Circulation Journal

Official Journal of the Japanese Circulation Society

ORIGINALARTICLE
http://www. j-circ.or.jp Cardiovascular Intervention

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
Masahiko Fujihara, MD; Yoshiaki Yokoi, MD, PhD; Takaaki Abe, MD, PhD;
Yoshimitsu Soga, MD, PhD; Takehiro Yamashita, MD, PhD; Yusuke Miyashita, MD, PhD;
Masato Nakamura, MD, PhD; Hiroyoshi Yokoi, MD; Sadayoshi Ito, MD, PhD
on behalf of the J-RAS Study Investigators

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.

MethodsandResults: 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 glo-
merular 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) signifi-
cantly decreased from 161.621mmHg at baseline to 137.021mmHg (P<0.0001). In the CKD group, there was no
significant difference in eGFR from 40.710mlmin11.73m2 at baseline to 40.813mlmin11.73m2 (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. (Circ J2015;
79: 351359)

Key Words: Atherosclerotic renal artery stenosis; Chronic kidney disease; Hypertension; Renal artery stenting

R
enal artery stenosis (RAS) can cause renovascular hy-
pertension (HTN), cardiac disturbance syndromes and/
or impaired renal function.1 Atherosclerotic renal ar-
tery 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 cor-
onary artery intervention.4 Additionally in diabetic patients,
combination with ARAS was the greater risk for cardiovascu-
lar-renal events compared with non-ARAS patients.5 The op-
timal treatment strategy for ARAS is intensive medical man-
agement 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 re-
cently, 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

Received August 13, 2014; accepted November 4, 2014; released online December 4, 2014 Time for primary review: 20 days
Kishiwada Tokushukai Hospital Cardiovascular Center, Kishiwada (M.F., Y.Y.); Tohoku University Graduate School of Medicine, Sendai
(T.A., S.I.); Kokura Memorial Hospital, Kitakyushu (Y.S.); Cardiovascular Center, Hokkaido Ohno Hospital, Sapporo (T.Y.); Shinshu
University Hospital, Matsumoto (Y.M.); Toho University Ohashi Medical Center, Tokyo (M.N.); and Fukuoka Sanno Hospital, Fukuoka
(H.Y.), Japan
Mailing address: Masahiko Fujihara, MD, Department of Cardiology, Kishiwada Tokushukai Hospital, 4-27-1 Kamori-cho, Kishiwada
596-8522, Japan. E-mail: masahiko-fujihara@themis.ocn.ne.jp
ISSN-1346-9843doi:10.1253/circj.CJ-14-0908
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal Vol.79,February2015

352
Figure1. Flow chart of the study. ARAS, atherosclerotic renal artery stenosis; CKD, chronic kidney disease; HTN, hypertension.
to assess the safety and impact of renal stenting on blood pres-
sure and renal function for up to 12 months in a large cohort
of Japanese patients with ARAS.
Editorial p295
Methods
Study Design and Patients
The present J-RAS study was a prospective, multicenter, sin-
gle-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 Janu-
ary 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) >180cm/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 diag-
nosis of significant RAS was made on selective renal artery
angiography, and renal artery stenting was indicated for an-
giographic stenosis >60% on visual estimation.
Clinical indications included HTN and/or CKD in combina-
tion with significant ARAS. HTN was defined as systolic
blood pressure (SBP) >135mmHg and/or diastolic blood pres-
sure (DBP) >85mmHg.12 CKD was defined as estimated glo-
merular filtration rate (eGFR) <60mlmin11.73m2.13 Ac-
cording to the formula recommended by the Japanese Society
of Nephrology, eGFR was defined as: male=194(serum
Circulation Journal Vol.79,February2015
FUJIHARA M et al.
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 ex-
cluded from the study. Patients with end-stage renal dysfunc-
tion on renal replacement therapy and in-stent restenosis were
also excluded. The Institutional Review Boards of the partici-
pating institutions approved the study. All patients signed in-
formed consent before enrollment and the trial complied with
the requirements of the Declaration of Helsinki.
Procedure
All investigators were proficient in endovascular revascular-
ization of the renal artery and were familiar with the use of the
Palmaz Genesis stent system. All patients received aspirin (100
or 200mg orally once daily) and clopidogrel (75mg 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 con-
firmed on visual assessment. Pre-dilatation with balloon an-
gioplasty was performed and a Palmaz Genesis stent deployed
according to the manufacturers instructions. The stents were
15 or 18mm in length with diameters ranging from 4 to 6mm.
Heparin was used as the anticoagulant agent. Following stent
placement, aspirin (100mg orally once daily) was continued
for a minimum of 12 months and clopidogrel (75mg orally
once daily) for 1 month.
Study Endpoints
Primary EndpointsThe primary efficacy endpoints were
Renal Artery Stenting Outcome in J-RAS Study 353

