Renovascular hypertension following by juxtaglomerular cell tumor: a challenging case with 12-year history of resistant hypertension and hypokalemia

Abstract

Background

Adolescents with secondary hyperaldosteronism often present with severe and treatment-resistant hypertension, along with hypokalemia. Renovascular hypertension is frequently caused by renal artery stenosis, primarily due to atherosclerosis and fibromuscular dysplasia (FMD). The presence of an accessory renal artery (ARA) is a common anatomical variation that can contribute to secondary renal vascular hypertension. However, FMD occurring in the ARA is a rare cause of renal vascular hypertension. Juxtaglomerular cell tumor (JGCT) represents a rare etiology of renal hypertension. The co-occurrence of the pathogenic ARA with JGCT is infrequently reported in the existing literature.

Case presentations

This case study presents a young individual with a 12-year history of resistant hypertension, initially diagnosed with pathogenic ARA but later confirmed as JGCT 4 years later. Following surgery for JGCT, the patient experienced only temporary stabilization of blood pressure without anti-hypertensive medication. Stenosis of the ARA was definitively diagnosed one and a half years post-surgery, with FMD occurring on the ARA strongly suspected. The patient underwent balloon dilatation angioplasty 3 years later, leading to sustained blood pressure stability with the use of two medications.

Conclusions

The case study discussed herein involves a patient with resistant hypertension initially diagnosed with ARA but later determined to have late-onset JGCT and renal artery stenosis. It is imperative to consider atypical JGCT in young patients exhibiting resistant hypertension, hypokalemia, and hyperreninemia. Adequate management of renal artery stenosis is crucial in the management of hyperreninemic hypertension.

Background

Adolescent individuals diagnosed with secondary hyperaldosteronism typically exhibit severe and refractory hypertension, as well as electrolyte imbalances, notably hypokalemia [1]. Renovascular hypertension commonly arises from renal artery stenosis, primarily attributed to atherosclerosis and FMD [2]. The diagnosis of FMD primarily relies on the findings of renal artery computer tomography angiography (CTA) scan [3]. FMD typically affects the middle and distal portions of the renal artery. The CTA morphology of the renal artery may exhibit characteristics such as crosstalk or focal stenosis, potentially indicating the presence of aneurysms, entrapment, or occlusions. ARA is a prevalent anatomical variation that has been identified as a contributing factor to secondary renal vascular hypertension [4, 5], with a thicker ARA being related to more severe hypertension [6]. If ARA becomes diseased, the blood supply to the corresponding renal parenchyma region will be jeopardized, and the lack of blood supply will activate the RAAS, leading to vasoconstriction, sodium retention, and so on. Chronic insufficiency of blood supply to the corresponding renal parenchyma results in renal atrophy, which reduces the secretion of renal sodium-removing hormones (e.g., prostaglandins, kinin, renal medullin) and leads to hyperreninemic hypertension. However, FMD occurring in the ARA is a rare etiology of renal vascular hypertension [7]. JGCT is also a rare cause of renal hypertension, with approximately 100 reported cases worldwide since its initial description in 1967 [8, 9]. JGCT, a renin-secreting tumor, typically presents with secondary hyperaldosteronism and resistant hypertension, particularly in young individuals [9]. The pathogenic ARA seldom coexists with JGCT according to previously published documents [10]. In this study, we present a case of a young individual with a 12-year history of resistant hypertension. She was initially diagnosed with pathogenic ARA but confirmed as JGCT 4-year later. Then she had surgery for JGCT, but her blood pressure (BP) only remained stable for half a year without any anti-hypertensive drugs. Stenosis of the ARA was definitively diagnosed one and half a years post-surgery. The patient underwent balloon dilatation angioplasty four years later, resulting in stable blood pressure maintained with the administration of two medications.

