New Advances for the Treatment of Renal Artery Stenosis

VASCULAR DISEASE MANAGEMENT 2012:9(12):E219-E223 

Abstract

Renal artery stenosis (RAS) is a common condition found in patients undergoing cardiac catheterization, patients evaluated for peripheral arterial disease, and patients with poorly controlled hypertension. Although RAS may result in renovascular hypertension, renal insufficiency due to ischemic nephropathy, or recurrent heart failure, there exists a complex relationship between the observation of RAS and any ensuing clinical syndrome. The current knowledge base prevents vascular specialists from knowing with certainty if any individual will benefit from renal artery stenting (RAST). In addition, reports of substantial complications following RAST warrant a reevaluation of selection methodology and technical approaches to improve the procedural safety profile.

Renal artery stenosis (RAS) is a common condition that is found in 5% to 15% of patients undergoing cardiac catheterization^1,2 and up to 40% of patients evaluated for peripheral arterial disease,^3,4 and it is also frequent in patients with poorly controlled hypertension.⁵ Although RAS may result in renovascular hypertension, renal insufficiency due to ischemic nephropathy, or recurrent heart failure, there exists a complex and non-deterministic relationship between the observation of RAS and any ensuing clinical syndrome.⁶ Consequently, the selection of patients with RAS who will benefit from endovascular intervention, primarily by means of renal artery stent placement (RAST), remains elusive and controversial. In fact, despite extensive observational evidence of depressor and functional responses following RAST,^7,8 randomized clinical trials have not clearly substantiated the value of this therapy in unselected populations, defined as individuals with incidentally observed RAS but no compelling clinical mandate for aggressive therapy.^9,10 In addition, reports of substantial complications following RAST¹¹ warrant a reevaluation of selection methodology and technical approaches to improve the procedural safety profile.

Maximizing Benefit of RAST

The current knowledge base prevents vascular specialists from knowing with certainty if any individual will benefit from RAST; decisions are predicated on the result of population studies and inherent statistical probabilities of procedural impact. However, diligence in case identification, procedural management, and postinterventional care can fundamentally improve outcomes (Table 1). Not every patient is a good candidate for intervention, and a thorough knowledge of appropriate clinical scenarios, diagnostic findings, and procedural options is critical.  Attention needs to be focused on three key components: (1) selection; (2) preparation;  and (3) technique. Finally, clinical competency and experience in performing renal interventions is mandatory to reducing complications and assuring successful outcomes.

Patient Selection

Principal to patient selection is identifying patients who are not good candidates for intervention or in whom limited benefit is anticipated (Table 2). Features such as advanced intrarenal structural or vascular compromise, lack of a usable access for catheterization, and anatomic unsuitability preclude consideration for RAST. These may be identified during initial imaging or during attempts at catheterization. In addition, some investigators have advocated limiting treatment to patients in whom the greatest benefit to risk ratio can be achieved, including individuals with accelerated or malignant hypertension or end-organ injury including heart failure, stroke, or declining renal function.¹² As a general guideline, persistent grade 2 or 3 hypertension despite maximal or near maximal doses of antihypertensive therapy are a prerequisite when considering RAST for hypertension management.

Hypertension

Selecting patients appropriate for RAST is unique for each presenting clinical syndrome. When treating hypertensive patients, cohort series have shown specific characteristics predictive of favorable blood pressure outcomes. These include a higher mean arterial pressure (MAP), grade 2 or 3 hypertension, shorter duration of hypertension, bilateral disease, an absence of renal dysfunction, and a greater baseline antihypertensive medication burden.^13-15 In a series of 215 patients with ≥70% stenosis in one or both renal arteries, Zeller et al found that female gender (P=.032), MAP at baseline (P<.001), and preserved parenchyma as demonstrated on ultrasound were associated with hypertension improvement following RAST.¹⁶ 

More recently, in a study of 149 patients undergoing RAST,¹⁷ one-third of patients were determined to benefit from intervention. Responders were noted to have four predictive criteria: ≥4 antihypertensive meds, clonidine use, and a baseline diastolic blood pressure of ≥90 mm Hg. A larger renal size measured by cross-sectional ultrasound volume was an additional discriminator of favorable outcome. A trend toward better outcomes in patients treated for bilateral RAS was also observed. Interestingly, responders as a group had lower baseline GFR than nonresponders.  

