Life After ASTRAL: Who Should Be Revascularized for Renal Artery Stenosis?

Introduction

Hemodynamically significant renal artery stenosis (RAS) induces hypoperfusion of the affected kidney leading to a constellation of physiologic responses.¹ Upregulation of the renin-angiotensin-aldosterone system (RAAS) results in arterial vasoconstriction, impaired natriuresis, and fluid retention.² Over time, hypoperfusion can lead to renal atrophy and fibrosis.³ Renal artery revascularization can restore perfusion to ischemic kidneys and prevent further injury.⁴ However, a great deal of controversy exists regarding the benefit of revascularization in patients with RAS. This controversy is a result of discordance between the excellent technical success with percutaneous renal intervention (PRI) and the modest clinical response rates.⁵ This disconnect suggests that interventions are being performed on lesions that are not hemodynamically significant or in patients whose clinical syndrome is not due to RAS.⁶ Two recent trials, Stent Placement in Patients with Atherosclerotic Renal Artery Stenosis and Impaired Renal Function (STAR) and Angioplasty and Stenting for Renal Artery Lesions (ASTRAL), compared the efficacy of PRI to medical therapy in patients with RAS.^7,8 These trials ultimately concluded that PRI demonstrated little or no benefit over optimal medical therapy. However, these trials suffered from serious methodologic flaws related to patient selection and lesion assessment that place their conclusions in doubt. This article will review the appropriate indications for PRI, discuss some of the shortcomings of the recent trials in this field and, finally, outline strategies to optimize outcomes with PRI.

Current Guidelines

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines define three clinical syndromes caused by hemodynamically significant RAS that may be managed with PRI: 1) renovascular hypertension; 2) ischemic nephropathy; and 3) cardiac disturbance syndromes (Table 1).⁹ PRI is indicated for resistant or malignant hypertension, hypertension with a unilateral small kidney or hypertension with medication intolerance (Class IIa).⁹ Ischemic nephropathy is defined as bilateral RAS or unilateral RAS with a solitary kidney associated with chronic kidney disease (CKD) (Class IIa) or CKD and unilateral RAS (Class IIb).⁹ Cardiac disturbance syndromes include “flash” pulmonary edema, recurrent heart failure and unstable angina. Sudden-onset pulmonary edema or refractory congestive heart failure are firm indications for PRI (Class I).⁹ Unstable angina aggravated by RAS is a Class IIa indication for PRI.⁹

Renovascular Hypertension

Renovascular ischemia induces a cascade of events: stimulation of the RAAS, oxidative stress and sympathoadrenergic signals. This response leads to arterial hypertension and eventually contributes to renal and cardiac dysfunction.¹⁰ A number of small randomized studies and a meta-analyses have shown improved blood pressure control with balloon angioplasty when compared to medical therapy.^11–14 Stent placement has been proven superior to balloon angioplasty, leading to a Class I ACC/AHA guideline recommendation for stent placement over angioplasty.^17,18 Patients with RAS and hypertension can expect a technical success rate of > 98% resulting in a clinical cure rate of only 4–18%, with blood pressure improvement in 65–79%.^19–22

Ischemic Nephropathy

Ischemic nephropathy occurs when the viability and function of the affected kidney is threatened by renal hypoperfusion. Ischemic nephropathy is strongly associated with progression to end-stage renal disease.²³ Renal revascularization in ischemic nephropathy is effective in stabilizing or improving renal function,²⁴ however, the relative benefit of medical therapy compared to PRI is unclear. Antihypertensive therapy can potentially lead to hypoperfusion of the stenotic kidney.²⁵ A recent study enrolled patients with unilateral RAS and CKD on medical therapy consisting of RAAS blockade. In this study, renal function improved after stopping RAAS blockade and improved even further following PRI.²⁶ A large single-center registry reported the results of PRI in 215 consecutive patients with hypertension and CKD. At 1-year follow-up, 52% of patients had improvement in serum creatinine and 76% showed improved control of hypertension.²⁴ These data were confirmed in a much larger multicenter, prospective, cohort-controlled trial that enrolled 908 patients with significant RAS and varying stages of CKD.²⁷ PRI showed twice as many patients with a 20% improvement in GFR compared to medical therapy. Moreover, the majority of responders were patients who had severe stage IV and V CKD (Figure 1).²⁷

