DISEASE OF THE MONTH J Am Soc Nephrol 12: 1781–1787, 2001 Eberhard Ritz, Feature Editor

Atheroembolic Renal Disease

KULWANT S. MODI and VENKATESWARA K. RAO Division of Nephrology, Department of Medicine, Hennepin County Medical Center, and University of Minnesota Medical School, Minneapolis, Minnesota.

Atheroembolic renal disease (AERD), also called atheroem- incidence of 4% in elderly subjects (age 65 yr and older) who bolism (1), (2,3), cholesterol atheroem- had minimal . However, the incidence increased bolic renal disease (4), or cholesterol crystal embolization (5), to 77% in older patients with severe atherosclerosis. Most of often is an underdiagnosed clinical illness. The is these later subjects had undergone surgical repair of an abdom- usually involved because of proximity of the renal to inal aortic . In a study, Jones and Iannaccone abdominal , wherein the erosion of atheromatous plaque is (14) reported an incidence of 1.1%. Of the 755 renal most likely to occur. Cholesterol embolism also can occur in reviewed in this study (all age groups), only 8 (1.1%) had other visceral organs, as well as in the upper and lower ex- features of AERD. Greenberg et al. (15) reviewed 500 renal tremities. Because the renal arteries have their origin from biopsies and detected AERD in 24 cases (1.6%). Preston et al. abdominal aorta and an enormous amount of blood flows (16) reported an incidence of 4.25% in older patients (age 65 yr through the kidney, it becomes a prime target in cholesterol and older) who underwent a . The low incidence of crystal embolization. AERD diagnosed on renal biopsy most likely is due to a selection bias. AERD was diagnosed as the primary cause of Definition of AERD renal failure in 1.9% of our patients accepted for chronic AERD can be defined as renal failure secondary to the dialysis between 1985 and 1990 and 2.7% between 1991 and occlusion of renal arteries, , and glomerular capillar- 1995. It is conceivable that there may have been other patients ies with atheromatous plaques that are dislodged from the aorta who had chronic renal failure secondary to AERD and who and other major arteries. The release of cholesterol plaques into were not in need of dialysis and were not included. the circulation can occur spontaneously or after intravascular The reported incidence of AERD varied in the literature trauma with angiographic catheters or after the use of antico- because of the differences in study design and the different agulants and thrombolytic agents. Like the native kidneys, a criteria used for making the diagnosis. For example, retrospec- transplanted kidney also can be affected with cholesterol em- tive data derived from or biopsy studies may exagger- bolism (6–8), and it should be considered in the differential ate the frequency by including many subclinical cases. Clinical diagnosis of worsening renal allograft function. Furthermore, observations that are based on a short duration of follow-up AERD should be distinguished from other embolic disorders, after an invasive vascular procedure and the infrequency of the such as atrial fibrillation, left atrial myxoma, and bacterial confirmatory renal biopsies can lead to an underestimation of . the true incidence of AERD. However, during the past few years, the observed incidence of AERD in clinical practice Incidence of AERD seems to have increased. The possible reasons include (1) The exact incidence of AERD is not known. The clinical increased clinical awareness, (2) increased longevity of pa- experience is limited to isolated case reports and clinicopath- tients with atherosclerotic , (3) an increase in ologic case discussion (9,10). There have been no prospective the number of invasive vascular procedures, and (4) the routine studies that focused on this problem in a systematic manner. use of thrombolytics and in clinical practice. From a historical perspective, Panum (11) first described this entity in 1862. Subsequently, Flory (12) published a series of autopsy cases of atheroembolism in 1945. Thurlbeck and Diagnosis of AERD There are many inherent difficulties in diagnosing AERD. It Castlemann (13) reviewed their autopsy cases and reported an therefore has been labeled as the great masquerader (2). The specific diagnosis can be made only by demonstrating the cholesterol crystals within the renal vessels and glomeruli in Received July 7, 2000. Accepted August 16, 2000. kidney biopsy or autopsy specimens. However, in older pa- Correspondence to Dr. Venkateswara K. Rao, Hennepin County Medical tients with atherosclerotic vascular disease (who are the prime Center, 701 Park Avenue, Minneapolis, MN 55415. Phone: 612-347-5813; Fax: 612-347-7549; E-mail: [email protected] subjects for AERD), there is a general reluctance on the part of 1046-6673/1208-1781 physicians to perform renal biopsies. Possible reasons for this Journal of the American Society of Nephrology reluctance include (1) advanced age of the patient and (2) Copyright © 2001 by the American Society of Nephrology smaller kidney size, from a coexisting renovascular disease. 1782 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1781–1787, 2001

