What are the likely causes and recommended work‑up for a sodium‑potassium disturbance in an adult when renal, cardiac, and adrenal imaging are normal?

Sodium-Potassium Imbalance with Normal Renal, Cardiac, and Adrenal Imaging

When initial imaging of the kidneys, heart, and adrenal glands is normal in a patient with sodium-potassium disturbances, the most likely causes are functional disorders rather than structural abnormalities—specifically primary aldosteronism (which can occur with bilateral adrenal hyperplasia showing normal imaging), medication-induced electrolyte disturbances, or inherited tubulopathies such as Bartter syndrome. 1

Diagnostic Framework

Primary Aldosteronism Despite Normal Imaging

Primary aldosteronism occurs in approximately 8-20% of hypertensive patients and can present with normal adrenal imaging when caused by bilateral adrenal hyperplasia (idiopathic hyperaldosteronism), which accounts for 50% of primary aldosteronism cases. 1 The increased aldosterone production induces hypertension, sodium retention, suppressed plasma renin activity, and increased potassium excretion. 1

• Hypokalemia is absent in the majority of primary aldosteronism cases and has low negative predictive value for diagnosis. 1
• Screen with plasma aldosterone-to-renin ratio under standardized conditions (correction of hypokalemia and withdrawal of aldosterone antagonists for 4-6 weeks). 1
• Confirmatory testing includes oral sodium loading test with 24-hour urine aldosterone or IV saline infusion test with plasma aldosterone at 4 hours. 1
• Even with normal adrenal CT imaging, adrenal vein sampling may be necessary to distinguish unilateral from bilateral disease. 1

Medication-Induced Electrolyte Disturbances

Drug-induced causes account for 2-4% of secondary hypertension and are a leading cause of electrolyte imbalance with normal structural imaging. 1

Critical medications to evaluate:

• Loop and thiazide diuretics cause significant urinary potassium losses through increased distal sodium delivery and secondary aldosterone stimulation. 1
• NSAIDs cause sodium retention, peripheral vasoconstriction, and impair renal potassium handling. 1
• Oral contraceptives, cyclosporine, tacrolimus can elevate blood pressure and alter electrolyte balance. 1
• Sympathomimetics (decongestants, anorectics), cocaine, amphetamines. 1
• Neuropsychiatric agents, erythropoiesis-stimulating agents, clonidine withdrawal. 1
• Corticosteroids cause hypokalemia through mineralocorticoid effects, with hydrocortisone causing more hypokalemia than methylprednisolone at equivalent doses. 2

Inherited Tubulopathies (Bartter Syndrome)

Bartter syndrome presents with hypokalemia, metabolic alkalosis, and normal blood pressure despite elevated renin and aldosterone—a key distinguishing feature from primary aldosteronism. 1

• Nephrocalcinosis and hypercalciuria are present in the majority of patients (except BS3). 1
• Chronic kidney disease is common, with BS1 and BS4 patients having more severe progression than BS2 and BS3. 1
• Electrocardiography should be performed to assess QT-interval duration, as hypokalemia with or without hypomagnesemia prolongs the QT interval and increases risk of ventricular arrhythmias. 1
• During pregnancy, target potassium level is 3.0 mmol/L, acknowledging this may not be achievable in some patients. 1

Recommended Work-Up Algorithm

Step 1: Medication Review and Urinary Drug Screen

• Obtain comprehensive medication history including over-the-counter substances, illicit drugs, and herbal products. 1
• Urinary drug screen for illicit drugs (cocaine, amphetamines). 1
• Response to withdrawal of suspected agent serves as confirmatory test. 1

Step 2: Plasma Aldosterone-to-Renin Ratio

Screen for primary aldosteronism using plasma aldosterone-to-renin ratio under standardized conditions. 1

• Correct hypokalemia before testing (target 4.0-5.0 mEq/L). 1, 2
• Withdraw aldosterone antagonists for 4-6 weeks prior to testing. 1
• If positive, referral to hypertension specialist or endocrinologist is recommended for confirmatory testing and adrenal vein sampling. 1

