- Email: [email protected]
Atheroembolic renal disease: A silent masquerader
the renal consult & 2008 International Society of Nephrology
Atheroembolic renal disease: A silent masquerader BV Mittal1, MP Alexander2, HG Rennke2 and AK Singh1 1 2
Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA and Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
RENAL BIOPSY
CASE PRESENTATION A 76-year-old white male with hypertension, progressive renal insufficiency, and proteinuria of unclear etiology was admitted for renal biopsy in June 2005. His kidney disease had steadily progressed over the past 3 years. On admission, he complained of fatigue with increased daytime somnolence, loss of appetite, weight loss, and increased itching. There was no nausea, vomiting, or other uremic symptoms. Review of systems revealed mild cold intolerance, complaints of occasional mild non-exertional chest pains lasting minutes, and bilateral knee pain. There were no neurologic symptoms. His past medical history was notable for gout, glaucoma, arthritis, hypertension, and chronic kidney disease. There was no history of any invasive vascular procedure, use of radio-contrast agent, or treatment with anticoagulant or thrombolytic agents. He had been taking amlodipine, hydrochlorothiazide, enalapril, and atorvastatin before admission. He was a nonsmoker and not a current alcohol user. On examination, he was a well-oriented alert elderly male, his peripheral pulse rate was 57 beats/minute regular in rate and rhythm, and his blood pressure was 153/ 77 mm Hg. His lower extremities were well perfused with no ischemic or gangrenous lesions. There was no livedo reticularis and no muscle tenderness. He did not have peripheral edema. Laboratory investigations (Table 1) revealed a white blood cell count of 5.86 K/ml, with a normal differential count and no evidence of eosinophilia. His blood urea nitrogen was 53 mg/dl, serum creatinine 4.4 mg/dl, and an estimated glomerular filtration rate was 14 ml/min/ 1.73 m2. Urine dipstick showed a urine albumin of 3 þ , and the sediment revealed 2–3 white blood cells and 0–1 red blood cell/high power field. Spot protein/creatinine ratio was 4.7 mg/g of creatinine. Chest X-ray revealed cardiomegaly with a tortuous atherosclerotic aorta.
A total of seven glomeruli were present: two were globally obsolescent and three showed focal segmental glomerulosclerosis. The remaining two glomeruli appeared mildly hypertrophic with mild mesangial hypercellularity and a slight expansion of mesangial matrix. Double contours were noted focally in capillary wall segments. The larger arteries displayed vascular sclerosis of the media with hyaline intimal thickening. Elongated, empty, cleft-like crystal spaces lodged within and occluding the lumina of an arteriole characteristic of cholesterol crystal emboli were observed (Figure 1). Cholesterol emboli were also noted in the wall of an interlobular artery in the tolidine blue-stained sections submitted for electron microscopic examination. There was no perivascular inflammation. Areas of ischemic injury with parenchymal scarring, extensive tubular atrophy, thickening of tubular basement membranes, numerous periodic acidSchiff-positive casts within atrophic tubules and extensive interstitial fibrosis (90%) were present (Figure 2). Immunofluorescence revealed no significant immune deposits, with only segmental IgM deposits ( þ þ þ /4 þ ) and C3 ( þ þ / 4 þ ) in two glomeruli. On electron microscopy, there was marked visceral epithelial cell foot process fusion with microvillous formation. Isolated loops revealed double contours and occasional sub-epithelial humps were seen along the capillary loops. The mesangial matrix showed a marked increase without electron dense/lucent deposits. DIAGNOSIS
Correspondence: AK Singh, Clinical Director, Renal Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA. E-mail: [email protected]
A diagnosis of progressive kidney failure secondary to spontaneous atheroembolic (AE) disease and small-vessel vascular disease was made. This was largely based on the kidney biopsy findings, which showed moderately severe vascular sclerosis, with AE disease; advanced focal and segmental glomerulosclerosis, secondary to vascular disease and potentially secondary to superimposed functional and structural adaptations. The presence of an occasional subepithelial ‘hump’-like deposit suggested the possibility of a prior and currently inactive episode of post-infectious glomerulonephritis.
Kidney International (2008) 73, 126–130; doi:10.1038/sj.ki.5002433; published online 1 August 2007
CLINICAL FOLLOW UP
Received 23 April 2007; revised 29 May 2007; accepted 19 June 2007; published online 1 August 2007
The patient’s blood pressure was managed with amlodipine 10 mg/day and enalapril 5 mg/day. He also received 10 mg day
126
Kidney International (2008) 73, 126–130
the renal consult
BV Mittal et al.: Atheroembolic renal disease
Table 1 | Laboratory findings Date
6/22/05
Serum/blood BUN (mg/dl) Creatinine (mg/dl)
53 4.4
MDRD-GFR ml/min/1.73 m2 Absolute eosinophil count (peripheral) (K/ml)
14 0.15
Urinalysis Blood Albumin Urinary eosinophils Spot creatinine Spot protein
Trace 3+ Nil 38.7 184.1
1/06
0.01
2/06
0.08
3+ 3+ Nil
9/06
11/06
12/06
1/07
36/19a 4.0
34 4.9
43/13a 5.6
58/15a 6.7
10 0.13
9 0.12
16 0.17
12
3+ 3+
BUN, blood urea nitrogen; MDRD-GFR, Modification of Diet in Renal Disease-glomerular filtration rate. a Pre and post-dialysis values.
