Why does hyperkalemia occur in adults taking finerenone, especially older patients with stage 3–4 chronic kidney disease, type 2 diabetes, or concomitant ACE inhibitor or ARB therapy?

Why Hyperkalemia Occurs with Finerenone

Finerenone causes hyperkalemia by blocking the mineralocorticoid receptor in the distal nephron, which reduces aldosterone-mediated potassium excretion through the principal cells of the collecting duct. 1

Mechanism of Hyperkalemia

Primary Mechanism: Reduced Renal Potassium Excretion

• Finerenone blocks mineralocorticoid receptors in the kidney, preventing aldosterone from stimulating sodium reabsorption and potassium secretion in the distal convoluted tubule and collecting duct 1
• This blockade directly impairs the kidney's ability to excrete potassium, leading to accumulation in the bloodstream 1
• The effect is predictable and dose-dependent, allowing for early identification and monitoring of at-risk patients 2

Why Finerenone is Different from Steroidal MRAs

• Finerenone has higher selectivity for the mineralocorticoid receptor compared to spironolactone and stronger MR-binding affinity than eplerenone 3
• Despite this selectivity, finerenone still causes hyperkalemia, though the risk may be somewhat lower than with steroidal MRAs like spironolactone 1, 4
• The nonsteroidal structure does not eliminate hyperkalemia risk—it remains a class effect of all mineralocorticoid receptor antagonists 1

High-Risk Patient Populations

Chronic Kidney Disease (Stage 3-4)

• Reduced eGFR is the strongest independent risk factor for hyperkalemia with finerenone, as impaired renal function limits potassium excretion capacity 5
• Patients with eGFR 25-60 mL/min/1.73 m² have substantially elevated risk, particularly when baseline potassium is already in the upper normal range 1
• Advanced CKD (up to 73% hyperkalemia incidence) dramatically amplifies risk when combined with MRA therapy 1

Concomitant RAAS Inhibitor Therapy

• ACE inhibitors and ARBs independently reduce potassium excretion by decreasing aldosterone secretion and reducing distal sodium delivery 1
• The combination of finerenone with ACE inhibitors or ARBs creates additive hyperkalemia risk, as both drug classes impair renal potassium handling through complementary mechanisms 1
• In FIDELIO-DKD, hyperkalemia led to 2.3% discontinuation with finerenone vs 0.9% with placebo, demonstrating the clinical impact of this combination 1

Type 2 Diabetes

• Diabetic patients often have hyporeninemic hypoaldosteronism (type 4 renal tubular acidosis), which already impairs potassium excretion 6
• Insulin deficiency in poorly controlled diabetes impairs cellular potassium uptake via Na/K-ATPase, keeping more potassium in the extracellular space 6
• Diabetic kidney disease combines multiple risk factors: reduced eGFR, albuminuria, and frequent RAAS inhibitor use 2, 5

Older Adults

• Age-related decline in renal function (even with "normal" creatinine due to reduced muscle mass) reduces potassium excretion capacity 1
• Older patients are more likely to be on multiple potassium-affecting medications: beta-blockers, NSAIDs, trimethoprim 1
• Female sex is an independent risk factor for hyperkalemia with finerenone, possibly due to lower muscle mass and different pharmacokinetics 5

Additional Contributing Factors

Medication Interactions

• Beta-blockers impair cellular potassium uptake by blocking β2-adrenergic receptors that normally drive Na/K-ATPase 1
• NSAIDs reduce renal potassium excretion by inhibiting prostaglandin-mediated renin release and reducing GFR 1
• Trimethoprim blocks epithelial sodium channels (ENaC) in the collecting duct, mimicking amiloride's effect 1

Baseline Potassium and Albuminuria

• Higher baseline serum potassium is an independent predictor of subsequent hyperkalemia with finerenone 5
• Increased urine albumin-creatinine ratio independently increases hyperkalemia risk, likely reflecting more severe kidney disease 5

Protective Factors

• Diuretic use (loop or thiazide) reduces hyperkalemia risk by increasing distal sodium delivery and potassium excretion 5
• SGLT2 inhibitor use reduces hyperkalemia risk by promoting natriuresis and improving tubular function, though the combination with finerenone still carries risk 5, 7

Clinical Implications

Monitoring Requirements

• Potassium must be ≤4.8 mmol/L before initiating finerenone per trial protocols 1
• Check potassium within 1 week of starting finerenone, then at 1 month, and periodically thereafter based on risk factors 1
• Patients with eGFR <60 mL/min, diabetes, or on RAAS inhibitors require more frequent monitoring (every 1-2 weeks initially) 1

Management Strategy

• Finerenone should be withheld when potassium >5.5 mmol/L and restarted at 10 mg daily once potassium ≤5.0 mmol/L 5
• Temporary dose reduction or discontinuation at potassium >6.0 mmol/L is recommended, with reinitiation at lower dose once stable 1
• Newer potassium binders (patiromer, sodium zirconium cyclosilicate) enable continuation of finerenone in patients who develop hyperkalemia, preserving cardiorenal benefits 1, 8

Key Pitfall to Avoid

Do not permanently discontinue finerenone for a single episode of mild hyperkalemia (5.0-5.5 mmol/L)—instead, address contributing factors (NSAIDs, dietary potassium, dehydration), optimize diuretics, and consider potassium binders to maintain this life-saving therapy 1, 8