INTRODUCTION
Fibromuscular dysplasia (FMD) is an idiopathic systemic noninflammatory arterial disease that narrows medium-sized arteries, causing stenosis, aneurysm, occlusion or dissection [1–3]. Renal arteries are the most commonly involved vessels, although arteries in other vascular territories can also be affected. In the FMD cohort of the United States (U.S.) registry, there were 66.1% [4] with renal lesions vs. some 90.7% in the European/International registry [5]. Renal artery FMD is the second most frequent cause of renal artery stenosis (RAS) and renovascular hypertension is the most common clinical presentation of FMD [6,7], especially in children [8]. The clinical characteristics of FMD in adults have been previously wildly described in the U.S. and European registries [9–12], while data on FMD in children are limited.
Although the pathogenesis of FMD is still not well understood, binary angiographic classification of renal artery FMD lesions into multifocal or focal is well established [13]. Multifocal FMD, characterized by the classical ‘string of beads’ appearance, is often reported as the most frequent type, unlike focal FMD, denoting a single area of concentric or tubular stenosis that is less commonly observed [5,11,13]. However, these data are mostly from Caucasian populations. In the U.S. and the European/International registry, only 0.5% [10] and 7.2% [5] were Asians, respectively. Moreover, the clinical phenotype of patients with FMD greatly differed between Asians and whites [14,15]. Yet, these were small sample size and single-centre studies.
Currently, there are no randomized controlled studies comparing revascularization to medical treatment for FMD patients. Usually, revascularization is recommended for patients with renal FMD to cure hypertension or improve BP control [16,17]. Renal balloon angioplasty with bailout stent placement is the first-line revascularization technique for renovascular hypertension caused by FMD [16–19]. According to a previous meta-analysis [20], the hypertension cure rate of renal FMD after angioplasty was 36% in adults, and BP outcome was strongly influenced by age. A recent review showed that angioplasty for renovascular hypertension was beneficial in 48.5–100% of paediatric patients and the cure rate of hypertension was 18–60%. In the long term, the success rate for angioplasty for FMD in children is lower than that reported for adults [21]. However, only a few studies compared the efficacy of angioplasty on FMD in children and adults.
Therefore, in the Asian population, especially the Chinese, the clinical characteristics, angiographic features and outcomes of percutaneous transluminal renal angioplasty (PTRA) of patients with renal artery FMD remain unclear. The aim of the present study was to investigate the clinical characteristics of renal artery FMD patients from two centres in China and to identify their cure rate of hypertension after PTRA.
MATERIALS AND METHODS
Design and study population
A total of 3866 hypertensive patients with RAS referred to two tertiary referral centres in China, that is the National Center for Cardiovascular Diseases, Fuwai Hospital, Beijing, and the Department of Hypertension, Ruijin Hospital, Shanghai, between January 2000 and August 2022 were retrospectively analysed. All of the patients suffered from hypertension. Most of them were admitted for screening for the causes of hypertension and were first diagnosed as RAS at Fuwai or Ruijin Hospital. The remainder were referred to the centres for the treatment of RAS. Before being referred to the two central hospitals, the patients were diagnosed with RAS by renal computed tomography angiography (CTA) or renal artery Duplex.
Among all the RAS patients, 3209 (83.0%) were with atherosclerosis, 366 (9.5%) were with Takayasu disease and 46 (1.2%) were with other conditions. The remaining 245 (6.3%) patients met the diagnostic criteria for FMD and were subsequently included in the study.
All patients underwent a detailed investigation, including demographic characteristics (age, sex, height and ethnicity), clinical characteristics (office BP, smoking, family history of hypertension or FMD, concomitant diseases, current medications, age at diagnosis of FMD, an angiographic subtype of FMD, symptoms of FMD at diagnosis and associated atheroma lesions), biochemical sampling (plasma aldosterone, plasma renin activity), Doppler ultrasonography of carotid arteries, magnetic resonance angiography (MRA) of the intracranial artery and CTA or MRA of the abdominal and renal artery. All patients diagnosed with FMD underwent catheter-based angiography and balloon angioplasty to treat renovascular hypertension, and stent implantation should not be performed unless balloon angioplasty was failed.
The ethics committees of Fuwai Hospital, National Center for Cardiovascular Disease in Beijing and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine in Shanghai approved their cohort study protocol, respectively. All participants gave written informed consent. The study was conducted in accordance with the Declaration of Helsinki.
Diagnostic criteria, definitions and blood sampling
FMD was diagnosed as nonatherosclerotic arterial encroachment or stenosis affecting the trunk or branches of medium-size arteries in the absence of aortic wall thickening, biochemical evidence of inflammation and known syndromic arterial disease [11]. For the FMD patients aged less than 18 years, there was no evidence of underlying syndromes such as mid-aortic syndrome, Williams syndrome, Alagille syndrome or type 1 neurofibromatosis.
Multifocal FMD was defined as the presence of alternating areas of stenosis and dilatation (‘string-of-beads’ appearance), especially in the mid and distal segments of the artery (Fig. 2a1 and e1). Focal FMD was defined as the presence of a single stenosis occurring in any part of the artery in the absence of arguments in favour of atherosclerotic, inflammatory or genetic arteriopathies (presence of a single focal, tubular stenosis and total artery occlusion; Fig. 2b1, c1 and d1). Patients with multifocal FMD lesions on a segment of renal arteries and focal FMD lesions on another segment or another vascular bed of renal arteries were classified as multifocal FMD. The presence of renal artery dissections or aneurysms with direct evidence of an FMD stenotic lesion was also diagnosed as FMD (Fig. 2e1, f1).
