Postgrad Med J-2001-Woolfson-68-74, Lekarski WLK SUM, lekarski, Patofizjologia, miażdżyca a pchn
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//-->Downloaded frompmj.bmj.comon December 18, 2013 - Published bygroup.bmj.com68Postgrad Med J2001;77:68–74REVIEWSRenal failure in atherosclerotic renovasculardisease: pathogenesis, diagnosis, and interventionR G WoolfsonAtherosclerotic renovascular disease (ARVD)is increasingly recognised as an importantcause of both chronic and end stage renal fail-ure. These patients tend to do badly ondialysis, which reflects their systemic athero-sclerotic burden. In an eVort to delay and per-haps prevent their need for renal replacementtherapy, some patients are subjected to avariety of medical, radiological and surgicalinterventions, although evidence for each issparse. The purpose of this review is todescribe the epidemiology and pathophysiol-ogy of renal failure in ARVD, discuss the avail-able diagnostic techniques, consider the evi-dence for benefit from intervention in thecontext of pathogenesis and finally, identifythose gaps in our knowledge which impede thepractice of evidence based medicine.Epidemiology of ARVDThe prevalence of ARVD in patients withchronic renal failure is not known but dialysisregistry data provide some epidemiologicalinformation about ARVD among patients whodevelop end stage renal failure (ESRF). Over a20 year period in an American haemodialysisunit, Maillouxet alreported a 16% incidenceof ARVD among new patients with a medianage of 70 years (range 37–86 years).1Similarly,in an 18 month retrospective study in a UKhaemodialysis unit, Scobleet alreported a14% incidence of ARVD among patients overthe age of 50 years.2ESRF patients withARVD generally present with substantialcomorbidities and have a poor prognosis ondialysis.1Given their poor prospects, manypatients may not be oVered dialysis and there-fore these figures are likely to underestimatethe true incidence of the disease. These stud-ies do identify age as a risk factor for ARVDand a cause for ESRF. Consistent with this, ina series of 133 hypertensive patients withchronic renal failure (mean (SD) creatinineclearance 51(26) ml/min) not due to glomeru-lonephritis or polycystic kidney disease, theincidence of atherosclerotic renal artery steno-sis (ARAS) was shown to rise progressivelywith age (see fig 1).3The prevalence of ARAS in patients who areundergoing investigation for atherosclerosis isin proportion to their burden of extrarenal dis-ease (see fig 2). Therefore it is much higher inpatients with aortoiliac disease than in patientsundergoing coronary angiography, in whomcardiac pain may be the result of a relativelysmall burden of atherosclerosis but with a par-ticularly critical distribution. This relationshipis confirmed by studies that have reported theprevalence of extrarenal vascular disease inpatients with proved high grade ARAS.4–6Louieet alinvestigated the prevalence ofcarotid and peripheral vascular disease in 60patients with ARAS graded as greater than orless than 60%.6In the less severe group, 25%and 50% of patients were aVected by carotidand peripheral vascular disease respectivelyincreasing to 46% and 73% for those withARAS exceeding 60%. Given that diabetesmellitus is a risk factor for systemic atheroscle-rosis, it is not surprising that it is also associatedwith an increased prevalence of ARAS.7 8The true incidence of ARVD may also beunderestimated as a result of its varied presen-tation which includes the patient with recur-rent “flash” pulmonary oedema. The diagnosismay be suspected in an elderly uraemicarteriopath with a normal urinary sedimentand absent proteinuria, however, the presenceof proteinuria, even up to nephrotic range, withor without evidence of glomerular bleeding,does not exclude the diagnosis.9 10Progression of ARASReported rates of progression of ARAS varybetween 18% and 53% over mean follow upperiods which range from 24 to 52 months.11–15The risk of progression appears to be deter-mined by the severity of disease at the time ofdiagnosis. Zierleret alused serial duplex Dop-pler scans to show that 8% of normal arteriesdeveloped a stenosis exceeding 60% at threeyears whereas 48% of those with a significantbut not critical (that is, <60%) stenosis atbaseline progressed.14The reported incidenceof complete occlusion ranges from 7% to16%11 12 14and this tends to aVect kidneys withbaseline stenoses exceeding 