Refractory Renovascular Hypertension from Paraganglioma: A Case Report

Introduction

Pheochromocytomas and paragangliomas are rare neuroendocrine tumors that secrete catecholamines from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia, respectively [1]. Phenylethanolamine N-methyltransferase, the enzyme responsible for converting noradrenaline to adrenaline, is expressed in the adrenal medulla. Consequently, pheochromocytomas secrete noradrenaline and adrenaline, whereas paragangliomas predominantly produce noradrenaline. However, pheochromocytoma and paraganglioma cannot be strictly differentiated and both have the potential to metastasize, and pheochromocytoma was defined as an intra-adrenal paraganglioma in the 2022 WHO bluebooks [2]. The clinical presentation of paragangliomas classically includes a triad of symptoms: headache, palpitations, and profuse sweating. However, some patients remain asymptomatic, and blood pressure is often within the normal range [3], making diagnosis particularly challenging.

Secondary hypertension accounts for approximately 5–10% of all hypertensive cases, with paraganglioma occurring in 0.2–0.5% of hypertensive patients. In contrast, renal artery stenosis is a more common cause of secondary hypertension, with an incidence ranging from 1.6% to 8.0% [4].

Here, we present the case of a young woman with suspected secondary hypertension. Despite percutaneous transluminal renal angioplasty (PTRA) procedures performed to address renal artery stenosis and presumed renovascular hypertension, stenosis of the right renal artery recurred. Ultimately, we identified a paraganglioma as the underlying cause of renal artery stenosis and secondary hypertension.

Case Report

BEFORE REFERRAL:

The patient was a young Japanese woman with a family history of hypertension, as her father was hypertensive. She was a former smoker, having smoked 10 cigarettes per day for 5 years until the age of 22, and a social drinker. She had no past medical history and was not taking any drugs, including illegal ones. She had been diagnosed with hypertension for 5 years following a workplace health checkup and was referred to the initial hospital at the age of 24 with a systolic blood pressure of approximately 200 mmHg despite no subjective symptoms.

Renal artery ultrasonography revealed a peak systolic velocity of 455 cm/s in the right renal artery and 63 cm/s in the left renal artery, suggestive of right renal artery stenosis. Plasma renin activity was 3.4 ng/mL/h, which increased to 30.1 ng/mL/h during the captopril challenge test. Magnetic resonance angiography confirmed the presence of right renal artery stenosis, leading to a diagnosis of renovascular hypertension. Consequently, she was referred to our institute for PTRA, considering her desire for future pregnancy.

ON THE FIRST REFERRAL:

Upon referral, the patient’s blood pressure was 154/112 mmHg without the use of antihypertensive medications, and her pulse rate was 76 beats per minute. She underwent successful PTRA for right renal artery stenosis (Figure 1A, 1B). Following the procedure, she was monitored at the referring hospital for further follow-up.

CLINICAL COURSE AFTER THE FIRST PTRA:

Following PTRA, her blood pressure decreased to approximately 120/90 mmHg without the use of antihypertensive medications. The peak systolic velocity in the right renal artery decreased to 200 cm/s, and plasma renin activity also declined to 1.2 ng/mL/h.

At the age of 27, she delivered her first child vaginally, and at age 30 she underwent a cesarean section for her second child due to partial placenta previa. Notably, no hypertension was observed during either pregnancy.

However, at the age of 32 – 8 years after the initial PTRA – she experienced a recurrence of hypertension, which was considered a recurrence of renal vascular hypertension, necessitating the administration of candesartan at 4 mg/day. When she failed to take her medication, she experienced headaches with systolic blood pressure reaching approximately 180 mmHg.

At 33 years old, contrast-enhanced computed tomography revealed recurrent right renal artery stenosis along with an aneurysm. Consequently, she was referred to our institute once again for further evaluation and management.

ON THE SECOND REFERRAL:

The patient’s physical measurements were: height 163 cm, weight 48.0 kg, and body mass index 18.1 kg/m². Her blood pressure was 140/100 mmHg in the left upper arm and 150/96 mmHg in the right upper arm. Her pulse rate was 62 beats per minute. No abdominal bruits were detected upon auscultation.

Her laboratory data are presented in Table 1, with no evidence of hyperglycemia. Endocrinological test results, shown in Table 2, indicated a plasma renin activity of 8.7 ng/mL/h and a plasma aldosterone concentration of 293 pg/mL, as measured by radioimmunoassay.

