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

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. Spatial analysis of human kidney biopsies reveals that acute interstitial nephritis differs from nonimmune kidney injury, identifying complement-producing injured tubules, T cell signaling and NAMPT as markers of sustained inflammatory niches.