In agreement with the International Consensus [11], multivessel FMD was defined as the presence of FMD lesions in at least two different arterial beds or, alternatively, FMD-related stenosis in one vascular bed and FMD-related lesions in one or more vascular beds, including cerebrovascular, renal, visceral, upper and lower extremity arteries. Renal asymmetry or atrophy was defined as a difference more than 15 mm in the bipolar length between the two kidneys on ultrasound [18]. Patients with an office SBP/DBP of at least 140/90 mmHg or on antihypertensive medications were defined as having hypertension. Resistant hypertension was defined by intake of three antihypertensive medications with complementary mechanisms of action (a diuretic should be one component) but without achieving control or when BP control was achieved but required at least four medications [22]. Hypertension cure was defined as a clinic BP less than 140/90 mmHg without any antihypertensive drug [13].
All patients were hospitalized overnight and blood samples were collected the next morning at approximately 0800 h in an upright position. All measurements were performed in a College of American Pathologists (no. 7217913) accredited laboratory. Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were measured by using radioimmunoassay following manufacturer's instructions (Beckman Coulter Corp., Brea, California, USA). The normal range for aldosterone is 29.4–313.3 pg/ml, whereas the normal range for PRA is 0.1–5.5 ng/ml/h. When PAC is higher than 313.3 pg/ml, it is defined as hyperaldosteronism. The estimated glomerular filtration rate (eGFR) was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) [23]. Diabetes was defined as a fasting plasma glucose of at least 7.0 mmol/l, a 2-h postoral glucose tolerance test plasma glucose of at least 11.1 mmol/l during antidiabetic treatment or having self-reported diabetes [24].
Renal angiography and angioplasty
In general, renal angiography procedure was performed via a femoral approach. Balloon angioplasty was performed with systemic heparinization (80 U/kg intravenously), a guidewire (Terumo Medical Corporation, Tokyo, Japan), guiding catheter (LIMA; Boston Scientific, Marlborough, Massachusetts, USA), 3–6 mm balloon catheters (Ultrasoft; Boston Scientific/Medi-Tech). We evaluated the degree of the renal artery stenoses for all patients by quantitative coronary angiography (QCA) during the procedure. And for the focal (including the tubular RAS) FMD, all the patients had renal artery stenoses more than 70% of the calibre of the vessel. The balloon diameter was selected to be equal to or slightly larger than the diameter of the renal artery that was estimated on an angiogram. Indications for stent placement (Express SD; Boston Scientific/Medi-Tech) were balloon angioplasty failure (dissection or elastic recoil resulting in >30% residual luminal narrowing).
Follow-up
After PTRA, antihypertensive drugs were adjusted according to the clinical needs of each patient. The patient's attending physician was in charge of these treatment adjustment. Patients were routinely followed up at 1 month, 6 months and every year after the procedure. Antihypertensive medications, blood pressure and postoperative complications were recorded during follow-up. All patients were asked to measure their blood pressure at home. They were also informed that they could return to our hospital if they had a recurrence of hypertension or unsatisfactory hypertension control. Determinants of hypertension cure and renal artery intervention at follow-up were analysed. The cure rate of hypertension was calculated based on the results of the last follow-up, at least 1 year after the intervention.
In our study, the responses were defined as follows: ‘cured’: patients became normotensive without medications; ‘improved’: patients became normotensive after intervention with the same (or reduced) number of medications, or had a SBP 10 mmHg below baseline with the same or reduced number of medications; ‘no effect’: patients had no change in hypertension after intervention or did not meet the criteria for cure or improvement, and were considered as having treatment failure.
Statistical analysis
SAS software version 9.4 (SAS Institute Inc, Cary, North Carolina, USA) was used for database management and statistical analyses. We performed comparisons between multifocal and focal FMD. Means and proportions were compared by the Student's t-test and Fisher's exact test, respectively. Quantitative variables were reported as medians and 25th and 75th percentiles and were compared with the Mann–Whitney test. Continuous variables with a skewed distribution were logarithmically transformed. Adjusted comparisons were performed with analysis of variance (ANOVA) for continuous variables and with the Mantel–Haenszel test for binary variables. Reported P values were two-sided.
RESULTS
Characteristics of fibromuscular dysplasia patients at the first visit
The flow chart of the study is summarized in Fig. 1. As summarized in Table 1, the mean age at FMD diagnosis was 26.9 ± 9.9 years (range 10–79 years; Fig. 2. The age distribution is shown in Fig. 3a. Patients were predominantly young people, where 94.2% (231 of 245) were less than 40 years old, and focal FMD was the most frequent type (73.5%). All patients had hypertension, 13.9% (n = 34) were with resistant hypertension, 46.1% (n = 113) had secondary hyperaldosteronism and 14.3% (n = 35) were smokers. The mean BMI and median estimated glomerular filtration rate (eGFR) were 21.4 ± 3.3 kg/m2 and 116.5 (96.9, 128.8 ml/min per 1.73 m2), according to the CKD-EPI equation, respectively. A family history of hypertension was reported by 48.9% (n = 120) of patients, while there was no family history of FMD. The presence of FMD-related aneurysms, dissections and total occlusions in the whole cohort was 21.6, 4.1 and 12.2%, respectively. The presence of multivessel FMD was 14.3% (n = 35) and kidney atrophy 32.2% (n = 79). The presence of extracranial vessels artery FMD, intracranial artery FMD, visceral artery FMD and other artery FMD were 4.5% (n = 11), 6.5% (n = 16), 2.9% (n = 7) and 3.3% (n = 8), respectively, while 95.1% of patients (n = 233) underwent at least an endovascular intervention. Two hundred and thirty-five (95.9%) patients were taking antihypertensive drugs before interventional therapy.
