Hypertension ATHEROSCLEROTIC RENAL ARTERY STENOSIS, ACE INHIBITORS, AND AVOIDING CARDIOVASCULAR DEATH

548 Hypertension ATHEROSCLEROTIC RENAL ARTERY STENOSIS, ACE INHIBITORS, AND AVOIDING CARDIOVASCULAR DEATH John Main WHY Correspondene to: Dr John Main, Renal Unit, James Cook University Hospital, Marton Road, Middlesbrough TS4 3BW, UK; john.main@stees.nhs.uk A Heart 2005; 91:548 552. doi: 10.1136/hrt.2003.019505 therosleroti renal artery stenosis (ARAS) has beome topial sine the development of perutaneous angioplasty and stenting. Studies defining the plae for intervention have been diffiult to perform and inonlusive. However, it is beoming lear that intervention makes only a modest ontribution to blood pressure ontrol. Furthermore, although ARAS is often present in elderly patients with renal impairment, the ontribution of intervention to preventing progression of renal failure has been disappointing. The inreasingly widespread use of angiotensin onverting enzyme (ACE) inhibitors and angiotensin II reeptor blokers (ARBs) has inreased the linial relevane of ARAS, and may be altering the indiations for intervention. ARAS is more likely to end in ardiovasular death than renal failure, suggesting that it may be more rewarding to fous on the heart than the kidneys in this ondition. HAVE CLINICAL TRIALS REVEALED SO LITTLE ABOUT ARAS? There is a stark differene in our understanding of the benefits of intervention in oronary artery disease (CAD) as opposed to ARAS. There are three prinipal reasons for this: the non-speifi nature of the linial sequelae of ARAS, all of whih have more ommon auses (table 1); a lak of understanding of the link between ARAS and renal damage; and the relative rarity of pathologially signifiant ARAS, whih preludes intervention trials of the size whih have informed the management of CAD. The relation between CAD and its linial sequelae is relatively lear ut. Coronary artery narrowing produes angina, and angina in the presene of oronary artery narrowing is almost invariable aused by that narrowing. Coronary artery narrowing inreases the risk of arterial thrombosis and myoardial infartion, and myoardial infartion has no other ommon ause. The relation between ARAS and linial disease is muh more omplex. Renal artery narrowing may ativate the renin angiotensin aldosterone system (RAAS) and raise blood pressure, but the vast majority of those with ARAS have pre-existing essential hypertension. ARAS and impaired renal funtion ommonly o-exist, but many patients with severe renal impairment (loss of 70% or more of renal funtion) have unilateral stenosis (whih at worst ould ause loss of 50%). In a reent example, 21 of 35 patients with ARAS and severe renal impairment (serum reatinine. 300 mmol/l) had only a unilateral stenosis. 1 Furthermore, in ases with unilateral ARAS and renal impairment, split funtion studies show equally severe loss of funtion in both kidneys. 2 Although it has often been assumed that the o-existene of ARAS and renal impairment implies ause and effet, this learly often annot be so. It is beoming inreasingly apparent that hroni progressive renal failure is ommon in arteriopaths whether or not they have ARAS, probably aused by a ombination of hypertensive nephropathy and so alled atherosleroti nephropathy. Atherosleroti nephropathy is not yet learly defined but is a useful onept to explain the progressive renal damage seen in some hypertensive arteriopaths. It is probably aused by a ombination of hypertensive and ishaemi damage, the latter arising from miro- and holesterol embolisation to the kidney. The shared predispositions explain the ommon o-ourrene with ARAS. Almost all studies of the inidene of ARAS in patients with end stage renal failure (ESRF) have assumed that the ARAS aused the ESRF they are therefore overestimates. Studies of the inidene of new ESRF developing in those with ARAS show that it is muh rarer than ardiovasular death. For example, during follow up of 98 patients with ARAS and initially poor renal funtion (mean reatinine learane 35.5 ml/min), 35 died (at least 25 of ardiovasular auses), whereas only nine progressed to ESRF. 3 There is no doubt that glomerular filtration rate (GFR) an be redued by ARAS and improve after intervention. For the most part, this is a haemodynami effet whih does not lead to nephron loss. Beyond a tight ARAS (probably at least 75%, see disussion below), GFR beomes proportional to systemi blood pressure. Suessful revasularisation will restore GFR and remove the dependene on blood pressure. Muh more ontroversial is the assumption that the nephrons beyond an ARAS are gradually dying beause of ishaemia. It is worth noting that progressive www.heartjnl.om