60% in patientswith bilateral disease.Aside from baseline severity, the identifica-tion of other risk factors for progression ofARAS remains contentious and does notexplain why only some stenoses progress. Somestudies report no correlation with blood100% StenosisDepartment ofNephrology, MiddlesexHospital, UCLH Trust,Mortimer Street,London W1N 8AA, UKCorrespondence to:Dr Woolfsonr.woolfson@ucl.ac.ukSubmitted 27 March 2000Accepted 22 June 2000755025No stenosis< 50% stenosis> 50% stenosis50–5960–69> 70Age (years)Figure 1Incidence of ARAS increases with age.3www.postgradmedj.comDownloaded frompmj.bmj.comon December 18, 2013 - Published bygroup.bmj.comRenal failure in atherosclerotic renovascular disease69504030AorticdiseasePeripheralvascular diseaseHeartfailureCoronaryangiography20MI10Figure 2 Prevalence of ARAS exceeding 50% found in patients under investigation foratherosclerotic disease elsewhere (MI = myocardial infarction). References for the figure arelisted at the end of the paper.pressure, smoking, diabetes mellitus, hyperlipi-daemia, or the presence of coronary or periph-eral vascular disease.11 12 16In contrast, Crowleyet alreported that age, female gender, hyper-tension, severity of coronary disease, andARVD at baseline were independent variablesfor progression of ARAS in 1214 patients witha mean follow up of 2.59 years.15Data whichsuggest that the rate of stenosis progression isfalling, perhaps secondary to better control ofhyperlipidaemia or hypertension, are not con-vincing.Development of renal atrophyThe important adverse outcome in ARAS isthe development of renal atrophy and dysfunc-tion which may result directly from thestenosis, as occurs in patients with fibromuscu-lar dysplasia (FMD).11In 85 patients withARAS who underwent repeated angiography,Schreiberet alnoted progression of stenoses in44% of kidneys, although renal atrophy (reduc-tion in renal length>1.5cm) aVected 70%.11When patients without progressive stenoses(n=48) were considered separately from thosewith progressive stenoses (n=37), renal atrophyand increased creatinine were significantlymore likely in the progressive group but evenso, approximately one quarter of the non-progressive group also demonstrated worsefunction and renal atrophy. This study providesstrong evidence that progressive parenchymalinjury and renal dysfunction reflects not justprogress of the underlying stenosis but alsoanother pathological process.Two subsequent studies have confirmed therelationship between severity of ARAS and riskof renal atrophy. Guzmanet alperformedrepeated duplex Doppler at six monthly inter-vals in 54 patients with ARAS over a mean fol-low up period of 44 months.17Renal atrophy(exceeding 1 cm) was not observed in kidneyswith baseline ARAS less than 60%, but by 12months had aVected 26% of kidneys withbaseline ARAS exceeding 60%. When patientswere subdivided into those with unilateral orbilateral ARAS, then the 12 month risk of atro-phy was 13% and 43% respectively. Similarly,Capset alreported a 24 month cumulativeincidence of renal atrophy (exceeding 1 cm) of5.5% in those with no baseline ARAS, 11.7%in those with stenoses less than 60% and20.8% in those with stenoses exceeding 60%.18The development of renal atrophy in non-progressive ARAS could be due to vasculardysfunction in the intrarenal microcirculationdistal to the stenosis rather than hypoperfusionsecondary to a critical stenosis. Lermanet alused electron beam computer tomography tomeasure whole kidney, cortical and medullaryblood flow in 42 patients with ARAS, FMD, oressential hypertension who had previouslyundergone renal angiography and werematched for blood pressure and baselinecreatinine.19Even when corrected for renal vol-ume, whole kidney perfusion and cortical per-fusion were significantly less in the ARASgroup compared with the groups with FMD oressential hypertension (p<0.05), althoughmedullary blood flow was conserved. Consist-ent with this evidence of abnormal corticalperfusion in ARAS, whole kidney and corticalblood flow correlated significantly with thedegree of renal artery stenosis in the FMDgroup but not in the patients with ARAS. Simi-lar results were reported by Tulliset alwhoused duplex Doppler to show bilateral abnor-mal renal haemodynamics in patients with uni-lateral ARAS exceeding 60%.20Farmer and colleagues have explored therelationship between ARAS and renal func-tion.21Seventy four patients with