AERD typically is observed after an invasive vascular proce- Renal dure or after thrombolytic/ therapy, but it also can The classic lesion in AERD is the occlusion of arcuate and develop spontaneously. The disease can present as sudden interlobular arteries and the glomerular with cho- onset of acute renal failure or have a smoldering course with lesterol emboli. The cholesterol crystal emboli generally are declining renal function over a period of several months. The recognized by the characteristic biconvex, needle-shaped clefts renal failure in this setting often is attributed to other condi- appearing as “ghosts” (Figure 1). The crystals normally are tions such as (1) radio-contrast nephropathy, (2) acute tubular dissolved during routine histologic preparation. However, , (3) drug-induced interstitial nephritis, and (4) intra- when specimens are snap-frozen with liquid nitrogen and the vascular volume depletion. Presence of cholesterol emboli in frozen specimen is examined under polarized light, one can other tissues will, of course, strengthen the diagnosis. In some demonstrate the birefringent character of the cholesterol crys- individuals, cholesterol emboli maybe found in the skin and tals (19). Although atherosclerosis contributes to blockage of muscle biopsy specimens but not in the kidney. This scenario the renal and its major branches, the atheroemboli typ- is more likely to occur when atheromatous plaques are dis- ically occlude the medium-sized arterioles (150 to 200 ␮min lodged from distal aorta, below the origin of renal arteries. The diameter) and glomerular capillaries. The involvement usually predisposing factors for the development of AERD are shown is patchy (1,14). in Table 1. Blakenship et al. (17) described cholesterol embolism in Evolution of Histologic Lesion in AERD 12% of patients who underwent coronary and In the initial stages of atheromatous occlusion, varying de- bypass surgery after an acute myocardial . They grees of polymorphonuclear and eosinophilic infiltration oc- found no difference in the incidence among patients treated curs around the occluded vessel. Subsequently, other mononu- conservatively or those given thrombolytics. The diagnosis clear cells accumulate in the infiltrate, because the crystals was based on the examination of two muscle biopsy specimens attract inflammatory cells to the site of injury. Frequently, and a skin biopsy specimen, which were taken at the time of multinucleated giant cells also are seen within this perivascular harvesting the saphenous for bypass surgery. Because the inflammatory cell infiltrate (20). Over a period of time, the patients were not systematically assessed for symptoms of affected blood vessels are occluded further from intimal hy- AERD after the bypass surgery, it is conceivable that some of perplasia and perivascular fibrosis. Although some affected them could have developed AERD at a later stage and thus vessels may recanalize, one can still find cholesterol crystals were not included in the 12% incidence reported earlier. Fur- within the vascular lumen. Because of the ongoing ischemic thermore, the diagnostic sensitivity of the muscle or skin injury, glomerular sclerosis, tubular atrophy, and interstitial biopsy specimen can vary, depending on the site of the biopsy. fibrosis are frequent findings in the later stages of this disease Maurizi et al. (18) reported that the sensitivity of a skin biopsy (21). The dislodged atheromatous debris may be showered into specimen was 41%, compared with 100% for a muscle biopsy. the circulation at different time intervals. Consequently, the One should consider the limitations of these studies, such as kidney biopsy specimens may reveal different stages of histo- the variability of sample size and the small number of speci- logic evolution in individual patients. Because of the limited mens examined. Because cholesterol embolism affects multi- sample size and the patchy nature of this disease, a renal biopsy ple organs and the disease progresses slowly over a period of may not always show the classic pathologic lesions in patients several weeks to months, it also can mimic systemic . who have AERD.

