Cross-species multi-omics integration reveals lung alterations in acute kidney injury across mouse, pig, and human airway organoid models

Abstract

Background: Acute kidney injury (AKI) is frequently associated with the development of distant acute lung injury (ALI); however, its broader clinical impact and the underlying temporal molecular mechanics remain incompletely characterized. Methods: We used aggregate deidentified Epic Cosmos data to describe all-cause mortality and hospital length of stay (LOS) in an AKI cohort (13,815,092 patients; 2016-2025) and a subgroup with subsequent lung injury (AKI-lung). Mechanistically, we integrated matched RNA-seq and proteomics from a hyper-acute pig model (4 h reperfusion), an established mouse model (24 h reperfusion), and primary lung organoids exposed to mtDAMP-conditioned media, using MOFA+, PROGENy, decoupleR/CollecTRI, and DIABLO. Candidates were validated in primary human donor lungs obtained from LifeLink, separated into Control (< 1.3 mg/dL, n = 4) and Clinical AKI ([≥] 1.3 mg/dL, n = 3) groups based on admission blood creatinine level. Results: The AKI-lung subgroup had higher observed mortality than the overall AKI cohort (36.67% vs. 25.45%, p < 0.001). Mean hospital LOS was 11.3 versus 6.9 days in the reported AKI-lung and AKI alone queries, respectively (unadjusted p < 0.001). Multi-omics analyses cross-species indicated a temporal shift in proteogenomic coupling. In the hyper-acute pig model, we observed a largely post-translational response (r = -0.06), including ciliary breakdown and metabolic changes associated with PDHA1 protein depletion (Log2FC = -1.53), with minimal transcript level changes. The established mouse model showed a coordinated transcriptional inflammatory response (r = 0.316), characterized by PI3K/Akt pathway activation and downregulation of vascular and immune regulators (Aplnr, Cd74). Human lung organoids exhibited transcriptional downregulation of tissue remodeling genes and persistent ATF6/ATF4-associated ER stress, consistent with a reparative phase under proteostatic strain. Unsupervised MOFA+ revealed conserved cross-species axes (Factors 6 and 7) linked to vascular repair and hemostasis. Upstream regulon analysis identified the endothelial integrity regulators, including FOXF1. Most importantly, targeted validation in primary human donor lungs confirmed a statistically significant, selective down-regulation of the core circadian regulator circadian locomotor output cycles kaput (CLOCK) transcript (p < 0.05), independent of donor age, sex, race. Conclusions: Aggregate clinical findings suggest an association between lung injury following AKI and worse outcome. Kidney-Lung crosstalk initiates as hyper-acute post-translational microvascular breakdown in swine and rapidly transitions into localized uncoupling of cell-autonomous pulmonary circadian machinery (CLOCK) in clinical human AKI, offering human-validated targets to intercept distant organ failure.