Table 1 auses Clinial presentation Clinial presentations of ARAS and alternative Alternative auses Hypertension Essential hypertension; renal impairment Renal failure Hypertensive or atherosleroti nephropathy Pulmonary oedema Left ventriular failure Table 2 Traditional pointers to possible ARAS Reent signifiant worsening of longstanding hypertension, espeially if assoiated with any rise in serum reatinine Rapid worsening of renal funtion (that is, over weeks). Gradual loss of renal funtion (over months and years) is more likely aused by atherosleroti or hypertensive nephropathy Sudden onset anuri renal failure, when ARAS to a single funtioning kidney progresses to aute olusion Aute pulmonary oedema espeially in assoiation with good left ventriular funtion 549 renal failure is highly unusual in ases of fibromusular disease of the renal artery, despite very tight stenoses. Again, although there is no doubt that bilateral ARAS an ause reurrent pulmonary oedema, 4 in the group of patients with pulmonary oedema and generalised arterial disease, hypertensive or ishaemi left ventriular failure are more likely auses. This very high level of onfounding pathologies produing similar linial problems makes it very diffiult to design and interpret trials of intervention in ARAS. Suh trials are further hampered by the number of possible ombinations of pathologial and linial abnormalities. Even if the severity of stenosis is only stratified into three levels (say,. 50%,. 90%, and olusion), there are two kidneys to onsider, and multiple linial senarios for example, level of renal funtion, rate of hange of renal funtion, degree of hypertension, and presene or absene of pulmonary oedema. Should patients with a 50% unilateral ARAS and a serum reatinine onentration of 500 mmol/l be in the same trial of intervention as those with a 95% stenosis to a solitary funtioning kidney and a serum reatinine of 180 mmol/l? Obviously not, unless reruitment is so vast as to allow adequate stratifiation, but the logistial problems of mounting separate trials for eah possible ombination seem insurmountable. New tehnology in imaging, angioplasty, and stenting and inreasing familiarity of operators with intervention are also reduing risk and restenosis rates. This further redues the usefulness of trials firstly, the risk of intervention is not that of the trial, it is that of the loal unit; and seondly, in the time any trial takes to omplete, tehnology improves, asting doubt on the urrent relevane of the results. The level at whih a stenosis starts to produe linial effets remains unlear. As with all new medial or surgial treatments, the invention of angioplasty enouraged ase finding erring on the side of over-diagnosis. Many reports opt for a diagnosti ut off of. 50% two dimensional luminal narrowing. It is likely that many stenoses at this level are not haemodynamially signifiant (that is, result in ativation of the RAAS). 5 A ut off of 75% is more likely to identify a group suffering adverse onsequenes of ARAS. 6 This disrepany partly explains the disparity between the apparently alarming frequeny with whih ARAS is found on sreening patients with vasular disease elsewhere (for example, 34% of elderly heart failure patients) 7 and the remarkable rarity of ACE inhibitor or ARB indued renal impairment in huge ardiologial trials of these drugs in patients with multiple risk fators for ARAS (for example, 2% in a trial of over 65 year olds with heart failure). 