angiographi-cally proved ARAS underwent simultaneousestimation of isotopic glomerular filtration rate(GFR) and DMSA scintigraphy to accuratelycalculate individual kidney function. A signifi-cant correlation (p=0.016) was demonstratedbetween the degree of stenosis and the GFR ofthe aVected kidney, but there was no significantdiVerence in GFR between paired kidneyswhen only one was stenosed. Ostensibly, thisstudy provides further evidence to support arelationship between renal function and degreeof stenoses. However, given that renal functionis similarly reduced in both stenosed and non-stenosed kidneys, it could also be concludedthat there is an underlying systemic processwhich aVects parenchymal function of bothkidneys and which is also responsible for theARAS. This conclusion is consistent with arecent report that the severity of renal dysfunc-tion did not correlate with the severity ofstenosis in 63 patients with ARAS.22CONCLUSION%Olinet al1990Jeanet al1994Choudhriet al1990Valentineet al1993Swartbolet al1992Hardinget al1992Brewsteret al1975Vetrovecet al1989Crowleyet al1996Salmonet al1990Wilmset al1990Uzuet al1997MacDowallet al1998Missouriset al1994The presence of progressive ARAS is animportant risk factor for the development ofrenal atrophy and dysfunction. However, evi-dence that renal atrophy and dysfunction candevelop in the absence of progressive stenosis isalso compelling. It is essential that diagnostictechniques and therapeutic strategies shouldrecognise both these processes.www.postgradmedj.comDownloaded frompmj.bmj.comon December 18, 2013 - Published bygroup.bmj.com70WoolfsonInvestigation of the patient with ARASA variety of techniques are available todiagnose ARAS. These include renal arteriog-raphy, ultrasound with duplex Doppler, mag-netic resonance angiography, and captoprilscintigraphy.Renal arteriographyhas long been consideredthe gold standard investigation despite the risksof radiocontrast nephropathy and the precipi-tation of cholesterol emboli syndrome.23 24Sig-nificant morbidity and mortality make thisinvestigation a relatively unattractive screeningtest, especially in an aging patient group withincreasing comorbidities and a high prevalenceof non-insulin dependent diabetes mellitus.Ultrasoundcan measure renal length toprovide evidence of renal asymmetry or aorticatherosclerosis, which may suggest the possi-bility of ARAS. Some departments routinelyundertake duplex Doppler, although the tech-nique is diYcult and time consuming. Repro-ducibility varies significantly from centre tocentre and even in expert hands, may beunsuccessful in up to 20% of patients.Common pitfalls include obscuration of vesselsby overlying bowel gas and shadows, poor con-trol of angle of beam, insensitivity to stenosesless than 50%, inability to diVerentiate betweensevere stenosis and occlusion, and failure todetect accessory vessels. The development ofintravascular ultrasound may usefully charac-terise atherosclerotic plaques, but the tech-nique is likely to be associated with the samecomplications as any other intervention.Magnetic resonance angiographyis fast be-coming the new gold standard investigation,especially with dynamic non-nephrotoxic con-trast medium infusion (guadolinium) whichhas reduced signal loss due to saturation andturbulence. Recent technical developmentshave significantly improved the speed of dataacquisition, quality of images and diagnosticsensitivity, but examinations remain lengthyand claustrophobic for patients. In contrast toangiography, radiographers can complete theinvestigation, although the computer recon-struction is highly skilled.Captopril scintigraphyis commonly used innon-uraemic patients with renovascular hyper-tension and is of proved eYcacy in bothdiagnosis and also prediction of blood pressurelowering outcome after intervention.25How-ever, careful patient preparation is critical:angiotensin converting enzyme (ACE) inhibi-tors, angiotensin II blockers, and diureticsshould be discontinued (which may be danger-ous in a patient with heart failure), and thepatient should be fasted but adequately hy-drated. The safety of administration of a singledose of captopril (25 mg or 50 mg) in patientswith high grade ARAS is unclear, although therisk of acute renal failure from therapeuticACE inhibition is well recognised. A variety ofisotopic tracers are available of which the tech-netium labels, and in particular99Tc-MAG3,give the best