Table 1. Predisposing factors for atheroembolic renal disease

Atherosclerosis systemic cigarette smoking hypercholesterolemia diabetes mellitus age Ͼ55 yr white race Trauma to atheromatous plaque invasive vascular procedure involving the aorta proximal to origin of renal arteries thrombolytic therapy blunt trauma Prevention of healing of the eroded plaque anticoagulant therapy Figure 1. Location of cholesterol crystals in the glomerular capillaries thrombolytics and renal arterioles in an elderly patient with atheroembolic renal disease. J Am Soc Nephrol 12: 1781–1787, 2001 Atheroembolic Renal Disease 1783

Atheromatous occlusion of the medium-sized arteries and infiltration. Six days after the infusion, intimal proliferation arterioles can lead to ischemic injury and tissue infarction. and luminal occlusion were observed frequently (20,21). Morphologic features of focal segmental necrotizing glomeru- lonephritis and crescentic glomerulonephritis also were noted Clinical and Laboratory Features in the renal biopsy specimens of patients with AERD (22). Because atherosclerosis seems to be a prerequisite for the Wrinkling of glomerular basement membrane is not development of AERD, it is not surprising that the disease is an uncommon finding. Because of the high prevalence of seen more commonly in patients older than 65 yr. They also hypertension in these elderly patients, arteriolar nephrosclero- have other risk factors for vascular occlusion, such as cigarette sis often is observed (23). Previous studies also showed a smoking, hypertension, and diabetes mellitus. In a series of 221 statistical correlation between AERD and focal segmental and patients with cholesterol embolism reported by Fine et al. (5), global glomerulosclerosis (15,23). Whether the focal sclerosis only 12 were younger than 51 yr. Also, there seems to be a is from aging process, chronic ischemic injury, or glomerular preferential involvement among white individuals (32). It is hyperfiltration is not known and remains a matter of specula- unclear whether the lower incidence in black individuals is due tion. Vidt et al. (24) from Cleveland Clinic noted concurrent to less frequent performance of the invasive vascular proce- renal artery in 19 of 24 patients (77%) with AERD. dures, greater difficulty in recognizing the cutaneous manifes- tations on a darker skin, or some unique properties of the Role of Complement atheromatous plaque with a lesser propensity for erosion. The disease is more prevalent in men (5,15,23,33). Hammerschmidt et al. (21) showed that the material ex- Because of the involvement of multiple organs, the clinical tracted from the human atheromatous plaques can trigger com- manifestations of AERD are extremely variable (Table 2). The plement pathway in vitro. They also observed in vivo comple- ment activation in a patient with AERD. Cosio et al. (20) noted hypocomplementemia in three patients with AERD. Subse- Table 2. Atheroembolic renal disease: clinical and quently, they measured serum complement levels in six addi- laboratory features tional patients and found that two thirds had decreased levels of serum complement (C3 and C4) in the absence of any other General known cause of the hypocomplementemia. Others have con- firmed these observations. The subacute and smoldering clin- ical course, characteristic renal , and evolving patchy around the occluded vessels suggest the possi- Renal bility that vascular inflammation plays a role in the pathogen- acute renal failure or acute on chronic renal failure esis of AERD. Previous studies showed that cholesterol embolism can oc- worsening of hypertension cur in other tissues, including the skin, subcutaneous tissue, proteinuria, occasionally in the nephrotic range skeletal muscle, prostate, , liver, , and renal infarction (1,5,25–27). Erosion of the atheromatous Cutaneous plaques from ascending aorta may cause embolic occlusions of digital mottling and nail pulp infarcts intracerebral vessels and retinal circulation (28). purple toes Experimental Models of AERD of toes Abdominal Very few experimental studies have dealt with AERD (29– 31). The animals used were either rats or rabbits. The experi- -vomiting ments consisted of injection of the plaque suspension (after it nonspecific is ground and filtered to keep the particle size below 200 ␮m) gastrointestinal hemorrhage into the animal’s left carotid artery or the aorta. The model has bowel infarction and perforation provided a unique opportunity to study the evolution of renal lesions, by serial examination of the tissue specimens. These abnormal liver enzymes experiments have confirmed further the complement activation Nervous