Concurrent Adrenal Adenoma,Unilateral Adrenal Hyperplasia,and Bilateral Renal Artery Stenosis in a 61-Year-Old Man

Abstract

We report a case of a very rare association of adrenal adenoma, unilateral adrenal hyperplasia, and bilateral renal artery stenosis. A 61-year-old man with a remarkable history of two severe strokes was admitted to the Nephrology department with hypertension associated with severe hypokalemia and metabolic alkalosis. Doppler of renal arteries was not conclusive, so contrast-enhanced scanning was done revealing a left adrenal adenoma, right adrenal hyperplasia, and bilateral moderate renal artery stenosis. After control of blood pressure with central anti-hypertensive drugs and calcium channel blockers and normalization of kalemia under potassium supplementation, the hormonal analysis was done showing an elevated plasma aldosterone concentration at 1,568 pmol/L, with a direct renin concentration below the detection level. Primary aldosteronism was confirmed and the prescription of an anti-aldosterone agent led to the control of blood pressure and potassium plasmatic levels. In front of arterial hypertension with hypokalemia, we recommend the assessment of secondary and primary hyperaldosteronism in a systematic way since the association of two or even three etiologies of hyperaldosteronism is possible and an appropriate diagnosis is essential for adequate treatment.

Introduction

Patients with hypertension have a secondary cause in 5% to 15% of cases (Williams et al., 2018). The most common causes of secondary hypertension are primary hyperaldosteronism (PA) and renal artery stenosis (RAS) (Williams et al., 2018). PA is caused by the adrenal gland’s aldosterone excess production. Idiopathic bilateral adrenal hyperplasia is the most common cause of PA (affecting two thirds of patients). A tumor in the zona glomerulosa, known as an adrenal adenoma (AA), affects the remaining one third of patients (Dominguez et al., 2022). It is estimated that PA represents up to 15% of patients with hypertension (Williams et al., 2018).

RAS is responsible for secondary hyperaldosteronism (Dominguez et al., 2022). The prevalence of RAS ranges between 1% and 10% among hypertensive patients (Williams et al., 2018).

PA and RAS may lead to severe hypertension and hypokalemia. Indeed, aldosterone acts on the epithelial sodium channels (ENaC) in the collecting tubules and causes sodium reabsorption. This creates a negative potential in the tubular lumen and, in turn, causes movement of cations (primarily potassium and hydrogen ions) into the tubular lumen to maintain electrical neutrality, resulting in hypokalemia and metabolic alkalosis. The increased reabsorption of sodium leads to hypertension and volume expansion (Papadopoulou-Marketou et al., 2000).

Reviewing the literature, only a small number of cases were reported with concurrent RAS and PA (Meng et al., 2021). The prevalence of PA associated with moderate RAS was estimated at 3,678% (Rossi et al., 2008). Only 18 cases of AA associated with RAS were reported between 1960 and 2012 (Stowasser & Gordon, 2016). Zhao et al. reported in a recent study that the prevalence of RAS in PA patients was 6.9% when aldosterone-to-renin concentration ratio tests and computerized tomography scanning of the adrenal were routinely conducted to screen for PA and RAS (Zhao et al., 2022).

We report a rare case of an elderly man who had a coexisting triple cause of hyperaldosteronism: AA, bilateral RAS, and unilateral adrenal hyperplasia.

Case Presentation

In December 2021, a 61-year-old man, a heavy cigarette smoker, was admitted to the Nephrology department for hypertension and severe hypokalemia causing muscle cramps.

In 2019, he suffered an ischemic stroke that left him with right hemiparesis, making it hard to perform everyday activities and aphasia. In March 2021, the subject had a hemorrhagic stroke with seizures and hypertension. He was hospitalized in Neurology, where he was put on calcium channel blockers. Despite not being on diuretic medication, he had hypokalemia, hypomagnesemia, and metabolic alkalosis. On discharge from Neurology, he was referred to the Nephrology department, but he did not consult and he stopped taking his blood pressure medication for the 6 months preceding his hospitalization in Nephrology.

On examination, the patient had a blood pressure of 180/100 mmHg with no vascular murmurs at auscultation of the bilateral renal arteries. The electrocardiogram showed a regular pulse with T-wave flattening and inversion.

The laboratory results revealed hypokalemia (K⁺ = 2.8 mmol/L), normal renal function (plasmatic creatinine = 73 µmol/L, urea = 6.3 mmol/L), metabolic alkalosis (bicarbonate = 30 mmol/L), and hypercholesterolemia with total serum cholesterol = 204.95 mg/dL and a high low-density lipoprotein cholesterol level of 142.3 mg/dL. The urinary ionogram showed that significant amounts of potassium and chloride were excreted in the urine (urinary K⁺ = 39.8 mmol/L, and urinary Cl⁻ = 219 mmol/L). Upfront this biological picture of hyperaldosteronism, we ordered an ultrasound Doppler of the renal arteries. It revealed two normal kidneys with normal bilateral ostium but a right thick atheromatous calcified plaque responsible for flow acceleration of 135 cm/s and a resistance index of 0.75. Additional contrast-enhanced scanning revealed a left adrenal adenoma measuring 20 × 12 mm. The right adrenal gland was found to have unilateral hyperplasia. The renal arteries had 50% and 55% bilateral stenosis on the right and left sides, respectively (Image 1). We conducted a hormonal study of the renin–angiotensin–aldosterone system to confirm the diagnosis. Before the tests, central anti-hypertensive drugs and calcium channel blockers were used to control blood pressure (<140/90 mmHg). Four weeks earlier, the patient stopped using antihypertensive medications that might impact on the renin–angiotensin–aldosterone system. The serum potassium concentration was maintained in the normal range using potassium chloride pills, intravenous supplementation, and a high potassium diet. The screening test showed an elevated plasma aldosterone concentration (PAC) of 1,568 pmol/L and the direct renin concentration was below the detection level.