images in patients with renalimpairment. A variety of diagnostic criteria areused and include changes in divided function,the time activity curve, and residual corticalactivity. In general, the inclusion of more crite-ria (and performance of scans before and aftercaptopril) increases diagnostic sensitivity butthere is still marked observer variability. Falsenegatives may occur in patients with single kid-neys, segmental stenoses, or bilateral disease.Although widely reported in non-uraemicpatients with renovascular hypertension,25there are few data regarding the use of captoprilscintigraphy to diagnose ARAS in uraemia.Datseriset alundertook captopril MAG3renography in 41 patients with a GFR less than41 ml/min/1.73m2.26Seven patients were cat-egorised as being at high risk of significantARAS and this was confirmed in five of thesepatients who subsequently underwent angio-graphy. The authors noted that scintigraphyfindings tended to be non-specific when theGFR was less than 10 ml/min/1.73m2or if thedivided function was less than 10%.A few studies have compared these diVerentinvestigations in patients with ARAS and mildrenal failure. Kaplan-Pavlovcic and Nadjacompared duplex Doppler with captopril scin-tigraphy in 28 patients with a mean blood pres-sure of 175/106 mm Hg of whom 36% had acreatinine greater than 120 µmol/l.27Usingangiography as gold standard, they reported nodiVerence in sensitivity, specificity, positivepredictive value, or negative predictive valuebetween these tests. In another study of 89patients (mean blood pressure 169/96 mm Hg,creatinine range 60–800 µmol/l) with angio-graphically proved ARAS exceeding 60%, thesensitivity and negative predictive value ofmagnetic resonance angiography (97% and98%, respectively) exceeded that of duplexDoppler (81% and 88%, respectively).28CONCLUSIONThe lack of comparative data regarding thesediVerent diagnostic techniques in patients withrenal failure is disappointing. But it seemslikely that, although currently limited by avail-ability, magnetic resonance angiography is des-tined to replace both contrast angiography andcaptopril scintigraphy as the investigation ofchoice in the patient with ARVD. What nuclearmedicine might be best positioned to oVer is ascan which can discriminate renal dysfunctionsecondary to critical stenosis from dysfunctiondue to obliterative microvascular disease,perhaps similar to those developed for hiber-nating myocardium. Until then, measurementof renal size, individual kidney GFR, and renalbiopsy are the only ways to ascertain that renaltissue is viable and that the consideration ofrevascularisation is worthwhile.Revascularisation in patients with ARASCurrent aims of revascularisation includerecovery or preservation of renal function andthe treatment of resistant hypertension. Butgiven the expanding indications for andbenefits from ACE inhibition (and angiotensinII receptor blockade) in cardiovascular disease,the demand for interventions which reverseangiotensin II dependent renal dysfunction isset to increase. Interventions commonly under-taken to treat patients with ARAS include avariety of surgical procedures, angioplastywww.postgradmedj.comDownloaded frompmj.bmj.comon December 18, 2013 - Published bygroup.bmj.comRenal failure in atherosclerotic renovascular disease71(PTRA) and PTRA with stent deployment(PTRAS). There are few randomised prospec-tive data comparing any of these interventionswith one another or even with “best” medicalmanagement; the history of intervention in thisdisease has largely been driven by technicaldevelopment.Current criteria for intervention in a sten-osed kidney include renal size, with bipolarlength less than 8 cm frequently used as a cutoV for revascularisation. In some centres, renalbiopsy is used to diVerentiate ischaemic butrecoverable renal parenchyme from irreparablydamaged tissue. Measurement of the singlekidney GFR allows the clinician to quantify thefunctional contribution from a stenosed kidneyand by comparison with the contralateralkidney may help diVerentiate between dysfunc-tion due to the ARAS as opposed to more gen-eralised microvascular obliteration. Anecdotalreports of the rescue of patients with progres-sive ARAS from dialysis by revascularisationsuggest that these criteria are best used incombination.SURGERY3 months10075502512 monthsDialysisWorseStableImproved%ABCABCEffect of PTRA on groupsFigure 3 Renal function at three months and 