Renal Angioplasty for Atherosclerotic Renal Artery Stenosis Revisited

– Efficacy and Safety of Renal Artery Stenting in the J-RAS Study –

Renal artery stenosis (RAS) leads to renovascular hypertension, a major cause of secondary hypertension, and occurs in approximately 1% of all hypertensive patients in Japan.¹ Atherosclerotic RAS (ARAS) is the primary cause in middle-aged and elderly patients, contrasting with fibromuscular dysplasia in younger patients, and usually involves the ostium and proximal one-third of 1 or both renal arteries.² ARAS is often complicated by other vascular diseases such as peripheral and coronary artery diseases.¹ Although many of the patients have normal renal function, hemodynamically significant unilateral or bilateral RAS causes progressive renal failure known as ischemic nephropathy, which may account for 10% of the underlying diseases of endstage renal failure.^1,3 In type 2 diabetic patients with suspected severe arteriosclerosis, who represent a major subset of patients with ‘high-risk’ clinical presentations, the presence of ARAS is a significant and independent risk factor for cardiovascular-renal events.⁴

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There are 2 major treatment strategies for ARAS: antihypertensive drug therapy and vascular reconstruction. Medical treatment often requires combination therapy, with a Class I recommendation of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers and β-blockers.⁵ The usefulness of vascular reconstruction using percutaneous transluminal renal angioplasty (PTRA) coupled with medication has long been debated. Two recent, large-scale randomized controlled trials (RCTs), STAR⁶ and ASTRAL,⁷ failed to show any further benefit of PTRA in improving renal function as compared with optimal medical therapy. Most recently, the CORAL study also reported negative results of renal revascularization in ‘hard’ endpoints, but with a slight improvement of blood pressure (BP) with stenting.⁸ These findings may suggest limited benefit and relatively higher risk of stenting for patients with moderate ARAS. In the ACCF/AHA Practice Guidelines for Management of Patients with Peripheral Artery Disease (revised in 2013),^9,10 and also in the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014),¹ the indications for PTRA are somehow confined to specific populations of ‘high-risk’ groups, such as those with rapidly declining renal function and/or flash pulmonary edema (Table 1), the types of patients who were not enrolled in any of the RCTs.

Table 1. Indications for Percutaneous Transluminal Renal Angioplasty

ACCF/AHA Guidelines

Class I

1. Hemodynamically significant RAS with unexplained recurrent CHF or sudden pulmonary edema

2. Stent placement for ostial atherosclerotic RAS, and balloon angioplasty (with stent) for FMD

Class IIa

1. Hemodynamically significant RAS with accelerated/resistant/malignant hypertension

2. Hemodynamically significant RAS with unstable angina

3. RAS and progressive CKD with bilateral lesion or with a solitary functioning kidney

Class IIb

1. Hemodynamically significant RAS with asymptomatic bilateral or a solitary viable kidney

2. Unilateral RAS with chronic renal insufficiency

JSH2014 Guidelines

1. Hemodynamically significant RAS and

1) Resistant hypertension to medical therapy alone

2) Exacerbating hypertension

3) Malignant hypertension

4) Hypertension with idiopathic unilateral kidney atrophy

5) Idiopathic pulmonary edema that suddenly develops

6) Repeated heart failure

7) Unstable angina

8) FMD

2. Bilateral RAS

3. Progressive CKD with RAS of a solitary functioning kidney

CHF, congestive heart failure; CKD, chronic kidney disease; FMD, fibromuscular dysplasia; RAS, renal artery stenosis. (Modified from references 1 and 10.)

In this issue of the Journal, Fujihara et al¹¹ report on clinical outcomes of renal artery stenting in 149 ARAS patients with hypertension and/or renal impairment, revealing a significant BP reduction and stabilization of renal function. Although this is a single-arm study, the results show promise that PTRA may be more beneficial than considered according to the results from the RCTs. The baseline clinical data in the present study were somewhat worse than in the 3 recent RCTs, but the outcomes seemed somewhat better (Table 2).

Table 2. Comparison of the Clinical Features of Patients in the Major Clinical Trials for Renal Artery Stenting

Study	STAR	ASTRAL	CORAL	J-RAS
Year	2009	2009	2014	2015
Patients enrolled (n)	64	403	459	149
Age (years)	66.5	70.5	69.3	72.7
Male (%)	67.2	63.0	51.0	82.6
Diabetes (%)	25.0	31.3	32.4	40.9
Dyslipidemia (%)	NA	NA	89.4	65.1
Heart failure (%)	9.0	NA	12.0	16.1
Coronary artery disease (%)	43.0	49.6	26.5 (MI)	57.1
SBP (mmHg) (baseline/follow-up)	160/151	148.8/141.2	149.9/133.3	154.2/137.0
DBP (mmHg) (baseline/follow-up)	83/77	76.3/73.0	NA	74.7/73.6
SCr (mg/dl) (baseline/follow-up)	1.74/1.76	2.03/2.37	NA	1.24
eGFR (ml·min−1·1.73 m−2) (baseline/follow-up)	45/50 (eCcr)	NA	58.0	40.7/40.8
CKD (%)	NA	59.6	49.6	79.2
Diameter stenosis (%) (baseline/follow-up)	NA	76.0/NA	72.5/NA	78.7/10.2
Primary outcome	Renal function	Renal function	Clinical endpoints	Blood pressure, Renal function
Duration of follow-up (months)	24	60	43 (median)	12
No. of antihypertensive drugs (baseline/follow-up)	2.8/2.6	2.79/2.77	2.1/3.3	2.2/2.1
Responders (%)	NA	NA	NA	56
Nonfatal myocardial infarction (n)	3	36	40	0
Mortality (n)	5	103	63	6
Renal event (n)	10	57	93	7
Chronic heart failure (n)	1	47	39	3
Stroke (n)	0	24	16	3

CKD, chronic kidney disease; DBP, diastolic blood pressure; eCcr, estimated creatinine clearance; eGFR, estimated glomerular filtration rate; NA, not available; SBP, systolic blood pressure; SCr, serum creatinine. (Modified from references 6, 7, 8 and 11.)

It should be again noted that these clinical trials may not reflect real clinical practice because of their inclusion and exclusion criteria. Elective percutaneous coronary intervention (PCI), for example, is now routine clinical practice, but most clinical studies failed to prove a clear benefit of PCI for ‘hard’ endpoints over optimal medical therapy.¹² Most recently, a meta-analysis of revascularization therapy for ARAS, including the aforementioned RCTs, has shown better BP control and less antihypertensive drug use for stenting.¹³ In conclusion, we should keep in mind that when truly needed, revascularization to restore renal blood flow remains a valuable and essential therapy for high-risk patients with moderate to severe ARAS.¹⁴

References

• 1.    Shimamoto  K,  Ando  K,  Fujita  T,  Hasebe  N,  Higaki  J,  Horiuchi  M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2014). Chapter 13: Secondary hypertension. Hypertens Res 2014; 37: 349–361.
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