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Abstract
Regulation of plasma potassium (K+) within a narrow range is essential for life. The kidney maintains K+ homeostasis by matching K+ intake and excretion, in part through the action of aldosterone (ALDO). K+ regulation is altered by disease states such as kidney dysfunction and by therapies that directly or indirectly alter ALDO such as mineralocorticoid receptor antagonists (MRAs). These conditions increase the risk for hyperkalemia and/or hypokalemia, serious complications that can be deadly.Predicting the effects of disease and therapies on plasma K+ levels is difficult. To address this challenge, a mathematical model was developed that integrates K+-ALDO regulation and therapeutic mechanisms.
This model mechanistically describes processes of renal K+ filtration, reabsorption, secretion, and ALDO regulation by K+ and Na+. K+- ALDO feedback was calibrated by fitting data from human subjects on high/low K+ and Na+ diets following K+ infusion.
The model describes observed baseline changes in plasma K+ and ALDO with changes in K+/Na+ intake, as well as dynamic changes in these variables with initiation and cessation of K+ infusion. The model was also fit to urinary K+ excretion data following spironolactone treatment.
As validation, the model predicted steady-state changes in plasma/urinary ALDO and K+ with sustained MRA spironolactone treatment in human subjects with hyperaldosteronism.
This K+- ALDO homeostasis model was then integrated into a well-established cardiorenal model of Na+ and blood pressure (BP) homeostasis.
The integrated model mechanistically describes processes of renal K+ and Na+, filtration, reabsorption, secretion, and ALDO regulation by K+ and Na+. The model was recalibrated to reproduce previously published plasma K+ and ALDO responses to K+ infusion during low/high K+ and Na+ diets and to reproduce the urinary K+, Na+ to spironolactone. It was then validated by predicting the chronic plasma K+ and BP response data for MRA antagonists.
The model was also used to describe the K+ response to sodium-glucose co-transporter inhibitors (SGLT2i), which was previously unclear. This model is a valuable tool for mechanistically understanding the effects of therapies on electrolyte homeostasis in both normal and impaired kidney function. It can aid in determining optimal drug dosing for balancing safety and efficacy.