal outcomes and may even result in an increased risk of mortality.[37](B3)

Lipid-lowering Therapies

Statins may have a positive effect on AERD by contributing to the stabilization of plaque and its regression through their anti-inflammatory and lipid-lowering properties.[38](B3)

Dialysis and Other Therapies

Patients with acute kidney injury may need renal replacement therapy. Both peritoneal dialysis and hemodialysis are useful means of treating renal failure in such patients.

Differential Diagnosis

Several other entities can have similar clinical presentations.

• In contrast nephropathy, an increase in serum creatinine starts a day or two after exposure to contrast. The serum creatinine peaks in approximately one week and returns to baseline within 10 to 14 days. On the other hand, AERD frequently has a delayed onset, usually days to weeks, and a protracted course. The outcome is often poor, resulting in progressive renal failure requiring dialysis.[32]
• Systemic vasculitis is another consideration since there is multisystem involvement and complement levels can be decreased in both atheroembolic renal disease and systemic vasculitis. Serological testing, biopsy of the affected organ, or angiography may be needed to rule out this disease, since the management and outcomes of vasculitis are very different.
• Subacute bacterial endocarditis may also enter into differential diagnosis due to multisystem manifestations and low complement levels.
• Rising serum creatinine, mild-to-moderate proteinuria, hematuria, and eosinophilia may also raise the possibility of acute interstitial nephritis.[9][31]
• Chronic forms of atheroembolic renal disease may be mistaken for hypertensive nephrosclerosis or ischemic nephropathy if peripheral manifestations are subtle or missed. Renal biopsy may be crucial in these cases to make the diagnosis.[6]

Prognosis

AERD is often associated with irreversible organ damage with a poor prognosis. The renal outcome varies, with some patients requiring maintenance dialysis and others improving but with a variable degree of residual chronic renal impairment. Renal function may improve in approximately one-third of these patients after variable time without further embolic events.[8][9] Some study results show that patients with AERD have the potential to recover renal function after a longer dialysis-dependent time than other etiologies of end-stage renal disease.[13]

Around 30% to 55% of cases of acute/subacute AERD need renal replacement therapy. Improvement in renal function has been observed in only 21% to 28% of these patients.[39][40] One- and 2-year survival rates of 87% and 75%, respectively, have been reported. However, mortality is linked more to the causes of AERD than the renal disease itself.[13][41] The most common cause of mortality is cardiovascular disease.[42]

Complications

Atheroembolic disease can lead to the following complications of which providers should be aware:

• Irreversible organ damage
• End-stage renal disease
• Visceral ischemia
• Membranous nephropathy