Figure 1 | An arteriole displays luminal occlusion by characteristic biconvex needle-shaped cleft-like empty spaces of cholesterol emboli. (Trichrome, original magnification 400).
of atorvastatin for his hypercholesterolemia. Over the next 8 months, his serum creatinine increased from 4.4 to 5.7 mg/dl (estimation of glomerular filtration rate of 10 ml/min/ 1.73 m2) and he continued to have proteinuria. He developed worse uremia. Hence, he was initiated on hemodialysis in February 2006. As of January 2007, he has remained stable on chronic maintenance hemodialysis. DISCUSSION
This patient presented clinically with progressive renal failure of unclear etiology. A diagnosis of AE renal disease was made on the basis of the renal biopsy. The presentation illustrates the importance of considering a wide differential diagnosis in elderly patients who present with progressive renal failure. Furthermore, the absence of precipitating factors or clinical stigmata of AE should not necessarily deter clinicians from considering this possibility in the differential diagnosis. The kidney biopsy showed prominent vascular disease with characteristic AE and cortical scarring. The advanced Kidney International (2008) 73, 126–130
Figure 2 | An area of the submitted tissue shows parenchymal scarring with a single sclerosed glomerulus, most probably reflective of the ischemic injury. (PAS, original magnification 200).
segmental and global sclerosis of glomeruli was probably secondary to the prominent vascular disease. In point of fact, the finding of sub-epithelial ‘hump’-like deposits and intramembranous deposits in the capillary loops without the changes by immunofluorescence microscopy suggests a previous episode of acute post-infectious glomerulonephritis, which is currently quiescent. The early nodular expansion of the mesangium noted in this biopsy is also unusual in the absence of diabetes mellitus. Other processes that could have led to the development of nodular glomerulosclerosis include healed mesangiolysis in patients with thrombotic angiopathies and paraprotein deposition disease, both of which were ruled out in this patient. Osler is quoted as saying ‘It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.’ This is underscored by the presentation reported herein. The absence of any history of vascular intervention or the use of anti-coagulant or thrombolytic 127
the renal consult
drugs, and the lack of external evidence of peripheral skin lesions made the clinical diagnosis of AE challenging. The only suggestive history was that of an elderly male with long-standing hypertension and hypercholesterolemia. The diagnostic lesion of AE was observed on renal biopsy examination. Indeed, in the absence of livedo reticularis, cyanosis, or distal gangrene, the diagnosis of AE may escape detection both in acute as well as chronic presentations unless a systematic approach of screening for risk factors in high-risk individuals is instituted. This case presentation illustrates the importance of considering the diagnosis of AE in any elderly patient with progressive kidney disease of unknown cause. The presentation also underscores the importance of performing a kidney biopsy to definitively make the diagnosis. AE, also known as cholesterol embolism, is a welldescribed entity, which results from peripheral embolization of small cholesterol crystals that fracture off of ruptured atherosclerotic plaques from proximal regions of the vasculature. Although atheroembolism syndrome was recognized as a clinicopathologic entity more than 50 years ago,1 it is attracting growing attention because of the exponential increase in the use of new invasive cardiovascular diagnostic and therapeutic procedures. With increasing age of renal transplant donors, it is also increasingly recognized as a cause of rapid graft failure (related to renal artery atherosclerosis).2 IS ATHEROEMBOLISM A RARE DISEASE OR UNDER-RECOGNIZED?
There is uncertainty regarding the prevalence and the clinical significance of AE. The prevalence of AE reported in clinical series is variable and appears to be dependent on sampling bias: AE is higher in autopsy series and in studies of selected populations. One of the earliest reports of AE was by Flory,1 who observed an incidence of 4.4% in consecutive autopsies. On the other hand, Kealy3 reported a low incidence of 0.79% in the 2126 autopsies performed in patients over 60 years of age. However, in the Kealy study, the prevalence of AE among patients who had underlying risk factors was not reported.3 Thurlbeck and Castleman4 reported an incidence of 77% among patients who died after abdominal surgery. Mayo and Swartz5 in their retrospective analysis of all inpatient nephrology consultations over 7 months observed 4% of in-patient nephrology consultations, representing approximately 5–10% of the acute renal failures, attributable to clinically significant AE. Mayo and Swartz suggest that the prevalence of AE is high. In their series AE was diagnosed every 2 weeks. CLINICAL FEATURES
AE is a multisystem disease and clinical features can be varied. Multifocal lesions and progressive tissue loss secondary to ischemic injury involving the kidney, skin, brain, myocardium, and intestines that mimic systemic vasculitis or sub-acute bacterial endocarditis.6–8 Commonly observed clinical findings include fever, myalgia and hypertension, 128
BV Mittal et al.: Atheroembolic renal disease
livedo reticularis and cyanotic changes in the skin,7,8 and distal gangrene or necrotic ulcers9,10 are also common. Extra-renal involvement of central nervous system and gastrointestinal changes and retinal emboli have been documented.8 Renal manifestations may vary from acute, sub-acute, or chronic kidney failure. In addition, kidney function may transiently improve in AE because areas of ischemic acute tubular necrosis that may be coincidentally present spontaneously recover. Peripheral or urinary eosinophilia and hypocomplementemia are commonly reported laboratory abnormalities; however, these are most often transient and mild. Other laboratory abnormalities, such as raised erythrocyte sediment rate, increased amylase, abnormal liver function tests, and raised creatine phosphokinase, as well as a positive antinuclear cytoplasmic antibody have all been reported.11 RISK FACTORS AND ‘TRIGGER’ EVENTS