Table1. Baseline Subject Characteristics Table2. Procedural Characteristics

Total patients Patients (n=149)/
Characteristics Characteristics
(n=149) Lesions (n=172)
Age (years) 72.78.5 Before procedure n=172
Male 82.6 (123/149) De novo lesion 100 (172/172)
Hypertension 81.2 (121/149) Bilateral lesions 26.7 (46/172)
CKD 79.2 (118/149) Ostium 75.6 (130/172)
Diabetes 40.9 (61/149) Non-ostium 27.9 (48/172)
Dyslipidemia 65.1 (97/149) Site reported diameter stenosis (%) 78.712.5
Current smoking 34.2 (51/149) Minimum lumen diameter (mm) 1.60.7
Obesity 24.8 (37/149) Reference vessel diameter (mm) 5.570.8
Heart failure 16.1 (24/149) Lesion length (mm) 12.54.3
Coronary artery disease 57.1 (85/149) Procedure
Carotid artery disease 15.4 (23/149) Procedure success 100 (149/149)
Peripheral arterial disease 34.8 (52/149) Stenting 94.8 (163/172)
Serum creatinine (mg/dl) 1.240.5 Stent diameter (mm) 5.50.6
eGFR (mlmin11.73m2) 48.821 Stent length (mm) 16.21.8
BNP (pg/dl) 110.8170.2 Contrast media dose (ml) 78.351
Anti-hypertensive medicine 2.241.3 After procedure
SBP (mmHg) 154.224 Diameter stenosis (%) 10.24.9
DBP (mmHg) 74.715 Minimum lumen diameter (mm) 5.20.7
Complications
Total lesions
Anatomic characteristics Major complications (%) 0 (0/149)
(n=172)
Method of identification of stenosis Minor complications (%) 1.3 (2/149)
Duplex echo (%) 96.5 (166/172) Data given as meanSD, % (n/N).
Angiography (%) 100 (172/172)
CTA (%) 9.9 (17/172)
MRA (%) 0.6 (1/172) symptoms of heart failure and received i.v. therapy. Progres-
Duplex findings n=166 sive renal insufficiency was defined as eGFR reduction 30%
PSV (cm/s) 304.297 from baseline. The primary safety endpoint was based on that
Renal/aorta ratio 4.932.1 of the CORAL trial.9
Resistance index 0.690.1 Secondary EndpointsThe secondary endpoints included:
Size (cm) 12.76.2 (1) procedural success; (2) primary patency; (3) freedom from
clinically driven target vessel revascularization (TVR); (4)
Anti-hypertensive medicine
HTN group clinical benefit for ARAS in the HTN group using multifactor
(n=121) analysis; and (5) improvement in ARAS with a multifactorial
Calcium channel blocker 81 (67.5) approach in the CKD group. Procedural success was defined
ACEI 13 (10.8) on a per-lesion basis as final result <30% residual stenosis, as
ARB 73 (61.0) determined on catheter angiography without procedure-related
Diuretic 39 (32.5) complications. Primary patency was defined on duplex ultra-
-blocker/- blocker 49 (40.8) sound as within-stent PSV <225cm/s, RAR >3.5 or <60%
diameter stenosis (DS) in the case of catheter angiography.15
Data given as meanSD, % (n/N), or n (%). ACEI, angiotensin-
converting enzyme inhibitor; ARB, angiotensin II receptor blocker; TVR was defined as any angioplasty performed for >60% DS
BNP, B-type natriuretic peptide; CKD, chronic kidney disease; at the original treatment site following the initial procedure in
CTA, computed tomography angiography; DBP, diastolic blood the presence of clinical symptoms or laboratory evidence in-
pressure; eGFR, estimated glomerular filtration rate; HTN, hyper- dicative of the need for revascularization. In the HTN group,
tension; MRA, magnetic resonance angiography; PSV, peak
systolic velocity; SBP, systolic blood pressure. patients with pre-procedure SBP between 150 and 180mmHg
were categorized as responders if their average post-proce-
dure SBP was reduced >10mmHg or for patients with a pre-
procedure SBP >180mmHg whose average post-procedure
change in blood pressure in the HTN group, and change in SBP was reduced >15mmHg and then maintained at 6 and 12
renal function as measured with eGFR in the CKD group dur- months.16 The remaining patients were categorized as non-
ing the 12-month follow-up period. The primary safety end- responders. In the CKD group, renal function outcomes were
point was a composite of freedom from major cardiovascular as follows: improved, increase 10% from baseline eGFR;
or renal event including all-cause mortality, stroke, myocar- failure, decrease 10% from baseline eGFR; and stabi-
dial infarction, hospitalization for congestive heart failure, lized, change of eGFR within a 10% range.17 We, thus,
progressive renal insufficiency, or the need for permanent defined improved as responders and stabilized or failure
renal replacement therapy during the 12-month follow-up as non-responders.
period. Myocardial infarction and stroke were defined on the
basis of clinical symptoms and the results of imaging. Hospi- Clinical Follow-up
talization for congestive heart failure was included for analysis Blood pressure and renal function measurements were per-
if the patient was hospitalized due to documented signs and formed before and after the procedure. Blood pressure was

