The Current Status of Angioplasty of Atherosclerotic Renal Artery Stenosis for the Treatment of Hypertension

Abstract

Atherosclerotic renal artery stenosis, a fairly common disease of older persons, is a manifestation of generalized atherosclerosis, and is often associated with coronary artery disease. It is frequently associated with hypertension and impaired renal function, and is perceived by many physicians to be the cause of hypertension and renal failure. For this reason, they believe that hypertension can be cured by performing percutaneous renal artery angioplasty (PTRA) with stent placement. This practice has led to an increase in angioplasties, especially by interventional cardiologists, although the results from several randomized studies comparing interventional therapy with medical therapy have shown no significant difference between the two treatment modalities in blood pressure reduction or change in renal function. Similar results have been found by nonrandomized trials with selective PTRA. For this review, a Medline search of the English literature was conducted from 2006 to 2012, and 13 pertinent studies were selected. These studies with collateral literature will be discussed in this concise review.

Significant atherosclerotic renal artery stenosis (ARAS) is a ≥50% narrowing of the lumen of the renal artery affecting the ostium or proximal one‐third segment of the artery and is present in 90% of cases.1 It is a disease of elderly persons, occurring in 6.3% to 38% of those undergoing diagnostic cardiac or abdominal angiography.2 However, in an autopsy study, the incidence of ARAS was much higher, about 49% in 256 normotensive and in 77% in 39 hypertensive patients older than 50 years.3 ARAS is a progressive disease and a frequent cause of hypertension and renal insufficiency.4, 5 In addition, the presence of ARAS signifies the existence of atherosclerosis in other vascular beds including the carotid arteries, the coronary arteries, and the peripheral arteries, and is frequently associated with coronary artery disease.5 Regarding the treatment of hypertension in patients with ARAS, renal artery revascularization by percutaneous renal artery angioplasty (PTRA) with stent placement has been popularized as a safe and effective procedure due to the belief by many interventional physicians that this procedure will cure hypertension. It has been estimated that between 1996 and 2000 the volume of PTRAs has increased from 13,380 to 21,660 (62%), mostly as a result of the increase in procedures performed by cardiologists whose volume of renal artery angioplasties has increased by more the 15‐fold during this period.6 However, the outcomes from several prospective randomized trials have failed to establish major benefits from these interventions, which are also associated with serious complications.7 For this review a Medline search of the English literature was conducted from 2006 to 2012, since the subject was reviewed in 2006,7 using the terms atherosclerotic renal artery stenosis and renal artery stenosis. From this search, 7 pertinent randomized trials comparing interventional treatment vs medical management, and 8 nonrandomized trials using PTRA with or without stent placement for the treatment of hypertension were selected and will be discussed in this concise review together with collateral literature.

Pathophysiology of Hypertension in Renal Artery Stenosis

There are two main types of renal artery stenosis (RAS), ARAS, which is the most common in older individuals, with a prevalence of 90%, and RAS caused by fibromuscular dysplasia (FMD), which is most prevalent in younger persons, primarily women, with an incidence of 10%.8 Hypertension caused by unilateral ARAS and FMD is mostly renin‐dependent and resembles hypertension produced from the classic experiments of Goldblatt in the mid‐1930s by constricting the renal arteries in dogs.9 The unilateral RAS in man resembles the two‐kidney one‐clip hypertension in rats, and the increase in blood pressure (BP) caused by the fall of BP distal to the obstruction resulting in renal ischemia. This leads to increased release of renin from the juxtaglomerular apparatus of the kidney and the increased production of angiotensin II (Ang II). The increased production of Ang II results in vasoconstriction, a rise in systemic vascular resistance, and elevation of BP (Figure). The elevated BP causes pressure diuresis from the healthy kidney resulting in plasma volume depletion and further stimulation of the renin‐angiotensin‐aldosterone system (RAAS) and the increased production of these hormones.10 The increased aldosterone increases the absorption of salt and water from the proximal renal tubule and results in plasma volume expansion, after prolonged RAS, with return of renin and Ang II close to normal levels. At this stage, release of the obstruction might still lead to normalization or significant decrease in BP, but the results are unpredictable because of the sustained vascular damage in the unobstructed kidney from the prolonged duration of hypertension. In patients with bilateral ARAS, there is no healthy kidney to respond to pressure diuresis from Ang II, which leads to sodium and water retention, volume expansion, suppression of renin, angiotensin and aldosterone levels, and a volume‐dependent hypertension.11 This type of hypertension is also similar to one‐kidney one‐clip hypertension in rats. In these patients, removal of the obstruction by PTRA may result in reduction of BP, but these patients will still depend on the support of medical therapy for optimal control of BP as has been shown by several randomized and nonrandomized studies in patients with bilateral ARAS.