Renal Impairment

Ischemic nephropathy describes the syndrome of impaired excretory function occurring secondary to RAS. Classically, this has been best represented in patients with RAS experiencing acute renal failure following the introduction of angiotensin-converting enzyme inhibitors or receptor blockers due to efferent arterial vasodilation and resulting impaired glomerular filtration pressures.¹⁸ However, reductions of renal plasma flow may also occur due to progressive atherosclerotic stenosis. Patients with more rapid declines in renal function prior to intervention are more likely to experience improved glomerular filtration rates after intervention; in contrast, long-standing disease and chronic insidious progression of renal insufficiency is associated with a less favorable response. The rate of decline prior to RAST has been demonstrated in multiple series to be a strong predictor of renal improvement.^19-22 In a series of 125 patients undergoing RAST for chronic kidney disease (CKD),²¹ 53 (42%) were considered “responders” (eGFR improved more than 20% from baseline) and an additional 31 (25%) stabilized renal function (eGFR ±20% of baseline). Responders had statistically significant differences in the slope of renal decline in the 6 months prior to intervention. Modrall et al identified a threshold of 0.46% per week reduction in preprocedural eGFR to have a sensitivity of 0.88 and negative predictive value of 0.94 for predicting outcomes of RAST in a small population of patients with renal insufficiency.¹⁷ However, specificity and positive predictive value were relatively low, suggesting that utilization of a strict cutoff value may limit the potential for benefit for some patients with more gradual onset of disease.  A benefit from intervention is notable, because responders are more likely to avoid or substantially delay the onset of renal replacement therapy.²² Although the influence of successful RAST on overall mortality has not been proven, two studies have suggested improved survival in patients who regain renal function after undergoing intervention.^23,24

Two recent reports have affirmed that RAST may be uniquely valuable in patients with predialytic (CKD stage 3 to stage 5) renal failure.^25,26 In a prospective review of 908 patients undergoing RAST for advanced kidney disease, Kalra et al reported an odds ratio for improvement in GFR of at least 20% 1 year after intervention to be 2.69 (1.55-4.68) for patients with eGFR ≤60 mL/min/1.73m² (stage 3 CKD), and 6.72 (3.59-12.56) for eGFR under 30 mL/min/1.73m² (stage 4-5 CKD). Both of these observations were strongly statistically significant.²⁵ 

Further data from the 251 patient ODORI registry noted 12-month increases of 12.9 mL/min/1.73m² mean eGFR in patients with baseline stage 4 CKD (P=.04); similar but non-statistically significant trends were noted in other CKD subsets. In contrast, significant decreases in eGFR were observed in patients with eFGR ≥60 mL/min/1.73m².²⁶ These findings of potential renal recovery warrant further investigation of the RAS screening and treatment paradigm in patients being audited for initial renal replacement therapy.

Heart Failure

RAS is associated with left ventricular (LV) dysfunction, including reduced diastolic compliance (measured as LV end diastolic volume) that can result in recurrent episodes of heart failure or otherwise unexplainable “flash” pulmonary edema despite a normal systolic ejection fraction.^27,28 Left ventricular hypertrophy may also occur secondary to systemic hypertension. Associated endothelial dysfunction and impaired peripheral flow mediated dilation further promote cardiovascular compromise.^29,30 

Alterations in resting QT intervals suggesting repolarization abnormalities observed in patients with RAS have an uncertain impact on cardiovascular disease, because there is no evidence that this results in disturbed coronary perfusion.³¹ RAST results in both improved LV dynamics^27,32 and reductions in cardiac events.^33,34 A contemporary trial by Kane et al compared medical therapy alone versus renal revascularization in patients with RAS and recurrent heart failure (HF). Revascularization in this series produced substantial and positive differences in subsequent HF severity, proportion of follow-up hospital admissions for HF, and time to first HF hospitalization.³⁴

Patient Preparation and Technique

The initial step when considering RAST is identifying the inherent risk-to-benefit profile. As noted earlier, a review of preinterventional imaging is important to identify anatomic suitability for treatment related to access sites, aortic disease, and target renal size. Imaging can also identify the best obliquity for profiling the renal artery to assure optimized stent positioning, and additionally it gives insights regarding the renal artery landing zone in cases in which distal embolic protection might be considered. Prior to intervention, all patients should be started on antiplatelet therapy, usually with a loading dose of clopidogrel. The value of the routine use of statins to reduce embolic events has not been determined for renal interventions but should be considered. There is no consensus regarding the discontinuation of antihypertensive medications before RAST, although angiotensin-converting enzyme inhibitors have been implicated in contrast-induced nephrotoxicity (CIN).³⁵