There is consensus that atherosclerosis is a pre-requisite for the development of AE. Not surprisingly, the disease is most commonly observed in those older than 50 years.1 Males are more commonly affected.10–13 Preferential occurrence in Caucasians has been observed.11,14 Other risk factors of vascular obstruction, such as smoking, hypertension, and diabetes mellitus, have also been reported.9 Spontaneous detachment of cholesterol emboli in patients with marked atherosclerotic arterial lesions has been observed15 AE is of iatrogenic etiology in three quarters of all patients. The ‘trigger’ events for AE are endovascular procedures, vascular surgery including coronary bypass grafting, and long-term anticoagulant or thrombolytic therapy.9–11,16–19 AE affecting the kidney is also a common complication of atherosclerotic renal artery disease. With higher numbers of donors and recipients of older age being accepted for transplantation, AE in renal transplant recipients is probably to become more common and will be increasingly considered as a cause of graft dysfunction.2,20 A typical triad of a ‘trigger’ event, subacute renal failure and peripheral lesions in skin/retina should strongly suggest the diagnosis. ‘Spontaneous’ cholesterol embolism, as noted in this case is rare. Cross,15 in a series of 372 necropsies, estimated the incidence of spontaneous cholesterol embolism to be 1.9%. Scolari et al,11 found that in his series of ninety five patients with AE, 13% had spontaneous AE. The clinical presentation is usually one of a low-grade clinically silent migration of crystals from the atherosclerotic plaque. On the other hand, since the ‘shower’ of cholesterol crystals occurs over a longer period of time and quite insidiously, it is possible that patients who present with spontaneous AE have more severe and complicated atherosclerosis. PATHOLOGIC FEATURES OF AE
While histological confirmation can be accomplished by biopsying any of the affected target organs, such as skin or muscle, the highest diagnostic yield comes from performing a kidney biopsy.8 However, an important caveat is that since Kidney International (2008) 73, 126–130
the renal consult
BV Mittal et al.: Atheroembolic renal disease
cholesterol crystal embolization is a patchy process, a focal lesion usually ensues. Hence, obtaining an adequate sample and careful scrutiny of multiple step sections is very important. AE is histologically characterized by elongated, biconvex transparent needle-shaped clefts, which represent the cholesterol crystals that are dissolved during tissue processing. These crystals are usually small and may not completely occlude the vessel lumen; however, they frequently induce an endothelial inflammatory response, which leads to a complete obstruction of the vessel within weeks or months. Ischemia secondary to vascular occlusion leads to glomerular shrinkage, wrinkling, and apparent thickening of glomerular basement membrane. Greenberg et al.13 have described accompanying focal and segmental glomerulosclerosis in 63% of biopsies with AE. In their study, the percentage of segmentally sclerosed glomeruli, and in particular the cellular variant of focal and segmental glomerulosclerosis, was higher in patients with AE and nephrotic range proteinuria.13 A proportional increase in the interstitial fibrosis and infiltration with mononuclear cells follows glomerular sclerosis. Occasionally, other associated conditions with AE have been noted, and Greenberg13 described one subject with membranous nephropathy along with AE. AE can be diagnosed on light microscopy. Direct immunofluorescence microscopy or transmission electron microscopy is not necessary for the initial diagnosis or confirmation of the diagnosis. However, both immunofluorescence and electron microscopy help in the identification of other associated lesions in the same biopsy. This point is underscored by the patient presented here who had a biopsy showing AE and evidence of a prior immune complex mediated process that was ultimately recognized on electron microscopy. DIFFERENTIAL DIAGNOSIS OF AE
Several conditions can mimic renal involvement in AE. The common conditions that need to be differentiated clinically from the chronic presentation of AE are hypertensive nephrosclerosis and renal artery stenosis. In both, renal impairment due to either of these conditions may precede the development of AE; both may be independent determinants of patient and renal outcome.11 In the presence of acute renal failure following radiocontrast use, differentiation of AE from radiocontrast-induced nephrotoxicity is important. Multisystem involvement noted in polyarteritis, disseminated angitis, or sub-acute bacterial endocarditis associated with disseminated thromboembolization may mimic AE. AE can induce eosinophilia as well as an anti-neutrophil cytoplasmic antibody negative angitis;6 indeed, reports of perinuclear anti-neutrophil cytoplasmic antibody have been reported in the literature, and in such cases, making a differentiation from true vasculitis becomes even more challenging.21 Immunoallergic interstitial nephritis also presents with acute renal failure with skin lesions and eosinophilia.22 The range of differential diagnosis should also include active interstitial Kidney International (2008) 73, 126–130
nephritis, acute tubular necrosis, and rapidly progressive glomerulonephritis. The extensive differential diagnosis underlines the necessity of histologic confirmation of AE. The prognosis of AE is generally quite poor.8,23 The cause of death is usually multiorgan failure due to visceral ischemia, in particular cardiovascular disease rather than end-stage kidney failure alone.11,23 The prognosis depends on the severity and number of comorbid risk factors (Table 2)5 and the number and size of cholesterol crystals. Scolari et al. have also reported that the age of the patient and the presence of diabetes mellitus are independent risk factors for patient mortality in AE renal disease. Male gender was associated with a decreased risk of mortality. Pre-existing renal impairment, which probably reflects co-existing often severe atherosclerosis/arteriolosclerosis has also been demonstrated to be an independent determinant of patient and renal outcomes.11,12,24 If AE is detected early, Theriault et al.25 have reported renal recovery in 12 out of 43 cases with renal failure requiring dialysis after a mean delay of 4097306 days. Peripheral eosinophilia was significantly higher in patients who had recovery of renal function.12 MANAGEMENT OF ATHEROEMBOLISM
There is no definitive treatment for AE; symptomatic and preventive measures have been advocated. Various treatment strategies have been pursued including with low-density lipoprotein apheresis26 and low-dose corticosteroids.27 Supportive measures include angiotensin blockade for predialysis patients and hemodialysis support for those who reach end-stage renal disease. Kryvoshey et al.28 have also reported successful renal transplantation in one patient following long-term control of atherosclerotic risk factors. Other important preventive measures include, secondary prevention of atherosclerotic risk factors, avoiding anticoagulant therapy, invasive radiology, and vascular surgery in subjects with extensive arteriosclerosis. The possibility of using a brachial approach for aortogram or coronary angiogram to prevent AE needs to be considered. Statins have been shown to have a plaque-stabilizing effect, perhaps
Table 2 | Summary of risk factors of AE renal disease Predisposing factors Atherosclerotic cardiovascular disease Hypertension Smoking Hypercholesterolemia Diabetes mellitus Age455 years Iatrogenic Angiography or angioplasty Vascular surgery Cardiopulmonary resuscitation Anticoagulant or thrombolytic therapy Blunt trauma Spontaneous 129
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BV Mittal et al.: Atheroembolic renal disease
10.