Case presentations

The 27-year-old female patient presented with severe hypertension in 2012, experiencing symptoms of severe vomiting and hypokalemic periodic paralysis. Her highest recorded BP was 196/120 mmHg, and her lowest serum potassium level was 1.9 mmol/L. Although she received timely intervention, the symptoms recurred multiple times. Despite the persistent severity of her condition, she has not adhered to regular anti-hypertensive treatment or BP monitoring since the initial diagnosis. Additionally, her mother, who developed hypertension at the age of 42, has managed her blood pressure levels well.

In 2015, the patient underwent an abdominal CT scan and renal artery CTA, revealing the presence of a right ARA branching from the abdominal aorta (Fig. 1A and B). The main renal artery is essentially the same diameter as the pararenal artery. Subsequent imaging did not show any specific abnormalities in the bilateral adrenal and renal areas (Fig. 2A). In 2017, the patient was hospitalized twice due to severe hypokalemia, prompting a repeat CTA scan on the renal artery and found the same abnormality, and there were also no other specific indications in the adrenal CT scan (Fig. 2B). To further investigate the appropriate ARA, invasive renal arteriography was conducted (Fig. 1C), revealing a normal caliber of the left renal artery (Fig. 1D). The renal artery situated inferiorly exhibits a reduced blood supply area compared to the upper one, so we define the former as the pararenal artery and the latter as the main renal artery. Interestingly, the main and accessory renal artery matches well to perfuse various renal areas (Fig. 1E and F). The perfusion density in the right kidney appeared to be lighter than that in the left kidney overall, as depicted in Fig. 1C. Supine and upright Renin-Angiotensin System (RAS) function tests revealed pronounced secondary hyperaldosteronism with markedly elevated plasma renin activity, as outlined in Table 1. The carotid ultrasound did not reveal any significant abnormalities in the carotid artery. The baseline level of creatinine was normal. The baseline level of low-density lipoprotein cholesterol (LDL-C) was elevated. In a young woman with new-onset resistant hypertension and 24 h urine protein being 110 mg, performing a renal biopsy is possible to find out about tubulo-interstitial, and interstitial vascularity for the presence or absence of pathology in the kidney, in addition to glomerular morphology. The patient underwent a renal biopsy revealing focal inflammatory cell infiltration with fibrosis in the renal interstitium and thickening of small artery walls, prompting consideration of changes indicative of hypertensive renal damage (Fig. 3A-H). Given the lack of bead changes on the CTA scan for renal arteries, FMD was not considered a potential cause of hypertension. In summary, the patient’s hypertension was provisionally classified as renal vascular hypertension based on the aforementioned factors, and treatment was initiated with spironolactone, amlodipine, and valsartan as antihypertensive medications along with concomitant potassium supplementation. Over the subsequent two years, her blood pressure fluctuated from 140/80 mmHg to 180/100 mmHg without experiencing hypokalemia.

Fig. 1

ARA on the right kidney in CTA and arteriography of the renal artery. A and B showed branches of the abdominal aorta from the front and back aspects respectively. C showed the overall perfusion of both kidneys and D showed the normal left renal artery in renal arteriography. In E and F for the main right renal artery and ARA respectively, we found that the perfusing area was matched between these two arteries

Fig. 2

Time-aligned imaging of the kidney in abdominal CT and MRI, as well as the final pathology of the tumor after surgery. A, B, and C showed renal images in December 2015, January 2017, and March 2019 respectively. In Fig. C, a hypointense mass sized about 1.5 × 1.7 cm under the left renal hilum was first presented. D, E, and F showed a slight signal lesion in the T2 sequence and T2 fat sat sequence of MRI imaging

Table 1 Main clinical and experimental features of the patient before and after JGCT surgery

Fig. 3

HE staining saw an increase in the number of cells in the glomerulus (A); PAS staining saw glomerular capsule wall fracture with periglomerular fibrosis and small cellular crescents (B); PASM staining showed no significant thickening of the basement membrane (C); Masson staining saw no significant diphosphoerythrin deposition in the glomerulus (D); Electron microscopy and immunofluorescence showed no specific lesions (E and F); PASM staining showed focal inflammatory cell infiltration with fibrosis in the renal interstitium (G); PAS staining showed thickening of small artery walls (H)