Circulation Journal Vol.79,February2015

354
Table3. Clinical Outcomes
(A) Change in CKD and HTN Parameters
Before
HTN group (n=121)
SBP (mmHg) 161.621 138.020
DBP (mmHg) 76.615 76.420
Anti-hypertensive medicine (n) 2.21.3 2.21.1
CKD group (n=108)
eGFR (mlmin11.73m2) 40.710 42.112
(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.
subsequently measured with an automatic monitoring twice in
the non-dominant arm, 2min apart (the average of the 2 read-
ings 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 ex-
pressed in terms of frequency, percentage, or meanSD.
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 regres-
sion model was used to determine the predictors of the end-
points. 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 inclu-
sion criteria and were used for primary analysis (Figure1).
RAS was identified on duplex ultrasound in 96.5%, CTA in
9.9%, and MRA in 0.6% of patients. Baseline patient charac-
teristics and anatomic characteristics are listed in Table1. A
total of 123 (82.6%) of the enrolled patients were male. The
mean patient age was 72.78.5 years old. Common clinical
characteristics included HTN (81.2%), CKD (79.2%), diabe-
tes (40.9%), dyslipidemia (65.1%), current smoking (34.2%),
and concomitant coronary artery disease (57.1%). Mean base-
line SBP/DBP was 154.224/74.715mmHg. Mean baseline
eGFR was 48.821mlmin11.73m2. On renal duplex ultra-
Circulation Journal Vol.79,February2015
FUJIHARA M et al.
1 month 3 months 6 months 12 months P value
138.720 137.122 137.021 <0.0001
74.714 75.112 73.611 0.16
2.11.3 2.11.2 2.11.2 0.19
41.612 43.916 40.813 0.32
sound, mean baseline PSV was 304.2cm/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 Table1.
Sixty-seven percent of patients were taking calcium channel
blockers, 61.0%, angiotensin II receptor blockers, 10.8%, an-
giotensin-converting enzyme inhibitors, and 32.5%, diuretics.
Stenting and Periprocedural Findings
One hundred and twenty-six patients (84.6%) underwent treat-
ment 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 5.50.6mm
with a mean stent length of 16.21.8mm. The mean percent
DS of the target vessel (on catheter angiography) was 78.7%
13% before the procedure and 10.25% after stent implanta-
tion. The mean consumption of iodinated contrast volume was
78.351ml (Table2). 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.
Primary Efficacy Endpoints
The primary efficacy endpoint of the HTN group (n=121) at
12 months was achieved at a mean SBP/DBP of 137.021/
73.611mmHg, respectively. There was a statistically signifi-
cant reduction in SBP (25mmHg) compared with the pre-
intervention level (P<0.0001). There was no reduction in the
number of anti-hypertensive medications (P=0.19). Compo-
nents of anti-hypertensive agents were not significantly differ-
ent between baseline and at 12 months. In the CKD group
(n=108), renal function as measured on eGFR remained un-
changed (40.710 vs. 40.813mlmin11.73m2; P=0.32;
Table3A).
Renal Artery Stenting Outcome in J-RAS Study
Figure2. 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).
Primary Safety Endpoints
The primary safety endpoint of freedom from a major cardio-
vascular or renal event at 12 months following renal artery
stenting was 89.4% (Figure2A). All-cause mortality was 4.0%
(6/149). Three patients (2.0%) were hospitalized for conges-
tive 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 (Table3B).
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
(Figures2B,C). In the HTN group, 56% (68/121) were re-
sponders 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
Circulation Journal Vol.79,February2015
355
level (P<0.0001, 0.0193). Non-responders had unchanged SBP
and DBP (Figure3). On multivariate analysis, predictors of
response in the HTN group were age (per year: OR, 0.93; 95%
CI: 0.880.99; P=0.026) and severity of baseline SBP (per
mmHg: OR, 1.06; 95% CI: 1.031.09; P<0.0001) before in-
tervention, but no other parameters relating to response were
identified (Table4). 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 pa-
tients categorized as having failure, eGFR was significantly
decreased (P<0.0001; Figure4). On multivariate analysis,
predictors of response (defined as improved) in the CKD
group were eGFR (per ml/min: OR, 0.93; 95% CI: 0.880.98;
P=0.11) and resistance index (RI) on duplex echocardiography
(per unit: OR, 0.006; 95% CI: 0.00.31; P=0.01; Table4).
356 FUJIHARA M et al.