12 monthsafter PTRA is determined by baseline function.32Meanbaseline creatinine: group A, 190 µmol/l; group B: 217µmol/l; and group C, 461 µmol/l.91%) stable function, and the remaining 21%(range 0%–45%) worse function.33 34PTRAS isassociated with a vigorous inflammatory reac-tion and average restenosis rates of 13% (range9%–25%) have been reported during follow up(range 12–24 months).33 34CONCLUSIONA full discussion of surgical procedures isbeyond the scope of this review but anecdotalreports suggest that surgery which bypasses thegrossly diseased aorta may oVer better results,perhaps by reduction of atheroembolic events.Renal outcomes after surgical revascularisationhave been reported by several groups over thelast 20 years.29These show improved renalfunction in 50% (range 22%–77%) of patients,stable function in 30% (range 12%–53%),worse function in 20% (11%–44%), and anoverall surgical mortality up to 17%. Patientselection is critical with analyses indicatingmuch greater risk for elderly patients, with dif-ferent determinants of survival at 30 days(ischaemic heart disease, congestive cardiacfailure, and cerebral vascular disease) com-pared with 90 days (preoperative renal func-tion, age, and presence of an abdominal aorticaneurysm).30ANGIOPLASTY(PTRA)After PTRA, studies report that about 40% ofpatients have improved renal function with theremainder split equally between stable or worsefunction.31One very informative study re-ported that renal function outcome at threeand 12 months after PTRA depended on themean creatinine before intervention.32As withsurgery, results were not at all encouraging inthose patients with poor baseline function(mean creatinine 461 µmol/l) of whom over50% had either worse function or requireddialysis at 12 months (see fig 3).PTRA PLUS STENT DEPLOYMENT(PTRAS)These studies do not provide overwhelmingencouragement to intervene in ARAS butostensibly indicate that surgical reconstructionis the best option; however, this is likely toreflect case selection and the use of stents inpatients with ostial stenoses which are usually amarker of more advanced atherosclerotic dis-ease. A recently published comparison betweenPTRA and PTRAS has shown improvedpatency rates in stented arteries, although thiswas not associated with functional benefit.35This mismatch between technical success andfunctional outcome has previously been re-ported,36 37and provides evidence of on-goingparenchymal injury, presumably due to con-tinuing uncontrolled atheroembolic diseasefrom proximal unstable atheroscleroticplaques; such reports question the contributionof the stenosisper seto renal dysfunction inARAS. Even if function is improved, there isonly very limited evidence to suggest that renalatrophy which is due to a proximal stenosis canbe reversed by intervention.38Most studiesreport improved blood pressure and reduceddosage of antihypertensive medication afterintervention, however, the need for medicationis rarely abolished and any benefit is not usuallysustained.34 39 40Medical interventionsA recent retrospective study from the MayoClinic has suggested that long term eVectivemanagement of hypertension and renal func-tion can be achieved in patients with unilateralARAS.41In contrast, overall mortality and kid-ney function were worse in medically managedpatients with bilateral ARAS or ARAS in a sin-gle kidney,41which is consistent with a previousreport of 38% two year mortality in patientswith bilateral ARAS managed medically.42Although specific evidence of benefit is absent,medical interventions routinely applied topatients with ARAS include the prescription ofaspirin and active management of conventionalrisk factors such as hypertension, dyslipidae-mia, diabetes mellitus, and cessation ofThe development of the stent has allowedinterventional radiologists to attempt treat-ment of more severe atherosclerotic lesions,particularly those extending from the renalostia. Perhaps as a result of this diVerent caseselection, results appear less satisfactory andonly 27% (range 15%–36%) of patients haveimproved renal function, 52% (range 29%–www.postgradmedj.comDownloaded frompmj.bmj.comon December 18, 2013 - Published bygroup.bmj.com72Woolfsonsmoking. There are also no data regarding spe-cific risk factors in uraemia, such as hyperho-mocysteinaemia, increased oxidative stress, orendogenous inhibitors of nitric oxide synthase.In short, “best medical treatment” in