Clinical Outcome of Renal Artery Stenting for Hypertension and Chronic Kidney Disease up to 12 Months in the J-RAS Study

– Prospective, Single-Arm, Multicenter Clinical Study –

Abstract

Background: Atherosclerotic renal artery stenosis (ARAS) causes renovascular hypertension (HTN) and impairs renal function, leading to chronic kidney disease (CKD). The J-RAS study was a prospective, multicenter study to assess the clinical outcome of renal artery stenting for up to 1 year in Japanese patients with ARAS.

Methods and Results: One hundred and forty-nine patients were enrolled between November 2010 and January 2013. The patients were classified into an HTN (n=121) group and a CKD (n=108) group in the primary analysis. The primary efficacy endpoints were change in blood pressure for the HTN group and change in estimated glomerular filtration rate (eGFR) for the CKD group at 1 months. The primary safety endpoint was freedom from major cardiovascular or renal events at 12 months. In the HTN group, the mean systolic blood pressure (SBP) significantly decreased from 161.6±21 mmHg at baseline to 137.0±21 mmHg (P<0.0001). In the CKD group, there was no significant difference in eGFR from 40.7±10 ml·min⁻¹·1.73 m⁻² at baseline to 40.8±13 ml·min⁻¹·1.73 m⁻² (P=0.32). The primary safety endpoint was 89.4% at 12 months.

Conclusions: In the J-RAS trial, significant SBP reduction was seen in the HTN group, and stabilization of renal function in the CKD group. Renal artery stenting for ARAS is safe and effective in Japanese patients.

Renal artery stenosis (RAS) can cause renovascular hypertension (HTN), cardiac disturbance syndromes and/or impaired renal function.¹ Atherosclerotic renal artery stenosis (ARAS) accounts for 90% of RAS cases, and typically involves the ostium of 1 or both renal arteries.^2,3 There is a high incidence of major cardiovascular events in patients with polyvascular disease including ARAS who undergo coronary artery intervention.⁴ Additionally in diabetic patients, combination with ARAS was the greater risk for cardiovascular-renal events compared with non-ARAS patients.⁵ The optimal treatment strategy for ARAS is intensive medical management while, in some cases, renal artery stenting should be considered for the resolution or stabilization of HTN and renal dysfunction. Previous renal artery stent registries have shown modest reductions in blood pressure.^6,7 In contrast, 2 large-scale randomized controlled trials (RCT), STAR and ASTRAL, found no benefit in the preservation of renal function when compared with optimal anti-hypertensive therapy.^8,9 More recently, the CORAL trial found that renal artery stenting for ARAS did not confer any significant benefit with respect to the prevention of clinical events in patients with HTN or chronic kidney disease (CKD).¹⁰ These negative results posed difficulties in selecting effective treatment for patients with ARAS. Nevertheless, considering the evidence linking ARAS to HTN and CKD, both conditions may be ameliorated by renal artery stenting. The primary aim of the J-RAS study was to assess the safety and impact of renal stenting on blood pressure and renal function for up to 12 months in a large cohort of Japanese patients with ARAS.

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Methods

Study Design and Patients

The present J-RAS study was a prospective, multicenter, single-arm clinical investigation of patients with significant RAS and HTN and/or CKD treated with a Palmaz Genesis stent system (Cordis; Johnson and Johnson, Waterloo, Belgium). The study was registered at the UMIN Clinical Trials Registry (UMIN No 000014225). Between November 2010 and January 2013, 168 patients were enrolled in the J-RAS study at 25 centers throughout Japan. The patients were classified into an HTN group and a CKD group in the primary analysis. The inclusion criteria were peak systolic velocity (PSV) >180 cm/s, renal aortic ratio (RAR) >3.5 on duplex ultrasound and/or >60% stenosis on computed tomography angiography (CTA) or magnetic resonance angiography (MRA).¹¹ The final diagnosis of significant RAS was made on selective renal artery angiography, and renal artery stenting was indicated for angiographic stenosis >60% on visual estimation.

