In a hypertensive patient with elevated plasma aldosterone and renin, normal laboratory studies and normal renal, cardiac, and adrenal imaging, what is the most likely cause and what diagnostic and treatment steps should be taken?

Atypical Primary Aldosteronism with Unsuppressed Renin

This presentation represents an uncommon variant of primary aldosteronism where renin has "escaped" suppression due to secondary hypertensive kidney damage, and you should proceed with confirmatory testing for primary aldosteronism followed by subtype determination, as the elevated aldosterone-to-renin ratio remains diagnostic despite the elevated renin. 1, 2

Understanding This Atypical Presentation

• Classical primary aldosteronism presents with elevated aldosterone and suppressed renin due to aldosterone-induced volume expansion, but in 3-5% of cases, severe hypertensive kidney damage allows renin to escape suppression while aldosterone remains inappropriately elevated. 2

• The key diagnostic insight is that the aldosterone-to-renin ratio (ARR) remains elevated because aldosterone is disproportionately high relative to renin, even though renin itself is not suppressed. 2

• This pattern typically occurs in patients with severe, longstanding hypertension who have developed hypertensive nephrosclerosis or renal arteriolosclerosis, which stimulates renin release despite ongoing aldosterone excess. 2

Why This Is Still Primary Aldosteronism

• The normal imaging and laboratory studies do not exclude primary aldosteronism—up to 50% of cases have normal potassium, and adrenal adenomas can be small enough to appear normal on routine imaging. 3

• Your patient likely has either an aldosterone-producing adenoma with secondary renal damage or bilateral adrenal hyperplasia with concurrent hypertensive kidney injury. 2

• The elevated renin indicates that renal perfusion is compromised enough to trigger renin release, but this is a consequence of the primary aldosterone excess causing severe hypertension, not a separate renovascular disease. 2

Diagnostic Algorithm

Step 1: Calculate the Aldosterone-to-Renin Ratio

• Calculate ARR = plasma aldosterone (ng/dL) ÷ plasma renin activity (ng/mL/hr), and the test is positive if ARR ≥20-30 AND plasma aldosterone ≥10-15 ng/dL. 3

• In your case, both aldosterone and renin are elevated, but if the ratio is ≥20-30 with aldosterone ≥10-15 ng/dL, this still screens positive for primary aldosteronism despite the unsuppressed renin. 2

Step 2: Perform Confirmatory Testing

• Do not skip confirmatory testing even though the clinical picture is suggestive—you must demonstrate autonomous aldosterone production that cannot be suppressed with sodium loading. 3, 1

• Choose one of these confirmatory tests: 3, 1

  • Oral sodium loading test: Administer high-sodium diet (>200 mEq/day) for 3 days, then measure 24-hour urine aldosterone on day 3. Failure to suppress urinary aldosterone below 12-14 mcg/24hr confirms autonomous production.
  • Intravenous saline suppression test: Infuse 2L normal saline over 4 hours. Failure to suppress plasma aldosterone below 5 ng/dL confirms the diagnosis.

• Critical preparation before confirmatory testing: 3, 1

  • Ensure potassium repletion to 4.0-5.0 mEq/L, as hypokalemia suppresses aldosterone and causes false-negatives
  • Withdraw mineralocorticoid receptor antagonists (spironolactone, eplerenone) for at least 4 weeks
  • Stop beta-blockers, diuretics, and centrally acting agents when feasible
  • Use calcium channel blockers or alpha-blockers for blood pressure control during the washout period

Step 3: Subtype Determination

• Once primary aldosteronism is confirmed, obtain non-contrast CT scan of the adrenal glands as initial imaging to look for unilateral adenoma versus bilateral hyperplasia. 3

• Adrenal venous sampling (AVS) is mandatory before offering adrenalectomy, as CT findings alone are misleading in up to 25% of cases—apparent adenomas may represent hyperplasia, and bilateral disease can appear unilateral on imaging. 3, 1

• The only exception to requiring AVS is patients <40 years old with a solitary unilateral macroadenoma (>1 cm) on CT and completely normal contralateral adrenal, as bilateral hyperplasia is rare in this age group. 3

Treatment Based on Subtype

For Unilateral Disease (Confirmed by AVS)

• Laparoscopic unilateral adrenalectomy is the treatment of choice, which improves blood pressure in virtually 100% of patients and achieves complete cure of hypertension in approximately 50%. 3

• Even if hypertension persists post-operatively due to vascular remodeling from longstanding disease, blood pressure control improves significantly and cardiovascular risk decreases. 3

For Bilateral Disease

• Lifelong medical therapy with mineralocorticoid receptor antagonists (MRAs) is the cornerstone of treatment. 3, 1

• Start spironolactone 50-100 mg once daily, titrating up to 300-400 mg daily if needed for blood pressure control. 3

• If anti-androgenic side effects occur (gynecomastia, erectile dysfunction, menstrual irregularities), switch to eplerenone, though it is less potent and requires twice-daily dosing. 3

Critical Monitoring in This Patient

• Monitor serum creatinine and potassium closely when starting spironolactone, as patients with pre-existing renal impairment (evidenced by the unsuppressed renin) are at high risk for hyperkalemia and acute worsening of renal function. 2

• Expect serum creatinine to increase by 0.3-0.5 mg/dL when starting MRA therapy in patients with baseline renal dysfunction—this is due to decreased glomerular filtration from reduced mineralocorticoid activity, not progressive kidney disease. 2

• Check potassium and creatinine within 1 week of starting therapy, then every 2-4 weeks during dose titration. 3

Common Pitfalls to Avoid

• Do not dismiss primary aldosteronism because renin is not suppressed—this is a well-described variant in patients with severe hypertension and secondary kidney damage. 2

• Do not rely on normal imaging to exclude the diagnosis—aldosterone-producing adenomas can be <1 cm and appear normal on CT, and bilateral hyperplasia always looks normal or shows only subtle nodularity. 3

• Do not proceed to adrenalectomy based on CT findings alone—up to 25% of patients would undergo unnecessary surgery without AVS confirmation of lateralization. 3

• Do not start aggressive spironolactone dosing without close monitoring—patients with renal impairment are at high risk for life-threatening hyperkalemia, especially if also taking ACE inhibitors or ARBs. 2

• Do not assume the elevated renin indicates renovascular disease—in the context of high aldosterone, this pattern reflects hypertensive kidney damage from the primary aldosteronism itself, not renal artery stenosis. 4, 2

Why Early Diagnosis Matters

• Primary aldosteronism confers dramatically higher cardiovascular risk than essential hypertension at equivalent blood pressure levels: 3.7-fold increase in heart failure, 4.2-fold increase in stroke, 6.5-fold increase in myocardial infarction, and 12.1-fold increase in atrial fibrillation. 3

• These excess risks are reversible with targeted therapy (surgery or MRA), making accurate diagnosis and treatment critical even in patients with apparent renal damage. 3, 2

• The fact that your patient has developed renal impairment severe enough to allow renin escape suggests longstanding, untreated disease—prompt intervention can still prevent further cardiovascular and renal complications. 2