Computed tomography angiography revealed right renal artery stenosis along with an aneurysm in a branch of the renal artery distal to the stenosis (Figure 2A). Based on these findings, she was diagnosed with renovascular hypertension due to recurrent right renal artery stenosis. Invasive angiography further confirmed the presence of right renal artery stenosis and an associated aneurysm (Figure 2B). A second PTRA was performed using balloon angioplasty, successfully alleviating the stenosis in the right renal artery (Figure 2C).

CLINICAL COURSE AFTER THE SECOND PTRA:

After PTRA, systolic blood pressure decreased to around 100 mmHg without requiring candesartan, plasma renin activity decreased to 2.4 ng/mL/hour, and plasma aldosterone concentration decreased to 89 pg/mL (Table 2). However, the results of the endocrinological tests taken on admission were received following the discharge, revealing high noradrenaline levels 1393 pg/mL and normal adrenaline levels 52 pg/mL (Table 2).

The contrast-enhanced computed tomography (CT) scan on the referral to our institute was reviewed, revealing a mosaic-patterned nodule, retroperitoneal tumor, between the aorta and inferior vena cava, adjacent to the right renal artery (Figure 3A, 3B). The retrospective review of the magnetic resonance imaging (MRI) obtained at the former institute before the first PTRA identified a retroperitoneal tumor around the right renal artery (Figure 1C).

The urine normetanephrine level was 1204 ng/mg of creatinine and the metanephrine level was 137 ng/mg of creatinine (Table 2). 123I-metaiodobenzylguanidine (MIBG) scintigraphy showed a strong increase in accumulation, consistent with the tumor (Figure 3C). No 123I-MIBG accumulation was observed in any area other than the tumor. Based on these findings, we diagnosed paraganglioma with right renal artery stenosis and aneurysm.

THERAPEUTIC INTERVENTION FOR PARAGANGLIOMA:

The patient was started on the alpha-adrenergic blocker doxazosin for preoperative therapy. Subsequently, percutaneous coil embolization was performed to treat the renal artery aneurysm (Figure 2D). Following this procedure, an open surgical resection of the paraganglioma was carried out. Hemodynamic stability was maintained throughout both interventions.

The resected tumor measured 45×25×15 mm and weighed 9 g. Histopathological analysis confirmed the definitive diagnosis of paraganglioma (Figure 4). Postoperatively, plasma noradrenaline levels and urinary metanephrines returned to normal ranges.

During the 6-year follow-up after surgery, no recurrence of the tumor was observed. At the patient’s request, genetic testing was not performed.

Discussion

PARAGANGLIOMA WITH RENAL ARTERY STENOSIS:

The estimated incidence of paraganglioma is approximately 0.2 cases per 100 000 person-years [5]. Renal artery stenosis due to paraganglioma is rare, and only a few studies have reported this association. Gill et al identified renal artery disease in 10 out of 269 patients (3.7%) with paraganglioma [6], whereas Kota et al reported renal artery stenosis in 4 out of 50 cases (8.0%) [7]. Another study found renal artery stenosis in 3.3% (2/60) of patients with pheochromocytoma and in 30% (3/10) of those with paraganglioma [8].

Several mechanisms have been proposed for renal artery stenosis in these cases, including external compression by the tumor, catecholamine-induced vasospasm, tissue adhesion following tumor resection, and generalized neuroectodermal dysplasia associated with pheochromocytoma and neurofibromatosis [9]. In the present case, anatomical compression of the renal artery by the extra-vascular tumor was likely the primary cause. Additionally, prolonged exposure to elevated noradrenaline levels may have contributed to vasospasm of the renal artery. The retrospective review of the imaging findings in the present case revealed that the paraganglioma was already present at the time of the first PTRA. If paraganglioma had been accurately diagnosed at the time of the initial onset of renal artery stenosis, recurrence of renal artery stenosis and a second interventional therapy could have been avoided. This case underscores the importance of thoroughly investigating potential underlying causes of renal artery stenosis to ensure accurate and fundamental diagnosis and appropriate management.

PARAGANGLIOMA WITH RENAL ARTERY ANEURYSM:

Our patient also presented with a renal artery aneurysm, a condition identified in approximately 0.01% of autopsy cases and 0.7–1.0% of imaging screenings [10]. While several studies have reported the co-occurrence of paraganglioma with abdominal aortic aneurysms [11,12], reports of their association with renal artery aneurysms are scarce [13,14].