Figure 1.

The pathophysiological mechanism of hypertension in unilateral renal artery stenosis (RAS). The RAS results in increased secretion of renin from the juxtaglomerular apparatus of the affected kidney, which, in turn, activates the RAAS cascade and increases the levels of angiotensin II and aldosterone leading to increase in blood pressure. Aldosterone causes salt and water retention by the kidneys, but the pressure dieresis for the heathy kidney causes plasma volume contraction and further stimulation of the renin‐angiotensin‐aldosterone system (RAAS) cascade. This leads to a vicious circle of angiotensin‐dependent hypertension. In bilateral RAS, the mechanism is the same at the outset. However, in this circumstance, there is no healthy kidney to respond to pressure diuresis. The end result is salt and water retention, expansion of plasma volume, suppression of the activity of RAAS, and the development of volume‐dependent hypertension. Adapted with permission from Garovic et al.11

Randomized Studies Comparing the BP‐Lowering Effect of Revascularization With Medical Therapy in Patients With ARAS

Seven randomized studies with unilateral or bilateral ARAS ≥50% were selected for analysis because they provided information on the effectiveness of revascularization compared with medical therapy in lowering the BP in patients with ARAS.12, 13, 14, 15, 16, 17, 18, 19 Two of these studies12, 13 showed superiority of renal revascularization compared with medical therapy in significantly lowering the BP in hypertensive patients with ARAS. However, these studies were small and of short duration of follow‐up. The other 5 studies were larger, had longer duration of follow‐up, and did not show any significant difference in the magnitude of BP reduction or change in renal function from baseline, measured by either serum creatinine or creatinine clearance in patients treated with PTRA or medical therapy (Table 1). In addition, patients treated with PTRA required medical therapy with ≥2 antihypertensive drugs to maintain BP control. Because of the small number of patients in these studies, the results from unilateral and bilateral ARAS were lumped together.

Table 1.

Randomized Studies Comparing Revascularization of the Renal Artery With Medical Therapy for the Treatment of Hypertension in Patients With ARAS

Author	Rev, No.	MT, No.	BBP, mm Hg		Change, mm Hg		Follow‐Up, mo	P Value
			Rev	MT	Rev	MT
Webster12	12	16	190/99	189/105	−34/11	−8/1	3–34	<.005
Plouin13	23	26	165/98	165.96	−14/8	−7/1	6	<.009
Van Jaarsveld14	56	50	179/104	180/110	−19/12	−17/7	12	NS
Bax15	62	74	160/83	163/82	−9/6	−8/3	24	<.40
Wheatley16	403	403	149/76	152/76	−8/3	−11/6	60	NS
Ziakka17	36	46	178/88	175/90	−21/8	−18/8	48	NS
Arthurs18	18	22	162/75	142/73	+4/+5	−5/+5	48	<.05, SBP

Abbreviations: BBP, baseline blood pressure; Rev, revascularization; MT, medical therapy; NS, not significant.

