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Atheroembolic renal disease
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/cqn
Review Article
Atheroembolic renal disease Jacob George* Professor and Head, Department of Nephrology, Medical College, Thiruvananthapuram, Kerala 695011, India
article info
abstract
Article history:
Atherosclerotic plaques are prone for thromboembolism with clots and atheroembolisa-
Received 18 October 2013
tion with cholesterol crystals. Atheroembolism occurs when the atherosclerotic plaque is
Accepted 16 November 2013
disrupted causing multiple showers of cholesterol crystal embolization resulting in partial
Available online 4 December 2013
or total occlusion of small arteries of multiple organs. Atheroembolic renal disease (AERD) refers to cholesterol crystal embolization of the renal arteries and is often associated with
Keywords:
multiorgan involvement. Diagnosis requires a high degree of suspicion in the clinical
Cholesterol crystal embolization
setting with renal failure, skin lesions, and sometimes hypocomplementemia and eosi-
Thromboembolism
nophiluria. Treatment is mainly supportive and overall prognosis is poor.
Eosinophiluria
1.
Introduction
People with atherosclerotic plaques are prone for (1) thromboembolism with clots and (2) atheroembolisation with cholesterol crystals.1 The former occurs when a thrombus dislodges from an underlying atherosclerotic plaque and tends to block medium or large sized arteries. The clinical manifestations are usually confined to a single organ and may include a cerebrovascular accident or acute ischemia of the extremities, intestine or solid organs. On the other hand, atheroembolism occurs when the atherosclerotic plaque is disrupted resulting in showers of cholesterol crystal embolization resulting in typically partial or total occlusion of small arteries of multiple organs and often associated with multiple episodes. Atheroembolic renal disease (AERD) refers to cholesterol crystal embolization of the renal arteries and is often associated with a multiorgan involvement.
Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.
2.
Risk factors
The following are the predisposing factors for AERD: (1) Male sex (2) Age more than 50 years (3) Risk factors for atherosclerosis: smoking, hypercholesterolemia, hypertension, obesity, diabetes mellitus etc (4) Interventions and surgical procedures involving the aorta. The causes of AERD may be broadly classified as (1) spontaneous and (2) iatrogenic (1) Spontaneous AERD is rare and can be contributed by hemodynamic stress and/or use of anticoagulation (heparin, warfarin, thrombolytic agents etc.). These
* Tel.: þ91 (0) 9447143992 (mobile). E-mail addresses: [email protected], [email protected]. 2211-9477/$ e see front matter Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cqn.2013.11.003
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
149
agents can interfere with healing of the ulcerated atheromatous plaque. (2) The vast majority (>70%) are iatrogenic following vascular interventions or surgery. Angiography accounts for more than 80% of them.2 Catheterization through the iliofemoral route is much more likely to cause AERD than the brachial artery approach.
3.
Clinical features
Most cases are asymptomatic and are detected only at autopsy (0.7e4%). As many as 75% of retrospective autopsy specimens in patients with atherosclerosis who underwent vascular interventions or surgery show evidence of AERD. Symptomatic patients with AERD often have a multisystem involvement along with renal failure.
3.1.
Fig. 1 e Blue or purple toes.
Renal involvement in AERD
There are classically 3 clinical presentations in patients with renal involvement: (1) Acute kidney injury This occurs within 1e2 weeks of the procedure and is usually caused by a complete occlusion by a clot. Patients with arrhythmias or following a myocardial infarction are at risk of this presentation. In view of the complete arterial occlusion, a renal infarct can occur. This can manifest as flank pain, hematuria, and elevated lactic dehydrogenase enzyme with normal serum transaminases.
(b) Mesenteric artery occlusion: this can present with abdominal pain, gastrointestinal bleed etc. (c) Pancreatitis: present as abdominal pain with raised serum amylase and lipase. (d) CNS involvement: this can manifest as transient ischemic attacks, visual blurring etc.
