Modelling ischaemic AKI in human kidney organoids reveals injury-associated epithelial states and macrophage-epithelial crosstalk

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BACKGROUND: Acute kidney injury (AKI) is a common clinical syndrome associated with high morbidity and progression to chronic kidney disease. Ischaemia is a leading cause of AKI, driving cellular stress, metabolic reprogramming, and injury-associated epithelial states. Scalable human models that enable controlled investigation of ischaemic injury, repair, and therapeutic targets in AKI remain limited. We therefore assessed the extent to which induced pluripotent stem cell (iPSC)-derived human kidney organoids recapitulate key features of ischaemic AKI. METHODS: Kidney organoids were subjected to hypoxic injury (1% O₂, 48 h) followed by normoxic recovery. Transcriptomic, proteomic, metabolomic, single-cell, and spatial profiling were performed across acute injury and recovery phases. iPSC-derived macrophages were integrated into organoids and analysed following hypoxic injury. RESULTS: Hypoxia induced acute stress responses, including hypoxia-inducible factor activation, glycolytic reprogramming, cell cycle arrest, and induction of injury markers. Following recovery, organoids exhibited sustained inflammatory signalling and persistent metabolic dysregulation. Single-cell analysis revealed loss of cell type-specific markers and key functional genes across nephron segments. After return to normoxia, podocyte and distal tubule markers were largely restored, whereas proximal tubule markers showed only partial recovery. Injury-associated and inflammatory programs persisted across all nephron cell types, including upregulation of GDF15, MMP7, SPP1, CXCL2, and ICAM1, with enrichment of complement, TNF-NFκB, and lipid-associated inflammatory pathways. Injured proximal tubules were enriched for adaptive/maladaptive repair signatures derived from human kidney biopsies and displayed heterogeneous recovery. While some cells restored canonical identity, others retained dedifferentiated injury-associated states, including focal expression of CDKN1A and VCAM1. Integrated macrophages transitioned from homeostatic, resident-like profiles to activated phenotypes following injury, exhibiting spatially localised interactions with injured tubules and increased expression of cytokines, chemokines, and matrix-remodelling factors. CONCLUSIONS: Human kidney organoids recapitulate key epithelial features of hypoxic injury, including segment-specific vulnerability, persistent inflammatory signalling, and heterogeneous recovery, with integrated macrophages adopting activated inflammatory states following injury. While constrained by developmental immaturity, this system provides a tractable human platform to investigate injury-associated epithelial states and macrophage-epithelial crosstalk in AKI.

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