Figure3. 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).

a relatively high event-free rate of 89.4% at 12 months. Con-

Discussion
It is clear that ARAS is associated with HTN, cardiac distur-
bance syndromes, and CKD.13 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 demon-
strated improvement in blood pressure control with renal ar-
tery 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.810 A prospective renal study, however,
had not been conducted with Japanese patients until the pres-
ent 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
sidering 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
180mmHg, 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 manage-
ment could be observed in at least 60% of the treated pa-
tients.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 dete-
rioration 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

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Renal Artery Stenting Outcome in J-RAS Study 357

Table4. Predictors of Response

Univariate Multivariate
Responder Non-responder Adjusted OR (95% CI)
P-value
(P-value)
HTN group n=68 n=53
Age (years) 718 749 0.04* (per year) 0.93 (0.880.99)
(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 (0.744.91)
(0.18)
SBP (mmHg) 17022 15013 <0.0001* (per mmHg) 1.06 (1.031.09)
(<0.0001*)
DBP (mmHg) 8016 7312 0.036*
CKD 72 (49/68) 75 (40/53) 0.54
eGFR (mlmin11.73m2) 5124 5018 0.70
Heart failure (%) 15 (10/68) 16 (8/53) 0.92
Bilateral lesions (%) 21 (14/68) 11 (6/53) 0.18 1.55 (0.554.55)
(0.40)
BNP (pg/dl) 84129 118156 0.20 (per pg/dl) 0.99 (0.991.00)
(0.24)
Anti-hypertensive medicine (n) 2.21.3 2.21.3 0.63
PSV (cm/s) 31198 30598 0.77
Renal/aorta ratio 5.12 4.91.8 0.49
Resistance index 0.70.1 0.70.1 0.36
CKD group n=35 n=72
Age (years old) 728 757 0.11 (per year) 0.95 (0.881.01)
(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) 14719 15327 0.26
DBP (mmHg) 7415 7313 0.92
eGFR (mlmin11.73m2) 3711 4310 0.0142* (per ml/min) 0.93 (0.88 0.98)
(0.11*)
Urine protein 1.41.0 1.61.1 0.42
BNP (pg/ml) 69101 146.4205 0.0472* (per pg/dl) 0.99 (0.991.00)
(0.06)
Bilateral lesions (%) 14 (5/35) 18 (13/72) 0.62
PSV (cm/s) 302100 311111 0.67
Renal/aorta ratio 5.02 5.22 0.71
Resistance index 0.650.2 0.730.1 0.01* (per unit) 0.006 (0.00.31)
(0.01*)
Contrast media (ml) 6433 7551 0.26
Data given as meanSD, % (n/N), or n (%). *Statistically significant difference P<0.05 with Cox regression model. Other abbreviations as in
Table 1.

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 130.2mmHg). Furthermore, in the CKD group,
33% of patients had significant improvement in eGFR (from
35.5 to 45.8mlmin11.73m2; 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 func-
tion 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 fea-
tures that can predict long-term improvement in blood pres-
sure and/or renal function for patients who have undergone
renal artery stenting. Resting and hyperemic peak systolic
gradient 21 or 20mmHg provided high accuracy in predict-
ing 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.2123 Further studies are needed to inves-

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358 FUJIHARA M et al.

Figure4. 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).

tigate 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 (>160mmHg, P<0.0001)
and lower age (<70 years old, P=0.0186). In the CKD group,
reduced baseline eGFR (<45mlmin11.73m2, P=0.09) and
low RI (<0.7, P=0.008) as measured on duplex ultrasound
were significantly associated with clinical benefits. Some stud-
ies 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 dif-
ference 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 as-
sociated 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 crite-
ria 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 bilat-
eral, 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, pro-
spective 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 ap-
propriate 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. Fur-
ther studies to explore predictors of clinical response are need-
ed to establish optimal treatment and/or management strate-
gies.
Disclosures
Conflict of Interest: The authors have no commercial, proprietary, or fi-
nancial interest in any products or companies described in this article.
Grant Sponsor: Cordis Japan, Johnson and Johnson Company.
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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).