Cross-sectional Study of Patients With Renal or Craniocervical Fibromuscular Dysplasia
Cross-sectional Study of Patients With Renal or Craniocervical Fibromuscular Dysplasia
ARCADIA is a national registry designed to document phenotypic and genetic traits in patients
 with renal and/or cervical artery fibromuscular dysplasia (FMD).

 FMD is a group of arterial diseases that most commonly involve renal and carotid arteries.
 Patients with FMD may present with renovascular hypertension and/or with cerebrovascular
 symptoms. Angiographic classification includes the multifocal type and the focal type. FMD
 may affect one or more vascular beds and progress to more severe stenosis and to renal or
 cerebrovascular complications. FMD may be familial (OMIM #135580).

 Our main objective is to create a FMD registry that will collect standardized information
 from all consenting patients diagnosed with the condition in 16 participating centers. This
 registry, along with a collection of leukocyte DNA, will constitute a resource for further
 clinical research on FMD. The first application will be the assessment of the frequency of
 multi-site FMD, i.e. the frequency of cervical artery FMD in patients presenting with renal
 artery FMD and vice-versa. The second application will be a case-control study to identify
 susceptibility genes for FMD.

 Patients are eligible in the registry if: (a) they have renal or cervical artery FMD with
 either multifocal or focal lesions at CT-angiography, MR-angiography, or intra-arterial
 angiography; (b) they give informed consent to leukocyte DNA analysis and to the collection
 of bioclinical and morphologic information. Phenotypic assessment will be performed in
 accordance with current recommendations and best clinical practice.

 Given the multicenter nature of the study and the recruitment capacity of each centre,
 enrollment of 500 FMD cases is expected over 5 years. This number will 1) allow an accurate
 estimation of the frequency of multi-site FMD: when the sample size is 500, a two-sided 95%
 confidence interval will extend 0.035 from the observed proportion for an expected proportion
 of 0.20 based on a previous report and from our unpublished data. 2) In addition to a
 collection of 400 renal FMD already collected at HEGP, give sufficient power for a
 genome-wide association study seeking for susceptibility genes
1. Background

 1. Definition

 FMD is a group of nonatherosclerotic, noninflammatory arterial diseases that most
 commonly involve the renal, cervical (carotid, and vertebral) arteries.
 Histological classification discriminates three main subtypes, intimal, medial and
 perimedial, which may be associated in a single patient. Angiographic
 classification includes the multifocal type, with multiple stenoses and the
 'string-of-beads' appearance that is related to medial FMD, and tubular and focal
 types, which are not clearly related to specific histological lesions (unclassified
 FMD).

 Aneurysms and dissections are considered to be complications of FMD but frequently
 arise in individuals with no FMD. Therefore, their presence without direct evidence
 of FMD does not suffice to diagnose the condition.

 2. Presentations

 The prevalence of symptomatic renal artery FMD is about 4/1000 and the prevalence
 of cervical FMD is probably half that.

 Renovascular hypertension is the most common manifestation of renal artery FMD.
 Multifocal stenoses with the 'string-of-beads' appearance are observed at
 angiography in more than 80% of cases, mostly in women aged between 30 and 50
 years; they generally involve the middle and distal two-thirds of the main renal
 artery and in some case also renal artery branches. Spontaneous renal artery
 dissections are rare but frequently coexist with FMD.

 Cervical FMD can be complicated by dissection with headache, Horner's syndrome or
 ischemic stroke, or associated with intracranial aneurysms. As intracranial
 aneurysms may rupture and lead to subarachnoid haemorrhage, the American Heart
 Association recommends performing magnetic resonance angiography (MRA) of
 intracranial arteries in patients with cervical artery FMD.

 Mesenteric and iliac arteries were examined during renal artery angiography and
 cervical arteries were systematically examined using ultrasonography. In the
 European Georges-Pompidou Hospital (HEGP) cohort (unpublished results), cervical
 arteries were not systematically examined. The prevalence of diagnosed multi-site
 FMD was 28.0% in the Zurich University Hospital study and 16.4% in HEGP patients.
 This is probably a bottom estimate because most cervical artery FMD lesions affect
 the C1-C2 segment of the carotid arteries, a segment difficult to examine using
 ultrasonography. In order to estimate study power and the number of patients
 needed, the prevalence is considered of multi-site FMD at 20-25%.

 3. Diagnosis

 The presence of renal artery FMD can be documented by the following non-invasive
 tests, in increasing order of accuracy: Doppler ultrasound, gadolinium-enhanced
 MRA, and computed tomographic angiography (CTA). Vasbinder et al. (2004)
 prospective multicenter comparative study found that CTA and MRA had reasonably
 good specificities for detecting renal artery stenosis due to FMD (92 and 84%,
 respectively). There is no published comparative study of non-invasive tests for
 detecting cervical artery FMD, although Doppler ultrasound may disclose irregular
 patterns of stenosis that are suggestive. CTA and MRA are probably more effective
 than ultrasonography for detecting lesions of the middle and distal portions of the
 carotid and vertebral arteries and may also document or rule out associated
 intracranial aneurysms.