(2) Subacute kidney injury This occurs 3e8 weeks after the inciting event and is the commonest presentation. There is an incomplete occlusion of the arteries usually by cholesterol crystals resulting in secondary ischemic atrophy with a foreign body type reaction of the blood vessel with intimal proliferation, surrounding giant cell reaction and progressive narrowing of the arteries causing a gradually worsening renal failure. The renal impairment can occur in staggered steps with intervening stable renal functions. This resembles a “staircase pattern” and is due to recurrent embolization or a foreign body reaction to the cholesterol crystals. (3) Chronic stable renal failure This may mimic ischemic nephropathy and often coexists with it. This is often incidentally detected on renal biopsy. These patients are often elderly with risk factors for atherosclerosis and present with slowly rising serum creatinine with no obvious cause. Extra renal manifestations are common considering the likelihood of multivessel occlusion, The common extra renal organs involved include: (a) The skin: commonest presentation of the microvascular occlusion of the skin are “blue/purple toes” (Fig. 1) and livedo reticularis3 (Fig. 2).
Fig. 2 e Livedo reticularis seen on the leg.
150
4.
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
Investigations (1) Urinalysis
Usually is benign with no striking abnormality, Occasionally proteinuria can occur which may rarely be of nephrotic range (>3 g/1.73 m2). Urine deposits may rarely show RBCs or RBC casts. Urinary eosinophils may be detected by special stains like Hansel’s stain and is highly suggestive of AERD, though it is seen only in the initial few days and can also be seen in allergic acute interstitial nephritis. (2) Blood eosinophilia may be seen in some patients. (3) Low C3 levels (hypocomplementemia) can occur due to immunologic activation. (4) Elevated serum lipase and amylase may be seen with associated pancreatitis.
5.
6.
Renal failure occurring after interventions of the main arteries may be due to several causes which need to be differentiated from AERD: (1) Contrast nephrotoxicity This is seen a few days following contrast administration and usually resolves in a few days. Multisystem involvement is usually not seen.4 (2) Ischemic acute tubular necrosis There may be an acute and progressive rise of serum creatinine in the setting of hypovolemia or hypotension. This usually resolves by 1e3 weeks whereas in AERD, renal failure peaks by 3e8 weeks.
Diagnosis
A high index of suspicion is needed especially in the presence of risk factors to diagnose AERD as most of the symptoms and signs can occur with other conditions. The diagnosis can be made in the presence of the classic triad of (a) precipitating events like intervention (b) subacute or acute kidney injury and (c) skin changes as described above. Other clinical evidences include observation of cholesterol crystals in the retina called Hollenhorst plaques. This is virtually diagnostic in the clinical setting and if seen, makes a histological confirmation unnecessary. Histological diagnosis is not essential but can be done in selected cases where the diagnosis is in doubt. A renal biopsy may show evidence of cholesterol crystal deposition in the arteries, As cholesterol crystals dissolve during fixation, their presence can be inferred by observing biconvex or needle shaped clefts in the occluded vessel (Fig. 3) with surrounding perivascular inflammation including eosinophils.
Differential diagnosis
(3) Acute interstitial nephritis This needs to be considered in the presence of eosinophilia or eosinophiluria.
7.
Treatment
There is no specific treatment. Treatment is mainly supportive and directed at preventing further episodes. Dialysis may be needed in renal failure. Heparin free dialysis may be preferable to avoid further embolization. Secondary prevention of cardiovascular events is essential considering these patients risk factors. Statins, antiplatelets and antihypertensives are essential. Cessation of modifiable risk factors like smoking and further vascular intervention must be stressed. There are anecdotal reports of benefits with steroids though this has not been confirmed.5
8.
Outcome
Around 25% recover renal functions though dialytic support may be needed. Endstage renal disease occurs in around 33%. In view of the diffuse vessel involvement, 30% die of cardiovascular or cerebrovascular diseases by 2 years.
Conflicts of interest The author has none to declare.
references
Fig. 3 e Needle shaped clefts in the artery representing dissolved cholesterol crystals.
1. Kronzon I, Saric M. Cholesterol embolization syndrome. Circulation. 2010;122:631e635. 2. Karalis DG, Quinn V, Victor MF, et al. Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic aorta. Am Heart J. 1996;131:1149e1152.