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FIGURE 1: Study flow chart. FMD, fibromuscular dysplasia; PTRA, percutaneous transluminal renal angioplasty.
TABLE 1 -
Overall characteristics of patients in the Renal artery FMD Registry
| Parameter of patients analysed |
n = 245 |
| Female, n (%) |
137/245 (55.9) |
| Age at diagnosis of FMD (years) |
26.9 ± 9.9 |
| Age at diagnosis of hypertension (years) |
23.4 ± 8.4 |
| BMI (kg/m2) |
21.4 ± 3.3 |
| eGFR, CKD-EPI (ml/min per 1.73 m2) |
116.5 (96.9,128.8) |
| Diabetes mellitus, n (%) |
5 (2.0) |
| Hyperlipidaemia, n (%) |
27 (11.0) |
| Current smoker, n (%) |
35 (14.3) |
| Family history of hypertension, n (%) |
120 (48.9) |
| Hypertension, n (%) |
245 (100) |
| Resistant hypertension, n (%) |
34 (13.9) |
| Number of antihypertensive drugs, n
|
2 (1.3) |
| CCB, n (%)a
|
123 (52.3) |
| ACEI, n (%)a
|
48 (20.4) |
| ARB, n (%)a
|
45 (19.1) |
| β-blocker, n (%)a
|
85 (36.2) |
| Diuretics, n (%)a
|
25 (10.6) |
| Others, n (%)a
|
28 (11.9) |
| Clinic SBP (mmHg) |
152.3 ± 21.5 |
| Clinic DBP (mmHg) |
97.4 ± 14.9 |
| Plasma aldosterone (pg/ml) |
240.2 (87.3, 582.0) |
| Plasma renin (ng/ml/h) |
6 (3.18, 7.76) |
| Secondary hyperaldosteronism, n (%) |
113 (46.1) |
| FMD site, n (%) |
| Right, unilateral |
122 (49.8) |
| Left, unilateral |
67 (27.3) |
| Bilateral |
56 (22.9) |
| Focal renal artery FMD, n (%) |
180 (73.5) |
| Multifocal renal artery FMD, n (%) |
65 (26.5) |
| Presence of multivessel FMD, n (%) |
37 (15.1) |
| Presence of renal artery aneurysms, n (%) |
53 (21.6) |
| Presence of renal artery dissections, n (%) |
10 (4.1) |
| Presence of renal artery total occlusion, n (%) |
30 (12.2) |
| Presence of kidney atrophy, n (%) |
68 (27.7) |
Values are mean ± SD or number of individuals (%) or geometric mean (25th,75th percentile). For the definition of resistant hypertension, hyperlipidaemia and diabetes mellitus, see Materials and methods.Assessed in the subset of patients who underwent full vascular screening (renal, cerebrovascular, visceral/limb arteries).BP, blood pressure; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; FMD, fibromuscular dysplasia.a Patients had specific antihypertensive drugs (n = 235).
FIGURE 2: Angiographic images of renal artery fibromuscular dysplasia lesions. Multifocal renal artery FMD with the classic ‘string of beads’ appearance on angiography (a1). After angioplasty, the stenosis was significantly improved, but (a2). Angiography showed unifocal stenosis (arrow) of the renal artery (b1). After angioplasty, angiography showed a successfully dilated vessel (b2). Angiography showed tubular stenosis (arrow) of the renal artery (c1). After angioplasty, the stenosis was improved (c2). Angiography showed a total occlusion lesion of the proximal right renal artery (arrow) (d1). After successful angioplasty, the renal artery reappeared (arrow) (d2). Angiography showed an aneurysm with a ‘string of beads’ appearance (arrow) of the renal artery (e1). Angiography showed complete obliteration of the aneurysm sac by a dense coil ball (arrow) with flow preservation (e2). Renal arteriography showed a dissection flap extending from proximal to distal of the accessory renal artery (f1). Intravascular ultrasound showed dissection and false lumen (arrow) (f’1). Renal artery angiogram following implanting renal artery stenting (f2).
FIGURE 3: (a) Age distribution at diagnosis of renal artery FMD. (b) Comparison of the proportion of multifocal/focal between children and adults.
Paediatric vs. adult fibromuscular dysplasia
Among included patients, 38 (15.5%) were classified as paediatric (< 18 years of age at the time of diagnosis), and 207 (84.5%) were considered adult FMD patients (≥ 18 years at the time of diagnosis). The mean age at diagnosis in the paediatric and adult FMD was 14.7 ± 1.7 years (range 10–17 years) and 29.3 ± 8.9 years (range 18–79 years), respectively. Paediatric patients with renal FMD were more likely to be focal (86.8 vs. 71.0%, P = 0.042) and took a smaller number of antihypertensive drugs (1.7 vs. 2.1, P = 0.038). Although there was a higher proportion of boys among paediatric patients than among adult FMD, there was no statistically significant difference (55.2 vs. 42.0%, P = 0.131) (Table 2).
