What are the differential diagnoses for a hypertensive patient presenting with hyponatremia, hypokalemia, hypocalcemia, and mildly elevated serum creatinine?

Differential Diagnosis for Hypertension with Hyponatremia, Hypokalemia, Hypocalcemia, and Elevated Creatinine

Primary aldosteronism is the most likely diagnosis in this hypertensive patient with hypokalemia and should be investigated first, given its 20% prevalence in resistant hypertension and its association with renal dysfunction. 1

Most Likely Diagnoses

Primary Aldosteronism

• This is the leading consideration because hypokalemia with hypertension strongly suggests mineralocorticoid excess, and primary aldosteronism occurs in approximately 20% of patients with resistant hypertension 1
• Hypokalemia is a late manifestation; many patients with primary aldosteronism initially present with normal potassium levels, so its presence indicates advanced disease 1
• The elevated creatinine reflects hypertension-mediated kidney damage from prolonged aldosterone excess 1
• Measure aldosterone-to-renin ratio as the initial screening test, recognizing that hypokalaemia itself can lower this ratio and create false negatives 1
• Confirm with 24-hour urinary aldosterone excretion during high dietary sodium intake if the ratio is elevated 1

Renovascular Hypertension (Renal Artery Stenosis)

• This represents a high-renin state that can cause hypertension with hypokalemia through secondary hyperaldosteronism 2
• The elevated creatinine may indicate bilateral disease or ischemic nephropathy 1
• Suspect this diagnosis particularly if: hypertension onset occurred before age 30 or after age 55, there is an abdominal bruit (especially with diastolic component), accelerated or resistant hypertension is present, or acute renal failure occurred after starting an ACE inhibitor 1
• Screen with renal Doppler ultrasound with bilateral renal arterial resistive index assessment, or proceed directly to CT or MR angiography 1, 3

Diuretic-Induced Electrolyte Disturbances

• Thiazide or loop diuretics can cause the entire constellation of hyponatremia, hypokalemia, hypocalcemia, and worsening renal function 4
• Indapamide and other thiazides cause severe hyponatremia (plasma sodium as low as 103 mmol/L) and hypokalemia (plasma potassium as low as 1.6 mmol/L) in 0.6-1.2% of treated patients 4
• Diuretic-induced hyponatremia can mimic SIADH and present with central nervous system symptoms 4
• Review medication history carefully; electrolyte disturbances typically develop 5-6 weeks after starting therapy 4

Secondary Considerations

Malignant Hypertension with Renal Injury

• Severe hypertension (>180/110 mmHg) can cause hyponatremic-hypertensive syndrome through pressure-forced diuresis, leading to urinary sodium wasting, hyponatremia, and transient massive proteinuria 5
• The elevated creatinine reflects acute hypertensive nephrosclerosis 5
• Hypocalcemia may result from renal calcium leak associated with essential hypertension and compensatory parathyroid overactivity 6
• Check for hypertensive emergency signs: encephalopathy, acute kidney injury, proteinuria, and end-organ damage 5

Pheochromocytoma

• This accounts for 0.1-0.6% of hypertension cases but is overrepresented in resistant hypertension 1
• Typically presents with paroxysmal hypertension, headache, palpitations, pallor, and perspiration 1
• Electrolyte abnormalities can occur from catecholamine-induced renal dysfunction 1
• Screen with 24-hour urinary or plasma metanephrines and normetanephrines 1

Cushing Syndrome

• Causes hypertension with hypokalemia through mineralocorticoid effects of excess cortisol 1
• Look for truncal obesity, glucose intolerance, and purple striae 1
• Screen with 24-hour urinary free cortisol or low-dose dexamethasone suppression test 1

Genetic Mineralocorticoid Excess Syndromes

• Liddle's syndrome, apparent mineralocorticoid excess (AME), and glucocorticoid-remediable aldosteronism (GRA) all cause hypertension with hypokalemia 2
• These are rare but should be considered in young patients with early-onset severe hypertension and family history 2
• GRA typically presents in childhood 1

Diagnostic Algorithm

Immediate Laboratory Workup

• Measure aldosterone-to-renin ratio to screen for primary aldosteronism, noting that hypokalemia and certain medications (beta-blockers, ACE inhibitors, ARBs) can affect results 1
• Calculate eGFR using CKD-EPI equation rather than relying on serum creatinine alone 3
• Obtain spot urine albumin-to-creatinine ratio and urinalysis with microscopy to distinguish glomerulonephritis (active sediment with RBC casts) from hypertensive nephrosclerosis (bland sediment) 3
• Measure plasma renin activity to differentiate high-renin (renovascular disease) from low-renin (primary aldosteronism, genetic syndromes) states 2

Imaging Studies

• Renal Doppler ultrasound to assess for renovascular disease and kidney structure 1, 3
• Consider CT or MR angiography if renovascular hypertension is strongly suspected 1
• Adrenal CT or MRI if primary aldosteronism is confirmed biochemically 1

Critical Pitfalls to Avoid

• Do not assume SIADH when encountering hyponatremia in a hypertensive patient; diuretic-induced hyponatremia and hyponatremic-hypertensive syndrome can mimic this 4, 5
• Do not stop ACE inhibitors/ARBs for creatinine rises <30% within 4 weeks of initiation, as this represents expected hemodynamic changes 7
• Avoid NSAIDs entirely in patients with renal dysfunction on RAS blockers, as the "triple whammy" (NSAID + ACE inhibitor/ARB + diuretic) markedly increases acute kidney injury risk 7
• Correct hypokalemia before measuring aldosterone-to-renin ratio when possible, as hypokalemia suppresses aldosterone and creates false-negative results 1

Monitoring and Follow-up

• Recheck serum creatinine, potassium, and sodium within 7-14 days after any medication adjustment 3
• Refer to nephrology if eGFR <30 mL/min/1.73 m², rapidly progressive kidney disease is present, active urinary sediment suggests glomerulonephritis, or diagnostic uncertainty exists 3