as a result of their cholesterol-lowering effect as well as anti-inflammatory and immunomodulatory properties.29 Improvement in patient and renal survival with aggressive management has been documented in some reports.25,30
12.
CONCLUSION
13.
AE is an under-recognized cause of kidney failure. It should be considered in the differential diagnosis of any patient who presents with progressive kidney failure, particularly if the patient is elderly with risk factors for atherosclerosis. Although poor outcomes have been associated with AE, early recognition and institution of aggressive therapies targeted at secondary prevention have been shown to stabilize and, in a limited number of cases, even improve renal function. A typical triad of a ‘trigger’ event, sub-acute kidney failure and peripheral lesions in skin/retina should strongly suggest the diagnosis. As a number of clinical conditions can mimic AE clinically, a biopsy diagnosis (skin, muscle, or kidney) will provide a definitive diagnosis and should be considered. However, as discussed in the patient presented here, AE may present with disease limited only to the kidneys, and a kidney biopsy becomes essential in making a diagnosis. Avoidance of interventional radiologic procedures, vascular surgery, and excess anticoagulation in elderly atherosclerotic patients is sensible but is often unavoidable. REFERENCES 1. Flory CM. Arterial occlusion produced by emboli from eroded aortic atheromatous plaques. Am J Pathol 1945; 21: 549–565. 2. Scolari F, Tardanico R, Pola A et al. Cholesterol crystal embolic disease in renal allografts. J Nephrol 2003; 16: 139–143. 3. Kealy W. Atheroembolism. J Clin Pathol 1978; 31: 984–989. 4. Thurlbeck WM, Castleman B. Atheromatous emboli to the kidneys after aortic surgery. New Engl J Med 1957; 257: 442–447. 5. Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996; 100: 524–529. 6. Peat DS, Mathieson PW. Cholesterol emboli may mimic systemic vasculitis. Br Med J 1996; 313: 546–547. 7. Aviles B, Ubeda I, Blanco J et al. Pauci-immune extracapillary glomerulonephritis and atheromatous embolization. Am J Kidney Dis 2002; 40: 847–851. 8. Scolari F, Tardanico R, Zani R et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000; 36: 1089–1109. 9. Dahlberg PJ, Frecentese DF, Cogbill TH. Cholesterol embolism: experience with 22 histologically proven cases. Surgery 1989; 105: 737–746.
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11.
14. 15. 16.
17.
18. 19.
20.
21.
22.
23. 24. 25.
26.
27.
28. 29.
30.
Fine MJ, Kapoor W, Falanga V. Crystal embolization: a review of 221 cases in the English literature. Angiology 1987; 38: 769–784. Scolari F, Ravani P, Pola A et al. Predictors of renal and patient outcomes in atheroembolic renal disease: a prospective study. J Am Soc Nephrol 2003; 14: 1584–1590. Hara S, Asada Y, Fujimoto S et al. Atheroembolic renal disease: clinical findings of 11 cases. J Atheroscler Thromb 2002; 9: 288–291. Greenberg A, Bastacky SI, Iqbal A et al. Focal segmental glomerulosclerosis associated with nephrotic syndrome in cholesterol atheroembolism: clinicopathological correlations. Am J Kidney Dis 1997; 29: 334–344. Saklayen M. Atheroembolic renal disease: preferential occurrence in whites only. Am J Nephrol 1989; 9: 87–88. Cross SS. How common is cholesterol embolism? J Clin Pathol 1991; 44: 859–861. Belenfant X, Meyrier A, Jacquot C. Supportive treatment improves survival in multivisceral cholesterol crystal embolism. Am J Kidney Dis 1999; 33: 840–850. Colt HG, Begg RJ, Saporito JJ et al. Cholesterol emboli after cardiac catheterization. Eight cases and a review of the literature. Medicine (Baltimore) 1988; 67: 389–400. Falanga V, Fine MJ, Kapoor WN. The cutaneous manifestations of cholesterol crystal embolization. Arch Dermatol 1986; 122: 1194–1198. Lin PH, Bush RL, Conklin BS et al. Late complication of aortoiliac stent placement atheroembolization of the lower extremities. J Surg Res 2002; 103: 153–159. Schonermarck U, Guba M, Weiss M et al. Cholesterol atheroembolic disease in kidney allografts-case report and review of the literature. Clin Nephrol 2006; 66: 386–390. Kaplan-Pavlovcic S, Vizjak A, Vene N et al. Antineutrophil cytoplasmic autoantibodies in atheroembolic disease. Nephrol Dial Transplant 1998; 13: 985–987. Espejo B, Herrero JC, Torres A et al. Immunoallergic interstitial nephritis vs. cholesterol atheroembolism. Differentiating characteristics. Nefrologia 2003; 23: 125–130. Meyrier A. Cholesterol crystal embolism: diagnosis and treatment. Kidney Int 2006; 69: 1308–1312. Zuccala A, Zucchelli P. A renal disease frequently found at postmortem, but rarely diagnosed in vivo. Nephrol Dial Transplant 1997; 12: 1762–1767. 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–c18. Sanai T, Matsui R, Hirano T. LDL apheresis for cholesterol embolism following coronary artery bypass graft surgery—a case report. Angiology 2006; 57: 379–382. Nakayama M, Nagata M, Hirano T et al. Low-dose prednisolone ameliorates acute renal failure caused by cholesterol crystal embolism. Clin Nephrol 2006; 66: 232–239. Kryvoshey D, Kammerl M, Hoffmann U et al. Cholesterol crystal embolism: diagnostic and treatment. Kidney Int 2006; 70: 1525. Martin-Ventura JL, Blanco-Colio LM, Gomez-Hernandez A et al. Intensive treatment with atorvastatin reduces inflammation in mononuclear cells and human atherosclerotic lesions in one month. Stroke 2005; 36: 1796–1800. Belenfant X. Cholesterol crystal embolism disease, diagnostic criteria. Presse Med 2002; 31: 1271–1276.
