Keywords: Atheroembolic, cholesterol crystal embolization, crescentic nephritis, nephrotic syndrome
|How to cite this article:|
Nadri Q, Aleouni WM. Renal Disease Masquerading Vasculitis Crescentic Atheroembolic Renal Disease. Saudi J Kidney Dis Transpl 2007;18:656-62
|How to cite this URL:|
Nadri Q, Aleouni WM. Renal Disease Masquerading Vasculitis Crescentic Atheroembolic Renal Disease. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2022 Aug 13];18:656-62. Available from: https://www.sjkdt.org/text.asp?2007/18/4/656/36531
| Introduction|| |
Atheroembolic renal disease (AERD) also called atheroembolism,  cholesterol embolism  or cholesterol crystal embolization (CCE)  often is an under diagnosed clinical illness.  It is caused by showers of cholesterol crystals from an atherosclerotic aorta that occludes small renal arteries. It is a common complication of arteriography, vascular surgery, thrombolytic and anticoagulation in a patient with severe atherosclerosis. ,, Spontaneous form of disease has been described.  AERD may give rise to different degree of renal impairment. Renal outcome may be variable. Some patient deteriorates or remains on dialysis, some improve or some remain with chronic renal impairment.  Acute abrupt onset of renal failure may be observed.  Atheroembolic disease is a great imitator ,, and may resemble vasculitis. , Nephrotic proteinuria or full blown nephrotic syndrome has been observed infrequently in AERD posing an interesting diagnostic and therapeutic challenge. ,, Renal histological examination shows characteristic needle shaped clefts in vessels. Other histological features have been describe such as necrotizing glomerulo-nephritis and crescentic changes.  We report a patient with nephrotic syndrome and crescentic GN associated with AERD documented histopathologically. Kidney biopsy ruled out other lesions that may have been responsible for the development of nephrotic syndrome and crescentic GN.
| Case|| |
This is a 63-year-old gentleman, retired and married with children, from Dammam, referred to Vascular Surgery at King Faisal Specialist Hospital and Research Centre (KFSHRC) for evaluation of aortic aneurysm. This aortic aneurysm was discovered incidentally by ultrasound when he was admitted for gallbladder surgery in November 2002 at Dammam City hospital.
Patient was followed up by Vascular Surgeon in KFSHRC. MRI done which revealed extensive fusiform saccular aneurysm extended from aortic arch to abdomen aorta [Figure - 1]. He was declared high risk for surgery and recommended conservative management. On 18 September 2005, Vascular Surgeon referred the patient to Nephrology for evaluation of renal insufficiency with the creatinine of 658 µmol/L. Baseline creatinine was 154 µmol/L in November 2003 at KFSHRC. Labs from Dammam hospital showed a creatinine of 190 µmol/L in December 2004. Patient had moderate hypertension for last 10 years, diabetes and hyperlipidemia for 3 years. Patient has been a smoker for last 30 years. On systemic review patient denied history of hematuria, renal colic, arthralgias, skin rash, mouth ulcers, weight loss, fever, hemoptysis. There was a history of progressive lower limbs swelling, lower extremities claudication and worsening hypertension.
On examination patient was a middle aged male, looked well. BP 150/80, heart rate 67/ min, fundus examination showed hypertensive retinopathy grade 2, JVP was not raised, CVS S1 S2 with no murmur, chest clear, abdomen normal exam apart from scar of cholecystectomy, lower limb 2+ oedema, peripheral pulses were absent in lower limbs. Differential diagnosis included CKD secondary to FSGS, IgA nephropathy, acute over chronic renal failure secondary to rhabdomyolysis, interstitial nephritis, RPGN, vasculitis, renal artery stenosis and obstructive uropathy. Laboratory investigations showed WBC 4.7, Hg 102g/l, platelets 269, polys 63.3%, eosinophils 2.85%. 24-hr urine protein excretion 8.2 g/day. Serum creatinine 786 µmol/l, albumin 26g/l, CK 103 U/L, LD 331 U/L, ALT 8 U/L, ALP 93 U/L. Other serologies Hepatitis B and C, HIV, P and C ANCA, ANA, Anti GBM, C3 and C4 were were all normal. SPEP was suggestive of inflammatory response. Urinanalysis: Ph 6.5, RBC >50, WBC O/HPF, Blood 3+, protein 3+, granular cast, no RBC cast. Ultrasound showed atrophic right kidney 6.3 cm and left kidney 11.6 cm, no hydronephrosis. MRA abdomen showed entire abdominal aorta is aneurysmally dilated with multiple endoluminal thrombi. Extensive atheromatous changes causing occlusion of celiac, superior mesenteric arteries with multiple collaterals. Right renal artery completely occluded and left renal artery 30% ostial occlusion. [Figure - 2] There is total occlusion of distal aorta via large eccentric thrombus. [Figure - 3] CXR showed cardiac enlargement and prominent pulmonary artery. Patient's renal function continued to deteriorate and was started on intermittent hemodialysis. Renal biopsy was done to rule out acute component or reversible cause of renal failure. Renal biopsy revealed nine glomeruli, seven of which are completely sclerosed. Remaining two glomeruli showed diffuse cellular proliferation and one with cellular crescent. No necrotizing lesion. Diffuse interstitial fibrosis and arteriosclerosis. [Figure - 4],[Figure - 5],[Figure - 6] Immunofluorescence negative. Patient remained dialysis dependent. He was switch to CAPD. Currently he is stable on peritoneal dialysis, had no complication from aneurysm and regular follows up with vascular surgery.