Nonrandomized Studies on the Effects of Revascularization in Patients With Hypertension and ARAS

In several nonrandomized studies of patients with unilateral or bilateral ARAS ≥50% with hypertension and renal function impairment were treated selectively with PTRA and stent placement with or without medical therapy. Selective treatment with PTRA did not result in significant reduction of BP or change in renal function from baseline measured by serum creatinine or creatinine clearance. Also, the majority of these patients required additional medical therapy with ≥2 antihypertensive drugs to maintain BP control (Table 2).

Table 2.

Nonrandomized Studies of Renal Artery Angioplasty for the Treatment of Hypertension in Patients With ARAS

Author	With ARAS
	Patients, No.	Age, y	BBP, mm Hg	Change, mm Hg	Follow‐Up, mo	P Value
Zhao19	81	76	160/79	−25/11	31.3	NR
Mohammad20	26	63	189/114	−11/37	12	<.001
Rimoldi21	74	70	147/71	−10/+8	6	.94
Jaff22	163	72	162/78	−17/3	9	<.001 (SBP)
Koivuviita23	19	69	199/90	−7/+1	3.4	NS
Rocha‐Singh24	286	71	179/83	−25/4	9	<.001 (SBP)
White25	100	67	173/88	−27/11	6	<.01

Abbreviations: ARAS, atherosclerotic renal artery stenosis; BBP, baseline blood pressure; NR, not reported; NS, not significant; SBP, systolic blood pressure.