 The commonly accepted gold standard for diagnosing renal artery FMD is
 intra-arterial angiogram with digital subtraction. However, this invasive test
 should be reserved for patients in whom it is clinically justified to proceed with
 revascularization in the same procedure. Stenosis quantification is, however,
 frequently difficult in medial FMD with the "string-of-beads" appearance because
 multiple web-like defects are often present in patients with FMD, contributing to
 clinically significant stenoses that may not be apparent on angiography.

 4. Management

 The value of treatment has not been established for renal artery FMD without
 hypertension. The management of hypertension associated with renal artery FMD
 involves revascularization and/or antihypertensive medication. Current
 recommendations reflect the knowledge acquired concerning atherosclerotic
 renovascular hypertension, although indications for balloon angioplasty are wider
 in FMD than in atherosclerotic renovascular disease because the BP outcome of
 angioplasty is more favourable in FMD than in atherosclerosis. Revascularization is
 recommended for patients with hemodynamically significant renal artery stenosis -
 i.e. with bilateral stenoses or a unilateral stenosis causing more than 60%
 reduction in luminal diameter - and accelerated hypertension, resistant
 hypertension, malignant hypertension, hypertension with an unexplained unilateral
 small kidney, and hypertension with intolerance to medication. It is also useful in
 young patients with recent-onset hypertension and hemodynamically significant renal
 artery stenosis due to FMD: in these cases the goal is to cure hypertension. The
 standard revascularization procedure is balloon angioplasty with bailout stent
 placement if necessary. Surgical reconstruction is indicated for patients with
 complex FMD that extends to segmental arteries and those with macroaneurysms.
 Antihypertensive drug treatment is indicated for patients with long-standing
 hypertension or in those with persistent hypertension following revascularization.

 Data on management of patients with symptomatic carotid or vertebral artery FMD are
 scarce. Carotid or vertebral artery dissections are usually treated with
 anticoagulation. In very rare patients with expanding or symptomatic
 pseudo-aneurysm, percutaneous angioplasty or surgical repair can be considered.

 5. Progression in FMD

 Renal artery FMD may progress to more severe stenosis and to renal atrophy, and/or
 to stenoses affecting more arteries within or outside the renal vasculature. The
 risk of progression as assessed from available studies was probably overestimated
 because documentation of progression was obtained from angiography, a procedure
 which is not routinely undertaken in patients with favourable clinical and
 biological outcomes. The disease is progressive, however, and a Slovut and Olin
 overview (2004) stated that patients with FMD should undergo yearly duplex
 ultrasonography to detect progression of disease, restenosis, or loss of kidney
 volume.

 There are very few data on prognosis of patients with symptomatic carotid or
 vertebral artery FMD. The risk of arterial disease progression over time is
 unknown. The risk of ischemic stroke ranged from 0 to about 3% per year in the few
 studies which assessed that issue.

 6. Best Clinical Practice

 Published recommendations include:

 -  Screening for any cause of secondary hypertension - including renal artery FMD
 - in case of juvenile, grade 3, malignant or resistant hypertension

 -  Irrespective of the severity of hypertension, screening for renal artery
 stenosis in cases with a clinical clue for the condition, such as the presence
 of paraombilical bruit or of asymmetrical kidneys

 -  Screening for cervical and intracranial FMD in case of renal artery FMD

 -  Renal revascularization in case of hemodynamic stenosis associated with
 hypertension in a patient aged 30 or less, or associated with accelerated,
 malignant or resistant hypertension, or associated with a small kidney or
 treatment intolerance

 -  In case of documented renal artery FMD, providing follow-up of blood pressure
 (BP), renal function and kidney height using ultrasonography on a yearly basis
 or in case of hypertension persistence or recurrence following
 revascularization, or in case with a poor control of BP.

 In case of renal artery FMD progression, further renal imaging tests and renal
 revascularization may be considered in accordance with the above indications for
 revascularization. The investigators also consider that documented progression of
 renal artery FMD is an indication to screen for new lesions or progression of
 pre-existing lesions in cervical arteries.

 7. Genetic factors

 FMD appears to be a familial disease in 10% of cases (OMIM #135580). The occurrence
 of renal FMD in sib pairs or identical twins first suggested its possible
 inheritability. Our retrospective analysis of 104 patients with renal FMD showed a
 prevalence of 11% for familial cases, i.e. 11% of cases had at least one sibling
 with angiographic evidence of renal artery FMD. Using high-resolution
 echo-tracking, elevated echo-tracking scores of the carotid artery in first-degree
 relatives of index cases are also found. FMD is diagnosed earlier, renal artery
 lesions are more frequently bilateral, and FMD lesions are more frequently found in
 extra-renal arteries in familial than in apparently sporadic cases. The presence of
 an underlying genetic disease could therefore be associated with disease
 progression in FMD.