All patients with extant renal insufficiency should be adequately hydrated to avoid CIN. In general, rigorous periprocedural intravenous hydration is the cornerstone of therapy. Despite some discordant results, the use of oral or intravenous N-acetylcysteine and bicarbonate saline infusions are usually harmless and may provide additional CIN prevention.³⁶ CO₂ gas may be used as an alternative contrast agent in patients with advanced CKD or hypersensitivity to iodinated contrast.³⁷

The techniques of renal artery intervention have evolved over the past several years. For the most part, lesion crossing is performed using appropriately shaped guide catheters or guide sheath (for example, renal double curve or LIMA shaped guides) and low profile 0.014- to 0.018-inch wires. The guides allow coaxial positioning for atraumatic lesion crossing. In patients with markedly atherosclerotic changes of the pararenal aorta, a “no touch”  technique can be used to prevent renal embolization.³⁸ All patients should be started on antiplatelet therapy prior to treatment and are given heparin or bivalirudin during intervention to prevent thrombotic complications. Simultaneous measurements of aortic and renal artery pressures to determine the trans-stenotic gradient is recommended for more moderate stenosis; a gradient of 20 mm Hg is considered a threshold for pursuing intervention. The value of more aggressive antiplatelet management with glycoprotein 2B3A inhibitors is uncertain, although the RESIST trial showed benefit for these agents for preventing post-procedural renal dysfunction when combined with the use of embolic protection devices (EPDs) only.³⁹ The putative mechanism for this synergistic effect was felt to be related to prevention of intrinsic platelet activation consequent to intrarenal emboli.⁴⁰

The routine use of distal embolic protection for renal interventions is not established.  Unfortunately, there are no dedicated renal devices, and anatomic constraints in the kidneys including a relatively short main renal artery length, and the frequent presence of prehilar branching imposes an inherent limitation for existing EPDs.  Holden described renal function preservation in 97% of patients treated with EPDs, which is much better than historical controls; this effect was preserved even in patients with stage 3B and stage 4 CKD.⁴¹ However, in contrast, a study by Singer et al showed no difference in outcomes for patients treated by stenting alone versus stenting with the use of EPDs.⁴² Limited data from the NIH sponsored Cardiovascular Outcomes in Renal Artery Lesions (CORAL) trial, due to begin reporting in 2013, may shed some light on the role of EPDs for RAST.⁴³

Complications

Serious adverse events following RAST are relatively uncommon, and can be reduced by optimal patient selection, meticulous technique, and operator experience. Potential complications include contrast induced nephropathy, emboli, dissection, perforation, failed stent delivery, and geographic misses during deployment. In a more recent review, procedure related dissection occurred in 0.3% to 13%, renal arterial thrombosis in 0.3% to 0.8%, transient renal failure in 1.5% to 13%, and peripheral emboli in 1.4% to 10%.⁴⁴ Renal loss is rare, and periprocedural death is describe in approximately 1% of patients.⁴⁴

Conclusions

The value of RAST is currently a source of considerable review. The major clinical challenge is to select patients who benefit from renal revascularization and for whom its risks are warranted. However, the majority of properly selected patients will benefit from intervention for hypertension, renal insufficiency, and congestive heart failure. New techniques are expected to reduce procedural risks, lower the threshold for percutaneous intervention, and prove the merits of renal revascularization.