system and hypocomplementemia, which has been noted often in patients with AERD (20,21). One day after the injection of the plaque suspension, frag- cerebrovascular accidents of sudden onset ments of were identified in the lumen of renal ves- paraparesis sels. Focal fibrin deposits were detected later in the glomeruli altered mental status and in medium-sized arterioles. Patchy cortical infarction was mononeuropathy common, perhaps the result of ischemic injury. Three days Eyes after the injection, the fibrin deposition was less prominent, but retinal emboli there was intense perivascular mononuclear and eosinophilic 1784 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1781–1787, 2001 disease generally presents as an acute or subacute renal failure picious. If a patient presents with worsening renal failure, in elderly patients who have a history of renal insufficiency. particularly after undergoing an invasive vascular procedure or Approximately 80% of these patients have serum thrombolytic therapy, one must look for evidence of choles- levels of 2.0 mg/dl or more at the time of the initial presenta- terol embolism in the kidney and other sites, including lower tion (5), and nearly 40% have far advanced renal failure, extremities, abdomen, and eyes. The diagnosis has to be con- needing dialysis. There frequently is a worsening of systemic firmed by demonstrating cholesterol crystals in the biopsy hypertension (9,33,34). The BP often is difficult to control; it specimens. Other diseases that should be considered in the can even be malignant on occasions because of excessive differential diagnosis are (1) radio-contrast nephropathy, (2) activation of the renin-angiotensin system. ischemic acute renal failure, (3) systemic vasculitis, (4) throm- Cholesterol embolization at other sites may lead to cutane- botic thrombocytopenia purpura, and (5) bacterial endocarditis ous, musculoskeletal, gastrointestinal, neurologic, and ophthal- (Table 3). In contrast nephropathy, the renal failure occurs mic manifestations (25–28,35–37). The classic cutaneous le- within 48 to 72 h after the dye infusion and generally resolves sions of AERD are livedo reticularis (purplish rash over the within 4 to 7 d. Ischemic acute renal failure is diagnosed by its lower extremities and abdominal wall), small nail bed infarcts, immediate onset, its association with , and the lack and purple toes (35). The patients also may develop symptoms of systemic manifestations such as skin rash, , and such as abdominal pain; nausea and/or vomiting; occult or hypocomplementemia. Because of the multisystem involve- frank blood loss; acute pancreatitis; and visceral perforation ment, cholesterol embolism can mimic other systemic diseases from cholesterol embolization in the gastrointestinal tract, such as vasculitis, bacterial endocarditis, polymyositis, and liver, pancreas, and spleen (26,37). The musculoskeletal fea- thrombotic thrombocytopenic purpura. These disorders have to tures include muscle pain, arthralgias, and, on occasion, rhab- be excluded through use of appropriate diagnostic studies. domyolysis (36). Mental confusion, focal neurologic deficits, Renal biopsy seems to be a reliable diagnostic test in patients and amaurosis fugax are the common with AERD. However, the procedure has some limitations. The findings (25). Funduscopic examination may show occlusion typical lesion, i.e., blockage of small arteries, arterioles, and of retinal arteries leading to pallor from retinal infarction the glomerular capillaries, usually is focal. In a patient with (Hollenhorst sign), which may be helpful as an additional AERD who died from acute renal failure, of the 12 renal diagnostic feature in this disease. cortical specimens studied at autopsy, only 9 (75%) showed the Constitutional symptoms of fever, malaise, and weight loss typical cholesterol emboli. The diagnostic sensitivity of a sin- often are present in these patients, which may add to the gle renal biopsy is 75%. However, with two biopsies on the diagnostic confusion. The hypocomplementemia, elevated sed- same patient, the sensitivity improves to 94%. In a patient who imentation rate, and increased level of C-reactive protein and presents with worsening renal failure, in the absence of kidney the peripheral blood eosinophilia are pseudo vasculitic presen- biopsy, demonstration of cholesterol emboli in other tissues tations, and AERD should be distinguished from the true would support the diagnosis. Even in patients who have end- vasculitis on the basis of other clinical findings and renal stage renal failure and are undergoing chronic dialysis, choles- histology. Subclinical involvement of