| Discussion|| |
AERD is a multi-systemic disorder with multi-organ involvement characterized by occlusion of small arteries by cholesterol crystals derived from eroded atherosclerotic plaques. First described more than 100 years ago by German pathologist, Panum.  AERD was recognized as clinicopathological entity in 1945 by Flory.  The kidney is a frequent target organ for atheroemboli. AERD has been frequently overlooked as a cause of renal dysfunction during life.  Cinderella of nephrology was the term given for AERD  : Cinderella (the patient and clinical findings) and the shoe (the final diagnosis of atheroembolic renal disease) are not usually matched in life. Better knowledge of the disease now permits a correct pre-mortem diagnosis in a significant number of cases in past few years. , Formation of atherosclerotic plaque is a prerequisite for AERD. 
Vascular surgery procedures known to precipitate AERD. Radiological instrumentation of aorta, aortography and coronary angiography, PTCA of coronary and renal vessels are predisposing factors. Spontaneous atheroembolization were reported in 40-69% in earlier reports.  In recent report AERD occurs more with precipitating factors.
Disturbance of atherosclerotic plaques by mechanical trauma expose cholesterol core to arterial circulation. Anticoagulation treatment with both heparin and warfarin and thrombolytic therapy lyses the thrombus covering atheroscloretic plaque.  Once in circulation crystals lodge in small arteries 150-200mcm in diameter, followed by foreign body inflammatory response involving macrophages and giant cell infiltration causing intimal proliferation and narrowing of lumen. This causes tissue ischemia and fibrosis distal to cholesterol crystal emboli. Results in interstitial fibrosis, tubular atrophy and glomerular sclerosis. 
Biconvex, needle-shaped cleft are seen in vessels after cholesterol has dissolved after fixation. This is a patchy process that may not show in the renal biopsy. Necrotizing glomerulonephritis and crescentric changes have been reported.  Because of associated HTN varying degrees of nephroangiosclerotic lesions may be seen. Incidence is 3-4%. Autopsy or biopsy studies may detect subclinical cases thus exacerbate the incidence of AERD. Typical scenario is an elderly man with a history of diffuse atherosclerosis predominantly white race more affected, with history of co-existing DM, HTN, PVD, CVD, ischemic nephropathy and smoker.
Renal involvement: Kidney is a frequent target organ for AERD. Renal clinical manifestations are found at presentation or during the course of the clinical illness in 50% of patients. ,, The mean interval from inciting events to the onset of renal symptoms is 5.3 weeks.
Three types of renal manifestations have been described: First type: acute sudden onset usually associated with evidence of cholesterol crystal emboilization elsewhere. Second type of atheroembolic renal disease, the most frequently observed, is characterized by sub acute time course, probably explained by the foreign body reaction or the cyclic occurrence of cholesterol crystal emboli shower. Third pattern is stable chronic renal impairment associated with clinical presentation of nephrosclerosis and or ischemic nephropathy. Other non renal systemic features include cutaneaous involvement causing blue toe syndrome and levidoreticularis; gastrointestinal-causing bowel ischemia, hemorrhage, pancreatitis; central nervous system TIA, infarction, acute confusion, retinal involvement; myositis, splenic infarct. Atheroembolism to lung is recognized as a new cause of pulmonary renal syndrome. Labs investigation shows elevated creatinine, urea. Urine investigation is non-specific.
