Pharmacodynamic effects of the K ⁺ binder patiromer in a novel chronic hyperkalemia model in spontaneously hypertensive rats

Abstract

Currently described hyperkalemia (HK) animal models are typically acute and cause significant distress and mortality to the animals, warranting new approaches for studying chronic HK in a more appropriate clinical setting. Using the spontaneously hypertensive rat (SHR) model as a more relevant disease template, as well as surgical (unilateral nephrectomy), dietary (3% potassium [K ⁺] supplementation), and pharmacological (amiloride) interventions, we were able to stably induce HK on a chronic basis for up to 12 weeks to serum K ⁺ elevations between 8 and 9 mmol/L, with minimal clinical stress to the animals. Short‐term proof‐of‐concept and long‐term chronic studies in hyperkalemic SHRs showed concomitant increases in serum aldosterone, consistent with the previously reported relationship between serum K ⁺ and aldosterone. Treatment with the K ⁺ binder patiromer demonstrated that the disease model was responsive to pharmacological intervention, with significant abrogation in serum K ⁺, as well as serum aldosterone to levels near baseline, and this was consistent in both short‐term and long‐term 12‐week chronic studies. Our results demonstrate the feasibility of establishing a chronic HK disease state, and this novel HK animal model may be suitable for further evaluating the effects of long‐term, K ⁺‐lowering therapies on effects such as renal fibrosis and end‐organ damage.

Abstract

Currently described hyperkalemia (HK) animal models are typically suboptimal for studying chronically elevated potassium, warranting new approaches for studying chronic HK. Using the spontaneously hypertensive rat model as well as surgical and minimal drug and dietary interventions, we achieved a reproducible animal disease model that maintains a stable, chronic HK state. Our results showed that the potassium binder, patiromer significantly reduced serum potassium and aldosterone in hyperkalemic rats, which may be suitable for further evaluating potassium‐lowering therapies, as well as evaluating long‐term effects on end‐organ damage and in studies of aldosterone regulation and actions.