Renal nerve stimulation modulates renal blood flow in a frequency-dependent manner

Background: Chronic overactivity of the renal nerves is a key pathophysiological attribute of drug-resistant hypertension. Indeed, catheter-based renal denervation can lower blood pressure by severing the brain-kidney (efferent nerves) and kidney-brain (afferent nerves) link, but its irreversibility and potential nerve reconnection limits adaptability and longevity, highlighting the need for alternative treatments. Kilohertz-frequency electrical stimulation is an approach known to reversibly inhibit peripheral nerve activity and has potential to reversibly modulate renal blood flow. Methods: This study investigated how electrical stimulation of the renal nerves affects renal blood flow in a non-diseased anesthetized swine. Using unilateral hook electrodes around the renal artery-nerve complex, we performed parameter sweeps of stimulation frequency (20–15000 Hz) and measured blood flow and blood pressure changes in the ipsilateral kidney. Results: Stimulation at low frequencies (≤ 100 Hz) resulted in a sustained reduction in renal blood flow. High stimulation frequencies (> 100 Hz) often resulted in an immediate decrease in blood flow through the kidneys, but the responses exhibited adaptation with continued isochronal pulsatile stimulation. Notably, while kilohertz-frequency stimulation did not directly increase renal blood flow in this experiment, it did induce a carryover effect on renal nerve sensitivities to low-frequency stimulation, reducing the effect of subsequent low-frequency stimulation on renal blood flow (from − 11.8% to -4.7%, median). Conclusions: Responses to renal nerve stimulation depend on stimulation frequency with effects that can persist or adapt as well as effects that can range from decreasing renal blood flow to decreasing the sensitivity of the renal nerve signaling pathway. These findings have important implications for future development of bioelectronic interfaces with the renal nerve for modulation of kidney function.