8 It is inreasingly easy to safely visualise the renal arteries, partiularly with magneti resonane angiography (MRA) whih avoids the risks of x ray exposure, arterial punture, and ontrast nephropathy (fig 1). It seems likely that the problem for liniians in the future will not be who to investigate but deiding when a demonstrated lesion is likely to be linially relevant, and whether the risks of intervention are exeeded by the potential benefits. It should be noted that we already know that inidental ARAS an for the most part be safely ignored, at least as a ause of renal failure. One hundred and twenty six patients were inidentally found to have an ARAS. 50% during angiography for peripheral vasular disease. None had renal revasularisation, and after 8 10 years follow up, none had developed ESRF. 10 ARAS IN THE ERA OF ACE INHIBITORS AND ARBS: EVERYTHING IS DIFFERENT The introdution of ACE inhibitors and ARBs has had profound effets on the diagnosis, investigation, and treatment of ARAS. It is probable that the renal effets of ACE inhibitors and ARBs in the presene of ARAS are lose enough to allow them to be onsidered idential and heneforth in this artile referene to ACE inhibitors implies ARBs as well. ACE inhibitor indued aute renal failure (ARF) ours in settings where glomerular afferent arteriolar blood flow is redued, and GFR is therefore dependent on AII mediated efferent arteriolar vasoonstrition. It should be stressed that ACE inhibitor indued ARF is not dependent on a drop in blood pressure or renal blood flow after the introdution of WHEN TO LOOK FOR ARAS This area was overed in the last review of ARAS for Heart. 9 The four linial settings traditionally thought to make it worth onsidering ARAS are shown in table 2. Figure 1 Magneti resonane angiogram showing right renal artery stenosis, left renal artery olusion, and aneurysmal dilation of the abdominal aorta. www.heartjnl.om

550 an ACE inhibitor. Indeed, in the presene of a signifiant stenosis, renal blood flow and GFR are blood pressure dependent so any intensifiation of antihypertensive treatment an ause redued GFR. A sudden rise in serum reatinine after introdution of an ACE inhibitor is partiularly likely to reflet ARAS if there has been no drop in blood pressure. ACE inhibitor indued ARF is not a speifi indiator of ARAS. It ours whenever GFR is AII dependent. In the patient population at risk of ARAS likely to be presribed ACE inhibitor treatment, the two most ommon other auses are low output heart failure and longstanding hypertension. In patients with longstanding hypertension, funtional or anatomial vasoonstrition of intrarenal arteries and arterioles is the ause of redued glomerular blood flow. An ACE inhibitor indued rise in serum reatinine is also usual in the presene of hroni renal failure of any ause. The normal ompensatory inrease in filtration rate in surviving nephrons is AII dependent and therefore abolished by ACE inhibition. This results in an inrease in reatinine (of no more than 30%) followed by stability, and atually indiates likely long term renal benefit from ontinued ACE 11 12 inhibitor treatment. Sudden loss of renal funtion in someone on long established ACE inhibitor treatment is not partiularly likely to represent new onset ARAS. Causes of dereased ardia output or hypovolaemia should be sought first. Sometimes, an apparently stable dose of ACE inhibitor is the ulprit. Most ACE inhibitors are renally exreted. In the fae of even mild pre-existing renal impairment, ACE inhibitor an start to aumulate. GFR in an ACE inhibitor treated kidney is blood pressure dependent, so a small drop in blood pressure redues GFR, ausing further aumulation of ACE inhibitor and so on. EFFECTS OF ACE INHIBITOR TREATMENT ON RENAL FUNCTION IN ARAS To understand further the diagnosti lues given by hanges in renal funtion after ACE inhibitor introdution in patients with ARAS, it helps to onsider a few different liniopathologial senarios. In ases of bilateral ARAS (most ommonly ARAS to a solitary funtioning kidney with a ontralateral longstanding renal artery olusion (RAO)) and reasonable baseline renal funtion (serum reatinine, 200 mmol/l), the introdution of ACE inhibitor treatment is highly likely to swith off most of GFR. Creatinine will rise signifiantly, usually within a few days. ACE inhibitor indued renal impairment is a highly sensitive test for the presene of bilateral ARAS. In 52 patients with bilateral ARAS, after ACE inhibitor treatment, reatinine rose by at least 20%, median 38%, maximum 101%. 