Fibromuscular Dysplasia: An Uncommon Cause of Secondary Hypertension

Abstract

Fibromuscular dysplasia is a noninflammatory vascular disease that commonly affects the distal two thirds of the renal artery and branch vessels, but occasionally involves other arteries. Progression of stenosis occurs in 16%–38% of renal arteries. Although the etiology is unknown, genetic studies suggest a relationship to the angiotensin‐converting enzyme I allele. Thin, young Caucasian women without a family history of hypertension are most commonly affected. An abdominal or flank systolic‐diastolic bruit is an important clue for the diagnosis. Most noninvasive screening tests are not sensitive or reproducible to be used to rule out renal artery stenosis, but digital subtraction renal angiography usually confirms the diagnosis. Percutaneous renal artery angioplasty is the treatment of choice, but may not result in normalization of blood pressure if diagnosis is delayed. Since restenosis occurs, continued follow‐up is necessary.

Resistant or secondary hypertension may be due to renovascular hypertension. ¹ In an 18‐year study, 4429 patients aged 18 years or older were referred for evaluation of secondary hypertension. ² Secondary hypertension was present among 10.2% of the cohort, and renovascular hypertension was the most frequent secondary cause of hypertension (3.1%). Fibromuscular dysplasia (Figure 1) was the cause of hypertension in 14% of patients with renovascular hypertension. Figure 2 displays the relationship between age and the type of renovascular hypertension. ²

Figure 1.

Fibromuscular dysplasia of the renal artery showing alternating constrictions and saccular aneurysms, described as a “string of beads.” The top panel is the renal arteriogram and the bottom panel is the digital subtraction image.

Figure 2.

Prevalence of renovascular hypertension according to etiology and age. Fibromuscular dysplasia most commonly occurs among patients younger than 50 years; whereas, atherosclerotic renovascular hypertension occurs in older patients. Derived from Anderson et al. ²

PATHOLOGY

Fibromuscular dysplasia (FMD) is a nonatherosclerotic and noninflammatory disease of small and medium arteries. The location on the vessel wall and frequency of FMD is intimal (1% 5%), medial (60% 85%), or periadventitial (10% 25%). ³ Medial FMD is further divided into subtypes, but medial fibroplasia, described as a “string of beads” (Figure 1), is the most common. The classic arteriographic appearance results from proliferation of the extracellular matrix, with disruption of the internal elastic lamina causing multiple stenoses and saccular aneurysms.

FMD affects the renal arteries with a frequency of 60%–75%. ⁴ Medial FMD is confined to the distal two thirds of the renal artery and involves the branch vessels in about 39% of patients. ⁵ The right renal artery is the dominant site of FMD, but it occurs bilaterally in 39%‐66% of cases. ⁵ , ⁶ Other vascular beds may be affected, including carotid (the most common), cerebral, vertebral, coronary, aorta, subclavian, axillary, iliac, popliteal, hepatic, splenic, celiac, and mesenteric arteries. ⁷ Unlike intimal or adventitial FMD, dissection or thrombosis is less likely to occur with medial FMD. ⁸ Progression of medial FMD occurs in 16%–38% of renal arteries, but total occlusion is rare. ³ , ⁷ , ⁹ Renal artery aneurysms are not uncommon, but these rarely rupture. ⁷

Although the creatinine level tends to be normal with FMD, there may be renal parenchymal loss. ¹⁰ In one small study, although renal length was similar, mean cortical thickness, as determined by spiral computed tomographic angiography (CTA), was reduced in the stenotic kidney (7.3 mm) and the unaffected kidney (7.8 mm) in FMD compared with kidneys in essential hypertension (9.2 mm; P<.0001). ¹⁰ The patients with FMD, however, had lower body mass index than those with essential hypertension due to a greater number of women.

PATHOPHYSIOLOGY

Hemodynamically significant stenosis of the renal artery reduces renal perfusion pressure and blood flow causing a decline in the glomerular filtration rate and sodium and water excretion. ¹¹ To compensate for this, increased activity of renin and angiotensin II produce vasoconstriction and blood pressure elevation.

GENETICS

A genetic predisposition, HLA‐DRw6 antigen, and cigarette smoking are thought to be of etiologic importance in FMD, but the cause is unknown. ¹² In a pedigree analysis of 20 index cases of FMD, 60% had at least one family member with suspected disease. ¹³ The investigators speculated that FMD was an autosomal dominant trait with variable penetrance, but there was no documentation of FMD. A better study reported a familial occurrence of 11% in first‐degree relatives of 33 women and was more common in patients with bilateral renal FMD. ⁶ There was no vertical transmission to offspring.

