What electrolyte abnormality is most commonly associated with angiotensin‑converting‑enzyme inhibitors (ACE inhibitors) and angiotensin‑II receptor blockers (ARBs)?

Hyperkalemia is the Primary Electrolyte Abnormality Associated with ACE Inhibitors and ARBs

The most common electrolyte abnormality associated with ACE inhibitors and ARBs is hyperkalemia (elevated serum potassium), which occurs because these medications reduce angiotensin II-mediated aldosterone secretion, thereby decreasing renal potassium excretion. 1

Mechanism and Incidence

• ACE inhibitors and ARBs block the renin-angiotensin-aldosterone system, which normally promotes potassium excretion through aldosterone's action on the distal nephron 1
• Hyperkalemia occurs in approximately 6-11% of patients treated with these agents, with most cases being mild (potassium increases of ~1 mEq/L) 1, 2
• Severe hyperkalemia (>6.0 mEq/L) is uncommon but can be life-threatening, causing cardiac arrhythmias and even sinusoidal rhythms requiring emergent treatment 1, 3

High-Risk Populations Requiring Vigilant Monitoring

Patients at highest risk for developing hyperkalemia include those with:

• Chronic kidney disease, particularly eGFR <60 mL/min/1.73 m² - the most important risk factor 1
• Diabetes mellitus - independently increases hyperkalemia risk 1, 4
• Heart failure - associated with increased incidence 1, 2
• Advanced age >70 years - independently predicts severe hyperkalemia 2
• Low body mass index - affects drug pharmacokinetics and potassium disposition 4
• Baseline serum creatinine >136 μmol/L (1.5 mg/dL) or BUN >6.4 mmol/L (18 mg/dL) 2

Critical Drug Interactions That Amplify Hyperkalemia Risk

The following medications dramatically increase hyperkalemia risk when combined with ACE inhibitors/ARBs and require extreme caution:

• Aldosterone antagonists (spironolactone, eplerenone) - additive potassium retention 1
• Potassium-sparing diuretics (amiloride, triamterene) - should be avoided without intensive monitoring 1, 5
• NSAIDs - reduce renal potassium excretion and should be minimized 1, 5
• Potassium supplements - contraindicated unless treating documented hypokalemia 1
• Direct renin inhibitors - combination with ACE inhibitors/ARBs is contraindicated 1

Important protective note: Loop diuretics (furosemide) and thiazide diuretics actually reduce hyperkalemia risk by promoting potassium excretion 2

Mandatory Monitoring Protocol

Before initiating ACE inhibitor or ARB therapy:

• Measure baseline serum potassium, creatinine, and eGFR 1
• Assess dietary potassium intake and review all concurrent medications 1

After initiation or dose adjustment:

• Check serum potassium and creatinine within 1 week of starting therapy 1
• For patients with eGFR <60 mL/min/1.73 m², monitor more frequently (every 3-5 months for stage 4 CKD) 1
• Continue monitoring at least annually, or more frequently if risk factors present 1

Management of Hyperkalemia During Treatment

For mild hyperkalemia (5.5-6.0 mEq/L):

• Review and discontinue potassium supplements, NSAIDs, and potassium-sparing agents 1
• Reduce dietary potassium intake 1
• Consider adding loop or thiazide diuretic if volume status permits 2
• Recheck potassium within 3-5 days 5

For severe hyperkalemia (>6.0 mEq/L):

• Temporarily discontinue ACE inhibitor/ARB immediately 1
• Do NOT substitute an ARB for an ACE inhibitor (or vice versa) as they have identical effects on potassium homeostasis 1
• Initiate acute hyperkalemia treatment: calcium for cardiac protection, insulin/glucose for potassium shifting, and consider dialysis if life-threatening 1, 3
• Investigate precipitating factors: volume depletion, acute kidney injury, medication changes 1

Acceptable Creatinine Rise vs. True Acute Kidney Injury

A critical distinction must be made between expected hemodynamic changes and true AKI:

• Serum creatinine increases up to 30% from baseline are expected and acceptable with ACE inhibitor/ARB initiation, representing hemodynamic changes rather than kidney injury 1
• This modest rise does not require medication discontinuation and actually correlates with long-term cardiovascular benefit 1
• However, rises >0.5 mg/dL (if baseline creatinine ≤2.0 mg/dL) or >1.0 mg/dL (if baseline >2.0 mg/dL) warrant medication cessation and evaluation for renal artery stenosis 1

When to Reinitiate Therapy After Hyperkalemia

ACE inhibitors/ARBs can generally be safely restarted after hyperkalemia resolves if:

• Precipitating factors (volume depletion, NSAIDs, dietary indiscretion) have been corrected 1
• Patient is <70 years with normal renal function - subsequent severe hyperkalemia is uncommon 2
• Bilateral renal artery stenosis has been excluded 1

Consider newer potassium binders (patiromer, sodium zirconium cyclosilicate) to facilitate continuation of ACE inhibitor/ARB therapy in patients with recurrent hyperkalemia, given the proven mortality benefit of these medications 1

Common Pitfalls to Avoid

• Never combine ACE inhibitors with ARBs - this increases adverse events (hyperkalemia, syncope, AKI) without added cardiovascular benefit 1
• Do not check creatinine sooner than several days after initiation unless oliguria or significant hypotension occurs - transient rises are expected 1
• Recognize that hyperkalemia frequently complicates ACE inhibitor-associated acute renal failure - monitor potassium closely during any AKI episode 1
• Remember that adequate dialysis protects against hyperkalemia - in CAPD patients with Kt/V >2, standard doses of ACE inhibitors/ARBs rarely cause hyperkalemia 6