Fibromuscular Dysplasia in Children and Adolescents

Figure 1. Conventional angiography. Panel A: Tight narrowing with a small aneurysm of 2 mm at the trifurcation of the left renal artery. Post balloon dilatation dimensions are shown in Panel B.
Figure 2. Conventional angiography. Panel A. In children, bilateral renal artery FMD is as common as unilateral FMD. Panel B. FMD rarely affects the carotid vessels in children, but these should be screened by CTA/MRA or at the time of conventional angiog
Figure 3. 3D CT angiography. Panel A. Left renal artery shows beading typical of FMD (arrow). Panel B. Renal artery with a long segment of narrowing with aneurysmal dilatation at the major bifurcation (arrow).
Figure 4. Conventional angiography. Tight stenosis of the right renal artery with marked post stenotic dilatation. Right nephrectomy was required after failed backbench repair to the thin-walled aneurysm.
Author(s): 

Kevin E. C. Meyers, MD1,2 and Neha Sharma BA IV1,2;
The Children's Hospital of Philadelphia1 and the University of Pennsylvania
Philadelphia, Pennsylvania

Furthermore, some may present with stroke, cardiac failure or other manifestations of end organ damage or ischemia. Typical clinical manifestations are renovascular hypertension, stroke, subarachnoid hemorrhage, abdominal angina or claudication of the legs or arms. In patients with symptoms, percutaneous transluminal angioplasty has emerged as the treatment of choice in most involved vascular beds.2

Etiology

The etiology of FMD is currently unknown, although genetic, hormonal, and mechanical factors have been suggested. 3 FMD is probably not a single disease entity. Most likely it has multiple etiologies with similar phenotypic expression and in some instances, may be an autosomal dominant disease with variable penetrance. 4 The absence of large FMD-affected pedigrees, however, precludes confirmation of this proposal. A majority of female FMD patients suggests a connection between exposure to endogenous or exogenous estrogens and the disease. This suggestion has not been proven. In addition, the risk of FMD may be elevated with smoking, a family history of hypertension, and disorders of the vasa vasorum. 5,6

Recent work from the National Institutes of Health suggests that there is a previously unrecognized variant of Ehlers-Danlos syndrome (EDS), distinct from the vascular form of EDS (mutations in COL3A1) and from the Loeys-Dietz syndrome (mutations in TGFBR1 or TGFBR2), with FMD as a major clinical feature in addition to the skin and joint abnormalities. 7

Clinical Presentations

In children, renovascular disease accounts for approximately 10% of all causes of secondary hypertension. The presence of hypertension is often determined during routine physical examination. Prior to the diagnosis of hypertension, children often report various non-specific symptoms including headache (42%), insomnia (27%), fatigue (26%) and chest or abdominal pain, which may be indicative of hypertension. 8 A minority of children with hypertension present with neurological symptoms including seizures, transient ischemic attacks, cerebral infarctions, subarachnoid hemorrhages, and cranial nerve palsies. A bruit may be present over the affected vascular bed, although absence of a bruit does not rule out significant vascular disease.

Classifications of FMD

FMD lesions are classified according to the arterial layer they affect: intima, media or adventitia. As stated previously, the most common form of FMD in children is intimal fibroplasia, which can occur in any arterial bed. Intimal fibroplasia may present as either a focal band-like narrowing, or a long, tubular narrowing, which is often mistaken for various vascular diseases, such as Takayasu arteritis. 1 The affected intima segment exhibits circumferential or eccentric collagen deposition that often projects into the lumen, and internal elastic lamina may be duplicated or disrupted but can be identified. 1 Medial hyperplasia is a rare form of FMD which presents as a concentric focal band of narrowing and may be a variant of intimal fibroplasia.