Clinical indications included HTN and/or CKD in combination with significant ARAS. HTN was defined as systolic blood pressure (SBP) >135 mmHg and/or diastolic blood pressure (DBP) >85 mmHg.¹² CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml·min⁻¹·1.73 m⁻².¹³ According to the formula recommended by the Japanese Society of Nephrology, eGFR was defined as: male=194×(serum creatinine)^−1.094×(age)^−0.287; female=eGFR (male)×0.739.¹⁴

Patients with unilateral or bilateral ARAS were eligible, but patients with totally occluded renal arteries, those with lesions located in the arteries supplying transplanted kidneys, or those with arteries already bypassed by surgical grafts were excluded from the study. Patients with end-stage renal dysfunction on renal replacement therapy and in-stent restenosis were also excluded. The Institutional Review Boards of the participating institutions approved the study. All patients signed informed consent before enrollment and the trial complied with the requirements of the Declaration of Helsinki.

Procedure

All investigators were proficient in endovascular revascularization of the renal artery and were familiar with the use of the Palmaz Genesis stent system. All patients received aspirin (100 or 200 mg orally once daily) and clopidogrel (75 mg orally once daily) for 2 days before the procedure. Periprocedural heparin anticoagulant therapy was undertaken according to routine hospital practice. Endovascular therapy was performed using the standard procedure. More than 60% RAS was confirmed on visual assessment. Pre-dilatation with balloon angioplasty was performed and a Palmaz Genesis stent deployed according to the manufacturer’s instructions. The stents were 15 or 18 mm in length with diameters ranging from 4 to 6 mm. Heparin was used as the anticoagulant agent. Following stent placement, aspirin (100 mg orally once daily) was continued for a minimum of 12 months and clopidogrel (75 mg orally once daily) for 1 month.

Study Endpoints

Primary Endpoints The primary efficacy endpoints were change in blood pressure in the HTN group, and change in renal function as measured with eGFR in the CKD group during the 12-month follow-up period. The primary safety endpoint was a composite of freedom from major cardiovascular or renal event including all-cause mortality, stroke, myocardial infarction, hospitalization for congestive heart failure, progressive renal insufficiency, or the need for permanent renal replacement therapy during the 12-month follow-up period. Myocardial infarction and stroke were defined on the basis of clinical symptoms and the results of imaging. Hospitalization for congestive heart failure was included for analysis if the patient was hospitalized due to documented signs and symptoms of heart failure and received i.v. therapy. Progressive renal insufficiency was defined as eGFR reduction ≥30% from baseline. The primary safety endpoint was based on that of the CORAL trial.⁹

Secondary Endpoints The secondary endpoints included: (1) procedural success; (2) primary patency; (3) freedom from clinically driven target vessel revascularization (TVR); (4) clinical benefit for ARAS in the HTN group using multifactor analysis; and (5) improvement in ARAS with a multifactorial approach in the CKD group. Procedural success was defined on a per-lesion basis as final result <30% residual stenosis, as determined on catheter angiography without procedure-related complications. Primary patency was defined on duplex ultrasound as within-stent PSV <225 cm/s, RAR >3.5 or <60% diameter stenosis (DS) in the case of catheter angiography.¹⁵ TVR was defined as any angioplasty performed for >60% DS at the original treatment site following the initial procedure in the presence of clinical symptoms or laboratory evidence indicative of the need for revascularization. In the HTN group, patients with pre-procedure SBP between 150 and 180 mmHg were categorized as “responders” if their average post-procedure SBP was reduced >10 mmHg or for patients with a pre-procedure SBP >180 mmHg whose average post-procedure SBP was reduced >15 mmHg and then maintained at 6 and 12 months.¹⁶ The remaining patients were categorized as “non-responders”. In the CKD group, renal function outcomes were as follows: “improved”, increase ≥10% from baseline eGFR; “failure”, decrease ≥10% from baseline eGFR; and “stabilized”, change of eGFR within a ±10% range.¹⁷ We, thus, defined “improved” as responders and “stabilized” or “failure” as non-responders.

Clinical Follow-up

Blood pressure and renal function measurements were performed before and after the procedure. Blood pressure was subsequently measured with an automatic monitoring twice in the non-dominant arm, 2 min apart (the average of the 2 readings was used for analysis), after a 5-min rest with the patient in a sitting position. The arm was always supported at heart level.¹² Follow-up examinations for blood pressure and renal duplex ultrasound were conducted at 1, 3, 6 and 12 months.