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
3. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol. 1986;122:1194e1198. 4. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiography: contrast media-associated
151
nephrotoxicity and atheroembolism e a critical review. Am J Kidney Dis. 1994;24:713e717. 5. Mann SJ, Sos TA. Treatment of atheroembolization with corticosteroids. Am J Hypertens. 2001;14:831e834.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/cqn
Review Article
Atheroembolic renal disease Jacob George* Professor and Head, Department of Nephrology, Medical College, Thiruvananthapuram, Kerala 695011, India
article info
abstract
Article history:
Atherosclerotic plaques are prone for thromboembolism with clots and atheroembolisa-
Received 18 October 2013
tion with cholesterol crystals. Atheroembolism occurs when the atherosclerotic plaque is
Accepted 16 November 2013
disrupted causing multiple showers of cholesterol crystal embolization resulting in partial
Available online 4 December 2013
or total occlusion of small arteries of multiple organs. Atheroembolic renal disease (AERD) refers to cholesterol crystal embolization of the renal arteries and is often associated with
Keywords:
multiorgan involvement. Diagnosis requires a high degree of suspicion in the clinical
Cholesterol crystal embolization
setting with renal failure, skin lesions, and sometimes hypocomplementemia and eosi-
Thromboembolism
nophiluria. Treatment is mainly supportive and overall prognosis is poor.
Eosinophiluria
1.
Introduction
People with atherosclerotic plaques are prone for (1) thromboembolism with clots and (2) atheroembolisation with cholesterol crystals.1 The former occurs when a thrombus dislodges from an underlying atherosclerotic plaque and tends to block medium or large sized arteries. The clinical manifestations are usually confined to a single organ and may include a cerebrovascular accident or acute ischemia of the extremities, intestine or solid organs. On the other hand, atheroembolism occurs when the atherosclerotic plaque is disrupted resulting in showers of cholesterol crystal embolization resulting in typically partial or total occlusion of small arteries of multiple organs and often associated with multiple episodes. Atheroembolic renal disease (AERD) refers to cholesterol crystal embolization of the renal arteries and is often associated with a multiorgan involvement.
Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved.
2.
Risk factors
The following are the predisposing factors for AERD: (1) Male sex (2) Age more than 50 years (3) Risk factors for atherosclerosis: smoking, hypercholesterolemia, hypertension, obesity, diabetes mellitus etc (4) Interventions and surgical procedures involving the aorta. The causes of AERD may be broadly classified as (1) spontaneous and (2) iatrogenic (1) Spontaneous AERD is rare and can be contributed by hemodynamic stress and/or use of anticoagulation (heparin, warfarin, thrombolytic agents etc.). These
* Tel.: þ91 (0) 9447143992 (mobile). E-mail addresses: [email protected], [email protected]. 2211-9477/$ e see front matter Copyright ª 2013, Reed Elsevier India Pvt. Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cqn.2013.11.003
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
149
agents can interfere with healing of the ulcerated atheromatous plaque. (2) The vast majority (>70%) are iatrogenic following vascular interventions or surgery. Angiography accounts for more than 80% of them.2 Catheterization through the iliofemoral route is much more likely to cause AERD than the brachial artery approach.
3.
Clinical features
Most cases are asymptomatic and are detected only at autopsy (0.7e4%). As many as 75% of retrospective autopsy specimens in patients with atherosclerosis who underwent vascular interventions or surgery show evidence of AERD. Symptomatic patients with AERD often have a multisystem involvement along with renal failure.
3.1.
Fig. 1 e Blue or purple toes.
Renal involvement in AERD
There are classically 3 clinical presentations in patients with renal involvement: (1) Acute kidney injury This occurs within 1e2 weeks of the procedure and is usually caused by a complete occlusion by a clot. Patients with arrhythmias or following a myocardial infarction are at risk of this presentation. In view of the complete arterial occlusion, a renal infarct can occur. This can manifest as flank pain, hematuria, and elevated lactic dehydrogenase enzyme with normal serum transaminases.
(b) Mesenteric artery occlusion: this can present with abdominal pain, gastrointestinal bleed etc. (c) Pancreatitis: present as abdominal pain with raised serum amylase and lipase. (d) CNS involvement: this can manifest as transient ischemic attacks, visual blurring etc.
(2) Subacute kidney injury This occurs 3e8 weeks after the inciting event and is the commonest presentation. There is an incomplete occlusion of the arteries usually by cholesterol crystals resulting in secondary ischemic atrophy with a foreign body type reaction of the blood vessel with intimal proliferation, surrounding giant cell reaction and progressive narrowing of the arteries causing a gradually worsening renal failure. The renal impairment can occur in staggered steps with intervening stable renal functions. This resembles a “staircase pattern” and is due to recurrent embolization or a foreign body reaction to the cholesterol crystals. (3) Chronic stable renal failure This may mimic ischemic nephropathy and often coexists with it. This is often incidentally detected on renal biopsy. These patients are often elderly with risk factors for atherosclerosis and present with slowly rising serum creatinine with no obvious cause. Extra renal manifestations are common considering the likelihood of multivessel occlusion, The common extra renal organs involved include: (a) The skin: commonest presentation of the microvascular occlusion of the skin are “blue/purple toes” (Fig. 1) and livedo reticularis3 (Fig. 2).