the adrenal glands, tes- terol embolization may occur after an invasive vascular pro- tes, prostate, thyroid gland, and avascular necrosis of the head cedure (42). AERD remains underdiagnosed because one of of the femur also were noted in autopsy studies of patients with the clues to the clinical diagnosis—worsening of renal fail- atheroembolism (19,27). ure—often is absent. In elderly dialysis patients, the cutaneous The urinalysis may show bland urine, microscopic hematu- manifestations of AERD, i.e., livido reticularis in the lower ria, or even red cell casts. The proteinuria can be minimal or extremities, often are mistaken for ischemic skin lesions re- high in the nephrotic range. Fine et al. (5) described proteinuria sulting from peripheral vascular disease. (1ϩ or more by dipstick) in 53% of patients with AERD. Nephrotic-range proteinuria, which once was considered a rare Relationship to Invasive Vascular Procedures finding, is now being reported more frequently (38,39). It was and Thrombolytic/Anticoagulant Agents suggested that the proteinuria and urinary sediment abnormal- AERD has a variable but temporal relationship to the per- ities are more likely to occur in patients who have glomerular formance of invasive vascular procedures and pharmacologic embolization than the more typical vascular occlusion. Eosi- treatment with thrombolytic/anticoagulant agents. The clinical nophiluria also was noted in 8 of 24 patients (33%) who had symptoms may develop immediately after the vascular proce- biopsy-proven AERD (40). Like in renal vasculitis, AERD patients frequently have an elevated erythrocyte sedimentation rate (5). However, in contrast to vasculitis, the platelet count Table 3. Atheroembolic renal disease: differential diagnosis usually is low (3). Both peripheral eosinophilia and eosinophi- Radio contrast nephropathy luria also were observed in this disease, but the findings are not from ischemic injury consistent (40,41). Kasinath et al. (41) described eosinophilia Systemic or renal vasculitis in 80% of patients with AERD. We also observed it in 60% of Thrombotic our patients (42). Hypocomplementemia is common, but, like Bacterial endocarditis with embolic occlusion of renal eosinophilia, it is not a consistent finding and lacks specificity. vessels The diagnosis of AERD requires that the physician be sus- J Am Soc Nephrol 12: 1781–1787, 2001 Atheroembolic Renal Disease 1785 dure or can evolve slowly over a period of weeks or months. use by Fedar and Auerbach in 1961 (49), may very Lack of awareness of this disease among nonrenal physicians, well be a manifestation of cholesterol embolization of small the variable clinical presentation, and the infrequency of ob- arterioles in the feet, and it may not always be associated with taining biopsy specimens often lead to an underestimation of renal failure (48). AERD is known to occur spontaneously, but the true incidence of AERD as a complication of the invasive it is rare. Spontaneous cholesterol embolization may occur vascular procedures. after a blunt trauma (10). In patients who experienced sponta- In a prospective study of 183 elderly patients who underwent neous atheroembolism, severe occlusive aorto-iliac disease or cardiac catheterization, Rich and Crecelius (43) noted acute an with intramural thrombus was the frequent renal failure in 19 patients (10.5%) within 48 h after angiog- finding. Cholesterol embolism also can be a recurrent process. raphy. Surprising, AERD was not even considered in the Of the 70 patients with AERD who were receiving chronic differential diagnosis of acute renal failure. Thirty to 85% of dialysis, we noted recurrent, spontaneous cholesterol emboli- patients with AERD have a history of antecedent invasive zation in 2 (42). vascular procedure such as aortography or coronary angiogra- phy. At our own institution, 85% of patients who presented AERD Affecting the Renal Allograft with AERD had had an invasive vascular procedure (abdomi- Twenty-one cases of biopsy-proven AERD were reported in nal aortography or carotid or coronary angiography) during the the renal allografts (6–8). The time of the diagnosis ranged previous 3 mo (42). from immediately before transplantation to 15 yr posttrans- Ramirez et al. (44) noted cholesterol emboli at autopsy in plantation (8). After reviewing 200 renal transplant biopsies 30% of patients who died within 6 mo after undergoing aor- performed at our center between 1990 and 1995, we found 2 tography and 25.5% of patients who died within 6 mo after other cases of cholesterol embolism. The source of cholesterol undergoing coronary angiography. In contrast, the incidence of emboli in the