Statistical Analysis

Statistical analysis was done using JMP version 10.0 (SAS Institute, Cary, NC, USA). The descriptive statistics are expressed in terms of frequency, percentage, or mean±SD. When baseline and follow-up data were available, paired t-test was used to compare the repeated measures for continuous variables. P<0.05 was considered significant. Survival and freedom from event curves were created using the Kaplan-Meier method and graphically presented using life tables. Prognostic variables for the endpoints were investigated using Cox univariate analysis, whereas a multivariate Cox regression model was used to determine the predictors of the endpoints. Factors with P<0.2 on univariate Cox analysis were entered into the multivariate regression models.

Results

Baseline Demographics and Clinical Characteristics

Between November 2010 and January 2013, 168 patients were enrolled in the J-RAS study from 25 participating sites. Among these 168 patients, 149 patients with 172 lesions met the inclusion criteria and were used for primary analysis (Figure 1). RAS was identified on duplex ultrasound in 96.5%, CTA in 9.9%, and MRA in 0.6% of patients. Baseline patient characteristics and anatomic characteristics are listed in Table 1. A total of 123 (82.6%) of the enrolled patients were male. The mean patient age was 72.7±8.5 years old. Common clinical characteristics included HTN (81.2%), CKD (79.2%), diabetes (40.9%), dyslipidemia (65.1%), current smoking (34.2%), and concomitant coronary artery disease (57.1%). Mean baseline SBP/DBP was 154.2±24/74.7±15 mmHg. Mean baseline eGFR was 48.8±21 ml·min⁻¹·1.73 m⁻². On renal duplex ultrasound, mean baseline PSV was 304.2 cm/s and RAR was 4.93. RAS was found only at the right in 76, only at the left in 50, and bilaterally in 23 patients. Therefore, RAS was present in the right renal arteries in 57.5% of patients (99/172) and in the left in 42.5% (73/172). Anti-hypertensive agents being taken on enrollment in the HTN group are also listed in Table 1. Sixty-seven percent of patients were taking calcium channel blockers, 61.0%, angiotensin II receptor blockers, 10.8%, angiotensin-converting enzyme inhibitors, and 32.5%, diuretics.

Figure 1.

Flow chart of the study. ARAS, atherosclerotic renal artery stenosis; CKD, chronic kidney disease; HTN, hypertension.

Table 1. Baseline Subject Characteristics

Characteristics	Total patients (n=149)
Age (years)	72.7±8.5
Male	82.6 (123/149)
Hypertension	81.2 (121/149)
CKD	79.2 (118/149)
Diabetes	40.9 (61/149)
Dyslipidemia	65.1 (97/149)
Current smoking	34.2 (51/149)
Obesity	24.8 (37/149)
Heart failure	16.1 (24/149)
Coronary artery disease	57.1 (85/149)
Carotid artery disease	15.4 (23/149)
Peripheral arterial disease	34.8 (52/149)
Serum creatinine (mg/dl)	1.24±0.5
eGFR (ml·min−1·1.73 m−2)	48.8±21
BNP (pg/dl)	110.8±170.2
Anti-hypertensive medicine	2.24±1.3
SBP (mmHg)	154.2±24
DBP (mmHg)	74.7±15
Anatomic characteristics	Total lesions (n=172)
Method of identification of stenosis
Duplex echo (%)	96.5 (166/172)
Angiography (%)	100 (172/172)
CTA (%)	9.9 (17/172)
MRA (%)	0.6 (1/172)
Duplex findings	n=166
PSV (cm/s)	304.2±97
Renal/aorta ratio	4.93±2.1
Resistance index	0.69±0.1
Size (cm)	12.7±6.2
Anti-hypertensive medicine	HTN group (n=121)
Calcium channel blocker	81 (67.5)
ACEI	13 (10.8)
ARB	73 (61.0)
Diuretic	39 (32.5)
β-blocker/α-β blocker	49 (40.8)

Data given as mean±SD, % (n/N), or n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; CTA, computed tomography angiography; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HTN, hypertension; MRA, magnetic resonance angiography; PSV, peak systolic velocity; SBP, systolic blood pressure.