Kidney International (2008) 73, 126–130
Atheroembolic renal disease: A silent masquerader BV Mittal1, MP Alexander2, HG Rennke2 and AK Singh1 1 2
Renal Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA and Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
RENAL BIOPSY
CASE PRESENTATION A 76-year-old white male with hypertension, progressive renal insufficiency, and proteinuria of unclear etiology was admitted for renal biopsy in June 2005. His kidney disease had steadily progressed over the past 3 years. On admission, he complained of fatigue with increased daytime somnolence, loss of appetite, weight loss, and increased itching. There was no nausea, vomiting, or other uremic symptoms. Review of systems revealed mild cold intolerance, complaints of occasional mild non-exertional chest pains lasting minutes, and bilateral knee pain. There were no neurologic symptoms. His past medical history was notable for gout, glaucoma, arthritis, hypertension, and chronic kidney disease. There was no history of any invasive vascular procedure, use of radio-contrast agent, or treatment with anticoagulant or thrombolytic agents. He had been taking amlodipine, hydrochlorothiazide, enalapril, and atorvastatin before admission. He was a nonsmoker and not a current alcohol user. On examination, he was a well-oriented alert elderly male, his peripheral pulse rate was 57 beats/minute regular in rate and rhythm, and his blood pressure was 153/ 77 mm Hg. His lower extremities were well perfused with no ischemic or gangrenous lesions. There was no livedo reticularis and no muscle tenderness. He did not have peripheral edema. Laboratory investigations (Table 1) revealed a white blood cell count of 5.86 K/ml, with a normal differential count and no evidence of eosinophilia. His blood urea nitrogen was 53 mg/dl, serum creatinine 4.4 mg/dl, and an estimated glomerular filtration rate was 14 ml/min/ 1.73 m2. Urine dipstick showed a urine albumin of 3 þ , and the sediment revealed 2–3 white blood cells and 0–1 red blood cell/high power field. Spot protein/creatinine ratio was 4.7 mg/g of creatinine. Chest X-ray revealed cardiomegaly with a tortuous atherosclerotic aorta.
A total of seven glomeruli were present: two were globally obsolescent and three showed focal segmental glomerulosclerosis. The remaining two glomeruli appeared mildly hypertrophic with mild mesangial hypercellularity and a slight expansion of mesangial matrix. Double contours were noted focally in capillary wall segments. The larger arteries displayed vascular sclerosis of the media with hyaline intimal thickening. Elongated, empty, cleft-like crystal spaces lodged within and occluding the lumina of an arteriole characteristic of cholesterol crystal emboli were observed (Figure 1). Cholesterol emboli were also noted in the wall of an interlobular artery in the tolidine blue-stained sections submitted for electron microscopic examination. There was no perivascular inflammation. Areas of ischemic injury with parenchymal scarring, extensive tubular atrophy, thickening of tubular basement membranes, numerous periodic acidSchiff-positive casts within atrophic tubules and extensive interstitial fibrosis (90%) were present (Figure 2). Immunofluorescence revealed no significant immune deposits, with only segmental IgM deposits ( þ þ þ /4 þ ) and C3 ( þ þ / 4 þ ) in two glomeruli. On electron microscopy, there was marked visceral epithelial cell foot process fusion with microvillous formation. Isolated loops revealed double contours and occasional sub-epithelial humps were seen along the capillary loops. The mesangial matrix showed a marked increase without electron dense/lucent deposits. DIAGNOSIS
Correspondence: AK Singh, Clinical Director, Renal Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA. E-mail: [email protected]
A diagnosis of progressive kidney failure secondary to spontaneous atheroembolic (AE) disease and small-vessel vascular disease was made. This was largely based on the kidney biopsy findings, which showed moderately severe vascular sclerosis, with AE disease; advanced focal and segmental glomerulosclerosis, secondary to vascular disease and potentially secondary to superimposed functional and structural adaptations. The presence of an occasional subepithelial ‘hump’-like deposit suggested the possibility of a prior and currently inactive episode of post-infectious glomerulonephritis.
