Abstract This clinical study proposal is being submitted in response to PAS-20-160 "Small R01s for Clinical Trials Targeting Diseases within the Mission of NIDDK, which does not require preliminary data." in order to address unmet needs in the acute kidney injury (AKI) field through a novel approach to ameliorate immunopathology. AKI is a devastating clinical disorder and major health burden with no FDA approved drugs for its prevention or treatment. Current barriers to successful treatment of AKI include off-target effects of pharmacological agents, the invasive nature of certain therapies, a lack of appropriate animal models of AKI that faithfully mimic human disease, and incomplete understanding of the pathophysiology of AKI. Since our first report that a simple ultrasound (US)-based protocol reduced tissue and systemic inflammation and prevented ischemia-reperfusion injury (IRI) in mice, we have demonstrated that this effect was dependent on the spleen and functional α7-nicotinic acetylcholine receptors (α7nAChRs). These observations are consistent with the hypothesis that US treatment activated the splenic inflammatory reflex, a neuro- immunomodulatory pathway. Our studies indicate that the protective effect of US depends on an intact spleen, the presence of T cells and bone marrow-derived α7nAChRs, and splenic innervation. US has wwoptogenetics we have mapped the neurocircuit of the inflammatory reflex pathway and are now poised to determine the effect in human AKI. In particular we will examine the effect of pulsed US on AKI induced from cardiac surgery, due to the importance of inflammation in this disorder. This clinical study proposal is intended to build upon and translate our preclinical studies over the past several years and is designed to test the hypothesis that pulsed US stimulation can be used effectively in human subjects to control pathogenic inflammatory responses through the stimulation of the cholinergic anti-inflammatory reflex pathway. Aim 1 will test the hypothesis that pulsed US stimulation within the FDA-approved limits of diagnostic ultrasonography is able to attenuate inflammation and alter the composition of immune cells collected from healthy subjects. Subjects will receive US targeting the splenic nerve and then immune cells will be isolated from their blood and treated ex vivo withw inflammatory stimuli to test their inflammatory capacity in comparison to immune cells collected prior to US. Aim 2 will test, in a pilot study, the hypothesis that prior ultrasound stimulation in a population at risk for the development of AKI, i.e. adults undergoing cardiac surgery, will reduce systemic inflammation and innate immunity. Additional goals will be to acertain if there are any side effects as well as to obtain necessary data and develop the necessary elements to conduct a large rmulticenter clinical trial to determine the efficacy of pulsed ultrasound to prevent AKI.