13 It should be noted that ACE inhibition is not an absolute even in the fae of bilateral ARAS, the phenomenon of ACE inhibitor indued ARF is partially dependent on ACE inhibitor dose, blood pressure, and volume state. Also, the observed hanges in renal funtion are entirely reversible after disontinuation of ACE inhibitor treatment. In ases of unilateral ARAS and bakground parenhymal damage in both kidneys, swithing off GFR in one kidney will approximately halve GFR. If baseline GFR is 50 60 ml/min or less, a halving of GFR will approximately double serum reatinine. This degree of hange should spark onsideration of ARAS. Whether intervention in this setting delays the onset of ESRF is ontroversial. Although in ardiology it may Abbreviations ACE: angiotensin onverting enzyme ARAS: atherosleroti renal artery stenosis ARB: angiotensin II reeptor bloker ARF: aute renal failure CAD: oronary artery disease ESRF: end stage renal failure GFR: glomerular filtration rate MRA: magneti resonane angiography RAAS: renin angiotensin aldosterone system RAO: renal artery olusion be true that an open artery is better than a losed one, 14 the rate of progression of most nephropathies is proportional to blood pressure. Restoring pateny to a renal artery and exposing the remaining glomeruli to the full fore of the systemi blood pressure ould hasten the onset of ESRF. In the presene of unilateral ARAS and good underlying renal funtion in both kidneys, the use of ACE inhibitor treatment will swith off GFR in one kidney but reatinine will probably remain normal. Whether ACE inhibition alters the outome in suh kidneys is not known. We know that the severity of stenosis predits risk of olusion, and olusion is usually (not neessarily immediately) followed by irreversible loss of funtion. There is neither ompelling reason nor evidene to suppose that ACE inhibitor indued swithing off of GFR aelerates nephron death. On the ontrary, it is oneivable that good blood pressure ontrol and pharmaologi suppression of the RAAS might delay the progression of ARAS and redue the risk of olusion. Arguably therefore, although full dose ACE inhibitor introdution without a signifiant rise in reatinine does not exlude the presene of unilateral ARAS, in the absene of poor blood pressure ontrol it allows us to ignore the possibility. ACE INHIBITION AS TREATMENT FOR RENOVASCULAR HYPERTENSION ACE inhibition is of ourse the logial treatment for any renin dependent omponent of high blood pressure. In the not unommon setting of a unilateral RAO with a small irreversibly damaged kidney providing, 10% of renal funtion, ACE inhibition is the treatment of hoie (these kidneys have suffiient ollateral blood supply to allow them to release signifiant quantities of renin). This situation is often suspeted in a typial patient with one small kidney on ultrasound sanning. Whether it is neessary to exlude ontralateral ARAS before ommening ACE inhibitor treatment, or reasonable to simply monitor renal funtion arefully immediately after introdution, is not lear. In theory one ould worry about the progression of a silent nonhaemodynamially signifiant ARAS to the good kidney after introdution of ACE inhibitor treatment. One ould equally argue that the use of ACE inhibitor treatment would at as an early warning system, as reatinine will rise before the (probably reversible) ARAS progresses to (possibly irreversible) RAO and therefore ESRF. RENAL REVASCULARISATION TO ALLOW ACE INHIBITOR USE The interlinked problems of renal revasularisation to permit ACE inhibitor use, and the high ardiovasular morbidity of ARAS patients, are perhaps urrently the most interesting www.heartjnl.om

Atherosleroti renal artery stenosis: key points Cardiovasular death is muh more likely than end stage renal failure in atherosleroti renal artery stenosis. This should influene investigation and management strategies The high ardiovasular death rate in this group may be related to ativation of the renin angiotensin aldosterone system (RAAS). Revasularisation may be indiated to diretly redue the stimulus to inreased RAAS, and also to allow further pharmoologial blokade of the system The diffiulties in learly attributing possible linial sequelae to renal artery stenosis are a major obstale to onduting meaningful trials of intervention aspets of this topi. As the evidene base for the benefits of ACE inhibitor treatment aumulates, it is beoming lear that nearly all patients with ARAS will have some indiation for ACE inhibitor use, beause of CAD, impaired left ventriular funtion, erebrovasular disease, or renal impairment with proteinuria. 