Discussion

ARAS is a disease of older persons and is frequently associated with atherosclerotic changes in other vascular beds of the body. In patients undergoing diagnostic catheterization for coronary artery disease (CAD) or abdominal aneurysm, ARAS was found in 23% to 38% of cases, and 18% had significant ARAS of ≥50% narrowing of the arterial lumen.26 The incidence of ARAS was even higher (62%) in patients with peripheral vascular disease. Although ARAS is mostly unilateral, 46% of patients have bilateral disease.25 The majority of patients with ARAS have hypertension and renal function impairment, and many interventional physicians believe that they can cure or prevent the worsening of BP and renal function by performing an angioplasty of the RAS. For this reason the number of PTRAs has increased significantly, especially by cardiologists whose practice has increased by 3.9‐fold between 1996 and 2000, and by 15‐fold in those practicing in the south east region of the country.6 However, data from several randomized and nonrandomized studies have shown that the long‐term success rate is very poor and has led to a great debate between interventionalists who prefer revascularization of RAS and the nephrologists who prefer medical management as the best choice for treatment of these patients.27, 28, 29 Therefore, it is important that the physician distinguish between association and causation of ARAS with hypertension and renal function impairment in patients with ARAS and critically appraise the potential for meaningful clinical improvement in the selection of patients for PTRA, because the high BP in patients with ARAS could be caused by the coexistence of essential hypertension with RAS. Thus, before any decision for intervention is made, the magnitude of RAS should be determined. This can be assessed invasively by angiography with measurement of the pressure gradient across the stenosis, which remains the gold standard, or noninvasively by several methods, one of which is the measurement of peak systolic velocity (PSV) of blood flow in the stenosed renal artery and also in the aorta above the stenosed renal artery by a duplex scan.4 From these measurements, the PSV ratio of renal to aortic artery (RAR) can be determined. The values for PSV and RAR for significant and nonsignificant RAS are listed in Table 3. The measurement of renal vein plasma renin activity is difficult to perform and is not very specific due to drug interaction. It should also be realized that the progression of ARAS to complete renal artery occlusion is slow, about 0.7% in 3 years for RAS <60%,30 and therefore, before any intervention is attempted, optimal medical therapy should be the preferred option. In addition, since ARAS is a manifestation of generalized atherosclerosis and often a sentinel for CAD, attention should be given to the management of coexisting risk factors such as hypertension, serum cholesterol, diabetes, and obesity, including lifestyle changes. However, the presence of severe, treatment‐resistant hypertension, rapid decline in renal function, and especially flash pulmonary edema are indications for significant RAS, and are compelling reasons for intervention. Also, the rapid increase in serum urea nitrogen and serum creatinine levels in a patient treated with an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker is an indication of severe bilateral renal artery stenosis and an indication for evaluation for possible intervention.31 The worsening of renal function with blockers of RAAS is due to the lowering of pressure in the efferent glomerular arteriole, which is controlled by Ang II and therefore, its blockade leads to a decrease in the glomerular filtration pressure and a decrease in glomerular filtration rate. However, the resultant azotemia is fully reversible in the majority of cases with the discontinuation of these drugs. On the subject of hypertension in patients with ARAS, the American Heart Association (AHA) has issued guidelines regarding the management of these patients.32 These AHA guidelines address medical or interventional management of these patients and are summarized in Table 4. Regarding medical management, the first line of therapy should be with drugs that block the RAAS in combination with diuretics, calcium channel blockers, and β‐blockers. Other drugs can be added as needed. The AHA guidelines for intervention concern patients with severe RAS >70% resistant to medical therapy; however, these recommendations are being challenged by some authors who believe that waiting for the RAS to progress to severe stenosis might cause irreparable renal damage and this, perhaps, could have been the reason for the poor results of the previous studies.33 They claim that there is evidence that renal functional abnormalities are already apparent in patients with mild RAS of <30%, and that these patients have a high risk for cardiovascular complications. Perhaps in line with this view are the findings of a study that compared all‐cause mortality, cardiovascular mortality, and a composite end point of angina pectoris, CAD, myocardial infarction, and ischemic stroke in patients with no RAS, those with RAS <50%, and those with RAS >50%.34 The patients were followed for 98 months and the results showed that in patients with no RAS, the incidence of all‐cause mortality, cardiovascular mortality, and the composite endpoint occurred in 11 of 165 (6.6%), 6 of 165 (3.6%), and 22 of 165 (13.3%), respectively. In those with RAS <50%, these complications occurred in 4 of 36 (11.1%), 2 of 36 (5.6%), and 11 of 36 (30.6%), respectively. In patients with RAS >50%, these complications occurred in 23 of 100 (23%), 23 of 100 (23%), and 46 of 100 (46%), respectively. This issue will hopefully be resolved from the currently ongoing multicenter National Institutes of Health–sponsored Cardiovascular Outcomes with Renal Atherosclerotic Lesions (CORAL) study when completed. This study includes patients with significant RAS ≥60% with a systolic pressure gradient of at least 20 mm Hg or RAS >80% without the requirement of gradient measurement. In addition, these patients must be resistant to medical treatment with systolic BP >155 mm Hg taking ≥2 antihypertensive drugs. This study will prove whether revascularization of ARAS in combination with medical treatment will be superior to medical treatment alone in controlling BP and reducing the incidence of cardiovascular and renal events.35

Table 3.

Classification of Renal Artery Stenosis by Duplex Scanning of the Renal Artery

Renal Artery Diameter Reduction	PSV	RAR
Normal	<180 cm/s	<3.5
<60%	≥180 cm/s	<3.5
≥60%	>180 cm/s	≥3.5
Occlusion	No signal	No signal

Abbreviations: PSV, peak systolic velocity; RAR, renal aortic ratio.

Table 4.

Clinical Factors Favoring Medical Therapy or Revascularization of RAS

Medical Therapy and Surveillance	Revascularization±Medical Therapy
Controlled blood pressure (BP) with stable renal function	Progressive decline in glomerular filtration rate (GFR) during treatment of hypertension
Advanced age or limited life expectancy	Failure to achieve adequate BP control with optimal medical therapy
Extensive comorbidities that make revascularization risky	Rapid or recurrent decline in GFR in association with BP reduction
High risk for atheroembolic complications	Decline in GFR with treatment with angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers
Concomitant renal parenchymal disease (eg, interstitial nephritis, diabetic nephropathy)	Recurrent congestive heart failure in patients with adequate left ventricular function

J Clin Hypertens (Greenwich). 2013;15:694–698. ©2013 Wiley Periodicals, Inc.24034664