REFERENCES

1. Rihal CS, et al. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc. 2002; 77(4):309-316.
2. Harding MB, Smith LR, Himmelstein SI, et al. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol. 1992;2(11):1608-1616.
3. Missouris CG, Buckenham T, Cappuccio FP, MacGregor GA. Renal artery stenosis: a common and important problem in patients with peripheral vascular disease. Am J Med. 1994;96(1):10-14.
4. Olin JW, Melia M, Young JR, Graor RA, Risius B. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med. 1990;881(1N):46N-51N.
5. de Mast Q, Beutler JJ. The prevalence of atherosclerotic renal artery stenosis in risk groups: a systematic literature review. J Hypertens. 2009;27(7):1333-1340.
6. Safian RD, Textor SC. Renal-artery stenosis. N Engl J Med. 2001;344(6):431-442.
7. Colyer WR Jr, Cooper CJ. Management of renal artery stenosis: 2010. Curr Treat Options Cardiovasc Med. 2011;13(2):103-113.
8. Balk E, Raman G, Chung M, et al. Effectiveness of management strategies for renal artery stenosis: a systematic review. Ann Intern Med. 2006;145(12):901-912.
9. Bax L, Woittiez AJ, Kouwenberg HJ, et al. Stent placement in patients with atherosclerotic renal artery stenosis and impaired renal function: a randomized trial. Ann Intern Med. 2009;150(12):840-848.
10. Wheatley K, Ives N, Gray R, et al, for the ASTRAL study. Revascularization versus medical therapy for renal-artery stenosis. N Engl J Med. 2009;361(20):1953-1962.
11. Eklöf H, Bergqvist D, Hägg A, Nyman R. Outcome after endovascular revascularization of atherosclerotic renal artery stenosis. Acta Radiol. 2009;50(3):256-264.
12. Hanzel G, Balon H, Wong O, Soffer D, Lee DT, Safian RD. Prospective evaluation of aggressive medical therapy for atherosclerotic renal artery stenosis, with renal artery stenting reserved for previously injured heart, brain, or kidney. Am J Cardiol. 2005;96(9):1322-1327.
13. Alhadad A, Mattiasson I, Ivancev K, Lindblad B, Gottsäter A. Predictors of long-term beneficial effects on blood pressure after percutaneous transluminal renal angioplasty in atherosclerotic renal artery stenosis. Int Angiol. 2009;28(2):106-112.
14. Ronden RA, Houben AJ, Kessels AG, Stehouwer CD, de Leeuw PW, Kroon AA. Predictors of clinical outcome after stent placement in atherosclerotic renal artery stenosis: a systematic review and meta-analysis of prospective studies. J Hypertens. 2010;28(12):2370-2377.
15. Beck AW, Nolan BW, De Martino R, et al. Predicting blood pressure response after renal artery stenting. J Vasc Surg. 2010;51(2):380-385.
16. Zeller T, Frank U, Müller C, et al. Predictors of improved renal function after percutaneous stent-supported angioplasty of severe atherosclerotic ostial renal artery stenosis. Circulation. 2003;108(18):2244-2249.
17. Modrall JG, Rosero EB, Leonard D, et al. Clinical and kidney morphologic predictors of outcome for renal artery stenting: data to inform patient selection. J Vasc Surg. 2011;53(5):1282-1289.
18. Onuigbo MA, Onuigbo NT. Renal failure and concurrent RAAS blockade in older CKD patients with renal artery stenosis: an extended Mayo Clinic prospective 63-month experience. Ren Fail. 2008;30(4):363-371.
19. Harden PN, MacLeod MJ, Rodger RS, et al. Effect of renal-artery stenting on progression of renovascular renal failure. Lancet. 1997;349(9059):1133-1136.
20. Pattynama PM, Becker GJ, Brown J, Zemel G, Benenati JF, Katzen BT. Percutaneous angioplasty for atherosclerotic renal artery disease: effect on renal function in azotemic patients. Cardiovasc Intervent Radiol. 1994;17(3):143-146.
21. Arthurs Z, Starnes B, Cuadrado D, Sohn V, Cushner H, Andersen C. Renal artery stenting slows the rate of renal function decline. J Vasc Surg. 2007;45(4):726-731.
22. Valluri A, Severn A, Chakraverty S. Do patients undergoing renal revascularization outside of the ASTRAL trial show any benefit? Results of a single centre observational study. Nephrol Dial Transplant. 2012;27(2):734-738.
23. Kennedy DJ, Colyer WR, Brewster PS, et al. Renal insufficiency as a predictor of adverse events and mortality after renal artery stent placement. Am J Kidney Dis. 2003;42(5):926-935. 
24. Pizzolo F, Mansueto G, Minniti S, et al. Renovascular disease: effect of ACE gene deletion polymorphism and endovascular revascularization. J Vasc Surg. 2004;39(1):140-147.