15 16 In patients with bilateral ARAS it is usually impossible to use ACE inhibitor treatment without unaeptable loss of renal funtion. It is, however, usually possible to re-introdue ACE inhibitor treatment after suessful renal revasularisation. Until now, the major reason for intervention in bilateral ARAS with stable renal funtion, aeptable blood pressure ontrol, and no pulmonary oedema has been to prevent RAO. It has not been shown that the benefits of suh a strategy outweigh the risks, although some nephrologists already onsider this so likely as to prelude randomised ontrolled trials. The added theoretial benefits of revasularisation to permit ACE inhibitor introdution make it more likely that intervention will beome the norm in this setting. The benefits of ACE inhibitors and also aldosterone antagonists 17 18 in ardiovasular disease have drawn attention to the multiple adverse effets of an ativated RAAS. 19 20 High renin hypertension has long been known to predit an adverse outome. 21 The severity of ARAS is a preditor of nonrenal mortality after adjustment for other risk fators. 6 Although this ould be simply beause ARAS is a marker of advaned generalised arterial disease, it is likely that an ativated RAAS, independently of any effets on blood pressure or volume status, aelerates the progression of atheroslerosis and ontributes to left ventriular dysfuntion. This suggests that we should intervene not simply to improve blood pressure ontrol or prevent progression of renal disease, but to swith off overativity in the RAAS and thereby redue ardio- and erebrovasular morbidity and mortality. This probably requires not only revasularisation but thereafter introdution of ACE inhibitors and also aldosterone antagonists. The RAAS will probably remain overative after revasularisation beause of almost inevitable o-existent intrarenal vasular and parenhymal damage, and the extra benefit seen with aldosterone antagonism on top of ACE inhibition in trials may be due to suppressing the phenomenon of aldosterone esape. 22 ARAS: THE NEAR FUTURE Perhaps the two ertainties about ARAS in the next few years are: firstly, that it will be inreasingly diagnosed (beause of the ready availability of MRA); and seondly, in deiding what to do about these lesions, big trials are unlikely to provide unequivoal guidane. However, we already know that the underlying disease proess in ARAS and CAD is the same. Furthermore, the outome for ARAS patients is broadly similar to those with CAD, and the treatments should also be similar aggressive risk fator management and the use of ACE inhibitors or ARBs and aldosterone antagonists. Introdution of ACE inhibitors whih does not result in a signifiant rise in serum reatinine may well be inreasingly used as a onvenient surrogate for the absene of linially relevant ARAS. If these drugs do produe an unaeptable loss of renal funtion and there is no other obvious ause for ACE inhibitor indued ARF, the safety of MRA makes it an attrative tool to onfirm or exlude ARAS. Amenable lesions will be stented to allow re-introdution of ACE inhibitor treatment. We know that ARAS is ommon in patients with CAD, and we also know that CAD is more ommon in arteriopaths when they also have ARAS. 23 Whether sreening for prognostially signifiant but linially silent CAD in ARAS is worthwhile is unknown. Unlike many questions surrounding ARAS, it is perhaps answerable. REFERENCES 1 Korsakas S, Mohaupt MG, Dinkel HP, et al. Delay of dialysis in end-stage renal failure: prospetive study on perutaneous renal artery intervention. Kidney Int 2004;65:251 8. 2 Farmer CK, Cook GJ, Blake GM, et al. Individual kidney funtion in atherosleroti nephropathy is not related to the presene of renal artery stenosis. Nephrol Dial Transplant 1999;14:2880 4. Shows unequivoally that in patients with o-existing renal impairment and ARAS, something other than arterial stenosis has usually aused the renal damage. 3 Wright JR, Shurrab AE, Cheung C, et al. A prospetive study of the determinants of renal funtional outome and mortality in atherosleroti renovasular disease. Am J Kidney Dis 2002;39:1153 61. 4 Gray BH, Olin JW, Childs MB, et al. Clinial benefit of renal artery angioplasty with stenting for the ontrol of reurrent and refratory ongestive heart failure. Vas Med 2002;7:275 9. 