The underlying mechanism remains unclear; however, prolonged exposure to elevated catecholamine levels may contribute to vascular injury and increased vessel wall vulnerability. Notably, the aneurysm in this case developed after the initial PTRA. We ruled out catheter-induced vascular injury as a potential cause, as no interventional devices were introduced into the specific arterial branch where the aneurysm later emerged.

The renal artery aneurysm in the present case was 7 mm in diameter. A single-center retrospective study showed a low growth rate of 0.2±4.4 mm per year in renal artery aneurysms with an initial size of less than 15 mm [15]. However, considering the risk of rupture by hemodynamic instability due to uncontrolled release of catecholamines during anesthesia and surgery, we considered that treatment for the renal artery aneurysm was necessary.

THERAPEUTIC STRATEGY IN THE PRESENT CASE:

Various therapeutic strategies have been proposed for the management of paraganglioma with concomitant renal artery disease due to their complex pathophysiology [6–8]. In the present case, multiple treatment options were considered, including surgical resection of the tumor and surgical repair of the renal artery aneurysm. Ultimately, we opted for coil embolization of the aneurysm, followed by surgical tumor resection to minimize surgical invasiveness. Coil embolization is one of the most common endovascular approaches for the treatment of renal artery aneurysms, and the safety of sac packing for branch artery aneurysm has been reported [16]. In addition, the effectiveness of transcatheter arterial embolization of collateral vessels perfusing the tumor as preoperative treatment for paraganglioma has also been reported [17]. In this case, it was possible that some of the arterial branches with aneurysm were also feeding the tumor. This case is the first reported instance of successful coil embolization of a renal artery aneurysm associated with renal artery stenosis secondary to external compression by the paraganglioma.

Coil embolization requires the use of a contrast agent, which should be used with caution in patients with paraganglioma due to the risk of hypertensive crisis. To mitigate this risk, we selected a non-ionic contrast agent, which has a lower likelihood of inducing hypertensive episodes [18]. Additionally, alpha-adrenergic blockers phentolamine were prepared in advance to manage any potential hypertensive crises.

Although the simultaneous occurrence of renal artery stenosis and renal artery aneurysm in paraganglioma is rare, PTRA for renal artery stenosis and coil embolization for renal artery aneurysm offer the advantage of minimally invasive preoperative management. Further studies are needed to establish optimal therapeutic strategies in this situation.

LIMITATIONS OF THE DIAGNOSIS IN THE PRESENT CASE:

To confirm the diagnosis of paragangliomas, genetic analysis for genetic predisposition syndromes is recommended [2]. Mutations in the succinate dehydrogenase subunit genes (SDH), including SDHA, SDHB, SDHC, SDHD, and SDHAF2, are the most frequent genetic causes, accounting for approximately half of all hereditary paragangliomas. Other suspected genetic mutations include RET, NF1, and MAX, and comprehensive genetic test using next-generation sequencers has been considered [19]. In the present case, at the patient’s request, genetic testing was not performed. However, we diagnosed the present case as paraganglioma based on the pathological findings of positive chromogranin A, biochemical findings of high levels of urine normetanephrine, and imaging findings of positive 123I-MIBG.

Nuclear medicine imaging plays a valuable role in the anatomical and functional localization of paragangliomas [20]. Although 123I-MIBG scintigraphy had been frequently used for imaging of paragangliomas, the sensitivity of 123I-MIBG scintigraphy varies widely, ranging from 52% to 75%, depending on the biological behavior and genetic background of the tumor [21]. To avoid missing metastatic lesions, it is important to use newer radiotracers such as 64Cu/68Ga-DOTA-somatostatin analog [20].

Conclusions

We report the case of a young woman with secondary hypertension caused by renal artery stenosis, which recurred despite PTRA. A renal artery aneurysm was also complicated at the time of recurrence of renal artery stenosis. Ultimately, a paraganglioma compressing the right renal artery was identified as the underlying etiology. Following successful preoperative PTRA and coil embolization, and subsequent surgical resection of the tumor, the patient remained free from hypertension for 6 years without requiring antihypertensive medication.

Although rare, paraganglioma should be considered as a potential cause of refractory renovascular hypertension, particularly when conventional interventions fail to achieve long-term blood pressure control.