Dr Philip A Kalra
Consultant Nephrologist
Hope Hospital, Salford, UK

Atherosclerotic renovascular disease (ARVD) is a very common condition which occurs in patients with generalised vascular disease and with ageing. It is frequently the cause of secondary hypertension, and it is commonly associated with chronic renal failure (CRF) [1] and end-stage renal failure (ESRF) [2]. However, it should be noted that a directly causal relationship between ARVD and the latter conditions is not always clear. Revascularisation procedures (usually angioplasty with or without stenting, direct stenting or much less often, reconstructive surgery) are frequently performed in ARVD patients with high-grade renal artery stenoses (RAS) but currently there is uncertainty regarding the beneficial effects of such procedures, which are themselves associated with a significant risk of serious complications [3].

Definite indications for renal revascularisation

Despite the lack of an adequate evidence base, most clinicians would agree that revascularisation is indicated for significant RAS in patients with recurrent flash pulmonary oedema. Other patients often considered worthy of this treatment include those with severe hypertension resistant to all medical therapy and those with ACE-inhibitor-related uraemia who require ACE inhibitors or angiotensin II blockers (e.g. for cardiac failure). With respect to patients with RAS and chronic renal failure, clinical practice varies widely, reflecting the absence of clinical trial evidence. However, one subgroup of patients for whom revascularisation would be justified by most clinicians is those with dialysis-dependent renal failure and severe RAS; in such patients there is probably little to be lost and much, potentially, to be gained by intervention.

Outcomes of randomised clinical trials of renal revascularisation in ARVD

At the present time there are only four published clinical trials which have tried to clarify the place of interventional procedures in patients with ARVD, and all have contained only relatively small patient numbers. Hence, Van Jaarsveld et al [4] randomised 106 patients with RAS >50% and significant hypertension [but only mild-moderate renal impairment (creatinine <200 µmol/l)], to angioplasty or medical therapy. No differences were noted in the primary endpoint of blood pressure control, or in renal function. Plouin et al [5] and Webster et al [6] incorporated a similar trial design in only 49 and 55 patients, respectively. Blood pressure control was not improved by angioplasty in the former study, but a significant effect was noted in the latter, Scottish and Newcastle study, albeit only in patients with bilateral disease. No differences in renal function were ascertained in either study. Finally, van de Ven et al [3] compared the effects of angioplasty with or without stenting in 87 patients with ostial RAS. The primary outcome measure was arterial patency, which was significantly improved after stenting; no differences were noted in the secondary endpoint of renal function between the two groups.

Uncertainty regarding the effects of renal revascularisation

The vast majority of the published literature that considers the clinical outcomes after renal revascularisation contains reviews of patient series, usually based in individual centres [7]. Several of these studies have involved meticulous examination of the effects of baseline clinical parameters, such as severity of renal dysfunction, hypertension and cardiovascular co-morbidity, upon renal functional and mortality outcomes after the interventional procedure. However, the clinical application of these findings is limited by the usual deficiencies of non-trial evidence, which are worthy of mention as they are central to the main argument of this article. Hence, all of the retrospective studies have necessarily failed to include a control group, which limits the assessment of the effect of revascularisation as no non-intervention groups were available for comparison. Further, in such patient series it is difficult to determine whether any form of patient selection occurred; also, the lack of similarity and clinical consistency in patient populations creates an inherent problem when trying to compare the findings of different investigating centres.

There are, therefore, several areas of uncertainty regarding the indications for and the effects of renal revascularisation in patients with ARVD, and most of these can only be properly addressed by randomised control trial (RCT) evidence. Each of the major issues worthy of further clarification are considered below.

Hypertension
As discussed above, there is uncertainty regarding the benefits of revascularisation upon hypertension control in patients with ARVD. The three RCTs which have investigated this issue have included small patient numbers [4—6]; two studies showed no significant difference in blood pressure control after angioplasty, whereas the other indicated a benefit to hypertensive patients with bilateral ARVD [6].