Microscopic hematuria occurs in 33-40%. Non nephrotic range proteinuria in 50-60%, minority of patient will have nephrotic range proteinuria. , Esinophilia most common extra renal laboratory feature in 80% of patients but usually transient. Thrombocytopenia and anemia may accompany esinophilia. Hypocomlementemia is found in 39% of patients which is usually mild and transient.  Other laboratory marker of acute inflammation ESR, CRP, fibrin level may be increased in substantial proportion of patients. Autoantibodies ANCA, ANA are negative. Other laboratory findings may indicate organ involvement such as, high transaminases in liver involvement hyperamylasemia in pancreatic involvement high CPK in myositis. Hypercholestremia is a well known risk factor for atherosclerosis, however most studies of atheroembolism have not documented the level and correlation. ,, Mayo and Swarts found 27% of their patients with atheroembolic disease had hypercholestoremia. Diagnosis is challenging, requires high index of suspicion.  Triad of precipitating factor, acute or sub acute renal failure and peripheral cholesterol embolization strongly suggest the diagnosis with negative auto antibodies. Renal biopsy may confirm atheroembolic renal disease.
| Management|| |
At present no effective therapy is available. Statin role in stabilization of atherosclerotic plaque needs to be evaluated in controlled studies. Role of steroid is controversial. 
Supportive medical treatment, including dialysis is needed in some patients. Mortality rate in 1 year may approach 79%.  Avoidance of anticoagulation, good control of HTN and heart failure, dialysis and adequate nutrition may improve survival. Dialysis may be required in 28% to 61% of the patients in both acute and sub acute cases. ,, The recovery of renal function is probably caused by several factors, such as reversal of inflammation, resolution of ATN in ischemic areas and hypertrophy in surviving neprhons. 
There is no contraindication to particular mode of dialysis; some investigators suggest that peritoneal dialysis, which avoids anticoagulation, could be preferred treatment modlity. 
Our patient did not have typical manifestations of AERD such as livido reticularis of skin, blue toes, low complement, eosinophilia and had not undergone any vascular procedure. Rather he had heavy proteinuria with hematuria and rapidly progressive glumerolonephritis. In biopsy, presence of crescentic GN with negative immunofluorescence was a noval observation. Even FSGS lesions were not present to account for proteinuria as reported earlier.
| Conclusion|| |
AERD manifestations are non specific, diverse and variable, explaining the notoriety of the disease as the great masquerader. Number of clinical entities can simulate cholesterol crystal embolization. Prevention is important. High index of suspicion in diagnosis and aggressive therapeutic measures may be associated with favorable outcome.
| Questions and answers|| |
Dr. Ramesh Kumar (Riyadh Medical Complex) Chairman of the Club: Now the presentation is open for discussion.
Dr. Kerchid (Security Forces Hospital): What measures could be done in order to prevent and to treat the atheroembolic renal disease?
Dr. Aleouni: As you know, there is no effective treatment in renal cholesterol crystal embolization, and only supportive measures as dialysis therapy and nutrition support will improve the patient survival rate. The use of statin is controversial and steroids has no role, but the use of aspirin is recommended in high risk patients with cardiovascular and atherosclerotic disease.
Audience: Is there any indication to use thrombolytic agents?
Dr. Aleouni: In general, we should avoid the use of thrombolytic and anticoagulant agents in such cases.
The Chairman: if the renal biopsy did not show any evidence of crystal embolization, how can we differentiate between crescentic GN and atheroembolic renal disease?
Dr. Aleouni: usually in Pauci immune disease, the serologic markers has great importance as the C-ANCA or P-ANCA, and the patient will have future of vasculitis or symptoms of arteritis or wegener's disease (such as pulmonary symptoms, fever, or arthralgia), which were all absent in our case. However, the crescentic GN in thromboembolic diseases was reported, and in general the finding in renal biopsy (or other biopsy) prove the presence of cholesterol crystal embolization.