patientswith ARAS remains unknown.HYPERTENSIONAlthough excessive blood pressure lowering inpatients with bilateral ARAS can lead toprogressive elevation of plasma creatinine,43data regarding optimal blood pressure levelsmay be inferred from large studies. Tight bloodpressure control was associated with improvedoutcomes in both the Modification of Diet inRenal Disease study and UK ProspectiveDiabetes Study Group studies,44 45both ofwhich likely included a significant proportionof patients with ARAS. Two other studies haveshown specific renoprotection from ACE inhi-bition in uraemic patients of whom a pro-portion will have had ARAS.46 47With regard totheir safe use in patients, clinicians should bereassured that no excess of adverse renal eventshas been reported in large multicentre studieswhich have investigated ACE inhibition in thetreatment of patients with heart failure, asignificant proportion of whom will have hadunderlying ARAS. Furthermore, two recentstudies have shown that control of hyper-tension by ACE inhibition is safe and eVectivein patients with ARAS and is not associatedwith an increased risk of renal atrophy.18 48Nevertheless, these drugs should be introducedat the lowest dose with renal function checkedafter three to five days.DYSLIPIDAEMIAFigure 4 (A) Characteristic histological appearance onlight microscopy of a cholesterol cleft in a small artery withevidence of intimal thickening, concentric hypertrophy, andinterstitial inflammation. Embolised cholesterol crystalsdissolve during the fixation process. (B) Electronmicrograph demonstrating a cholesterol cleft in an aVerentglomerular arteriole. The destination vessel depends oncrystal size and this variability may determine the clinicalpresentation.Dyslipidaemia is a risk factor for atherosclero-sis, although curiously several studies demon-strated no relationship between cholesterolconcentrations and progression of ARAS.11 12 16However, subtle lipid abnormalities may becharacteristic.49There are no data that reportbenefit from cholesterol lowering in ARVD.PLAQUE INSTABILITYRecent data reports increased cardiovascularmorbidity and mortality in patients withirregular as opposed to smooth carotidplaques.50The increased risk, which mustreflect a systemic predisposition to unstableatherosclerotic plaques, did not correlate withconventional risk factors and this suggestsadditional as yet unrecognised factor(s) forplaque progression. Similarly, the very highincidence of recurrent disease after coronaryangioplasty in haemodialysis patients suggeststhat plaques behave diVerently in uraemia.51Unstable atherosclerotic plaques may embolisecholesterol crystals and other debris that lodgein the dependent circulation, even down to thecapillary level. In the kidney, cholesterolembolisation can lead to progressive microvas-cular obliteration, chronic inflammation andworsening renal failure, with the diagnosisclinched by the characteristic appearance ofintravascular cholesterol clefts on renal biopsy(see fig 4).The recent association between raised acutephase proteins, unstable atheroscleroticplaques and increased risk of myocardialinfarction suggests that systemic inflammationpredisposes to plaque instability. Theimportance of this observation is supported byrecent data which show that reduction in Creactive protein is associated with reduction incoronary risk.52A similar association betweenraised acute phase proteins and atherosclerosishas also been shown in dialysis and renal failurepatients,53 54although there are no data fromintervention studies.Statins can cause atherosclerotic plaqueregression and may also have a specific role inthe management of the unstable plaque. Aswell as inhibition of hepatocyte synthesis ofcholesterol, statins decrease macrophage chol-esterol synthesis; increase macrophage lowdensity lipoprotein degradation; inhibit plateletderived growth factor induced proliferation ofvascular smooth muscle cells and fibroblasts;inhibit thrombosis; improve endothelial func-tion; and suppress inflammation.55Theseproperties may promote plaque stability andexplain the reduction in levels of acute phaseproteins observed in patients treated with astatin in the Cholesterol and Recurrent Eventsstudy.52Consistent with this role, we recentlyreported the successful treatment of a patientwith spontaneous cholesterol emboli syndromewww.postgradmedj.com
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