What other urine tests are used in the workup for secondary hypertension, particularly in patients with suspected Cushing's syndrome or resistant hypertension?

Urine Tests for Secondary Hypertension Workup

Beyond basic urinalysis, the key urine tests for secondary hypertension workup are urinary albumin-to-creatinine ratio (for all patients), 24-hour urinary free cortisol (for suspected Cushing's syndrome), and 24-hour urinary fractionated metanephrines (for suspected pheochromocytoma). 1

Essential Urine Tests for All Patients

• Urinary albumin-to-creatinine ratio should be measured in all patients being evaluated for secondary hypertension to assess for kidney damage and renal parenchymal disease 1
• Basic dipstick urinalysis remains the initial screening test to detect hematuria, proteinuria, or signs of urinary tract infection that may suggest renal parenchymal disease 1

Targeted Urine Tests Based on Clinical Suspicion

For Suspected Cushing's Syndrome

• 24-hour urinary free cortisol (UFC) is recommended as one of the primary screening tests when Cushing's syndrome is suspected, particularly in patients with resistant hypertension, rapid weight gain with central distribution, proximal muscle weakness, wide violaceous striae, or fatty deposits 1, 2
• The diagnostic threshold is >100 μg/24 hours (1.6 μmol/24 hours) in symptomatic patients, though 40 μg/24 hours provides better sensitivity 2
• Obtain at least 2-3 separate 24-hour collections before making diagnostic decisions, as intra-patient variability can reach 50% between collections 2

Critical pitfalls to avoid:

• Ensure complete 24-hour urine collection with documented total volume and creatinine excretion to validate the collection 2
• Several conditions cause mildly elevated urinary cortisol without true Cushing's syndrome: severe obesity, uncontrolled diabetes, depression, alcohol use disorder, and polycystic ovary syndrome 2
• Renal impairment, polyuria, and oral estrogen/contraceptives can invalidate results 2
• Cyclic Cushing's syndrome can produce false-negative results; repeat collections during symptomatic periods may be necessary 2

For Suspected Pheochromocytoma/Paraganglioma

• 24-hour urinary fractionated metanephrines is the recommended screening test when pheochromocytoma is suspected based on paroxysmal hypertension, episodic spells (headache, sweating, palpitations, pallor), resistant hypertension, or adrenal incidentaloma 1
• The metanephrine-to-creatinine ratio has 100% sensitivity and 98% specificity for pheochromocytoma diagnosis 3
• Measuring the ratio corrects for incomplete urine collections, which is a common source of error 3

Critical pitfall:

• Acute events (stress, illness, pain) may increase urinary metanephrine excretion to tumor-level ranges, causing false-positives 3
• Incorrect urinary volume input by the laboratory can lead to false elevations—always verify the reported volume matches the actual collection 4

For Suspected Primary Aldosteronism

While primary aldosteronism screening primarily uses plasma aldosterone-to-renin ratio, confirmatory testing may include:

• 24-hour urine aldosterone during oral sodium loading test (with documented sodium intake >200 mEq/day) 1
• Urine aldosterone >12-14 μg/24 hours during sodium loading confirms autonomous aldosterone secretion 1

Algorithmic Approach to Urine Testing

Step 1: All patients with suspected secondary hypertension should have:

• Urinary albumin-to-creatinine ratio 1
• Dipstick urinalysis 1

Step 2: Add targeted urine tests based on clinical features:

• If Cushingoid features present (central obesity, moon face, wide striae, proximal weakness): Order 24-hour urinary free cortisol (at least 2-3 collections) 1, 2
• If paroxysmal symptoms present (episodic headaches, sweating, palpitations, BP lability): Order 24-hour urinary fractionated metanephrines 1
• If resistant hypertension with hypokalemia: Plasma aldosterone-to-renin ratio first, then 24-hour urine aldosterone during sodium loading for confirmation 1

Step 3: For positive screening results, refer to specialist centers with expertise in confirmatory testing and management 2, 5

Important Considerations

The 2020 International Society of Hypertension guidelines emphasize that while basic dipstick urinalysis is part of routine evaluation, urinary albumin-to-creatinine ratio provides more quantitative assessment of kidney damage and should be obtained in all patients with hypertension 1

For Cushing's syndrome specifically, the Endocrine Society recommends using at least two different screening tests to confirm hypercortisolism, which may include 24-hour UFC combined with either late-night salivary cortisol or overnight 1-mg dexamethasone suppression test 2, 6