<p>Sepsis-associated acute kidney injury (SA-AKI) remains a frequent and life-threatening complication of sepsis, yet its pathophysiology is still not fully understood, owing to the complex interplay of immune, vascular and parenchymal responses. Closing this knowledge gap is essential for developing urgently needed targeted therapies. Although bulk and single-cell transcriptomics, as well as proteomic approaches, have advanced our understanding of the molecular mechanisms involved in SA-AKI, they lack the spatial context required to fully interpret tissue heterogeneity and microenvironmental changes. The integration of high-resolution spatial transcriptomics with single-cell RNA sequencing and other multi-omics approaches offers a novel lens through which to dissect the cellular and molecular architecture of septic kidneys. In SA-AKI, discrete inflammatory, vascular and tubular niches can cause substantial functional impairment even though global histological changes may be much milder. Integrative spatial transcriptomics localizes pathological signalling and how it is transmitted across immune, endothelial and epithelial cells. By resolving niche-specific crosstalk, these approaches might highlight druggable pathways and lead to the identification of clinical biomarker candidates. These insights, in turn, facilitate the identification of mechanistic endotypes that align more closely with prognosis than with conventional staging. Importantly, translation into clinical trials will require standardized endotype definitions, endotype validation and standardized sampling strategies, as well as scalable analytical pipelines to enable endotype identification at the bedside.</p>