Fibromuscular dysplasia with unilateral renal agenesis

Abstract

Fibromuscular dysplasia (FMD) is predominantly diagnosed in women and is a congenital malformation damaging the arterial cell walls of numerous arteries, most prominently impacting the renal arteries. Although previously believed to be a disease of young women, older patients have been shown to make up a large percentage of this patient population as well. FMD is underdiagnosed, and the misdiagnosis of this disease has life-threatening consequences. Here, we present the case of a 24-year-old woman with hypertension who did not receive adequate workup until her symptoms were unrelenting. Her hypertension was presumed to be a result of her generalised anxiety disorder. However, once she began to experience vision changes and significant headaches, further workup ensued. This case exemplifies the importance of performing a thorough evaluation of all patients that present with hypertension of unknown origin, especially young women. To decrease the risk of permanent consequences such as strokes, renal failure and even death, the correct diagnosis of FMD is vital.

Background

Fibromuscular dysplasia (FMD) is a disease of medium-sized arteries. The pathology involves accumulation of fibrous tissue and fibrous webs within the arterial cell wall.¹ While previously thought to only damage renal arteries, FMD has been demonstrated to involve extrarenal arteries as well. The most common extrarenal arterial beds include the internal carotid arteries, vertebral arteries, cerebral arteries and mesenteric arteries.² There are also two different variants of FMD: multifocal and focal, which are differentiated based on the angiographic appearance of the involved arteries. Multifocal FMD is described as a ‘string of beads’, producing alternating segments of fibrous deposition with segments of arterial dilation. Focal FMD consists of a single continuous fibrous deposition without alternating segments of dilation. Ninety per cent of the cases are multifocal FMD.¹

Until recently, FMD was not a well understood disease. Because it also presents with relatively vague symptoms of hypertension, headache and pulsatile tinnitus, it is often underdiagnosed in favour of essential hypertension.² As a result, the prevalence of FMD remains unknown.³ However, greater than 90% of those diagnosed with FMD are women, and according to the US FMD registry, the average age at time of diagnosis is 52 with an age range of 5–83 years.⁴ Moreover, the female predominance is less pronounced in the paediatric population, occurring in an approximate women to men ratio of 2:1.⁵ Secondary to damaged arterial walls in affected arteries, many deleterious complications can occur, such as heart failure, renal failure, stroke, arterial dissection and aneurysm formation.⁵ Therefore, the consequence of not properly diagnosing a patient with FMD is substantial and can result in death.

Case presentation

A 24-year-old Caucasian woman with a medical history of medication-controlled generalised anxiety disorder (GAD) and panic disorder presented to her primary care physician with symptoms of progressively severe headache, neck pain and blurred vision that began 2 weeks prior to presentation. The patient denies any current or previous alcohol, tobacco or substance use. Her current medications include 100 mg of sertraline daily, which has been efficacious for treatment of her GAD since the patient was 15 years of age. She has no known drug allergies. Her family history is significant for diabetes mellitus type 2, hypercholesterolaemia, hypothyroidism and hypertension in her father, a history of cervical cancer in her mother, and Hodgkin’s Lymphoma in her brother.

Review of medical records revealed three prior consecutive encounters with elevated blood pressure within the year prior to current presentation with the following readings: 142/88, 154/92 and 154/114. No further workup was initiated at those visits due to the patient’s lack of symptoms. On additional interview, the patient reports that her blood pressure has been elevated since adolescence and recalled her paediatrician attributing her elevated blood pressure readings to anxiety.

The patient’s vital signs upon symptomatic presentation to her primary care physician include: blood pressure 174/117 mm Hg, heart rate 41 beats/min, temperature 36.8°C, respiratory rate 13 breaths/min, oxygen saturation 98% on room air. Comprehensive metabolic panel, complete blood count, TSH, T4, and FT3 were all within normal limits. Specifically, BUN was 13 mg/dL, creatinine was 0.81 mg/dL, and the patient’s estimated glomerular filtration rate (GFR) was reportedly greater than 60 mL/min.

Investigations

Further investigation into the aetiology of the patient’s hypertension was initiated given new-onset symptoms, which began with an abdominal ultrasound and a duplex renal ultrasound.

