Effect of Low-Frequency Therapeutic Ultrasound on Induction of Nitric Oxide in CKD: Potential to Prevent Acute Kidney Injury

Abstract

Introduction: Post-contrast acute kidney injury (PC-AKI) develops in a significant proportion of patients with CKD after invasive cardiology procedures and is strongly associated with adverse outcomes.

Objective: We sought to determine whether increased intrarenal nitric oxide (NO) would prevent PC-AKI.

Methods: To create a large animal model of CKD, we infused 250 micron particles into the renal arteries in 56 ± 8 kg pigs. We used a low-frequency therapeutic ultrasound device (LOTUS - 29 kHz, 0.4 W/cm2) to induce NO release. NO and laser Doppler probes were used to assess changes in NO content and blood flow. Glomerular filtration rate (GFR) was measured by technetium-diethylene-triamine-pentaacetic acid (Tc-99m-DTPA) radionuclide imaging. PC-AKI was induced by intravenous infusion of 7 cm3/kg diatrizoate. In patients with CKD, we measured GFR at baseline and during LOTUS using Tc-99m-DTPA radionuclide imaging.

Results: In the pig model, CKD developed over 4 weeks (serum creatinine [Cr], mg/dL, 1.0 ± 0.2-2.6 ± 0.9, p < 0.01, n = 12). NO and renal blood flow (RBF) increased in cortex and medulla during LOTUS. GFR increased 75 ± 24% (p = 0.016, n = 3). PC-AKI developed following diatrizoate i.v. infusion (Cr 2.6 ± 0.7 baseline to 3.4 ± 0.6 at 24 h, p < 0.01, n = 3). LOTUS (starting 15 min prior to contrast and lasting for 90 min) prevented PC-AKI in the same animals 1 week later (Cr 2.5 ± 0.4 baseline to 2.6 ± 0.7 at 24 h, p = ns, n = 3). In patients with CKD (n = 10), there was an overall 25% increase in GFR in response to LOTUS (p < 0.01).

Conclusions: LOTUS increased intrarenal NO, RBF, and GFR and prevented PC-AKI in a large animal model of CKD, and significantly increased GFR in patients with CKD. This novel approach may provide a noninvasive nonpharmacological means to prevent PC-AKI in high-risk patients.

Keywords: Contrast-induced acute kidney injury; Low-frequency ultrasound; Nitric oxide.

Conflict of interest statement

M.W.D. is a co-founder, chief medical officer, director, stockholder, and patent holder for Sonogenix. R.J.S. is a paid consultant to Sonogenix. K.D.L., D.W.G., and C.A.S. report no conflicts of interest to declare.

Copyright © 2020 by S. Karger AG, Basel.

Figures

Fig. 1

(Left) Arteriograms of renal flow pre-embolization in right and left kidney (above). Post-embolization arteriograms show decreased perfusion of the upper pole of the right kidney, and total occlusion of flow to the left kidney (below). (Right) Serial changes in serum creatinine from baseline (pre-embolization) to 4 weeks post-embolization.

Fig. 2

With LOTUS on (thick red line, duration 15 min), NO concentration in the medulla and cortex increased. Microvascular blood flow also increased in medulla and cortex during LOTUS. LOTUS, low-frequency therapeutic ultrasound device.

Fig. 3

a Changes in GFR for each kidney (n = 6) in 3 pigs at baseline (BL) and during LOTUS. b Total GFR change in response to LOTUS. Total GFR increased an average of 75 ± 25%, (p = 0.016). LOTUS, low-frequency therapeutic ultrasound device; GFR, glomerular filtration rate.

Fig. 4

Serial changes in serum Cr following intravenous diatrizoate (Pre-LOTUS in blue, Post-LOTUS 1 week later in red). The increase in serum Cr at 24 h Pre-LOTUS was blocked with the application of LOTUS. Cr, creatinine; LOTUS, low-frequency therapeutic ultrasound device.

Fig. 5

CT scan showing alignment of the transducers with the kidneys. Percent change in GFR relative to baseline GFR in patients with CKD (upper right). Mean changes in heart rate and blood pressure at baseline, during, and post-LOTUS are shown below. GFR, glomerular filtration rate; LOTUS, low-frequency therapeutic ultrasound device.