Medial fibroplasia most commonly affects women between the ages of 25-50 and accounts for approximately 75% to 80% of all FMD cases. 9 Upon angiographic observation, the appearance of the affected artery resembles a string of beads. Thickened segments of the media, alternating with thinned segments of the media, produce an aneurysmal dilatation. Thickened media is replaced by collagen and the internal elastic lamina may be thinned or fragmented. When FMD affects the renal arteries, the aneurysms normally occur in the middle and distal portions of the vessels and tend to affect both arteries (35%).

Perimedial fibroplasia accounts for fewer than 10% of FMD cases and tends to occur in females between 15-30 years of age. This subtype preferentially affects the mid-portion of the renal arteries and is similar in appearance to medial fibroplasias, as it forms the same bead-like pattern. However, there are fewer beads with diameters smaller than the normal artery size. 1 Collagen deposition often occurs in the outer half of the media, replacing the external elastic lamina. The adventitial connective tissue, however, is intact. Failure to treat bilateral renovascular perimedial fibroplasia may result in renal failure.

Adventitial fibroplasia, also known as periarterial fibroplasia, is very rare and accounts for less than 1% of FMD cases. Collagen replaces the fibrous adventitia and may extend beyond artery into surrounding tissues.

Diagnosis of FMD

FMD can be diagnosed by invasive and non-invasive means. Non-invasive testing includes captopril renal scintigraphy, duplex ultrasonography, magnetic resonance angiography, gadolinium-enhanced magnetic resonance angiography, and computed tomographic angiography (CTA). 10 Access to higher quality non-invasive diagnostic techniques has decreased the utilization of captopril renography in primary renal-artery stenosis screening. 9 Duplex ultrasonography can determine blood flow and pressure waveforms, but exhibits a 10-20% failure rate attributed to the presence of obesity, bowel gas or operator inexperience. 5 Despite being non-nephrotoxic, magnetic resonance angiography (MRA) does present with shortcomings, including image resolution that is not yet adequate to detect FMD lesions in small branch vessels. 9 The accepted gold standard has been conventional angiography (CA) (Figures 1 and 2). However, by virtue of its invasive nature and concern about contrast-related nephrotoxicity, it may not be an optimum first-line diagnostic tool. Of note, CTA and MRA are incrementally replacing CA. In a recent study that compared the utilization of CA with CTA in the diagnosis of FMD, CTA proved to be a non-invasive, cost-effective, accessible, quick method for evaluation, and had 100% diagnostic accuracy of FMD lesions in the main and accessory renal arteries11 (Figure 3). In children where the 3rd and 4th order renal vessels are frequently involved, CTA’s diagnostic accuracy is unproven.

Treatment of FMD in Children and Adolescents

Various options for treatment of FMD exist, including both medical and surgical interventions. The principals of treatment involve controlling high blood pressure, re-establishing vascular flow, preventing clotting of the affected vessel(s), and eliminating factors that contribute to further vessel damage (e.g., smoking in teenagers).

Medical therapy for hypertension in children follows the guidelines from the Fourth Task Force Report. 12 When the renal disease is unilateral, it is safe to use angiotensin-converting enzyme inhibitor (ACE inhibitors) and/or angiotensin II receptor blockers. Bilateral renovascular disease is more problematic and typically requires multiple anti-hypertensive medications, including a diuretic, calcium channel blocker, and beta-blocker to control the hypertension. Aspirin may also be administered in children with FMD as anti-platelet therapy to prevent thrombosis in affected vessels.