Kidney International (2008) 73, 126–130; doi:10.1038/sj.ki.5002433; published online 1 August 2007
CLINICAL FOLLOW UP
Received 23 April 2007; revised 29 May 2007; accepted 19 June 2007; published online 1 August 2007
The patient’s blood pressure was managed with amlodipine 10 mg/day and enalapril 5 mg/day. He also received 10 mg day
126
Kidney International (2008) 73, 126–130
the renal consult
BV Mittal et al.: Atheroembolic renal disease
Table 1 | Laboratory findings Date
6/22/05
Serum/blood BUN (mg/dl) Creatinine (mg/dl)
53 4.4
MDRD-GFR ml/min/1.73 m2 Absolute eosinophil count (peripheral) (K/ml)
14 0.15
Urinalysis Blood Albumin Urinary eosinophils Spot creatinine Spot protein
Trace 3+ Nil 38.7 184.1
1/06
0.01
2/06
0.08
3+ 3+ Nil
9/06
11/06
12/06
1/07
36/19a 4.0
34 4.9
43/13a 5.6
58/15a 6.7
10 0.13
9 0.12
16 0.17
12
3+ 3+
BUN, blood urea nitrogen; MDRD-GFR, Modification of Diet in Renal Disease-glomerular filtration rate. a Pre and post-dialysis values.
Figure 1 | An arteriole displays luminal occlusion by characteristic biconvex needle-shaped cleft-like empty spaces of cholesterol emboli. (Trichrome, original magnification 400).
of atorvastatin for his hypercholesterolemia. Over the next 8 months, his serum creatinine increased from 4.4 to 5.7 mg/dl (estimation of glomerular filtration rate of 10 ml/min/ 1.73 m2) and he continued to have proteinuria. He developed worse uremia. Hence, he was initiated on hemodialysis in February 2006. As of January 2007, he has remained stable on chronic maintenance hemodialysis. DISCUSSION
This patient presented clinically with progressive renal failure of unclear etiology. A diagnosis of AE renal disease was made on the basis of the renal biopsy. The presentation illustrates the importance of considering a wide differential diagnosis in elderly patients who present with progressive renal failure. Furthermore, the absence of precipitating factors or clinical stigmata of AE should not necessarily deter clinicians from considering this possibility in the differential diagnosis. The kidney biopsy showed prominent vascular disease with characteristic AE and cortical scarring. The advanced Kidney International (2008) 73, 126–130
Figure 2 | An area of the submitted tissue shows parenchymal scarring with a single sclerosed glomerulus, most probably reflective of the ischemic injury. (PAS, original magnification 200).
segmental and global sclerosis of glomeruli was probably secondary to the prominent vascular disease. In point of fact, the finding of sub-epithelial ‘hump’-like deposits and intramembranous deposits in the capillary loops without the changes by immunofluorescence microscopy suggests a previous episode of acute post-infectious glomerulonephritis, which is currently quiescent. The early nodular expansion of the mesangium noted in this biopsy is also unusual in the absence of diabetes mellitus. Other processes that could have led to the development of nodular glomerulosclerosis include healed mesangiolysis in patients with thrombotic angiopathies and paraprotein deposition disease, both of which were ruled out in this patient. Osler is quoted as saying ‘It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.’ This is underscored by the presentation reported herein. The absence of any history of vascular intervention or the use of anti-coagulant or thrombolytic 127
the renal consult
drugs, and the lack of external evidence of peripheral skin lesions made the clinical diagnosis of AE challenging. The only suggestive history was that of an elderly male with long-standing hypertension and hypercholesterolemia. The diagnostic lesion of AE was observed on renal biopsy examination. Indeed, in the absence of livedo reticularis, cyanosis, or distal gangrene, the diagnosis of AE may escape detection both in acute as well as chronic presentations unless a systematic approach of screening for risk factors in high-risk individuals is instituted. This case presentation illustrates the importance of considering the diagnosis of AE in any elderly patient with progressive kidney disease of unknown cause. The presentation also underscores the importance of performing a kidney biopsy to definitively make the diagnosis. AE, also known as cholesterol embolism, is a welldescribed entity, which results from peripheral embolization of small cholesterol crystals that fracture off of ruptured atherosclerotic plaques from proximal regions of the vasculature. Although atheroembolism syndrome was recognized as a clinicopathologic entity more than 50 years ago,1 it is attracting growing attention because of the exponential increase in the use of new invasive cardiovascular diagnostic and therapeutic procedures. With increasing age of renal transplant donors, it is also increasingly recognized as a cause of rapid graft failure (related to renal artery atherosclerosis).2 IS ATHEROEMBOLISM A RARE DISEASE OR UNDER-RECOGNIZED?