Stenting and Periprocedural Findings

One hundred and twenty-six patients (84.6%) underwent treatment for a single lesion and 23 patients (15.4%) were treated for bilateral ARAS. Lesions were located in an ostial position in 75.6% (130/172). The mean stent diameter was 5.5±0.6 mm with a mean stent length of 16.2±1.8 mm. The mean percent DS of the target vessel (on catheter angiography) was 78.7%±13% before the procedure and 10.2±5% after stent implantation. The mean consumption of iodinated contrast volume was 78.3±51 ml (Table 2). Procedural success was achieved in 98.7% (147/149) of patients. Flow-limiting dissection needing additional stenting occurred in 1 case (0.7%). In 1 case (0.7%), puncture site complications of an arteriovenous fistula at the common femoral artery arose. This patient was observed with no further deterioration.

Table 2. Procedural Characteristics

Characteristics	Patients (n=149)/Lesions (n=172)
Before procedure	n=172
De novo lesion	100 (172/172)
Bilateral lesions	26.7 (46/172)
Ostium	75.6 (130/172)
Non-ostium	27.9 (48/172)
Site reported diameter stenosis (%)	78.7±12.5
Minimum lumen diameter (mm)	1.6±0.7
Reference vessel diameter (mm)	5.57±0.8
Lesion length (mm)	12.5±4.3
Procedure
Procedure success	100 (149/149)
Stenting	94.8 (163/172)
Stent diameter (mm)	5.5±0.6
Stent length (mm)	16.2±1.8
Contrast media dose (ml)	78.3±51
After procedure
Diameter stenosis (%)	10.2±4.9
Minimum lumen diameter (mm)	5.2±0.7
Complications
Major complications (%)	0 (0/149)
Minor complications (%)	1.3 (2/149)

Data given as mean±SD, % (n/N).

Primary Efficacy Endpoints

The primary efficacy endpoint of the HTN group (n=121) at 12 months was achieved at a mean SBP/DBP of 137.0±21/73.6±11 mmHg, respectively. There was a statistically significant reduction in SBP (–25 mmHg) compared with the pre-intervention level (P<0.0001). There was no reduction in the number of anti-hypertensive medications (P=0.19). Components of anti-hypertensive agents were not significantly different between baseline and at 12 months. In the CKD group (n=108), renal function as measured on eGFR remained unchanged (40.7±10 vs. 40.8±13 ml·min⁻¹·1.73 m⁻²; P=0.32; Table 3A).

Table 3. Clinical Outcomes

(A) Change in CKD and HTN Parameters
	Before	1 month	3 months	6 months	12 months	P value
HTN group (n=121)
SBP (mmHg)	161.6±21	138.0±20	138.7±20	137.1±22	137.0±21	<0.0001
DBP (mmHg)	76.6±15	76.4±20	74.7±14	75.1±12	73.6±11	0.16
Anti-hypertensive medicine (n)	2.2±1.3	2.2±1.1	2.1±1.3	2.1±1.2	2.1±1.2	0.19
CKD group (n=108)
eGFR (ml·min−1·1.73 m−2)	40.7±10	42.1±12	41.6±12	43.9±16	40.8±13	0.32
(B) Clinical Safety Endpoint
	Patients (n=149)
Death from any cause	4 (6/149)
Death from cardiovascular causes	0.6 (1/149)
Death from renal causes	0.6 (1/149)
Stroke	2 (3/149)
Myocardial infarction	0 (0/149)
Hospitalization for CHF	2 (3/149)
Progressive renal insufficiency	4 (6/149)
Permanent renal-replacement therapy	0.6 (1/149)

Data given as % (n/N). CHF, congestive heart failure. Other abbreviations as in Table 1.

Primary Safety Endpoints

The primary safety endpoint of freedom from a major cardiovascular or renal event at 12 months following renal artery stenting was 89.4% (Figure 2A). All-cause mortality was 4.0% (6/149). Three patients (2.0%) were hospitalized for congestive heart failure and 3 patients (2.0%) had a major stroke. Six patients (4%) had progressive renal insufficiency and 1 patient required permanent renal replacement therapy (Table 3B).

Figure 2.

Kaplan-Meier curve for (A) freedom from major cardiovascular and renal events; (B) primary patency; and (C) freedom from clinically driven target vessel revascularization (TVR).