TABLE 2 -
Main characteristics of female/male and paediatric/adult patients with renal artery fibromuscular dysplasia
|
Women (n = 137) |
Men (n = 108) |
P
|
<18 years (n = 38) |
≥ 18 years (n = 207) |
P
|
| Female, n (%) |
– |
– |
|
17 (44.8) |
120 (58.0) |
0.131 |
| Age at diagnosis of FMD (years) |
27.2 ± 9.0 |
26.8 ± 10.7 |
0.798 |
14.7 ± 1.7 |
29.3 ± 8.9 |
<0.0001 |
| Age at diagnosis of hypertension (years) |
23.8 ± 8.2 |
22.9 ± 8.7 |
0.408 |
13.4 ± 2.1 |
25.2 ± 7.8 |
<0.0001 |
| Family history of hypertension, n (%) |
72 (52.5) |
48 (44.4) |
0.207 |
16 (42.1) |
104 (50.2) |
0.356 |
| Resistant hypertension, n (%) |
16 (11.7) |
18 (16.7) |
0.262 |
4 (10.5) |
30 (14.5) |
0.515 |
| Number of antihypertensive drugs, n
|
1.9 ± 0.9 |
2.2 ± 1.1 |
0.024 |
1.7 ± 1.0 |
2.1 ± 1.0 |
0.038 |
| Diabetes mellitus, n (%) |
3 (2.2) |
2 (1.9) |
0.852 |
0 (0) |
5 (2.4) |
0.333 |
| Hyperlipidaemia, n (%) |
15 (10.9) |
12 (11.1) |
0.967 |
0 (0) |
27 (13.0) |
0.018 |
| Current smoker, n (%) |
2 (1.5) |
33 (30.6) |
<0.0001 |
0 (0) |
35 (16.9) |
0.006 |
| BMI (kg/m2) |
21.4 ± 2.4 |
22.4 ± 1.9 |
0.0006 |
21.1 ± 2.0 |
22.0 ± 2.3 |
0.035 |
| eGFR, CKD-EPI (ml/min per 1.73 m2) |
117.3 (101.9, 126.7) |
114.3 (92.5, 132.9) |
0.856 |
137.3 (127.7, 146.5) |
112.5 (92.4, 124.7) |
<0.0001 |
| Clinic SBP (mmHg) |
147.0 ± 18.0 |
161.2 ± 23.0 |
<0.0001 |
155.6 ± 19.6 |
151.9 ± 21.6 |
0.398 |
| Clinic DBP (mmHg) |
96.4 ± 13.6 |
98.9 ± 16.8 |
0.319 |
96.4 ± 15.5 |
96.9 ± 14.8 |
0.422 |
| Plasma aldosterone (pg/ml) |
396.9 (109.0, 707.0) |
167.0 (53.0, 318.7) |
0.002 |
166.2 (59.9, 593.0) |
241.9 (98.3, 562.9) |
0.724 |
| Plasma renin (ng/ml/h) |
5.9 (3.3, 7.4) |
6.0 (3.1, 8.1) |
0.087 |
5.2 (3.2, 7.4) |
6.0 (3.2, 7.8) |
0.237 |
| Secondary hyperaldosteronism, n (%) |
75 (54.7) |
38 (35.2) |
0.002 |
18 (47.4) |
95 (45.9) |
0.867 |
| FMD site, n (%) |
|
|
0.743 |
|
|
0.283 |
| Right, unilateral |
69 (50.3) |
53 (49.1) |
|
18 (47.4) |
104 (50.2) |
|
| Left, unilateral |
35 (25.6) |
32 (29.6) |
|
14 (36.8) |
53 (25.6) |
|
| Bilateral |
33 (24.1) |
23 (21.3) |
|
6 (15.8) |
50 (24.2) |
|
| Presence of renal artery aneurysms, n (%) |
31 (22.6) |
24 (22.2) |
0.939 |
7 (18.4) |
48 (23.2) |
0.517 |
| Presence of renal artery dissections, n (%) |
5 (3.7) |
5 (4.6) |
0.701 |
1 (2.6) |
9 (4.4) |
0.623 |
| Presence of kidney atrophy, n (%) |
44 (32.1) |
35 (32.4) |
0.961 |
17 (44.7) |
62 (29.9) |
0.073 |
| Presence of multivessel FMD, n (%) |
18 (51.4) |
17 (48.6) |
0.563 |
4 (10.5) |
31 (14.9) |
0.471 |
| Presence of renal artery total occlusion, n (%) |
16 (11.7) |
14 (12.9) |
0.760 |
6 (15.8) |
24 (11.6) |
0.468 |
| Presence of multifocal FMD, n (%) |
46 (33.6) |
19 (17.6) |
0.004 |
5 (13.2) |
60 (29.0) |
0.042 |
| Presence of focal FMD, n (%) |
91 (66.4) |
89 (82.4) |
0.004 |
33 (86.8) |
147 (71.0) |
0.042 |
Values are mean ± SD or number of individuals (%) or geometric mean (25th,75th percentile). For the definition of resistant hypertension, hyperlipidaemia and diabetes mellitus, see Materials and methods.Assessed in the subset of patients who underwent full vascular screening (renal, cerebrovascular, visceral/limb arteries).BP, blood pressure; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; FMD, fibromuscular dysplasia; eGFR, estimated glomerular filtration rate.
Female vs. male fibromuscular dysplasia
Among these patients, 137 (55.9%) were women. Compared with women with FMD, men had higher SBP (161.2 ± 23.0 vs. 147.0 ± 18.0, P < 0.0001), more frequently focal FMD (82.4 vs. 66.4%, P = 0.004) and they took more antihypertensive agents (2.2 vs. 1.9, P = 0.024). Furthermore, men had a higher prevalence of smokers (30.6 vs. 1.5%, P < 0.0001) (Table 2).
