Megan L Baker, Vijayakumar R Kakade, Tifanny Budiman, Marlene Weiß, Joseph M Cunningham, Sagar Sadarangani, Gabriel Lerner, Gilbert Moeckel, Avi Z Rosenberg, Chirag R Parikh, Yuval Kluger, Dennis G Moledina, Lloyd G Cantley
Acute interstitial nephritis (AIN) is present in 15-20% of all acute kidney injury cases but lacks proven effective therapies beyond corticosteroids. Using high-resolution imaging mass cytometry and single-cell spatial transcriptomics to analyze human kidney biopsies with AIN, acute tubular injury (ATI), and reference tissue, we show that interferon-γ-induced CXCL9-CXCR3 signaling is markedly increased in AIN, with significantly more predicted interactions relative to ATI, dominated by homotypic T cell-T cell amplification networks concentrated in lymphoid aggregates. Tubular cells, predominantly VCAM1+ injured proximal tubules, markedly upregulate complement components, with local enrichment of C3AR1+ immune cells, linking tubular injury to immune activation in AIN. Nicotinamide phosphoribosyltransferase (NAMPT) is the strongest spatial correlate 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 nominate potential therapeutic targets for improving clinical management and preventing progression to chronic kidney disease.