Abdominal ultrasound failed to visualise the patient’s left kidney and was remarkable for a normal-appearing right kidney without evidence of stones or obstruction. Duplex renal ultrasound suggested the presence of moderate distal right renal artery stenosis in the setting of a moderately increased systolic velocity of 338 cm/s, with a velocity of 136 cm/s corresponding to the proximal aspect of the right renal artery. To further evaluate the renal artery stenosis, a CT-angiogram was warranted. CT-angiogram confirmed left renal agenesis, likely congenital in origin (figure 1). In addition, a ‘string of beads’ appearance was noted on the segmental and subsegmental right renal arteries (figure 2), which is consistent with the findings of renal multifocal FMD when correlated to the patient’s clinical symptomatology.

Figure 1.

Abdominal CT angiogram demonstrating left renal agenesis.

Figure 2.

Abdominal CT angiogram demonstrating a widely patent main renal artery. There is a mild irregular appearance of the proximal segmental and subsegmental renal arteries with an apparent ‘string of beads’ appearance on the coronal reformatted images.

To further evaluate for extrarenal involvement of FMD, the patient underwent head and neck MRI and magnetic resonance angiography (MRA). Head MRI was positive for a small, incidental cystic pituitary lesion, suspected to represent a Rathke cleft cyst. Head MRA was unremarkable with no evidence of FMD. Neck MRA showed patent vertebral arteries but was remarkable for ‘multifocal beading and irregularity of the bilateral cervical internal carotid arteries with more pronounced pathology on the left’, suggesting the diagnosis of extrarenal multifocal FMD in addition to renal multifocal FMD.

Treatment

Once FMD is confirmed, it can be treated medically or surgically, via angioplasty. While there are no trials that assess the utility of medical management in FMD or prospective studies that compare the efficacy of medical management to intervention, the use of antihypertensive and antiplatelet agents are reasonable due to the pathophysiology of the disease.⁶ Namely, the majority of patients with FMD receive medical management with antihypertensives for treatment of hypertension caused by renovascular arterial involvement. Antiplatelet therapy is also conventional in management in both symptomatic and asymptomatic patients unless otherwise contraindicated, as the stenotic and tortuous vessels associated with FMD can serve as a nidus for thrombus formation.⁶ While aspirin 75–100 mg is commonly used, there are no studies that directly compare it to other antiplatelet agents and the decision as to which antiplatelet therapy to prescribe, if any, should be decided on a case-by-case basis. While any antihypertensive medication can be prescribed, ACE inhibitors (ACE-I) or angiotensin receptor blockers (ARB) have been recommended in this setting due to their ability to inhibit the renin-angiotensin-aldosterone cascade, which is primarily responsible for the elevation of blood pressure in these patients.⁶ Further, if the patient’s blood pressure remains elevated, a thiazide diuretic and/or a dihydropyridine calcium channel blocker can be added to the regimen. If triple therapy with an ACE-I (or ARB), thiazide diuretic and dihydropyridine calcium channel blocker fails, evaluation for revascularisation via angioplasty is needed.⁷ Overall, patients with multifocal FMD are generally well-controlled on a 2-drug antihypertensive regimen.⁷ However, female patients of childbearing age who are prescribed ACE-Is or ARBs should be counselled about their potential for teratogenicity. While there is controversy regarding the potential association between these medications and teratogenicity during the first trimester, there remains a well-documented association between ACE-Is and ARBs in the second and third trimesters.⁸ Notably, a 2012 systematic review of 68 unique cases of intrauterine exposure to an ACE-I or ARB reported renal failure or the need for dialysis, anuria, oligohydramnios and death (either intrauterine or after birth) as the most common teratogenic outcomes.⁸ Thus, we recommend an in-depth discussion between the provider and the patient regarding the risks, benefits and potential alternative therapies in women of childbearing age.

Outcome and follow-up

Following a similar discussion to the one suggested above, the patient described in this case was initially started on lisinopril 20 mg/day. Due to significant dry cough, she was subsequently switched to losartan 50 mg/day. Her blood pressure is currently well-controlled with losartan 50 mg/day, with average readings of approximately 128/81 over the past 4 months. Likewise, she will require yearly serum creatinine measurements as well as yearly abdominal ultrasounds to monitor for any progression of her disease. In the event of progressive worsening of renal function or her blood pressure remains elevated while on three antihypertensive agents, she will then be considered for angioplasty. However, angioplasty, although an effective adjuvant therapy, is not a curative treatment for FMD in itself. Thirty-three percent of patients who undergo renal artery angioplasty for treatment of FMD will also require at least one antihypertensive agent to maintain a blood pressure below 140/90.⁹ She was also initiated on aspirin, 81 mg, for antiplatelet therapy in the setting of not having any contraindications.