Focal vs. multifocal fibromuscular dysplasia
The presentation characteristics of patients with focal and multifocal FMD are reported in Table 3. Compared with patients with focal FMD, patients with multifocal FMD were older (+2.3 years, P = 0.03), more often female (70.8 vs. 50.6%, P = 0.004) and with more renal artery dissections (9.2 vs. 2.2%. P = 0.01), while multifocal FMD patients had less antihypertensive drugs (1.7 vs. 2.1, P = 0.001) and lower presence of kidney atrophy (20 vs. 36.7%) (P = 0.01). SBP and DBP were similar between focal and multifocal individuals (P > 0.05). The prevalence of focal FMD was similar between men and women, regardless of paediatric or adult FMD. Among paediatric patients, boys and girls had a similar prevalence of multifocal FMD (10.5 vs. 2.6%, P = 0.246), while among adults, the prevalence of multifocal FMD was significantly higher in women than in men (21.7 vs. 7.3%, P = 0.001) (Fig. 3b).
TABLE 3 -
Characteristics at diagnosis of fibromuscular dysplasia in patients with focal or multifocal renal artery lesions
|
Multifocal FMD (n = 65) |
Focal FMD (n = 180) |
P
|
| Female, n (%) |
46 (70.8) |
91 (50.6) |
0.004 |
| Age at diagnosis of FMD (years) |
26.0 ± 10.4 |
23.7 ± 5.8 |
0.021 |
| Age at diagnosis of Hypertension (years) |
25.4 ± 9.0 |
22.6 ± 8.1 |
0.025 |
| Family history of hypertension, n (%) |
38 (58.4) |
82 (45.6) |
0.074 |
| Resistant hypertension, n (%) |
5 (7.7) |
29 (16.1) |
0.092 |
| Number of antihypertensive drugs, n
|
1.7 ± 0.9 |
2.1 ± 1.0 |
0.002 |
| Diabetes mellitus, n (%) |
2 (3.1) |
3 (1.7) |
0.491 |
| Hyperlipidaemia, n (%) |
6 (9.2) |
21 (11.7) |
0.591 |
| Current smoker, n (%) |
11 (16.9) |
24 (13.3) |
0.478 |
| BMI (kg/m2) |
21.8 ± 2.4 |
21.8 ± 2.3 |
0.964 |
| eGFR, CKD-EPI (ml/min per 1.73 m2) |
117.6 (96.2, 127.9) |
116.2 (96.1, 129.3) |
0.845 |
| Clinic SBP (mmHg) |
148.7 ± 15.4 |
154.7 ± 22.9 |
0.048 |
| Clinic DBP (mmHg) |
96.4 ± 12.3 |
97.7 ± 15.7 |
0.644 |
| Plasma aldosterone (pg/ml) |
240.9 (76.1, 538.1) |
240.2 (87.6, 593) |
0.899 |
| Plasma renin (ng/ml/h) |
6.68 (2.65, 6.68) |
6.32 (3.56, 7.88) |
0.064 |
| Secondary hyperaldosteronism, n (%) |
29 (44.6) |
84 (46.7) |
0.776 |
| FMD site, n (%) |
|
|
0.071 |
| Right, unilateral |
31 (47.7) |
91 (50.6) |
|
| Left, unilateral |
13 (20.0) |
54 (30.0) |
|
| Bilateral |
21 (47.3) |
35 (19.4) |
|
| Presence of renal artery aneurysms, n (%) |
12 (18.5) |
43 (23.9) |
0.368 |
| Presence of renal artery dissections, n (%) |
6 (9.2) |
4 (2.2) |
0.014 |
| Presence of kidney atrophy, n (%) |
13 (20.0) |
66 (36.7) |
0.013 |
| Presence of renal artery total occlusion, n (%) |
10 (15.4) |
20 (11.1) |
0.367 |
| Presence of multivessel FMD, n (%) |
11 (16.9) |
24 (13.3) |
0.478 |
Values are mean ± SD or number of individuals (%) or geometric mean (25th,75th percentile). For the definition of resistant hypertension, hyperlipidaemia and diabetes mellitus, see Materials and methods.Assessed in the subset of patients who underwent full vascular screening (renal, cerebrovascular, visceral/limb arteries).CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; FMD, fibromuscular dysplasia.
Renal artery interventions and characteristics at follow-up
A total of 233 (95.1%) patients had technical success with PTRA, as defined by less than s30% residual stenosis in all vessels on angiographic imaging. Angioplasty failed in 12 patients, of whom eight had total occlusive disease, three had stenosis associated with complex aneurysms and one had multiple bifurcation lesions. Among them, most (170 of 180, 94.4%) patients with focal FMD and multifocal FMD (63 of 65, 96.9%) underwent a renal artery intervention for the first time; 189 (81.1%) had balloon angioplasty (Fig. 2a2, b2, c2, d2), 44 (18.9%) implanted bailout stenting (Fig. 2 f1, f2) and 2 (0.9%) had coil embolization for aneurysm (Fig. 2e1, e2).
