{"doi":"10.1093/ndt/gfaf234","title":"Pulsed ultrasound activation of neural reflexes: a therapeutic strategy against AKI and inflammation?","abstract":"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 systemi","journal":"Nephrology Dialysis Transplantation","year":2025,"id":579879,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":267115,"name":"Mark D. Okusa","orcid":"0000-0002-0801-0532","position":1,"is_corresponding":false},{"id":36557,"name":"Carmine Zoccali","orcid":"0000-0002-6616-1996","position":2,"is_corresponding":false},{"id":108958,"name":"Claudio Ronco","orcid":"0000-0002-6697-4065","position":3,"is_corresponding":false},{"id":108940,"name":"Faeq Husain‐Syed","orcid":"0000-0001-6742-5052","position":4,"is_corresponding":false},{"id":1435333,"name":"Gonzalo Ramírez‐Guerrero","orcid":"0000-0002-1696-9997","position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41183490","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}