Two studies examined gene polymorphisms in renal FMD. Since deficiency of the common proteinase inhibitor α₁‐antitrypsin protein results in the destruction of elastin protein in the extracellular matrix, polymorphisms of the α₁‐antitrypsin gene (PiM₁, PiZ, and PiS) were studied in 732 normotensives, 333 hypertensives, and 161 patients with proven renal FMD. ¹⁴ No association was observed. Another study examined angiotensin‐converting enzyme (ACE) I/D, angiotensin II type 1 receptor A1166C, and angiotensinogen M235T and T174M in 43 renal FMD patients and 89 controls. ¹⁵ Only the ACE I allele, which is associated with reduced levels of ACE and possibly angiotensin II, was more common in patients with FMD than controls (64% vs 47%; P=.026). The authors hypothesized that since the disease is seen in young women, low angiotensin II, estrogen, and ACE I may interact to produce FMD.

CLINICAL MANIFESTATIONS

The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure ¹⁶ advises health care providers to suspect renovascular hypertension due to FMD if the onset of hypertension is before the age of 30 in the absence of family history, an abdominal bruit with a diastolic component is detected, accelerated or resistant hypertension is present, recurrent flash pulmonary edema occurs, renal failure without proteinuria or an abnormal urine sediment is found, or acute renal failure is triggered by an ACE inhibitor or angiotensin receptor blocker. It should be noted, however, that FMD is also present in normotensive individuals.

In the Cooperative Study of Renovascular Hypertension, ¹⁷ 339 cases of essential hypertension were compared with 84 cases of renovascular hypertension due to FMD. Among patients with FMD, there were more women (81% vs 40%; P<.01), fewer African Americans (10% vs 29%, P<.01), a lower rate of a family history of hypertension (41% vs 67%; P<.01), and a thinner body habitus (30% vs 6%; P<.05). ¹⁸ Duration of hypertension was shorter with FMD than essential hypertension (2.0 vs 3.1 years; P<.01). Blood pressure was similar, but abdominal (55% vs 6%; P<.05) and flank (20% vs 1%; P<.05) bruits were more common. A potassium level <3.4 mEq/L was present in 17% of fibromuscular patients compared with 7% of patients with essential hypertension (P<.05).

An abdominal bruit is common (25%–45%) in normotensive patients aged 15–30 years. ¹⁹ A high‐pitched systolic‐diastolic bruit, however, is distinctive for renovascular hypertension and is uncommon in essential hypertension. Timing is determined by palpation of the carotid artery.

If other vessels are involved with FMD, other symptoms (eg, angina pectoris, intestinal angina, claudication, headache, transient ischemic attack) and signs may be present. Several reports have documented the association of a pheochromocytoma with fibromuscular dyspasia. ²⁰ , ²¹

DIAGNOSIS

The ideal test should define the anatomy of the renal artery and its functional significance and report kidney sizes and cortical thickness. Noninvasive testing with captopril radionuclide renal scintigraphy, color‐flow duplex ultrasonography, CTA, and gadolinium‐enhanced magnetic resonance angiography (MRA) is often performed as a screening study. A meta‐analysis reported that CTA and gadolinium‐enhanced MRA performed better than the captopril test, captopril radionuclide renal scintigraphy, ultrasonography, and non‐contrasted MRA ²² ; however, a subsequent prospective study comparing CTA and contrast‐enhanced MRA with digital subtraction angiography (DSA) in 356 patients reported that neither noninvasive test was sufficiently sensitive or reproducible to be used to rule out renal artery stenosis. ²² , ²³

Duplex ultrasonography has sensitivity of 17%–100% and specificity of 76%–98%. ²² Turbulent flow can be observed with color‐flow mapping at the stenotic site. A peak systolic velocity >180–200 cm/s or a renal‐aortic systolic flow velocity >3.5 indicates hemodynamically renal artery stenosis (≥60%). ²⁴ , ²⁵ Distal to the stenosis, early systolic acceleration is delayed or prolonged and the amplitude of the systolic peak is diminished and rounded. To assess the functional significance of a stenosis, the resistive index is calculated:

1 − (minimum diastolic velocity/maximum systolic velocity) × 100

A value exceeding 80 predicts less benefit from revascularization. ²⁶ An inadequate examination occurs in 10%‐20% of patients. The accuracy of this test is largely operator‐dependent and is also complicated by the body habitus of obese patients.

