What is the appropriate workup for a patient suspected of having Conn's syndrome, considering their past medical history of cardiovascular disease, including hypertension, heart failure, and impaired renal function?

Workup for Conn's Syndrome in a Patient with Cardiovascular Disease and Renal Impairment

In a patient with cardiovascular disease, hypertension, heart failure, and impaired renal function suspected of having Conn's syndrome, begin with measurement of the aldosterone-renin ratio (ARR) as the primary screening test, followed by confirmatory testing, adrenal imaging with CT, and selective adrenal vein sampling to lateralize aldosterone production before considering surgical intervention. 1

Initial Screening: Aldosterone-Renin Ratio

The ARR measurement is the first-line screening test for primary aldosteronism and should be performed under optimized conditions. 1

Pre-test Optimization Requirements

Before measuring ARR, optimize the following conditions to ensure accurate results:

• Adjust antihypertensive medications: Ideally discontinue medications that interfere with the renin-angiotensin-aldosterone system, though this may be challenging in patients with severe hypertension and heart failure 1
• Correct potassium balance: Ensure normokalemia through supplementation, as hypokalemia suppresses aldosterone secretion and can lead to false-negative results 1, 2
• Measure at rest: Obtain samples after the patient has been seated or supine for at least 15 minutes 1
• Morning collection: Draw blood in the morning to account for circadian variation 1

Interpretation of ARR

An elevated ARR warrants proceeding to confirmatory testing, particularly when accompanied by:

• Spontaneous hypokalemia (potassium <3.5 mEq/L) 2, 3
• Undetectable or suppressed plasma renin activity 2, 3
• Elevated serum aldosterone concentration 2, 3

Basic Laboratory Evaluation

Essential Blood Tests

Obtain the following laboratory studies to assess cardiovascular risk, identify comorbidities, and guide treatment 4:

• Complete blood count to assess for anemia, which can exacerbate cardiac symptoms 4
• Comprehensive metabolic panel including:
  • Serum electrolytes (sodium, potassium, chloride, bicarbonate) to identify hypokalemia and metabolic alkalosis 2, 3
  • Serum creatinine with eGFR calculation to assess renal function 4
  • Blood urea nitrogen 4
  • Glucose and HbA1c to screen for diabetes mellitus, which is associated with primary aldosteronism 1
• Lipid profile including LDL-C for cardiovascular risk stratification 4
• Thyroid-stimulating hormone to exclude thyroid disease as a contributor to hypertension 4
• Calcium and magnesium levels 4

Urinary Studies

• 24-hour urine collection for potassium excretion to document inappropriate kaliuresis (urinary potassium >30 mEq/day despite hypokalemia) 2
• Urinalysis with albumin-to-creatinine ratio to assess for proteinuria as a marker of kidney damage 4

Confirmatory Testing for Primary Aldosteronism

When ARR is elevated, proceed with confirmatory testing to establish the diagnosis of autonomous aldosterone production. 1

Available confirmatory tests include:

• Oral sodium loading test: Administer high sodium diet (>200 mEq/day) for 3 days with measurement of 24-hour urinary aldosterone on day 3
• Saline infusion test: Infuse 2 liters of 0.9% saline over 4 hours and measure aldosterone; failure to suppress aldosterone to <5-10 ng/dL confirms autonomous production
• Fludrocortisone suppression test: Administer fludrocortisone with sodium supplementation for 4 days

Critical caveat: Exercise caution with sodium loading tests in patients with heart failure and renal impairment, as volume expansion may precipitate acute decompensation 4. In such patients, consider the captopril challenge test as a safer alternative, though it has lower sensitivity.

Cardiovascular and Renal Assessment

Cardiac Evaluation

Given the patient's cardiovascular disease and heart failure, perform comprehensive cardiac assessment 4:

• 12-lead electrocardiogram to assess for left ventricular hypertrophy (Sokolow-Lyon >38 mm or Cornell >2440 mm/ms), arrhythmias, and ischemic changes 4
• Transthoracic echocardiography with Doppler to evaluate:
  • Left ventricular ejection fraction and volumes 4
  • Left ventricular wall thickness and mass index (>125 g/m² in men, >110 g/m² in women indicates LVH) 4
  • Diastolic function 4
  • Valvular abnormalities 4
  • Right ventricular function and estimated pulmonary artery pressure 4

Rationale: Patients with primary aldosteronism have more pronounced left ventricular hypertrophy and higher cardiovascular event rates than those with essential hypertension at comparable blood pressure levels 5. This assessment establishes baseline cardiac function and identifies target organ damage.

Renal Function Assessment

In patients with impaired renal function, detailed assessment is essential as chronic kidney disease affects both diagnosis and treatment decisions 4:

• Serial creatinine measurements with eGFR calculation using CKD-EPI equation 4
• Staging of CKD based on eGFR: Stage 3 (30-59 mL/min/1.73 m²), Stage 4 (15-29 mL/min/1.73 m²), or Stage 5 (<15 mL/min/1.73 m²) 4
• Assessment for structural kidney abnormalities on imaging 4

Vascular Assessment

• Carotid ultrasound with measurement of intima-media thickness (>0.9 mm indicates subclinical atherosclerosis) or presence of plaques 4
• Ankle-brachial index (<0.9 indicates peripheral arterial disease) 4

Adrenal Imaging

Computed Tomography of Adrenal Glands

Once primary aldosteronism is confirmed biochemically, obtain dedicated adrenal CT to identify adrenal adenoma or bilateral hyperplasia. 1, 2, 3