There were 229 patients who were followed up for more than 1 year. Six patients were lost to follow-up, resulting in a follow-up rate of 97.4% (223 of 229). Among patients who underwent a clinical face-to-face follow-up visit at our unit more than 1 year after the diagnosis of FMD, 38 out of 163 (23.3%) with focal FMD and 13 out of 60 (21.7%) with multifocal FMD underwent another renal artery intervention because of restenosis with recurrent hypertension. The paediatric and adult groups had similar rates of restenosis (24.2 vs. 22.6%, P = 0.83). The time of follow-up occurred the renal artery restenosis duration after first renal artery intervention for was 2.8 years (1.0–6.0) and the clinic SBP and DBP were 142.8 ± 17.0 and 92.1 ± 13.1 mmHg, respectively. The reduction in SBP and DBP and the number of administered antihypertensive agents were similar for patients with focal and multifocal FMD (Table 4). After a median of 7.0 (1.0–21.8) years of follow-up, 60.1% were cured, 31.8% of FMD patients were improved and 8.1% had no effect after PTRA. Multifocal FMD had a higher rate of hypertension cure than focal FMD (71.7 vs. 55.8%, P = 0.032) and women had a higher cure rate than men (71.2 vs. 45.9%, P < 0.001) after revascularization (Fig. 4a, b). Meanwhile, the rate of hypertension cure was higher in women than in men with focal FMD (68.3 vs. 43.2%, P = 0.001) (Fig. 4c).
TABLE 4 -
Characteristics at follow-up more than 1 year for patients with focal or multifocal renal artery fibromuscular dysplasia with first visit before 31 August 2022
|
Multifocal FMD (n = 60) |
Focal FMD (n = 163) |
P
|
| Follow-up duration (years) |
8.27 (4.9, 12.3) |
6.6 (3.9, 9.9) |
0.017 |
| Hypertension cure rate at last follow-up, n (%) |
43 (71.7) |
91 (55.8) |
0.032 |
| Renal artery re-intervention during follow-up, n (%) |
13 (21.7) |
38 (23.3) |
0.861 |
| Time duration after first renal artery intervention (years) |
5.4 (3.0,6.0) |
2.2 (0.7, 4.0) |
0.108 |
| Current smoker at last follow-up, n (%) |
8 (14.0) |
19 (12.4) |
0.685 |
| BMI at last follow-up (kg/m2) |
22.1 ± 4.0 |
21.1 ± 3.1 |
0.310 |
| eGFR at last follow-up, CKD-EPI (ml/min per 1.73 m2) |
106.1 (93.1,116.1) |
111.1 (96.1, 124.5) |
0.431 |
| Change in eGFR, CKD-EPI (ml/min per 1.73 m2) |
1.1 (−15.1, 8.4) |
−3.5 (−12.8, 6.2) |
0.372 |
| Number of antihypertensive drugs at last follow-up, n
|
0.5 ± 0.7 |
0.6 ± 0.9 |
0.452 |
| Change in number of antihypertensive drugs |
−1.2 ± 1.2 |
−1.6 ± 1.1 |
0.029 |
| Clinic SBP, at last follow-up (mmHg) |
121.9 ± 8.4 |
124.0 ± 13.2 |
0.366 |
| Change in SBP (mmHg) |
−27.3 ± 17.7 |
−28.9 ± 19.5 |
0.667 |
| Clinic DBP, at last follow-up (mmHg) |
78.1 ± 6.4 |
75.7 ± 9.9 |
0.164 |
| Change in DBP (mmHg) |
−19.2 ± 12.9 |
−20.9 ± 17.2 |
0.591 |
Values are mean ± SD or number of individuals (%) or geometric mean (25th,75th percentile). For the definition of diabetes mellitus, see Materials and methods.CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; FMD, fibromuscular dysplasia; eGFR, estimated glomerular filtration rate.
FIGURE 4: (a, b) Comparison of the rate of hypertension cure between multifocal/focal (a) and male/female FMD (b). (c) Comparison of the rate of hypertension cure between multifocal and focal FMD in female/male after PTRA.
DISCUSSION
The main findings in the present study were that in Chinese patients, renovascular hypertension associated with FMD occurred primarily in younger patients, with little sex predilection and frequently as a focal type. In addition, focal renal artery FMD had a lower hypertension cure rate.
To the best of our knowledge, the present study provided the largest number of individuals with renal artery FMD in China. A total of 245 patients with renal artery FMD were enrolled, which is far more than in other studies involving Eastern Asian populations [14,15,25]. In this study, the mean age at diagnosis of FMD was 26.9 years, which was similar to previous reports from other East Asian countries but much younger than the patients in the U.S. Registry (54.5 years) [4] and ARCADIA Registry (52.7 years) [26]. The mean age at diagnosis of FMD in adults (>18 years) was 29.3 years and the duration of hypertension was about 4 years. It is likely that many of those were hypertensive since an earlier age and had a late diagnosis. In the present study, the proportion of females was 55.9%, which is quite different from other studies. FMD has been reported to be more common in women. In the ARCADIA Registry [26], 84.5% of patients were female vs. 95.7% in the U.S. Registry [4]. These inconsistencies might be because patients enrolled in our study were all hypertensive patients with RAS diagnosed at a young age, while those with other symptoms suggesting intracranial arteries FMD without hypertension were left out. Some patients referred or transferred to our hospital had been diagnosed with RAS, which might lead to selection bias.
In addition, our results showed that 180 out of the 245 patients (73.5%) were with focal FMD, which is much higher than that reported in the United States FMD registry (2.4%) [11], ARCADIA Registry (8.5%) [26] and a Japanese study (48%) [15], but close to a Chinese study (76.5%) [14] with a small sample size (n = 64) reported in 2016. The main reason for the observed difference may be the younger age of our patients. In the present study, 15.5% were children and adolescents. Meanwhile, we also investigated the distinctive features between focal and multifocal renal artery FMD. Multifocal FMD patients took fewer antihypertensive drugs and had a lower presence of renal artery aneurysms and kidney atrophy than focal FMD. Similarly, Savard et al.[13] reported a higher proportion of male patients with focal FMD and earlier diagnosis of focal FMD.