CTA has a sensitivity of 55%–73% and a specificity of 90%–95% for the detection of renal artery stenosis compared with DSA. ²³ It has better spacial resolution than MRA. In one retrospective study, helical (or spiral) CTA detected 86.8% of 38 lesions in 20 cases of arteriographically proven FMD. ²⁷ The use of maximum‐intensity projection or shaded‐surface display reconstruction techniques improved detection beyond transverse arterial section examination, but identifying distal isolated lesions was problematic. Multidetector‐row CTA may improve the noninvasive diagnosis of renal artery stenosis since the accuracy was 96.9% compared with DSA. ²⁸

Gadolinium‐enhanced MRA has a sensitivity of 54%–71% and a specificity of 81%–87% for the detection of renal artery stenosis compared with DSA. ²³ The ability to detect FMD is substantially poorer because of the difficulty in visualizing the distal segments of the renal artery. ²³ , ²⁹

In most centers, DSA is usually performed to make the diagnosis of renal FMD ²⁴ ; however, the degree of stenosis is difficult to judge with FMD. ³⁰ Renal angiography may not always correctly identify renal FMD that is suggested by color‐flow duplex imaging. ³¹ Intravascular ultrasound at the time of arteriography can identify the discrete membranes of FMD.

TREATMENT

The goal of therapy is to control blood pressure and preserve renal function. The treatment options consist of pharmacologic treatment of blood pressure; balloon angioplasty with or without stenting; renal artery bypass surgery; and, as a last resort, nephrectomy.

Angioplasty

Renal artery angioplasty has emerged as the treatment of choice for renal FMD. ³⁰ , ³² Stenting is not commonly performed unless there is a residual pressure gradient, a renal artery aneurysm, or a complication of angioplasty. In a prospective study of 27 patients, hemodynamically significant restenosis (≥60%) after 12 months was 23%. ³³ Recurrent hypertension was a predictor of restenosis.

In a retrospective analysis of 105 patients with FMD from 1980–1993 at the Mayo Clinic in Rochester, MN, angioplasty was technically successful (<30% residual stenosis) for 85.7% of 140 lesions. ³⁴ Complications included subintimal dissection (6.7%), renal artery perforation or rupture (2.9%), renal embolization (1.0%), transient ischemic attack (1.0%), and renal artery thrombus (4.8%).

Average follow‐up was 42.7 months. Mean arterial pressure declined 48‐hour post‐procedure from 118.7 mm Hg to 97.6 mm Hg. At the last follow‐up, mean arterial pressure increased to 104.0 mm Hg. The average number of antihypertensive medications used decreased from 2.3 at baseline to 1.5 at the last follow‐up. A cure, defined as a blood pressure ≤140/90 mm Hg on no antihypertensive medications, was observed in only 22% of patients; 15% of patients had no change in blood pressure or a reduction in the number of medications. There was no change in serum creatinine, and no patient needed dialysis; 5.7% of patients underwent redilation, and 9.5% required surgical revascularization.

A 7‐year retrospective follow‐up study of 56 FMD patients undergoing angioplasty reported a cure in 24% of patients. ²⁸ Blood pressure significantly decreased 34/17 mm Hg (P<.0001), and the average number of antihypertensive medications was reduced (2.3 vs 1.6; P<.01). Serum creatinine also improved. Duration of hypertension, increased age, and involvement of branch arteries negatively affected the efficacy of the intervention.

Surgery

In the modern era, surgery is reserved for angioplasty failures or complications. In the past, surgical revascularization achieved a blood pressure ≤140/90 mm Hg postoperatively in 63% of patients with FMD. ³⁵ The Cooperative Study of Renovascular Hypertension ³⁶ reported a cure (diastolic blood pressure <90 mm Hg and a 10‐mm Hg decline in preoperative blood pressure) or improvement (≥15% decrease in diastolic blood pressure in patients with a diastolic blood pressure >90 mm Hg and <110 mm Hg) in 91% for unilateral FMD with 80%–99% stenosis and 81% with 25%–50% stenosis. Surgical revascularization successfully treated 75% of 74 patients with unilateral FMD, ³⁷ and 62.3% of 61 patients were treated successfully with nephrectomy. Overall operative mortality for surgical revascularization and nephrectomy was 3.4%. ³⁸

Current reports are disappointing. One study reported that only 36% of 61 FMD patients achieved a diastolic blood pressure <90 mm Hg on no medication after 5 years of surgical revascularization. ³⁹ Another study reported a cure rate of 33% in 40 patients. ⁴⁰ Cure was most commonly achieved in FMD patients younger than 45 years who had a duration of hypertension <2 years.

CONCLUSIONS

FMD is a disease of young women. Although renovascular hypertension may be the consequence, other blood vessels can be involved. Digital subtraction renal angiography will confirm the clinical suspicion of FMD. Percutaneous renal artery angioplasty is the treatment of choice, but may not result in a cure if diagnosis is delayed.