Cross-species multi-omics integration reveals lung alterations in acute kidney injury across mouse, pig, and human airway organoid models
Year: 2026
Type: preprint
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 mechanisms 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 = 5) and AKI (≥ 1.3 mg/dL, n = 5) groups based on the highest blood creatinine level measured in hospital. 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, including ciliary breakdown and metabolic 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). 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.
Authors: Zhi Tian, Nohely Hernandez Soto, Diane Allen-Gipson, Georgina Agyekum, Xiaoqi Sun, Nadezhda N. Zheleznova, David Raj Chellappan, Nathan Hall, Kristof Williams, Runze Ni, Yuqian Tian, Sebastian Cuadrao, Vijay Subramanian, Lucian Lozonschi, Kiran Dhanireddy, Isabella Lozonschi, Carlos Esquivel, Colby L. Parris, Minh H. Tran, Lei Wang, Ruisheng Liu
Language: English
Topic: Acute Kidney Injury Research
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7222628651