There is uncertainty regarding the prevalence and the clinical significance of AE. The prevalence of AE reported in clinical series is variable and appears to be dependent on sampling bias: AE is higher in autopsy series and in studies of selected populations. One of the earliest reports of AE was by Flory,1 who observed an incidence of 4.4% in consecutive autopsies. On the other hand, Kealy3 reported a low incidence of 0.79% in the 2126 autopsies performed in patients over 60 years of age. However, in the Kealy study, the prevalence of AE among patients who had underlying risk factors was not reported.3 Thurlbeck and Castleman4 reported an incidence of 77% among patients who died after abdominal surgery. Mayo and Swartz5 in their retrospective analysis of all inpatient nephrology consultations over 7 months observed 4% of in-patient nephrology consultations, representing approximately 5–10% of the acute renal failures, attributable to clinically significant AE. Mayo and Swartz suggest that the prevalence of AE is high. In their series AE was diagnosed every 2 weeks. CLINICAL FEATURES
AE is a multisystem disease and clinical features can be varied. Multifocal lesions and progressive tissue loss secondary to ischemic injury involving the kidney, skin, brain, myocardium, and intestines that mimic systemic vasculitis or sub-acute bacterial endocarditis.6–8 Commonly observed clinical findings include fever, myalgia and hypertension, 128
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livedo reticularis and cyanotic changes in the skin,7,8 and distal gangrene or necrotic ulcers9,10 are also common. Extra-renal involvement of central nervous system and gastrointestinal changes and retinal emboli have been documented.8 Renal manifestations may vary from acute, sub-acute, or chronic kidney failure. In addition, kidney function may transiently improve in AE because areas of ischemic acute tubular necrosis that may be coincidentally present spontaneously recover. Peripheral or urinary eosinophilia and hypocomplementemia are commonly reported laboratory abnormalities; however, these are most often transient and mild. Other laboratory abnormalities, such as raised erythrocyte sediment rate, increased amylase, abnormal liver function tests, and raised creatine phosphokinase, as well as a positive antinuclear cytoplasmic antibody have all been reported.11 RISK FACTORS AND ‘TRIGGER’ EVENTS
There is consensus that atherosclerosis is a pre-requisite for the development of AE. Not surprisingly, the disease is most commonly observed in those older than 50 years.1 Males are more commonly affected.10–13 Preferential occurrence in Caucasians has been observed.11,14 Other risk factors of vascular obstruction, such as smoking, hypertension, and diabetes mellitus, have also been reported.9 Spontaneous detachment of cholesterol emboli in patients with marked atherosclerotic arterial lesions has been observed15 AE is of iatrogenic etiology in three quarters of all patients. The ‘trigger’ events for AE are endovascular procedures, vascular surgery including coronary bypass grafting, and long-term anticoagulant or thrombolytic therapy.9–11,16–19 AE affecting the kidney is also a common complication of atherosclerotic renal artery disease. With higher numbers of donors and recipients of older age being accepted for transplantation, AE in renal transplant recipients is probably to become more common and will be increasingly considered as a cause of graft dysfunction.2,20 A typical triad of a ‘trigger’ event, subacute renal failure and peripheral lesions in skin/retina should strongly suggest the diagnosis. ‘Spontaneous’ cholesterol embolism, as noted in this case is rare. Cross,15 in a series of 372 necropsies, estimated the incidence of spontaneous cholesterol embolism to be 1.9%. Scolari et al,11 found that in his series of ninety five patients with AE, 13% had spontaneous AE. The clinical presentation is usually one of a low-grade clinically silent migration of crystals from the atherosclerotic plaque. On the other hand, since the ‘shower’ of cholesterol crystals occurs over a longer period of time and quite insidiously, it is possible that patients who present with spontaneous AE have more severe and complicated atherosclerosis. PATHOLOGIC FEATURES OF AE
While histological confirmation can be accomplished by biopsying any of the affected target organs, such as skin or muscle, the highest diagnostic yield comes from performing a kidney biopsy.8 However, an important caveat is that since Kidney International (2008) 73, 126–130
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cholesterol crystal embolization is a patchy process, a focal lesion usually ensues. Hence, obtaining an adequate sample and careful scrutiny of multiple step sections is very important. AE is histologically characterized by elongated, biconvex transparent needle-shaped clefts, which represent the cholesterol crystals that are dissolved during tissue processing. These crystals are usually small and may not completely occlude the vessel lumen; however, they frequently induce an endothelial inflammatory response, which leads to a complete obstruction of the vessel within weeks or months. Ischemia secondary to vascular occlusion leads to glomerular shrinkage, wrinkling, and apparent thickening of glomerular basement membrane. Greenberg et al.13 have described accompanying focal and segmental glomerulosclerosis in 63% of biopsies with AE. In their study, the percentage of segmentally sclerosed glomeruli, and in particular the cellular variant of focal and segmental glomerulosclerosis, was higher in patients with AE and nephrotic range proteinuria.13 A proportional increase in the interstitial fibrosis and infiltration with mononuclear cells follows glomerular sclerosis. Occasionally, other associated conditions with AE have been noted, and Greenberg13 described one subject with membranous nephropathy along with AE. AE can be diagnosed on light microscopy. Direct immunofluorescence microscopy or transmission electron microscopy is not necessary for the initial diagnosis or confirmation of the diagnosis. However, both immunofluorescence and electron microscopy help in the identification of other associated lesions in the same biopsy. This point is underscored by the patient presented here who had a biopsy showing AE and evidence of a prior immune complex mediated process that was ultimately recognized on electron microscopy. DIFFERENTIAL DIAGNOSIS OF AE