Discussion

Here, we present a case of a young woman with persistent hypertension since adolescence that was presumed to be secondary to GAD. FMD was not included in the original differential diagnosis on presentation during adolescence due to symptomatology being explained by GAD at that time. The diagnosis of FMD is often delayed due to non-specific signs and symptoms; the diagnosis is further complicated by the varying presentation of FMD depending on the location of the affected vasculature.¹⁰ Patients with extrarenal FMD commonly present with symptoms of headache (57%), neck pain (27%) and pulsatile tinnitus (33%) depending on the involved vascular bed.¹⁰ However, patients with renal artery FMD commonly present with hypertension (67%) that may show measurements greater than 180/110 and may be refractory to medication.¹ The diagnosis of FMD begins with non-invasive measures such as a renal duplex ultrasonography, CT angiography (CTA) and MRA.⁶ CTA is the preferred diagnostic method and is able to detect milder forms of FMD that are often missed with MRA and ultrasound.¹¹ To determine extrarenal involvement, it is recommended that every patient diagnosed with FMD undergo one-time imaging from head-to-pelvis.⁶ MRA is preferred for the head and neck, with CTA preferred for the abdomen and pelvis.⁷

Regarding angioplasty, renal artery revascularisation has been used to improve blood pressure control in select patients with the goal of improving renal function and maximising protection from deleterious effects caused by hypertension.⁹ Revascularisation should be considered in patients with recent onset hypertension that is refractory to antihypertensive oral therapy.^{9 10} Giavarini et al studied patients with multifocal FMD and found in 60% of cases, patients were managed conservatively with similar BP outcome compared with revascularisation. Therefore, it is not recommended for patients with multifocal FMD to undergo immediate revascularisation, as medication alone often provides adequate blood pressure control in a large number of patients.¹² According to recent guidelines, renal artery revascularisation is recommended for young patients with focal FMD, in patients with enduring evidence of kidney damage, and patients with recent-onset and refractory hypertension.

Moreover, aneurysms occur in approximately one in five patients with FMD and dissections in the vascular bed are seen in about one in four, most commonly involving the carotid and intracranial arterial beds.² Additionally, FMD is responsible for about 20% of cerebrovascular accidents in patients aged <45 years.² Thus, it is recommended that all patients diagnosed with FMD undergo imaging of all vasculature, regardless of specific site of vascular bed involvement in primary FMD, as FMD may alter previously unaffected vascular beds and result in further complications.⁶ The ARCADIA-POL study in 2020 evaluated 232 patients with FMD confirmed in at least one vascular bed and showed that in patients newly diagnosed with FMD, additional lesions were found in 34.1% of patients, and previously undetected vascular complications were found in 25% of patients. Furthermore, one out of every four patients qualified for interventional treatment due to the discovery of FMD in new vasculature or associated vascular complications. This confirms the recommendation that patients need an extensive workup including CTA or MRA of the abdomen, head and neck to identify additional further FMD lesions and screening for potential aneurysms, dissections and involvement of new vascular beds over time.

Patient’s perspective.

I am incredibly thankful that I was diagnosed with fibromuscular dysplasia before I suffered any permanent consequences. Although I feel that I should have been diagnosed during adolescence since I continuously presented with elevated blood pressure, I do understand that anxiety may mask my diagnosis. I feel as though I had a very thorough workup during my initial symptomatic presentation and was not only surprised to be diagnosed with FMD, but to also have a solitary kidney. Although I fear for the future, I am elated that my blood pressure is currently controlled on losartan. I am hopeful that my story will reach physicians and patients and will allow earlier detection in those struggling with undiagnosed FMD.

Learning points.

• Never assume that elevated blood pressure readings at consecutive visits since childhood and adolescence is primary hypertension. A thorough workup and evaluation is indicated, especially in women.

• The first sign of fibromuscular dysplasia may be asymptomatic hypertension in adolescence. If symptomatic, the patient usually presents with broad and non-specific findings such as headache (57%), pulsatile tinnitus (33%) and neck pain (27%).

• Failing to perform a secondary workup for hypertension in a relatively healthy adolescent can have detrimental outcomes such as aneurysms, strokes and renal failure.