5 Murphy TP, Rundbak JH, Cooper C, et al. Chroni renal ishaemia: impliations for ardiovasular disease risk. J Vas Interv Radiol 2002;13:1187 98. A omprehensive literature review with extensive referening, emphasising the inreased ardiovasular risk in ARAS. 6 Conlon PJ, Little MA, Pieper K, et al. Severity of renal vasular disease predits mortality in patients undergoing oronary angiography. Kidney Int 2001;60:1490 7. Routine abdominal aortography in 3987 patients undergoing oronary angiography. Survival analysis by degree of ARAS. 7 MaDowall P, Kalra PA, O Donoghue D, et al. Risk of morbidity from renovasular disease in elderly patients with ongestive heart failure. Lanet 1998;352:13 16. 8 Pitt B, Segal R, Martinez M, et al. Randomised trial of losartan versus aptopril in patients over 65 with heart failure. Lanet 1997;349:747 52. 9 Haller C. Arteriosleroti renal artery stenosis: onservative versus interventional management. Heart 2002;88:193 7. 10 Leertouwer TC, Pattynama PMT, van den Berg-Huysmans A. Inidental renal artery stenosis in peripheral vasular disease: a ase for treatment? Kidney Int 2001;59:1480 3. 11 Palmer BF. Renal dysfuntion ompliating the treatment of hypertension. N Engl J Med 2002;347:1256 61. A review of the mehanisms by whih hypertension and the major lasses of antihypertensive drugs affet renal funtion. 12 Bakris GL, Weir MR. Angiotensin-onverting enzyme inhibitorassoiated elevations in serum reatinine. Arh Intern Med 2000;160:685 93. An overview of 12 randomised ontrolled trials of the effet of ACE inhibition on renal funtion both immediately and in the medium term. 13 Van de Ven PGJ, Beutler JJ, Kaatee R, et al. Angiotensin onverting enzyme inhibitor-indued renal dysfuntion in atherosleroti renovasular disease. Kidney Int 1998;53:986 93. 14 White CJ. Open renal arteries are better than losed arteries. Cathet Cardiovas Diagn 1998;45:9 10. 15 Lewis EJ, Hunsiker LG, Clarke WR, et al. Renoprotetive effet of the angiotensin reeptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851 60. 16 Lip GYH, Beevers DG. More evidene on bloking the reninangiotensin-aldosterone system in ardiovasular disease and the long-term treatment of hypertension: data from reent linial trials (CHARM, 551 www.heartjnl.om

552 EUROPA, ValHEFT, HOPE-TOO and SYST-EUR2). J Hum Hypertens 2003;17:747 50. 17 Pitt B, Zannad F, Remme WJ, et al. The effet of spironolatone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 17. 18 Pitt B, Remme W, Zannad F, et al. Eplerenone, a seletive aldosterone bloker, in patients with left ventriular dysfuntion after myoardial infartion. N Engl J Med 2003;348:1309 21. 19 Jaoby DS, Rader DJ. Renin-angiotensin system and atherothromboti disease: from genes to treatment. Arh Intern Med 2003;163:1155 62. 20 Volpe M, Savoia C, de Paolis P, et al. The renin-angiotensin system as a risk fator and therapeuti target for ardiovasular and renal disease. J Am So Nephrol 2002;13:S173 8. 21 Alderman MH, Madhavan S, Ooi WL, et al. Assoiation of the renin-sodium profile with the risk of myoardial infartion in patients with hypertension. N Engl J Med 1991;324:1098 104. 22 Epstein M. Aldosterone reeptor blokade and the role of eplerenone: evolving perspetives. Nephrol Dial Transplant 2003;18:1984 92. 23 Valentine RJ, Clagett P, Miller GL, et al. The oronary risk of unsuspeted renal artery stenosis. J Vas Surg 1993;18:433 40. LEARNING ON THE WEB... Case 9: A mother s heartahe A 35 year old white woman presented with hest pain and breathlessness 10 days following an eletive aesarean setion. This was her seond pregnany, whih had proeeded to term without ompliations. Up until then, she had been ompletely fit and well. Her ECGs were found to be abnormal, and the ultrasound study of her heart gave serious ause for onern. This interative ase report harts the evolution of the patient s linial ourse and provides onise and up-to-date literature reviews on two ardia onditions that share a prediletion for women in the peripartum period. To aess the interative ase visit BMJ Online Learning http://pd.bmjjournals.om/gi/hierarhy/pd_ourse;cbhvol 2005iss3 (free aess; registration required) F T Leong Department of Cardiology, Addenbrooke s Hospital, Cambridge, UK L O Hughes Department of Cardiology, Norfolk and Norwih University Hospital, Norwih, UK Correspondene to: Dr Fong Leong, F.T.Leong@leeds.a.uk www.heartjnl.om