Fibromuscular Dysplasia

Etiology

Several theories have been proposed as to the etiology of FMD, including environmental and genetic factors, each with partial supporting evidence.

The fact that FMD is more common among women suggests that hormonal factors may be important, but the exact association remains unclear. Of the 57 women in one study, 9, or 16%, had a previous diagnosis of hypertension during pregnancy, compared with 4% to 5% of pregnancies affected by hypertension in the general population. The number of pregnancies and the frequency of oral contraceptive use or hormonal therapy did not differ between patients with FMD and the general population, however.

Vessel wall ischemia, mechanically induced, may also be important for the development of FMD. The vasa vasorum of muscular arteries, which supply oxygen and nutrients to the arterial wall, originate from branch points of the parent arteries. Occlusion of the vasa vasorum induces the formation of dysplastic lesions in animal studies. The vessels most commonly affected by FMD – such as the renal, internal carotid, and vertebral arteries – have long segments that lack branches and thus have fewer vasa vasorum. These arteries are subjected to repeated stretching during motion and respiration, which may injure the sparse vasa vasorum, causing arterial wall ischemia and subsequent development of FMD. This hypothesis is supported by the observation that FMD is more common in the right renal artery, which is longer than the left. Its greater length makes the right kidney more susceptible to renal ptosis, which is also common among patients with renal FMD. Vasospasm in the vessel wall might also induce ischemia in the vasa vasorum, and cases of FMD combined with Raynaud disease have been reported. In vitro studies have also demonstrated increased production of collagen, hyaluronan, and chondroitin sulfate in arteries exposed to cyclic stretching. Mural ischemia due to functional defects in the vasa vasorum, possibly in association with developmental renal malposition, has also been postulated as a cause of FMD. However, these theories do not explain the gender difference.

FMD is associated with cigarette smoking. The prevalence of smoking is higher among patients with FMD than in matched controls, and patients with FMD who smoke have more severe arterial disease than nonsmokers. In the U.S. Registry for Fibromuscular Dysplasia, 37% of patients were current or former smokers compared with 18% reported for US women. The mechanisms by which smoking contributes to FMD have not been elucidated.

The occurrence of renal FMD in siblings and identical twins suggests possible inheritance of the disease. Rushton suggested that FMD is transmitted in an autosomal dominant manner, with incomplete penetrance and variable clinical symptoms. A French study of renal FMD showed that 11% of patients had at least one sibling with renal FMD. The U.S. Registry study reported a 7% incidence in relatives; however, it also reported that stroke (54%), aneurysm (24%), and sudden death (20%) were common in first- or second-degree relatives. The presence of FMD can be easily overlooked in relatives because it may be associated with only mild hypertension or may be asymptomatic. Subclinical dysplasia of the carotid artery also occurs in patients with renal FMD, in accordance with a possible autosomal dominant transmission. ^,

Along with the high prevalence of asymptomatic FMD (∼3%–6%) and the influence of environmental factors, a complex genetic basis is suspected. Associations with polymorphisms in the angiotensin-converting enzyme (ACE) insertion allele ACE-I have been reported, and an autoimmune origin of FMD has been suggested by genetic associations with HLA-Drw6. Currently several groups are trying to delineate further gene patterns predisposing individuals for the development of FMD. ^,

FMD might coexist with other diseases of the vessel wall and endocrine system. Ehlers–Danlos syndrome type IV has been associated with medial fibroplasias and should be suspected in patients with multiple aneurysms and FMD. FMD has also been reported in association with pheochromocytoma, Marfan syndrome, Alport syndrome, and Takayasu arteritis.

Differential Diagnosis

FMD is primarily a stenotic disease but aneurysm, dissection, and arterial tortuosity frequently occur in affected patients. It is important, however, to recognize that the presence of aneurysms, dissections, or tortuosity in the absence of a focal or multifocal FMD stenotic lesion does not suffice to establish a diagnosis.