Cardiac Disturbance Syndromes

Cardiac disturbance syndromes result from a pressor response induced by renal artery stenosis causing an upregulation of RAAS activity which leads to volume retention, arterial vasoconstriction, and ventricular hypertrophy.²⁸ Renal intervention in patients presenting with an acute coronary syndrome or heart failure leads to improvement in blood pressure and functional status.^18,28,29 In a study of 48 patients presenting with RAS and an acute coronary syndrome, PRI was associated with improvement of blood pressure and symptoms in 88% of patients.¹⁸ In 163 heart failure patients undergoing PRI, a five-fold lower rate of hospital readmission rate and a mean decrease of 1.9 in New York Heart Association (NYHA) class was demonstrated when compared to age-matched controls treated with medical therapy.²⁸ An improvement in left ventricular mass and hypertrophy following PRI has also been demonstrated.^30,31 In a randomized, controlled study of 1,026 patients with RAS treated with medical therapy or PRI, there was a 10% reduction in left ventricular mass index in the intervention group and a 9% increase in left ventricular mass index in the medical therapy arm at 2 years. This improvement in left ventricular dimensions occurred regardless of the blood pressure response.³⁰

Recent Trials

Two recently completed large randomized, controlled trials examined the benefit of PRI in patients with renovascular hypertension and/or ischemic nephropathy. The STAR trial enrolled 140 patients with CKD and RAS determined by noninvasive imaging.⁷ The study compared PRI with medical therapy to medical therapy alone. The primary endpoint was a 20% decrease in creatinine clearance. STAR concluded that stent placement conferred no benefit over medial therapy alone and was associated with significant procedural complications.⁷ However, STAR had significant limitations. The inclusion criteria included any > 50% stenosis by noninvasive imaging or angiography.⁷ In the final analysis, 19% of lesions believed to be > 50% by noninvasive imaging were 7 Another confounding factor was that about 30% of patients in the intervention arm did not receive a stent due to a variety of factors including patient refusal and the presence of 7 These mild cases of RAS and the large percentage of patients in the intervention arm who did not truly require intervention skewed the results in favor of medical therapy.⁷ Finally, it appeared that relatively inexperienced operators were chosen for PRI, which may have biased the study against intervention. The ASTRAL trial enrolled 806 patients with RAS and hypertension or renal insufficiency. An unusual entry criterion was that patients had to have an “uncertain benefit” from renal revascularization.⁸ The primary endpoint was a decline in renal function (inverse slope of change in serum creatinine) at the 5-year follow-up point.⁸ The ASTRAL investigators concluded that there were substantial risks and no benefits with PRI. ASTRAL was another seriously compromised trial in that it contained patients with very mild CKD, with 25% of the study population having normal renal function.⁸ The mean systolic blood pressure in the population was 149 mmHg and the average number of antihypertensive medications used was ^2.79.8 According to the current ACC/AHA guidelines, only 41% of the study population would have had an indication for renal revascularization.³² Given that many of the patients entered into ASTRAL would not be considered candidates for PRI, it is not surprising that renal intervention had no effect on the primary endpoint.8 ASTRAL also suffered from inexperienced, low-volume renal interventionalists who had complications much higher than that reported from experienced centers.

Optimizing Outcomes After STAR and ASTRAL

STAR and ASTRAL demonstrated several common pitfalls in the management of RAS. First, STAR admitted difficulty in assessing lesion severity by noninvasive imaging and angiography, causing them to enroll many patients who were not candidates for revascularization. ASTRAL also suffered from skewed patient selection by enrolling patients unlikely or uncertain to benefit from PRI. Both trials allowed relatively inexperienced operators to perform renal artery interventions, which is not recommended. A number of strategies are emerging to better assess lesion severity and patient selection for PRI.