In March 2019, the patient was readmitted to our department presenting with severe hypertension and sudden muscle weakness following the cessation of spironolactone therapy for two days. Upon admission, her blood pressure was measured at 180/110 mmHg, and serum potassium levels were recorded at 2.1 mmol/L. A random blood sample revealed a serum aldosterone level of 3123 pg/ml, with no detectable plasma renin activity at that time. A CTA scan confirmed the presence of the previously identified renal artery abnormality, as well as the discovery of a hypointense mass measuring approximately 1.5 × 1.7 cm beneath the left renal hilum, as depicted in Fig. 2C. To verify the presence of the lesion, an abdominal MRI with contrast was conducted, revealing the mass as exhibiting a slight signal in the T2 and T2 fat sat sequences (Fig. 2D and E, and 2F). Subsequent contrast administration resulted in a slight intensification of the mass, which remained hypointense compared to the surrounding renal parenchyma. Based on the patient’s clinical presentation, notable secondary hyperaldosteronism, and specific imaging findings, the mass was suspected to be a JGCT.

Subsequently, the tumor was surgically removed via laparoscopic excision, exhibiting a bluish hue, measuring approximately 1.5 × 1.5 cm, and precisely situated at the inferior back hilum of the left kidney. Upon histological examination (Fig. 4A and B), the neoplastic cells displayed a linear distribution and consisted of polygonal, round, or fusiform nuclei with eosinophilic, granular cytoplasm. Additionally, a dense network of blood capillaries was observed within the tumor’s mesenchyme. A specialized Periodic Acid-Schiff (PAS) staining (Fig. 4C and D) revealed potential positive renin granule accumulation in the cytoplasm of tumor cells. Additional positive immunohistochemical expressions of vimentin, actin, and CD34 further confirmed the diagnosis of JGCT based on histological findings.

Fig. 4

Upon histological examination (A and B), the neoplastic cells displayed a linear distribution and consisted of polygonal, round, or fusiform nuclei with eosinophilic, granular cytoplasm. Additionally, a dense network of blood capillaries was observed within the tumor’s mesenchyme. A specialized Periodic Acid-Schiff (PAS) staining (C and D) revealed potential positive renin granule accumulation in the cytoplasm of tumor cells. Additional positive immunohistochemical expressions of vimentin, actin, and CD34 further confirmed the diagnosis of JGCT based on histological findings

Three days post-operation, the patient’s serum potassium levels returned to within the

normal range without the need for additional supplementation. Additionally, her blood pressure decreased to normal levels, with the lowest reading recorded at 100/64mmHg, leading to the discontinuation of all anti-hypertensive medications one week post-operation. A follow-up assessment conducted two months after surgery revealed a serum potassium level of 3.6 mmol/l and normalized results for all parameters related to the RAS, except for a slightly elevated BP reading of 140/96 mmHg (Table 1). The patient expressed reluctance to resume any anti-hypertensive medications.

However, the patient’s BP increased again half a year after the operation, fluctuating between 140–160/80-100mmHg. Amlodipine and bisoprolol were subsequently prescribed, resulting in the stabilization of blood pressure. In September 2020, there was a trend towards an increase in BP levels. A review of abdominal CT scans did not reveal any recurrence of JGCT, but renal artery CTA indicated stenosis at the opening of the right ARA (Fig. 5A and B). It was recommended that the patient undergo renal arteriography, however, she declined. Subsequently, the patient continued to take bisoprolol only, with the dosage gradually reduced to 2.5 mg once daily for maintenance.

