What is the best approach to rule out secondary causes of hypertension in a patient?

Ruling Out Secondary Causes of Hypertension

Screen all patients with confirmed hypertension using plasma aldosterone-to-renin ratio (ARR), as primary aldosteronism is the most common treatable secondary cause (8-20% of resistant hypertension), and the 2024 ESC guidelines now recommend universal screening (Class IIa). 1, 2

When to Suspect Secondary Hypertension

Pursue aggressive workup in these clinical scenarios:

• Age of onset <30 years (especially before puberty) 1, 2
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive drugs including a diuretic) 1
• Sudden onset or sudden deterioration of previously controlled hypertension 1, 2
• Hypertensive urgency or emergency 2
• Target organ damage disproportionate to duration or severity of hypertension 2

Initial Laboratory Screening (Order for ALL Suspected Cases)

Complete this basic panel before expensive imaging:

• Plasma aldosterone-to-renin ratio (ARR) - now recommended for all confirmed hypertension 1, 2
• Serum electrolytes (sodium, potassium) - hypokalemia strongly suggests primary aldosteronism 1
• Serum creatinine and eGFR 1
• Urinalysis with microscopy - look for blood, protein, casts suggesting renal disease 1
• Urinary albumin-to-creatinine ratio 1
• Fasting blood glucose or HbA1c 1
• Thyroid-stimulating hormone (TSH) 1
• Fasting lipid panel 1
• 12-lead ECG - assess for left ventricular hypertrophy 1

Critical pitfall: Do not order expensive imaging (CT, MRI, angiography) before completing this basic screening. 2, 3

Targeted Investigations Based on Clinical Clues

Primary Aldosteronism (Most Common - 8-20% of Resistant HTN)

Screen with ARR in all confirmed hypertension. A ratio >20 with elevated aldosterone and suppressed renin is positive. 1, 2

Medication effects on ARR interpretation: 1

• False positives: Beta-blockers, alpha-2 agonists (clonidine, methyldopa), NSAIDs, steroids (all suppress renin more than aldosterone)
• False negatives: ACE inhibitors, ARBs, calcium channel blockers, potassium-sparing diuretics, potassium-wasting diuretics (all raise renin)

Confirmatory testing (after positive ARR): 1

• Oral sodium loading test with 24-hour urine aldosterone, OR
• IV saline infusion test with plasma aldosterone at 4 hours

Localization studies (after biochemical confirmation): 1

• Adrenal CT scan
• Adrenal vein sampling for lateralization

Renovascular Disease (5-34% in Selected Populations)

Order workup when: 1, 3

• Abrupt onset or sudden worsening of previously controlled hypertension
• Flash pulmonary edema (suggests atherosclerotic disease)
• Serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB
• Severe hypertension with unilateral smaller kidney or kidney size difference >1.5 cm
• Abdominal systolic-diastolic bruit on examination
• Age <40 years (suspect fibromuscular dysplasia, especially in women)
• Age >60 years with acute BP change (suspect atherosclerosis)

Screening tests: 1

• Renal Duplex Doppler ultrasound (initial)
• CT or MRI angiography (confirmatory)

Obstructive Sleep Apnea (25-50% of Resistant HTN)

Screen when: 1, 3

• Resistant hypertension
• Snoring, witnessed apneas, daytime sleepiness
• Obesity (BMI >30)
• Non-dipping or reverse-dipping pattern on 24-hour BP monitoring

Diagnostic test: 1

• Overnight ambulatory polysomnography (confirms diagnosis with AHI >5)
• Severity: mild AHI <15; moderate AHI 15-30; severe AHI >30

Pheochromocytoma (Uncommon but Dangerous)

Screen when: 1, 2, 3

• Episodic symptoms (headache, palpitations, sweating)
• Labile or paroxysmal hypertension
• Hypertensive crisis during anesthesia or surgery
• Family history of pheochromocytoma or multiple endocrine neoplasia

Screening test: 1

• 24-hour urinary metanephrines and normetanephrines, OR
• Plasma metanephrines

Cushing Syndrome

Screen when: 1, 3

• Central obesity with thin extremities
• Purple striae, easy bruising
• Proximal muscle weakness
• Moon facies, buffalo hump, supraclavicular fat pads

Screening tests: 1

• 24-hour urinary free cortisol
• Low-dose dexamethasone suppression test

Renal Parenchymal Disease

Screen when: 1

• History of urinary tract infections, obstruction, hematuria
• Urinary frequency and nocturia
• Family history of polycystic kidney disease
• Elevated serum creatinine
• Abnormal urinalysis (blood, protein, casts)

Screening test: 1

• Renal ultrasound

Coarctation of the Aorta

Screen when: 1

• Radio-femoral pulse delay
• Blood pressure differential between upper and lower extremities
• Systolic murmur over the back

Screening tests: 1

• Echocardiogram
• Aortic CT angiography

Common Pitfalls to Avoid

• Medication-induced hypertension: Review all medications before extensive workup, including NSAIDs, oral contraceptives (especially those containing drospirenone), steroids, decongestants, and illicit substances. 2, 4
• Inadequate ARR interpretation: The 2024 ESC guidelines represent a paradigm shift—measure renin and aldosterone in ALL adults with confirmed hypertension, not just those with resistant hypertension or hypokalemia. 1, 2
• Lack of suggestive symptoms does not rule out OSAS: Up to 60% of patients with resistant hypertension have OSAS, even without classic symptoms. 1
• Delayed diagnosis leads to vascular remodeling: This affects renal function and results in residual hypertension even after treating the underlying cause. 2

When to Refer to Specialist

Refer to a physician with expertise in secondary hypertension when: 1

• Screening tests are positive and confirmatory testing is needed
• Complex cases requiring specialized diagnostic procedures (e.g., adrenal vein sampling)
• Surgical intervention is being considered (e.g., adrenalectomy, renal angioplasty)