Important differential diagnoses for FMD are type 1 neurofibromatosis, vascular Ehlers–Danlos syndrome, Williams syndrome, and vasculitis. ^, The diagnoses of these conditions rely on associated phenotypic traits: characteristic skin lesions in type 1 neurofibromatosis ; acrogeric dysmorphism, skin elasticity, and distal joint laxity in vascular Ehlers–Danlos syndrome ; and facial dysmorphism, supra-aortic stenosis, and particular behavior in Williams syndrome. Genetic tests can also be used to rule out these conditions as alternative diagnoses.

Because FMD is a noninflammatory process, it is not associated with anemia, thrombocytopenia, or the increased acute-phase reactants that often occur in patients with vasculitis. Large-vessel vasculitis sometimes occurs in the absence of changes in acute-phase reactants. It might therefore be difficult to distinguish FMD from inflammatory vessel disease in the absence of tissue samples and without laboratory markers confirming inflammation.

Classification

Traditionally a histopathologic scheme was used to classify FMD, but in the current era fewer patients are undergoing surgical procedures to obtain specimens. The classification now uses an angiographic system, the most common of which is the American Heart Association system adopted in 2014 that distinguishes between multifocal, characterized by the string-of-beads appearance, and focal (or unifocal) FMD, with a single area of stenosis. There is international consensus on this classification. Unifocal FMD has less female predominance, is diagnosed in younger individuals, and is treated with better short- and long-term results than multifocal FMD. This classification has not been applied to FMD in children.

The histopathologic scheme classified FMD into three categories related to the pathologic layer of the arterial wall affected – fibroplasia of the intima, media, or adventitia (periarterial fibroplasia) ( Table 143.2 ; Figs. 143.1–143.4 ). FMD affecting the media is by far the most common type and is further subdivided into medial fibroplasia, perimedial fibroplasia, and medial hyperplasia. Although this classification was initially proposed for the renal arteries, it is also applicable to other arterial beds and has been angiographically correlated with FMD elsewhere. Complications of arterial dysplasia – such as aneurysm formation (in 17% of patients with FMD, one-third in the renal artery) and dissection (in 20% of patients with FMD, more common in carotid and vertebral arteries, one-fifth in the renal artery) – should be classified as secondary events and differentiated from primary dysplastic lesions.

Epidemiology

Symptomatic fibrodysplastic RAS occurs in 0.4% of the population, but the prevalence of asymptomatic FMD in potential renal donors is around 4%. ^{, ,} The true prevalence is difficult to ascertain because there are no easily applicable screening tests. FMD is usually diagnosed in patients 15 to 70 years of age but it has been reported from infancy to age 89. ^{, , ,} Lesions may be bilateral, but in unilateral disease the right renal artery is affected more often than the left.

FMD is more likely to manifest in patients with treatment-resistant or malignant hypertension than in the general hypertensive population and accounts for up to 10% of all cases of renovascular hypertension ; most of the remaining cases of renovascular hypertension are caused by atherosclerosis. Compared with patients with atherosclerotic RAS, patients with FMD are younger and have both fewer risk factors for atherosclerosis and a lower occurrence of atherosclerosis in other vessels.

FMD is diagnosed most often in whites and is reported less frequently in Hispanic and Asian populations. In the U.S. Registry, which contains data for 447 patients, 95% are white, 2% are African American, and 1% are Hispanic and Asian. Diagnostic criteria vary and prevalence data are often derived from selected cohorts or autopsy studies, so the prevalence of FMD might be overestimated.

Multiple arterial involvements have been reported in 8 of 34 and 9 of 102 renovascular patients with FMD in earlier series; in the U.S. Registry report, two vascular beds were affected in 35% of patients and three in 22%. ^{, , ,} In the ARCADIA-POL study (Assessment of Renal and Cervical Artery Dysplasia – Poland), all FMD patients underwent a detailed clinical evaluation including whole body CTA. Newly diagnosed FMD lesions were found in 34.1% of the patients, and previously undetected vascular complications were found in 25% of the patients. This new information reinforces the need for a good clinical examination and imaging of all vessels from brain to pelvis, at least once and usually with CTA or MRA, to identify other areas of FMD, as well as to screen for occult aneurysms and dissections.

