Kidney International, Vol. 56, Suppl. 71 (1999), pp. S-106–S-109

Atherosclerotic nephropathy

JOHN E. SCOBLE

Guy’s Hospital, London, United Kingdom

Atherosclerotic nephropathy. kidney in response to decreased blood flow [4]. JacobsonBackground. Lipid moieties may have direct or indirect ef- described the processes associated with renal artery nar-

fects on the kidney. The association of aortic atherosclerosis rowing as “ischemic nephropathy” [5]. Considerable ef-and renal artery stenosis has focused interest on this as anfort has been put into diagnosing this condition as it isimportant cause of end-stage renal failure. This article seeksa potentially reversible cause of end-stage renal failure.to examine the evidence for the entity of atherosclerotic ne-

phropathy. However, it has become clear that the pathological pro-Methods. Published data on the incidence of atherosclerotic cesses involved in renal disease in patients with extensive

renal artery stenosis as the cause of end-stage renal failure are atherosclerosis are complex [6]. Unlike other mecha-presented, as well as the associated features of atheroscleroticnisms of lipid toxicity in renal disease associated withrenal stenosis.severe atherosclerosis, the effect may be an indirect oneResults. Atherosclerotic renal artery stenosis (ARAS) has

been estimated to be the cause of between 14 and 25% of that is secondary to aortic atheroma. The associationpatients reaching end-stage renal failure in older age groups. of aortic atherosclerosis and renal artery stenosis hasThere is considerable evidence of proteinuria in patients with

focused interest on this as an important cause of end-ARAS. Recent data have shown that renal length may decreasestage renal failure.by 1 cm or more in 35% of kidneys with .60% stenosis. How-

ever, other data suggest that renal function in kidneys withoutrenal artery stenosis but with contralateral renal artery stenosis

PREVALENCE AND INCIDENCE OFmay be similarly decreased.Conclusion. Many processes contribute to renal dysfunction ATHEROSCLEROTIC RENAL DISEASE

in atherosclerotic aortic disease. Although ischemia may playEarly reports of renal artery occlusion leading to renala role, there is considerable evidence that processes such as

failure were anecdotal, and usually were reported when aatheroembolic disease may be important, and it would be betterto use the term “atherosclerotic nephropathy” for this impor- positive outcome was achieved with surgical interventiontant disease entity. [7]. Meyrier et al, however, examined the importance of

renovascular disease as a cause of renal impairment andconcluded that it was responsible for between 0.5 and

The direct effects of lipid moieties on renal, and spe- 0.9% of the end-stage renal failure program, dependingcifically glomerular [1], function have been extensively on whether retrospective or prospective analysis was per-described. However, atherosclerosis is a consequence of formed [8]. Our group prospectively examined by angi-deranged lipid metabolism and is the single most impor- ography all patients presenting to a single unit withouttant cause of cardiac and cerebral disease in many coun- a proven renal diagnosis, but who had evidence of ath-tries. It has not been thought of as an important cause erosclerotic disease. This evidence was assessed on theof renal disease until relatively recently. This may reflect basis of either proven episodes of cerebrovascular, car-the younger age of patients taken onto dialysis therapy diac or peripheral vascular disease or signs of these dis-at the outset of our ability to provide dependable long- eases. We found that these patients accounted for 14%term dialysis. The importance of renal artery narrowing of those over the age of 50 years who were going ontoas a cause of hypertension was elegantly described by dialysis [9]. Mailloux et al have looked at a large dialysisGoldblatt et al [2], and Marcussen has examined similar population and calculated that 25% of patients over thechanges in human nephrectomy specimens where renal age of 60 years have atherosclerotic renovascular diseaseartery stenosis was present [3]. Recent experimental as the cause of renal failure [10]. In the United Kingdomwork has established the processes that occur in the it is the patient group over the age of 60 years where

there has been considerable expansion in the last decade,and therefore, if this trend continues, the importance ofKey words: renal artery stenosis, aortic atherosclerosis, end-stage renal

failure. atherosclerotic disease will be magnified in the future. Itis interesting that both of these articles excluded dialysis 1999 by the International Society of Nephrology

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Scoble: Atherosclerotic nephropathy S-107

patients who had a known renal diagnosis [9, 10]. We disease is well described in patients with severe aorticatheroma and also in those with atherosclerotic renalhave recently reported a patient with adult polycystic

kidney disease who reached end-stage renal failure; an artery narrowing, although in most instances both arepresent [15, 16]. It has also been shown to be the histolog-investigation in fact revealed renovascular disease as

well. The patient did not need dialysis after angioplasty ical diagnosis in 10% of a large series of patients overthe age of 65 years [20]. Recently, focal segmental glo-[11]. Peripheral vascular disease is common in older age

groups and can be present in association with other merulosclerosis has been described in association withrenal artery stenosis by Thadhani et al [18]. In the experi-causes of renal failure. Specifically, the presence of femo-

ral bruits was found in 85% of cases in one series [12]. mental rat model the predominant features were of inter-stitial damage, with the authors commenting that theThe clinical absence in these patients of iliac or femoral

bruits in the presence of vascular disease makes the like- “structure of the glomeruli were suprisingly well pre-served” although there was some mild focal segmentallihood of atherosclerotic renal artery stenosis (ARAS)

in these patients unlikely in the author’s experience. mesangial sclerosis [4].The second piece of evidence is the very variable func-However, a number of patients may have no symptoms

of peripheral vascular disease because of comorbid con- tional response to revascularization. Even in those stud-ies with a positive outcome there was a progressive lossditions preventing them reaching their claudication dis-

tance. In these patients the presence of iliac/femoral of function in a large minority of patients [19, 21]. Wehave recently reported a group of patients with singlebruits is clinically useful. The important issue yet to be