 The investigators have already collected lymphocyte DNA and assessed baseline
 characteristics, including renal artery morphology, in about 400 patients with
 renal artery FMD who gave informed written consent to a familial study of renal
 artery FMD (Sponsor INSERM, RBM#00-028, CPP Paris-Cochin). Data from patients
 included in this previous study will be used for an extended case-control study.

 8. Justification for an extended genome-wide study

 As indicated above, several arguments exist for the presence of susceptibility genes for
 FMD. Despite this evidence, only limited and negative candidate gene studies have been
 conducted up to now, probably because of the low frequency of the disease, its
 phenotypic heterogeneity and the absence of large national or international collection
 of affected subjects. In the meantime, the knowledge acquired on the structure and
 variations of the human genes by the Human Genome Project and the possibility of rapidly
 genotyping hundreds or thousands of single nucleotide polymorphisms (SNPs) through
 high-throughput technologies facilitate large case-control studies. Case control studies
 are indeed powerful methods to investigate the implication of genetic SNPs in complex
 traits. It can be applied either to candidate genes or through the microarray
 technology. With this technique, it can test three to five hundreds of thousands SNPs
 (300 to 500K) along the human genome (genome-wide association (GWA) studies). Compared
 to candidate genes, GW-SNPs typing offers the advantage that new pathways can be
 uncovered. Whereas this strategy usually requires large number of cases and controls in
 complex traits, it has also been used with success for some categorical traits in
 experimental settings investigating a small number of well characterized subjects. To
 our knowledge, GWA studies have never been performed for FMD. The collection of 400 FMD
 at HEGP together with the national prospective study now makes this objective realistic.

 2. Objectives of the ARCADIA registry

 1. To collect standardized clinical, radiological, and biological data in patients
 with FMD through a national registry.

 The prospective collection of clinical, radiological and biological standardized
 records should lead in a short period of time to a unique source of well-phenotyped
 FMD cases that could help to standardize diagnostic and therapeutic procedures at
 the national level. This unique database and collaboration between centres will
 greatly stimulate basic, clinical and therapeutic research and will help in the
 identification of new pathophysiological mechanisms.

 This collection of symptomatic patients will be established from centres dedicated
 to hypertension care (renovascular lesions) or to cerebrovascular diseases care
 (cervical lesions). It is expected to recruit 400 patients presenting with
 renovascular lesions and 100 patients presenting with cervical FMD over three
 years.

 2. To estimate the prevalence of multiple sites disease, i.e. the prevalence of
 cervical artery FMD in patients with renal artery FMD and vice versa.

 As indicated above, screening for cervicocranial FMD is currently recommended in
 patients with renal FMD. Although there is no similar recommendation to screen for
 renal artery FMD in patients with cervical FMD, such screening is required at least
 in patients with high blood pressure, i.e. with a clue for renovascular disease. It
 is also useful in cases without definite hypertension as the presence of renal
 artery FMD lesions would also help to confirm the FMD nature of cervical lesions.
 The investigators therefore consider that a non-invasive investigation of renal
 arteries in patients with probable or suspected cervical FMD reasonably falls
 within best clinical practices.

 3. To identify susceptibility genes for renal artery FMD and polymorphisms that could
 play a role in disease progression and to assess potential phenotype-genotype
 correlations.

 4. To organize a clinical, radiological and biological database and a biobank that
 will constitute a unique resource to initiate further clinical research.

 Our goal is to share a common anonymous standardized database, the items of which have been
 accepted by the participating centres, that will serve as a unique national FMD database
 available for all Hypertension Reference Centres (ESH Hypertension Reference Centres) and
 vascular neurologists involved in the study. The creation and the development of this
 database will be a unique tool for future national studies and will stimulate similar
 initiatives at the European level.
Inclusion Criteria:

 -  Patient with renal or craniocervical fibromuscular dysplasia diagnosed during the 4
 years before inclusion

 -  Who understood and signed inform consent form

 -  Affiliated to the French health insurance system

 -  The fibromuscular dysplasia is documented by imaging (angiography, CT-angiography,
 MR-angiography) of less than 4 years and validated by a radiologist investigator

 Exclusion Criteria:

 -  Patient with renal or craniocervical atherosclerosis, or inflammatory vascular disease
 as dominant pathological features

 -  Patient with renal or craniocervical arteries dissection or aneurysm without any other
 evidence of fibromuscular dysplasia

 -  Patient under 18 or under tutorship

 -  Known pregnancy