Injured epithelial cell states impact kidney allograft survival after T-cell-mediated rejection

TL;DR

The study finds that injured epithelial cells in the kidney after T-cell rejection affect transplant survival, highlighting a new target for improving outcomes.

Contribution

The study identifies specific injured epithelial cell states in kidney transplants that correlate with poor outcomes after T-cell-mediated rejection.

Findings

Injured epithelial cell states in mouse kidney allografts are induced by T-cell-mediated rejection.

Severely injured epithelial states in human samples correlate with transplant survival and persist after rejection resolution.

Spatial transcriptomics reveals heterogeneous localization and interactions of injured epithelial cells with immune cells.

Abstract

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure, despite being considered treatable. Its impact reflects a limited understanding of the underlying molecular mechanisms and their clinical consequences. To address this, we induced acute TCMR in mouse kidney transplants and profiled molecular changes using single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics and immunofluorescence. Results were compared with human snRNA-seq data from TCMR and stable allografts, as well as single-cell deconvolution analysis of bulk transcriptomic data from kidney transplant biopsies. Here we show that TCMR induces injured epithelial cell states in mouse kidney allografts, particularly in proximal tubules and thick ascending limbs. Spatial transcriptomics of these injured epithelial states demonstrated heterogeneous localization, interactions with immune cells and cellular microenvironments. Cross-species analysis confirmed similar severely injured epithelial states in human samples, whose abundances correlated with transplant survival and persisted despite TCMR resolution. Collectively, our results identify epithelial injury cell states as a determinant of outcome after TCMR.

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

Figures