Step 3: Assess for Functional Renal Tubular Disorders

If aldosterone-to-renin ratio is elevated (suggesting secondary hyperaldosteronism):

• Measure 24-hour urine potassium excretion to distinguish renal from extrarenal losses. 2
• Spot urine potassium-to-creatinine ratio can substitute when 24-hour collection is impractical. 2
• Urine potassium >20 mEq/day (or spot K/Cr >1.5) with hypokalemia indicates renal potassium wasting. 2
• Assess acid-base status: metabolic alkalosis with renal potassium wasting suggests Bartter syndrome, diuretic use, or primary aldosteronism. 1, 2

Step 4: Genetic Testing for Bartter Syndrome

Consider genetic testing when clinical features suggest inherited tubulopathy: 1

• Hypokalemia with metabolic alkalosis and normal blood pressure
• Elevated renin and aldosterone (distinguishing from primary aldosteronism)
• Hypercalciuria and/or nephrocalcinosis on imaging
• Family history of early-onset hypertension or electrolyte disorders
• Onset in childhood or young adulthood

Step 5: Cardiac Risk Assessment

Obtain 12-lead ECG in all patients with potassium <3.0 mEq/L or any cardiac symptoms. 1, 2

• Moderate hypokalemia (2.5-2.9 mEq/L) markedly increases risk of cardiac arrhythmias, including ventricular tachycardia, torsades de pointes, and ventricular fibrillation. 2
• Typical ECG changes include ST-segment depression, T-wave flattening, and prominent U waves. 1, 2
• Hypokalemia prolongs QT interval, which can lead to increased risk of ventricular arrhythmias and sudden death. 1
• Consider Holter monitoring or stress testing if palpitations or chest pain present. 2

Critical Monitoring and Management Considerations

Magnesium Assessment is Mandatory

Check serum magnesium immediately in all patients with hypokalemia, as hypomagnesemia is the most common reason for refractory hypokalemia and must be corrected before potassium levels will normalize. 2, 3

• Target magnesium >0.6 mmol/L (>1.5 mg/dL). 2
• Approximately 40% of hypokalemic patients have concurrent hypomagnesemia. 2
• Use organic magnesium salts (aspartate, citrate, lactate) rather than oxide or hydroxide due to superior bioavailability. 2

Target Potassium Range

Maintain serum potassium between 4.0-5.0 mEq/L, as both hypokalemia and hyperkalemia increase mortality risk, particularly in patients with cardiac disease. 2, 3

• Potassium levels outside 4.0-5.0 mEq/L show U-shaped mortality correlation in heart failure patients. 2
• For Bartter syndrome patients, a reasonable target may be 3.0 mmol/L, acknowledging complete normalization may not be achievable. 1, 2

Monitoring Protocol

Check potassium and renal function within 2-3 days and again at 7 days after initiating treatment, then every 1-2 weeks until values stabilize, followed by monitoring at 3 months and every 6 months thereafter. 2, 3

• More frequent monitoring required in patients with renal impairment, heart failure, diabetes, or on medications affecting potassium homeostasis. 2
• When adding potassium-sparing diuretics, monitor every 5-7 days until values stabilize. 2

Common Pitfalls to Avoid

• Never supplement potassium without checking and correcting magnesium first—this is the single most common reason for treatment failure. 2, 3
• Do not assume normal adrenal imaging excludes primary aldosteronism; bilateral adrenal hyperplasia accounts for 50% of cases and may appear normal on CT. 1
• Avoid administering digoxin before correcting hypokalemia, as this significantly increases risk of life-threatening arrhythmias. 2
• Do not overlook medication-induced causes; obtain comprehensive history including over-the-counter drugs, supplements, and illicit substances. 1
• Failing to measure aldosterone-to-renin ratio under standardized conditions (after correcting hypokalemia and withdrawing interfering medications) leads to false results. 1