Several conditions can mimic renal involvement in AE. The common conditions that need to be differentiated clinically from the chronic presentation of AE are hypertensive nephrosclerosis and renal artery stenosis. In both, renal impairment due to either of these conditions may precede the development of AE; both may be independent determinants of patient and renal outcome.11 In the presence of acute renal failure following radiocontrast use, differentiation of AE from radiocontrast-induced nephrotoxicity is important. Multisystem involvement noted in polyarteritis, disseminated angitis, or sub-acute bacterial endocarditis associated with disseminated thromboembolization may mimic AE. AE can induce eosinophilia as well as an anti-neutrophil cytoplasmic antibody negative angitis;6 indeed, reports of perinuclear anti-neutrophil cytoplasmic antibody have been reported in the literature, and in such cases, making a differentiation from true vasculitis becomes even more challenging.21 Immunoallergic interstitial nephritis also presents with acute renal failure with skin lesions and eosinophilia.22 The range of differential diagnosis should also include active interstitial Kidney International (2008) 73, 126–130
nephritis, acute tubular necrosis, and rapidly progressive glomerulonephritis. The extensive differential diagnosis underlines the necessity of histologic confirmation of AE. The prognosis of AE is generally quite poor.8,23 The cause of death is usually multiorgan failure due to visceral ischemia, in particular cardiovascular disease rather than end-stage kidney failure alone.11,23 The prognosis depends on the severity and number of comorbid risk factors (Table 2)5 and the number and size of cholesterol crystals. Scolari et al. have also reported that the age of the patient and the presence of diabetes mellitus are independent risk factors for patient mortality in AE renal disease. Male gender was associated with a decreased risk of mortality. Pre-existing renal impairment, which probably reflects co-existing often severe atherosclerosis/arteriolosclerosis has also been demonstrated to be an independent determinant of patient and renal outcomes.11,12,24 If AE is detected early, Theriault et al.25 have reported renal recovery in 12 out of 43 cases with renal failure requiring dialysis after a mean delay of 4097306 days. Peripheral eosinophilia was significantly higher in patients who had recovery of renal function.12 MANAGEMENT OF ATHEROEMBOLISM
There is no definitive treatment for AE; symptomatic and preventive measures have been advocated. Various treatment strategies have been pursued including with low-density lipoprotein apheresis26 and low-dose corticosteroids.27 Supportive measures include angiotensin blockade for predialysis patients and hemodialysis support for those who reach end-stage renal disease. Kryvoshey et al.28 have also reported successful renal transplantation in one patient following long-term control of atherosclerotic risk factors. Other important preventive measures include, secondary prevention of atherosclerotic risk factors, avoiding anticoagulant therapy, invasive radiology, and vascular surgery in subjects with extensive arteriosclerosis. The possibility of using a brachial approach for aortogram or coronary angiogram to prevent AE needs to be considered. Statins have been shown to have a plaque-stabilizing effect, perhaps
Table 2 | Summary of risk factors of AE renal disease Predisposing factors Atherosclerotic cardiovascular disease Hypertension Smoking Hypercholesterolemia Diabetes mellitus Age455 years Iatrogenic Angiography or angioplasty Vascular surgery Cardiopulmonary resuscitation Anticoagulant or thrombolytic therapy Blunt trauma Spontaneous 129
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10.
as a result of their cholesterol-lowering effect as well as anti-inflammatory and immunomodulatory properties.29 Improvement in patient and renal survival with aggressive management has been documented in some reports.25,30
12.
CONCLUSION
13.
AE is an under-recognized cause of kidney failure. It should be considered in the differential diagnosis of any patient who presents with progressive kidney failure, particularly if the patient is elderly with risk factors for atherosclerosis. Although poor outcomes have been associated with AE, early recognition and institution of aggressive therapies targeted at secondary prevention have been shown to stabilize and, in a limited number of cases, even improve renal function. A typical triad of a ‘trigger’ event, sub-acute kidney failure and peripheral lesions in skin/retina should strongly suggest the diagnosis. As a number of clinical conditions can mimic AE clinically, a biopsy diagnosis (skin, muscle, or kidney) will provide a definitive diagnosis and should be considered. However, as discussed in the patient presented here, AE may present with disease limited only to the kidneys, and a kidney biopsy becomes essential in making a diagnosis. Avoidance of interventional radiologic procedures, vascular surgery, and excess anticoagulation in elderly atherosclerotic patients is sensible but is often unavoidable. REFERENCES 1. Flory CM. Arterial occlusion produced by emboli from eroded aortic atheromatous plaques. Am J Pathol 1945; 21: 549–565. 2. Scolari F, Tardanico R, Pola A et al. Cholesterol crystal embolic disease in renal allografts. J Nephrol 2003; 16: 139–143. 3. Kealy W. Atheroembolism. J Clin Pathol 1978; 31: 984–989. 4. Thurlbeck WM, Castleman B. Atheromatous emboli to the kidneys after aortic surgery. New Engl J Med 1957; 257: 442–447. 5. Mayo RR, Swartz RD. Redefining the incidence of clinically detectable atheroembolism. Am J Med 1996; 100: 524–529. 6. Peat DS, Mathieson PW. Cholesterol emboli may mimic systemic vasculitis. Br Med J 1996; 313: 546–547. 7. Aviles B, Ubeda I, Blanco J et al. Pauci-immune extracapillary glomerulonephritis and atheromatous embolization. Am J Kidney Dis 2002; 40: 847–851. 8. Scolari F, Tardanico R, Zani R et al. Cholesterol crystal embolism: a recognizable cause of renal disease. Am J Kidney Dis 2000; 36: 1089–1109. 9. Dahlberg PJ, Frecentese DF, Cogbill TH. Cholesterol embolism: experience with 22 histologically proven cases. Surgery 1989; 105: 737–746.
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