Secondary Endpoints

The secondary endpoint of primary patency as measured on duplex ultrasound was 80.1%, and freedom from clinically driven TVR was 97.0% at 12 months after renal artery stenting (Figures 2B,C). In the HTN group, 56% (68/121) were responders and 44% (53/121) were non-responders. For patients categorized as responders, there was a statistically significant reduction in SBP and DBP compared with the pre-intervention level (P<0.0001, 0.0193). Non-responders had unchanged SBP and DBP (Figure 3). On multivariate analysis, predictors of response in the HTN group were age (per year: OR, 0.93; 95% CI: 0.88–0.99; P=0.026) and severity of baseline SBP (per mmHg: OR, 1.06; 95% CI: 1.03–1.09; P<0.0001) before intervention, but no other parameters relating to response were identified (Table 4). In the CKD group, 35 patients (33%) were categorized as improved, 41 patients (38%) as stabilized and 31 patients (29%) as having failure. For patients who were categorized as improved, there was a statistically significant improvement in renal function on eGFR (P<0.0002). In patients categorized as having failure, eGFR was significantly decreased (P<0.0001; Figure 4). On multivariate analysis, predictors of response (defined as improved) in the CKD group were eGFR (per ml/min: OR, 0.93; 95% CI: 0.88–0.98; P=0.11) and resistance index (RI) on duplex echocardiography (per unit: OR, 0.006; 95% CI: 0.0–0.31; P=0.01; Table 4).

Figure 3.

Responders and non-responders in the hypertension group: 56% responders and 44% non-responders. A statistically significant reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) was seen in patients categorized as responders compared with pre-intervention levels (P<0.0001, 0.0193).

Figure 4.

Improvement, stabilization, and failure in the chronic kidney disease group: 33% categorized as improved, 38% as stabilized and 29% as having failure. A statistically significant improvement in renal function was seen in patients categorized as improved, as measured using estimated glomerular filtration rate (eGFR; P<0.0002). In patients with failure, eGFR significantly decreased (P<0.0001).

Table 4. Predictors of Response

	Responder	Non-responder	Univariate	Multivariate
			P-value	Adjusted OR (95% CI) (P-value)
HTN group	n=68	n=53
Age (years)	71±8	74±9	0.04*	(per year) 0.93 (0.88–0.99) (0.026*)
Male	84 (57/68)	43/53	0.86
Diabetes	41 (28/68)	42 (22/53)	0.90
Dyslipidemia	59 (40/68)	70 (37/53)	0.16	1.87 (0.74–4.91) (0.18)
SBP (mmHg)	170±22	150±13	<0.0001*	(per mmHg) 1.06 (1.03–1.09) (<0.0001*)
DBP (mmHg)	80±16	73±12	0.036*
CKD	72 (49/68)	75 (40/53)	0.54
eGFR (ml·min−1·1.73 m−2)	51±24	50±18	0.70
Heart failure (%)	15 (10/68)	16 (8/53)	0.92
Bilateral lesions (%)	21 (14/68)	11 (6/53)	0.18	1.55 (0.55–4.55) (0.40)
BNP (pg/dl)	84±129	118±156	0.20	(per pg/dl) 0.99 (0.99–1.00) (0.24)
Anti-hypertensive medicine (n)	2.2±1.3	2.2±1.3	0.63
PSV (cm/s)	311±98	305±98	0.77
Renal/aorta ratio	5.1±2	4.9±1.8	0.49
Resistance index	0.7±0.1	0.7±0.1	0.36
CKD group	n=35	n=72
Age (years old)	72±8	75±7	0.11	(per year) 0.95 (0.88–1.01) (0.16)
Male (%)	80 (28/35)	88 (63/72)	0.31	–
Diabetes (%)	40 (14/35)	38 (27/72)	0.80	–
Dyslipidemia (%)	66 (23/35)	64 (46/72)	0.85	–
Hypertension (%)	74 (26/35)	76 (55/72)	0.81	–
Heart failure (%)	14 (5/35)	13 (9/72)	0.79	–
SBP (mmHg)	147±19	153±27	0.26	–
DBP (mmHg)	74±15	73±13	0.92	–
eGFR (ml·min−1·1.73 m−2)	37±11	43±10	0.0142*	(per ml/min) 0.93 (0.88– 0.98) (0.11*)
Urine protein	1.4±1.0	1.6±1.1	0.42	–
BNP (pg/ml)	69±101	146.4±205	0.0472*	(per pg/dl) 0.99 (0.99–1.00) (0.06)
Bilateral lesions (%)	14 (5/35)	18 (13/72)	0.62	–
PSV (cm/s)	302±100	311±111	0.67	–
Renal/aorta ratio	5.0±2	5.2±2	0.71	–
Resistance index	0.65±0.2	0.73±0.1	0.01*	(per unit) 0.006 (0.0–0.31) (0.01*)
Contrast media (ml)	64±33	75±51	0.26	–

Data given as mean±SD, % (n/N), or n (%). *Statistically significant difference P<0.05 with Cox regression model. Other abbreviations as in Table 1.

