What investigations are recommended to rule out secondary hypertension?

Investigations to Rule Out Secondary Hypertension

When to Investigate for Secondary Hypertension

Screen for secondary hypertension when patients present with age of onset <30 or >50 years, resistant hypertension (BP >140/90 mmHg despite ≥3 medications including a diuretic), sudden onset or deterioration of previously controlled hypertension, hypertensive urgency/emergency, or target organ damage disproportionate to hypertension duration. 1, 2

Clinical Red Flags Requiring Investigation

• Age-related clues: Onset before age 30 suggests fibromuscular dysplasia, coarctation, or endocrine disorders; onset after age 50 suggests atherosclerotic renovascular disease 1, 3
• Resistant hypertension: Requiring >3 medications from different classes is the strongest clinical indicator 1, 2
• Specific symptoms: Muscle weakness/tetany/arrhythmias suggest primary aldosteronism; episodic sweating/palpitations/headaches suggest pheochromocytoma 1, 2
• Physical findings: Abdominal bruits (renovascular disease), delayed femoral pulses (coarctation), cushingoid features, or enlarged kidneys on palpation 4, 1

Basic Laboratory Investigations (Perform in ALL Suspected Cases)

The 2025 guidelines represent a paradigm shift: measure aldosterone-to-renin ratio in ALL adults with confirmed hypertension (ESC 2024 Class IIa recommendation), not just those with resistant hypertension. 2

Essential First-Line Tests

• Serum electrolytes: Sodium and potassium (unprovoked hypokalemia suggests primary aldosteronism or renovascular disease) 1, 2, 5
• Renal function: Serum creatinine and estimated glomerular filtration rate (eGFR) 1, 2, 6
• Urinalysis: Screen for proteinuria, hematuria, or leucocyturia suggesting renal parenchymal disease 1, 6
• Urine albumin-to-creatinine ratio: Elevated in parenchymal renal disease 1, 6
• Fasting glucose or HbA1c: Hyperglycemia may suggest Cushing syndrome or pheochromocytoma 1, 3
• Lipid profile: Part of comprehensive cardiovascular risk assessment 1
• Thyroid-stimulating hormone (TSH): Screen for thyroid disorders 1, 2
• 12-lead ECG: Assess for left ventricular hypertrophy and arrhythmias 1, 2

Critical New Recommendation

• Aldosterone-to-renin ratio (ARR): The ESC 2024 guidelines now recommend measuring renin and aldosterone in ALL adults with confirmed hypertension, representing a major departure from traditional selective screening 2

Targeted Advanced Investigations Based on Clinical Suspicion

For Primary Aldosteronism (8-20% of Resistant Hypertension)

Primary aldosteronism is the most common endocrine cause and requires systematic evaluation in resistant hypertension. 2

• Aldosterone-to-renin ratio: High ratio (>20) with elevated aldosterone and suppressed renin is suggestive 2
• Confirmatory testing: Intravenous saline suppression test or oral sodium loading test 1, 2
• Adrenal CT imaging: For localization of adenoma vs. bilateral hyperplasia 1, 2
• Adrenal vein sampling: Gold standard for lateralization before surgical intervention 1, 2

Important caveat: Certain antihypertensive medications affect ARR interpretation—mineralocorticoid receptor antagonists raise aldosterone, while beta-blockers and direct renin inhibitors lower renin. 2

For Renovascular Disease (5-34% in Selected Populations)

Suspect renovascular disease with abrupt onset/worsening hypertension, flash pulmonary edema, or early-onset hypertension in women (fibromuscular dysplasia). 2

• Renal ultrasound with Doppler duplex: Initial non-invasive screening 1, 2, 6
• CT or MR angiography: Confirmatory imaging for precise localization of stenosis 1, 2, 6
• Assess for reduced renal size (<9 cm suggests chronic parenchymal disease) 6

For Pheochromocytoma (Uncommon but Dangerous)

Screen only when episodic symptoms, labile hypertension, or specific clinical features are present—not routinely. 2

• Plasma free metanephrines or 24-hour urinary catecholamines/metanephrines: High negative predictive value 1, 2
• Abdominal/adrenal imaging (CT or MRI): After biochemical confirmation 1, 2

For Obstructive Sleep Apnea (25-50% of Resistant Hypertension)

OSA is highly prevalent in resistant hypertension and associated with non-dipping nocturnal BP pattern. 2

• Clinical assessment: Snoring, daytime sleepiness, obesity, witnessed apneas 2
• Home sleep apnea testing or polysomnography: Definitive diagnosis 2

For Renal Parenchymal Disease

• History: Urinary tract infections, obstruction, hematuria, urinary frequency, nocturia, family history of polycystic kidney disease 2
• Renal ultrasound: Assess kidney size, echogenicity, and structural abnormalities 1, 6
• eGFR <60 ml/min/1.73m²: Indicates chronic kidney disease 6

Imaging Studies

Cardiovascular Imaging

• Echocardiography: Evaluate left ventricular hypertrophy, systolic/diastolic dysfunction, atrial dilation, and aortic coarctation 1, 2
• Carotid ultrasound: Assess for plaques and stenosis 1

Specialized Imaging

• Fundoscopy: Evaluate for retinal changes, hemorrhages, papilledema (grade III-IV retinopathy suggests severe secondary hypertension) 2, 3

Diagnostic Algorithm

Follow a stepwise approach starting with basic screening and advancing to specialized testing only when clinical clues warrant further investigation. 1

Step 1: Identify Clinical Clues

• Age of onset, severity, resistance to treatment, specific symptoms, physical examination findings 1, 2

Step 2: Perform Basic Laboratory Screening

• Electrolytes, renal function, urinalysis, aldosterone-to-renin ratio (now recommended for ALL confirmed hypertension), TSH, glucose, lipids, ECG 1, 2

Step 3: Targeted Testing Based on Initial Findings

• If ARR elevated → confirmatory testing and adrenal imaging for primary aldosteronism 1, 2
• If renal dysfunction or abnormal urinalysis → renal ultrasound with Doppler 1, 6
• If episodic symptoms → plasma metanephrines for pheochromocytoma 1, 2
• If snoring/obesity/daytime sleepiness → sleep study for OSA 2

Step 4: Confirmatory and Localization Studies

• Proceed with specialized imaging (CT/MR angiography, adrenal vein sampling) based on positive screening results 1, 2

Critical Pitfalls to Avoid

Failure to recognize drug-induced or substance-induced hypertension before extensive workup is a common and costly error. 1

• Medication review is essential: Oral contraceptives, NSAIDs, decongestants, glucocorticoids, cyclosporine, cocaine, amphetamines can all cause hypertension 4, 1
• Do not perform expensive imaging before completing basic laboratory screening 2
• Do not combine two RAS blockers (ACE inhibitor and ARB) during evaluation 1
• Delayed diagnosis leads to vascular remodeling: This can result in residual hypertension even after treating the underlying cause 2
• Consider referral to specialized centers for complex cases requiring adrenal vein sampling or advanced interventions 2, 7

Prevalence Context

Secondary hypertension affects 5-10% of all hypertensive patients, but this increases substantially in resistant hypertension populations where specific causes like primary aldosteronism (8-20%) and OSA (25-50%) are much more common. 2, 7 This justifies the aggressive screening approach in resistant cases while maintaining selectivity in uncomplicated hypertension.