Percutaneous transluminal renal angioplasty (PTRA) remains the treatment of choice for renal-artery FMD. 2 Indications for this intervention include recent or rapid onset of hypertension, difficulty in controlling high blood pressure despite the use of a comprehensive antihypertensive regimen, intolerance to anti-hypertensive medications, patient non-adherence issues, and loss of renal volume due to ischemia. 1 In addition, this procedure is often an appropriate alternative to lifelong dependency on a medication in a relatively young individual. 13 Effective PTRAs result in cured or controlled blood pressure, which is often signified by reductions in plasma rennin activity and angiotensin II levels. 9 When compared with surgery, percutaneous balloon angioplasty is less costly, able to be performed on an outpatient basis, results in lower morbidity, and the use of stenting is not primarily necessary. 9 Follow up with duplex ultrasonography is recommended to monitor blood flow in the previously narrowed arterial segment and to ensure the effectiveness of the treatment. 1 There is a subset of children with FMD, however, that appear to be resistant to PTRA. Associated adverse events may include recurrent stenosis, arterial occlusion with renal loss, and arterial rupture with extravasations and pseudo aneurysm formation. These patients are often treated surgically. Furthermore, the development of the Cutting Balloon (Boston Scientific, Natick, MA) may provide a minimally invasive alternative to surgery in these individuals. 14 Careful selection of patients for PTRA is important for increasing the success rate, and follow-up to detect restenosis is required. 15 Due to the advent of various medical therapies and percutaneous balloon angioplasty, surgical revascularization is only required in specific instances.

Surgical reconstruction is reserved for patients with complex FMD that penetrates into the segmental arteries or those that present with macroaneurysms. 10 Various surgical approaches exist, including aortorenal bypass, extracorporeal revascularization and autotransplantation, spleno- or hepato-renal bypass (Figure 4). Their specific utilization is based on the type of FMD lesion and its position.16 Success rates range from 89-97%. Approximately half the patients are cured of their hypertension, one-third experience an improvement in their hypertension and the remainder fails to improve after surgery. 9 Factors that may decrease this success rate include longer duration of hypertension, associated atherosclerotic disease (adults), and complex branch-vessel repair (not infrequent in children). 9

Prognosis

There are presently no specific studies or reports on the long-term prognosis and outcome of FMD in children (Meyers, personal observations). There are, however, pediatric case reports and results of treatment of renovascular hypertension in children. 17,18 O’Neill described 45 children with renovascular FMD, 17 with aortic involvement. The average age at diagnosis was 9 years. Three children had renal failure. Twenty-three of the 45 (51%) had bilateral vessel involvement. A variety of surgical approaches were used, depending on the pathology encountered. Thirty-eight patients underwent revascularization, seven underwent primary nephrectomy, five underwent primary partial nephrectomy and 12 had aortoaortic bypass performed. Seventy percent were cured, 26% improved and 4% did not respond to treatment, with up to 16 years of follow-up. There was no mortality. 17

In adults, Goncharenko et al reported on forty-two hypertensive patients with various forms of FMD who had progression of the disease over an eleven-year observation period. 19 Schreiber et al observed progression of medial hyperplasia in 22/66 patients (33%) with renal artery involvement. 20 Asymptomatic adults with incidental findings of renal artery FMD determined upon evaluation for LRD kidney donation develop hypertension at a rate greater than that of age-matched control subjects with normal blood pressure. 21 Of note, FMD is unlikely to progress to renal failure in adults. 22 In children, renovascular causes of hypertension, including FMD, are not listed as a separate cause for ESRD. 23 In addition, progression to renal artery stenosis has been seen after successful allografting in kidneys taken from donors with FMD. 24,25

While no prospective studies have evaluated the surgical treatment of renovascular FMD in children and young adults, it is reassuring to know that in selected patients less than 25 years of age, blood pressure is well-controlled and the majority of patients do not require anti-hypertensive medication post vascular repair. 26

The causes, natural history, management and long-term outcomes of FMD in children requires further research and evaluation.

The authors can be contacted at:
Kevin Meyers, MD
Pediatric Nephrologist

Assistant Professor of Pediatrics
Second Floor Main Building
The Children’s Hospital of Philadelphia Cnr
34th Street and Civic Center Boulevard
Philadelphia, PA 19104
Telephone: (215) 590-4155
Fax: (215) 590-3705
Email: meyersk@email.chop.edu

Note: This article underwent double-blind peer review by members of the Cath Lab Digest Editorial Board.

References: 
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