Another interesting finding of the present study was the high prevalence of renal FMD in children. In the present study, 15.5% (38 of 245) patients were children, while only 3.2% (33 of 1032) paediatric FMD were confirmed in the U.S. FMD registry [27]. Although the clinical features of renal artery FMD in adult patients in the present study are quite different from those reported in White populations, there was little difference in children. In our study, the proportion of boys with FMD was 55.2%, and the main angiographic classification was a focal type (86.8%), which is consistent with the previous studies [28,29].
Among patients with a follow-up of more than 1 year, the reduction in SBP and DBP for patients who underwent renal artery interventions was similar between focal and multifocal FMD. The rate of cure of hypertension after angioplasty was 60.1%, which is higher than that reported in some previous reports [20,30,31] but lower than others [25,32,33]. One study showed that the cure rate of hypertension of renal FMD was influenced by classification, where patients with focal FMD had a higher cure rate than patients with multifocal FMD (54 vs. 26%) [13], which is opposite to our results. In our study, the hypertension cure rate was higher in patients with multifocal FMD (71.7%) than in those with focal FMD (55.8%). However, coincidentally, the hypertension cure rate of focal FMD was almost the same (55.8 vs. 54%) in both studies. The main reason for the completely different result may be the younger age. The young age of patients, rather than ethnic differences, may well explain the discrepancies found in this study with respect to those carried out in Europe or USA. The age at diagnosis of FMD was much younger in the present study (26 vs. 49 years). Patients around 50 years of age were more likely to be complicated with essential hypertension, so their cure rate was low. Another possible reason might be that more female patients with multifocal FMD had a shorter hypertensive duration and displayed renal asymmetry less frequently than focal FMD. Yang et al.[14] also confirmed that female patients had better blood pressure response to PTRA. Although Trinquart et al.[20] reported that the cure rate of hypertension in patients with renal FMD was strongly influenced by age, we found no difference in the cure rate of hypertension between paediatric and adult FMD (but most of them were young, 94.2% <40 years), while the rate of hypertension cure was higher in patients with multifocal FMD in paediatric patients. These results suggested that the renal angiographic classification might influence the BP outcome. Young renovascular hypertensive patients with multifocal renal artery FMD had a better BP outcome after PTRA.
Strengths and limitations
The present study should be interpreted within the context of its strengths and limitations. The study was based on a relatively large sample with renal artery FMD recruited from two centres in China, and all individuals were diagnosed by catheter-based renal angiography, which is the gold standard for diagnosis of RAS. Fuwai Hospital and Ruijin Hospital are the largest centres for diagnosing and treating hypertension and RAS in north and southeast China, respectively. However, the present study still had some limitations. First, our study had a retrospective design exposed to referral biases. Second, we might underestimate the FMD involved with other vessels. As individuals in our study were all hypertensive patients for the BP control, we excluded those who presented with symptoms suggesting cervical or mesenteric arteries FMD but were without hypertension. Third, we only evaluated the stenosis by imaging and did not use a pressure guide wire to evaluate the blood pressure gradient, which lacked haemodynamic assessment of stenosis.
In conclusion, the present study showed in Chinese patients, renovascular hypertension associated with FMD occurred primarily in younger patients, with little sex predilection and frequently as a focal type, which showed a worse BP outcome after PTRA than multifocal FMD.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the voluntary participation of the study participants and the expert investigators’ technical assistance in Ruijin and Fuwai hospitals.
The authors were financially supported by the National Natural Science Foundation of China (81170245 and 81270373), the Shanghai Commissions of Science and Technology (21ZR1454100) and the Shanghai Bureau of Health (20204Y0007, 201940413).
Original data are available upon reasonable request from corresponding authors.
Conflicts of interest
All the authors declared no conflict of interest.
REFERENCES
1. Olin JW, Gornik HL, Bacharach JM, Biller J, Fine LJ, Gray BH, et al. Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association.
Circulation 2014; 129:1048–1078.
2. Persu A, Giavarini A, Touze E, Januszewicz A, Sapoval M, Azizi M, et al. European consensus on the diagnosis and management of fibromuscular dysplasia.
J Hypertens 2014; 32:1367–1378.
3. Slovut DP, Olin JW. Fibromuscular dysplasia.
N Engl J Med 2004; 350:1862–1871.
4. Dicks AB, Gornik HL, Gu X, Bacharach JM, Fendrikova Mahlay N, Froehlich JB, et al. Association of fibromuscular dysplasia and pulsatile tinnitus: a report of the US registry for fibromuscular dysplasia.
J Am Heart Assoc 2021; 10:e021962.
5. Pappaccogli M, Di Monaco S, Warchol-Celinska E, Lorthioir A, Amar L, Aparicio LS, et al. The European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)-clinical phenotypes and their predictors based on a cohort of 1000 patients.
Cardiovasc Res 2021; 117:950–959.
6. Baumgartner I, Lerman LO. Renovascular hypertension: screening and modern management.
Eur Heart J 2011; 32:1590–1598.
7. Safian RD, Textor SC. Renal-artery stenosis.
N Engl J Med 2001; 344:431–442.
8. Tullus K, Brennan E, Hamilton G, Lord R, McLaren CA, Marks SD, et al. Renovascular hypertension in children.
Lancet 2008; 371:1453–1463.
