Pulsed ultrasound activation of neural reflexes: a therapeutic strategy against AKI and inflammation?

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Acute kidney injury (AKI) affects about 20% of hospitalized patients and is a major contributor to multiorgan dysfunction and progression to chronic kidney disease (CKD) [1]. Inflammation is a key, modifiable cause of AKI, triggered by events such as ischemia–reperfusion injury, major surgery, sepsis or drugs [2]. Yet despite its pivotal role, our therapeutic tools for modulating inflammation in AKI remain limited. Recent advances in neuroimmunology, however, highlight pulsed ultrasound (pUS) as a noninvasive and promising intervention for inflammation and AKI. This approach builds on the inflammatory reflex—a vagus nerve circuit that connects inflammation in the body to immune control via the cholinergic anti-inflammatory pathway (CAP) (Fig. 1). CAP activation stimulates the splenic nerve, leading to norepinephrine release by splenic choline acetyltransferase-positive T cells and subsequent suppression of cytokine production by α7-nicotinic acetylcholine receptor (α7nAChR)-expressing macrophages and subsequently reduced cytokine production by immune cells. Neuroimmune regulation of inflammation via the CAP, with potential activation by pUS. Inflammatory signals activate vagal afferents, which project to the brainstem and trigger efferent output via the splenic nerve. This stimulates acetylcholine release from ChAT⁺ T cells, which binds to α7nAChR on macrophages to suppress cytokine production. pUS applied externally to the splenic region can noninvasively activate this pathway, mimicking the anti-inflammatory effects of vagus nerve stimulation. ACh, acetylcholine; ChAT+, choline acetyltransferase-positive; NE, norepinephrine. Preclinical studies show that non-invasive pUS targeting the spleen can activate CAP and reduce inflammation, similar to vagus nerve stimulation (VNS) [3, 4]. In animal studies, a single 2-min pUS session to the spleen, given 24 h before kidney injury, prevented AKI and reduced inflammation [3, 4]. This protective effect appears to be specific, as it is abolished in chemically or surgically splenectomized mice, after surgical ablation of the splenic nerve or in those deficient in α7nAChR signaling, demonstrating that pUS acts through splenic neuroimmune signaling that mediates specific immunological effects [3–5]. pUS is clinically feasible and can be delivered with standard Food and Drug Administration (FDA)-approved ultrasound settings. Notably, splenic pUS has already been translated into early-phase human studies. In both healthy volunteers and patients with rheumatoid arthritis, a brief pUS session significantly reduced tumor necrosis factor production from lipopolysaccharide-stimulated whole blood ex vivo, suggesting that the anti-inflammatory reflex can be reliably and reproducibly activated in humans [6, 7]. Although the report by Graham et al. [7] is a preprint that has not undergone peer review, it is included here to illustrate clinical feasibility rather than to support outcome interpretation. While pUS has shown robust anti-inflammatory effects in rodents and encouraging feasibility in humans, intermediate studies in large-animal models are still lacking. The spleen in mice is comparable in size to the ultrasound focus, allowing whole-organ insonation, whereas in humans the spleen’s larger size, depth and motion introduce challenges for targeted stimulation. Studies in larger species such as pigs or sheep would therefore be valuable to optimize ultrasound targeting, dosing and reproducibility under conditions that better approximate human anatomy. One promising use of pUS is preventing AKI after major surgeries, such as cardiac surgery. Given that the anti-inflammatory effect of pUS in animal models persists for 24–48 h, pUS could serve as a bedside, preemptive, non-pharmacological therapy to mitigate the cytokine surge associated with cardiac surgery. In critically ill patients, it might also offer a means to beneficially modulate the trajectory of sepsis-associated AKI or attenuate systemic multiorgan dysfunction. The strategy with pUS is similar to other methods that use the nervous system to control inflammation. For instance, remote ischemic preconditioning (RIPC), a more established technique involving transient limb ischemia, has also been shown to activate neuronal, humoral and systemic anti-inflammatory mechanisms similar to those of the CAP–VNS axis [8]. Preclinical data demonstrate that RIPC’s protective effects depend on intact autonomic signaling and are abolished by vagotomy or spinal cord transection, underscoring its reliance on the same neuroimmune reflexes targeted by pUS [9, 10]. Although less anatomically specific, RIPC has shown clinical promise: in a recent randomized trial, Jia et al. reported that delayed RIPC significantly reduced the incidence of AKI in patients undergoing high-risk cardiac surgery [11]. These findings further support the concept that peripheral neuromodulatory strategies, even when non-specific, can engage endogenous anti-inflammatory circuits to confer organ protection. Compared with RIPC, pUS offers greater anatomic specificity by directly engaging the splenic neuroimmune axis rather than relying on systemic signaling from transient limb ischemia. This precision could reduce variability in response and minimize discomfort for patients. However, RIPC currently benefits from a more substantial clinical evidence base, including randomized controlled trials in cardiac surgery patients, whereas pUS is still at the proof-of-concept stage. The best ultrasound settings for humans have yet to be defined. Most pUS studies to date have been conducted in animal models, and early human investigations remain limited in sample size, duration and clinical endpoints. Key questions remain unanswered, including the optimal dosing regimens, durability of anti-inflammatory effects, and whether modulation of ex vivo cytokine production translates into improved patient-centered outcomes such as reduced AKI incidence and improved survival. From a safety perspective, pUS is delivered using standard clinical diagnostic ultrasound systems and within established safety limits (Mechanical Index <1.9; spatial-peak temporal-average intensity <720 mW/cm2, according to current FDA regulatory limits). Diagnostic ultrasound has an excellent safety record over decades of clinical use, and no adverse effects were observed in initial studies of healthy volunteers and patients with rheumatoid arthritis [6, 7]. Ongoing trials (ClinicalTrials.gov: NCT05685108) are systematically evaluating safety and immune responses to refine dosing parameters and confirm clinical tolerability. Nonetheless, the optimal dosing, exposure duration and long-term safety in patient populations remain to be defined. Without larger clinical trials, the clinical utility of pUS remains uncertain, and its integration into routine practice premature. Moreover, we need to better understand how pUS interacts with underlying inflammatory states, comorbidities (including degree of kidney function and body mass index) and concomitant medications, and whether repeated sessions might enhance therapeutic benefit, for example by mitigating AKI-to-CKD transition. Immunological markers, circulating cytokine levels, immune cell phenotypes and splenic Doppler findings may help guide treatment decisions and monitor efficacy. In conclusion, pUS could be a major advance, offering targeted, precise inflammation control with fewer side effects than drugs. Its therapeutic potential extends beyond AKI, with implications for autoimmune diseases and transplant immunomodulation, but also in cardiovascular disease, where autonomic imbalance and inflammation play a critical role [12]. Because inflammation drives both acute and chronic diseases, noninvasive immune control like pUS could change critical care and surgery. While we await more human data, pUS appears to be a promising new tool for controlling inflammation and deserves more attention. This work was

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