Fig. 2 e Livedo reticularis seen on the leg.
150
4.
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
Investigations (1) Urinalysis
Usually is benign with no striking abnormality, Occasionally proteinuria can occur which may rarely be of nephrotic range (>3 g/1.73 m2). Urine deposits may rarely show RBCs or RBC casts. Urinary eosinophils may be detected by special stains like Hansel’s stain and is highly suggestive of AERD, though it is seen only in the initial few days and can also be seen in allergic acute interstitial nephritis. (2) Blood eosinophilia may be seen in some patients. (3) Low C3 levels (hypocomplementemia) can occur due to immunologic activation. (4) Elevated serum lipase and amylase may be seen with associated pancreatitis.
5.
6.
Renal failure occurring after interventions of the main arteries may be due to several causes which need to be differentiated from AERD: (1) Contrast nephrotoxicity This is seen a few days following contrast administration and usually resolves in a few days. Multisystem involvement is usually not seen.4 (2) Ischemic acute tubular necrosis There may be an acute and progressive rise of serum creatinine in the setting of hypovolemia or hypotension. This usually resolves by 1e3 weeks whereas in AERD, renal failure peaks by 3e8 weeks.
Diagnosis
A high index of suspicion is needed especially in the presence of risk factors to diagnose AERD as most of the symptoms and signs can occur with other conditions. The diagnosis can be made in the presence of the classic triad of (a) precipitating events like intervention (b) subacute or acute kidney injury and (c) skin changes as described above. Other clinical evidences include observation of cholesterol crystals in the retina called Hollenhorst plaques. This is virtually diagnostic in the clinical setting and if seen, makes a histological confirmation unnecessary. Histological diagnosis is not essential but can be done in selected cases where the diagnosis is in doubt. A renal biopsy may show evidence of cholesterol crystal deposition in the arteries, As cholesterol crystals dissolve during fixation, their presence can be inferred by observing biconvex or needle shaped clefts in the occluded vessel (Fig. 3) with surrounding perivascular inflammation including eosinophils.
Differential diagnosis
(3) Acute interstitial nephritis This needs to be considered in the presence of eosinophilia or eosinophiluria.
7.
Treatment
There is no specific treatment. Treatment is mainly supportive and directed at preventing further episodes. Dialysis may be needed in renal failure. Heparin free dialysis may be preferable to avoid further embolization. Secondary prevention of cardiovascular events is essential considering these patients risk factors. Statins, antiplatelets and antihypertensives are essential. Cessation of modifiable risk factors like smoking and further vascular intervention must be stressed. There are anecdotal reports of benefits with steroids though this has not been confirmed.5
8.
Outcome
Around 25% recover renal functions though dialytic support may be needed. Endstage renal disease occurs in around 33%. In view of the diffuse vessel involvement, 30% die of cardiovascular or cerebrovascular diseases by 2 years.
Conflicts of interest The author has none to declare.
references
Fig. 3 e Needle shaped clefts in the artery representing dissolved cholesterol crystals.
1. Kronzon I, Saric M. Cholesterol embolization syndrome. Circulation. 2010;122:631e635. 2. Karalis DG, Quinn V, Victor MF, et al. Risk of catheter-related emboli in patients with atherosclerotic debris in the thoracic aorta. Am Heart J. 1996;131:1149e1152.
c l i n i c a l q u e r i e s : n e p h r o l o g y 2 ( 2 0 1 3 ) 1 4 8 e1 5 1
3. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol. 1986;122:1194e1198. 4. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Nephrotoxic risks of renal angiography: contrast media-associated
151
nephrotoxicity and atheroembolism e a critical review. Am J Kidney Dis. 1994;24:713e717. 5. Mann SJ, Sos TA. Treatment of atheroembolization with corticosteroids. Am J Hypertens. 2001;14:831e834.