transplanted kidneys could be (1) an unsuspected cholesterol embolism was 4.3% in age-matched controls who AERD in the donor kidney and (2) spontaneous dislodgment of had not undergone a previous invasive vascular procedure. The an atheromatous plaque from the aorta of an elderly transplant cholesterol emboli in the control group may have resulted from recipient. AERD may remain as an incidental finding without spontaneous erosion of atheromatous plaques or from previous any obvious clinical abnormalities such as hematuria, protein- anticoagulant or thrombolytic therapy. The authors did not uria, or decreased allograft function. The clinical course of indicate whether there were any cases of renal failure associ- these patients varied from complete recovery of renal function ated with atheroembolism in either the control or the reference to permanent graft loss. group. The low incidence most likely is due to underdiagnosis, because renal function was not systematically monitored in Therapy patients after the angiography. Whether the approach used for There is no specific therapy directed against the existing aortogram or coronary angiogram has any impact on subse- vascular lesions. The interventions included (1) interposition of quent development of AERD remains only as a speculation. In prosthetic bypass grafts, (2) angioplasty, and (3) extracorporeal a retrospective study of 1579 cases of coronary angiography, arterial reconstruction (52). These surgical maneuvers may not Johnson et al. (45) did not find any difference in peripheral be successful if the source of atheroembolism is in the supra- vascular complications between the brachial and femoral ap- renal part of the aorta. With reference to medical management, proach. Only a single patient had cholesterol embolism after there are a few case reports that documented recovery of renal the femoral approach, which was the routine site used at their function and disappearance of cyanotic features after the use of center. lipid lowering agents (53,54). However, no studies have ana- AERD was found to occur more frequently after thrombo- lyzed the benefits of one form of therapy over the other in the lytic therapy than after the use of anticoagulants (6,46–51). management of patients with AERD. Previous studies showed that 13 to 22% of patients with cholesterol embolism had previous anticoagulant therapy (ei- Clinical Outcome ther heparin or warfarin). This temporal relationship also was The prognosis in this disease is considered to be very poor. noted in several case reports (49–51). In a prospective study, The reported mortality has varied from 64 to 81% (5). The high Blankenship et al. (17) failed to find any increase in AERD mortality most likely is due to a selection bias, because most of after thrombolytic therapy, but the study had many limitations. the published cases were diagnosed at autopsy. Over the past Because the superficial clots stabilize the ruptured atheroscle- decade, a few case reports documenting the recovery of renal rotic plaque, dissolution of these by thrombolytic agents may function in patients with AERD appeared in the literature (53). cause showering into the systemic circulation and subsequent To assess the course of AERD in the patients undergoing lodging in other organs. dialysis, we compared the rate of hospitalization and survival Despite the widespread use of anticoagulants and thrombo- on dialysis of 40 patients with end-stage renal failure from lytic agents, the incidence of AERD in the absence of a AERD (mean age, 70.5 yr) and 1063 age-matched controls preceding invasive vascular procedure remains low, at 4.3%. (mean age, 70.3 yr) who had other causes of end-stage renal One might conclude from these observations that AERD is not failure. All patients included in the study were accepted for a common complication of these medications. However, “pur- dialysis between 1986 and 1992. The diagnosis of AERD was ple toes syndrome,” which was described as a complication of made on the basis of the classic clinical presentation and the 1786 Journal of the American Society of Nephrology J Am Soc Nephrol 12: 1781–1787, 2001 demonstration of cholesterol crystals in tissue specimens. Our References results showed that patients who were undergoing dialysis and 1. Carvajal JA, Anderson WR, Weiss L, Grismer J, Berman R: who had a primary diagnosis of AERD had no significant Atheroembolism: An etiologic factor in renal insufficiency, gas- increase in rate of hospitalization or mortality, compared with trointestinal hemorrhages, and peripheral vascular diseases. Arch age-matched controls (42). 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