9. Kadian-Dodov D, Gornik HL, Gu X, Froehlich J, Bacharach JM, Chi YW, et al. Dissection and aneurysm in patients with fibromuscular dysplasia: findings from the U.S. Registry for FMD.
J Am Coll Cardiol 2016; 68:176–185.
10. Olin JW, Froehlich J, Gu X, Bacharach JM, Eagle K, Gray BH, et al. The United States Registry for Fibromuscular Dysplasia: results in the first 447 patients.
Circulation 2012; 125:3182–3190.
11. Gornik HL, Persu A, Adlam D, Aparicio LS, Azizi M, Boulanger M, et al. First international consensus on the diagnosis and management of fibromuscular dysplasia.
J Hypertens 2019; 37:229–252.
12. Kim ESH, Olin JW, Froehlich JB, Gu X, Bacharach JM, Gray BH, et al. Clinical manifestations of fibromuscular dysplasia vary by patient sex: a report of the United States registry for fibromuscular dysplasia.
J Am Coll Cardiol 2013; 62:2026–2028.
13. Savard S, Steichen O, Azarine A, Azizi M, Jeunemaitre X, Plouin PF. Association between 2 angiographic subtypes of renal artery fibromuscular dysplasia and clinical characteristics.
Circulation 2012; 126:3062–3069.
14. Yang YK, Zhang Y, Meng X, Yang KQ, Jiang XJ, Wu HY, et al. Clinical characteristics and treatment of renal artery fibromuscular dysplasia with percutaneous transluminal angioplasty: a long-term follow-up study.
Clin Res Cardiol 2016; 105:930–937.
15. Mishima E, Umezawa S, Suzuki T, Fujimura M, Abe M, Hashimoto J, et al. Low frequency of cervicocranial artery involvement in Japanese with renal artery fibromuscular dysplasia compared with that of Caucasians.
Clin Exp Nephrol 2018; 22:1294–1299.
16. Aboyans V, Ricco JB, Bartelink MEL, Bjorck M, Brodmann M, Cohnert T, et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries endorsed by: the European Stroke Organization (ESO)The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS).
Eur Heart J 2018; 39:763–816.
17. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
Hypertension 2018; 71:1269–1324.
18. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss L, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol 2013; 61:1555–1570.
19. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension.
Eur Heart J 2018; 39:3021–3104.
20. Trinquart L, Mounier-Vehier C, Sapoval M, Gagnon N, Plouin PF. Efficacy of revascularization for
renal artery stenosis caused by fibromuscular dysplasia: a systematic review and meta-analysis.
Hypertension 2010; 56:525–532.
21. Patel PA, Cahill AM. Renovascular hypertension in children.
CVIR Endovasc 2021; 4:10.
22. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association.
Hypertension 2018; 72:e53–e90.
23. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate.
Ann Intern Med 2009; 150:604–612.
24. American Diabetes Association. Report of the expert committee on the diagnosis and classification of diabetes mellitus.
Diabetes Care 2003; 26: (Suppl 1): S5–S20.
25. Kim HJ, Do YS, Shin SW, Park KB, Cho SK, Choe YH, et al. Percutaneous transluminal angioplasty of renal artery fibromuscular dysplasia: mid-term results.
Korean J Radiol 2008; 9:38–44.
26. Plouin PF, Baguet JP, Thony F, Ormezzano O, Azarine A, Silhol F, et al. High prevalence of multiple arterial bed lesions in patients with fibromuscular dysplasia: the ARCADIA Registry (Assessment of Renal and Cervical Artery Dysplasia).
Hypertension 2017; 70:652–658.
27. Green R, Gu X, Kline-Rogers E, Froehlich J, Mace P, Gray B, et al. Differences between the pediatric and adult presentation of fibromuscular dysplasia: results from the US Registry.
Pediatr Nephrol 2016; 31:641–650.
28. Louis R, Levy-Erez D, Cahill AM, Meyers KE. Imaging studies in pediatric fibromuscular dysplasia (FMD): a single-center experience.
Pediatr Nephrol 2018; 33:1593–1599.
29. Coleman DM, Heider A, Gordon D, Ganesh SK, Eliason JL, Stanley JC. Histologic and morphologic character of pediatric renal artery occlusive disease.
J Vasc Surg 2021; 73:161–171.
30. Alhadad A, Mattiasson I, Ivancev K, Gottsater A, Lindblad B. Revascularisation of
renal artery stenosis caused by fibromuscular dysplasia: effects on blood pressure during 7-year follow-up are influenced by duration of hypertension and branch artery stenosis.
J Hum Hypertens 2005; 19:761–767.
31. Giavarini A, Savard S, Sapoval M, Plouin PF, Steichen O. Clinical management of renal artery fibromuscular dysplasia: temporal trends and outcomes.
J Hypertens 2014; 32:2433–2438. discussion 2438.
32. Mousa AY, Campbell JE, Stone PA, Broce M, Bates MC, AbuRahma AF. Short- and long-term outcomes of percutaneous transluminal angioplasty/stenting of renal fibromuscular dysplasia over a ten-year period.
J Vasc Surg 2012; 55:421–427.
33. Barrier P, Julien A, Guillaume C, Philippe O, Herve R, Francis J. Technical and clinical results after percutaneous angioplasty in nonmedial fibromuscular dysplasia: outcome after endovascular management of unifocal renal artery stenoses in 30 patients.
Cardiovasc Intervent Radiol 2010; 33:270–277.
