Spatial Transcriptomics Identify T Cell-Driven Mechanisms of Kidney Damage in Immune Checkpoint Inhibitor-Associated Acute Interstitial Nephritis

Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common histopathological finding among patients with ICI-associated acute kidney injury (ICI-AKI). However, mechanisms of inflammation in ICI-AIN are not well-understood. Using sub-cellular spatial transcriptomics (Xenium Prime 5K), we compared the cellular composition of kidney biopsy tissue from 8 patients (4 with ICI-AIN, 4 ICI-treated patients with acute tubular necrosis [ICI-ATN]). Through spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-γ)/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8+ T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8+ T cell-derived IFN-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signalling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. Spatial transcriptomics thus reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN, with IFN-γ-producing CD8+ T cells as likely key drivers of ICI-AIN and therefore potential future therapeutic targets.