| References|| |
|1.||Carvajal JA Anderson WR, Weiss L, Grismer J, Berman R. Atheroembolism: An etiologic factor in renal insufficiency, gastrointestinal hemorrhages and peripheral vascular diseases. Arch Intern Med 1967;119:593-9 |
|2.||Darsee JR. Cholesterol embolism: The great masquerader. South Med J 1979;72:174 -80. [PUBMED] |
|3.||Fine MJ, Kapoor W, Falanga V. Cholesterol crystal embolization: A review of 221 cases in the English literature. Angiology 1987; 42:769-84. |
|4.||Scolari F, Ravani P, Gaggi R, et al. The challenge of diagnosing atheroembolic renal disease. Circulation 2007;116:298-304. [PUBMED] [FULLTEXT]|
|5.||Kassirer J. Atheroembolic renal disease. N Engl J Med 1969;280:812-8. |
|6.||Lye WC, Cheah JS, Sinniah R. Renal cholesterol embolic disease: Case report and review of the literature. Am J Nephrol 1993; 13:489-93. [PUBMED] |
|7.||Gore I, Collins DP. Spontaneous atheromatous embolization. Review of the literature and report of 16 additional cases. Am J Clin Pathol 1960;33:416-26. |
|8.||Theriault J, Agharazzi M, Dumont M, et al. Atheroembolic renal failure requiring dialysis: potential for renal recovery? A review of 43 cases. Nephron Clin Pract 2003;94:c11-8. |
|9.||Wong FK, Chan SK, Ing TS, Li CS. Acute renal failure after streptokinase therapy in a patient with acute myocardial infarction. Am J Kidney Dis 1995;26:508-10. [PUBMED] |
|10.||Mittal B, Alexander MP, Rennke HG, Singh AK. Atheroembolic renal disease: A silent masquerader. Kidney Int 2007; (in press) |
|11.||Lie JT. Cholesterol atheromatous embolism. The great masquerader revisited. Pathol Annu 1992;27:17-50. |
|12.||Cappiello RA, Espinoza LR, Adelman H, Aguilar J, Vasey FB, Germain BF. Cholesterol embolism: A pseudovasculitic syndrome. Semin Arthritis Rheum 1989;18:240-1. [PUBMED] |
|13.||Ballesteros AL, Bromsoms J, Valles M, et al. Vasculitis look-alikes: Variants of renal atheroembolic disease. Nephrol Dial Transplant 1999;14:430-3. |
|14.||Haqqie SS, Urizar RE, Singh J. Nephroticrange proteinuria in renal atheroembolic disease: Report of four cases. Am J Kidney Dis 1996;28:493-501. [PUBMED] |
|15.||Williams HH, Wall BM, Cooke CR. Reversible nephrotic range proteinuria and renal failure in atheroembolic renal disease. Am J Med Sci 1990;299:58-61. [PUBMED] |
|16.||Greenberg A, Bastacky SI, Iqbal A, Borochovitz D, Johnson JP. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism. Clinicopathologic correlations. Am J Kidney Dis 1987;29:334-44. |
|17.||Goldman M, Thoua Y, Dhaene M, Toussaint C. Necrotising glomerulonephritis associated with cholesterol microemboli. Br Med J 1985;290:205-6. |
|18.||Panum PL. Experimental one contributing to the theory of the Embolie. Virchows Arch 1962;25:308-10. |
|19.||Flory CM. Arterial occlusion produced by emboli from eroded aortic atheromatous plaques. Am J Pathol 1945;21:549-65. |
|20.||Scoble JE, O'Donnell PJ. Renal atheroembolic disease: the Cinderella of nephrology. Nephrol Dial Transplant 1996;11:1516-7. [PUBMED] [FULLTEXT]|
|21.||Scolari F, Bracchi M, Valzorio B, et al. Cholesterol atheromatous embolism: An increasingly recognized cause of acute renal failure. Nephrol Dial Transplant 1996;11: 1607-12. [PUBMED] [FULLTEXT]|
|22.||Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996;100:524-9. [PUBMED] [FULLTEXT]|
|23.||Scolari F, Tardanico R, Zani R, et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000;36:1089-109. [PUBMED] |
|24.||Belenfant X, Meyrier A, Jacquot C. Supportive treatment improves survival in multivisceral cholesterol crystal embolism. Am J Kidney Dis 1999;33:840-50. [PUBMED] |
|25.||Siemons L, Van Den Heuvel P, Parizel G, Buyssens N, De Broe ME, Cuykens JJ. Peritoneal dialysis in acute renal failure due to cholesterol embolism: Two cases of recovery of renal function and extended survival. Clin Nephrol 1987;28:205-8. [PUBMED] |
King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211
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[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6]