In childhood, renovascular hypertension is a more important cause of hypertension. It is found in 8% to 10% of all hypertensive children and in up to 25% of those with secondary hypertension. The causes of pediatric RAS differ in different populations. ^, FMD is the most common cause of pediatric renovascular hypertension in North America and western Europe, whereas Takayasu arteritis dominates in Asia and Africa.

Pathophysiology

Multiple septa in the renal arteries may together induce a significant reduction in renal perfusion in patients with FMD, resulting in renovascular hypertension, but the degree of RAS is often difficult to evaluate from imaging.

Subsequent reduction of arterial perfusion pressure leads to activation of the renin–angiotensin–aldosterone (RAA) system, resulting in volume expansion and hypertension. Several mechanisms – including increased endothelin-1 (ET-1) production, local RAA activation, arterial wall remodeling, and oxidative stress – help to sustain the hypertension, which now depends not only on the RAA system but also on local vasoconstrictive proliferative effects in the arterial wall, gradually leading to resistance to therapy. Inflammatory mediators such as high-sensitivity C-reactive protein, tumor necrosis factor-α, interleukin-6, and neopterin and vasoconstrictive mediators such as ET-1 are increased in patients with renovascular hypertension. A separate analysis of patients with FMD, however, showed that neopterin and ET-1 were lower in patients with renovascular hypertension due to FMD than in those with RAS of atherosclerotic origin. ^, This finding suggests that inflammatory activation might be less important for the pathophysiology of renovascular hypertension caused by FMD than for that caused by atherosclerosis.

Luminal narrowing leads to renal parenchymal damage and ischemic nephropathy in patients with FMD. However, this seems to be less important in patients with FMD than in those with atherosclerotic RAS; the latter show more pronounced reductions of total kidney and cortical perfusion. In addition, renal perfusion correlates inversely with the degree of stenosis in FMD but not in atherosclerotic RAS, further emphasizing that FMD hypertension is more truly renin-dependent than hypertension due to atherosclerosis.

The contralateral kidney may be damaged by exposure to hypertension in FMD. Deterioration of renal function in a patient with FMD affecting one renal artery suggests the development of bilateral stenosis, parenchymal disease, or both.

History and Physical Examination

Arterial hypertension of acute onset or that is increasingly difficult to treat suggests the presence of secondary hypertension – that is, a specific cause of blood pressure elevation, which can be identified in about 5% of adult hypertensive patients. Renovascular hypertension caused by one or more stenoses of the extrarenal arteries is the second most common cause of secondary hypertension (after renal parenchymal disease) and occurs in approximately 2% of adult patients with blood pressure elevation assessed in specialized centers. A physical sign suggesting RAS is abdominal bruit with lateralization. In patients with either high-grade stenosis of a single kidney or bilateral disease, often with one renal artery occluded and the other stenosed, acute pulmonary edema may occur, with or without renal failure. Typically, these patients present with severe and rapid-onset “flash” pulmonary edema, which can also occur in FMD and may be confused with coronary syndromes. Among patients with RAS, the absence of general atherosclerosis suggests that the stenosis is caused by FMD, whereas signs of atherosclerotic disease in other vessels indicate a greater possibility of an atherosclerotic cause.

Screening for Secondary Hypertension

The patient’s history can reveal acute-onset hypertension, concomitant flushing, or other paroxysmal symptoms. Physical examination may reveal abdominal bruits, and routine laboratory investigations may show signs of renal disease, hypokalemia, or hyperthyroidism. Secondary hypertension is also suggested by a severe blood pressure elevation, a sudden onset or worsening of hypertension, and blood pressure that responds poorly to appropriate doses of at least three drugs, including a diuretic. In these cases, specific diagnostic procedures for the evaluation of potential secondary hypertension should be considered, as outlined in Box 143.1 .