Fig. 5

Stenosis of right ARA in CTA and arteriography of the renal artery. A and B showed stenosis at the opening of the right ARA. C showed a moderate narrowing of the lumen of the right ARA by angiographic review and D showed significant improvement in the stenosis of ARA after balloon dilatation angioplasty

In June 2023, the patient experienced uncontrolled BP with frequent fluctuations around 200/140mmHg despite treatment with antihypertensive medications such as terazosin, nifedipine, and bisoprolol, and serum potassium levels were recorded at 2.9 mmol/L (Table 2). The patient had taken blood gas analysis along with serum potassium every time, but the result showed no metabolic alkalosis or acidosis. Subsequently, the patient underwent double renal arteriography and balloon dilatation angioplasty, revealing a moderate narrowing of the lumen of the renal artery by approximately 50-60% (Fig. 5C). A 3 mm balloon was used to slowly dilate the stenotic segment, resulting in significant improvement in the stenosis as confirmed by angiographic review (Fig. 5D). After the operation, the patient was prescribed four types of antihypertensive medications, resulting in BP fluctuations ranging from 112–128/90-104mmHg. For the subsequent two months, the patient gradually tapered off the medication regimen and transitioned to a daily dose of bisoprolol 5 mg and sacubitril valsartan 1 tablet, which has been consistently maintained to date, leading to stable BP levels of about 125/78 mmHg (Table 2). Considering that the patient kept taking bisoprolol before and after surgery, results for parameters related to the RAS did not reflect the true renin levels due to a false negative effect (Table 2). This patient’s estimated glomerular filtration rate (eGFR) remained above 90 ml/min/1.73 m² before and after physical interventions or medication.

Table 2 Main clinical and experimental features of the patient before and after renal angioplasty

Discussions

The etiology of renal hypertension poses challenges in clinical elucidation. Renal parenchymal and vascular disorders are known to contribute to secondary hypertension [1], with pathogenic ARA and JGCT being rare causes. The patient in this case initially presented with ARA, followed by JGCT several years later. After JGCT resection, secondary stenosis of the ARA occurred, necessitating balloon dilatation of the stenotic renal arteries to stabilize blood pressure. This case presents a significant challenge and opportunity, as the delayed onset of JGCT may go undetected if clinicians rely solely on ARA findings and fail to conduct appropriate imaging follow-up. While both ARA and JGCT were present concurrently in this patient, it is evident that JGCT may have been the primary factor contributing to secondary hyperaldosteronism in the early stages, as indicated by the therapeutic response to surgery. The development of renal artery stenosis secondary to ARA is identified as the primary etiology of late-onset secondary hyperaldosteronism.

The chronic reninism accompanying the ARA may be an important stimulus for the formation of JGCT, and it can be assumed that this JGCT may be a secondary change, adding a clinical clue to the exploration of the etiology of JGCT. Similarly, Daniele et al. [11] recently reported a latent JGCT occurred 10 years after hypertension in a young woman. Taken together, we suggest that JGCT should be undoubtfully suspected in young patients with resistant hypertension and secondary hyperaldosteronism, or recurrent hypokalemia [12]. Regular follow-up of essential radiological approaches and endocrinological tests over an extended duration is imperative.

As to radiology, several factors may interfere with the JGCT diagnosis. Various factors may impede the accurate diagnosis of JGCT through radiology. It has been noted that an abdominal CT scan without the administration of contrast media is a frequent reason for overlooking the diagnosis of JGCT [13]. Alternatively, certain JGCT that exhibit iso-density and minimal enhancement post-contrast may be mistakenly identified as cystic lesions, underscoring the importance of utilizing functional MRI techniques like diffusion-weighted imaging (DWI) to enhance tumor visualization [14]. Renal vein renin sampling aims to find out the advantage kidney that secretes renin for the diagnosis of JGCT. Some scholars advocate for the use of renal vein sampling to measure renin concentration in patients suspected of having JGCT [15], while others view this method as a supplementary tool for detecting various forms of renin [16]. Actually, the sensitivity of renal vein sampling for diagnosing JGCT was just 56% without full preparation and technical support [17]. In patients with suspected renin-driven hypertension, renal vein renin sampling seems not that necessary, and this patient didn’t take such an examination.