Renal function
An overall improvement in renal function may be seen following revascularisation, and the results of the various endoluminal procedures and direct surgery are broadly similar [8]. The existing literature would suggest that renal functional stability after revascularisation is more likely to be seen in patients with mild—moderate chronic renal failure [e.g. serum creatinine 132—265 µmol/l (1.5—3.0 mg/ml)], whereas those with severe renal failure [creatinine >265 µmol/l (> 3.0 mg/ml)] are more at risk of progression to ESRF [8,9]. However, the latter compose the group with greatest mortality risk [2,10] and it would appear counter-intuitive to deny individual patients the chance of revascularisation on the basis of limited evidence. The renal functional outcome dilemma is enhanced by recent studies which show that function is often unrelated to RAS severity in ARVD [10,11], inferring that intra-renal parenchymal injury (usually manifest by proteinuria [12]) may be more important than the haemodynamic effects of a stenosis in many patients with ARVD. The rate of renal functional progression prior to the revascularisation procedure is also thought to have a major bearing upon outcome [13], but this has not been systematically investigated.

Mortality
There are numerous studies which indicate that ARVD is a strong independent predictor of long-term mortality, and the almost invariable co-morbid association of ARVD with extra-renal vascular disease is undoubtedly a major contributor [14]. There is also a strong link between decreasing renal function and mortality, with patients at ESRF having a relative risk of death almost 30 times greater than those ARVD patients with well-preserved renal function [10]. Indeed, once ARVD patients reach the dialysis programmes they have a very poor outlook, with an even higher likelihood of mortality than diabetics; mean survival on dialysis may only be 27 months and 5-year survival 18% [2]. To date, no investigations have shown any survival benefit from revascularisation procedures in this high-risk population.

What constitutes a ‘significant’ RAS lesion
There is currently no consensus regarding what degree of luminal narrowing at renal angiography is representative of significant RAS; many studies select 75% narrowing, while others suggest a cut-off of >50% narrowing [15]. The measurement of pressure gradients across RAS lesions has attempted to provide a scientific basis for intervention. A recent investigation involving three-dimensional MRA coupled with direct intra-arterial pressure measurements suggested that a functionally significant stenosis was associated with a pressure gradient of >15 mmHg; most RAS lesions >50% were shown to manifest this gradient [16]. Other investigators believe that a gradient of 20 mmHg should be accepted as the cut-off for functional significance, and hence the rationale for non-intervention in lesser grade (e.g. <60—75%) lesions [17]. However, it should be noted that such gradients have been assimilated according to the outcome of hypertension control rather than of any renal functional change after revascularisation. Evidence is again lacking in the latter situation.

Renal size
Uncertainty also surrounds the issue of what minimum size of kidney, supplied by an RAS lesion, is worthy of revascularisation. Detailed consideration is beyond the scope of this brief review.

The ASTRAL (Angioplasty and STent for Renal Artery Lesions) trial

Within the ASTRAL trial design about 1000 patients with ARVD will be recruited from multiple centres during a 5-year period. Half of these will be randomised to each of revascularisation (angioplasty with or without stenting, but with best medical therapy) or best medical therapy. The progress of patients will be followed for at least a year. The primary comparison is the rate of progression of renal failure, as assessed by reciprocal creatinine plots over the course of the trial. Secondary endpoints include blood pressure control and the occurrence of serious vascular events (e.g. myocardial infarction and stroke). The following pre-specified subgroup analyses will enable the effects of important baseline characteristics on renal functional outcome to be compared:

• Serum creatinine: three groups of <150, 150—300 and >300 µmol/l
  
• Creatinine clearance (as an estimate of GFR): measured by the Cockroft and Gault method. Three groups of <25, 25—50 and >50 ml/min
  
• Severity of RAS: three groups of RAS <50%, 50—70% and >70%
  
• Ultrasound renal length: groups of <8, 8—10 and >10 cm
  
• Rate of progression of renal dysfunction: the renal functional changes of the patient prior to randomisation will be taken into account (rapid increase in creatinine — yes, no or not known).

Rationale for and potential benefits of the ASTRAL trial

There are thus several areas of uncertainty regarding the indications for renal revascularisation in patients with ARVD, as well as the outcomes after such procedures. Despite this, many revascularisation procedures are still performed in the Western world, often without clear indications; it is well recognised that these procedures carry a significant risk of morbidity, and a distinct, albeit small, risk of mortality [3]. The arguments in favour of a randomised controlled trial, such as ASTRAL, which will help guide future practice, are listed below.

Renal functional change
The chief aim of ASTRAL is to identify whether or not revascularisation in ARVD is associated with any overall improvement in renal function.

Guiding selection of appropriate patients for revascularisation — better use of resources and minimising unnecessary patient morbidity
It is hoped that the pre-specified subgroup analyses within the ASTRAL trial will identify those patients most likely to manifest clinical improvement (e.g. in terms of renal function, hypertension or survival) after revascularisation. This will help to avoid many patients being unnecessarily subjected to such procedures, with concomitant benefit in terms of use of resources, cost and patient morbidity.