Discussion

It is clear that ARAS is associated with HTN, cardiac disturbance syndromes, and CKD.^1–3 Current consensus guidelines suggest that stenting for ARAS may be beneficial in patients with hemodynamically significant stenosis and accelerated, resistant HTN in either unilateral and/or bilateral ARAS. Moreover, unexplained HTN in unilateral ARAS, progressive CKD with bilateral ARAS or ARAS in a solitary functioning kidney (class IIa recommendation) may be indicators for renal artery stenting.¹⁸ Single-arm prospective trials have demonstrated improvement in blood pressure control with renal artery stent revascularization. In contrast, RCT comparing renal artery revascularization with medical therapy alone in ARAS patients have failed to demonstrate clear benefits as compared with medical therapy.^8–10 A prospective renal study, however, had not been conducted with Japanese patients until the present trial. This study was undertaken even after CORAL to clarify the effect of renal artery stenting for ARAS.

Primary Endpoint

The goal of renal artery stenting for ARAS is not only to lower blood pressure in HTN and stabilize renal function, but also to thereby lead to reduction of cardiovascular and renal events. In the present trial, these 2 important clinical outcomes for HTN and renal function were associated with positive results. In the CORAL study, the event-free rate after 3 years was 35.1% in the stent plus medical therapy group, and 35.8% for those who received medical therapy alone.¹⁰ The present J-RAS study, which applied the same primary safety endpoint, found a relatively high event-free rate of 89.4% at 12 months. Considering the mean patient age, which was approximately 4 years older than that in the CORAL study, the event-free rate at 1 year in the J-RAS study was assumed to be higher than that of the CORAL study.

The objective performance goal (OPG) of renal artery bare stenting was defined as estimated blood pressure response.¹⁶ According to this OPG in patients with SBP between 155 and 180 mmHg, a decrease in SBP would be linearly proportional to baseline, and at least a 10-mmHg decline from the baseline could be expected. Such an improvement in HTN management could be observed in at least 60% of the treated patients.¹⁶ The present J-RAS study found an average 25-mmHg reduction in SBP from baseline. This SBP reduction met the criterion of the OPG in 56% of the patients. With regard to OPG, change in renal function was not 1 of the documented objectives. In the present study, however, there was no deterioration or significant change of renal function, therefore renal artery stenting was considered to be effective among the CKD patients.

Secondary Endpoint

The OPG of the binary restenosis rate was set at 21% at 9 months.¹⁶ The present binary restenosis rate (19.9% at 12 months) was lower than that of the OPG, and the procedural success rate (98.7%) was high. These results were similar or superior compared with previous studies.^6,7,15,19

We identified the clinical features that discriminate patients who benefit from renal artery stenting. These patients were termed “responders” and could be separated from those who did not obtain clear benefit from the procedure, that is, the “non-responders”. A total of 56% of the HTN patients were considered to be responders and 44% were non-responders. The responders had statistically significant reduction in SBP (from 171.1 to 130.2 mmHg). Furthermore, in the CKD group, 33% of patients had significant improvement in eGFR (from 35.5 to 45.8 ml·min⁻¹·1.73 m⁻²; P=0.0002). Leertouwer et al reported, in a meta-analysis, on renal arterial stent placement in comparison with renal PTA. They reported that renal function was improved in 30% and stabilized in 38% of patients after renal artery stent implantation.²⁰ The present findings are similar to these. At present, however, it is still difficult to predict which subset of patients will be responders or non-responders.

Several trials have reported on pre-intervention clinical features that can predict long-term improvement in blood pressure and/or renal function for patients who have undergone renal artery stenting. Resting and hyperemic peak systolic gradient ≥21 or 20 mmHg provided high accuracy in predicting HTN improvement after renal artery stenting. In inducing hyperemic response, renal fractional flow reserve is said to be promising for identifying patients likely to benefit from renal stenting. These studies, however, used small samples and had inconclusive results.^21–23 Further studies are needed to investigate the importance of renal flow reserve in patients with RAS.