clarified is whether or not this is an important cause functional kidneys in whom there was a progressive lossin renal function. Angioplasty was performed and a goodof renal disease in older type 2 diabetics (non-insulin-

dependent diabetes mellitus). In one post-mortem series, initial response was found with a fall in creatinine in allfour patients. However, there was a subsequent decline50% of the patients identified as having atherosclerotic

renal disease had type 2 diabetes [13]. in renal function after the initial improvement, and thiswas thought to be due to restenosis, yet angiographyHowever, ARAS or even just severe atheroscleroticshowed no evidence of restenosis [22]. This suggests thataortic disease is associated with atheroembolic diseaseprocesses independent of a reduction in renal blood flow[14, 15] as well as renal artery narrowing. It is unclearwere present in these cases. There was proteinuria inhow common this problem is as a cause of renal diseasethree of the four patients suggesting parenchymal dis-in the older population because of the difficulty in inter-ease. Using estimations of individual kidney function,preting renal biopsy material if it does not contain awe have not been able to demonstrate an overall im-cholesterol cleft [16]. The only absolute way to excludeprovement in renal function within three months of angi-the diagnosis is on a nephrectomy or post-mortem speci-oplasty [23]. The response to angioplasty is variable withmen where multiple sections from many areas can bea small number of patients benefiting, but in a large num-examined.ber of patients in the published series, progressive renalOne feature that has been reported in association withdysfunction occurred in spite of angioplasty [19, 23].atherosclerotic renal disease with great frequency has

The third piece of evidence is based on the clinicalbeen proteinuria. These reports have tended to be anec-observation that a number of patients investigated fordotal, but nephrotic range proteinuria has been reportedatherosclerotic renovascular disease are found to havein both renal artery stenosis and atheroembolic diseasetwo equally sized kidneys with a unilateral renal artery[17, 18]. It is difficult to ascertain from the literature thestenosis but with impaired renal function. This is not atrue incidence of proteinuria in atherosclerotic nephrop-pattern seen in fibromuscular dysplasia, although it mayathy, but Harden et al, in their report on renal arterybe a consequence of different age groups for the twostenting, give a median proteinuria of 0.95 g per day forconditions. Preliminary results are available using singletheir patients with severe atherosclerotic renovascularkidney glomerular filtration rates, which show that sizedisease [19].and function based on routine ultrasound bipolar lengthestimations do not correlate in patients with atheroscle-

IS ATHEROSCLEROTIC RENAL DISEASE rotic renal disease both in kidneys with and withoutDIFFERENT FROM ISCHEMIC stenosis [24]. However, it is also an important clinicalRENAL DISEASE? observation that a number of patients present with se-

What is the evidence that the renal disease is not vere ARAS and yet relatively preserved renal functionpurely related to renal artery narrowing and renal ische- but severely symptomatic “flash pulmonary edema.” Itmia? There are three important pieces of evidence. The is easy to imagine that atheroembolic disease will befirst is the demonstration of two specific histological present in both kidneys if there is severe aortic atheromachanges not related specifically to experimental ischemic even if there is only a unilateral renal artery narrowing.

However, it is important to realize the dramatic produc-damage. As stated earlier in this article, atheroembolic

Scoble: Atherosclerotic nephropathyS-108

Fig. 1. The atherosclerotic aorta and the cyto-kines known to be in atherosclerotic plaques.These are the potential agents for “down-stream” damage. Cholesterol crystals are cur-rently the only proven substance to producedownstream damage.

tion of cytokines by any atherosclerotic lesion. These tate dialysis treatment. The role of angioplasty or surgerypatients on angiography invariably demonstrate severe in unilateral or mild bilateral disease is unclear as thereaortic atheroma. Figure 1 shows the substances that are are no large randomized trials to examine functionalproduced in atherosclerotic plaques. Many of them un- outcome. This is a major issue in the field of nephrology,der different circumstances have been demonstrated as because in some countries angioplasty is being per-producing changes in renal and glomerular function. formed by cardiologists when ARAS is found inciden-However, the studies that have sought to demonstrate tally at a coronary angiography. If the renal dysfunctionin situ transcription of these cytokines within the kidney is due to ischemic nephropathy with its implication ofcould not detect upstream production. Cholesterol crys- reversibility, then this is a wise move. If, however, theretals give us an elegant demonstration of “downstream are a number of processes involved in atheroscleroticdamage” from the atherosclerotic lesion. It is important nephropathy, then these procedures may be meddlesometo note that the atherosclerotic disease is invariably lim- and unwarranted. It is hoped that such a study will beited to the first centimeter of the renal artery [25]. In established in the United Kingdom in the near future tomany respects aortic wall disease spills over into the address this important problem.renal artery rather than into intrinsic renal artery disease, Although the management of atherosclerotic renalas can be seen in fibromuscular dysplasia. The only sub- disease in terms of restoration of blood flow is now ele-stance produced by the endothelium that would be de- gant and sophisticated, the same cannot be said of thegraded between the atherosclerotic aorta and the glo- medical management of these patients who represent amerulus is nitric oxide. major group of patients with end-stage renal disease.

The investigation and management of patients with ath-erosclerotic nephropathy in the future will present im-POTENTIAL THERAPEUTIC INTERVENTIONSportant and interesting challenges to nephrologists.IN ATHEROSCLEROTIC RENAL DISEASE

Reprint requests to Dr. John E. Scoble, Renal Unit, Thomas GuyAt present, the physical interventions to improve renalHouse, Guy’s Hospital London, SE1 RT, United Kingdom.blood flow can have impressive, but unpredictable effectsE-mail: j.scoble@umds.co.uk

on renal function [19, 23]. Some anecdotal evidence sug-gests that atheroembolic disease found both peripherally

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