Financial benefits to the Health Service
The techniques involved in renal revascularisation are not cheap, especially if endovascular stenting is employed. The future appropriate selection of patients to undergo this procedure can only improve its overall cost-effectiveness. Further, once patients progress to ESRF, the majority are offered dialysis therapy, and the cost of this can be over £25,000 per annum. Preventing or delaying the need for dialysis in even a minority of UK ARVD patients in the future is likely to result in substantial savings to the Health Service.

Evidence-based practice
Why should we overlook the opportunity to accumulate the evidence for best management of ARVD patients when simple coordination, within a multi-centre trial, will allow this?

References

[1] Dean RH, Tribble RW, Hansen KJ, O’Neil E, Craven TE, Redding JF. Evolution of renal insufficiency in ischemic nephropathy. Ann Surg 1991; 213: 446—56.

[2] Mailloux LU, Napolitano B, Bellucci AG, Vernace M, Wilkes BM, Mossey RT. Renal vascular disease causing end-stage renal disease, incidence, clinical correlates and outcomes: A 20 year clinical experience. Am J Kidney Dis 1994; 24: 622—29.

[3] van de Ven PJG, Kaatee R, Beutler JJ, Beek FJA, Woittiez AJ, Buskens E, Koomans HA, Mali WPT. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease : a randomised trial. Lancet 1999; 353: 282—86.

[4] van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FHM, Deinum J, Postma CT et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal artery stenosis. N Engl J Med 2000; 342: 1007—14.

[5] Plouin PF, Chatellier G, Darne B, Raynaud A (for the EMMA study group). Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis. A randomized trial. Hypertension 1998; 31: 823—29.

[6] Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, Loose H et al. Randomised comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. J Human Hypertens 1998; 12: 329—35.

[7] Conlon PJ, O’Riordan E, Kalra PA. New insights into the epidemiologic and clinical manifestations of atherosclerotic renovascular disease. Am J Kidney Dis 2000; 35: 573—87.

[8] Textor SC. Revascularisation in atherosclerotic renal artery disease. Kidney Int 1998; 53: 799—811.

[9] Middleton JP. Ischemic disease of the kidney: how and why to consider revascularisation. J Nephrol 1998; 11: 123—36.

[10] Cheung CM, Wright JR, Shurrab AE, Mamtora H, Foley RN, O’Donoghue DJ et al. Epidemiology of renal dysfunction and patient outcome in atherosclerotic renal artery occlusion. J Am Soc Nephrol 2002; 13: 149—57.

[11] Suresh M, Laboi P, Mamtora H, Kalra PA. Relationship of renal dysfunction to proximal arterial disease severity in atherosclerotic renovascular disease. Nephrol Dial Transplant 2000; 15: 631—36.

[12] Makanjuola AD, Suresh M, Laboi P, Kalra PA, Scoble JE. Proteinuria in atherosclerotic renovascular disease. Quart J Med 1999; 92: 515—18.

[13] Harden PN, MacLeod MJ, Rodger RSC, Baxter GM, Connell JMC, Dominicza KAF, Junor BJR, Briggs JD, Moss JG. Effect of renal artery stenting on progression of renovascular renal failure. Lancet 1997; 349: 1133—36.

[14] Connolly JO, Higgins RM, Walters HL, Mackie ADR, Drury PI, Hendry BM, Scoble JE. Presentation, clinical features and outcome in different patterns of atherosclerotic renovascular disease. Quart J Med 1994; 87: 413—21.

[15] Blum U, Krumme B, Flugel P, Gabelman A, Lehnert T, Buitrago Tellez C, Schollmeyer P, Langer M. Treatment of ostial renal artery stenosis with vascular endoprosthesis after unsuccessful balloon angioplasty. N Engl J Med 1997; 336: 459—65.

[16] Wasser MN, Weatenberg J, van der Hulst VP, van Baalen J, van Bockel JH, van Erkel AR, Pattynama PM. Haemodynamic significance of renal artery stenosis: digital subtraction angiography versus systolically gated three dimensional phase contrast MR angiography. Radiology 1997; 202: 333—38.

[17] Nahman NS Jr, Manian P, Hernandez RA Jr, Falkenhain M, Hebert LA, Kantor BS, Stockum AE, Van Aman ME, Spigos DG. Renal artery pressure gradients in patients with angiographic evidence of atherosclerotic renal artery stenosis. Am J Kidney Dis 1994; 24: 695—99.