Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: Clinical Evidence, Pharmacology, and Drug–Drug Interactions for Personalized Management of Hyperkalemia

Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug–drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient’s medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA.