Single-Cell Transcriptomics of a Human Kidney Allograft Biopsy Specimen Defines a Diverse Inflammatory Response

Single cell genomics are revolutionizing our ability to characterize complex tissues. By contrast, the techniques used to analyze the renal biopsy are little changed over the past several decades. In this study we have tested the hypothesis that single cell RNA sequencing (sc-RNA-seq) can comprehensively describe cell types and states in a human kidney biopsy. We generated 8,746 single cell cell transcriptomes from a healthy adult kidney and a single kidney transplant biopsy core by sc-RNA-seq. Unsupervised clustering analysis of the biopsy identified 16 distinct cell types, including all of the major immune cell types and most native kidney cell types in this biopsy whose histologic read was mixed rejection. Endothelial cells formed three distinct sub-clusters: resting cells and two activated endothelial cell clusters, including expression of Fc-receptor pathway activation and immunoglobulin internalization genes, consistent with the pathologic diagnosis of antibody-mediated rejection. Monocytes formed two sub-clusters representing a non-classical CD16+ group and a classical CD16- group expressing dendritic cell maturation markers. The presence of both monocyte cell subtypes was validated by staining of of independent transplant biopsies. Comparison of healthy kidney epithelial transcriptomes to their biopsy counterparts identified novel segment specific pro-inflammatory responses. We mapped previously defined genes that associate with rejection outcomes to single cell types and generated a searchable online gene expression database. These findings represent a first step towards incorporation of single cell transcriptomics into kidney biopsy interpretation, describe a heterogeneous immune response in mixed rejection and provide a searchable resource for the scientific community.

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