Founder and Principal Consultant Cardiorenal QSP, LLC, Georgia, United States
Disclosure(s):
Melissa Hallow, PhD: No financial relationships to disclose
Background: Hyperkalemia is a critical concern in the management of patients with cardiovascular and kidney disease, especially those receiving multiple concomitant therapies that affect potassium homeostasis. The development of new cardiovascular therapies is often constrained by the need to avoid perturbations in potassium regulation, as both hypo- and hyperkalemia increase the risk of adverse outcomes. Several rare genetic disorders of renal ion transport present with characteristic patterns of dyskalemia and blood pressure dysregulation, providing mechanistic insight into the complex interplay between renal sodium and potassium handling.
Objectives: To extend and validate a mechanistic, systems-level model of cardiorenal function to describe potassium regulation and predict the effects of perturbations in renal transporter function, hormonal signaling, and pharmacological intervention on potassium and blood pressure.
Methods: We extended an established quantitative systems pharmacology (QSP) model of cardiorenal function to incorporate detailed mechanisms of potassium regulation, including aldosterone-mediated control and sodium-potassium coupling via NKCC, NCC, ENaC, and ROMK. We validated this model in two phases. First, we simulated five rare genetic syndromes affecting renal potassium transporters—Gitelman’s (NCC loss), Bartter’s (NKCC loss), Gordon’s (NCC gain), Liddle syndrome (ENaC gain), and Pseudohypoaldosteronism Type I (ENaC/MR loss)—and assessed the model’s ability to reproduce directional changes in plasma potassium and blood pressure. Second, we tested the model’s ability to simultaneously describe potassium and blood pressure responses to standard-of-care antihypertensive and cardiorenal therapies, including thiazide and loop diuretics, calcium channel blockers, ACE inhibitors, and ARBs. After calibrating drug effects in healthy subjects, we evaluated model performance in predicting combination therapy responses.
Results: The model successfully captured the expected qualitative changes in plasma potassium and blood pressure for each of the five rare transporter disorders. It also reproduced the observed changes in potassium, blood pressure, and sodium excretion in response to monotherapy and combination therapy in hypertensive and chronic kidney disease patients. Notably, the model highlighted the central role of renin sensing via NKCC activity in the macula densa in coordinating integrated responses in potassium and blood pressure regulation.
Conclusions: This validated systems model provides a tool to explore the impact of novel therapies or regimens on potassium homeostasis, both in rare disorders and in complex patients with cardiovascular disease receiving multiple comedications. It offers a quantitative framework to optimize drug development strategies and minimize the risk of hyperkalemia in cardiorenal populations.