Assessment of Lesion Severity

Visual assessment of angiographic RAS is fraught with problems in reproducibility and precision. Quantitative hemodynamic measurements of RAS provide greater reproducibility and accuracy.⁴ De Bruyne et al carefully defined hemodynamically significant RAS.³³ In this study, a pressure wire was introduced into a renal artery after a renal stent had been placed. Next, a balloon was inflated within the stent to create a controlled stenosis. Bilateral renal vein sampling was performed at short intervals. A significant obstructive lesion was identified by a rapid increase in ipsilateral renal vein renin levels (Figure 2). The required ratio of systolic pressures in the aorta and distal to the lesion (Pd/Pa) to induce a rise in ipsilateral renal vein renin levels was 0.9.³³ Fractional flow reserve (FFR) determines differences in flow across a lesion by measurements of pressure at maximal hyperemia. If maximal vasodilation or hyperemia is achieved, resistance is presumed to be negligible.³⁴ Under these conditions, flow across a lesion is proportional to the pressure gradient across the lesion. In a study of FFR-guided renal intervention, 17 patients with unilateral RAS underwent renal stenting. At 3-month follow-up, an FFR 35 Another study examined 62 patients with unilateral RAS and hypertension undergoing renal stent placement and compared the translesional hyperemic gradient (THG), FFR and intravascular ultrasound in predicting blood pressure response.³⁶ The highest sensitivity and specificity in predicting blood pressure response was obtained by using a THG ≥ 21 mmHg (Figure 3).³⁶ These findings were confirmed in a recent trial which demonstrated the threshold for improvement in blood pressure in 53 patients with unilateral RAS undergoing renal artery intervention to be a THG of ≥ 20 mmHG (Table 2).³⁷ An alternative method for assessing the degree of renal ischemia is angiographic blush or renal frame count measurement. These techniques have been used in the coronary circulation and show promise in RAS.³⁸ Renal frame counts are defined as the number of cine frames that are required for the smallest distal vessel of the renal parenchyma to opacify with contrast.³⁹ Mahmud et al examined renal frame count scores and renal blush grades in 17 patients referred for renal angiography. They demonstrated that renal frame counts and renal blush grades were impaired in patients with significant RAS. Moreover, improvement in renal frame counts was associated with improvement in blood pressure.⁴⁰ Atheroembolism often occurs during renal intervention and has been implicated as a cause of declining renal function following intervention.^43,44 Embolic protection in the form of distal balloon occlusion⁴⁵ and filters46 has been used safely in the renal circulation and show high rates of debris retrieval.⁴⁷ One cohort study and two retrospective studies demonstrated that the greatest benefit from EPDs was seen in patients with more severe CKD.^21,43,44,47 The use of glycoprotein IIb/IIIa inhibitors may diminish the damage caused by atheroemboli.⁴⁸ A few trials have looked at abciximab in renal interventions, but none have shown a significant benefit.^44,48 A small randomized, controlled trial evaluating abciximab, distal embolic protection, or both, demonstrated that either treatment alone did not benefit renal function, but there was a positive intereraction when both were used.⁴⁴

Patient Selection

The current AHA/ACC guidelines reasonably outline patients who are likely to benefit from PRI. In an attempt to further improve the response rate to stenting, newer methods are emerging as predictors of outcomes following PRI. The rate of decline in renal function predicts outcomes following renal intervention in patients with CKD (Figure 4).^24,49 The presence of proteinuria or elevated renal resistance indices have also been suggested as markers for nephrosclerosis and unresponsiveness to PRI.⁵⁰ Two small observational studies have suggested that proteinuria as a surrogate measure of nephrosclerosis may be a negative predictor of outcomes following renal revascularization.^51,52 Several observational studies using balloon angioplasty have shown that a resistance index > 0.7 predicts a poor response to renal revascularization.^51,53,54 However, this finding has been contradicted by a larger study which looked at 176 patients with resistance indices > 0.7 who underwent PRI with significant improvement in renal function.⁵⁵ Brain natriuretic peptide (BNP) has been proposed as a predictor of treatment response following PRI. BNP promotes natriuresis, diuresis and arterial vasodilation, but its effects are blunted in patients with significant RAS.^56,57 In a study of 27 patients undergoing PRI, elevated BNP (> 80 pg/mL) predicted improvement in blood pressure.⁵⁷ In a larger study of 120 patients undergoing PRI, a BNP cutoff > 50 pg/mL also predicted a blood pressure response.⁵⁸

Summary

For patients with symptomatic, hemodynamically significant RAS, reperfusion by stent placement is the treatment of choice. Patients with significant RAS who benefit most from PRI are those with: 1) ischemic nephropathy in a viable kidney with declining renal function; 2) poorly controlled hypertension on adequate medical therapy; and 3) cardiac destabilization syndromes, i.e., flash pulmonary edema, recurrent congestive heart failure or refractory unstable angina. Hemodynamically significant RAS should be defined as either: 1) a severe (> 70%) angiographically confirmed stenosis, or 2) moderate (50–70%) stenoses as determined by angiography that are accompanied by hemodynamic evidence of renal ischemia documented by either a hyperemic systolic gradient > 20 mmHg, or renal fractional flow reserve of Conclusions Chronic renal ischemia induces a complex sequence of physiologic responses that can lead to renovascular hypertension, ischemic nephropathy and cardiac destabilization syndromes. Percutaneous renal intervention with stent placement is the preferred method of revascularization. Two seriously flawed trials, STAR and ASTRAL, have helped to focus the discussion regarding the potential benefits of renal revascularization. A number of new techniques are emerging which will improve positive outcomes after PRI including better patient selection and more careful lesion assessment in patients with RAS.

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VASCULAR DISEASE MANAGEMENT 2011;8(2):E28-E33