25. Kalra PA, Chrysochou C, Green D, et al. The benefits of renal artery stenting in patients with atheromatous renovascular disease and advanced chronic kidney disease. Catheter Cardiovasc Interv. 2010;75(1):1-10.
26. Sapoval M, Tamari I, Goffette P, et al. One year clinical outcomes of renal artery stenting: the results of the ODORI registry. Cardiovasc Intervent Radiol. 2010;33(3):475-483.
27. Rzeznik D, Przewlocki T, Kablak-Ziembicka A, et al. Effect of renal artery revascularization on left ventricular hypertrophy, diastolic function, blood pressure, and the one-year outcome. J Vasc Surg. 2011;53(3):692-697. 
28. Wright JR, Shurrab AE, Cooper A, Kalra PR, Foley RN, Kalra PA. Progression of cardiac dysfunction in patients with atherosclerotic renovascular disease. QJM. 2009;102(10):695-704.
29. Jacomella V, Husmann M, Thalhammer C, Uike K, Pfammatter T, Amann-Vesti B. Impact of endovascular treatment of atherosclerotic renal artery stenosis on endothelial function and arterial blood pressure. Int Angiol. 2012;31(1):70-76.
30. Koivuviita N, Tertti R, Luotolahti M, et al. The effect of revascularization of atherosclerotic renal artery stenosis on coronary flow reserve and peripheral endothelial function.  Nephron Clin Pract. 2011;118(3):241-248.
31. Maule S, Bertollo, C, Rabbia F, et al. Ventricular repolarization before and after treatment in patients with secondary hypertension due to renal-artery stenosis and primary aldosteronism. Hypertens Res. 2011;34(10):1078-1081.
32. Chrysochou C, Schmitt M, Siddals K, Hudson J, Fitchet A, Kalra PA.  Reverse cardiac remodeling and renal functional improvement following bilateral renal artery stenting for flash pulmonary oedema.  Nephrol Dial Transplant. 2012 [epub ahead of print].
33. Kalra PA. Renal revascularization for heart failure in patients with atherosclerotic renovascular disease. Nephrol Dial Transplant. 2010;25(3):661-663.
34. Kane GC, Xu N, Mistrik E, Roubicek T, Stanson AW, Garovic VD. Renal artery revascularization improves heart failure control in patients with atherosclerotic renal artery stenosis. Nephrol Dial Transplant. 2010;25(3):813-820.
35. Umruddin Z, Moe K, Superdock K. ACE inhibitor or angiotensin II receptor blocker use is a risk factor for contrast-induced nephropathy. J Nephrol. 2012;25(5)776-781.
36. Rundback JH, Nahl D, Yoo V.  Contrast-induced nephropathy. J Vasc Surg. 2011;54(2):575-579.
37. Hawkins IF, Cho KJ, Caridi JG. Carbon dioxide in angiography to reduce the risk of contrast-induced nephropathy. Radiol Clin North Am. 2009;47(5):813-825.
38. Feldman RL, Wargovich TJ, Bittl JA. No-touch technique for reducing aortic wall trauma during renal artery stenting. Catheter Cardiovasc Interv. 1999;46(2):245-248.
39. Cooper CJ, Halyer ST, Colyer W, et al. Embolic protection and platelet inhibition during renal artery stenting. Circulation. 2008;117(21): 2752-2760.
40. Haller S, Adlakha S, Reed G, et al. Platelet activation in patients with atherosclerotic renal artery stenosis undergoing stent revascularization. Clin J Am Soc Nephrol. 2011;6(9):2185-2191. 
41. Holden A, Hill A, Jaff MR, Pilmore H. Renal artery revascularization with embolic protection in patients with ischemic nephropathy. Kidney Int. 2006;7(5):948-955.
42. Singer GM, Setaro JF, Curtis JP, Remetz MS. Distal embolic protection during renal artey stenting:  impact on hypertensive patients with renal dysfunction. J Clin Hypertens (Greenwich). 2008;10(11):830–836. 
43. Murphy TP, Cooper CJ, Dworkin LD, et al. The Cardiovascular Outcomes with Renal Atherosclerotic Lesions (CORAL) study: rationale and methods. J Vasc Interv Radiol. 2005;16(10):1295-1300.
44. Balk E, Raman G, Chung M. Comparative Effectiveness of Management Strategies for Renal Artery Stenosis. Rockville, Md: United States Agency for Healthcare Research and Quality; 2006.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein. 

Manuscript received April 16, 2012, provisional acceptance given April 27, 2012, final version accepted May 23, 2012.

Address for correspondence: John Rundback, MD, FAHA, FSVM, FSIR, Holy Name Medical Center, Interventional Institute, Teaneck, NJ, 07666, USA. Email: jrundback@airsllp.com