This patient was taking valsartan, amlodipine, and spironolactone before JGCT surgery. Her BP remained stable for half a year after JGCT surgery without taking any antihypertensive drugs, but the patient had a combination of pararenal artery, and the preferred antihypertensive drugs were ACEIs and aldosterone receptor antagonists. The patient’s BP elevated with an increased heart rate six months after the JGCT operation, and bisoprolol was tried in order to stabilize the heart rate; at the same time, bisoprolol can inhibit renin activity, which may have an advantage in terms of BP lowering, and the result was that the patient was able to control her BP at a reasonable level with even bisoprolol alone for a long period, as we expected, which was a meaningful clinical exploration. However, spironolactone and valsartan can cause secondary hyperreninism, and we needed to be concerned about any additional effects on the renal vascular origin. And two months after renal arteriography, we kept the prescription of bisoprolol and added sacubitril valsartan to maintain her BP levels.

Reninism is a common manifestation of both JGCT and renal artery stenosis, two conditions necessitating surgical intervention and known to induce hypertension and hypokalemia. In the pharmacological management of these conditions, targeting reninism through antagonism of the renin-angiotensin system is considered essential. There is significant knowledge available regarding the management of diseases linked to primary reninism resulting from JGCT and renal artery stenosis secondary to the activation of the renin-angiotensin system. Aliskiren, a direct renin antagonist designed for the treatment of essential hypertension, may be the preferred therapeutic option in such cases.

The patient experienced a recurrence of elevated blood pressure six months post-JGCT surgery and found the rapid development of stenosis in the ARA. Despite the presence of hyperlipidemia, the lack of bead-like changes on the CTA scan of the renal arteries, and the absence of vascular lesions beyond the renal arteries, the rapid progression of the disease in a young female raises suspicion that the etiology of renal artery stenosis is more likely FMD rather than atherosclerosis. Percutaneous renal artery balloon dilatation is currently recommended as the preferred treatment for stenosis resulting from renal artery FMD [18].

Indeed, significant distinctions exist between individuals with renal artery FMD in the Chinese demographic and those documented in the latest international consensus data [3]. A case study by Zeina et al. [7] highlighted a 35-year-old female patient presenting with refractory hypertension. Angiographic findings revealed stenosis of the renal artery with characteristic FMD morphology. Subsequent balloon angioplasty successfully lowered the patient’s blood pressure to the target range with the use of a single antihypertensive agent. This patient was initially diagnosed with hypertension caused by the ARA, and then 7 years later was diagnosed with a JGCT, followed by stenosis of the ARA. Her condition was quite complex and rare, and each change in the condition was manifested by dramatic fluctuations in blood pressure and hypokalaemia. Although she underwent timely surgery for the JGCT, and she didn’t need any blood pressure-lowering medication for half a year, she didn’t take angioplasty promptly after diagnosing the stenosis of ARA due to personal reasons for 3 years. After all, she suffered hypertension for a history of 12 years, the impact of atherosclerosis is significant and may have produced irreversible changes. Therefore, the patient still needs to take two kinds of antihypertensive medications after renal angioplasty, which meet the expected clinical efficacy. It is recommended that diligent monitoring and follow-up be maintained for the patient to assess the potential development of additional arterial stenosis.

Conclusions

In conclusion, we have presented a complex case involving resistant hypertension in a patient initially diagnosed with apparent ARA but later found to have a late-onset JGCT and renal artery stenosis. Both conditions have the potential to cause hyperreninemic hypertension. It is important to consider atypical JGCT in young patients with resistant hypertension, hypokalemia, and hyperreninemia. Proper management of renal artery stenosis is essential in the treatment of hyperreninemic hypertension.