Important consideration for renal impairment: CCTA and contrast-enhanced CT are not recommended in patients with severe renal failure (eGFR <30 mL/min/1.73 m²) 4. In such cases:

• Consider non-contrast CT, though it has reduced sensitivity for characterizing adrenal lesions
• MRI with group II gadolinium-based contrast agents at lowest diagnostic dose may be used if eGFR is 30-60 mL/min/1.73 m² 4
• Ultrasound contrast media are not nephrotoxic and represent an alternative for vascular imaging 4

Imaging Findings

Look for:

• Unilateral adrenal adenoma (typically <3 cm, homogeneous, low attenuation on non-contrast CT) suggesting Conn's syndrome 1, 2, 3
• Bilateral adrenal hyperplasia suggesting idiopathic hyperaldosteronism 1
• Normal-appearing adrenal glands (does not exclude microscopic adenoma or hyperplasia) 1

Adrenal Vein Sampling

Selective adrenal vein sampling remains the gold standard for differentiating unilateral from bilateral aldosterone production and is essential for surgical planning. 1

Indications for AVS

Perform AVS in all patients who are:

• Confirmed to have primary aldosteronism biochemically 1
• Surgical candidates willing to undergo adrenalectomy 1
• Have imaging findings that are equivocal or show bilateral abnormalities 1

Interpretation

• Lateralization index >4:1 (ratio of aldosterone/cortisol from dominant side to non-dominant side) indicates unilateral disease amenable to surgery 1
• No lateralization indicates bilateral disease requiring medical management 1

Critical pitfall: Do not proceed to adrenalectomy based on imaging alone without AVS confirmation, as CT findings may not correlate with functional aldosterone production 1. Non-functioning incidentalomas are common and can lead to unnecessary surgery.

Risk Stratification in Context of Cardiovascular Disease

Assessment of Cardiovascular Risk

Patients with primary aldosteronism and pre-existing cardiovascular disease are at dramatically increased risk for cardiovascular events. 4, 5

Document the following to stratify risk 4:

• Established cardiovascular disease: Previous myocardial infarction, angina, coronary revascularization, heart failure, stroke, or transient ischemic attack
• Target organ damage:
  • Electrocardiographic or echocardiographic LVH 4
  • Carotid wall thickening or plaque 4
  • Increased arterial stiffness (carotid-femoral pulse wave velocity >12 m/s) 4
  • Microalbuminuria (30-300 mg/24h) or proteinuria (>300 mg/24h) 4
  • Advanced retinopathy 4
• Additional cardiovascular risk factors: Smoking, dyslipidemia, diabetes mellitus, family history of premature CVD 4

Biomarkers for Heart Failure Assessment

In patients with known heart failure 4:

• BNP or NT-proBNP measurement is useful to support clinical decision-making regarding volume status and prognosis 4
• Serial monitoring may guide diuretic therapy intensity 4
• Cardiac troponin may be considered for additional risk stratification 4

Special Considerations for This Patient Population

Medication Review

Review all current medications, as many antihypertensives interfere with ARR testing 1:

• Continue: Calcium channel blockers (preferred for BP control during workup), alpha-blockers, hydralazine, prazosin 1
• Discontinue if possible: ACE inhibitors, ARBs (interfere with renin measurement), beta-blockers (suppress renin), direct renin inhibitors, mineralocorticoid receptor antagonists 1
• Assess diuretic use: May need to continue for heart failure management despite interference with testing 4

Contrast Agent Considerations

Given renal impairment, carefully weigh risks and benefits of contrast-enhanced imaging 4:

• Iodinated contrast: Generally avoided in acute kidney injury; in CKD, risk-benefit ratio depends on level and acuity of kidney disease 4
• Adequate hydration and avoidance of other nephrotoxic drugs are essential 4
• Patients on hemodialysis may undergo contrast-enhanced CT if no residual renal function 4

Hypokalemia Management During Workup

Correct hypokalemia before ARR testing, but document baseline potassium and inappropriate kaliuresis first 2, 3:

• Measure serum potassium and 24-hour urinary potassium before supplementation 2
• Replete potassium to normalize levels for accurate ARR measurement 1
• Severe hypokalemia (<2.5 mEq/L) can precipitate life-threatening arrhythmias, particularly in patients with heart disease 3

Diagnostic Algorithm Summary

1. Screen with ARR under optimized conditions (corrected potassium, adjusted medications, at rest) 1
2. If ARR elevated: Perform confirmatory testing (choose test based on heart failure severity and renal function) 1
3. If confirmed: Obtain adrenal CT imaging (consider contrast limitations with renal impairment) 1, 2
4. If surgical candidate: Proceed to adrenal vein sampling for lateralization 1
5. Throughout: Assess cardiovascular risk, target organ damage, and optimize management of heart failure and renal disease 4

Common Pitfalls to Avoid

• Do not rely on imaging alone to determine surgical candidacy; AVS is essential for lateralization 1
• Do not perform sodium loading tests in patients with decompensated heart failure or severe renal impairment without careful consideration of volume status 4
• Do not measure ARR during severe hypokalemia as it suppresses aldosterone and yields false-negative results 1, 2
• Do not use contrast-enhanced CT in patients with eGFR <30 mL/min/1.73 m² without considering alternatives 4
• Do not attribute resistant hypertension solely to essential hypertension in patients requiring multiple antihypertensives; screen for secondary causes including primary aldosteronism 4, 1