On multivariate analysis, the predictors for response in the HTN group were high baseline SBP (>160 mmHg, P<0.0001) and lower age (<70 years old, P=0.0186). In the CKD group, reduced baseline eGFR (<45 ml·min⁻¹·1.73 m⁻², P=0.09) and low RI (<0.7, P=0.008) as measured on duplex ultrasound were significantly associated with clinical benefits. Some studies confirmed a predictive role of increased RI for either renal function and blood pressure outcome, while in other studies the association of increased RI and renal or blood pressure outcome was inconsistent.^24,25 In the present study, low RI was associated with better response in the CKD group. The low RI might reflect viable kidney function and could be a valuable predictor of response in CKD. In contrast, PSV and RAR on duplex ultrasound has become 1 of the most important tools in detecting significant stenosis.^11,26,27 In analysis of these duplex ultrasound parameters, there was no significant statistical difference between the responders and non-responders. Previous clinical studies reported that higher brain natriuretic peptide (BNP) is a good predictor of blood pressure response after stent implantation.^28,29 In the present study, BNP was not associated with responder patients in the HTN group. In the CKD group, in contrast, lower BNP predicted better response in renal function, despite univariate analysis. The reasons for such discrepancy are currently not known, but considering the differences in patient background, we think that the usefulness of BNP to predict response is still controversial and should await further clarification. Notably, there was no statistically significant difference between unilateral and bilateral lesions. Compared to pediatric patients, there are no established criteria for solitary functioning kidney in RAS. To avoid this confusion, we separated RAS into unilateral or bilateral. In the case of unilateral RAS, there may be some cases of solitary function. And regardless of whether RAS is unilateral or bilateral, viable kidney function is the key factor in recovering renal function. As long as it is clinically indicated, we think that patients with unilateral RAS can benefit from renal artery stenting.

In the study of ARAS, the main aim is to predict which HTN and/or CKD patients will have response. Further research is required to identify the predictors of response in large, prospective studies.

Study Limitations

The major limitation of this study was that it was a single-arm registry without comparison with an optimal medical therapy arm. Second, the follow-up period was relatively short. A follow-up period >1 year is necessary to evaluate cumulative event-free rate and long-term outcome.

Conclusions

The present J-RAS study has demonstrated high freedom from major cardiovascular or renal events at 12 months. There was statistically significant SBP reduction in the HTN group and stabilization of renal function in the CKD group. When appropriate patient selection is carried out and significant RAS is confirmed, renal artery stenting for ARAS produces SBP reduction and has a positive impact on kidney function. Further studies to explore predictors of clinical response are needed to establish optimal treatment and/or management strategies.

Disclosures

Conflict of Interest: The authors have no commercial, proprietary, or financial interest in any products or companies described in this article. Grant Sponsor: Cordis Japan, Johnson and Johnson Company.

Appendix

Principal Investigator

Sadayoshi Ito, MD, PhD, Division of Nephrology, Endocrinology and Hypertension, Tohoku University Graduate School of Medicine.

Lists of Participating Investigators in the J-RAS Study

Yamamoto K. (Sakakibara Heart Institute of Okayama, Okayama); Ishikawa T. (Saitama Cardiovascular and Respiratory Center, Saitama); Ando H. (Kasukabe Chuo General Hospital, Saitama); Kasayuki N. (Ishikiri Seiki Hospital); Taniguchi N. (Takahashi Hospital, Hyogo); Sasaki S. (Saka General Hospital, Shimogama); Munemasa M. (National Hospital Organization Okayama Medical Center, Okayama); Takahashi H. (Yamagata University Hospital, Yamagata); Miki K. (Okazaki City Hospital, Okazaki, Aichi); Ikari Y. (Tokai University Hospital, Kanagawa); Okutsu M. (Nozaki Tokushukai Hospital, Osaka); Jujo K. (Nishiarai Heart Center Hospital, Tokyo); Zen K. (Omihachiman Community Medical Center, Shiga); Hirabayashi T. (Sunagawa City Medical Center, Hokkaido); Asahi H. (Tosei General Hospital, Aichi); Oda H. (Niigata City General Hospital, Niigata); Uesugi M. (Ogaki Municipal Hospital, Gifu); Matsumoto Y. (Sasebo City General Hospital, Nagasaki); Shintani Y. (Shin Koga Hospital, Fukuoka).

References

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