Image 1.

CT Scan in an Adult With Primary Hyperaldosteronism Showing Right Renal Artery Stenosis (A), Left Renal Artery Stenosis (B), Left Adrenal Nodule (C), and Right Adrenal Hyperplasia (D)

According to the guidelines of Funder et al. concerning the diagnosis of PA, there was no need for additional confirmatory testing of PA because the PAC was greater than 550 pmol/L (Funder et al., 2016). The systematic dosage of catecholamine was normal (Table 1). The subsequent diagnosis of primary hyperaldosteronism led to the prescription of an anti-aldosterone agent, allowing blood pressure balance and normalization of kalemia.

Table 1.

Hormonal Analysis in a Patient With Concurrent Primary Aldosteronism and Bilateral Renal Artery Stenosis

Parameters	Results	Normal rang
Direct renin concentration (pg/mL)	Low	3.18–32.6
Aldosterone plasmatic activity (pmol/L)	1,568	137–487
Normetanephrine (nmol/L)	0.53	<1.07
Metanephrine (nmol/L)	0.13	<0.13

Discussion

The reported patient hosted three causes of hyperaldosteronism that hardly ever meet AA, bilateral RAS, and unilateral adrenal hyperplasia. In the series of Zhao et al., only four cases among the 71 patients associating PA with RAS had nodules and thickening on both sides of the adrenal gland (Zhao et al., 2022). Apart from that, we could not find a case report similar to the patient’s clinical presentation in the scientific literature.

Actually, in front of the clinicobiological picture of hyperaldosteronism, we first suspected renovascular hypertension of atheromatous origin. Indeed, he had many atherosclerotic and cardiovascular risk factors particularly increasing age, smoking, high blood pressure, and high cholesterol, and he had a remarkable personal history of severe strokes. RAS causes an increase in renin synthesis and constriction of the post-glomerular arterioles, increasing systemic blood pressure (Herrmann & Textor, 2019). This diagnosis would have explained clinical and biological findings.

Initially, the Doppler ultrasound exploration of the renal arteries was not conclusive. The computed tomography scan not only confirmed the bilateral RAS but also detected two other possible causes of secondary hypertension and hyperaldosteronism: a unilateral AA associated with unilateral adrenal hyperplasia. To elucidate the main cause of hyperaldosteronism, hormonal assays of serum renin and aldosterone were conducted confirming the diagnosis of PA.

PA is defined by low or undetectable renin levels, excessive aldosterone secretion, and an increase in the aldosterone–renin ratio (Chowdhury & Lasker, 1997). The main two causes are unilateral AA and bilateral adrenal hyperplasia (Reincke et al., 2021). Unilateral adrenal hyperplasia was also described as a cause of PA responsible for resistant hypertension. It is considered a different entity, not simply a symmetric variant of bilateral adrenal hyperplasia (Rubio-Puchol et al., 2016).

In cases of concurrent RAS and PA, the stenosis is often atherosclerotic (85.5%) (Zhao et al., 2022). Although establishing a cause-and-effect relationship between these clinical conditions is difficult, PA was discovered to be a common factor that induces atherosclerotic RAS (Pillai et al., 2020).

In the reported case, the AA and/or unilateral hyperplasia would have explained the bilateral RAS. Other atherosclerosis risk factors may have worsened the clinical presentation.

RAS could lead to autonomous hyperaldosteronism in the end. Indeed, hyper-functional and autonomous adrenal adenomas would result from excessive angiotensin II stimulation of the adrenals caused by renal artery stenosis. This autonomous hyperaldosteronism is known as “tertiary hyperaldosteronism” (Tziomalos, 2020). However, it is still a theory that has yet to be proven.

Aldosterone’s over-activation of mineral corticoid receptors in the kidney causes volume expansion, hypertension, hypokalemia, and metabolic alkalosis (Young, 2003). Electrolyte imbalances and prolonged high blood pressure increase the risk for serious complications, including heart attack or heart failure, irregular heartbeat, kidney failure, stroke, temporary paralysis, or the inability to move. Many of these characteristics were observed in our patient.

Another unique feature of the reported patient is the recurrence of multiple cardiovascular events in a short period. PA has been linked to a higher vascular risk than matched patients with essential hypertension (Zhao et al., 2022). Its association with bilateral renal artery stenosis may have exacerbated the cardiovascular risk.

The senior patient had two strokes in a row, which should have led to immediate intervention after the first hospital admission. If the cause of hypertension is left untreated, blood pressure may increase to dangerous levels and disrupt the balance of electrolytes in the body. If the disease is unilateral, adrenalectomy may be necessary. If surgery is not an option or there is a bilateral cause, mineralocorticoid receptor antagonists are used to ensure treatment (Scholl, 2021).

Conclusion

In front of arterial hypertension with hypokalemia, the assessment of secondary and primary hyperaldosteronism should be done in a systematic way. Indeed, the association of two or even three etiologies of hyperaldosteronism is possible and an appropriate diagnosis is essential since the treatment depends on it.