Spatial analysis reveals the cellular microenvironments and mechanisms of inflammation and kidney injury in acute interstitial nephritis

Baker, M. L.; Kakade, V. R.; Budiman, T.; Weiss, M.; Cunningham, J. M.; Sadarangani, S.; Lerner, G.; Moeckel, G.; Rosenberg, A. Z.; Parikh, C. R.; Kluger, Y.; Moledina, D. G.; Cantley, L. G.

doi:10.1101/2025.10.29.684811

bioRxiv · 10.1101/2025.10.29.684811

Spatial analysis reveals the cellular microenvironments and mechanisms of inflammation and kidney injury in acute interstitial nephritis

Baker, M. L.·Kakade, V. R.·Budiman, T.·Weiss, M.·Cunningham, J. M.·Sadarangani, S.·Lerner, G.·Moeckel, G.·Rosenberg, A. Z.·Parikh, C. R.·Kluger, Y.·Moledina, D. G.·Cantley, L. G.

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Abstract

Acute interstitial nephritis (AIN) causes 15-20% of all acute kidney injury cases but lacks effective therapies beyond corticosteroids. Using high-resolution imaging mass cytometry and single-cell spatial transcriptomics to analyze human kidney biopsies with AIN, non-immunologic acute tubular injury (ATI), and reference tissue, the CXCL9-CXCR3 axis was identified as the defining immunologic signature of AIN, with 44-fold higher predicted CXCL9-CXCR3 interactions than ATI, creating homotypic inflammatory T cell amplification networks concentrated in lymphoid aggregates. C3AR1+ immune cells were enriched in peritubular neighborhoods of complement 3-expressing injured tubule cells, predominantly VCAM1+ injured proximal tubules, linking tubular injury to immune activation in AIN. Nicotinamide phosphoribosyltransferase (NAMPT) was the strongest predictor of VCAM1+ tubular microenvironments, with expression by both injured tubules and surrounding immune cells coordinating metabolic-inflammatory niches. These findings reveal distinct molecular circuits underlying AIN pathogenesis and identify potential therapeutic targets for improving clinical management and preventing progression to chronic kidney disease.

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Baker, M. L., Kakade, V. R., Budiman, T., Weiss, M., Cunningham, J. M., Sadarangani, S., Lerner, G., Moeckel, G., Rosenberg, A. Z., Parikh, C. R., Kluger, Y., Moledina, D. G., Cantley, L. G.. 2025-10-30. Spatial analysis reveals the cellular microenvironments and mechanisms of inflammation and kidney injury in acute interstitial nephritis. https://doi.org/10.1101/2025.10.29.684811

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